Lymphoma & Plasma Cell Disorders

Updated clinical guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL) include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.

The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.

Major changes or additions include:

Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.

“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.

IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.

Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.

Updated clinical guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL) include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.

The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.

Major changes or additions include:

Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.

“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.

IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.

Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.

Updated clinical guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL) include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.

The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.

Major changes or additions include:

Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.

“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.

IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.

Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.

Image from Darryl Leja, NHGRI

Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.

Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.

The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.

These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.

The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”

“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.

“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”

The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.

“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.

The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.

Cell of origin

In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.

The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.

“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.

“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”

“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”

Oncogenic processes

The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.

The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.

“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”

“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.

“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”

Signaling pathways

The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.

The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.

Image from Darryl Leja, NHGRI

Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.

Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.

The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.

These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.

The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”

“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.

“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”

The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.

“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.

The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.

Cell of origin

In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.

The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.

“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.

“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”

“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”

Oncogenic processes

The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.

The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.

“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”

“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.

“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”

Signaling pathways

The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.

The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.

Image from Darryl Leja, NHGRI

Through extensive analyses of data from The Cancer Genome Atlas (TCGA), researchers have produced a new resource known as the Pan-Cancer Atlas.

Multiple research groups analyzed data on more than 10,000 tumors spanning 33 types of cancer, including acute myeloid leukemia and diffuse large B-cell lymphoma.

The work revealed new insights regarding cells of origin, oncogenic processes, and signaling pathways.

These insights make up the Pan-Cancer Atlas and are described in 27 papers published in Cell Press journals. The entire collection of papers is available through a portal on cell.com.

The Pan-Cancer Atlas is the final output of TCGA, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to “collect, select, and analyze human tissues for genomic alterations on a very large scale.”

“This project is the culmination of more than a decade of ground-breaking work,” said Francis S. Collins, MD, PhD, director of the National Institutes of Health.

“This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better informed clinical trials and future treatments.”

The project focused on genome sequencing as well as other analyses, such as investigating gene and protein expression profiles and associating them with clinical and imaging data.

“The Pan-Cancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013,” said Jean Claude Zenklusen, PhD, director of the TCGA Program Office at NCI.

The Pan-Cancer Atlas is divided into 3 main categories—cell of origin, oncogenic processes, and signaling pathways—each anchored by a summary paper that recaps the core findings for the topic. Companion papers report in-depth explorations of individual topics within these categories.

Cell of origin

In the first Pan-Cancer Atlas summary paper, the authors review the findings from analyses using a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications.

The analyses suggest that tumor types cluster by their possible cells of origin, a finding that has implications for the classification and treatment of various cancers.

“Rather than the organ of origin, we can now use molecular features to identify the cancer’s cell of origin,” said Li Ding, PhD, of Washington University School of Medicine in St. Louis, Missouri.

“We are looking at what genes are turned on in the tumor, and that brings us to a particular cell type. For example, squamous cell cancers can arise in the lung, bladder, cervix, and some tumors of the head and neck. We traditionally have treated cancers in these areas as completely different diseases, but, [by] studying their molecular features, we now know such cancers are closely related.”

“This new molecular-based classification system should greatly help in the clinic, where it is already explaining some of the similar clinical behavior of what we thought were different tumor types,” said Charles Perou, PhD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

“These findings also provide many new therapeutic opportunities, which can and will be tested in the next phase of human clinical trials.”

Oncogenic processes

The second Pan-Cancer Atlas summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression.

The research revealed insights into 3 critical oncogenic processes—germline and somatic mutations, the influence of the tumor’s underlying genome and epigenome on gene and protein expression, and the interplay of tumor and immune cells.

“For the 10,000 tumors we analyzed, we now know—in detail—the inherited mutations driving cancer and the genetic errors that accumulate as people age, increasing the risk of cancer,” Dr Ding said. “This is the first definitive summary of the genetics behind 33 major types of cancer.”

“TCGA has created a catalogue of alterations that occur in a variety of cancer types,” said Katherine Hoadley, PhD, of University of North Carolina at Chapel Hill.

“Having this catalogue of alterations is really important for us to look, in future studies, at why these alterations are there and to predict outcomes for patients.”

Signaling pathways

The final Pan-Cancer Atlas summary paper details TCGA research on the genomic alterations in the signaling pathways that control cell-cycle progression, cell death, and cell growth. The work highlights the similarities and differences in these processes across a range of cancers.

The researchers believe these studies have revealed new patterns of potential vulnerabilities that might aid the development of targeted and combination therapies.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin.

With this BLA, AstraZeneca is seeking approval for moxetumomab pasudotox for the treatment of adults with hairy cell leukemia (HCL) who have received at least 2 prior lines of therapy.

The FDA expects to make a decision on the BLA in the third quarter of this year.

The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

About moxetumomab pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is composed of a binding portion of an anti-CD22 antibody fused to a toxin. After binding to CD22, the molecule is internalized, processed, and releases its modified protein toxin, which inhibits protein translation and leads to apoptosis.

In addition to priority review, moxetumomab pasudotox has received orphan drug designation from the FDA.

Moxetumomab pasudotox has been tested in a phase 1 trial. Initial results from this trial were published in the Journal of Clinical Oncology in 2012. Long-term follow-up was presented at the 2017 ASH Annual Meeting.

The ASH data included 49 patients with relapsed/refractory HCL. Their median age was 57 (range, 40-77), most (n=41) were male, and they had a median of 35 (range, 1-60,444) circulating HCL cells/mm³ at baseline (in 48 evaluable patients).

Twenty-eight patients received moxetumomab pasudotox in the dose-escalation portion of the study—at 5, 10, 20, 30, 40, or 50 µg/kg—and 21 received the drug at 50 µg/kg for the extension portion of the study.

Among the 33 patients who received moxetumomab pasudotox at 50 µg/kg, the overall response rate was 88%, and the complete response (CR) rate was 64% (n=21). The median time to CR was 3.6 months, and the median duration of CR was 70.3 months.

The median follow-up was 75 months for the entire study population. At 72 months, the progression-free survival (PFS) rate was 77%.

The researchers found that minimal residual disease (MRD) negativity (via immunohistochemistry) was associated with extended response duration and prolonged PFS.

The MRD evaluation included 19 MRD+ patients and 18 MRD- patients. Forty-seven percent of the MRD+ patients (n=9) and 94% of the MRD- patients (n=17) had a CR as their best response.

The median duration of CR was 13.1 months among the MRD+ patients and was not reached among the MRD- patients (P=0.0002). The median PFS was 82.1 months among the MRD+ patients and not reached among the MRD- patients (P=0.0031).

Moxetumomab pasudotox did not undergo phase 2 testing but proceeded to a phase 3 trial. In this single-arm study, researchers evaluated the drug in HCL patients who had received at least 2 prior therapies.

According to AstraZeneca, the study’s primary endpoint—durable CR—was met. The company said the phase 3 results will be presented at an upcoming medical meeting.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin.

With this BLA, AstraZeneca is seeking approval for moxetumomab pasudotox for the treatment of adults with hairy cell leukemia (HCL) who have received at least 2 prior lines of therapy.

The FDA expects to make a decision on the BLA in the third quarter of this year.

The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

About moxetumomab pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is composed of a binding portion of an anti-CD22 antibody fused to a toxin. After binding to CD22, the molecule is internalized, processed, and releases its modified protein toxin, which inhibits protein translation and leads to apoptosis.

In addition to priority review, moxetumomab pasudotox has received orphan drug designation from the FDA.

Moxetumomab pasudotox has been tested in a phase 1 trial. Initial results from this trial were published in the Journal of Clinical Oncology in 2012. Long-term follow-up was presented at the 2017 ASH Annual Meeting.

The ASH data included 49 patients with relapsed/refractory HCL. Their median age was 57 (range, 40-77), most (n=41) were male, and they had a median of 35 (range, 1-60,444) circulating HCL cells/mm³ at baseline (in 48 evaluable patients).

Twenty-eight patients received moxetumomab pasudotox in the dose-escalation portion of the study—at 5, 10, 20, 30, 40, or 50 µg/kg—and 21 received the drug at 50 µg/kg for the extension portion of the study.

Among the 33 patients who received moxetumomab pasudotox at 50 µg/kg, the overall response rate was 88%, and the complete response (CR) rate was 64% (n=21). The median time to CR was 3.6 months, and the median duration of CR was 70.3 months.

The median follow-up was 75 months for the entire study population. At 72 months, the progression-free survival (PFS) rate was 77%.

The researchers found that minimal residual disease (MRD) negativity (via immunohistochemistry) was associated with extended response duration and prolonged PFS.

The MRD evaluation included 19 MRD+ patients and 18 MRD- patients. Forty-seven percent of the MRD+ patients (n=9) and 94% of the MRD- patients (n=17) had a CR as their best response.

The median duration of CR was 13.1 months among the MRD+ patients and was not reached among the MRD- patients (P=0.0002). The median PFS was 82.1 months among the MRD+ patients and not reached among the MRD- patients (P=0.0031).

Moxetumomab pasudotox did not undergo phase 2 testing but proceeded to a phase 3 trial. In this single-arm study, researchers evaluated the drug in HCL patients who had received at least 2 prior therapies.

According to AstraZeneca, the study’s primary endpoint—durable CR—was met. The company said the phase 3 results will be presented at an upcoming medical meeting.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin.

With this BLA, AstraZeneca is seeking approval for moxetumomab pasudotox for the treatment of adults with hairy cell leukemia (HCL) who have received at least 2 prior lines of therapy.

The FDA expects to make a decision on the BLA in the third quarter of this year.

The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

About moxetumomab pasudotox

Moxetumomab pasudotox (formerly CAT-8015 or HA22) is composed of a binding portion of an anti-CD22 antibody fused to a toxin. After binding to CD22, the molecule is internalized, processed, and releases its modified protein toxin, which inhibits protein translation and leads to apoptosis.

In addition to priority review, moxetumomab pasudotox has received orphan drug designation from the FDA.

Moxetumomab pasudotox has been tested in a phase 1 trial. Initial results from this trial were published in the Journal of Clinical Oncology in 2012. Long-term follow-up was presented at the 2017 ASH Annual Meeting.

The ASH data included 49 patients with relapsed/refractory HCL. Their median age was 57 (range, 40-77), most (n=41) were male, and they had a median of 35 (range, 1-60,444) circulating HCL cells/mm³ at baseline (in 48 evaluable patients).

Twenty-eight patients received moxetumomab pasudotox in the dose-escalation portion of the study—at 5, 10, 20, 30, 40, or 50 µg/kg—and 21 received the drug at 50 µg/kg for the extension portion of the study.

Among the 33 patients who received moxetumomab pasudotox at 50 µg/kg, the overall response rate was 88%, and the complete response (CR) rate was 64% (n=21). The median time to CR was 3.6 months, and the median duration of CR was 70.3 months.

The median follow-up was 75 months for the entire study population. At 72 months, the progression-free survival (PFS) rate was 77%.

The researchers found that minimal residual disease (MRD) negativity (via immunohistochemistry) was associated with extended response duration and prolonged PFS.

The MRD evaluation included 19 MRD+ patients and 18 MRD- patients. Forty-seven percent of the MRD+ patients (n=9) and 94% of the MRD- patients (n=17) had a CR as their best response.

The median duration of CR was 13.1 months among the MRD+ patients and was not reached among the MRD- patients (P=0.0002). The median PFS was 82.1 months among the MRD+ patients and not reached among the MRD- patients (P=0.0031).

Moxetumomab pasudotox did not undergo phase 2 testing but proceeded to a phase 3 trial. In this single-arm study, researchers evaluated the drug in HCL patients who had received at least 2 prior therapies.

According to AstraZeneca, the study’s primary endpoint—durable CR—was met. The company said the phase 3 results will be presented at an upcoming medical meeting.

The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.

In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.

In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.

“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.

Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.

Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.

Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.

SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.

The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.

In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.

In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.

“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.

Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.

Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.

Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.

SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.

The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.

In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.

In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.

“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.

Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.

Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.

Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.

SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended changing the terms of marketing authorization for fosaprepitant (Ivemend).

The product is already approved in the European Union (EU) for the prevention of acute and delayed nausea and vomiting associated with moderately or highly emetogenic cancer chemotherapy in adults.

Now, the CHMP is recommending that fosaprepitant be authorized for the same indication in pediatric patients age 6 months and older.

As it is in adults, fosaprepitant would be given to children as part of combination therapy.

The CHMP’s opinion on fosaprepitant will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the EU. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Merck Sharp & Dohme Corp., the company developing fosaprepitant, has conducted a phase 2 trial assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in children.

Patients ages 2 to 17 were randomized to receive 1 of 4 doses of fosaprepitant (0.4 mg/kg, 1.2 mg/kg, 3 mg/kg, and 5 mg/kg) or placebo in cycle 1. All patients also received ondansetron, with or without dexamethasone. Patients ages 0 to 11 were invited to participate in optional cycles 2 to 6, during which they received fosaprepitant at 3 mg/kg or 5 mg/kg.

Results from this trial have been posted on its clinicaltrials.gov page (NCT01697579).

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended changing the terms of marketing authorization for fosaprepitant (Ivemend).

The product is already approved in the European Union (EU) for the prevention of acute and delayed nausea and vomiting associated with moderately or highly emetogenic cancer chemotherapy in adults.

Now, the CHMP is recommending that fosaprepitant be authorized for the same indication in pediatric patients age 6 months and older.

As it is in adults, fosaprepitant would be given to children as part of combination therapy.

The CHMP’s opinion on fosaprepitant will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the EU. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Merck Sharp & Dohme Corp., the company developing fosaprepitant, has conducted a phase 2 trial assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in children.

Patients ages 2 to 17 were randomized to receive 1 of 4 doses of fosaprepitant (0.4 mg/kg, 1.2 mg/kg, 3 mg/kg, and 5 mg/kg) or placebo in cycle 1. All patients also received ondansetron, with or without dexamethasone. Patients ages 0 to 11 were invited to participate in optional cycles 2 to 6, during which they received fosaprepitant at 3 mg/kg or 5 mg/kg.

Results from this trial have been posted on its clinicaltrials.gov page (NCT01697579).

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended changing the terms of marketing authorization for fosaprepitant (Ivemend).

The product is already approved in the European Union (EU) for the prevention of acute and delayed nausea and vomiting associated with moderately or highly emetogenic cancer chemotherapy in adults.

Now, the CHMP is recommending that fosaprepitant be authorized for the same indication in pediatric patients age 6 months and older.

As it is in adults, fosaprepitant would be given to children as part of combination therapy.

The CHMP’s opinion on fosaprepitant will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the EU. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Merck Sharp & Dohme Corp., the company developing fosaprepitant, has conducted a phase 2 trial assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in children.

Patients ages 2 to 17 were randomized to receive 1 of 4 doses of fosaprepitant (0.4 mg/kg, 1.2 mg/kg, 3 mg/kg, and 5 mg/kg) or placebo in cycle 1. All patients also received ondansetron, with or without dexamethasone. Patients ages 0 to 11 were invited to participate in optional cycles 2 to 6, during which they received fosaprepitant at 3 mg/kg or 5 mg/kg.

Results from this trial have been posted on its clinicaltrials.gov page (NCT01697579).

In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.

Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.

“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.

The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.

Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.

In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.

The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).

Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.

Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.

In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.

“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.

The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.

Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.

Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.

SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.

In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.

Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.

“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.

The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.

Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.

In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.

The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).

Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.

Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.

In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.

“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.

The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.

Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.

Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.

SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.

In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.

Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.

“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.

The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.

Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.

In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.

The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).

Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.

Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.

In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.

“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.

The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.

Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.

Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.

SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.

Photo from Novartis

The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.

ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.

The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.

“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.

Net health benefit

ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).

The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.

The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.

Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.

The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.

Toxicity and uncertainty

The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”

In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.

Cost-effectiveness

The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.

For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.

For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.

For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.

The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.

Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).

Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.

However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.

Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.

This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.

“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.

Panel voting results

ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.

Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.

After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.

Policy recommendations

Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.

Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.

“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.

Some of ICER’s recommendations include:

• When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
• Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
• Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
• Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
• Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
• Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
• Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.

Additional recommendations and more details are available in ICER’s report.

About ICER

ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.

ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.

ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.

These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.

Photo from Novartis

The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.

ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.

The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.

“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.

Net health benefit

ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).

The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.

The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.

Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.

The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.

Toxicity and uncertainty

The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”

In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.

Cost-effectiveness

The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.

For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.

For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.

For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.

The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.

Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).

Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.

However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.

Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.

This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.

“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.

Panel voting results

ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.

Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.

After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.

Policy recommendations

Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.

Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.

“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.

Some of ICER’s recommendations include:

• When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
• Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
• Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
• Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
• Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
• Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
• Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.

Additional recommendations and more details are available in ICER’s report.

About ICER

ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.

ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.

ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.

These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.

Photo from Novartis

The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.

ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.

The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.

“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.

Net health benefit

ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).

The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.

The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.

Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.

The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.

Toxicity and uncertainty

The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”

In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.

Cost-effectiveness

The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.

For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.

For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.

For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.

The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.

Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).

Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.

However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.

Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.

This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.

“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.

Panel voting results

ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.

Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.

After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.

Policy recommendations

Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.

Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.

“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.

Some of ICER’s recommendations include:

• When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
• Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
• Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
• Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
• Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
• Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
• Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.

Additional recommendations and more details are available in ICER’s report.

About ICER

ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.

ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.

ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.

These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.

Syringe

Health Canada has approved a subcutaneous (SC) formulation of rituximab (Rituxan®) to treat patients with chronic lymphocytic leukemia (CLL).

The product is now approved for use in combination with fludarabine and cyclophosphamide to treat patients with previously treated or untreated CLL, Binet Stage B or C.

The SC formulation is intended to provide a more convenient delivery method than intravenous (IV) rituximab. The SC formulation enables administration of the drug in large volumes under the skin.

“The approval of Rituxan SC is exciting news and a meaningful advancement for those living with CLL, as intravenous treatments can take around 4 hours to receive, requiring patients to spend up to a half day sitting in the chemo suite,” said Robin Markowitz, chief executive officer of Lymphoma Canada.

“The administration of Rituxan SC only takes 7 minutes, giving patients valuable time back in their day.”

SAWYER study

Health Canada’s approval of SC rituximab is based on data from the phase 1b SAWYER study. This randomized study was conducted in patients with previously untreated CLL to investigate the pharmacokinetic profile, safety, and efficacy of SC rituximab in combination with chemotherapy.

Results from this study were published in The Lancet Haematology in March 2016.

The trial included 176 patients who were randomized to receive SC rituximab (1600 mg, n=88) or IV rituximab (500 mg/m², n=88) on day 1 from cycles 2 to 6. In cycle 1, both groups received IV rituximab (375 mg/m²) on day 0.

All patients also received fludarabine (IV 25 mg/m² on days 1-3 of all cycles or orally at either 25 mg/m² on days 1-5 of all cycles or 30-40 mg/m² on days 1-3 of all cycles) and cyclophosphamide (IV at 250 mg/m² on days 1-3 of all cycles or orally at either 150 mg/m² on days 1-5 of all cycles or 200-250 mg/m² on days 1-3 of all cycles) every 4 weeks for up to 6 cycles.

The primary endpoint was pharmacokinetic noninferiority of SC to IV rituximab assessed at cycle 5. At that time, the geometric mean trough serum concentration in the SC rituximab arm was noninferior to that in the IV arm—97.5 µg/mL and 61.5 µg/mL, respectively—with an adjusted geometric mean ratio of 1.53 (90% CI, 1.27 to 1.85).

Safety was a secondary endpoint, and efficacy was an exploratory endpoint.

The overall response rate was 85% in the SC arm and 81% in the IV arm. Complete response rates were 26% and 33%, respectively.

Rates of adverse events (AEs) were 96% in the SC arm and 91% in the IV arm. Rates of grade 3 or higher AEs were 69% and 71%, respectively, and rates of serious AEs were 29% and 33%, respectively.

The most common serious AE overall was febrile neutropenia, which occurred in 11% of patients in the SC arm and 4% in the IV arm.

The most common AEs of any grade (occurring in >20% of patients in either arm) were:

• Neutropenia—65% with SC and 58% with IV
• Thrombocytopenia—24% with SC and 26% with IV
• Anemia—13% with SC and 24% with IV
• Nausea—38% with SC and 35% with IV
• Vomiting—21% with SC and 22% with IV
• Pyrexia—32% with SC and 25% with IV
• Injection-site erythema—26% with SC and 0% with IV.

Local cutaneous reactions were reported in 42% of patients in the SC arm. The most common of these were injection-site erythema (26%) and injection-site pain (16%).

Syringe

Health Canada has approved a subcutaneous (SC) formulation of rituximab (Rituxan®) to treat patients with chronic lymphocytic leukemia (CLL).

The product is now approved for use in combination with fludarabine and cyclophosphamide to treat patients with previously treated or untreated CLL, Binet Stage B or C.

The SC formulation is intended to provide a more convenient delivery method than intravenous (IV) rituximab. The SC formulation enables administration of the drug in large volumes under the skin.

“The approval of Rituxan SC is exciting news and a meaningful advancement for those living with CLL, as intravenous treatments can take around 4 hours to receive, requiring patients to spend up to a half day sitting in the chemo suite,” said Robin Markowitz, chief executive officer of Lymphoma Canada.

“The administration of Rituxan SC only takes 7 minutes, giving patients valuable time back in their day.”

SAWYER study

Health Canada’s approval of SC rituximab is based on data from the phase 1b SAWYER study. This randomized study was conducted in patients with previously untreated CLL to investigate the pharmacokinetic profile, safety, and efficacy of SC rituximab in combination with chemotherapy.

Results from this study were published in The Lancet Haematology in March 2016.

The trial included 176 patients who were randomized to receive SC rituximab (1600 mg, n=88) or IV rituximab (500 mg/m², n=88) on day 1 from cycles 2 to 6. In cycle 1, both groups received IV rituximab (375 mg/m²) on day 0.

All patients also received fludarabine (IV 25 mg/m² on days 1-3 of all cycles or orally at either 25 mg/m² on days 1-5 of all cycles or 30-40 mg/m² on days 1-3 of all cycles) and cyclophosphamide (IV at 250 mg/m² on days 1-3 of all cycles or orally at either 150 mg/m² on days 1-5 of all cycles or 200-250 mg/m² on days 1-3 of all cycles) every 4 weeks for up to 6 cycles.

The primary endpoint was pharmacokinetic noninferiority of SC to IV rituximab assessed at cycle 5. At that time, the geometric mean trough serum concentration in the SC rituximab arm was noninferior to that in the IV arm—97.5 µg/mL and 61.5 µg/mL, respectively—with an adjusted geometric mean ratio of 1.53 (90% CI, 1.27 to 1.85).

Safety was a secondary endpoint, and efficacy was an exploratory endpoint.

The overall response rate was 85% in the SC arm and 81% in the IV arm. Complete response rates were 26% and 33%, respectively.

Rates of adverse events (AEs) were 96% in the SC arm and 91% in the IV arm. Rates of grade 3 or higher AEs were 69% and 71%, respectively, and rates of serious AEs were 29% and 33%, respectively.

The most common serious AE overall was febrile neutropenia, which occurred in 11% of patients in the SC arm and 4% in the IV arm.

The most common AEs of any grade (occurring in >20% of patients in either arm) were:

• Neutropenia—65% with SC and 58% with IV
• Thrombocytopenia—24% with SC and 26% with IV
• Anemia—13% with SC and 24% with IV
• Nausea—38% with SC and 35% with IV
• Vomiting—21% with SC and 22% with IV
• Pyrexia—32% with SC and 25% with IV
• Injection-site erythema—26% with SC and 0% with IV.

Local cutaneous reactions were reported in 42% of patients in the SC arm. The most common of these were injection-site erythema (26%) and injection-site pain (16%).

Syringe

Health Canada has approved a subcutaneous (SC) formulation of rituximab (Rituxan®) to treat patients with chronic lymphocytic leukemia (CLL).

The product is now approved for use in combination with fludarabine and cyclophosphamide to treat patients with previously treated or untreated CLL, Binet Stage B or C.

The SC formulation is intended to provide a more convenient delivery method than intravenous (IV) rituximab. The SC formulation enables administration of the drug in large volumes under the skin.

“The approval of Rituxan SC is exciting news and a meaningful advancement for those living with CLL, as intravenous treatments can take around 4 hours to receive, requiring patients to spend up to a half day sitting in the chemo suite,” said Robin Markowitz, chief executive officer of Lymphoma Canada.

“The administration of Rituxan SC only takes 7 minutes, giving patients valuable time back in their day.”

SAWYER study

Health Canada’s approval of SC rituximab is based on data from the phase 1b SAWYER study. This randomized study was conducted in patients with previously untreated CLL to investigate the pharmacokinetic profile, safety, and efficacy of SC rituximab in combination with chemotherapy.

Results from this study were published in The Lancet Haematology in March 2016.

The trial included 176 patients who were randomized to receive SC rituximab (1600 mg, n=88) or IV rituximab (500 mg/m², n=88) on day 1 from cycles 2 to 6. In cycle 1, both groups received IV rituximab (375 mg/m²) on day 0.

All patients also received fludarabine (IV 25 mg/m² on days 1-3 of all cycles or orally at either 25 mg/m² on days 1-5 of all cycles or 30-40 mg/m² on days 1-3 of all cycles) and cyclophosphamide (IV at 250 mg/m² on days 1-3 of all cycles or orally at either 150 mg/m² on days 1-5 of all cycles or 200-250 mg/m² on days 1-3 of all cycles) every 4 weeks for up to 6 cycles.

The primary endpoint was pharmacokinetic noninferiority of SC to IV rituximab assessed at cycle 5. At that time, the geometric mean trough serum concentration in the SC rituximab arm was noninferior to that in the IV arm—97.5 µg/mL and 61.5 µg/mL, respectively—with an adjusted geometric mean ratio of 1.53 (90% CI, 1.27 to 1.85).

Safety was a secondary endpoint, and efficacy was an exploratory endpoint.

The overall response rate was 85% in the SC arm and 81% in the IV arm. Complete response rates were 26% and 33%, respectively.

Rates of adverse events (AEs) were 96% in the SC arm and 91% in the IV arm. Rates of grade 3 or higher AEs were 69% and 71%, respectively, and rates of serious AEs were 29% and 33%, respectively.

The most common serious AE overall was febrile neutropenia, which occurred in 11% of patients in the SC arm and 4% in the IV arm.

The most common AEs of any grade (occurring in >20% of patients in either arm) were:

• Neutropenia—65% with SC and 58% with IV
• Thrombocytopenia—24% with SC and 26% with IV
• Anemia—13% with SC and 24% with IV
• Nausea—38% with SC and 35% with IV
• Vomiting—21% with SC and 22% with IV
• Pyrexia—32% with SC and 25% with IV
• Injection-site erythema—26% with SC and 0% with IV.

Local cutaneous reactions were reported in 42% of patients in the SC arm. The most common of these were injection-site erythema (26%) and injection-site pain (16%).

Voxtalisib, an investigational agent that targets both mTOR and multiple isoforms of PI3K, showed “promising” efficacy with acceptable safety in patients with relapsed or refractory follicular lymphoma (FL), results of a phase 2 trial indicate.

Among 46 patients with FL, the overall response rate was 41.3%, including five (10.9%) complete responses. The median progression-free survival in this group was 58 weeks, reported Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and her colleagues.

“The observed activity of voxtalisib in relapsed or refractory follicular lymphoma, notable for inducing complete responses in 10.9% of patients, warrants further study,” the investigators wrote in a study published in the Lancet Haematology.

Efficacy of the drug was limited, however, against aggressive malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Voxtalisib (XL765) is a potent inhibitor of all four class I PI3Ks, as well as a less robust inhibitor of the mammalian target of rapamycin (mTOR). In contrast, idelalisib (Zydelig) – which is approved by the Food and Drug Administration for treatment of relapsed/refractory FL or for CLL, in combination with rituximab – inhibits only the delta isoform of PI3K, and does not have marked anti–mTOR properties.

The investigators conducted an open-label, nonrandomized trial of voxtalisib in 30 centers in the United States, Belgium, France, Germany, the Netherlands, and Australia.

Adults 18 years or older with relapsed or refractory MCL, FL, DLBCL or CLL/SLL with Eastern Cooperative Oncology Group performance status of 2 or less were enrolled. All patients received voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

All patients who received more the 4 weeks of treatment and had both a baseline and one or more on-treatment tumor assessments were included in the efficacy analysis. Patients with lymphoma had received a median of three prior lines of therapy, and those with CLL had received a median of four prior lines.

The overall response rate in the entire study population was 18.3% (30 patients), including 22 partial and 8 complete responses. ORR rates were as follows:

• FL: 41.3% (19 of 46 patients).
• MCL: 11.9% (5 of 42 patients).
• DLBCL: 4.9% (2 of 41 patients).
• CLL/SLL: 11.4% (4 of 35 patients).

The safety analysis, which included all 167 patients enrolled, was consistent with that of previous studies of voxtalisib, the investigators said. The most frequently reported adverse events of any grade or type were diarrhea in 35% of patients, fatigue in 32%, nausea in 27%, pyrexia in 26%, cough 24%, and decreased appetite in 21%.

Grade 3 or greater adverse events include anemia in 12%, and pneumonia and thrombocytopenia in 8% each. Slightly more than half of all patients (58.1%) had a serious adverse event.

The investigators noted that voxtalisib’s short plasma half-life may explain the drug’s lack of efficacy against the aggressive lymphomas and CLL/SLL. Longer-acting formulations of the drug or more frequent dosing might address this problem, although the latter solution could be challenging for patients to follow, the investigators acknowledged.

In light of the results, no further studies of voxtalisib in CLL are planned, thought investigation of the drug alone or in combination with chemoimmunotherapy is warranted for patients with follicular lymphoma, the investigators wrote.

The study was funded by Sanofi. Dr. Brown reported consulting for Janssen, Gilead, Celgene, Sun BioPharma, Novartis, AbbVie, Pfizer, AstraZeneca, Astellas, RedX, Pharmacyclics, Genentech/Roche, Verastem, and TG Therapeutics, and grants from Gilead and Sun BioPharma.

SOURCE: Brown J et al. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30030-9.
 

Voxtalisib, an investigational agent that targets both mTOR and multiple isoforms of PI3K, showed “promising” efficacy with acceptable safety in patients with relapsed or refractory follicular lymphoma (FL), results of a phase 2 trial indicate.

Among 46 patients with FL, the overall response rate was 41.3%, including five (10.9%) complete responses. The median progression-free survival in this group was 58 weeks, reported Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and her colleagues.

“The observed activity of voxtalisib in relapsed or refractory follicular lymphoma, notable for inducing complete responses in 10.9% of patients, warrants further study,” the investigators wrote in a study published in the Lancet Haematology.

Efficacy of the drug was limited, however, against aggressive malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Voxtalisib (XL765) is a potent inhibitor of all four class I PI3Ks, as well as a less robust inhibitor of the mammalian target of rapamycin (mTOR). In contrast, idelalisib (Zydelig) – which is approved by the Food and Drug Administration for treatment of relapsed/refractory FL or for CLL, in combination with rituximab – inhibits only the delta isoform of PI3K, and does not have marked anti–mTOR properties.

The investigators conducted an open-label, nonrandomized trial of voxtalisib in 30 centers in the United States, Belgium, France, Germany, the Netherlands, and Australia.

Adults 18 years or older with relapsed or refractory MCL, FL, DLBCL or CLL/SLL with Eastern Cooperative Oncology Group performance status of 2 or less were enrolled. All patients received voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

All patients who received more the 4 weeks of treatment and had both a baseline and one or more on-treatment tumor assessments were included in the efficacy analysis. Patients with lymphoma had received a median of three prior lines of therapy, and those with CLL had received a median of four prior lines.

The overall response rate in the entire study population was 18.3% (30 patients), including 22 partial and 8 complete responses. ORR rates were as follows:

• FL: 41.3% (19 of 46 patients).
• MCL: 11.9% (5 of 42 patients).
• DLBCL: 4.9% (2 of 41 patients).
• CLL/SLL: 11.4% (4 of 35 patients).

The safety analysis, which included all 167 patients enrolled, was consistent with that of previous studies of voxtalisib, the investigators said. The most frequently reported adverse events of any grade or type were diarrhea in 35% of patients, fatigue in 32%, nausea in 27%, pyrexia in 26%, cough 24%, and decreased appetite in 21%.

Grade 3 or greater adverse events include anemia in 12%, and pneumonia and thrombocytopenia in 8% each. Slightly more than half of all patients (58.1%) had a serious adverse event.

The investigators noted that voxtalisib’s short plasma half-life may explain the drug’s lack of efficacy against the aggressive lymphomas and CLL/SLL. Longer-acting formulations of the drug or more frequent dosing might address this problem, although the latter solution could be challenging for patients to follow, the investigators acknowledged.

In light of the results, no further studies of voxtalisib in CLL are planned, thought investigation of the drug alone or in combination with chemoimmunotherapy is warranted for patients with follicular lymphoma, the investigators wrote.

The study was funded by Sanofi. Dr. Brown reported consulting for Janssen, Gilead, Celgene, Sun BioPharma, Novartis, AbbVie, Pfizer, AstraZeneca, Astellas, RedX, Pharmacyclics, Genentech/Roche, Verastem, and TG Therapeutics, and grants from Gilead and Sun BioPharma.

SOURCE: Brown J et al. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30030-9.
 

Voxtalisib, an investigational agent that targets both mTOR and multiple isoforms of PI3K, showed “promising” efficacy with acceptable safety in patients with relapsed or refractory follicular lymphoma (FL), results of a phase 2 trial indicate.

Among 46 patients with FL, the overall response rate was 41.3%, including five (10.9%) complete responses. The median progression-free survival in this group was 58 weeks, reported Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and her colleagues.

“The observed activity of voxtalisib in relapsed or refractory follicular lymphoma, notable for inducing complete responses in 10.9% of patients, warrants further study,” the investigators wrote in a study published in the Lancet Haematology.

Efficacy of the drug was limited, however, against aggressive malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Voxtalisib (XL765) is a potent inhibitor of all four class I PI3Ks, as well as a less robust inhibitor of the mammalian target of rapamycin (mTOR). In contrast, idelalisib (Zydelig) – which is approved by the Food and Drug Administration for treatment of relapsed/refractory FL or for CLL, in combination with rituximab – inhibits only the delta isoform of PI3K, and does not have marked anti–mTOR properties.

The investigators conducted an open-label, nonrandomized trial of voxtalisib in 30 centers in the United States, Belgium, France, Germany, the Netherlands, and Australia.

Adults 18 years or older with relapsed or refractory MCL, FL, DLBCL or CLL/SLL with Eastern Cooperative Oncology Group performance status of 2 or less were enrolled. All patients received voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

All patients who received more the 4 weeks of treatment and had both a baseline and one or more on-treatment tumor assessments were included in the efficacy analysis. Patients with lymphoma had received a median of three prior lines of therapy, and those with CLL had received a median of four prior lines.

The overall response rate in the entire study population was 18.3% (30 patients), including 22 partial and 8 complete responses. ORR rates were as follows:

• FL: 41.3% (19 of 46 patients).
• MCL: 11.9% (5 of 42 patients).
• DLBCL: 4.9% (2 of 41 patients).
• CLL/SLL: 11.4% (4 of 35 patients).

The safety analysis, which included all 167 patients enrolled, was consistent with that of previous studies of voxtalisib, the investigators said. The most frequently reported adverse events of any grade or type were diarrhea in 35% of patients, fatigue in 32%, nausea in 27%, pyrexia in 26%, cough 24%, and decreased appetite in 21%.

Grade 3 or greater adverse events include anemia in 12%, and pneumonia and thrombocytopenia in 8% each. Slightly more than half of all patients (58.1%) had a serious adverse event.

The investigators noted that voxtalisib’s short plasma half-life may explain the drug’s lack of efficacy against the aggressive lymphomas and CLL/SLL. Longer-acting formulations of the drug or more frequent dosing might address this problem, although the latter solution could be challenging for patients to follow, the investigators acknowledged.

In light of the results, no further studies of voxtalisib in CLL are planned, thought investigation of the drug alone or in combination with chemoimmunotherapy is warranted for patients with follicular lymphoma, the investigators wrote.

The study was funded by Sanofi. Dr. Brown reported consulting for Janssen, Gilead, Celgene, Sun BioPharma, Novartis, AbbVie, Pfizer, AstraZeneca, Astellas, RedX, Pharmacyclics, Genentech/Roche, Verastem, and TG Therapeutics, and grants from Gilead and Sun BioPharma.

SOURCE: Brown J et al. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30030-9.
 

The Food and Drug Administration has received 414 reports of cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), including nine deaths.

This figure includes all medical device reports received by the agency between 2011 and September 2017. The FDA recently provided an update on ALCL linked to breast implants and an estimate of lifetime risk of developing ALCL.

Based on available medical literature, the lifetime risk of developing BIA-ALCL for patients with textured breast implants ranges from 1 in 3,817 to 1 in 30,000, according to the update.

Of the 272 reports with data on surface type, 242 were textured implants and 30 were smooth implants. In addition, 413 reports include information on the implant fill type: 234 used silicone gel and 179 were saline filled.

“The FDA has been closely tracking the relationship between breast implants and a rare type of non-Hodgkin’s lymphoma since we first identified this possible association. We’ve been working to gather additional information to better characterize and quantify the risk so that patients and providers can have more informed discussions about breast implants,” said Binita Ashar, MD, director of the division of surgical devices in the FDA’s Center for Devices and Radiological Health. “As part of that effort, we are working to update and enhance the information we have on this association, including updating the total number of known cases of BIA-ALCL and the lifetime risk of developing BIA-ALCL as reported in medical literature.”

The possible association between breast implants and the development of anaplastic large cell lymphoma (ALCL) was first identified in 2011. At that time, there were not enough cases of to determine what factors increased a patient’s risk of developing the disease. As more information became available, the World Health Organization designated BIA-ALCL as a T-cell lymphoma that can develop following breast implants.

ilacy@mdedge.com

The Food and Drug Administration has received 414 reports of cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), including nine deaths.

This figure includes all medical device reports received by the agency between 2011 and September 2017. The FDA recently provided an update on ALCL linked to breast implants and an estimate of lifetime risk of developing ALCL.

Based on available medical literature, the lifetime risk of developing BIA-ALCL for patients with textured breast implants ranges from 1 in 3,817 to 1 in 30,000, according to the update.

Of the 272 reports with data on surface type, 242 were textured implants and 30 were smooth implants. In addition, 413 reports include information on the implant fill type: 234 used silicone gel and 179 were saline filled.

“The FDA has been closely tracking the relationship between breast implants and a rare type of non-Hodgkin’s lymphoma since we first identified this possible association. We’ve been working to gather additional information to better characterize and quantify the risk so that patients and providers can have more informed discussions about breast implants,” said Binita Ashar, MD, director of the division of surgical devices in the FDA’s Center for Devices and Radiological Health. “As part of that effort, we are working to update and enhance the information we have on this association, including updating the total number of known cases of BIA-ALCL and the lifetime risk of developing BIA-ALCL as reported in medical literature.”

The possible association between breast implants and the development of anaplastic large cell lymphoma (ALCL) was first identified in 2011. At that time, there were not enough cases of to determine what factors increased a patient’s risk of developing the disease. As more information became available, the World Health Organization designated BIA-ALCL as a T-cell lymphoma that can develop following breast implants.

ilacy@mdedge.com

The Food and Drug Administration has received 414 reports of cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), including nine deaths.

This figure includes all medical device reports received by the agency between 2011 and September 2017. The FDA recently provided an update on ALCL linked to breast implants and an estimate of lifetime risk of developing ALCL.

Based on available medical literature, the lifetime risk of developing BIA-ALCL for patients with textured breast implants ranges from 1 in 3,817 to 1 in 30,000, according to the update.

Of the 272 reports with data on surface type, 242 were textured implants and 30 were smooth implants. In addition, 413 reports include information on the implant fill type: 234 used silicone gel and 179 were saline filled.

“The FDA has been closely tracking the relationship between breast implants and a rare type of non-Hodgkin’s lymphoma since we first identified this possible association. We’ve been working to gather additional information to better characterize and quantify the risk so that patients and providers can have more informed discussions about breast implants,” said Binita Ashar, MD, director of the division of surgical devices in the FDA’s Center for Devices and Radiological Health. “As part of that effort, we are working to update and enhance the information we have on this association, including updating the total number of known cases of BIA-ALCL and the lifetime risk of developing BIA-ALCL as reported in medical literature.”

The possible association between breast implants and the development of anaplastic large cell lymphoma (ALCL) was first identified in 2011. At that time, there were not enough cases of to determine what factors increased a patient’s risk of developing the disease. As more information became available, the World Health Organization designated BIA-ALCL as a T-cell lymphoma that can develop following breast implants.

ilacy@mdedge.com