Lymphoma & Plasma Cell Disorders

Photo by Larry Young

SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).

The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.

The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.

Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.

The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.

“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.

The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.

On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.

Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.

A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.

SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.

So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.

While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.

“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.

He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.

Photo by Larry Young

SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).

The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.

The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.

Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.

The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.

“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.

The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.

On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.

Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.

A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.

SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.

So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.

While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.

“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.

He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.

Photo by Larry Young

SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).

The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.

The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.

Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.

The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.

“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.

The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.

On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.

Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.

A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.

SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.

So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.

While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.

“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.

He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.

Photo by Petr Kratochvil

Exercise and/or psychological therapy work better than medications to reduce cancer-related fatigue, according to research published in JAMA Oncology.

Researchers conducted a review and meta-analysis of more than 113 studies and found that exercise and psychological interventions, as well as a combination of both, were associated with reduced fatigue during and after cancer treatment.

However, pharmaceutical interventions were not associated with the same magnitude of improvement.

The researchers therefore concluded that exercise and psychological therapy should be recommended over medications.

“If a cancer patient is having trouble with fatigue, rather than looking for extra cups of coffee, a nap, or a pharmaceutical solution, consider a 15-minute walk,” said study author Karen Mustian, PhD, of the University of Rochester Medical Center in Rochester, New York.

“It’s a really simple concept, but it’s very hard for patients and the medical community to wrap their heads around it because these interventions have not been front-and-center in the past. Our research gives clinicians a valuable asset to alleviate cancer-related fatigue.”

Dr Mustian and her colleagues reached their conclusions after analyzing data from 113 randomized clinical trials testing various treatments for cancer-related fatigue.

There were 11,525 patients enrolled in these studies. Nearly half (46.9%) were women with breast cancer. Ten studies focused on other types of cancer and enrolled only men.

Dr Mustian and her colleagues performed a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the fatigue treatments.

The team found that exercise alone—whether aerobic or anaerobic—reduced cancer-related fatigue most significantly. The WES was 0.30 (95% CI, 0.25-0.36; P<0.001).

Psychological interventions—such as therapy designed to provide education, change personal behavior, and adapt the way a person thinks about his or her circumstances—also improved fatigue. The WES was 0.27 (95% CI, 0.21-0.330.30; P<0.001).

A combination of psychological interventions and exercise had a significant improvement on fatigue as well. The WES was 0.26 (95% CI, 0.13-0.38; P<0.001).

However, the drugs tested for treating cancer-related fatigue—paroxetine hydrochloride, modafinil, armodafinil, methylphenidate hydrochloride, dexymethylphenidate, dexamphetamine, and methylprednisolone—were not as effective as the other interventions. The WES was 0.09 (95% CI, 0.00-0.19; P=0.05).

“The literature bears out that these drugs don’t work very well, although they are continually prescribed,” Dr Mustian said. “Cancer patients already take a lot of medications, and they all come with risks and side effects. So any time you can subtract a pharmaceutical from the picture it usually benefits patients.”

Photo by Petr Kratochvil

Exercise and/or psychological therapy work better than medications to reduce cancer-related fatigue, according to research published in JAMA Oncology.

Researchers conducted a review and meta-analysis of more than 113 studies and found that exercise and psychological interventions, as well as a combination of both, were associated with reduced fatigue during and after cancer treatment.

However, pharmaceutical interventions were not associated with the same magnitude of improvement.

The researchers therefore concluded that exercise and psychological therapy should be recommended over medications.

“If a cancer patient is having trouble with fatigue, rather than looking for extra cups of coffee, a nap, or a pharmaceutical solution, consider a 15-minute walk,” said study author Karen Mustian, PhD, of the University of Rochester Medical Center in Rochester, New York.

“It’s a really simple concept, but it’s very hard for patients and the medical community to wrap their heads around it because these interventions have not been front-and-center in the past. Our research gives clinicians a valuable asset to alleviate cancer-related fatigue.”

Dr Mustian and her colleagues reached their conclusions after analyzing data from 113 randomized clinical trials testing various treatments for cancer-related fatigue.

There were 11,525 patients enrolled in these studies. Nearly half (46.9%) were women with breast cancer. Ten studies focused on other types of cancer and enrolled only men.

Dr Mustian and her colleagues performed a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the fatigue treatments.

The team found that exercise alone—whether aerobic or anaerobic—reduced cancer-related fatigue most significantly. The WES was 0.30 (95% CI, 0.25-0.36; P<0.001).

Psychological interventions—such as therapy designed to provide education, change personal behavior, and adapt the way a person thinks about his or her circumstances—also improved fatigue. The WES was 0.27 (95% CI, 0.21-0.330.30; P<0.001).

A combination of psychological interventions and exercise had a significant improvement on fatigue as well. The WES was 0.26 (95% CI, 0.13-0.38; P<0.001).

However, the drugs tested for treating cancer-related fatigue—paroxetine hydrochloride, modafinil, armodafinil, methylphenidate hydrochloride, dexymethylphenidate, dexamphetamine, and methylprednisolone—were not as effective as the other interventions. The WES was 0.09 (95% CI, 0.00-0.19; P=0.05).

“The literature bears out that these drugs don’t work very well, although they are continually prescribed,” Dr Mustian said. “Cancer patients already take a lot of medications, and they all come with risks and side effects. So any time you can subtract a pharmaceutical from the picture it usually benefits patients.”

Photo by Petr Kratochvil

Exercise and/or psychological therapy work better than medications to reduce cancer-related fatigue, according to research published in JAMA Oncology.

Researchers conducted a review and meta-analysis of more than 113 studies and found that exercise and psychological interventions, as well as a combination of both, were associated with reduced fatigue during and after cancer treatment.

However, pharmaceutical interventions were not associated with the same magnitude of improvement.

The researchers therefore concluded that exercise and psychological therapy should be recommended over medications.

“If a cancer patient is having trouble with fatigue, rather than looking for extra cups of coffee, a nap, or a pharmaceutical solution, consider a 15-minute walk,” said study author Karen Mustian, PhD, of the University of Rochester Medical Center in Rochester, New York.

“It’s a really simple concept, but it’s very hard for patients and the medical community to wrap their heads around it because these interventions have not been front-and-center in the past. Our research gives clinicians a valuable asset to alleviate cancer-related fatigue.”

Dr Mustian and her colleagues reached their conclusions after analyzing data from 113 randomized clinical trials testing various treatments for cancer-related fatigue.

There were 11,525 patients enrolled in these studies. Nearly half (46.9%) were women with breast cancer. Ten studies focused on other types of cancer and enrolled only men.

Dr Mustian and her colleagues performed a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the fatigue treatments.

The team found that exercise alone—whether aerobic or anaerobic—reduced cancer-related fatigue most significantly. The WES was 0.30 (95% CI, 0.25-0.36; P<0.001).

Psychological interventions—such as therapy designed to provide education, change personal behavior, and adapt the way a person thinks about his or her circumstances—also improved fatigue. The WES was 0.27 (95% CI, 0.21-0.330.30; P<0.001).

A combination of psychological interventions and exercise had a significant improvement on fatigue as well. The WES was 0.26 (95% CI, 0.13-0.38; P<0.001).

However, the drugs tested for treating cancer-related fatigue—paroxetine hydrochloride, modafinil, armodafinil, methylphenidate hydrochloride, dexymethylphenidate, dexamphetamine, and methylprednisolone—were not as effective as the other interventions. The WES was 0.09 (95% CI, 0.00-0.19; P=0.05).

“The literature bears out that these drugs don’t work very well, although they are continually prescribed,” Dr Mustian said. “Cancer patients already take a lot of medications, and they all come with risks and side effects. So any time you can subtract a pharmaceutical from the picture it usually benefits patients.”

 

Image by Ed Uthman

 

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

 

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

 

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

 

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

 

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

 

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

 

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

 

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

 

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

 

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

 

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

 

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

 

Image by Ed Uthman

 

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

 

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

 

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

 

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

 

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

 

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

 

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

 

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

 

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

 

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

 

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

 

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

 

Image by Ed Uthman

 

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

 

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

 

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

 

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

 

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

 

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

 

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

 

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

 

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

 

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

 

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

 

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

INTRODUCTION

Mantle cell lymphoma (MCL) is an uncommon, distinct clinical subtype of non-Hodgkin lymphoma (NHL) that comprises approximately 8% of all lymphoma diagnoses in the United States and Europe.^1,2 Considered incurable, MCL often presents in advanced stages, particularly with involvement of the lymph nodes, spleen, bone marrow, and gastrointestinal tract in the form of lymphomatous polyps. MCL disproportionately affects males, and incidence rises with age, with a median age at diagnosis of 68 years.² Historically, the prognosis of patients with MCL has been among the poorest among B-cell lymphoma patients, with a median overall survival (OS) of 3 to 5 years, and time to treatment failure (TTF) of 18 to 24 months, although this is improving in the modern era.³ Less frequently, patients with MCL display isolated bone marrow, peripheral blood, and splenic involvement. These cases tend to behave more indolently with longer survival.^4,5 Recent advances in therapy have dramatically impacted treatment alternatives and outcomes for MCL. As such, the therapeutic and prognostic landscape of MCL is evolving rapidly.

PATHOGENESIS

The histologic diagnosis of MCL by morphology alone is often challenging. Accurate diagnosis relies on immunohistochemical staining for the purposes of immunophenotyping.⁶ MCL typically expresses B-cell markers CD5 and CD20, and lacks both CD10 and CD23. The genetic hallmark of MCL is the t(11;14) (q13;q32) chromosomal translocation leading to upregulation of the cyclin D1 protein, a critical regulator of the G1 phase of the cell cycle. Specifically, the t(11;14) translocation, present in virtually all cases of MCL, juxtaposes the proto-oncogene CCND1 to the immunoglobulin heavy chain gene.⁷ Consequently, cyclin D1, normally not expressed in B lymphocytes, becomes constitutively overexpressed. This alteration is thought to facilitate the deregulation of the cell cycle at the G1-S phase transition.⁸

Gene expression profiling studies have underscored the importance of cell cycle deregulation in MCL, and high proliferation is associated with a worse prognosis.⁹ More than 50% of the genes associated with poor outcomes were derived from the “proliferation signature” that was more highly expressed in dividing cells. In the seminal Rosenwald study, a gene expression–based outcome model was constructed in which the proliferation signature average represents a linear variable that assigns a discrete probability of survival to an individual patient.⁹ The proliferative index, or proliferative signature, of MCL can be estimated by the percentage of Ki-67–positive cells present in the tumor through immunohistochemistry. This is often used as a marker of poor outcomes, and as a surrogate for the proliferative signature in MCL that can be incorporated into clinical practice (as opposed to gene expression profiling). Statistically significant differences in OS have emerged between groups of MCL patients with Ki-67–positive cells comprising less than 30% of their tumor sample (favorable) and those with Ki-67–positive cells comprising 30% or greater (unfavorable).¹⁰

Recent data has also identified the importance of the transcription factor SOX 11 (SRY-related HMG-box), which regulates multiple cellular transcriptional events, including cell proliferation and differentiation, apoptosis, and angiogenesis.¹¹ MCL expressing SOX 11 behaves more aggressively than MCL variants lacking SOX 11 expression, and tends to accumulate more genetic alterations.¹² Moreover, lack of SOX 11 expression characterizes a subset of MCL that does not carry the t(11;14) translocation.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 62-year-old man with a history of diabetes mellitus and hypertension presents with cervical lymphadenopathy, fatigue, and early satiety over the past several months. He is otherwise in good health. His Eastern Cooperative Oncology Group (ECOG) performance status is 1. On physical examination, 3-cm lymphadenopathy in the bilateral cervical chain is noted. Bilateral axillary lymph nodes measure 2 to 4 cm. His spleen is enlarged and is palpable at approximately 5 cm below the costal margin. A complete blood count reveals a total white blood cell (WBC) count of 14,000 cells/μL, with 68% lymphocytes and a normal distribution of neutrophils. Hemoglobin is 11 g/dL, and platelet count is 112,000/μL. The lactate dehydrogenase (LDH) level is 322 U/L (upper limit of normal: 225 U/L).

• How is MCL diagnosed?

Diagnosis of MCL requires review by expert hematopathologists.¹³ Whenever possible, an excisional biopsy should be performed for the adequate characterization of lymph node architecture and evaluation by immunohistochemistry. Aside from the characteristic expression of CD5 and CD20 and absence of CD23, MCL should express cyclin D1, which reflects t(11;14). If cyclin D1 is inconclusive or unavailable, fluorescent in situ hybridization (FISH) for t(11;14) should be performed.⁸ Patients often have circulating malignant lymphocytes, or leukemic phase MCL. Flow cytometry of the peripheral blood can detect traditional surface markers, and FISH can also be performed on circulating abnormal lymphocytes.

 

For disease staging, bone marrow biopsy and aspiration are required. Radiographic staging using computed tomography (CT) scans and/or positron emission tomography (PET) scans had traditionally followed the Ann Arbor staging system, but recently the Lugano classification has emerged, which delineates only early or advanced stage.¹⁴ Gastrointestinal evaluation of MCL with endoscopy and colonoscopy with blind biopsies has been recommended to evaluate for the presence of lymphomatous polyps, but this is not an absolute requirement.¹⁵

RISK STRATIFICATION

At diagnosis, patients should undergo risk stratification in order to understand prognosis and possibly guide treatment. In MCL, the MCL international prognostic index (MIPI) is used. The MIPI is a prognostic tool developed exclusively for patients with MCL using data from 455 patients with advanced-stage MCL treated within 3 European clinical trials.¹⁶ The MIPI classified patients into risk groups based on age, ECOG performance status, LDH level, and WBC count. Patients were categorized into low-risk (44% of patients, median OS not reached), intermediate-risk (35%, median OS 51 months), and high-risk groups (21%, median OS 29 months). This is done through a logarithmic calculation, which can be accessed through online calculators (a prototype example can be found at www.qxmd.com/calculate-online/hematology/prognosis-mantle-cell-lymphoma-mipi). Cell proliferation using the Ki-67 index was evaluated in an exploratory analysis (the biologic [“B”] MIPI), and also demonstrated strong prognostic relevance.¹⁶ Currently, treatment of MCL patients is not stratified by MIPI outside of a clinical trial, but this useful tool assists in assessing patient prognosis and has been validated for use with both conventional chemoimmunotherapy and in the setting of autologous stem cell transplant (autoSCT).^16,17 At this point in time, the MIPI score is not used to stratify treatment, although some clinical trials are incorporating the use of the MIPI score at diagnosis. Nonetheless, given its prognostic importance, the MIPI should be performed for all MCL patients undergoing staging and evaluation for treatment to establish disease risk.

As noted, the proliferative signature, represented by the Ki-67 protein, is also highly prognostic in MCL. Ki-67 is expressed in the late G1, S, G2, and M phases of the cell cycle. The Ki-67 index is defined by the hematopathologist as the percentage of lymphoma cells staining positive for Ki-67 protein, based on the number of cells per high-power field. There is significant interobserver variability in this process, which can be minimized by assessing Ki-67 quantitatively using computer software. The prognostic significance of Ki-67 at diagnosis was established in large studies of MCL patient cohorts, with survival differing by up to 3 years.^18,19 Determann et al demonstrated the utility of the proliferative index in patients with MCL treated with standard chemoimmunotherapy.¹⁰ In this study, 249 patients with advanced-stage MCL treated within randomized trials conducted by the European MCL Network were analyzed. The Ki-67 index was found to be extremely prognostic of OS, independent of other clinical risk factors, including the MIPI score. As a continuous variable, Ki-67 indices of greater than 10% correlated with poor outcomes. The Ki-67 index has also been confirmed as prognostic in relapsed MCL.²⁰ It is important to note that, as a unique feature, the Ki-67 index has remained an independent prognostic factor, even when incorporated into the “B” MIPI.

TREATMENT

CASE CONTINUED

The patient undergoes an excisional biopsy of a cervical lymph node, which demonstrates an abnormal proliferation of small-medium–sized lymphocytes with slightly irregular nuclear contours. Immunohistochemistry shows that the abnormal lymphocytes are positive for CD20 and CD5, negative for CD10 and CD23, and diffusely positive for cyclin D1, consistent with a diagnosis of MCL. The proliferative index, as measured by the Ki-67 immunostain, is 40%. A bone marrow aspirate and biopsy are then obtained, which show a clonal population of B lymphocytes expressing the same immunophenotype as the lymph node (positive for CD20 and CD5, negative for CD10 and CD23, cyclin D1 positive). A CT scan of the neck, chest, abdomen, and pelvis with contrast is obtained, along with a PET scan. These studies identify extensive hypermetabolic lymphadenopathy in the bilateral cervical chains, supraclavicular areas, mediastinum, and hilum. Mesenteric lymph nodes are also enlarged and hypermetabolic, as are retroperitoneal lymph nodes. The spleen is noted to be enlarged with multiple hypermetabolic lesions. Based on the presence of extensive lymphadenopathy as well as bone marrow involvement, the patient is diagnosed with stage IV MCL. He undergoes risk-stratification with the MIPI. His MIPI score is 6.3, high risk.

 

• What is the approach to upfront therapy for MCL?

FRONTLINE THERAPY

Role of Watchful Waiting

A small proportion of MCL patients have indolent disease that can be observed. This population is more likely to have leukemic-phase MCL with circulating lymphocytes, splenomegaly, and bone marrow involvement and absent or minimal lymphadenopathy.^4,5 A retrospective study of 97 patients established that deferment of initial therapy in MCL is acceptable in some patients.⁵ In this study, approximately one third of patients with MCL were observed for more than 3 months before initiating systemic therapy, and the median time to treatment for the observation group was 12 months. Most patients undergoing observation had a low-risk MIPI. Patients were not harmed by observation, as no OS differences were observed among groups. This study underscores that deferred treatment can be an acceptable alternative in selected MCL patients for a short period of time. In practice, the type of patient who would be appropriate for this approach is someone who is frail, elderly, and with multiple comorbidities. Additionally, expectant observation could be considered for patients with limited-stage or low-volume MCL, low Ki-67 index, and low-risk MIPI scores.

Approach to Therapy

Treatment of MCL is generally approached by evaluating patient age and fitness for treatment. While there is no accepted standard, for younger patients healthy enough to tolerate aggressive approaches, treatment often involves an intensive cytarabine-containing regimen, which is consolidated with an autoSCT. This approach results in the longest remission duration, with some series suggesting a plateau in survival after 5 years, with no relapses.²¹ Nonintensive conventional chemotherapy alone is often reserved for the frailer or older patient. Given that remission durations with chemotherapy alone in MCL are short, goals of treatment focus on maximizing benefit and remission duration and minimizing risk of toxicity.

Standard Chemotherapy: Elderly and/or Frail Patients

Conventional chemotherapy alone for the treatment of MCL results in a 70% to 85% overall response rate (ORR) and 7% to 30% complete response (CR) rate.²² Rituximab, a mouse humanized monoclonal IgG1 anti-CD20 antibody, is used as standard of care in combination with chemotherapy, since its addition has been found to increase response rates and extend both progression-free survival (PFS) and OS compared to chemotherapy alone.^23,24 However, chemoimmunotherapy approaches do not provide long-term control of MCL and are considered noncurative. Various regimens have been studied and include anthracycline-containing regimens such as R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, prednisone),²² combination chemotherapy with antimetabolites such as R-hyper-CVAD (hyper-fractionated rituximab with cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine),²⁵ purine analogue–based regimens such as R-FC (rituximab with fludarabine and cyclophosphamide),²⁶ bortezomib-containing regimens,²⁷ and alkylator-based treatment with BR (bendamustine and rituximab) (Table 1).^28,29 Among these, the most commonly used are R-CHOP and BR.

Two large randomized studies compared R-CHOP for 6 cycles to BR for 6 cycles in patients with indolent NHL and MCL. Among MCL patients, BR resulted in superior PFS compared to R-CHOP (69 months versus 26 months) but no benefit in OS.^28,29 The ORR to R-CHOP was approximately 90%, with a PFS of 21 months in the Rummel et al study.²⁹ This study included more than 80 centers in Germany and enrolled 549 patients with MCL, follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia. Patients were randomized in a 1:1 fashion. Among these, 46 patients received BR and 48 received R-CHOP (18% for both, respectively). It should be noted that patients in the BR group had significantly less toxicity and experienced fewer side effects than did those in the R-CHOP group. Similarly, BR-treated patients had a lower frequency of hematologic side effects and infections of any grade. However, drug-associated skin reactions and allergies were more common with BR compared to R-CHOP. The study by Flinn and colleagues was an international randomized, noninferiority phase 3 study designed to evaluate the efficacy and safety of BR compared with R-CHOP or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) for treatment-naive patients with MCL or other indolent NHL. The primary endpoint was CR. In this study, BR was found to be noninferior to R-CHOP and R-CVP based on CR rate (31% versus 25%, respectively; P = 0.0225). Response rates in general were high: 97% for BR and 91% for R-CHOP/R-CVP (P = 0.0102). Here, BR-treated patients experienced more nausea, emesis, and drug-induced hypersensitivity compared to the R-CHOP and R-CVP groups.

 

Another approach studied in older patients is the use of R-CHOP with rituximab maintenance. In a large European study, 560 patients 60 years of age or older with advanced-stage MCL were randomly assigned to either R-FC (rituximab, fludarabine, and cyclophosphamide) every 28 days for 6 cycles, or R-CHOP every 21 days for 8 cycles. Patients who had a response then underwent a second randomization, with one group receiving rituximab maintenance therapy. Maintenance was continued until progression of disease. Patients in this study were not eligible for high-dose chemotherapy and autoSCT. The study found that rates of CR were similar with both R-FC and R-CHOP (40% and 34%, respectively; P = 0.10). However, the R-FC arm underperformed in several arenas. Disease progression occurred more frequently with R-FC (14% versus 5% with R-CHOP), and OS was shorter (4-year OS, 47% versus 62%; P = 0.005, respectively). More patients also died in the R-FC group, and there was greater hematologic toxicity compared to R-CHOP. At 4 years, 58% of the patients receiving rituximab remained in remission. Among patients who responded to R-CHOP, rituximab maintenance led to a benefit in OS, reducing the risk of progression or death by 45%.²⁶ At this time, studies are ongoing to establish the benefit of rituximab maintenance after BR.

Bendamustine in combination with other agents has also been studied in the frontline setting. Visco and colleagues evaluated the combination of bendamustine with rituximab and cytarabine (R-BAC) in older patients with MCL (age 65 or older).⁶³ This phase 2, two-stage study enrolled 40 patients and had a dose-finding arm for cytarabine in combination with BR. It permitted relapsed/refractory patients, but 50% had newly diagnosed, previously untreated MCL. The regimen had an impressive ORR of 100%, with CR rates of 95% for previously untreated patients. PFS at 2 years was 95%. R-BAC was well tolerated, with the primary toxicity being reversible myelosuppression.

BR was combined with the proteasome inhibitor bortezomib and dexamethasone in a phase 2 study.⁶⁴ This Lymphoma Study Association (LYSA) study evaluated 76 patients with newly diagnosed MCL older than age 65 years. BR was administered in standard doses (bendamustine 90 mg/m² on days 1 and 2 and rituximab 375 mg/m² IV on day 1) and bortezomib was administered subcutaneously on days 1, 4, 8, and 11, with acyclovir for viral prophylaxis. Patients received 6 cycles. The ORR was 87% and the CR was 60%. Patients experienced toxicity, and not all bortezomib doses were administered due to neurotoxic or hematologic side effects.

A randomized phase 3 study compared R-CHOP to the VR-CAP regimen (R-CHOP regimen but bortezomib replaces vincristine on days 1, 4, 8, 11, at 1.3 mg/m²) in 487 newly diagnosed MCL patients.²⁷ Median PFS was superior in the VR-CAP group compared with R-CHOP (14.4 months versus 24.7 months, respectively). Additionally, rates of CR were superior in the VR-CAP group (53% compared to 42% with R-CHOP). However, there was more hematologic toxicity with VR-CAP. On the basis of these findings, the U.S. Food and Drug Administration approved bortezomib for the frontline treatment of MCL.

Other chemoimmunotherapy combinations containing bortezomib have been studied in frontline MCL treatment, with promising results. These include bortezomib in combination with R-CHOP or modified R-hyper-CVAD, as well as bortezomib in combination with CHOP-like treatments and purine analogues.^27,30–32 The ongoing ECOG 1411 study is currently evaluating bortezomib added to BR for induction therapy of newly diagnosed MCL in a 4-arm randomized trial. Patients receive BR with or without bortezomib during induction and are then randomly assigned to maintenance with either rituximab alone or rituximab with lenalidomide. Other novel combination agents are actively being studied in frontline MCL treatment, including lenalidomide and rituximab and BR with lenalidomide.

Intensification of Therapy and AutoSCT: Fitter and/or Younger Patients

Short response duration has created the need for post-remission therapy in MCL. One approach to improve remission duration in MCL is to intensify induction through the use of cytarabine-containing regimens and/or consolidation with high-dose chemotherapy, typically using BEAM (carmustine, etoposide, cytarabine, melphalan) and autoSCT (Table 2). The cytarabine-containing R-hyper-CVAD regimen, developed at the MD Anderson Cancer Center, resulted in a 97% ORR and an 87% CR rate, with TTF of nearly 5 years. However, nearly one third of patients were unable to complete treatment due to toxicity, and 5 patients developed secondary myelodysplastic syndrome or acute myeloid leukemia.³³ The feasibility of this R-hyper-CVAD regimen was tested in a multicenter cooperative group setting, but similar results were not seen; in this study, nearly 40% of patients were unable to complete the full scheduled course of treatment due to toxicity.³⁴

 

​Other ways to intensify therapy in MCL involve adding a second non-cross-resistant cytarabine-containing regimen to R-CHOP after remission, such as DHAP (dexamethasone, high-dose cytarabine, cisplatin), followed by consolidation with an autoSCT. A retrospective registry from the National Comprehensive Cancer Network sought to compare the efficacy of different treatment approaches in the frontline setting. They studied 167 patients with MCL and compared 4 groups: treatment with R-hyper-CVAD, either with or without autoSCT, and treatment with R-CHOP, either with or without autoSCT. This study found that in patients younger than 65, R-CHOP followed by autoSCT or R-hyper-CVAD without autoSCT resulted in similar PF and OS, but was superior to R-CHOP alone for newly diagnosed MCL patients.³⁵ These data support more intensive regimens in younger and fitter patients. Several other prospective and randomized studies have demonstrated clinical benefit for patients with MCL undergoing autoSCT in first remission. Of particular importance is the seminal phase 3 study of the European MCL Network, which established the role of autoSCT in this setting.⁶¹ In this prospective randomized trial involving 122 newly diagnosed MCL patients who responded to CHOP-like induction, patients in CR derived a greater benefit from autoSCT.

More recent studies have demonstrated similar benefits using cytarabine-based autoSCT. The Nordic MCL2 study evaluated 160 patients using R-CHOP, alternating with rituximab and high-dose cytarabine, followed by autoSCT. This study used “maxi-CHOP,” an augmented CHOP regimen (cyclophosphamide 1200 mg/m², doxorubicin 75 mg/m², but standard doses of vincristine [2 mg] and prednisone [100 mg days 1–5]), alternating with 4 infusions of cytarabine at 2 g/m² and standard doses of rituximab (375 mg/m²). Patients then received conditioning with BEAM and autoSCT. Patients were evaluated for the presence of minimal residual disease (MRD) and for the t(11;14) or clonal immunoglobulin heavy chain gene rearrangement with polymerase chain reaction (PCR). Patients with MRD were offered therapy with rituximab at 375 mg/m² weekly for 4 doses. This combination resulted in 10-year OS rates of 58%.³⁶ In a multicenter study involving 78 patients from the Cancer and Leukemia Group B (CALGB), R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT resulted in a 5-year OS of 64%.³⁷ A single-arm phase 2 study from the Netherlands also tested R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT. Nonhematologic toxicities were 22% after high-dose cytarabine, and 55% after BEAM. The ORR was 70%, with a 64% CR rate and 66% OS at 4 years.³⁸ The French GELA group used 3 cycles of R-CHOP and 3 cycles of R-DHAP in a phase 2 study of young (under age 66) MCL patients. Following R-CHOP, the ORR was 93%, and following R-DHAP the ORR was 95%. Five-year OSA was 75%.³⁹ A large randomized phase 3 study by Hermine and colleagues of the EMCLN confirmed the benefit of this approach in 497 patients with newly diagnosed MCL. R-CHOP for 6 cycles followed by autoSCT was compared to R-CHOP for 3 cycles alternating with R-DHAP for 3 cycles and autoSCT with a cytarabine-based conditioning regimen. The addition of cytarabine significantly increased rates of CR, TTF, and OS, without increasing toxicity.⁴⁰

CASE CONTINUED

The patient is treated with R-CHOP chemotherapy for 3 cycles followed by R-DHAP. His course is complicated by mild tinnitus and acute kidney injury from cisplatin that promptly resolves. Three weeks following treatment, a restaging PET/CT scan shows resolution of all lymphadenopathy, with no hypermetabolic uptake, consistent with a complete remission. A repeat bone marrow biopsy shows no involvement with MCL. He subsequently undergoes an autoSCT, and restaging CT/PET 3 months following autoSCT shows continued remission. He is monitored every 3 to 6 months over the next several years.

He has a 4.5-year disease remission, after which he develops growing palpable lymphadenopathy on exam and progressive anemia and thrombocytopenia. A bone marrow biopsy is repeated, which shows recurrent MCL. Restaging diagnostic imaging with a CT scan reveals lymphadenopathy above and below the diaphragm. An axillary lymph node biopsy also demonstrates recurrent MCL. At this time the patient is otherwise in fairly good health, except for feeling fatigued. His ECOG performance status is 1. He begins therapy with bortezomib at a dose of 1.3 mg/m² intravenously on days 1, 4, 8, and 11 for 6 cycles. His treatment course is complicated by painful sensory peripheral neuropathy of the bilateral lower extremities. Restaging studies at the completion of therapy demonstrate that he has achieved a partial response, with a 50% reduction in the size of involved lymphadenopathy and some residual areas of hypermetabolic uptake. His peripheral cytopenias improve moderately.

 

• What are the therapeutic options for relapsed MCL?

TREATMENT OF RELAPSED MCL

Single-Agent and Combination Chemotherapy

Whenever possible, and since there is no standard, patients with relapsed MCL should be offered a clinical trial. Outside of a clinical study, many of the treatment regimens used at diagnosis can also be applied in the relapsed setting. In relapsed MCL, Rummel et al showed that BR for 4 cycles resulted in an ORR of 90%, with a CR of 60%. The median PFS was 24 months.⁴¹ Bortezomib, an inhibitor of the proteasome-ubiquitin pathway, leads to apoptosis and cell cycle arrest in MCL.⁴² Multiple studies have evaluated bortezomib both as a single agent and in combination for patients with relapsed MCL. In 2006, bortezomib became the first agent approved by the FDA in relapsed or refractory MCL, based on the phase 2 PINNACLE study. This prospective multicenter study involving 155 patients demonstrated an ORR of 33%, CR rate of 8%, and median treatment duration of 9 months. The median time to progression was 6 months.⁴³ Subsequently, bortezomib-containing combinations evolved. In a multicenter study of relapsed and refractory indolent NHL and MCL, Friedberg and colleagues evaluated bortezomib in combination with BR.⁴⁴ In the MCL cohort, the ORR was 71%. These promising results led to the study of this combination in the frontline setting. The ongoing ECOG 1411 study is using BR for the frontline treatment of MCL with or without bortezomib as induction. This study also includes rituximab maintenance, and randomizes patients to undergo maintenance with or without the immunomodulator lenalidomide. Bortezomib has been associated with herpes simplex and herpes zoster reactivation. Neuropathy has also been observed with bortezomib, which can be attenuated by administering it subcutaneously.

Lenalidomide is an immunomodulatory agent derived from thalidomide. It has significant activity and is a mainstay of treatment in multiple myeloma. Lenalidomide acts by enhancing cellular immunity, has antiproliferative effects, and inhibits T-cell function leading to growth inhibitory effects in the tumor microenvironment.⁴⁵ In MCL, lenalidomide has demonstrated clinical activity both as a single agent and in combination, as well as in preclinical studies establishing its pro-apoptotic effects.⁴⁶ The pivotal EMERGE study evaluated monotherapy with lenalidomide in heavily pretreated relapsed and refractory MCL. This multicenter international study of 134 patents reported an ORR of 28% with a 7.5% CR rate and median PFS of 4 months. All patients had relapsed or progressed following bortezomib. This led to the approval of lenalidomide by the FDA in 2013 for the treatment of patients with MCL whose disease relapsed or progressed following 2 prior therapies, one of which included bortezomib.⁴⁷ Lenalidomide has been associated with neutropenia, secondary cancers, and deep venous thrombosis.

In combination with other agents in the relapsed setting, lenalidomide shows broader activity. A phase 1/2 study by Wang and colleagues demonstrated an ORR of 57%; the median response duration was 19 months when lenalidomide was combined with rituximab for relapsed/refractory MCL.⁴⁸

Novel Therapies

More recently, novel treatment approaches have been tested in MCL based on an increased understanding of aberrant signaling pathways in this disease (Table 3). Constitutive activation of B-cell receptor signaling is critical for the survival and proliferation of lymphomas, and has led to the development of targeted agents inhibiting B-cell receptor–associated protein kinases. Bruton’s tyrosine kinase (BTK) is one essential component of the B-cell receptor.⁴⁹ In particular, proteins upstream of the BTK pathway have been implicated in growth and proliferation of MCL, suggesting that inhibition of BTK may impede lymphomagenesis.⁵⁰ Ibrutinib is an oral inhibitor of BTK, and demonstrates activity in multiple lymphoma subtypes. In a phase 1 study of ibrutinib in relapsed and refractory hematologic malignancies, an ORR of 60% was observed in 50 evaluable patients, with 16% CR. Median PFS was 13 months. Among these, 7 of 9 patients with MCL responded, including 3 CRs.⁵¹ Given these promising results, a phase 2 multicenter study evaluating ibrutinib in relapsed and refractory MCL was completed.⁵² At a dose of 560 mg daily, the response rate was 68%, with CR of 21%. The most common observed treatment-related side effects included diarrhea, fatigue, and nausea. Neutropenia and thrombocytopenia were also observed. Of importance, 5% of patients had grade 3 or higher bleeding events, including subdural hematoma, gastrointestinal bleeding, and hematuria. The estimated OS rate was 58% at 18 months. On the basis of this study, the FDA approved ibrutinib for relapsed and refractory MCL in November 2013.

 

The PI3K pathway is another survival pathway that is dysfunctional in several hematologic disorders, including MCL. Overexpression of PI3K and its downstream targets contributes to MCL pathogenesis.⁵³ Idelalisib is an oral small molecule inhibitor of the delta isoform of PI3K that is dosed daily; it was approved by the FDA for the treatment of relapsed and refractory follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia. It is being further evaluated in MCL. A dose-escalation phase 1 study in heavily pre-treated MCL patients established safety and tolerability.⁵⁴ Efficacy analysis showed an ORR of 40%, CR of 5%, and 1-year OS of 22%. Further phase 2 studies testing idelalisib as a single agent and in combination for MCL are ongoing. Side effects of idelalisib include elevated liver enzymes, pneumonitis, and diarrhea.

The BCL family of proteins is involved in both pro-and anti-apoptotic functions. BCL2 is an intracellular protein that blocks apoptosis. ABT-199 is an oral BCL2 inhibitor that in early clinical trials has shown very promising activity in MCL. In a phase 1 study of 31 relapsed and refractory NHL patients, all 8 MCL patients (100% ORR) responded to ABT-199 therapy.⁵⁵ Given these promising initial results, multiple studies evaluating ABT-199 are ongoing in MCL as part of first-line treatment as well as for relapsed disease. ABT-199 has been implicated in tumor lysis syndrome, and in early studies of chronic lymphocytic leukemia, fatal tumor lysis was observed.

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has been evaluated in relapsed MCL. It is given weekly at 250 mg intravenously. Response rates to single-agent temsirolimus are approximately 20% to 35%, and are higher when combined with rituximab.^56,57 The phase 2 study evaluating temsirolimus as a single agent enrolled 35 heavily pre-treated patients. ORR was 38% with only 1 CR. The duration of response was 7 months. Temsirolimus is approved for relapsed MCL in Europe but not in the United States. Similar to the other targeted agents, temsirolimus is actively being studied in combination with other active agents in MCL. Adverse effects noted with temsirolimus include diarrhea, stomatitis, and rash. Thrombocytopenia requiring dose reductions is another frequently observed complication.

Radioimmunotherapy

Radioimmunotherapy (RIT) has been studied extensively in MCL. RIT consists of anti-CD 20 antibodies coupled to radioactive particles that deliver radiation to targeted cells, minimizing toxicity to surrounding tissues. RIT is not used as frequently in the modern era as it had been in the past. At this time, only yttrium-90-ibritumomab tiuxetan is available.

RIT has been evaluated in MCL both at the time of relapse⁵⁸ and more recently, as part of a conditioning regimen prior to autoSCT, with good tolerability.^65–67 Averse events noted with RIT include hematologic toxicity (can be prolonged), hypothyroidism, and in rare cases, myelodysplastic syndrome and acute leukemia. The bone marrow must have less than 25% involvement with disease prior to administration. Wang and colleagues evaluated yttrium-90-ibritumomab tiuxetan in 34 heavily pretreated patients with MCL.⁵⁸ They observed an ORR of 31%. The median event-free survival (EFS) was 6 months, but in patients achieving either CR or PR, EFS was 28 months. A 21-month OS was noted.

In the upfront setting, RIT has been added as a mechanism of intensification. A recent Nordic group study of RIT with autoSCT did not find benefit with the addition of RIT.⁵⁹ An ECOG study recently added yttrium-90-ibritumomab tiuxetan after CHOP chemotherapy in the upfront treatment of MCL, with good tolerability.⁵⁵ However, when added to R-hyper-CVAD, the combination had unexpected high rates of hematologic toxicity, including grade 3/4 cytopenias and an unacceptably high rate of secondary malignancies.⁶⁸

AutoSCT or Allogeneic Transplant

While many studies noted above have established the beneficial role of autoSCT in MCL in first remission, the role of allogeneic transplant (alloSCT) in MCL remains controversial. A recent large retrospective study conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) evaluated 519 patients with MCL who underwent both autoSCT and alloSCT.⁶⁰ Patients were grouped into an early cohort (transplant in first PR or CR, and 2 or fewer treatments) and late cohort (all other patients). The analysis had mature follow up. A multivariate analysis demonstrated that early autoSCT was associated with superior outcomes compared to autoSCT performed later. While it was not possible to demonstrate a survival benefit favoring autoSCT over reduced intensity (RIC) alloSCT, patients transplanted later in their disease course had shorter OS. For patients receiving autoSCT in CR 1 following only 1 prior line of therapy, OS at 5 years was 75% and PFS was 70%. Patients undergoing RIC followed by alloSCT had fewer relapses, but this was negated by higher nonrelapse mortality (25%), resulting in a PFS similar to autoSCT.

 

CASE CONCLUSION

After treatment with bortezomib the patient is well for 9 months. Subsequently, however, he develops increasing lymphadenopathy and progressive fatigue. He is then started on lenalidomide 25 mg orally daily for 21 out of 28 days. He experiences significant fatigue with lenalidomide and prolonged neutropenia requiring dose delays, despite dose modification to 10 mg orally daily. He requires discontinuation of lenalidomide. Given persistent disease, the patient then begins treatment with ibrutinib. Within a few days of starting ibrutinib therapy, he experiences a marked but transient leukocytosis. Two months later, the patient’s palpable lymphadenopathy has decreased, and his anemia and thrombocytopenia related to MCL are improving. He has tolerated treatment well. His course has been complicated only by a mild, pruritic maculopapular eruption on his chest, back, and arms, that was responsive to topical low-dose steroids. He remains on ibrutinib 1 year later.

CONCLUSION

Advances in our understanding of MCL treatment are revolutionizing the approach to this once deadly disease. Over the next several years, these gains will weave themselves into the current treatment paradigm and likely alter the treatment landscape for MCL as we know it.

INTRODUCTION

Mantle cell lymphoma (MCL) is an uncommon, distinct clinical subtype of non-Hodgkin lymphoma (NHL) that comprises approximately 8% of all lymphoma diagnoses in the United States and Europe.^1,2 Considered incurable, MCL often presents in advanced stages, particularly with involvement of the lymph nodes, spleen, bone marrow, and gastrointestinal tract in the form of lymphomatous polyps. MCL disproportionately affects males, and incidence rises with age, with a median age at diagnosis of 68 years.² Historically, the prognosis of patients with MCL has been among the poorest among B-cell lymphoma patients, with a median overall survival (OS) of 3 to 5 years, and time to treatment failure (TTF) of 18 to 24 months, although this is improving in the modern era.³ Less frequently, patients with MCL display isolated bone marrow, peripheral blood, and splenic involvement. These cases tend to behave more indolently with longer survival.^4,5 Recent advances in therapy have dramatically impacted treatment alternatives and outcomes for MCL. As such, the therapeutic and prognostic landscape of MCL is evolving rapidly.

PATHOGENESIS

The histologic diagnosis of MCL by morphology alone is often challenging. Accurate diagnosis relies on immunohistochemical staining for the purposes of immunophenotyping.⁶ MCL typically expresses B-cell markers CD5 and CD20, and lacks both CD10 and CD23. The genetic hallmark of MCL is the t(11;14) (q13;q32) chromosomal translocation leading to upregulation of the cyclin D1 protein, a critical regulator of the G1 phase of the cell cycle. Specifically, the t(11;14) translocation, present in virtually all cases of MCL, juxtaposes the proto-oncogene CCND1 to the immunoglobulin heavy chain gene.⁷ Consequently, cyclin D1, normally not expressed in B lymphocytes, becomes constitutively overexpressed. This alteration is thought to facilitate the deregulation of the cell cycle at the G1-S phase transition.⁸

Gene expression profiling studies have underscored the importance of cell cycle deregulation in MCL, and high proliferation is associated with a worse prognosis.⁹ More than 50% of the genes associated with poor outcomes were derived from the “proliferation signature” that was more highly expressed in dividing cells. In the seminal Rosenwald study, a gene expression–based outcome model was constructed in which the proliferation signature average represents a linear variable that assigns a discrete probability of survival to an individual patient.⁹ The proliferative index, or proliferative signature, of MCL can be estimated by the percentage of Ki-67–positive cells present in the tumor through immunohistochemistry. This is often used as a marker of poor outcomes, and as a surrogate for the proliferative signature in MCL that can be incorporated into clinical practice (as opposed to gene expression profiling). Statistically significant differences in OS have emerged between groups of MCL patients with Ki-67–positive cells comprising less than 30% of their tumor sample (favorable) and those with Ki-67–positive cells comprising 30% or greater (unfavorable).¹⁰

Recent data has also identified the importance of the transcription factor SOX 11 (SRY-related HMG-box), which regulates multiple cellular transcriptional events, including cell proliferation and differentiation, apoptosis, and angiogenesis.¹¹ MCL expressing SOX 11 behaves more aggressively than MCL variants lacking SOX 11 expression, and tends to accumulate more genetic alterations.¹² Moreover, lack of SOX 11 expression characterizes a subset of MCL that does not carry the t(11;14) translocation.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 62-year-old man with a history of diabetes mellitus and hypertension presents with cervical lymphadenopathy, fatigue, and early satiety over the past several months. He is otherwise in good health. His Eastern Cooperative Oncology Group (ECOG) performance status is 1. On physical examination, 3-cm lymphadenopathy in the bilateral cervical chain is noted. Bilateral axillary lymph nodes measure 2 to 4 cm. His spleen is enlarged and is palpable at approximately 5 cm below the costal margin. A complete blood count reveals a total white blood cell (WBC) count of 14,000 cells/μL, with 68% lymphocytes and a normal distribution of neutrophils. Hemoglobin is 11 g/dL, and platelet count is 112,000/μL. The lactate dehydrogenase (LDH) level is 322 U/L (upper limit of normal: 225 U/L).

• How is MCL diagnosed?

Diagnosis of MCL requires review by expert hematopathologists.¹³ Whenever possible, an excisional biopsy should be performed for the adequate characterization of lymph node architecture and evaluation by immunohistochemistry. Aside from the characteristic expression of CD5 and CD20 and absence of CD23, MCL should express cyclin D1, which reflects t(11;14). If cyclin D1 is inconclusive or unavailable, fluorescent in situ hybridization (FISH) for t(11;14) should be performed.⁸ Patients often have circulating malignant lymphocytes, or leukemic phase MCL. Flow cytometry of the peripheral blood can detect traditional surface markers, and FISH can also be performed on circulating abnormal lymphocytes.

 

For disease staging, bone marrow biopsy and aspiration are required. Radiographic staging using computed tomography (CT) scans and/or positron emission tomography (PET) scans had traditionally followed the Ann Arbor staging system, but recently the Lugano classification has emerged, which delineates only early or advanced stage.¹⁴ Gastrointestinal evaluation of MCL with endoscopy and colonoscopy with blind biopsies has been recommended to evaluate for the presence of lymphomatous polyps, but this is not an absolute requirement.¹⁵

RISK STRATIFICATION

At diagnosis, patients should undergo risk stratification in order to understand prognosis and possibly guide treatment. In MCL, the MCL international prognostic index (MIPI) is used. The MIPI is a prognostic tool developed exclusively for patients with MCL using data from 455 patients with advanced-stage MCL treated within 3 European clinical trials.¹⁶ The MIPI classified patients into risk groups based on age, ECOG performance status, LDH level, and WBC count. Patients were categorized into low-risk (44% of patients, median OS not reached), intermediate-risk (35%, median OS 51 months), and high-risk groups (21%, median OS 29 months). This is done through a logarithmic calculation, which can be accessed through online calculators (a prototype example can be found at www.qxmd.com/calculate-online/hematology/prognosis-mantle-cell-lymphoma-mipi). Cell proliferation using the Ki-67 index was evaluated in an exploratory analysis (the biologic [“B”] MIPI), and also demonstrated strong prognostic relevance.¹⁶ Currently, treatment of MCL patients is not stratified by MIPI outside of a clinical trial, but this useful tool assists in assessing patient prognosis and has been validated for use with both conventional chemoimmunotherapy and in the setting of autologous stem cell transplant (autoSCT).^16,17 At this point in time, the MIPI score is not used to stratify treatment, although some clinical trials are incorporating the use of the MIPI score at diagnosis. Nonetheless, given its prognostic importance, the MIPI should be performed for all MCL patients undergoing staging and evaluation for treatment to establish disease risk.

As noted, the proliferative signature, represented by the Ki-67 protein, is also highly prognostic in MCL. Ki-67 is expressed in the late G1, S, G2, and M phases of the cell cycle. The Ki-67 index is defined by the hematopathologist as the percentage of lymphoma cells staining positive for Ki-67 protein, based on the number of cells per high-power field. There is significant interobserver variability in this process, which can be minimized by assessing Ki-67 quantitatively using computer software. The prognostic significance of Ki-67 at diagnosis was established in large studies of MCL patient cohorts, with survival differing by up to 3 years.^18,19 Determann et al demonstrated the utility of the proliferative index in patients with MCL treated with standard chemoimmunotherapy.¹⁰ In this study, 249 patients with advanced-stage MCL treated within randomized trials conducted by the European MCL Network were analyzed. The Ki-67 index was found to be extremely prognostic of OS, independent of other clinical risk factors, including the MIPI score. As a continuous variable, Ki-67 indices of greater than 10% correlated with poor outcomes. The Ki-67 index has also been confirmed as prognostic in relapsed MCL.²⁰ It is important to note that, as a unique feature, the Ki-67 index has remained an independent prognostic factor, even when incorporated into the “B” MIPI.

TREATMENT

CASE CONTINUED

The patient undergoes an excisional biopsy of a cervical lymph node, which demonstrates an abnormal proliferation of small-medium–sized lymphocytes with slightly irregular nuclear contours. Immunohistochemistry shows that the abnormal lymphocytes are positive for CD20 and CD5, negative for CD10 and CD23, and diffusely positive for cyclin D1, consistent with a diagnosis of MCL. The proliferative index, as measured by the Ki-67 immunostain, is 40%. A bone marrow aspirate and biopsy are then obtained, which show a clonal population of B lymphocytes expressing the same immunophenotype as the lymph node (positive for CD20 and CD5, negative for CD10 and CD23, cyclin D1 positive). A CT scan of the neck, chest, abdomen, and pelvis with contrast is obtained, along with a PET scan. These studies identify extensive hypermetabolic lymphadenopathy in the bilateral cervical chains, supraclavicular areas, mediastinum, and hilum. Mesenteric lymph nodes are also enlarged and hypermetabolic, as are retroperitoneal lymph nodes. The spleen is noted to be enlarged with multiple hypermetabolic lesions. Based on the presence of extensive lymphadenopathy as well as bone marrow involvement, the patient is diagnosed with stage IV MCL. He undergoes risk-stratification with the MIPI. His MIPI score is 6.3, high risk.

 

• What is the approach to upfront therapy for MCL?

FRONTLINE THERAPY

Role of Watchful Waiting

A small proportion of MCL patients have indolent disease that can be observed. This population is more likely to have leukemic-phase MCL with circulating lymphocytes, splenomegaly, and bone marrow involvement and absent or minimal lymphadenopathy.^4,5 A retrospective study of 97 patients established that deferment of initial therapy in MCL is acceptable in some patients.⁵ In this study, approximately one third of patients with MCL were observed for more than 3 months before initiating systemic therapy, and the median time to treatment for the observation group was 12 months. Most patients undergoing observation had a low-risk MIPI. Patients were not harmed by observation, as no OS differences were observed among groups. This study underscores that deferred treatment can be an acceptable alternative in selected MCL patients for a short period of time. In practice, the type of patient who would be appropriate for this approach is someone who is frail, elderly, and with multiple comorbidities. Additionally, expectant observation could be considered for patients with limited-stage or low-volume MCL, low Ki-67 index, and low-risk MIPI scores.

Approach to Therapy

Treatment of MCL is generally approached by evaluating patient age and fitness for treatment. While there is no accepted standard, for younger patients healthy enough to tolerate aggressive approaches, treatment often involves an intensive cytarabine-containing regimen, which is consolidated with an autoSCT. This approach results in the longest remission duration, with some series suggesting a plateau in survival after 5 years, with no relapses.²¹ Nonintensive conventional chemotherapy alone is often reserved for the frailer or older patient. Given that remission durations with chemotherapy alone in MCL are short, goals of treatment focus on maximizing benefit and remission duration and minimizing risk of toxicity.

Standard Chemotherapy: Elderly and/or Frail Patients

Conventional chemotherapy alone for the treatment of MCL results in a 70% to 85% overall response rate (ORR) and 7% to 30% complete response (CR) rate.²² Rituximab, a mouse humanized monoclonal IgG1 anti-CD20 antibody, is used as standard of care in combination with chemotherapy, since its addition has been found to increase response rates and extend both progression-free survival (PFS) and OS compared to chemotherapy alone.^23,24 However, chemoimmunotherapy approaches do not provide long-term control of MCL and are considered noncurative. Various regimens have been studied and include anthracycline-containing regimens such as R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, prednisone),²² combination chemotherapy with antimetabolites such as R-hyper-CVAD (hyper-fractionated rituximab with cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine),²⁵ purine analogue–based regimens such as R-FC (rituximab with fludarabine and cyclophosphamide),²⁶ bortezomib-containing regimens,²⁷ and alkylator-based treatment with BR (bendamustine and rituximab) (Table 1).^28,29 Among these, the most commonly used are R-CHOP and BR.

Two large randomized studies compared R-CHOP for 6 cycles to BR for 6 cycles in patients with indolent NHL and MCL. Among MCL patients, BR resulted in superior PFS compared to R-CHOP (69 months versus 26 months) but no benefit in OS.^28,29 The ORR to R-CHOP was approximately 90%, with a PFS of 21 months in the Rummel et al study.²⁹ This study included more than 80 centers in Germany and enrolled 549 patients with MCL, follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia. Patients were randomized in a 1:1 fashion. Among these, 46 patients received BR and 48 received R-CHOP (18% for both, respectively). It should be noted that patients in the BR group had significantly less toxicity and experienced fewer side effects than did those in the R-CHOP group. Similarly, BR-treated patients had a lower frequency of hematologic side effects and infections of any grade. However, drug-associated skin reactions and allergies were more common with BR compared to R-CHOP. The study by Flinn and colleagues was an international randomized, noninferiority phase 3 study designed to evaluate the efficacy and safety of BR compared with R-CHOP or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) for treatment-naive patients with MCL or other indolent NHL. The primary endpoint was CR. In this study, BR was found to be noninferior to R-CHOP and R-CVP based on CR rate (31% versus 25%, respectively; P = 0.0225). Response rates in general were high: 97% for BR and 91% for R-CHOP/R-CVP (P = 0.0102). Here, BR-treated patients experienced more nausea, emesis, and drug-induced hypersensitivity compared to the R-CHOP and R-CVP groups.

 

Another approach studied in older patients is the use of R-CHOP with rituximab maintenance. In a large European study, 560 patients 60 years of age or older with advanced-stage MCL were randomly assigned to either R-FC (rituximab, fludarabine, and cyclophosphamide) every 28 days for 6 cycles, or R-CHOP every 21 days for 8 cycles. Patients who had a response then underwent a second randomization, with one group receiving rituximab maintenance therapy. Maintenance was continued until progression of disease. Patients in this study were not eligible for high-dose chemotherapy and autoSCT. The study found that rates of CR were similar with both R-FC and R-CHOP (40% and 34%, respectively; P = 0.10). However, the R-FC arm underperformed in several arenas. Disease progression occurred more frequently with R-FC (14% versus 5% with R-CHOP), and OS was shorter (4-year OS, 47% versus 62%; P = 0.005, respectively). More patients also died in the R-FC group, and there was greater hematologic toxicity compared to R-CHOP. At 4 years, 58% of the patients receiving rituximab remained in remission. Among patients who responded to R-CHOP, rituximab maintenance led to a benefit in OS, reducing the risk of progression or death by 45%.²⁶ At this time, studies are ongoing to establish the benefit of rituximab maintenance after BR.

Bendamustine in combination with other agents has also been studied in the frontline setting. Visco and colleagues evaluated the combination of bendamustine with rituximab and cytarabine (R-BAC) in older patients with MCL (age 65 or older).⁶³ This phase 2, two-stage study enrolled 40 patients and had a dose-finding arm for cytarabine in combination with BR. It permitted relapsed/refractory patients, but 50% had newly diagnosed, previously untreated MCL. The regimen had an impressive ORR of 100%, with CR rates of 95% for previously untreated patients. PFS at 2 years was 95%. R-BAC was well tolerated, with the primary toxicity being reversible myelosuppression.

BR was combined with the proteasome inhibitor bortezomib and dexamethasone in a phase 2 study.⁶⁴ This Lymphoma Study Association (LYSA) study evaluated 76 patients with newly diagnosed MCL older than age 65 years. BR was administered in standard doses (bendamustine 90 mg/m² on days 1 and 2 and rituximab 375 mg/m² IV on day 1) and bortezomib was administered subcutaneously on days 1, 4, 8, and 11, with acyclovir for viral prophylaxis. Patients received 6 cycles. The ORR was 87% and the CR was 60%. Patients experienced toxicity, and not all bortezomib doses were administered due to neurotoxic or hematologic side effects.

A randomized phase 3 study compared R-CHOP to the VR-CAP regimen (R-CHOP regimen but bortezomib replaces vincristine on days 1, 4, 8, 11, at 1.3 mg/m²) in 487 newly diagnosed MCL patients.²⁷ Median PFS was superior in the VR-CAP group compared with R-CHOP (14.4 months versus 24.7 months, respectively). Additionally, rates of CR were superior in the VR-CAP group (53% compared to 42% with R-CHOP). However, there was more hematologic toxicity with VR-CAP. On the basis of these findings, the U.S. Food and Drug Administration approved bortezomib for the frontline treatment of MCL.

Other chemoimmunotherapy combinations containing bortezomib have been studied in frontline MCL treatment, with promising results. These include bortezomib in combination with R-CHOP or modified R-hyper-CVAD, as well as bortezomib in combination with CHOP-like treatments and purine analogues.^27,30–32 The ongoing ECOG 1411 study is currently evaluating bortezomib added to BR for induction therapy of newly diagnosed MCL in a 4-arm randomized trial. Patients receive BR with or without bortezomib during induction and are then randomly assigned to maintenance with either rituximab alone or rituximab with lenalidomide. Other novel combination agents are actively being studied in frontline MCL treatment, including lenalidomide and rituximab and BR with lenalidomide.

Intensification of Therapy and AutoSCT: Fitter and/or Younger Patients

Short response duration has created the need for post-remission therapy in MCL. One approach to improve remission duration in MCL is to intensify induction through the use of cytarabine-containing regimens and/or consolidation with high-dose chemotherapy, typically using BEAM (carmustine, etoposide, cytarabine, melphalan) and autoSCT (Table 2). The cytarabine-containing R-hyper-CVAD regimen, developed at the MD Anderson Cancer Center, resulted in a 97% ORR and an 87% CR rate, with TTF of nearly 5 years. However, nearly one third of patients were unable to complete treatment due to toxicity, and 5 patients developed secondary myelodysplastic syndrome or acute myeloid leukemia.³³ The feasibility of this R-hyper-CVAD regimen was tested in a multicenter cooperative group setting, but similar results were not seen; in this study, nearly 40% of patients were unable to complete the full scheduled course of treatment due to toxicity.³⁴

 

​Other ways to intensify therapy in MCL involve adding a second non-cross-resistant cytarabine-containing regimen to R-CHOP after remission, such as DHAP (dexamethasone, high-dose cytarabine, cisplatin), followed by consolidation with an autoSCT. A retrospective registry from the National Comprehensive Cancer Network sought to compare the efficacy of different treatment approaches in the frontline setting. They studied 167 patients with MCL and compared 4 groups: treatment with R-hyper-CVAD, either with or without autoSCT, and treatment with R-CHOP, either with or without autoSCT. This study found that in patients younger than 65, R-CHOP followed by autoSCT or R-hyper-CVAD without autoSCT resulted in similar PF and OS, but was superior to R-CHOP alone for newly diagnosed MCL patients.³⁵ These data support more intensive regimens in younger and fitter patients. Several other prospective and randomized studies have demonstrated clinical benefit for patients with MCL undergoing autoSCT in first remission. Of particular importance is the seminal phase 3 study of the European MCL Network, which established the role of autoSCT in this setting.⁶¹ In this prospective randomized trial involving 122 newly diagnosed MCL patients who responded to CHOP-like induction, patients in CR derived a greater benefit from autoSCT.

More recent studies have demonstrated similar benefits using cytarabine-based autoSCT. The Nordic MCL2 study evaluated 160 patients using R-CHOP, alternating with rituximab and high-dose cytarabine, followed by autoSCT. This study used “maxi-CHOP,” an augmented CHOP regimen (cyclophosphamide 1200 mg/m², doxorubicin 75 mg/m², but standard doses of vincristine [2 mg] and prednisone [100 mg days 1–5]), alternating with 4 infusions of cytarabine at 2 g/m² and standard doses of rituximab (375 mg/m²). Patients then received conditioning with BEAM and autoSCT. Patients were evaluated for the presence of minimal residual disease (MRD) and for the t(11;14) or clonal immunoglobulin heavy chain gene rearrangement with polymerase chain reaction (PCR). Patients with MRD were offered therapy with rituximab at 375 mg/m² weekly for 4 doses. This combination resulted in 10-year OS rates of 58%.³⁶ In a multicenter study involving 78 patients from the Cancer and Leukemia Group B (CALGB), R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT resulted in a 5-year OS of 64%.³⁷ A single-arm phase 2 study from the Netherlands also tested R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT. Nonhematologic toxicities were 22% after high-dose cytarabine, and 55% after BEAM. The ORR was 70%, with a 64% CR rate and 66% OS at 4 years.³⁸ The French GELA group used 3 cycles of R-CHOP and 3 cycles of R-DHAP in a phase 2 study of young (under age 66) MCL patients. Following R-CHOP, the ORR was 93%, and following R-DHAP the ORR was 95%. Five-year OSA was 75%.³⁹ A large randomized phase 3 study by Hermine and colleagues of the EMCLN confirmed the benefit of this approach in 497 patients with newly diagnosed MCL. R-CHOP for 6 cycles followed by autoSCT was compared to R-CHOP for 3 cycles alternating with R-DHAP for 3 cycles and autoSCT with a cytarabine-based conditioning regimen. The addition of cytarabine significantly increased rates of CR, TTF, and OS, without increasing toxicity.⁴⁰

CASE CONTINUED

The patient is treated with R-CHOP chemotherapy for 3 cycles followed by R-DHAP. His course is complicated by mild tinnitus and acute kidney injury from cisplatin that promptly resolves. Three weeks following treatment, a restaging PET/CT scan shows resolution of all lymphadenopathy, with no hypermetabolic uptake, consistent with a complete remission. A repeat bone marrow biopsy shows no involvement with MCL. He subsequently undergoes an autoSCT, and restaging CT/PET 3 months following autoSCT shows continued remission. He is monitored every 3 to 6 months over the next several years.

He has a 4.5-year disease remission, after which he develops growing palpable lymphadenopathy on exam and progressive anemia and thrombocytopenia. A bone marrow biopsy is repeated, which shows recurrent MCL. Restaging diagnostic imaging with a CT scan reveals lymphadenopathy above and below the diaphragm. An axillary lymph node biopsy also demonstrates recurrent MCL. At this time the patient is otherwise in fairly good health, except for feeling fatigued. His ECOG performance status is 1. He begins therapy with bortezomib at a dose of 1.3 mg/m² intravenously on days 1, 4, 8, and 11 for 6 cycles. His treatment course is complicated by painful sensory peripheral neuropathy of the bilateral lower extremities. Restaging studies at the completion of therapy demonstrate that he has achieved a partial response, with a 50% reduction in the size of involved lymphadenopathy and some residual areas of hypermetabolic uptake. His peripheral cytopenias improve moderately.

 

• What are the therapeutic options for relapsed MCL?

TREATMENT OF RELAPSED MCL

Single-Agent and Combination Chemotherapy

Whenever possible, and since there is no standard, patients with relapsed MCL should be offered a clinical trial. Outside of a clinical study, many of the treatment regimens used at diagnosis can also be applied in the relapsed setting. In relapsed MCL, Rummel et al showed that BR for 4 cycles resulted in an ORR of 90%, with a CR of 60%. The median PFS was 24 months.⁴¹ Bortezomib, an inhibitor of the proteasome-ubiquitin pathway, leads to apoptosis and cell cycle arrest in MCL.⁴² Multiple studies have evaluated bortezomib both as a single agent and in combination for patients with relapsed MCL. In 2006, bortezomib became the first agent approved by the FDA in relapsed or refractory MCL, based on the phase 2 PINNACLE study. This prospective multicenter study involving 155 patients demonstrated an ORR of 33%, CR rate of 8%, and median treatment duration of 9 months. The median time to progression was 6 months.⁴³ Subsequently, bortezomib-containing combinations evolved. In a multicenter study of relapsed and refractory indolent NHL and MCL, Friedberg and colleagues evaluated bortezomib in combination with BR.⁴⁴ In the MCL cohort, the ORR was 71%. These promising results led to the study of this combination in the frontline setting. The ongoing ECOG 1411 study is using BR for the frontline treatment of MCL with or without bortezomib as induction. This study also includes rituximab maintenance, and randomizes patients to undergo maintenance with or without the immunomodulator lenalidomide. Bortezomib has been associated with herpes simplex and herpes zoster reactivation. Neuropathy has also been observed with bortezomib, which can be attenuated by administering it subcutaneously.

Lenalidomide is an immunomodulatory agent derived from thalidomide. It has significant activity and is a mainstay of treatment in multiple myeloma. Lenalidomide acts by enhancing cellular immunity, has antiproliferative effects, and inhibits T-cell function leading to growth inhibitory effects in the tumor microenvironment.⁴⁵ In MCL, lenalidomide has demonstrated clinical activity both as a single agent and in combination, as well as in preclinical studies establishing its pro-apoptotic effects.⁴⁶ The pivotal EMERGE study evaluated monotherapy with lenalidomide in heavily pretreated relapsed and refractory MCL. This multicenter international study of 134 patents reported an ORR of 28% with a 7.5% CR rate and median PFS of 4 months. All patients had relapsed or progressed following bortezomib. This led to the approval of lenalidomide by the FDA in 2013 for the treatment of patients with MCL whose disease relapsed or progressed following 2 prior therapies, one of which included bortezomib.⁴⁷ Lenalidomide has been associated with neutropenia, secondary cancers, and deep venous thrombosis.

In combination with other agents in the relapsed setting, lenalidomide shows broader activity. A phase 1/2 study by Wang and colleagues demonstrated an ORR of 57%; the median response duration was 19 months when lenalidomide was combined with rituximab for relapsed/refractory MCL.⁴⁸

Novel Therapies

More recently, novel treatment approaches have been tested in MCL based on an increased understanding of aberrant signaling pathways in this disease (Table 3). Constitutive activation of B-cell receptor signaling is critical for the survival and proliferation of lymphomas, and has led to the development of targeted agents inhibiting B-cell receptor–associated protein kinases. Bruton’s tyrosine kinase (BTK) is one essential component of the B-cell receptor.⁴⁹ In particular, proteins upstream of the BTK pathway have been implicated in growth and proliferation of MCL, suggesting that inhibition of BTK may impede lymphomagenesis.⁵⁰ Ibrutinib is an oral inhibitor of BTK, and demonstrates activity in multiple lymphoma subtypes. In a phase 1 study of ibrutinib in relapsed and refractory hematologic malignancies, an ORR of 60% was observed in 50 evaluable patients, with 16% CR. Median PFS was 13 months. Among these, 7 of 9 patients with MCL responded, including 3 CRs.⁵¹ Given these promising results, a phase 2 multicenter study evaluating ibrutinib in relapsed and refractory MCL was completed.⁵² At a dose of 560 mg daily, the response rate was 68%, with CR of 21%. The most common observed treatment-related side effects included diarrhea, fatigue, and nausea. Neutropenia and thrombocytopenia were also observed. Of importance, 5% of patients had grade 3 or higher bleeding events, including subdural hematoma, gastrointestinal bleeding, and hematuria. The estimated OS rate was 58% at 18 months. On the basis of this study, the FDA approved ibrutinib for relapsed and refractory MCL in November 2013.

 

The PI3K pathway is another survival pathway that is dysfunctional in several hematologic disorders, including MCL. Overexpression of PI3K and its downstream targets contributes to MCL pathogenesis.⁵³ Idelalisib is an oral small molecule inhibitor of the delta isoform of PI3K that is dosed daily; it was approved by the FDA for the treatment of relapsed and refractory follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia. It is being further evaluated in MCL. A dose-escalation phase 1 study in heavily pre-treated MCL patients established safety and tolerability.⁵⁴ Efficacy analysis showed an ORR of 40%, CR of 5%, and 1-year OS of 22%. Further phase 2 studies testing idelalisib as a single agent and in combination for MCL are ongoing. Side effects of idelalisib include elevated liver enzymes, pneumonitis, and diarrhea.

The BCL family of proteins is involved in both pro-and anti-apoptotic functions. BCL2 is an intracellular protein that blocks apoptosis. ABT-199 is an oral BCL2 inhibitor that in early clinical trials has shown very promising activity in MCL. In a phase 1 study of 31 relapsed and refractory NHL patients, all 8 MCL patients (100% ORR) responded to ABT-199 therapy.⁵⁵ Given these promising initial results, multiple studies evaluating ABT-199 are ongoing in MCL as part of first-line treatment as well as for relapsed disease. ABT-199 has been implicated in tumor lysis syndrome, and in early studies of chronic lymphocytic leukemia, fatal tumor lysis was observed.

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has been evaluated in relapsed MCL. It is given weekly at 250 mg intravenously. Response rates to single-agent temsirolimus are approximately 20% to 35%, and are higher when combined with rituximab.^56,57 The phase 2 study evaluating temsirolimus as a single agent enrolled 35 heavily pre-treated patients. ORR was 38% with only 1 CR. The duration of response was 7 months. Temsirolimus is approved for relapsed MCL in Europe but not in the United States. Similar to the other targeted agents, temsirolimus is actively being studied in combination with other active agents in MCL. Adverse effects noted with temsirolimus include diarrhea, stomatitis, and rash. Thrombocytopenia requiring dose reductions is another frequently observed complication.

Radioimmunotherapy

Radioimmunotherapy (RIT) has been studied extensively in MCL. RIT consists of anti-CD 20 antibodies coupled to radioactive particles that deliver radiation to targeted cells, minimizing toxicity to surrounding tissues. RIT is not used as frequently in the modern era as it had been in the past. At this time, only yttrium-90-ibritumomab tiuxetan is available.

RIT has been evaluated in MCL both at the time of relapse⁵⁸ and more recently, as part of a conditioning regimen prior to autoSCT, with good tolerability.^65–67 Averse events noted with RIT include hematologic toxicity (can be prolonged), hypothyroidism, and in rare cases, myelodysplastic syndrome and acute leukemia. The bone marrow must have less than 25% involvement with disease prior to administration. Wang and colleagues evaluated yttrium-90-ibritumomab tiuxetan in 34 heavily pretreated patients with MCL.⁵⁸ They observed an ORR of 31%. The median event-free survival (EFS) was 6 months, but in patients achieving either CR or PR, EFS was 28 months. A 21-month OS was noted.

In the upfront setting, RIT has been added as a mechanism of intensification. A recent Nordic group study of RIT with autoSCT did not find benefit with the addition of RIT.⁵⁹ An ECOG study recently added yttrium-90-ibritumomab tiuxetan after CHOP chemotherapy in the upfront treatment of MCL, with good tolerability.⁵⁵ However, when added to R-hyper-CVAD, the combination had unexpected high rates of hematologic toxicity, including grade 3/4 cytopenias and an unacceptably high rate of secondary malignancies.⁶⁸

AutoSCT or Allogeneic Transplant

While many studies noted above have established the beneficial role of autoSCT in MCL in first remission, the role of allogeneic transplant (alloSCT) in MCL remains controversial. A recent large retrospective study conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) evaluated 519 patients with MCL who underwent both autoSCT and alloSCT.⁶⁰ Patients were grouped into an early cohort (transplant in first PR or CR, and 2 or fewer treatments) and late cohort (all other patients). The analysis had mature follow up. A multivariate analysis demonstrated that early autoSCT was associated with superior outcomes compared to autoSCT performed later. While it was not possible to demonstrate a survival benefit favoring autoSCT over reduced intensity (RIC) alloSCT, patients transplanted later in their disease course had shorter OS. For patients receiving autoSCT in CR 1 following only 1 prior line of therapy, OS at 5 years was 75% and PFS was 70%. Patients undergoing RIC followed by alloSCT had fewer relapses, but this was negated by higher nonrelapse mortality (25%), resulting in a PFS similar to autoSCT.

 

CASE CONCLUSION

After treatment with bortezomib the patient is well for 9 months. Subsequently, however, he develops increasing lymphadenopathy and progressive fatigue. He is then started on lenalidomide 25 mg orally daily for 21 out of 28 days. He experiences significant fatigue with lenalidomide and prolonged neutropenia requiring dose delays, despite dose modification to 10 mg orally daily. He requires discontinuation of lenalidomide. Given persistent disease, the patient then begins treatment with ibrutinib. Within a few days of starting ibrutinib therapy, he experiences a marked but transient leukocytosis. Two months later, the patient’s palpable lymphadenopathy has decreased, and his anemia and thrombocytopenia related to MCL are improving. He has tolerated treatment well. His course has been complicated only by a mild, pruritic maculopapular eruption on his chest, back, and arms, that was responsive to topical low-dose steroids. He remains on ibrutinib 1 year later.

CONCLUSION

Advances in our understanding of MCL treatment are revolutionizing the approach to this once deadly disease. Over the next several years, these gains will weave themselves into the current treatment paradigm and likely alter the treatment landscape for MCL as we know it.

INTRODUCTION

Mantle cell lymphoma (MCL) is an uncommon, distinct clinical subtype of non-Hodgkin lymphoma (NHL) that comprises approximately 8% of all lymphoma diagnoses in the United States and Europe.^1,2 Considered incurable, MCL often presents in advanced stages, particularly with involvement of the lymph nodes, spleen, bone marrow, and gastrointestinal tract in the form of lymphomatous polyps. MCL disproportionately affects males, and incidence rises with age, with a median age at diagnosis of 68 years.² Historically, the prognosis of patients with MCL has been among the poorest among B-cell lymphoma patients, with a median overall survival (OS) of 3 to 5 years, and time to treatment failure (TTF) of 18 to 24 months, although this is improving in the modern era.³ Less frequently, patients with MCL display isolated bone marrow, peripheral blood, and splenic involvement. These cases tend to behave more indolently with longer survival.^4,5 Recent advances in therapy have dramatically impacted treatment alternatives and outcomes for MCL. As such, the therapeutic and prognostic landscape of MCL is evolving rapidly.

PATHOGENESIS

The histologic diagnosis of MCL by morphology alone is often challenging. Accurate diagnosis relies on immunohistochemical staining for the purposes of immunophenotyping.⁶ MCL typically expresses B-cell markers CD5 and CD20, and lacks both CD10 and CD23. The genetic hallmark of MCL is the t(11;14) (q13;q32) chromosomal translocation leading to upregulation of the cyclin D1 protein, a critical regulator of the G1 phase of the cell cycle. Specifically, the t(11;14) translocation, present in virtually all cases of MCL, juxtaposes the proto-oncogene CCND1 to the immunoglobulin heavy chain gene.⁷ Consequently, cyclin D1, normally not expressed in B lymphocytes, becomes constitutively overexpressed. This alteration is thought to facilitate the deregulation of the cell cycle at the G1-S phase transition.⁸

Gene expression profiling studies have underscored the importance of cell cycle deregulation in MCL, and high proliferation is associated with a worse prognosis.⁹ More than 50% of the genes associated with poor outcomes were derived from the “proliferation signature” that was more highly expressed in dividing cells. In the seminal Rosenwald study, a gene expression–based outcome model was constructed in which the proliferation signature average represents a linear variable that assigns a discrete probability of survival to an individual patient.⁹ The proliferative index, or proliferative signature, of MCL can be estimated by the percentage of Ki-67–positive cells present in the tumor through immunohistochemistry. This is often used as a marker of poor outcomes, and as a surrogate for the proliferative signature in MCL that can be incorporated into clinical practice (as opposed to gene expression profiling). Statistically significant differences in OS have emerged between groups of MCL patients with Ki-67–positive cells comprising less than 30% of their tumor sample (favorable) and those with Ki-67–positive cells comprising 30% or greater (unfavorable).¹⁰

Recent data has also identified the importance of the transcription factor SOX 11 (SRY-related HMG-box), which regulates multiple cellular transcriptional events, including cell proliferation and differentiation, apoptosis, and angiogenesis.¹¹ MCL expressing SOX 11 behaves more aggressively than MCL variants lacking SOX 11 expression, and tends to accumulate more genetic alterations.¹² Moreover, lack of SOX 11 expression characterizes a subset of MCL that does not carry the t(11;14) translocation.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 62-year-old man with a history of diabetes mellitus and hypertension presents with cervical lymphadenopathy, fatigue, and early satiety over the past several months. He is otherwise in good health. His Eastern Cooperative Oncology Group (ECOG) performance status is 1. On physical examination, 3-cm lymphadenopathy in the bilateral cervical chain is noted. Bilateral axillary lymph nodes measure 2 to 4 cm. His spleen is enlarged and is palpable at approximately 5 cm below the costal margin. A complete blood count reveals a total white blood cell (WBC) count of 14,000 cells/μL, with 68% lymphocytes and a normal distribution of neutrophils. Hemoglobin is 11 g/dL, and platelet count is 112,000/μL. The lactate dehydrogenase (LDH) level is 322 U/L (upper limit of normal: 225 U/L).

• How is MCL diagnosed?

Diagnosis of MCL requires review by expert hematopathologists.¹³ Whenever possible, an excisional biopsy should be performed for the adequate characterization of lymph node architecture and evaluation by immunohistochemistry. Aside from the characteristic expression of CD5 and CD20 and absence of CD23, MCL should express cyclin D1, which reflects t(11;14). If cyclin D1 is inconclusive or unavailable, fluorescent in situ hybridization (FISH) for t(11;14) should be performed.⁸ Patients often have circulating malignant lymphocytes, or leukemic phase MCL. Flow cytometry of the peripheral blood can detect traditional surface markers, and FISH can also be performed on circulating abnormal lymphocytes.

 

For disease staging, bone marrow biopsy and aspiration are required. Radiographic staging using computed tomography (CT) scans and/or positron emission tomography (PET) scans had traditionally followed the Ann Arbor staging system, but recently the Lugano classification has emerged, which delineates only early or advanced stage.¹⁴ Gastrointestinal evaluation of MCL with endoscopy and colonoscopy with blind biopsies has been recommended to evaluate for the presence of lymphomatous polyps, but this is not an absolute requirement.¹⁵

RISK STRATIFICATION

At diagnosis, patients should undergo risk stratification in order to understand prognosis and possibly guide treatment. In MCL, the MCL international prognostic index (MIPI) is used. The MIPI is a prognostic tool developed exclusively for patients with MCL using data from 455 patients with advanced-stage MCL treated within 3 European clinical trials.¹⁶ The MIPI classified patients into risk groups based on age, ECOG performance status, LDH level, and WBC count. Patients were categorized into low-risk (44% of patients, median OS not reached), intermediate-risk (35%, median OS 51 months), and high-risk groups (21%, median OS 29 months). This is done through a logarithmic calculation, which can be accessed through online calculators (a prototype example can be found at www.qxmd.com/calculate-online/hematology/prognosis-mantle-cell-lymphoma-mipi). Cell proliferation using the Ki-67 index was evaluated in an exploratory analysis (the biologic [“B”] MIPI), and also demonstrated strong prognostic relevance.¹⁶ Currently, treatment of MCL patients is not stratified by MIPI outside of a clinical trial, but this useful tool assists in assessing patient prognosis and has been validated for use with both conventional chemoimmunotherapy and in the setting of autologous stem cell transplant (autoSCT).^16,17 At this point in time, the MIPI score is not used to stratify treatment, although some clinical trials are incorporating the use of the MIPI score at diagnosis. Nonetheless, given its prognostic importance, the MIPI should be performed for all MCL patients undergoing staging and evaluation for treatment to establish disease risk.

As noted, the proliferative signature, represented by the Ki-67 protein, is also highly prognostic in MCL. Ki-67 is expressed in the late G1, S, G2, and M phases of the cell cycle. The Ki-67 index is defined by the hematopathologist as the percentage of lymphoma cells staining positive for Ki-67 protein, based on the number of cells per high-power field. There is significant interobserver variability in this process, which can be minimized by assessing Ki-67 quantitatively using computer software. The prognostic significance of Ki-67 at diagnosis was established in large studies of MCL patient cohorts, with survival differing by up to 3 years.^18,19 Determann et al demonstrated the utility of the proliferative index in patients with MCL treated with standard chemoimmunotherapy.¹⁰ In this study, 249 patients with advanced-stage MCL treated within randomized trials conducted by the European MCL Network were analyzed. The Ki-67 index was found to be extremely prognostic of OS, independent of other clinical risk factors, including the MIPI score. As a continuous variable, Ki-67 indices of greater than 10% correlated with poor outcomes. The Ki-67 index has also been confirmed as prognostic in relapsed MCL.²⁰ It is important to note that, as a unique feature, the Ki-67 index has remained an independent prognostic factor, even when incorporated into the “B” MIPI.

TREATMENT

CASE CONTINUED

The patient undergoes an excisional biopsy of a cervical lymph node, which demonstrates an abnormal proliferation of small-medium–sized lymphocytes with slightly irregular nuclear contours. Immunohistochemistry shows that the abnormal lymphocytes are positive for CD20 and CD5, negative for CD10 and CD23, and diffusely positive for cyclin D1, consistent with a diagnosis of MCL. The proliferative index, as measured by the Ki-67 immunostain, is 40%. A bone marrow aspirate and biopsy are then obtained, which show a clonal population of B lymphocytes expressing the same immunophenotype as the lymph node (positive for CD20 and CD5, negative for CD10 and CD23, cyclin D1 positive). A CT scan of the neck, chest, abdomen, and pelvis with contrast is obtained, along with a PET scan. These studies identify extensive hypermetabolic lymphadenopathy in the bilateral cervical chains, supraclavicular areas, mediastinum, and hilum. Mesenteric lymph nodes are also enlarged and hypermetabolic, as are retroperitoneal lymph nodes. The spleen is noted to be enlarged with multiple hypermetabolic lesions. Based on the presence of extensive lymphadenopathy as well as bone marrow involvement, the patient is diagnosed with stage IV MCL. He undergoes risk-stratification with the MIPI. His MIPI score is 6.3, high risk.

 

• What is the approach to upfront therapy for MCL?

FRONTLINE THERAPY

Role of Watchful Waiting

A small proportion of MCL patients have indolent disease that can be observed. This population is more likely to have leukemic-phase MCL with circulating lymphocytes, splenomegaly, and bone marrow involvement and absent or minimal lymphadenopathy.^4,5 A retrospective study of 97 patients established that deferment of initial therapy in MCL is acceptable in some patients.⁵ In this study, approximately one third of patients with MCL were observed for more than 3 months before initiating systemic therapy, and the median time to treatment for the observation group was 12 months. Most patients undergoing observation had a low-risk MIPI. Patients were not harmed by observation, as no OS differences were observed among groups. This study underscores that deferred treatment can be an acceptable alternative in selected MCL patients for a short period of time. In practice, the type of patient who would be appropriate for this approach is someone who is frail, elderly, and with multiple comorbidities. Additionally, expectant observation could be considered for patients with limited-stage or low-volume MCL, low Ki-67 index, and low-risk MIPI scores.

Approach to Therapy

Treatment of MCL is generally approached by evaluating patient age and fitness for treatment. While there is no accepted standard, for younger patients healthy enough to tolerate aggressive approaches, treatment often involves an intensive cytarabine-containing regimen, which is consolidated with an autoSCT. This approach results in the longest remission duration, with some series suggesting a plateau in survival after 5 years, with no relapses.²¹ Nonintensive conventional chemotherapy alone is often reserved for the frailer or older patient. Given that remission durations with chemotherapy alone in MCL are short, goals of treatment focus on maximizing benefit and remission duration and minimizing risk of toxicity.

Standard Chemotherapy: Elderly and/or Frail Patients

Conventional chemotherapy alone for the treatment of MCL results in a 70% to 85% overall response rate (ORR) and 7% to 30% complete response (CR) rate.²² Rituximab, a mouse humanized monoclonal IgG1 anti-CD20 antibody, is used as standard of care in combination with chemotherapy, since its addition has been found to increase response rates and extend both progression-free survival (PFS) and OS compared to chemotherapy alone.^23,24 However, chemoimmunotherapy approaches do not provide long-term control of MCL and are considered noncurative. Various regimens have been studied and include anthracycline-containing regimens such as R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, prednisone),²² combination chemotherapy with antimetabolites such as R-hyper-CVAD (hyper-fractionated rituximab with cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine),²⁵ purine analogue–based regimens such as R-FC (rituximab with fludarabine and cyclophosphamide),²⁶ bortezomib-containing regimens,²⁷ and alkylator-based treatment with BR (bendamustine and rituximab) (Table 1).^28,29 Among these, the most commonly used are R-CHOP and BR.

Two large randomized studies compared R-CHOP for 6 cycles to BR for 6 cycles in patients with indolent NHL and MCL. Among MCL patients, BR resulted in superior PFS compared to R-CHOP (69 months versus 26 months) but no benefit in OS.^28,29 The ORR to R-CHOP was approximately 90%, with a PFS of 21 months in the Rummel et al study.²⁹ This study included more than 80 centers in Germany and enrolled 549 patients with MCL, follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia. Patients were randomized in a 1:1 fashion. Among these, 46 patients received BR and 48 received R-CHOP (18% for both, respectively). It should be noted that patients in the BR group had significantly less toxicity and experienced fewer side effects than did those in the R-CHOP group. Similarly, BR-treated patients had a lower frequency of hematologic side effects and infections of any grade. However, drug-associated skin reactions and allergies were more common with BR compared to R-CHOP. The study by Flinn and colleagues was an international randomized, noninferiority phase 3 study designed to evaluate the efficacy and safety of BR compared with R-CHOP or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) for treatment-naive patients with MCL or other indolent NHL. The primary endpoint was CR. In this study, BR was found to be noninferior to R-CHOP and R-CVP based on CR rate (31% versus 25%, respectively; P = 0.0225). Response rates in general were high: 97% for BR and 91% for R-CHOP/R-CVP (P = 0.0102). Here, BR-treated patients experienced more nausea, emesis, and drug-induced hypersensitivity compared to the R-CHOP and R-CVP groups.

 

Another approach studied in older patients is the use of R-CHOP with rituximab maintenance. In a large European study, 560 patients 60 years of age or older with advanced-stage MCL were randomly assigned to either R-FC (rituximab, fludarabine, and cyclophosphamide) every 28 days for 6 cycles, or R-CHOP every 21 days for 8 cycles. Patients who had a response then underwent a second randomization, with one group receiving rituximab maintenance therapy. Maintenance was continued until progression of disease. Patients in this study were not eligible for high-dose chemotherapy and autoSCT. The study found that rates of CR were similar with both R-FC and R-CHOP (40% and 34%, respectively; P = 0.10). However, the R-FC arm underperformed in several arenas. Disease progression occurred more frequently with R-FC (14% versus 5% with R-CHOP), and OS was shorter (4-year OS, 47% versus 62%; P = 0.005, respectively). More patients also died in the R-FC group, and there was greater hematologic toxicity compared to R-CHOP. At 4 years, 58% of the patients receiving rituximab remained in remission. Among patients who responded to R-CHOP, rituximab maintenance led to a benefit in OS, reducing the risk of progression or death by 45%.²⁶ At this time, studies are ongoing to establish the benefit of rituximab maintenance after BR.

Bendamustine in combination with other agents has also been studied in the frontline setting. Visco and colleagues evaluated the combination of bendamustine with rituximab and cytarabine (R-BAC) in older patients with MCL (age 65 or older).⁶³ This phase 2, two-stage study enrolled 40 patients and had a dose-finding arm for cytarabine in combination with BR. It permitted relapsed/refractory patients, but 50% had newly diagnosed, previously untreated MCL. The regimen had an impressive ORR of 100%, with CR rates of 95% for previously untreated patients. PFS at 2 years was 95%. R-BAC was well tolerated, with the primary toxicity being reversible myelosuppression.

BR was combined with the proteasome inhibitor bortezomib and dexamethasone in a phase 2 study.⁶⁴ This Lymphoma Study Association (LYSA) study evaluated 76 patients with newly diagnosed MCL older than age 65 years. BR was administered in standard doses (bendamustine 90 mg/m² on days 1 and 2 and rituximab 375 mg/m² IV on day 1) and bortezomib was administered subcutaneously on days 1, 4, 8, and 11, with acyclovir for viral prophylaxis. Patients received 6 cycles. The ORR was 87% and the CR was 60%. Patients experienced toxicity, and not all bortezomib doses were administered due to neurotoxic or hematologic side effects.

A randomized phase 3 study compared R-CHOP to the VR-CAP regimen (R-CHOP regimen but bortezomib replaces vincristine on days 1, 4, 8, 11, at 1.3 mg/m²) in 487 newly diagnosed MCL patients.²⁷ Median PFS was superior in the VR-CAP group compared with R-CHOP (14.4 months versus 24.7 months, respectively). Additionally, rates of CR were superior in the VR-CAP group (53% compared to 42% with R-CHOP). However, there was more hematologic toxicity with VR-CAP. On the basis of these findings, the U.S. Food and Drug Administration approved bortezomib for the frontline treatment of MCL.

Other chemoimmunotherapy combinations containing bortezomib have been studied in frontline MCL treatment, with promising results. These include bortezomib in combination with R-CHOP or modified R-hyper-CVAD, as well as bortezomib in combination with CHOP-like treatments and purine analogues.^27,30–32 The ongoing ECOG 1411 study is currently evaluating bortezomib added to BR for induction therapy of newly diagnosed MCL in a 4-arm randomized trial. Patients receive BR with or without bortezomib during induction and are then randomly assigned to maintenance with either rituximab alone or rituximab with lenalidomide. Other novel combination agents are actively being studied in frontline MCL treatment, including lenalidomide and rituximab and BR with lenalidomide.

Intensification of Therapy and AutoSCT: Fitter and/or Younger Patients

Short response duration has created the need for post-remission therapy in MCL. One approach to improve remission duration in MCL is to intensify induction through the use of cytarabine-containing regimens and/or consolidation with high-dose chemotherapy, typically using BEAM (carmustine, etoposide, cytarabine, melphalan) and autoSCT (Table 2). The cytarabine-containing R-hyper-CVAD regimen, developed at the MD Anderson Cancer Center, resulted in a 97% ORR and an 87% CR rate, with TTF of nearly 5 years. However, nearly one third of patients were unable to complete treatment due to toxicity, and 5 patients developed secondary myelodysplastic syndrome or acute myeloid leukemia.³³ The feasibility of this R-hyper-CVAD regimen was tested in a multicenter cooperative group setting, but similar results were not seen; in this study, nearly 40% of patients were unable to complete the full scheduled course of treatment due to toxicity.³⁴

 

​Other ways to intensify therapy in MCL involve adding a second non-cross-resistant cytarabine-containing regimen to R-CHOP after remission, such as DHAP (dexamethasone, high-dose cytarabine, cisplatin), followed by consolidation with an autoSCT. A retrospective registry from the National Comprehensive Cancer Network sought to compare the efficacy of different treatment approaches in the frontline setting. They studied 167 patients with MCL and compared 4 groups: treatment with R-hyper-CVAD, either with or without autoSCT, and treatment with R-CHOP, either with or without autoSCT. This study found that in patients younger than 65, R-CHOP followed by autoSCT or R-hyper-CVAD without autoSCT resulted in similar PF and OS, but was superior to R-CHOP alone for newly diagnosed MCL patients.³⁵ These data support more intensive regimens in younger and fitter patients. Several other prospective and randomized studies have demonstrated clinical benefit for patients with MCL undergoing autoSCT in first remission. Of particular importance is the seminal phase 3 study of the European MCL Network, which established the role of autoSCT in this setting.⁶¹ In this prospective randomized trial involving 122 newly diagnosed MCL patients who responded to CHOP-like induction, patients in CR derived a greater benefit from autoSCT.

More recent studies have demonstrated similar benefits using cytarabine-based autoSCT. The Nordic MCL2 study evaluated 160 patients using R-CHOP, alternating with rituximab and high-dose cytarabine, followed by autoSCT. This study used “maxi-CHOP,” an augmented CHOP regimen (cyclophosphamide 1200 mg/m², doxorubicin 75 mg/m², but standard doses of vincristine [2 mg] and prednisone [100 mg days 1–5]), alternating with 4 infusions of cytarabine at 2 g/m² and standard doses of rituximab (375 mg/m²). Patients then received conditioning with BEAM and autoSCT. Patients were evaluated for the presence of minimal residual disease (MRD) and for the t(11;14) or clonal immunoglobulin heavy chain gene rearrangement with polymerase chain reaction (PCR). Patients with MRD were offered therapy with rituximab at 375 mg/m² weekly for 4 doses. This combination resulted in 10-year OS rates of 58%.³⁶ In a multicenter study involving 78 patients from the Cancer and Leukemia Group B (CALGB), R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT resulted in a 5-year OS of 64%.³⁷ A single-arm phase 2 study from the Netherlands also tested R-CHOP followed by high-dose cytarabine and BEAM-based autoSCT. Nonhematologic toxicities were 22% after high-dose cytarabine, and 55% after BEAM. The ORR was 70%, with a 64% CR rate and 66% OS at 4 years.³⁸ The French GELA group used 3 cycles of R-CHOP and 3 cycles of R-DHAP in a phase 2 study of young (under age 66) MCL patients. Following R-CHOP, the ORR was 93%, and following R-DHAP the ORR was 95%. Five-year OSA was 75%.³⁹ A large randomized phase 3 study by Hermine and colleagues of the EMCLN confirmed the benefit of this approach in 497 patients with newly diagnosed MCL. R-CHOP for 6 cycles followed by autoSCT was compared to R-CHOP for 3 cycles alternating with R-DHAP for 3 cycles and autoSCT with a cytarabine-based conditioning regimen. The addition of cytarabine significantly increased rates of CR, TTF, and OS, without increasing toxicity.⁴⁰

CASE CONTINUED

The patient is treated with R-CHOP chemotherapy for 3 cycles followed by R-DHAP. His course is complicated by mild tinnitus and acute kidney injury from cisplatin that promptly resolves. Three weeks following treatment, a restaging PET/CT scan shows resolution of all lymphadenopathy, with no hypermetabolic uptake, consistent with a complete remission. A repeat bone marrow biopsy shows no involvement with MCL. He subsequently undergoes an autoSCT, and restaging CT/PET 3 months following autoSCT shows continued remission. He is monitored every 3 to 6 months over the next several years.

He has a 4.5-year disease remission, after which he develops growing palpable lymphadenopathy on exam and progressive anemia and thrombocytopenia. A bone marrow biopsy is repeated, which shows recurrent MCL. Restaging diagnostic imaging with a CT scan reveals lymphadenopathy above and below the diaphragm. An axillary lymph node biopsy also demonstrates recurrent MCL. At this time the patient is otherwise in fairly good health, except for feeling fatigued. His ECOG performance status is 1. He begins therapy with bortezomib at a dose of 1.3 mg/m² intravenously on days 1, 4, 8, and 11 for 6 cycles. His treatment course is complicated by painful sensory peripheral neuropathy of the bilateral lower extremities. Restaging studies at the completion of therapy demonstrate that he has achieved a partial response, with a 50% reduction in the size of involved lymphadenopathy and some residual areas of hypermetabolic uptake. His peripheral cytopenias improve moderately.

 

• What are the therapeutic options for relapsed MCL?

TREATMENT OF RELAPSED MCL

Single-Agent and Combination Chemotherapy

Whenever possible, and since there is no standard, patients with relapsed MCL should be offered a clinical trial. Outside of a clinical study, many of the treatment regimens used at diagnosis can also be applied in the relapsed setting. In relapsed MCL, Rummel et al showed that BR for 4 cycles resulted in an ORR of 90%, with a CR of 60%. The median PFS was 24 months.⁴¹ Bortezomib, an inhibitor of the proteasome-ubiquitin pathway, leads to apoptosis and cell cycle arrest in MCL.⁴² Multiple studies have evaluated bortezomib both as a single agent and in combination for patients with relapsed MCL. In 2006, bortezomib became the first agent approved by the FDA in relapsed or refractory MCL, based on the phase 2 PINNACLE study. This prospective multicenter study involving 155 patients demonstrated an ORR of 33%, CR rate of 8%, and median treatment duration of 9 months. The median time to progression was 6 months.⁴³ Subsequently, bortezomib-containing combinations evolved. In a multicenter study of relapsed and refractory indolent NHL and MCL, Friedberg and colleagues evaluated bortezomib in combination with BR.⁴⁴ In the MCL cohort, the ORR was 71%. These promising results led to the study of this combination in the frontline setting. The ongoing ECOG 1411 study is using BR for the frontline treatment of MCL with or without bortezomib as induction. This study also includes rituximab maintenance, and randomizes patients to undergo maintenance with or without the immunomodulator lenalidomide. Bortezomib has been associated with herpes simplex and herpes zoster reactivation. Neuropathy has also been observed with bortezomib, which can be attenuated by administering it subcutaneously.

Lenalidomide is an immunomodulatory agent derived from thalidomide. It has significant activity and is a mainstay of treatment in multiple myeloma. Lenalidomide acts by enhancing cellular immunity, has antiproliferative effects, and inhibits T-cell function leading to growth inhibitory effects in the tumor microenvironment.⁴⁵ In MCL, lenalidomide has demonstrated clinical activity both as a single agent and in combination, as well as in preclinical studies establishing its pro-apoptotic effects.⁴⁶ The pivotal EMERGE study evaluated monotherapy with lenalidomide in heavily pretreated relapsed and refractory MCL. This multicenter international study of 134 patents reported an ORR of 28% with a 7.5% CR rate and median PFS of 4 months. All patients had relapsed or progressed following bortezomib. This led to the approval of lenalidomide by the FDA in 2013 for the treatment of patients with MCL whose disease relapsed or progressed following 2 prior therapies, one of which included bortezomib.⁴⁷ Lenalidomide has been associated with neutropenia, secondary cancers, and deep venous thrombosis.

In combination with other agents in the relapsed setting, lenalidomide shows broader activity. A phase 1/2 study by Wang and colleagues demonstrated an ORR of 57%; the median response duration was 19 months when lenalidomide was combined with rituximab for relapsed/refractory MCL.⁴⁸

Novel Therapies

More recently, novel treatment approaches have been tested in MCL based on an increased understanding of aberrant signaling pathways in this disease (Table 3). Constitutive activation of B-cell receptor signaling is critical for the survival and proliferation of lymphomas, and has led to the development of targeted agents inhibiting B-cell receptor–associated protein kinases. Bruton’s tyrosine kinase (BTK) is one essential component of the B-cell receptor.⁴⁹ In particular, proteins upstream of the BTK pathway have been implicated in growth and proliferation of MCL, suggesting that inhibition of BTK may impede lymphomagenesis.⁵⁰ Ibrutinib is an oral inhibitor of BTK, and demonstrates activity in multiple lymphoma subtypes. In a phase 1 study of ibrutinib in relapsed and refractory hematologic malignancies, an ORR of 60% was observed in 50 evaluable patients, with 16% CR. Median PFS was 13 months. Among these, 7 of 9 patients with MCL responded, including 3 CRs.⁵¹ Given these promising results, a phase 2 multicenter study evaluating ibrutinib in relapsed and refractory MCL was completed.⁵² At a dose of 560 mg daily, the response rate was 68%, with CR of 21%. The most common observed treatment-related side effects included diarrhea, fatigue, and nausea. Neutropenia and thrombocytopenia were also observed. Of importance, 5% of patients had grade 3 or higher bleeding events, including subdural hematoma, gastrointestinal bleeding, and hematuria. The estimated OS rate was 58% at 18 months. On the basis of this study, the FDA approved ibrutinib for relapsed and refractory MCL in November 2013.

 

The PI3K pathway is another survival pathway that is dysfunctional in several hematologic disorders, including MCL. Overexpression of PI3K and its downstream targets contributes to MCL pathogenesis.⁵³ Idelalisib is an oral small molecule inhibitor of the delta isoform of PI3K that is dosed daily; it was approved by the FDA for the treatment of relapsed and refractory follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia. It is being further evaluated in MCL. A dose-escalation phase 1 study in heavily pre-treated MCL patients established safety and tolerability.⁵⁴ Efficacy analysis showed an ORR of 40%, CR of 5%, and 1-year OS of 22%. Further phase 2 studies testing idelalisib as a single agent and in combination for MCL are ongoing. Side effects of idelalisib include elevated liver enzymes, pneumonitis, and diarrhea.

The BCL family of proteins is involved in both pro-and anti-apoptotic functions. BCL2 is an intracellular protein that blocks apoptosis. ABT-199 is an oral BCL2 inhibitor that in early clinical trials has shown very promising activity in MCL. In a phase 1 study of 31 relapsed and refractory NHL patients, all 8 MCL patients (100% ORR) responded to ABT-199 therapy.⁵⁵ Given these promising initial results, multiple studies evaluating ABT-199 are ongoing in MCL as part of first-line treatment as well as for relapsed disease. ABT-199 has been implicated in tumor lysis syndrome, and in early studies of chronic lymphocytic leukemia, fatal tumor lysis was observed.

The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has been evaluated in relapsed MCL. It is given weekly at 250 mg intravenously. Response rates to single-agent temsirolimus are approximately 20% to 35%, and are higher when combined with rituximab.^56,57 The phase 2 study evaluating temsirolimus as a single agent enrolled 35 heavily pre-treated patients. ORR was 38% with only 1 CR. The duration of response was 7 months. Temsirolimus is approved for relapsed MCL in Europe but not in the United States. Similar to the other targeted agents, temsirolimus is actively being studied in combination with other active agents in MCL. Adverse effects noted with temsirolimus include diarrhea, stomatitis, and rash. Thrombocytopenia requiring dose reductions is another frequently observed complication.

Radioimmunotherapy

Radioimmunotherapy (RIT) has been studied extensively in MCL. RIT consists of anti-CD 20 antibodies coupled to radioactive particles that deliver radiation to targeted cells, minimizing toxicity to surrounding tissues. RIT is not used as frequently in the modern era as it had been in the past. At this time, only yttrium-90-ibritumomab tiuxetan is available.

RIT has been evaluated in MCL both at the time of relapse⁵⁸ and more recently, as part of a conditioning regimen prior to autoSCT, with good tolerability.^65–67 Averse events noted with RIT include hematologic toxicity (can be prolonged), hypothyroidism, and in rare cases, myelodysplastic syndrome and acute leukemia. The bone marrow must have less than 25% involvement with disease prior to administration. Wang and colleagues evaluated yttrium-90-ibritumomab tiuxetan in 34 heavily pretreated patients with MCL.⁵⁸ They observed an ORR of 31%. The median event-free survival (EFS) was 6 months, but in patients achieving either CR or PR, EFS was 28 months. A 21-month OS was noted.

In the upfront setting, RIT has been added as a mechanism of intensification. A recent Nordic group study of RIT with autoSCT did not find benefit with the addition of RIT.⁵⁹ An ECOG study recently added yttrium-90-ibritumomab tiuxetan after CHOP chemotherapy in the upfront treatment of MCL, with good tolerability.⁵⁵ However, when added to R-hyper-CVAD, the combination had unexpected high rates of hematologic toxicity, including grade 3/4 cytopenias and an unacceptably high rate of secondary malignancies.⁶⁸

AutoSCT or Allogeneic Transplant

While many studies noted above have established the beneficial role of autoSCT in MCL in first remission, the role of allogeneic transplant (alloSCT) in MCL remains controversial. A recent large retrospective study conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) evaluated 519 patients with MCL who underwent both autoSCT and alloSCT.⁶⁰ Patients were grouped into an early cohort (transplant in first PR or CR, and 2 or fewer treatments) and late cohort (all other patients). The analysis had mature follow up. A multivariate analysis demonstrated that early autoSCT was associated with superior outcomes compared to autoSCT performed later. While it was not possible to demonstrate a survival benefit favoring autoSCT over reduced intensity (RIC) alloSCT, patients transplanted later in their disease course had shorter OS. For patients receiving autoSCT in CR 1 following only 1 prior line of therapy, OS at 5 years was 75% and PFS was 70%. Patients undergoing RIC followed by alloSCT had fewer relapses, but this was negated by higher nonrelapse mortality (25%), resulting in a PFS similar to autoSCT.

 

CASE CONCLUSION

After treatment with bortezomib the patient is well for 9 months. Subsequently, however, he develops increasing lymphadenopathy and progressive fatigue. He is then started on lenalidomide 25 mg orally daily for 21 out of 28 days. He experiences significant fatigue with lenalidomide and prolonged neutropenia requiring dose delays, despite dose modification to 10 mg orally daily. He requires discontinuation of lenalidomide. Given persistent disease, the patient then begins treatment with ibrutinib. Within a few days of starting ibrutinib therapy, he experiences a marked but transient leukocytosis. Two months later, the patient’s palpable lymphadenopathy has decreased, and his anemia and thrombocytopenia related to MCL are improving. He has tolerated treatment well. His course has been complicated only by a mild, pruritic maculopapular eruption on his chest, back, and arms, that was responsive to topical low-dose steroids. He remains on ibrutinib 1 year later.

CONCLUSION

Advances in our understanding of MCL treatment are revolutionizing the approach to this once deadly disease. Over the next several years, these gains will weave themselves into the current treatment paradigm and likely alter the treatment landscape for MCL as we know it.

There is strong evidence linking adiposity to esophageal adenocarcinoma, multiple myeloma, and cancer of the colon, rectum, biliary tract, pancreas, endometrium, kidney, and postmenopausal breast, according to the authors of an umbrella review published in the Feb. 28 edition of the BMJ.

“Several meta-analyses support the link between obesity and cancer, but substantial heterogeneity exists between studies,” wrote Maria Kyrgiou, MD, of Imperial College London and her coauthors. “The reported associations may be causal, but they may also be flawed, as inherent study biases such as residual confounding and selective reporting of positive results may exaggerate the effect of obesity on cancer.”

In this umbrella review, researchers analyzed 49 papers that included a total of 204 meta-analyses, which in turn summarized 2,179 individual study estimates from 507 unique cohort or case-control studies.

okeyphotos/iStockphoto

However, only 95 of the meta-analyses used cohort studies that used a continuous scale to measure adiposity, such as body mass index, waist circumference, hip circumference, or waist-to-hip ratio. Of these, 12 (13%) were supported by strong evidence, the authors reported (BMJ 2017;356:j477).

When researchers applied a threshold for significance of P less than .000001, the summary random effects were significant in 35 meta-analyses; 31 of these found increased risk with adiposity of esophageal adenocarcinoma, multiple myeloma, and cancers of the colon, rectum, liver, biliary tract system (cancers of gallbladder, extrahepatic bile duct, and ampulla of Vater), pancreas, postmenopausal breast, endometrium, and kidney.

“The effect of obesity on the incidence and mortality of cancer is well recognized and was evident in our umbrella review, with approximately 77% of the included meta-analyses reporting a nominally statistically significant summary random effects estimate,” the authors reported.

Overall, the summary estimates were similar between men and women for esophageal adenocarcinoma, esophageal squamous cell carcinoma, multiple myeloma, leukemia, and gastric, lung, kidney, and thyroid cancers.

However, men had a 30% higher risk of colon cancer per 5-kg/m² increase of body mass index, compared with a 9% increase in risk in women for the same rise in BMI. Men also showed an increased risk of melanoma with increasing BMI, whereas women did not.

Women who had never used hormone therapy showed an 11% increase in the risk of postmenopausal breast cancer with each 5 kg of weight gained. Similarly, each 0.1 increase in waist-to-hip ratio in these women was associated with a 21% increase in the risk of endometrial cancer.

The analysis also revealed an inverse relationship in four meta-analyses for esophageal squamous cell carcinoma and lung cancer.

The authors said their findings agree with those of the World Cancer Research Fund, which currently states there is a convincing causal relationship with obesity for esophageal adenocarcinoma and cancers of the pancreas, colorectum, postmenopausal breast, endometrium, kidney, and liver.

While this umbrella analysis did not find strong evidence for an association with liver cancer, the authors said the evidence was “highly suggestive” but suffered from small study effects, excess significance bias, and substantial heterogeneity between studies.

“To draw firmer conclusions, we need prospective studies and large consortiums with better assessment of the changing nature of body fatness and with comprehensive standardized reporting of analyses,” they wrote. “As obesity becomes one of the greatest public health problems worldwide, evidence of the strength of the associations between obesity and cancer may allow finer selection of people at high risk, who could be selected for personalized primary and secondary prevention strategies.”

The study was supported by the Genesis Research Trust, Sigrid Jusélius Fellowship, the World Cancer Research Fund International Regular Grant Programme, Ovarian Cancer Action, the Imperial Experimental Cancer Medicine Centre, the Cancer Research UK Imperial Centre, Imperial Healthcare NHS Trust NIHR BRC. No relevant conflicts of interest were declared.

There is strong evidence linking adiposity to esophageal adenocarcinoma, multiple myeloma, and cancer of the colon, rectum, biliary tract, pancreas, endometrium, kidney, and postmenopausal breast, according to the authors of an umbrella review published in the Feb. 28 edition of the BMJ.

“Several meta-analyses support the link between obesity and cancer, but substantial heterogeneity exists between studies,” wrote Maria Kyrgiou, MD, of Imperial College London and her coauthors. “The reported associations may be causal, but they may also be flawed, as inherent study biases such as residual confounding and selective reporting of positive results may exaggerate the effect of obesity on cancer.”

In this umbrella review, researchers analyzed 49 papers that included a total of 204 meta-analyses, which in turn summarized 2,179 individual study estimates from 507 unique cohort or case-control studies.

okeyphotos/iStockphoto

However, only 95 of the meta-analyses used cohort studies that used a continuous scale to measure adiposity, such as body mass index, waist circumference, hip circumference, or waist-to-hip ratio. Of these, 12 (13%) were supported by strong evidence, the authors reported (BMJ 2017;356:j477).

When researchers applied a threshold for significance of P less than .000001, the summary random effects were significant in 35 meta-analyses; 31 of these found increased risk with adiposity of esophageal adenocarcinoma, multiple myeloma, and cancers of the colon, rectum, liver, biliary tract system (cancers of gallbladder, extrahepatic bile duct, and ampulla of Vater), pancreas, postmenopausal breast, endometrium, and kidney.

“The effect of obesity on the incidence and mortality of cancer is well recognized and was evident in our umbrella review, with approximately 77% of the included meta-analyses reporting a nominally statistically significant summary random effects estimate,” the authors reported.

Overall, the summary estimates were similar between men and women for esophageal adenocarcinoma, esophageal squamous cell carcinoma, multiple myeloma, leukemia, and gastric, lung, kidney, and thyroid cancers.

However, men had a 30% higher risk of colon cancer per 5-kg/m² increase of body mass index, compared with a 9% increase in risk in women for the same rise in BMI. Men also showed an increased risk of melanoma with increasing BMI, whereas women did not.

Women who had never used hormone therapy showed an 11% increase in the risk of postmenopausal breast cancer with each 5 kg of weight gained. Similarly, each 0.1 increase in waist-to-hip ratio in these women was associated with a 21% increase in the risk of endometrial cancer.

The analysis also revealed an inverse relationship in four meta-analyses for esophageal squamous cell carcinoma and lung cancer.

The authors said their findings agree with those of the World Cancer Research Fund, which currently states there is a convincing causal relationship with obesity for esophageal adenocarcinoma and cancers of the pancreas, colorectum, postmenopausal breast, endometrium, kidney, and liver.

While this umbrella analysis did not find strong evidence for an association with liver cancer, the authors said the evidence was “highly suggestive” but suffered from small study effects, excess significance bias, and substantial heterogeneity between studies.

“To draw firmer conclusions, we need prospective studies and large consortiums with better assessment of the changing nature of body fatness and with comprehensive standardized reporting of analyses,” they wrote. “As obesity becomes one of the greatest public health problems worldwide, evidence of the strength of the associations between obesity and cancer may allow finer selection of people at high risk, who could be selected for personalized primary and secondary prevention strategies.”

The study was supported by the Genesis Research Trust, Sigrid Jusélius Fellowship, the World Cancer Research Fund International Regular Grant Programme, Ovarian Cancer Action, the Imperial Experimental Cancer Medicine Centre, the Cancer Research UK Imperial Centre, Imperial Healthcare NHS Trust NIHR BRC. No relevant conflicts of interest were declared.

There is strong evidence linking adiposity to esophageal adenocarcinoma, multiple myeloma, and cancer of the colon, rectum, biliary tract, pancreas, endometrium, kidney, and postmenopausal breast, according to the authors of an umbrella review published in the Feb. 28 edition of the BMJ.

“Several meta-analyses support the link between obesity and cancer, but substantial heterogeneity exists between studies,” wrote Maria Kyrgiou, MD, of Imperial College London and her coauthors. “The reported associations may be causal, but they may also be flawed, as inherent study biases such as residual confounding and selective reporting of positive results may exaggerate the effect of obesity on cancer.”

In this umbrella review, researchers analyzed 49 papers that included a total of 204 meta-analyses, which in turn summarized 2,179 individual study estimates from 507 unique cohort or case-control studies.

okeyphotos/iStockphoto

However, only 95 of the meta-analyses used cohort studies that used a continuous scale to measure adiposity, such as body mass index, waist circumference, hip circumference, or waist-to-hip ratio. Of these, 12 (13%) were supported by strong evidence, the authors reported (BMJ 2017;356:j477).

When researchers applied a threshold for significance of P less than .000001, the summary random effects were significant in 35 meta-analyses; 31 of these found increased risk with adiposity of esophageal adenocarcinoma, multiple myeloma, and cancers of the colon, rectum, liver, biliary tract system (cancers of gallbladder, extrahepatic bile duct, and ampulla of Vater), pancreas, postmenopausal breast, endometrium, and kidney.

“The effect of obesity on the incidence and mortality of cancer is well recognized and was evident in our umbrella review, with approximately 77% of the included meta-analyses reporting a nominally statistically significant summary random effects estimate,” the authors reported.

Overall, the summary estimates were similar between men and women for esophageal adenocarcinoma, esophageal squamous cell carcinoma, multiple myeloma, leukemia, and gastric, lung, kidney, and thyroid cancers.

However, men had a 30% higher risk of colon cancer per 5-kg/m² increase of body mass index, compared with a 9% increase in risk in women for the same rise in BMI. Men also showed an increased risk of melanoma with increasing BMI, whereas women did not.

Women who had never used hormone therapy showed an 11% increase in the risk of postmenopausal breast cancer with each 5 kg of weight gained. Similarly, each 0.1 increase in waist-to-hip ratio in these women was associated with a 21% increase in the risk of endometrial cancer.

The analysis also revealed an inverse relationship in four meta-analyses for esophageal squamous cell carcinoma and lung cancer.

The authors said their findings agree with those of the World Cancer Research Fund, which currently states there is a convincing causal relationship with obesity for esophageal adenocarcinoma and cancers of the pancreas, colorectum, postmenopausal breast, endometrium, kidney, and liver.

While this umbrella analysis did not find strong evidence for an association with liver cancer, the authors said the evidence was “highly suggestive” but suffered from small study effects, excess significance bias, and substantial heterogeneity between studies.

“To draw firmer conclusions, we need prospective studies and large consortiums with better assessment of the changing nature of body fatness and with comprehensive standardized reporting of analyses,” they wrote. “As obesity becomes one of the greatest public health problems worldwide, evidence of the strength of the associations between obesity and cancer may allow finer selection of people at high risk, who could be selected for personalized primary and secondary prevention strategies.”

The study was supported by the Genesis Research Trust, Sigrid Jusélius Fellowship, the World Cancer Research Fund International Regular Grant Programme, Ovarian Cancer Action, the Imperial Experimental Cancer Medicine Centre, the Cancer Research UK Imperial Centre, Imperial Healthcare NHS Trust NIHR BRC. No relevant conflicts of interest were declared.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

 

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

 

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

 

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo courtesy of CDC

ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.

Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).

She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”

So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.

The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).

The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.

Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.

“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”

Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.

Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.

They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).

They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.

The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.

Demographics

Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.

Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).

Results

At baseline, patients in each group had comparable QOL and mood scores.

However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.

In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.

At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and  PTSD symptom (P=0.002) scores were significantly improved in the intervention group.

And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.

The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.

“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.

 

“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”

The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.

Photo courtesy of CDC

ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.

Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).

She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”

So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.

The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).

The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.

Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.

“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”

Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.

Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.

They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).

They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.

The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.

Demographics

Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.

Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).

Results

At baseline, patients in each group had comparable QOL and mood scores.

However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.

In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.

At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and  PTSD symptom (P=0.002) scores were significantly improved in the intervention group.

And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.

The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.

“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.

 

“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”

The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.

Photo courtesy of CDC

ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.

Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).

She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”

So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.

The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).

The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.

Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.

“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”

Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.

Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.

They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).

They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.

The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.

Demographics

Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.

Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).

Results

At baseline, patients in each group had comparable QOL and mood scores.

However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.

In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.

At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and  PTSD symptom (P=0.002) scores were significantly improved in the intervention group.

And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.

The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.

“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.

 

“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”

The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.

Photo by Rhoda Baer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the antiemetic agent rolapitant (Varuby) as a treatment for adults with cancer.

The drug is intended to be used in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy.

The CHMP’s recommendation regarding rolapitant has been forwarded to the European Commission, which is expected to make a decision about the drug within 2 months.

If the commission authorizes marketing of rolapitant, the drug will be available as 90 mg film-coated tablets.

The applicant for rolapitant is Tesaro UK Limited.

Rolapitant clinical trials

Results from three phase 3 trials suggested that rolapitant (at 180 mg) in combination with a 5-HT3 receptor antagonist and dexamethasone was more effective than the 5-HT3 receptor antagonist and dexamethasone on their own (active control).

The 3-drug combination demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25- to 120-hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens.

In addition, patients who received rolapitant reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy.

Highly emetogenic chemotherapy

The clinical profile of rolapitant in cisplatin-based, highly emetogenic chemotherapy (HEC) was confirmed in two phase 3 studies: HEC1 and HEC2. Results from these trials were published in The Lancet Oncology in August 2015.

Both trials met their primary endpoint of complete response (CR) and demonstrated statistical superiority of the rolapitant combination compared to active control.

In HEC1, 264 patients received the rolapitant combination, and 262 received active control. The proportion of patients achieving a CR was 72.7% and 58.4%, respectively (P<0.001).

In HEC2, 271 patients received the rolapitant combination, and 273 received active control. The proportion of patients achieving a CR was 70.1% and 61.9%, respectively (P=0.043).

The most common adverse events (in the rolapitant and control groups, respectively) were neutropenia (9% and 8%), hiccups (5% and 4%), and abdominal pain (3% and 2%).

Moderately emetogenic chemotherapy

Researchers conducted another phase 3 trial to compare the rolapitant combination with active control in 1332 patients receiving moderately emetogenic chemotherapy. Results from this trial were also published in The Lancet Oncology in August 2015.

This trial met its primary endpoint of CR and demonstrated statistical superiority of the rolapitant combination compared to active control. The proportion of patients achieving a CR was 71.3% and 61.6%, respectively (P<0.001).

The most common adverse events (in the rolapitant and control groups, respectively) were decreased appetite (9% and 7%), neutropenia (7% and 6%), dizziness (6% and 4%), dyspepsia (4% and 2%), urinary tract infection (4% and 3%), stomatitis (4% and 2%), and anemia (3% and 2%).

Photo by Rhoda Baer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the antiemetic agent rolapitant (Varuby) as a treatment for adults with cancer.

The drug is intended to be used in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy.

The CHMP’s recommendation regarding rolapitant has been forwarded to the European Commission, which is expected to make a decision about the drug within 2 months.

If the commission authorizes marketing of rolapitant, the drug will be available as 90 mg film-coated tablets.

The applicant for rolapitant is Tesaro UK Limited.

Rolapitant clinical trials

Results from three phase 3 trials suggested that rolapitant (at 180 mg) in combination with a 5-HT3 receptor antagonist and dexamethasone was more effective than the 5-HT3 receptor antagonist and dexamethasone on their own (active control).

The 3-drug combination demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25- to 120-hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens.

In addition, patients who received rolapitant reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy.

Highly emetogenic chemotherapy

The clinical profile of rolapitant in cisplatin-based, highly emetogenic chemotherapy (HEC) was confirmed in two phase 3 studies: HEC1 and HEC2. Results from these trials were published in The Lancet Oncology in August 2015.

Both trials met their primary endpoint of complete response (CR) and demonstrated statistical superiority of the rolapitant combination compared to active control.

In HEC1, 264 patients received the rolapitant combination, and 262 received active control. The proportion of patients achieving a CR was 72.7% and 58.4%, respectively (P<0.001).

In HEC2, 271 patients received the rolapitant combination, and 273 received active control. The proportion of patients achieving a CR was 70.1% and 61.9%, respectively (P=0.043).

The most common adverse events (in the rolapitant and control groups, respectively) were neutropenia (9% and 8%), hiccups (5% and 4%), and abdominal pain (3% and 2%).

Moderately emetogenic chemotherapy

Researchers conducted another phase 3 trial to compare the rolapitant combination with active control in 1332 patients receiving moderately emetogenic chemotherapy. Results from this trial were also published in The Lancet Oncology in August 2015.

This trial met its primary endpoint of CR and demonstrated statistical superiority of the rolapitant combination compared to active control. The proportion of patients achieving a CR was 71.3% and 61.6%, respectively (P<0.001).

The most common adverse events (in the rolapitant and control groups, respectively) were decreased appetite (9% and 7%), neutropenia (7% and 6%), dizziness (6% and 4%), dyspepsia (4% and 2%), urinary tract infection (4% and 3%), stomatitis (4% and 2%), and anemia (3% and 2%).

Photo by Rhoda Baer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the antiemetic agent rolapitant (Varuby) as a treatment for adults with cancer.

The drug is intended to be used in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy.

The CHMP’s recommendation regarding rolapitant has been forwarded to the European Commission, which is expected to make a decision about the drug within 2 months.

If the commission authorizes marketing of rolapitant, the drug will be available as 90 mg film-coated tablets.

The applicant for rolapitant is Tesaro UK Limited.

Rolapitant clinical trials

Results from three phase 3 trials suggested that rolapitant (at 180 mg) in combination with a 5-HT3 receptor antagonist and dexamethasone was more effective than the 5-HT3 receptor antagonist and dexamethasone on their own (active control).

The 3-drug combination demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25- to 120-hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens.

In addition, patients who received rolapitant reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy.

Highly emetogenic chemotherapy

The clinical profile of rolapitant in cisplatin-based, highly emetogenic chemotherapy (HEC) was confirmed in two phase 3 studies: HEC1 and HEC2. Results from these trials were published in The Lancet Oncology in August 2015.

Both trials met their primary endpoint of complete response (CR) and demonstrated statistical superiority of the rolapitant combination compared to active control.

In HEC1, 264 patients received the rolapitant combination, and 262 received active control. The proportion of patients achieving a CR was 72.7% and 58.4%, respectively (P<0.001).

In HEC2, 271 patients received the rolapitant combination, and 273 received active control. The proportion of patients achieving a CR was 70.1% and 61.9%, respectively (P=0.043).

The most common adverse events (in the rolapitant and control groups, respectively) were neutropenia (9% and 8%), hiccups (5% and 4%), and abdominal pain (3% and 2%).

Moderately emetogenic chemotherapy

Researchers conducted another phase 3 trial to compare the rolapitant combination with active control in 1332 patients receiving moderately emetogenic chemotherapy. Results from this trial were also published in The Lancet Oncology in August 2015.

This trial met its primary endpoint of CR and demonstrated statistical superiority of the rolapitant combination compared to active control. The proportion of patients achieving a CR was 71.3% and 61.6%, respectively (P<0.001).

The most common adverse events (in the rolapitant and control groups, respectively) were decreased appetite (9% and 7%), neutropenia (7% and 6%), dizziness (6% and 4%), dyspepsia (4% and 2%), urinary tract infection (4% and 3%), stomatitis (4% and 2%), and anemia (3% and 2%).