Lymphoma & Plasma Cell Disorders

 

 

AACR Annual Meeting 2015

 

PHILADELPHIA—A retrospective study has revealed factors that appear to influence a person’s susceptibility to Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and other malignancies.

Study investigators looked at patients diagnosed with WM or LPL over a 20-year period and found about a 50% excess of second primary cancers in this population.

The patients had a significantly increased risk of multiple hematologic and solid tumor malignancies, and a few of these malignancies had shared susceptibility factors with WM/LPL.

The investigators believe that identifying these factors may prove useful for determining genetic susceptibility to WM/LPL.

Mary L. McMaster, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues presented these findings at the AACR Annual Meeting 2015 (abstract 3709).

The team used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SSER) database to evaluate the risk of subsequent primary cancer in 3825 patients diagnosed with WM (n=2163) or LPL (n=1662) from 1992 to 2011. The patients’ median age was 70, most of them were male (n=2221), and most were white (n=3153).

Dr McMaster said she and her colleagues looked at both WM and LPL in this study because SEER does not include information about immunoglobulin subtype, which makes it difficult to identify all WM cases with absolute certainty.

“[D]epending on what information a pathologist has when they review a bone marrow biopsy, for example, they may or may not know whether there’s IgM present,” Dr McMaster said. “So you may have a diagnosis of LPL and not have the information required to make the diagnosis of WM. For that reason, we combined both entities for this study.”

Dr McMaster and her colleagues calculated the observed-to-expected standardized incidence ratios (SIRs) for invasive cancers. After adjusting for multiple comparisons, the team found that survivors of WM/LPL had a significantly increased risk of developing a second primary malignancy (SIR=1.49).

This increased risk was seen for males and females and persisted throughout follow-up. The risk was higher for patients younger than 65 years of age (SIR=1.95).

Hematologic malignancies

WM/LPL survivors had a significantly increased risk of several hematologic malignancies. The SIR was 4.09 for all hematologic malignancies, 4.29 for lymphomas, and 3.16 for leukemias.

Dr McMaster pointed out that several lymphoma subtypes can have lymphoplasmacytic differentiation, the most common being marginal zone lymphoma. And this could potentially result in misclassification.

“So we actually ran the study with and without marginal zone lymphoma and saw no difference in the results,” she said. “So we don’t think misclassification accounts for the majority of what we’re seeing.”

The investigators found that WM/LPL survivors had the highest risk of developing Burkitt lymphoma (SIR=13.45), followed by Hodgkin lymphoma (SIR=9.80), T-cell non-Hodgkin lymphoma (SIR=6.62), mantle cell lymphoma (SIR=5.37), diffuse large B-cell lymphoma (DLBCL, SIR=4.76), multiple myeloma (SIR=4.40), any non-Hodgkin lymphoma (SIR=4.08), and acute myeloid leukemia (AML, SIR=3.27).

“Waldenström’s is known to transform, on occasion, to DLBCL,” Dr McMaster said. “So that may well account for the excess of DLBCL that we see in this population.”

She also noted that, prior to the early 2000s, WM was typically treated with alkylating agents. And alkylating agents have been linked to an increased risk of AML.

In this population, the risk of AML peaked 5 to 10 years after WM/LPL diagnosis and was only present in patients treated prior to 2002. This suggests the AML observed in this study was likely treatment-related.

Dr McMaster and her colleagues also found that WM/LPL survivors did not have a significantly increased risk of developing acute lymphocytic leukemia (SIR=0), hairy cell leukemia (SIR=0), chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR=0.97), or follicular lymphoma (SIR=2.25).

Solid tumors

WM/LPL survivors did have a significantly increased risk of certain solid tumor malignancies. The overall SIR for solid tumors was 1.21.

The risk was significant for non-epithelial skin cancers (SIR=5.15), thyroid cancers (SIR=3.13), melanoma (SIR=1.72), and cancers of the lung and bronchus (SIR=1.44) or respiratory system (SIR=1.42).

“Melanoma has an immunological basis, as does Waldenström’s, so we think there may be some shared etiology there,” Dr McMaster said.

She also noted that a strong risk factor for thyroid cancer, particularly papillary thyroid cancer, is a history of autoimmune thyroid disease.

“Autoimmune disease of any sort is a risk factor for Waldenström’s macroglobulinemia,” she said. “So again, we think there might be a basis for shared susceptibility there.”

Dr McMaster said this research suggests that multiple primary cancers may occur in a single individual because of shared genetic susceptibility, shared environmental exposures, treatment effects, or chance. She believes future research will show that both genetic and environmental factors contribute to WM.

Investigators are currently conducting whole-exome sequencing studies and genome-wide association studies in patients with familial and spontaneous WM, with the hopes of identifying genes that contribute to WM susceptibility.

 

 

AACR Annual Meeting 2015

 

PHILADELPHIA—A retrospective study has revealed factors that appear to influence a person’s susceptibility to Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and other malignancies.

Study investigators looked at patients diagnosed with WM or LPL over a 20-year period and found about a 50% excess of second primary cancers in this population.

The patients had a significantly increased risk of multiple hematologic and solid tumor malignancies, and a few of these malignancies had shared susceptibility factors with WM/LPL.

The investigators believe that identifying these factors may prove useful for determining genetic susceptibility to WM/LPL.

Mary L. McMaster, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues presented these findings at the AACR Annual Meeting 2015 (abstract 3709).

The team used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SSER) database to evaluate the risk of subsequent primary cancer in 3825 patients diagnosed with WM (n=2163) or LPL (n=1662) from 1992 to 2011. The patients’ median age was 70, most of them were male (n=2221), and most were white (n=3153).

Dr McMaster said she and her colleagues looked at both WM and LPL in this study because SEER does not include information about immunoglobulin subtype, which makes it difficult to identify all WM cases with absolute certainty.

“[D]epending on what information a pathologist has when they review a bone marrow biopsy, for example, they may or may not know whether there’s IgM present,” Dr McMaster said. “So you may have a diagnosis of LPL and not have the information required to make the diagnosis of WM. For that reason, we combined both entities for this study.”

Dr McMaster and her colleagues calculated the observed-to-expected standardized incidence ratios (SIRs) for invasive cancers. After adjusting for multiple comparisons, the team found that survivors of WM/LPL had a significantly increased risk of developing a second primary malignancy (SIR=1.49).

This increased risk was seen for males and females and persisted throughout follow-up. The risk was higher for patients younger than 65 years of age (SIR=1.95).

Hematologic malignancies

WM/LPL survivors had a significantly increased risk of several hematologic malignancies. The SIR was 4.09 for all hematologic malignancies, 4.29 for lymphomas, and 3.16 for leukemias.

Dr McMaster pointed out that several lymphoma subtypes can have lymphoplasmacytic differentiation, the most common being marginal zone lymphoma. And this could potentially result in misclassification.

“So we actually ran the study with and without marginal zone lymphoma and saw no difference in the results,” she said. “So we don’t think misclassification accounts for the majority of what we’re seeing.”

The investigators found that WM/LPL survivors had the highest risk of developing Burkitt lymphoma (SIR=13.45), followed by Hodgkin lymphoma (SIR=9.80), T-cell non-Hodgkin lymphoma (SIR=6.62), mantle cell lymphoma (SIR=5.37), diffuse large B-cell lymphoma (DLBCL, SIR=4.76), multiple myeloma (SIR=4.40), any non-Hodgkin lymphoma (SIR=4.08), and acute myeloid leukemia (AML, SIR=3.27).

“Waldenström’s is known to transform, on occasion, to DLBCL,” Dr McMaster said. “So that may well account for the excess of DLBCL that we see in this population.”

She also noted that, prior to the early 2000s, WM was typically treated with alkylating agents. And alkylating agents have been linked to an increased risk of AML.

In this population, the risk of AML peaked 5 to 10 years after WM/LPL diagnosis and was only present in patients treated prior to 2002. This suggests the AML observed in this study was likely treatment-related.

Dr McMaster and her colleagues also found that WM/LPL survivors did not have a significantly increased risk of developing acute lymphocytic leukemia (SIR=0), hairy cell leukemia (SIR=0), chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR=0.97), or follicular lymphoma (SIR=2.25).

Solid tumors

WM/LPL survivors did have a significantly increased risk of certain solid tumor malignancies. The overall SIR for solid tumors was 1.21.

The risk was significant for non-epithelial skin cancers (SIR=5.15), thyroid cancers (SIR=3.13), melanoma (SIR=1.72), and cancers of the lung and bronchus (SIR=1.44) or respiratory system (SIR=1.42).

“Melanoma has an immunological basis, as does Waldenström’s, so we think there may be some shared etiology there,” Dr McMaster said.

She also noted that a strong risk factor for thyroid cancer, particularly papillary thyroid cancer, is a history of autoimmune thyroid disease.

“Autoimmune disease of any sort is a risk factor for Waldenström’s macroglobulinemia,” she said. “So again, we think there might be a basis for shared susceptibility there.”

Dr McMaster said this research suggests that multiple primary cancers may occur in a single individual because of shared genetic susceptibility, shared environmental exposures, treatment effects, or chance. She believes future research will show that both genetic and environmental factors contribute to WM.

Investigators are currently conducting whole-exome sequencing studies and genome-wide association studies in patients with familial and spontaneous WM, with the hopes of identifying genes that contribute to WM susceptibility.

 

 

AACR Annual Meeting 2015

 

PHILADELPHIA—A retrospective study has revealed factors that appear to influence a person’s susceptibility to Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and other malignancies.

Study investigators looked at patients diagnosed with WM or LPL over a 20-year period and found about a 50% excess of second primary cancers in this population.

The patients had a significantly increased risk of multiple hematologic and solid tumor malignancies, and a few of these malignancies had shared susceptibility factors with WM/LPL.

The investigators believe that identifying these factors may prove useful for determining genetic susceptibility to WM/LPL.

Mary L. McMaster, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues presented these findings at the AACR Annual Meeting 2015 (abstract 3709).

The team used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SSER) database to evaluate the risk of subsequent primary cancer in 3825 patients diagnosed with WM (n=2163) or LPL (n=1662) from 1992 to 2011. The patients’ median age was 70, most of them were male (n=2221), and most were white (n=3153).

Dr McMaster said she and her colleagues looked at both WM and LPL in this study because SEER does not include information about immunoglobulin subtype, which makes it difficult to identify all WM cases with absolute certainty.

“[D]epending on what information a pathologist has when they review a bone marrow biopsy, for example, they may or may not know whether there’s IgM present,” Dr McMaster said. “So you may have a diagnosis of LPL and not have the information required to make the diagnosis of WM. For that reason, we combined both entities for this study.”

Dr McMaster and her colleagues calculated the observed-to-expected standardized incidence ratios (SIRs) for invasive cancers. After adjusting for multiple comparisons, the team found that survivors of WM/LPL had a significantly increased risk of developing a second primary malignancy (SIR=1.49).

This increased risk was seen for males and females and persisted throughout follow-up. The risk was higher for patients younger than 65 years of age (SIR=1.95).

Hematologic malignancies

WM/LPL survivors had a significantly increased risk of several hematologic malignancies. The SIR was 4.09 for all hematologic malignancies, 4.29 for lymphomas, and 3.16 for leukemias.

Dr McMaster pointed out that several lymphoma subtypes can have lymphoplasmacytic differentiation, the most common being marginal zone lymphoma. And this could potentially result in misclassification.

“So we actually ran the study with and without marginal zone lymphoma and saw no difference in the results,” she said. “So we don’t think misclassification accounts for the majority of what we’re seeing.”

The investigators found that WM/LPL survivors had the highest risk of developing Burkitt lymphoma (SIR=13.45), followed by Hodgkin lymphoma (SIR=9.80), T-cell non-Hodgkin lymphoma (SIR=6.62), mantle cell lymphoma (SIR=5.37), diffuse large B-cell lymphoma (DLBCL, SIR=4.76), multiple myeloma (SIR=4.40), any non-Hodgkin lymphoma (SIR=4.08), and acute myeloid leukemia (AML, SIR=3.27).

“Waldenström’s is known to transform, on occasion, to DLBCL,” Dr McMaster said. “So that may well account for the excess of DLBCL that we see in this population.”

She also noted that, prior to the early 2000s, WM was typically treated with alkylating agents. And alkylating agents have been linked to an increased risk of AML.

In this population, the risk of AML peaked 5 to 10 years after WM/LPL diagnosis and was only present in patients treated prior to 2002. This suggests the AML observed in this study was likely treatment-related.

Dr McMaster and her colleagues also found that WM/LPL survivors did not have a significantly increased risk of developing acute lymphocytic leukemia (SIR=0), hairy cell leukemia (SIR=0), chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR=0.97), or follicular lymphoma (SIR=2.25).

Solid tumors

WM/LPL survivors did have a significantly increased risk of certain solid tumor malignancies. The overall SIR for solid tumors was 1.21.

The risk was significant for non-epithelial skin cancers (SIR=5.15), thyroid cancers (SIR=3.13), melanoma (SIR=1.72), and cancers of the lung and bronchus (SIR=1.44) or respiratory system (SIR=1.42).

“Melanoma has an immunological basis, as does Waldenström’s, so we think there may be some shared etiology there,” Dr McMaster said.

She also noted that a strong risk factor for thyroid cancer, particularly papillary thyroid cancer, is a history of autoimmune thyroid disease.

“Autoimmune disease of any sort is a risk factor for Waldenström’s macroglobulinemia,” she said. “So again, we think there might be a basis for shared susceptibility there.”

Dr McMaster said this research suggests that multiple primary cancers may occur in a single individual because of shared genetic susceptibility, shared environmental exposures, treatment effects, or chance. She believes future research will show that both genetic and environmental factors contribute to WM.

Investigators are currently conducting whole-exome sequencing studies and genome-wide association studies in patients with familial and spontaneous WM, with the hopes of identifying genes that contribute to WM susceptibility.

Inside the Pennsylvania

Convention Center, site of the

AACR Annual Meeting 2015

PHILADELPHIA—When current treatment approaches failed to save a young patient with non-Hodgkin lymphoma (NHL), a researcher from The Children’s Hospital of Philadelphia was driven to investigate new therapeutic options.

The investigation led the researcher, Mala Talekar, MBBS, to ONC201 (formerly TIC10), a small molecule that induces apoptosis by increasing surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Preclinical experiments showed that ONC201 is active against NHL as a single agent, and it synergizes with chemotherapeutic drugs that are already used to treat NHL.

Dr Talekar and her colleagues described these experiments in a poster presented at the AACR Annual Meeting 2015 (abstract 5387). Some of the investigators involved in this research are employed by Oncoceutics, Inc., the company developing ONC201.

A researcher’s inspiration

“When I was doing my fellowship training, I had a teenage boy who had a rare form of non-Hodgkin’s lymphoma,” Dr Talekar explained. “He did not survive, despite receiving multiple treatments that are available for pediatric non-Hodgkin’s lymphoma.”

The boy’s death inspired Dr Talekar to seek new and better approaches to treat NHL. A search of the medical literature unearthed several articles detailing a TRAIL-based approach to treating lymphoma. So she decided to further investigate the effects of TRAIL in NHL.

“I first tried TRAIL in one lymphoma cell line,” she said. “And even though it did kill the cancer cells, it did not really give a satisfactory response.”

So Dr Talekar turned to the TRAIL agonist antibodies lexatumumab and mapatumumab, introducing each of them to human lymphoma cells. Although the antibodies caused more cell death than TRAIL itself, the response was still not satisfactory, she said.

“Fortunately for me, while I was working in the lab, one of the postdocs, Joshua Allen, discovered a new molecule called TRAIL-inducing compound 10, or TIC10,” Dr Talekar said. “So I tried TIC10—it is now called ONC201—and it gave a beautiful dose-response curve, causing complete cell death of the lymphoma cells.”

Dr Talekar was “very inspired” by this result and decided to test ONC201 in 8 different NHL cell lines—4 Burkitt lymphoma (Daudi, Raji, Ramos, and BJAB), 1 anaplastic large-cell lymphoma (Karpas299), and 3 mantle cell lymphoma (UPN2, Granta, and NCEB) cell lines.

“I found a beautiful dose-response curve,” Dr Talekar said, “suggesting that this molecule works in micromolar concentrations across all of the lymphoma cell lines.”

Elucidating the mechanism

Dr Talekar then set out to determine exactly how ONC201 causes cell death in NHL. Flow cytometry revealed that, as the dose of ONC201 increases, cell death increases, as does sub-G1 DNA content. This suggests the drug is causing cell death by apoptosis.

Next, Dr Talekar introduced ONC201 to NHL cell lines along with a pan-caspase inhibitor. She found the inhibitor blocked ONC201-induced apoptosis, which suggests ONC201 works via the caspase-mediated apoptotic pathway.

“The initial mechanism of action proposed for ONC201 was dual inactivation of two kinases, Akt and ERK,” Dr Talekar noted. “The dual inactivation causes dephosphorylation of Foxo3a. This causes its translocation to the nucleus and downstream upregulation of TRAIL, and, therefore, increased surface TRAIL expression. And we know increases in surface TRAIL cause cell death by apoptosis.”

With this in mind, Dr Talekar looked for increases in surface TRIAL after she incubated lymphoma cells with ONC201. She observed a dose-dependent increase in surface TRAIL and a linear correlation between the increase in TRAIL and apoptosis.

Then, she introduced ONC201 and a TRAIL-sequestering antibody, RIK-2, to lymphoma cells. RIK-2 inhibited apoptosis, which suggests ONC201 works as an anti-apoptotic agent via the TRAIL pathway.

Further testing

As a final step, Dr Talekar tested ONC201 in combination with chemotherapy drugs that are already used to treat pediatric NHL. She observed at least an additive effect, and sometimes a synergistic effect, between the drugs. The best responses occurred when she combined ONC201 with cytarabine, bortezomib, or doxorubicin.

Now, Dr Talekar is working on testing ONC201 in combination with cytarabine in a xenograft model of Burkitt lymphoma.

She noted that other in vivo research has suggested ONC201 has a “very benign safety profile.” In another poster presented at AACR 2015 (abstract 4479), researchers reported results indicating that ONC201 is safe.

“They have tested it in mice and dogs and found that, at 10-fold the therapeutic dose, you don’t see much toxicity at all,” Dr Talekar said.

ONC201 is also being tested in a phase 1 study of adults with advanced solid tumors. Phase 1 studies of the drug in relapsed or refractory NHL and relapsed or refractory acute leukemias and high-risk myelodysplastic syndromes are not yet recruiting patients.

Inside the Pennsylvania

Convention Center, site of the

AACR Annual Meeting 2015

PHILADELPHIA—When current treatment approaches failed to save a young patient with non-Hodgkin lymphoma (NHL), a researcher from The Children’s Hospital of Philadelphia was driven to investigate new therapeutic options.

The investigation led the researcher, Mala Talekar, MBBS, to ONC201 (formerly TIC10), a small molecule that induces apoptosis by increasing surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Preclinical experiments showed that ONC201 is active against NHL as a single agent, and it synergizes with chemotherapeutic drugs that are already used to treat NHL.

Dr Talekar and her colleagues described these experiments in a poster presented at the AACR Annual Meeting 2015 (abstract 5387). Some of the investigators involved in this research are employed by Oncoceutics, Inc., the company developing ONC201.

A researcher’s inspiration

“When I was doing my fellowship training, I had a teenage boy who had a rare form of non-Hodgkin’s lymphoma,” Dr Talekar explained. “He did not survive, despite receiving multiple treatments that are available for pediatric non-Hodgkin’s lymphoma.”

The boy’s death inspired Dr Talekar to seek new and better approaches to treat NHL. A search of the medical literature unearthed several articles detailing a TRAIL-based approach to treating lymphoma. So she decided to further investigate the effects of TRAIL in NHL.

“I first tried TRAIL in one lymphoma cell line,” she said. “And even though it did kill the cancer cells, it did not really give a satisfactory response.”

So Dr Talekar turned to the TRAIL agonist antibodies lexatumumab and mapatumumab, introducing each of them to human lymphoma cells. Although the antibodies caused more cell death than TRAIL itself, the response was still not satisfactory, she said.

“Fortunately for me, while I was working in the lab, one of the postdocs, Joshua Allen, discovered a new molecule called TRAIL-inducing compound 10, or TIC10,” Dr Talekar said. “So I tried TIC10—it is now called ONC201—and it gave a beautiful dose-response curve, causing complete cell death of the lymphoma cells.”

Dr Talekar was “very inspired” by this result and decided to test ONC201 in 8 different NHL cell lines—4 Burkitt lymphoma (Daudi, Raji, Ramos, and BJAB), 1 anaplastic large-cell lymphoma (Karpas299), and 3 mantle cell lymphoma (UPN2, Granta, and NCEB) cell lines.

“I found a beautiful dose-response curve,” Dr Talekar said, “suggesting that this molecule works in micromolar concentrations across all of the lymphoma cell lines.”

Elucidating the mechanism

Dr Talekar then set out to determine exactly how ONC201 causes cell death in NHL. Flow cytometry revealed that, as the dose of ONC201 increases, cell death increases, as does sub-G1 DNA content. This suggests the drug is causing cell death by apoptosis.

Next, Dr Talekar introduced ONC201 to NHL cell lines along with a pan-caspase inhibitor. She found the inhibitor blocked ONC201-induced apoptosis, which suggests ONC201 works via the caspase-mediated apoptotic pathway.

“The initial mechanism of action proposed for ONC201 was dual inactivation of two kinases, Akt and ERK,” Dr Talekar noted. “The dual inactivation causes dephosphorylation of Foxo3a. This causes its translocation to the nucleus and downstream upregulation of TRAIL, and, therefore, increased surface TRAIL expression. And we know increases in surface TRAIL cause cell death by apoptosis.”

With this in mind, Dr Talekar looked for increases in surface TRIAL after she incubated lymphoma cells with ONC201. She observed a dose-dependent increase in surface TRAIL and a linear correlation between the increase in TRAIL and apoptosis.

Then, she introduced ONC201 and a TRAIL-sequestering antibody, RIK-2, to lymphoma cells. RIK-2 inhibited apoptosis, which suggests ONC201 works as an anti-apoptotic agent via the TRAIL pathway.

Further testing

As a final step, Dr Talekar tested ONC201 in combination with chemotherapy drugs that are already used to treat pediatric NHL. She observed at least an additive effect, and sometimes a synergistic effect, between the drugs. The best responses occurred when she combined ONC201 with cytarabine, bortezomib, or doxorubicin.

Now, Dr Talekar is working on testing ONC201 in combination with cytarabine in a xenograft model of Burkitt lymphoma.

She noted that other in vivo research has suggested ONC201 has a “very benign safety profile.” In another poster presented at AACR 2015 (abstract 4479), researchers reported results indicating that ONC201 is safe.

“They have tested it in mice and dogs and found that, at 10-fold the therapeutic dose, you don’t see much toxicity at all,” Dr Talekar said.

ONC201 is also being tested in a phase 1 study of adults with advanced solid tumors. Phase 1 studies of the drug in relapsed or refractory NHL and relapsed or refractory acute leukemias and high-risk myelodysplastic syndromes are not yet recruiting patients.

Inside the Pennsylvania

Convention Center, site of the

AACR Annual Meeting 2015

PHILADELPHIA—When current treatment approaches failed to save a young patient with non-Hodgkin lymphoma (NHL), a researcher from The Children’s Hospital of Philadelphia was driven to investigate new therapeutic options.

The investigation led the researcher, Mala Talekar, MBBS, to ONC201 (formerly TIC10), a small molecule that induces apoptosis by increasing surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Preclinical experiments showed that ONC201 is active against NHL as a single agent, and it synergizes with chemotherapeutic drugs that are already used to treat NHL.

Dr Talekar and her colleagues described these experiments in a poster presented at the AACR Annual Meeting 2015 (abstract 5387). Some of the investigators involved in this research are employed by Oncoceutics, Inc., the company developing ONC201.

A researcher’s inspiration

“When I was doing my fellowship training, I had a teenage boy who had a rare form of non-Hodgkin’s lymphoma,” Dr Talekar explained. “He did not survive, despite receiving multiple treatments that are available for pediatric non-Hodgkin’s lymphoma.”

The boy’s death inspired Dr Talekar to seek new and better approaches to treat NHL. A search of the medical literature unearthed several articles detailing a TRAIL-based approach to treating lymphoma. So she decided to further investigate the effects of TRAIL in NHL.

“I first tried TRAIL in one lymphoma cell line,” she said. “And even though it did kill the cancer cells, it did not really give a satisfactory response.”

So Dr Talekar turned to the TRAIL agonist antibodies lexatumumab and mapatumumab, introducing each of them to human lymphoma cells. Although the antibodies caused more cell death than TRAIL itself, the response was still not satisfactory, she said.

“Fortunately for me, while I was working in the lab, one of the postdocs, Joshua Allen, discovered a new molecule called TRAIL-inducing compound 10, or TIC10,” Dr Talekar said. “So I tried TIC10—it is now called ONC201—and it gave a beautiful dose-response curve, causing complete cell death of the lymphoma cells.”

Dr Talekar was “very inspired” by this result and decided to test ONC201 in 8 different NHL cell lines—4 Burkitt lymphoma (Daudi, Raji, Ramos, and BJAB), 1 anaplastic large-cell lymphoma (Karpas299), and 3 mantle cell lymphoma (UPN2, Granta, and NCEB) cell lines.

“I found a beautiful dose-response curve,” Dr Talekar said, “suggesting that this molecule works in micromolar concentrations across all of the lymphoma cell lines.”

Elucidating the mechanism

Dr Talekar then set out to determine exactly how ONC201 causes cell death in NHL. Flow cytometry revealed that, as the dose of ONC201 increases, cell death increases, as does sub-G1 DNA content. This suggests the drug is causing cell death by apoptosis.

Next, Dr Talekar introduced ONC201 to NHL cell lines along with a pan-caspase inhibitor. She found the inhibitor blocked ONC201-induced apoptosis, which suggests ONC201 works via the caspase-mediated apoptotic pathway.

“The initial mechanism of action proposed for ONC201 was dual inactivation of two kinases, Akt and ERK,” Dr Talekar noted. “The dual inactivation causes dephosphorylation of Foxo3a. This causes its translocation to the nucleus and downstream upregulation of TRAIL, and, therefore, increased surface TRAIL expression. And we know increases in surface TRAIL cause cell death by apoptosis.”

With this in mind, Dr Talekar looked for increases in surface TRIAL after she incubated lymphoma cells with ONC201. She observed a dose-dependent increase in surface TRAIL and a linear correlation between the increase in TRAIL and apoptosis.

Then, she introduced ONC201 and a TRAIL-sequestering antibody, RIK-2, to lymphoma cells. RIK-2 inhibited apoptosis, which suggests ONC201 works as an anti-apoptotic agent via the TRAIL pathway.

Further testing

As a final step, Dr Talekar tested ONC201 in combination with chemotherapy drugs that are already used to treat pediatric NHL. She observed at least an additive effect, and sometimes a synergistic effect, between the drugs. The best responses occurred when she combined ONC201 with cytarabine, bortezomib, or doxorubicin.

Now, Dr Talekar is working on testing ONC201 in combination with cytarabine in a xenograft model of Burkitt lymphoma.

She noted that other in vivo research has suggested ONC201 has a “very benign safety profile.” In another poster presented at AACR 2015 (abstract 4479), researchers reported results indicating that ONC201 is safe.

“They have tested it in mice and dogs and found that, at 10-fold the therapeutic dose, you don’t see much toxicity at all,” Dr Talekar said.

ONC201 is also being tested in a phase 1 study of adults with advanced solid tumors. Phase 1 studies of the drug in relapsed or refractory NHL and relapsed or refractory acute leukemias and high-risk myelodysplastic syndromes are not yet recruiting patients.

Patient receives chemotherapy

Photo by Rhoda Baer

Survivors of Hodgkin lymphoma (HL) have an increased risk of developing cardiovascular diseases throughout their lives, according to a study published in JAMA Internal Medicine.

Previous research suggested that HL treatment is associated with an increased risk of cardiovascular diseases.

However, those studies did not determine how long the increased risk persists or pinpoint the risk factors for various cardiovascular diseases.

So Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, and her colleagues decided to investigate.

The team examined the risk for cardiovascular disease in HL survivors up to 40 years after they received treatment and compared that with the risk for cardiovascular disease in the general population. The researchers also studied treatment-related risk factors.

The study included 2524 Dutch patients who were diagnosed with HL when they were younger than 51 years of age. The patients’ median age was 27.3 years.

The patients were treated from 1965 through 1995 and had survived for at least 5 years after diagnosis. In all, 2052 patients (81.3%) had received mediastinal radiotherapy, and 773 (30.6%) had received chemotherapy containing an anthracycline.

At a median of 20.3 years of follow-up, there were 1713 cardiovascular events in 797 patients (31.6%), and 410 of those patients (51.4%) had experienced 2 events or more.

The most frequently occurring cardiovascular disease was coronary heart disease (CHD), with 401 patients developing it as their first event. This was followed by valvular heart disease (VHD, 374 events) and heart failure (HF, 140 events).

HL survivors had a 3.2-fold increased risk of developing CHD and a 6.8-fold increased risk of developing HF compared to the general population.

HL survivors who had been treated before age 25 had a 4.6-fold to 7.5-fold increased risk of CHD and a 10.9-fold to 40.5-fold increased risk of HF, depending on the age they ultimately attained.

HL survivors treated at 35 to 50 years of age had a 2.0-fold to 2.3-fold increased risk of CHD and a 3.1-fold to 5.2-fold increased risk of HF, depending on their attained age.

The risks of CHD and HF remained significantly increased beyond 35 years after HL treatment. The standardized incidence ratios were 3.9 and 5.8, respectively.

The median times between HL treatment and first cardiovascular disease events were 18 years for CHD, 24 years for VHD, and 19 years for HF.

The cumulative risk of any type of cardiovascular disease was 50% at 40 years after HL diagnosis. For patients who were treated for HL before they were 25, the cumulative risk of developing a cardiovascular disease at 60 years of age or older was 20% for CHD, 31% for VHD, and 11% for HF.

The study also suggested that mediastinal radiotherapy increased the risk of CHD, VHD, and HF. But anthracycline-containing chemotherapy only increased the risk of VHD and HF.

Dr van Leeuwen and her colleagues concluded that both physicians and patients should be aware that HL survivors have a persistently increased risk of developing cardiovascular diseases throughout their lives. The team also believes the results of their study may direct guidelines for follow-up in HL survivors.

A commentary related to this research is available in JAMA Internal Medicine as well.

Patient receives chemotherapy

Photo by Rhoda Baer

Survivors of Hodgkin lymphoma (HL) have an increased risk of developing cardiovascular diseases throughout their lives, according to a study published in JAMA Internal Medicine.

Previous research suggested that HL treatment is associated with an increased risk of cardiovascular diseases.

However, those studies did not determine how long the increased risk persists or pinpoint the risk factors for various cardiovascular diseases.

So Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, and her colleagues decided to investigate.

The team examined the risk for cardiovascular disease in HL survivors up to 40 years after they received treatment and compared that with the risk for cardiovascular disease in the general population. The researchers also studied treatment-related risk factors.

The study included 2524 Dutch patients who were diagnosed with HL when they were younger than 51 years of age. The patients’ median age was 27.3 years.

The patients were treated from 1965 through 1995 and had survived for at least 5 years after diagnosis. In all, 2052 patients (81.3%) had received mediastinal radiotherapy, and 773 (30.6%) had received chemotherapy containing an anthracycline.

At a median of 20.3 years of follow-up, there were 1713 cardiovascular events in 797 patients (31.6%), and 410 of those patients (51.4%) had experienced 2 events or more.

The most frequently occurring cardiovascular disease was coronary heart disease (CHD), with 401 patients developing it as their first event. This was followed by valvular heart disease (VHD, 374 events) and heart failure (HF, 140 events).

HL survivors had a 3.2-fold increased risk of developing CHD and a 6.8-fold increased risk of developing HF compared to the general population.

HL survivors who had been treated before age 25 had a 4.6-fold to 7.5-fold increased risk of CHD and a 10.9-fold to 40.5-fold increased risk of HF, depending on the age they ultimately attained.

HL survivors treated at 35 to 50 years of age had a 2.0-fold to 2.3-fold increased risk of CHD and a 3.1-fold to 5.2-fold increased risk of HF, depending on their attained age.

The risks of CHD and HF remained significantly increased beyond 35 years after HL treatment. The standardized incidence ratios were 3.9 and 5.8, respectively.

The median times between HL treatment and first cardiovascular disease events were 18 years for CHD, 24 years for VHD, and 19 years for HF.

The cumulative risk of any type of cardiovascular disease was 50% at 40 years after HL diagnosis. For patients who were treated for HL before they were 25, the cumulative risk of developing a cardiovascular disease at 60 years of age or older was 20% for CHD, 31% for VHD, and 11% for HF.

The study also suggested that mediastinal radiotherapy increased the risk of CHD, VHD, and HF. But anthracycline-containing chemotherapy only increased the risk of VHD and HF.

Dr van Leeuwen and her colleagues concluded that both physicians and patients should be aware that HL survivors have a persistently increased risk of developing cardiovascular diseases throughout their lives. The team also believes the results of their study may direct guidelines for follow-up in HL survivors.

A commentary related to this research is available in JAMA Internal Medicine as well.

Patient receives chemotherapy

Photo by Rhoda Baer

Survivors of Hodgkin lymphoma (HL) have an increased risk of developing cardiovascular diseases throughout their lives, according to a study published in JAMA Internal Medicine.

Previous research suggested that HL treatment is associated with an increased risk of cardiovascular diseases.

However, those studies did not determine how long the increased risk persists or pinpoint the risk factors for various cardiovascular diseases.

So Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, and her colleagues decided to investigate.

The team examined the risk for cardiovascular disease in HL survivors up to 40 years after they received treatment and compared that with the risk for cardiovascular disease in the general population. The researchers also studied treatment-related risk factors.

The study included 2524 Dutch patients who were diagnosed with HL when they were younger than 51 years of age. The patients’ median age was 27.3 years.

The patients were treated from 1965 through 1995 and had survived for at least 5 years after diagnosis. In all, 2052 patients (81.3%) had received mediastinal radiotherapy, and 773 (30.6%) had received chemotherapy containing an anthracycline.

At a median of 20.3 years of follow-up, there were 1713 cardiovascular events in 797 patients (31.6%), and 410 of those patients (51.4%) had experienced 2 events or more.

The most frequently occurring cardiovascular disease was coronary heart disease (CHD), with 401 patients developing it as their first event. This was followed by valvular heart disease (VHD, 374 events) and heart failure (HF, 140 events).

HL survivors had a 3.2-fold increased risk of developing CHD and a 6.8-fold increased risk of developing HF compared to the general population.

HL survivors who had been treated before age 25 had a 4.6-fold to 7.5-fold increased risk of CHD and a 10.9-fold to 40.5-fold increased risk of HF, depending on the age they ultimately attained.

HL survivors treated at 35 to 50 years of age had a 2.0-fold to 2.3-fold increased risk of CHD and a 3.1-fold to 5.2-fold increased risk of HF, depending on their attained age.

The risks of CHD and HF remained significantly increased beyond 35 years after HL treatment. The standardized incidence ratios were 3.9 and 5.8, respectively.

The median times between HL treatment and first cardiovascular disease events were 18 years for CHD, 24 years for VHD, and 19 years for HF.

The cumulative risk of any type of cardiovascular disease was 50% at 40 years after HL diagnosis. For patients who were treated for HL before they were 25, the cumulative risk of developing a cardiovascular disease at 60 years of age or older was 20% for CHD, 31% for VHD, and 11% for HF.

The study also suggested that mediastinal radiotherapy increased the risk of CHD, VHD, and HF. But anthracycline-containing chemotherapy only increased the risk of VHD and HF.

Dr van Leeuwen and her colleagues concluded that both physicians and patients should be aware that HL survivors have a persistently increased risk of developing cardiovascular diseases throughout their lives. The team also believes the results of their study may direct guidelines for follow-up in HL survivors.

A commentary related to this research is available in JAMA Internal Medicine as well.

Vials of chemotherapy drugs

Photo by Bill Branson

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or customer.service@mylan.com, Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Vials of chemotherapy drugs

Photo by Bill Branson

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or customer.service@mylan.com, Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Vials of chemotherapy drugs

Photo by Bill Branson

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or customer.service@mylan.com, Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Researcher in the lab

Photo courtesy of NIH

MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in

Leukemia Research.

Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.

However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.

“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.

Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.

Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).

The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.

They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.

And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.

The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.

Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.

The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.

The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).

Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.

Researcher in the lab

Photo courtesy of NIH

MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in

Leukemia Research.

Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.

However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.

“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.

Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.

Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).

The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.

They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.

And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.

The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.

Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.

The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.

The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).

Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.

Researcher in the lab

Photo courtesy of NIH

MicroRNA (miR) expression may help us predict long-term prognosis in diffuse large B-cell lymphoma (DLBCL), according to a study published in

Leukemia Research.

Investigators identified 8 miRs that were differently expressed in DLBCL patients with poor prognosis and patients with favorable prognosis.

However, many of the miRs that have been linked to DLBCL prognosis in previous studies were not associated with prognosis in this study.

“Our data are in agreement with previous findings showing that miR signature is predictive of prognosis for patients with DLBCL, although with different miRs achieving statistical significance,” said study author Meir Lahav, MD, of Tel Aviv University in Israel.

Dr Lahav and his colleagues analyzed miR signatures from tissue biopsies taken from 83 patients with DLBCL who were treated between 1995 and 2003.

Patients who relapsed within 9 months from the start of treatment were defined as poor prognosis (n=43), and patients with disease-free survival of at least 5 years were defined as good prognosis (n=40).

The investigators analyzed RNA using microarrays developed by Rosetta Genomics. To validate the microarray results, the team used quantitative real-time polymerase chain reaction (qRT-PCR) and an independent set of 13 samples.

They found that 4 miRs were upregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-17-5p, hsa-miR-19b-3p, hsa-miR-20a-5p, and hsa-miR-106a-5p.

And 4 miRs were downregulated in the poor-prognosis group compared to the good-prognosis group: hsa-miR-150-5p, hsa-miR-342-3p, hsa-miR-181a-5p, and hsa-miR-140-3p.

The investigators said the strongest and most consistent correlation was for miR-342-3p and miR-150-5p, which discriminated between the 2 prognostic groups in the microarray analysis, qRT-PCR, and the independent validation set.

Several miRs that were found to have prognostic value in previous studies did not differentiate the prognostic groups in this study. These were miR-155-5p, miR-21-5p, miR-18a-5p, miR-221-3p, and miR-222-3p. However, one miR—miR-181a-5p—had prognostic value in a previous study and the current study.

The investigators said the differences in miRs might be explained by the fact that this study had a larger sample size and longer follow-up than previous studies.

The differences might also reflect prognostic changes with rituximab treatment, as the patients in this study did not receive rituximab (only CHOP).

Either way, the investigators said these results suggest that analyzing miR expression can potentially improve our ability to predict prognosis in DLBCL and may therefore have a significant clinical impact.

Targeting a tumor with CIVO

Image courtesy of

Presage Biosciences

A device that tests multiple cancer drugs in living tumor tissue could guide treatment selection in patients with lymphoma and other cancers, according to researchers.

They also believe the device, called CIVO, could help speed up drug development by testing the efficacy of candidate drugs in very small doses while sparing patients side effects.

CIVO is a handheld microinjection platform that can deliver small doses of up to 8 drugs or combinations of drugs into a tumor.

The device proved effective for testing multiple cancer drugs in xenograft mouse models, dogs, and humans with lymphoma.

Richard Klinghoffer, PhD, of Presage Biosciences in Seattle, Washington, and his colleagues described their research with CIVO in Science Translational Medicine. The research was funded by Presage Biosciences, the National Institutes of Health, and Seattle Children’s Hospital Neuro-Oncology Fund.

About CIVO

CIVO is designed for tumors near the skin surface, such as lymphoma or skin and breast cancer.

The technology enables the placement of multiple columns of drugs directly into the tumor along the needle axis, spanning the full depth of the tumor. This makes it possible to assess drug effects with multiple biomarkers and in multiple regions along the injection axis to capture the heterogeneity of response within the tumor.

Later (typically 24 to 72 hours after injection), the tumor is resected for subsequent analysis, and responses are measured with multiple immunohistochemistry-based assays and high-resolution scanning.

Results in mice

In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of each drug. And the observed localized responses predicted responses to the same drugs systemically delivered in animals.

In pair-matched drug-resistant and drug-sensitive lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine.

The researchers also identified an unexpected enhanced sensitivity to the active form of cyclophosphamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas.

And a CIVO-enabled in vivo screen of oncology agents revealed that a novel mTOR pathway inhibitor exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors.

Results in dogs and humans

Dogs with lymphoma showed no toxicity when injected with drugs via CIVO. And the researchers said they observed robust, easily tracked, drug-specific responses in the animals.

For lymphoma patients, the researchers used CIVO to inject microdoses of vincristine into the tumors in patients’ lymph nodes. Cells surrounding the injections died, and there were no serious adverse events, although patients did report mild discomfort.

“This analysis creates a comprehensive portrait of drug response that has never been seen before this early in the drug development process,” Dr Klinghoffer said. “Using this technology, we can assess how drugs, both as single agents and in combinations, impact the biology of tumor cells in the context of the native tumor microenvironment.”

“[T]ranslation of CIVO to the clinical setting has enabled assessment on all aspects of tumor biology, including drug effects on tumor-infiltrating immune cells. This sets the stage for a new type of pre-phase 1 clinical study in which multiple drugs or drug combinations can be tested simultaneously, directly in a patient’s own tumor, without toxicity associated with systemic drug delivery.”

Targeting a tumor with CIVO

Image courtesy of

Presage Biosciences

A device that tests multiple cancer drugs in living tumor tissue could guide treatment selection in patients with lymphoma and other cancers, according to researchers.

They also believe the device, called CIVO, could help speed up drug development by testing the efficacy of candidate drugs in very small doses while sparing patients side effects.

CIVO is a handheld microinjection platform that can deliver small doses of up to 8 drugs or combinations of drugs into a tumor.

The device proved effective for testing multiple cancer drugs in xenograft mouse models, dogs, and humans with lymphoma.

Richard Klinghoffer, PhD, of Presage Biosciences in Seattle, Washington, and his colleagues described their research with CIVO in Science Translational Medicine. The research was funded by Presage Biosciences, the National Institutes of Health, and Seattle Children’s Hospital Neuro-Oncology Fund.

About CIVO

CIVO is designed for tumors near the skin surface, such as lymphoma or skin and breast cancer.

The technology enables the placement of multiple columns of drugs directly into the tumor along the needle axis, spanning the full depth of the tumor. This makes it possible to assess drug effects with multiple biomarkers and in multiple regions along the injection axis to capture the heterogeneity of response within the tumor.

Later (typically 24 to 72 hours after injection), the tumor is resected for subsequent analysis, and responses are measured with multiple immunohistochemistry-based assays and high-resolution scanning.

Results in mice

In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of each drug. And the observed localized responses predicted responses to the same drugs systemically delivered in animals.

In pair-matched drug-resistant and drug-sensitive lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine.

The researchers also identified an unexpected enhanced sensitivity to the active form of cyclophosphamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas.

And a CIVO-enabled in vivo screen of oncology agents revealed that a novel mTOR pathway inhibitor exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors.

Results in dogs and humans

Dogs with lymphoma showed no toxicity when injected with drugs via CIVO. And the researchers said they observed robust, easily tracked, drug-specific responses in the animals.

For lymphoma patients, the researchers used CIVO to inject microdoses of vincristine into the tumors in patients’ lymph nodes. Cells surrounding the injections died, and there were no serious adverse events, although patients did report mild discomfort.

“This analysis creates a comprehensive portrait of drug response that has never been seen before this early in the drug development process,” Dr Klinghoffer said. “Using this technology, we can assess how drugs, both as single agents and in combinations, impact the biology of tumor cells in the context of the native tumor microenvironment.”

“[T]ranslation of CIVO to the clinical setting has enabled assessment on all aspects of tumor biology, including drug effects on tumor-infiltrating immune cells. This sets the stage for a new type of pre-phase 1 clinical study in which multiple drugs or drug combinations can be tested simultaneously, directly in a patient’s own tumor, without toxicity associated with systemic drug delivery.”

Targeting a tumor with CIVO

Image courtesy of

Presage Biosciences

A device that tests multiple cancer drugs in living tumor tissue could guide treatment selection in patients with lymphoma and other cancers, according to researchers.

They also believe the device, called CIVO, could help speed up drug development by testing the efficacy of candidate drugs in very small doses while sparing patients side effects.

CIVO is a handheld microinjection platform that can deliver small doses of up to 8 drugs or combinations of drugs into a tumor.

The device proved effective for testing multiple cancer drugs in xenograft mouse models, dogs, and humans with lymphoma.

Richard Klinghoffer, PhD, of Presage Biosciences in Seattle, Washington, and his colleagues described their research with CIVO in Science Translational Medicine. The research was funded by Presage Biosciences, the National Institutes of Health, and Seattle Children’s Hospital Neuro-Oncology Fund.

About CIVO

CIVO is designed for tumors near the skin surface, such as lymphoma or skin and breast cancer.

The technology enables the placement of multiple columns of drugs directly into the tumor along the needle axis, spanning the full depth of the tumor. This makes it possible to assess drug effects with multiple biomarkers and in multiple regions along the injection axis to capture the heterogeneity of response within the tumor.

Later (typically 24 to 72 hours after injection), the tumor is resected for subsequent analysis, and responses are measured with multiple immunohistochemistry-based assays and high-resolution scanning.

Results in mice

In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of each drug. And the observed localized responses predicted responses to the same drugs systemically delivered in animals.

In pair-matched drug-resistant and drug-sensitive lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine.

The researchers also identified an unexpected enhanced sensitivity to the active form of cyclophosphamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas.

And a CIVO-enabled in vivo screen of oncology agents revealed that a novel mTOR pathway inhibitor exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors.

Results in dogs and humans

Dogs with lymphoma showed no toxicity when injected with drugs via CIVO. And the researchers said they observed robust, easily tracked, drug-specific responses in the animals.

For lymphoma patients, the researchers used CIVO to inject microdoses of vincristine into the tumors in patients’ lymph nodes. Cells surrounding the injections died, and there were no serious adverse events, although patients did report mild discomfort.

“This analysis creates a comprehensive portrait of drug response that has never been seen before this early in the drug development process,” Dr Klinghoffer said. “Using this technology, we can assess how drugs, both as single agents and in combinations, impact the biology of tumor cells in the context of the native tumor microenvironment.”

“[T]ranslation of CIVO to the clinical setting has enabled assessment on all aspects of tumor biology, including drug effects on tumor-infiltrating immune cells. This sets the stage for a new type of pre-phase 1 clinical study in which multiple drugs or drug combinations can be tested simultaneously, directly in a patient’s own tumor, without toxicity associated with systemic drug delivery.”

Anne Kirchoff, PhD

Photo courtesy of

Huntsman Cancer Institute

A new study indicates that childhood cancer survivors (CCSs) are more likely than individuals without a cancer history to enroll on federal programs that provide disability benefits.

CCSs diagnosed between 1970 and 1986 were about 2 to 5 times as likely as control subjects to utilize such a program.

“The long-term impact of cancer can affect other issues besides health outcomes,” said study author Anne Kirchhoff, PhD, of the Huntsman Cancer Institute at the University of Utah.

“We need to do a better job of helping people function throughout their lives, not just when they’re finishing their cancer therapy.”

Dr Kirchhoff and her colleagues conducted this research and detailed the results in the Journal of the National Cancer Institute.

The researchers looked at health insurance surveys completed in 2011 and 2012 by a random sample of 698 CCSs who were diagnosed between the ages of 0 and 20 years. Today, they range in age from 20s to early 60s.

The patients are part of a National Cancer Institute initiative, called the Childhood Cancer Survivor Study, which has followed more than 14,000 children and adolescents since 1994 who were diagnosed with cancer and survived at least 5 years after diagnosis. A comparison group of 210 siblings without cancer also responded to the survey and were used as controls.

Dr Kirchhoff and her colleagues looked at current or former enrollment on 2 federal disability programs:

• Supplemental security income (SSI), which is for people with limited income who have no prior work history
• Social security disability insurance (SSDI), which pays disability benefits to adults ages 18 years and older who have worked and paid social security taxes.

In all, 13.5% of CCSs reported being enrolled on SSI in the past or present, and 10% of survivors reported being enrolled on SSDI at some point. This was substantially higher than for the comparison group, in which 2.6% of patients reported SSI enrollment and 5.4% reported SSDI enrollment.

In addition, CCSs reported current enrollment in SSI more frequently than the US population, at rates of 7.3% and 2.5%, respectively.

Dr Kirchoff and her colleagues also identified survivor socio-demographic and treatment characteristics that were associated with a higher rate of enrollment in federal support programs.

“Survivors that were younger at diagnosis, age 4 or under, were about 7 times more likely to be on SSI than we see with survivors that were diagnosed in their adolescence,” she said.

SSI enrollment was more likely for female CCSs and for survivors with a history of cranial radiation treatment as well.

Dr Kirchhoff noted that, over the years, research on CCSs has caused hospitals to rethink how to better care for cancer survivors.

“There’s really a growing strategy to support survivors in the long-term,” she said. “For example, here at Huntsman Cancer Institute, we have a pediatric cancer late-effects clinic, which helps manage issues that might come up with childhood cancer survivors in the long term, including health-management support, health-behavior support, and access to providers to help them with other issues.”

Anne Kirchoff, PhD

Photo courtesy of

Huntsman Cancer Institute

A new study indicates that childhood cancer survivors (CCSs) are more likely than individuals without a cancer history to enroll on federal programs that provide disability benefits.

CCSs diagnosed between 1970 and 1986 were about 2 to 5 times as likely as control subjects to utilize such a program.

“The long-term impact of cancer can affect other issues besides health outcomes,” said study author Anne Kirchhoff, PhD, of the Huntsman Cancer Institute at the University of Utah.

“We need to do a better job of helping people function throughout their lives, not just when they’re finishing their cancer therapy.”

Dr Kirchhoff and her colleagues conducted this research and detailed the results in the Journal of the National Cancer Institute.

The researchers looked at health insurance surveys completed in 2011 and 2012 by a random sample of 698 CCSs who were diagnosed between the ages of 0 and 20 years. Today, they range in age from 20s to early 60s.

The patients are part of a National Cancer Institute initiative, called the Childhood Cancer Survivor Study, which has followed more than 14,000 children and adolescents since 1994 who were diagnosed with cancer and survived at least 5 years after diagnosis. A comparison group of 210 siblings without cancer also responded to the survey and were used as controls.

Dr Kirchhoff and her colleagues looked at current or former enrollment on 2 federal disability programs:

• Supplemental security income (SSI), which is for people with limited income who have no prior work history
• Social security disability insurance (SSDI), which pays disability benefits to adults ages 18 years and older who have worked and paid social security taxes.

In all, 13.5% of CCSs reported being enrolled on SSI in the past or present, and 10% of survivors reported being enrolled on SSDI at some point. This was substantially higher than for the comparison group, in which 2.6% of patients reported SSI enrollment and 5.4% reported SSDI enrollment.

In addition, CCSs reported current enrollment in SSI more frequently than the US population, at rates of 7.3% and 2.5%, respectively.

Dr Kirchoff and her colleagues also identified survivor socio-demographic and treatment characteristics that were associated with a higher rate of enrollment in federal support programs.

“Survivors that were younger at diagnosis, age 4 or under, were about 7 times more likely to be on SSI than we see with survivors that were diagnosed in their adolescence,” she said.

SSI enrollment was more likely for female CCSs and for survivors with a history of cranial radiation treatment as well.

Dr Kirchhoff noted that, over the years, research on CCSs has caused hospitals to rethink how to better care for cancer survivors.

“There’s really a growing strategy to support survivors in the long-term,” she said. “For example, here at Huntsman Cancer Institute, we have a pediatric cancer late-effects clinic, which helps manage issues that might come up with childhood cancer survivors in the long term, including health-management support, health-behavior support, and access to providers to help them with other issues.”

Anne Kirchoff, PhD

Photo courtesy of

Huntsman Cancer Institute

A new study indicates that childhood cancer survivors (CCSs) are more likely than individuals without a cancer history to enroll on federal programs that provide disability benefits.

CCSs diagnosed between 1970 and 1986 were about 2 to 5 times as likely as control subjects to utilize such a program.

“The long-term impact of cancer can affect other issues besides health outcomes,” said study author Anne Kirchhoff, PhD, of the Huntsman Cancer Institute at the University of Utah.

“We need to do a better job of helping people function throughout their lives, not just when they’re finishing their cancer therapy.”

Dr Kirchhoff and her colleagues conducted this research and detailed the results in the Journal of the National Cancer Institute.

The researchers looked at health insurance surveys completed in 2011 and 2012 by a random sample of 698 CCSs who were diagnosed between the ages of 0 and 20 years. Today, they range in age from 20s to early 60s.

The patients are part of a National Cancer Institute initiative, called the Childhood Cancer Survivor Study, which has followed more than 14,000 children and adolescents since 1994 who were diagnosed with cancer and survived at least 5 years after diagnosis. A comparison group of 210 siblings without cancer also responded to the survey and were used as controls.

Dr Kirchhoff and her colleagues looked at current or former enrollment on 2 federal disability programs:

• Supplemental security income (SSI), which is for people with limited income who have no prior work history
• Social security disability insurance (SSDI), which pays disability benefits to adults ages 18 years and older who have worked and paid social security taxes.

In all, 13.5% of CCSs reported being enrolled on SSI in the past or present, and 10% of survivors reported being enrolled on SSDI at some point. This was substantially higher than for the comparison group, in which 2.6% of patients reported SSI enrollment and 5.4% reported SSDI enrollment.

In addition, CCSs reported current enrollment in SSI more frequently than the US population, at rates of 7.3% and 2.5%, respectively.

Dr Kirchoff and her colleagues also identified survivor socio-demographic and treatment characteristics that were associated with a higher rate of enrollment in federal support programs.

“Survivors that were younger at diagnosis, age 4 or under, were about 7 times more likely to be on SSI than we see with survivors that were diagnosed in their adolescence,” she said.

SSI enrollment was more likely for female CCSs and for survivors with a history of cranial radiation treatment as well.

Dr Kirchhoff noted that, over the years, research on CCSs has caused hospitals to rethink how to better care for cancer survivors.

“There’s really a growing strategy to support survivors in the long-term,” she said. “For example, here at Huntsman Cancer Institute, we have a pediatric cancer late-effects clinic, which helps manage issues that might come up with childhood cancer survivors in the long term, including health-management support, health-behavior support, and access to providers to help them with other issues.”

PET scan of the body

Image by Jens Langner

Performing PET scans immediately after chemotherapy may reveal which Hodgkin lymphoma (HL) patients need radiotherapy (RT).

A study published in NEJM showed similar rates of progression-free survival in HL patients who werePET-negative after chemotherapy, whether they received subsequent RT or not.

However, the investigators said longer follow-up is needed to determine if eliminating RT in PET-negative patients will lead to fewer late effects and improved overall survival.

The 602 patients who agreed to take part in this trial, known as RAPID, had a PET scan performed after chemotherapy. Patients who tested positive received RT.

Those who tested negative were divided into 2 groups. One group of 211 patients received no further treatment, and the other group of 209 patients had the standard RT.

At a median of 60 months of follow-up, the proportion of patients who were alive and disease-free was 94.6% in the RT group and 90.8% in the group that hadn’t received further treatment.

Eight patients in the RT group progressed, and 8 died (3 with disease progression, 1 of whom died from HL). Five of the deaths occurred in patients who did not ultimately receive RT.

In the untreated group, 20 patients progressed, and 4 patients died (2 with disease progression and none from HL).

“This research is an important step forward,” said study author John Radford, of The University of Manchester and The Christie NHS Foundation Trust in the UK.

“The results of RAPID show that, in early stage Hodgkin lymphoma, radiotherapy after initial chemotherapy marginally reduces the recurrence rate, but this is bought at the expense of exposing to radiation all patients with negative PET findings, most of whom are already cured.”

PET scan of the body

Image by Jens Langner

Performing PET scans immediately after chemotherapy may reveal which Hodgkin lymphoma (HL) patients need radiotherapy (RT).

A study published in NEJM showed similar rates of progression-free survival in HL patients who werePET-negative after chemotherapy, whether they received subsequent RT or not.

However, the investigators said longer follow-up is needed to determine if eliminating RT in PET-negative patients will lead to fewer late effects and improved overall survival.

The 602 patients who agreed to take part in this trial, known as RAPID, had a PET scan performed after chemotherapy. Patients who tested positive received RT.

Those who tested negative were divided into 2 groups. One group of 211 patients received no further treatment, and the other group of 209 patients had the standard RT.

At a median of 60 months of follow-up, the proportion of patients who were alive and disease-free was 94.6% in the RT group and 90.8% in the group that hadn’t received further treatment.

Eight patients in the RT group progressed, and 8 died (3 with disease progression, 1 of whom died from HL). Five of the deaths occurred in patients who did not ultimately receive RT.

In the untreated group, 20 patients progressed, and 4 patients died (2 with disease progression and none from HL).

“This research is an important step forward,” said study author John Radford, of The University of Manchester and The Christie NHS Foundation Trust in the UK.

“The results of RAPID show that, in early stage Hodgkin lymphoma, radiotherapy after initial chemotherapy marginally reduces the recurrence rate, but this is bought at the expense of exposing to radiation all patients with negative PET findings, most of whom are already cured.”

PET scan of the body

Image by Jens Langner

Performing PET scans immediately after chemotherapy may reveal which Hodgkin lymphoma (HL) patients need radiotherapy (RT).

A study published in NEJM showed similar rates of progression-free survival in HL patients who werePET-negative after chemotherapy, whether they received subsequent RT or not.

However, the investigators said longer follow-up is needed to determine if eliminating RT in PET-negative patients will lead to fewer late effects and improved overall survival.

The 602 patients who agreed to take part in this trial, known as RAPID, had a PET scan performed after chemotherapy. Patients who tested positive received RT.

Those who tested negative were divided into 2 groups. One group of 211 patients received no further treatment, and the other group of 209 patients had the standard RT.

At a median of 60 months of follow-up, the proportion of patients who were alive and disease-free was 94.6% in the RT group and 90.8% in the group that hadn’t received further treatment.

Eight patients in the RT group progressed, and 8 died (3 with disease progression, 1 of whom died from HL). Five of the deaths occurred in patients who did not ultimately receive RT.

In the untreated group, 20 patients progressed, and 4 patients died (2 with disease progression and none from HL).

“This research is an important step forward,” said study author John Radford, of The University of Manchester and The Christie NHS Foundation Trust in the UK.

“The results of RAPID show that, in early stage Hodgkin lymphoma, radiotherapy after initial chemotherapy marginally reduces the recurrence rate, but this is bought at the expense of exposing to radiation all patients with negative PET findings, most of whom are already cured.”