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Drug’s benefits outweigh risks, PRAC says
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.
However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.
And the committee updated its previous recommendations to manage this risk.
The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the review
The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
PRAC’s recommendations
The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.
Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.
Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.
Furthermore, idelalisib should not be started in patients with a generalized infection.
At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.
Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed. 
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.
However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.
And the committee updated its previous recommendations to manage this risk.
The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the review
The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
PRAC’s recommendations
The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.
Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.
Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.
Furthermore, idelalisib should not be started in patients with a generalized infection.
At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.
Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.
However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.
And the committee updated its previous recommendations to manage this risk.
The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the review
The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
PRAC’s recommendations
The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.
Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.
Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.
Furthermore, idelalisib should not be started in patients with a generalized infection.
At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.
Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.
Cancer cell lines predict drug response, study shows
Image from PNAS
A study published in Cell has shown that patient-derived cancer cell lines harbor most of the same genetic changes found in patients’ tumors and could therefore be used to learn how cancers are likely to respond to new drugs.
Researchers believe this discovery could help advance personalized cancer medicine by leading to results that help doctors predict the best available drugs or the most suitable clinical trials for each individual patient.
“We need better ways to figure out which groups of patients are more likely to respond to a new drug before we run complex and expensive clinical trials,” said study author Ultan McDermott, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“Our research shows that cancer cell lines do capture the molecular alterations found in tumors and so can be predictive of how a tumor will respond to a drug. This means the cell lines could tell us much more about how a tumor is likely to respond to a new drug before we try to test it in patients. We hope this information will ultimately help in the design of clinical trials that target those patients with the greatest likelihood of benefiting from treatment.”
The researchers said this is the first systematic, large-scale study to combine molecular data from patients, cancer cell lines, and drug sensitivity.
For the study, the team looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different cancer types, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, and multiple myeloma.
The researchers built a catalogue of the genetic changes that cause cancer in patients and mapped these alterations onto 1000 cancer cell lines. Next, they tested the cell lines for sensitivity to 265 different cancer drugs to understand which of these changes affect sensitivity.
This revealed that the majority of molecular abnormalities found in patients’ cancers are also found in cancer cells in the laboratory.
The work also showed that many of the molecular abnormalities detected in the thousands of patient samples can, both individually and in combination, have a strong effect on whether a particular drug affects a cancer cell’s survival.
The results suggest cancer cell lines could be better exploited to learn which drugs offer the most effective treatment to which patients.
“If a cell line has the same genetic features as a patient’s tumor, and that cell line responded to a specific drug, we can focus new research on this finding,” said study author Francesco Iorio, PhD, of the European Bioinformatics Institute in Cambridge, UK.
“This could ultimately help assign cancer patients into more precise groups based on how likely they are to respond to therapy. This resource can really help cancer research. Most importantly, it can be used to create tools for doctors to select a clinical trial which is most promising for their cancer patient. That is still a way off, but we are heading in the right direction.”
Image from PNAS
A study published in Cell has shown that patient-derived cancer cell lines harbor most of the same genetic changes found in patients’ tumors and could therefore be used to learn how cancers are likely to respond to new drugs.
Researchers believe this discovery could help advance personalized cancer medicine by leading to results that help doctors predict the best available drugs or the most suitable clinical trials for each individual patient.
“We need better ways to figure out which groups of patients are more likely to respond to a new drug before we run complex and expensive clinical trials,” said study author Ultan McDermott, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“Our research shows that cancer cell lines do capture the molecular alterations found in tumors and so can be predictive of how a tumor will respond to a drug. This means the cell lines could tell us much more about how a tumor is likely to respond to a new drug before we try to test it in patients. We hope this information will ultimately help in the design of clinical trials that target those patients with the greatest likelihood of benefiting from treatment.”
The researchers said this is the first systematic, large-scale study to combine molecular data from patients, cancer cell lines, and drug sensitivity.
For the study, the team looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different cancer types, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, and multiple myeloma.
The researchers built a catalogue of the genetic changes that cause cancer in patients and mapped these alterations onto 1000 cancer cell lines. Next, they tested the cell lines for sensitivity to 265 different cancer drugs to understand which of these changes affect sensitivity.
This revealed that the majority of molecular abnormalities found in patients’ cancers are also found in cancer cells in the laboratory.
The work also showed that many of the molecular abnormalities detected in the thousands of patient samples can, both individually and in combination, have a strong effect on whether a particular drug affects a cancer cell’s survival.
The results suggest cancer cell lines could be better exploited to learn which drugs offer the most effective treatment to which patients.
“If a cell line has the same genetic features as a patient’s tumor, and that cell line responded to a specific drug, we can focus new research on this finding,” said study author Francesco Iorio, PhD, of the European Bioinformatics Institute in Cambridge, UK.
“This could ultimately help assign cancer patients into more precise groups based on how likely they are to respond to therapy. This resource can really help cancer research. Most importantly, it can be used to create tools for doctors to select a clinical trial which is most promising for their cancer patient. That is still a way off, but we are heading in the right direction.”
Image from PNAS
A study published in Cell has shown that patient-derived cancer cell lines harbor most of the same genetic changes found in patients’ tumors and could therefore be used to learn how cancers are likely to respond to new drugs.
Researchers believe this discovery could help advance personalized cancer medicine by leading to results that help doctors predict the best available drugs or the most suitable clinical trials for each individual patient.
“We need better ways to figure out which groups of patients are more likely to respond to a new drug before we run complex and expensive clinical trials,” said study author Ultan McDermott, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“Our research shows that cancer cell lines do capture the molecular alterations found in tumors and so can be predictive of how a tumor will respond to a drug. This means the cell lines could tell us much more about how a tumor is likely to respond to a new drug before we try to test it in patients. We hope this information will ultimately help in the design of clinical trials that target those patients with the greatest likelihood of benefiting from treatment.”
The researchers said this is the first systematic, large-scale study to combine molecular data from patients, cancer cell lines, and drug sensitivity.
For the study, the team looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different cancer types, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, and multiple myeloma.
The researchers built a catalogue of the genetic changes that cause cancer in patients and mapped these alterations onto 1000 cancer cell lines. Next, they tested the cell lines for sensitivity to 265 different cancer drugs to understand which of these changes affect sensitivity.
This revealed that the majority of molecular abnormalities found in patients’ cancers are also found in cancer cells in the laboratory.
The work also showed that many of the molecular abnormalities detected in the thousands of patient samples can, both individually and in combination, have a strong effect on whether a particular drug affects a cancer cell’s survival.
The results suggest cancer cell lines could be better exploited to learn which drugs offer the most effective treatment to which patients.
“If a cell line has the same genetic features as a patient’s tumor, and that cell line responded to a specific drug, we can focus new research on this finding,” said study author Francesco Iorio, PhD, of the European Bioinformatics Institute in Cambridge, UK.
“This could ultimately help assign cancer patients into more precise groups based on how likely they are to respond to therapy. This resource can really help cancer research. Most importantly, it can be used to create tools for doctors to select a clinical trial which is most promising for their cancer patient. That is still a way off, but we are heading in the right direction.”
NHL patients may have higher risk of second cancer
Photo courtesy of NIH
Compared to patients with other common cancers, patients with non-Hodgkin lymphoma (NHL) have a higher risk of developing a second, unrelated malignancy, according to a new study.
Researchers looked at data on more than 2.1 million patients with 10 of the most common cancers and found that patients with NHL or bladder cancer had the highest risk of developing a second malignancy.
The researchers reported these findings in Cancer.
For this study, Karim Chamie, MD, of the University of California, Los Angeles, and his colleagues looked at data from Surveillance, Epidemiology, and End Results database.
The team identified patients age 18 and older who were diagnosed with one of the 10 most common cancers—NHL, melanoma, and prostate, breast, lung, colon, rectal, bladder, uterine, and kidney cancers—between 1992 and 2008.
Of the 2,116,163 patients identified, 170,865 (8.1%) developed a second primary malignancy.
In multivariable analysis, patients with NHL or bladder cancer had the highest risk of developing a second malignancy.
The hazard ratios for patients with NHL were 2.70 for men and 2.88 for women. The hazard ratios for bladder cancer were 1.88 for men and 1.66 for women.
Lung cancer was a common second malignancy for both NHL and bladder cancer patients. NHL patients also tended to develop prostate and breast cancer.
Among patients with 2 incident cancers, 13% died of their initial cancer, and 55% died of their second primary malignancy. Lung cancer was the cause of death in 12% of the patients.
“As clinicians, we can become so focused on surveilling our patients to see if a primary cancer recurs that we sometimes may not be aware that patients can be at risk of developing a second, unrelated cancer,” Dr Chamie said.
He and his colleagues believe this study makes a case for monitoring cancer patients for second malignancies.
Photo courtesy of NIH
Compared to patients with other common cancers, patients with non-Hodgkin lymphoma (NHL) have a higher risk of developing a second, unrelated malignancy, according to a new study.
Researchers looked at data on more than 2.1 million patients with 10 of the most common cancers and found that patients with NHL or bladder cancer had the highest risk of developing a second malignancy.
The researchers reported these findings in Cancer.
For this study, Karim Chamie, MD, of the University of California, Los Angeles, and his colleagues looked at data from Surveillance, Epidemiology, and End Results database.
The team identified patients age 18 and older who were diagnosed with one of the 10 most common cancers—NHL, melanoma, and prostate, breast, lung, colon, rectal, bladder, uterine, and kidney cancers—between 1992 and 2008.
Of the 2,116,163 patients identified, 170,865 (8.1%) developed a second primary malignancy.
In multivariable analysis, patients with NHL or bladder cancer had the highest risk of developing a second malignancy.
The hazard ratios for patients with NHL were 2.70 for men and 2.88 for women. The hazard ratios for bladder cancer were 1.88 for men and 1.66 for women.
Lung cancer was a common second malignancy for both NHL and bladder cancer patients. NHL patients also tended to develop prostate and breast cancer.
Among patients with 2 incident cancers, 13% died of their initial cancer, and 55% died of their second primary malignancy. Lung cancer was the cause of death in 12% of the patients.
“As clinicians, we can become so focused on surveilling our patients to see if a primary cancer recurs that we sometimes may not be aware that patients can be at risk of developing a second, unrelated cancer,” Dr Chamie said.
He and his colleagues believe this study makes a case for monitoring cancer patients for second malignancies.
Photo courtesy of NIH
Compared to patients with other common cancers, patients with non-Hodgkin lymphoma (NHL) have a higher risk of developing a second, unrelated malignancy, according to a new study.
Researchers looked at data on more than 2.1 million patients with 10 of the most common cancers and found that patients with NHL or bladder cancer had the highest risk of developing a second malignancy.
The researchers reported these findings in Cancer.
For this study, Karim Chamie, MD, of the University of California, Los Angeles, and his colleagues looked at data from Surveillance, Epidemiology, and End Results database.
The team identified patients age 18 and older who were diagnosed with one of the 10 most common cancers—NHL, melanoma, and prostate, breast, lung, colon, rectal, bladder, uterine, and kidney cancers—between 1992 and 2008.
Of the 2,116,163 patients identified, 170,865 (8.1%) developed a second primary malignancy.
In multivariable analysis, patients with NHL or bladder cancer had the highest risk of developing a second malignancy.
The hazard ratios for patients with NHL were 2.70 for men and 2.88 for women. The hazard ratios for bladder cancer were 1.88 for men and 1.66 for women.
Lung cancer was a common second malignancy for both NHL and bladder cancer patients. NHL patients also tended to develop prostate and breast cancer.
Among patients with 2 incident cancers, 13% died of their initial cancer, and 55% died of their second primary malignancy. Lung cancer was the cause of death in 12% of the patients.
“As clinicians, we can become so focused on surveilling our patients to see if a primary cancer recurs that we sometimes may not be aware that patients can be at risk of developing a second, unrelated cancer,” Dr Chamie said.
He and his colleagues believe this study makes a case for monitoring cancer patients for second malignancies.
New type of CAR T cells can produce responses in NHL
Image courtesy of NIAID
Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.
The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.
There was 1 adverse event considered possibly related to the treatment.
The researchers reported these results in The Journal of Clinical Investigation.
The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.
“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.
He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).
The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.
Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×108 to 2×108 κ.CAR T cells/m2).
“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.
One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.
Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.
Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.
“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.
Image courtesy of NIAID
Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.
The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.
There was 1 adverse event considered possibly related to the treatment.
The researchers reported these results in The Journal of Clinical Investigation.
The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.
“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.
He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).
The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.
Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×108 to 2×108 κ.CAR T cells/m2).
“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.
One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.
Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.
Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.
“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.
Image courtesy of NIAID
Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.
The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.
There was 1 adverse event considered possibly related to the treatment.
The researchers reported these results in The Journal of Clinical Investigation.
The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.
“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.
He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).
The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.
Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×108 to 2×108 κ.CAR T cells/m2).
“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.
One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.
Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.
Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.
“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.
Combo shows promise for treating DLBCL
The mTOR inhibitor everolimus may provide an additional benefit when combined with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) to treat patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), according to researchers.
The combination was considered well-tolerated in a phase 1 trial, and 96% of patients responded to the treatment.
“There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma,” said Patrick Johnston, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.
“This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial.”
Results from this study were published in The Lancet Haematology.
Patients and treatment
Dr Johnston and his colleagues conducted this study in 24 previously untreated DLBCL patients. Their median age was 58.5 (range, 49.5-71.5), and 58% were male. Most patients had stage IV disease (54%), followed by stage II (25%), and stage III (21%). Five patients (21%) had bulky disease.
The patients received standard R-CHOP-21 (rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, doxorubicin at 50 mg/m2, and vincristine at 1.4 mg/m2—all on day 1 of the 21-day cycle—as well as oral prednisone at 100 mg/m2 each day on days 1–5 of the cycle) for 6 cycles, with scheduled pegfilgrastim at 6 mg on day 2 of each cycle.
They also received everolimus at 10 mg/day on 2 different schedules. Nine patients were enrolled initially—3 given everolimus on days 1–10 and 6 receiving it on days 1–14. As there were no dose-limiting toxicities in these patients, another 15 patients went on to receive everolimus on days 1–14.
Results
The median follow-up was 21.5 months. Twenty-three patients (96%) achieved an overall response and a complete metabolic response as assessed by PET. The remaining patient withdrew consent during cycle 1 and achieved a complete response with R-CHOP alone.
The 12-month event-free survival rate was 100%. Nine patients had sufficient follow-up and were event-free at 24 months. At last follow-up (March 30, 2016), no deaths or relapses had occurred.
The most common adverse events were hematologic, such as grade 4 neutropenia (75%) and grade 3 febrile neutropenia (21%).
Three patients experienced “significant” toxicity, according to the researchers. One patient had a treatment delay of 12 days due to grade 3 hypokalemia, which was considered possibly related to everolimus.
A second patient had grade 4 sepsis that was possibly related to treatment, and a third patient had a treatment delay of 10 days due to grade 3 infection that was possibly related to everolimus.
Ten patients (42%) had their dose of everolimus reduced, 2 patients permanently discontinued the drug after cycles 3 and 4, respectively, and 2 patients omitted everolimus for 1 and 2 cycles, respectively, then resumed everolimus for subsequent cycles.
“This study is the first to integrate a P13K-mTOR agent with standard R-CHOP,” Dr Johnston said.
“The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients.”
The mTOR inhibitor everolimus may provide an additional benefit when combined with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) to treat patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), according to researchers.
The combination was considered well-tolerated in a phase 1 trial, and 96% of patients responded to the treatment.
“There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma,” said Patrick Johnston, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.
“This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial.”
Results from this study were published in The Lancet Haematology.
Patients and treatment
Dr Johnston and his colleagues conducted this study in 24 previously untreated DLBCL patients. Their median age was 58.5 (range, 49.5-71.5), and 58% were male. Most patients had stage IV disease (54%), followed by stage II (25%), and stage III (21%). Five patients (21%) had bulky disease.
The patients received standard R-CHOP-21 (rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, doxorubicin at 50 mg/m2, and vincristine at 1.4 mg/m2—all on day 1 of the 21-day cycle—as well as oral prednisone at 100 mg/m2 each day on days 1–5 of the cycle) for 6 cycles, with scheduled pegfilgrastim at 6 mg on day 2 of each cycle.
They also received everolimus at 10 mg/day on 2 different schedules. Nine patients were enrolled initially—3 given everolimus on days 1–10 and 6 receiving it on days 1–14. As there were no dose-limiting toxicities in these patients, another 15 patients went on to receive everolimus on days 1–14.
Results
The median follow-up was 21.5 months. Twenty-three patients (96%) achieved an overall response and a complete metabolic response as assessed by PET. The remaining patient withdrew consent during cycle 1 and achieved a complete response with R-CHOP alone.
The 12-month event-free survival rate was 100%. Nine patients had sufficient follow-up and were event-free at 24 months. At last follow-up (March 30, 2016), no deaths or relapses had occurred.
The most common adverse events were hematologic, such as grade 4 neutropenia (75%) and grade 3 febrile neutropenia (21%).
Three patients experienced “significant” toxicity, according to the researchers. One patient had a treatment delay of 12 days due to grade 3 hypokalemia, which was considered possibly related to everolimus.
A second patient had grade 4 sepsis that was possibly related to treatment, and a third patient had a treatment delay of 10 days due to grade 3 infection that was possibly related to everolimus.
Ten patients (42%) had their dose of everolimus reduced, 2 patients permanently discontinued the drug after cycles 3 and 4, respectively, and 2 patients omitted everolimus for 1 and 2 cycles, respectively, then resumed everolimus for subsequent cycles.
“This study is the first to integrate a P13K-mTOR agent with standard R-CHOP,” Dr Johnston said.
“The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients.”
The mTOR inhibitor everolimus may provide an additional benefit when combined with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) to treat patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), according to researchers.
The combination was considered well-tolerated in a phase 1 trial, and 96% of patients responded to the treatment.
“There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma,” said Patrick Johnston, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.
“This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial.”
Results from this study were published in The Lancet Haematology.
Patients and treatment
Dr Johnston and his colleagues conducted this study in 24 previously untreated DLBCL patients. Their median age was 58.5 (range, 49.5-71.5), and 58% were male. Most patients had stage IV disease (54%), followed by stage II (25%), and stage III (21%). Five patients (21%) had bulky disease.
The patients received standard R-CHOP-21 (rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, doxorubicin at 50 mg/m2, and vincristine at 1.4 mg/m2—all on day 1 of the 21-day cycle—as well as oral prednisone at 100 mg/m2 each day on days 1–5 of the cycle) for 6 cycles, with scheduled pegfilgrastim at 6 mg on day 2 of each cycle.
They also received everolimus at 10 mg/day on 2 different schedules. Nine patients were enrolled initially—3 given everolimus on days 1–10 and 6 receiving it on days 1–14. As there were no dose-limiting toxicities in these patients, another 15 patients went on to receive everolimus on days 1–14.
Results
The median follow-up was 21.5 months. Twenty-three patients (96%) achieved an overall response and a complete metabolic response as assessed by PET. The remaining patient withdrew consent during cycle 1 and achieved a complete response with R-CHOP alone.
The 12-month event-free survival rate was 100%. Nine patients had sufficient follow-up and were event-free at 24 months. At last follow-up (March 30, 2016), no deaths or relapses had occurred.
The most common adverse events were hematologic, such as grade 4 neutropenia (75%) and grade 3 febrile neutropenia (21%).
Three patients experienced “significant” toxicity, according to the researchers. One patient had a treatment delay of 12 days due to grade 3 hypokalemia, which was considered possibly related to everolimus.
A second patient had grade 4 sepsis that was possibly related to treatment, and a third patient had a treatment delay of 10 days due to grade 3 infection that was possibly related to everolimus.
Ten patients (42%) had their dose of everolimus reduced, 2 patients permanently discontinued the drug after cycles 3 and 4, respectively, and 2 patients omitted everolimus for 1 and 2 cycles, respectively, then resumed everolimus for subsequent cycles.
“This study is the first to integrate a P13K-mTOR agent with standard R-CHOP,” Dr Johnston said.
“The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients.”
Team maps chromatin landscape in CLL
Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).
And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.
The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.
The work has been published in Nature Communications.
The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.
For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.
The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.
The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.
Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.
“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.
“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”
Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).
And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.
The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.
The work has been published in Nature Communications.
The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.
For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.
The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.
The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.
Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.
“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.
“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”
Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).
And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.
The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.
The work has been published in Nature Communications.
The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.
For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.
The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.
The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.
Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.
“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.
“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”
CHMP rejects ofatumumab as maintenance
Photo courtesy of GSK
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended against expanding the approved indication for ofatumumab (Arzerra).
Novartis, which is developing ofatumumab in cooperation with Genmab, had submitted an application requesting that ofatumumab be authorized as maintenance therapy for patients with relapsed chronic lymphocytic leukemia (CLL).
But the CHMP has advised the European Commission (EC) not to grant this authorization.
The CHMP noted that, in the phase 3 PROLONG trial, ofatumumab maintenance improved progression-free survival (PFS) in CLL patients.
However, the committee said the importance of this improvement is not clear because the PFS results were not supported by other measures, such as overall survival or a significant improvement in patients’ quality of life.
The CHMP also said the use of ofatumumab for maintenance treatment should be seen in the context of its side effects. Common side effects of ofatumumab in the PROLONG trial were infusion reactions, neutropenia, and upper respiratory tract infections.
In the end, the CHMP decided that the PROLONG data were not sufficient to conclude that maintenance treatment with ofatumumab is of more benefit than no treatment. So the committee recommended against expanding the drug’s marketing authorization.
This decision does not have any impact on ongoing clinical trials with ofatumumab.
About ofatumumab
Ofatumumab has been authorized for use in the European Union since April 2010.
The EC first granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Then, in 2014, the EC granted ofatumumab conditional approval for use in combination with chlorambucil or bendamustine in CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses in the aforementioned indications. Ofatumumab will not receive full approval until the drug’s developers submit results of additional research to the EC.
About the PROLONG trial
The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.
These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).
There was no significant difference in the median overall survival, which was not reached in either treatment arm.
The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.
Photo courtesy of GSK
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended against expanding the approved indication for ofatumumab (Arzerra).
Novartis, which is developing ofatumumab in cooperation with Genmab, had submitted an application requesting that ofatumumab be authorized as maintenance therapy for patients with relapsed chronic lymphocytic leukemia (CLL).
But the CHMP has advised the European Commission (EC) not to grant this authorization.
The CHMP noted that, in the phase 3 PROLONG trial, ofatumumab maintenance improved progression-free survival (PFS) in CLL patients.
However, the committee said the importance of this improvement is not clear because the PFS results were not supported by other measures, such as overall survival or a significant improvement in patients’ quality of life.
The CHMP also said the use of ofatumumab for maintenance treatment should be seen in the context of its side effects. Common side effects of ofatumumab in the PROLONG trial were infusion reactions, neutropenia, and upper respiratory tract infections.
In the end, the CHMP decided that the PROLONG data were not sufficient to conclude that maintenance treatment with ofatumumab is of more benefit than no treatment. So the committee recommended against expanding the drug’s marketing authorization.
This decision does not have any impact on ongoing clinical trials with ofatumumab.
About ofatumumab
Ofatumumab has been authorized for use in the European Union since April 2010.
The EC first granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Then, in 2014, the EC granted ofatumumab conditional approval for use in combination with chlorambucil or bendamustine in CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses in the aforementioned indications. Ofatumumab will not receive full approval until the drug’s developers submit results of additional research to the EC.
About the PROLONG trial
The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.
These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).
There was no significant difference in the median overall survival, which was not reached in either treatment arm.
The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.
Photo courtesy of GSK
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended against expanding the approved indication for ofatumumab (Arzerra).
Novartis, which is developing ofatumumab in cooperation with Genmab, had submitted an application requesting that ofatumumab be authorized as maintenance therapy for patients with relapsed chronic lymphocytic leukemia (CLL).
But the CHMP has advised the European Commission (EC) not to grant this authorization.
The CHMP noted that, in the phase 3 PROLONG trial, ofatumumab maintenance improved progression-free survival (PFS) in CLL patients.
However, the committee said the importance of this improvement is not clear because the PFS results were not supported by other measures, such as overall survival or a significant improvement in patients’ quality of life.
The CHMP also said the use of ofatumumab for maintenance treatment should be seen in the context of its side effects. Common side effects of ofatumumab in the PROLONG trial were infusion reactions, neutropenia, and upper respiratory tract infections.
In the end, the CHMP decided that the PROLONG data were not sufficient to conclude that maintenance treatment with ofatumumab is of more benefit than no treatment. So the committee recommended against expanding the drug’s marketing authorization.
This decision does not have any impact on ongoing clinical trials with ofatumumab.
About ofatumumab
Ofatumumab has been authorized for use in the European Union since April 2010.
The EC first granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Then, in 2014, the EC granted ofatumumab conditional approval for use in combination with chlorambucil or bendamustine in CLL patients who have not received prior therapy and are not eligible for fludarabine-based therapy.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses in the aforementioned indications. Ofatumumab will not receive full approval until the drug’s developers submit results of additional research to the EC.
About the PROLONG trial
The PROLONG trial was designed to compare ofatumumab maintenance to no further treatment in patients with a complete or partial response after second- or third-line treatment for CLL. Interim results of the study were presented at ASH 2014.
These results—in 474 patients—suggested that ofatumumab can significantly improve PFS. The median PFS was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive maintenance therapy (P<0.0001).
There was no significant difference in the median overall survival, which was not reached in either treatment arm.
The researchers said there were no unexpected safety findings. The most common adverse events (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection.
Obinutuzumab approved to treat FL
The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).
The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.
Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.
Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.
GADOLIN trial
The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.
Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.
Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).
The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.
The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.
The median overall survival has not yet been reached in either study arm.
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).
The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).
The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).
The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.
Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.
Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.
GADOLIN trial
The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.
Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.
Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).
The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.
The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.
The median overall survival has not yet been reached in either study arm.
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).
The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).
The European Commission (EC) has approved the use of obinutuzumab (Gazyvaro), an anti-CD20 monoclonal antibody, in patients with follicular lymphoma (FL).
The approval means obinutuzumab can be given, first in combination with bendamustine and then alone as maintenance therapy, to FL patients who did not respond to, progressed during, or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen.
Obinutuzumab was previously granted approval by the EC for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia and comorbidities that make them unsuitable for full-dose fludarabine-based therapy.
Obinutuzumab is being developed by Roche. The drug is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the rest of the world.
GADOLIN trial
The EC’s approval of obinutuzumab in FL is based on results from the phase 3 GADOLIN trial. The study included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including 321 patients with FL, 46 with marginal zone lymphoma, and 28 with small lymphocytic lymphoma.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). The secondary endpoints were PFS assessed by investigator review, best overall response, complete response (CR), partial response (PR), duration of response, overall survival, and safety profile.
Among patients with FL, the obinutuzumab regimen improved PFS compared to bendamustine alone, as assessed by the IRC (hazard ratio [HR]=0.48, P<0.0001). The median PFS was not reached in patients receiving the obinutuzumab regimen but was 13.8 months in those receiving bendamustine alone.
Investigator-assessed PFS was consistent with IRC-assessed PFS. Investigators said the median PFS with the obinutuzumab regimen was more than double that with bendamustine alone—29.2 months vs 13.7 months (HR=0.48, P<0.0001).
The best overall response for patients receiving the obinutuzumab regimen was 78.7% (15.5% CR, 63.2% PR), compared to 74.7% (18.7% CR, 56% PR) for those receiving bendamustine alone, as assessed by the IRC.
The median duration of response was not reached for patients receiving the obinutuzumab regimen and was 11.6 months for those receiving bendamustine alone.
The median overall survival has not yet been reached in either study arm.
The most common grade 3/4 adverse events observed in patients receiving the obinutuzumab regimen were neutropenia (33%), infusion reactions (11%), and thrombocytopenia (10%).
The most common adverse events of any grade were infusion reactions (69%), neutropenia (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), thrombocytopenia (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), anemia (12%), general weakness (11%), and urinary tract infection (10%).
HIV not a contraindication for transplant in lymphoma
cultured lymphocyte
Image courtesy of CDC
With the advent of effective anti-retroviral therapy, patients with HIV-related lymphoma receive standard therapeutic regimens and achieve outcomes comparable to those of non-HIV-infected individuals.
Based on results of a multicenter phase 2 study, this now extends to treatment with autologous stem cell transplant (ASCT).
Researchers found that outcomes were not significantly different between HIV-infected patients who received ASCT and matched controls.
“These findings are remarkably important for a group of patients who, up until now, have been inconsistently treated,” said lead study author Joseph C. Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection.”
To arrive at this recommendation, investigators enrolled 43 HIV-infected patients with relapsed or persistent non-Hodgkin lymphoma (NHL) or classical Hodgkin lymphoma (HL) onto the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AIDS Malignancy Consortium (AMC) 071 study.
They reported their findings in Blood.
Eligibility
Patients had to be 15 years or older, have documented evidence of HIV infection, and have a Karnofsky performance status of greater than 70%.
They had to have persistent or recurrent diffuse large B-cell lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, Burkitt lymphoma, Burkitt-like NHL, or classic HL.
Patients could have had no more than 3 prior treatment regimens or 2 or fewer salvage regimens.
They had to have adequate organ function, fewer than 10% blasts in their marrow, no prior autologous or allogeneic transplant, and adequate hematopoietic progenitor cell mobilization of more than 1.5 x 106 CD34+ cells/kg to be eligible.
Transplant regimen
Patients received the BEAM (carmustine, etoposide, cytarabine, and melphalan) transplant regimen on day 0. They did not receive antiretroviral therapy from the time of the start of BEAM until 7 days after completion of the preparative regimen.
Efavirenz was held for 2 weeks prior to BEAM initiation, and an alternative agent was substituted during this time period. Zidovudine was prohibited following transplant because of its myelosuppressive effects.
Patients received growth factor, transfusion, and antimicrobial supportive care according to institutional standards of the transplant center.
Patient characteristics
Of the original 43 patients enrolled, 3 patients experienced disease progression prior to the conditioning regimen and did not undergo transplant. Therefore, investigators did not include them in the study analysis.
Forty patients received ASCT at 16 different transplant centers. They were a median age of 46.9 (range, 22.5–62.2), and 35 were male.
All patients received peripheral blood stem cell grafts at a median dose of 3.9 x 106 CD34+ cells/kg (range, 1.6–11.0). And all patients were able to mobilize hematopoietic progenitor cells in a median of 2 apheresis collections (range, 1–5).
Most patients (n=32; 80%) had a pre-transplant HIV viral load that was undetectable. The median viral load for those 8 patients with detectable disease was 80 copies/mL (range, 50–17,455).
Patients had a median pre-transplant CD4+ T-cell count of 249.0 CD4+/μL (range, 39–797).
Investigators followed the patients for a median of 24.8 months (range, 2.8–27.2).
Response
Seven patients died during the follow-up period, 5 within 1 year of transplant. Four of the deaths within 1 year of transplant were due to relapse or disease progression.
One-year transplant-related mortality (TRM) was 5.2%.
The 1-year overall survival (OS) probability was 87.3%, and, at 2 years, it was 82%. The 2-year progression-free survival (PFS) was 79.8%, and the cumulative incidence of relapse/progression at 2 years was 12.5%.
The probabilities for OS and PFS at 2 years were comparable for both NHL and HL patients.
The median time to post-transplant neutrophil recovery was 11 days, and 97.5% of patients recovered their neutrophil counts by day 28.
The median time to platelet recovery was 18 days, and 92.5% of patients recovered their platelet counts by day 100.
At 100 days post-transplant, 28.9% of the evaluable patients (11/38) had recovered hematologic function. And at 1 year, 74.2% (23/31) had recovered hematologic function.
Adverse events
A little more than half (55%) the patients had at least 1 infectious event within a year of transplant, including 11 who had a severe infection.
Of the 57 infections that occurred post-transplant, 25 were due to bacteria, 22 to viruses, 6 to fungal organisms, 2 to protozoa, and 2 to other organisms. No patient developed Pneumocystis jiroveci pneumonia after transplant.
Nine patients experienced a total of 13 grade 3–5 adverse events. This included infection/sepsis (5 events), venous thromboembolism (2 events), and 1 event each for esophageal candidiasis, enteritis, hyperglycemia, hypernatremia, acute appendicitis, and acute coronary syndrome.
Sixteen patients had to be re-admitted to the hospital after the transplant, for a total of 34 readmissions. Infection (18) and fever (6) were the most common reasons for readmission.
Data comparison
The investigators compared the OS and PFS results to a control group identified through the Center for International Bone Marrow Transplant Research (CIBMTR).
One hundred fifty-one controls matched for age, performance status, primary disease, and disease status at transplant were identified for the 40 HIV-lymphoma cases.
The 1-year OS for the control group was 87.7%, and the 2-year PFS was 69.5%. This compared with the 87.3% and 79.8% for OS and PFS, respectively, for the HIV-lymphoma patients.
These results, the investigators wrote, were not significantly different from outcomes of CIBMTR controls, with a hazard ratio for overall mortality in the HIV-lymphoma patients of 0.67 (95% CI: 0.30–1.50, P=0.33) compared to controls.
And the hazard ratio for treatment failure in the HIV-lymphoma patients was 0.52 (95% CI: 0.2927–1.03, P=0.06) compared to controls.
The investigators concluded that HIV infection alone should not be considered a contraindication to ASCT for patients who otherwise meet transplant inclusion criteria. And ASCT should be considered the standard of care for patients with HIV-related lymphoma, provided that the HIV infection is treatment-responsive.
The team added that these patients should also be considered “appropriate potential participants” for future ASCT clinical trials.
cultured lymphocyte
Image courtesy of CDC
With the advent of effective anti-retroviral therapy, patients with HIV-related lymphoma receive standard therapeutic regimens and achieve outcomes comparable to those of non-HIV-infected individuals.
Based on results of a multicenter phase 2 study, this now extends to treatment with autologous stem cell transplant (ASCT).
Researchers found that outcomes were not significantly different between HIV-infected patients who received ASCT and matched controls.
“These findings are remarkably important for a group of patients who, up until now, have been inconsistently treated,” said lead study author Joseph C. Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection.”
To arrive at this recommendation, investigators enrolled 43 HIV-infected patients with relapsed or persistent non-Hodgkin lymphoma (NHL) or classical Hodgkin lymphoma (HL) onto the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AIDS Malignancy Consortium (AMC) 071 study.
They reported their findings in Blood.
Eligibility
Patients had to be 15 years or older, have documented evidence of HIV infection, and have a Karnofsky performance status of greater than 70%.
They had to have persistent or recurrent diffuse large B-cell lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, Burkitt lymphoma, Burkitt-like NHL, or classic HL.
Patients could have had no more than 3 prior treatment regimens or 2 or fewer salvage regimens.
They had to have adequate organ function, fewer than 10% blasts in their marrow, no prior autologous or allogeneic transplant, and adequate hematopoietic progenitor cell mobilization of more than 1.5 x 106 CD34+ cells/kg to be eligible.
Transplant regimen
Patients received the BEAM (carmustine, etoposide, cytarabine, and melphalan) transplant regimen on day 0. They did not receive antiretroviral therapy from the time of the start of BEAM until 7 days after completion of the preparative regimen.
Efavirenz was held for 2 weeks prior to BEAM initiation, and an alternative agent was substituted during this time period. Zidovudine was prohibited following transplant because of its myelosuppressive effects.
Patients received growth factor, transfusion, and antimicrobial supportive care according to institutional standards of the transplant center.
Patient characteristics
Of the original 43 patients enrolled, 3 patients experienced disease progression prior to the conditioning regimen and did not undergo transplant. Therefore, investigators did not include them in the study analysis.
Forty patients received ASCT at 16 different transplant centers. They were a median age of 46.9 (range, 22.5–62.2), and 35 were male.
All patients received peripheral blood stem cell grafts at a median dose of 3.9 x 106 CD34+ cells/kg (range, 1.6–11.0). And all patients were able to mobilize hematopoietic progenitor cells in a median of 2 apheresis collections (range, 1–5).
Most patients (n=32; 80%) had a pre-transplant HIV viral load that was undetectable. The median viral load for those 8 patients with detectable disease was 80 copies/mL (range, 50–17,455).
Patients had a median pre-transplant CD4+ T-cell count of 249.0 CD4+/μL (range, 39–797).
Investigators followed the patients for a median of 24.8 months (range, 2.8–27.2).
Response
Seven patients died during the follow-up period, 5 within 1 year of transplant. Four of the deaths within 1 year of transplant were due to relapse or disease progression.
One-year transplant-related mortality (TRM) was 5.2%.
The 1-year overall survival (OS) probability was 87.3%, and, at 2 years, it was 82%. The 2-year progression-free survival (PFS) was 79.8%, and the cumulative incidence of relapse/progression at 2 years was 12.5%.
The probabilities for OS and PFS at 2 years were comparable for both NHL and HL patients.
The median time to post-transplant neutrophil recovery was 11 days, and 97.5% of patients recovered their neutrophil counts by day 28.
The median time to platelet recovery was 18 days, and 92.5% of patients recovered their platelet counts by day 100.
At 100 days post-transplant, 28.9% of the evaluable patients (11/38) had recovered hematologic function. And at 1 year, 74.2% (23/31) had recovered hematologic function.
Adverse events
A little more than half (55%) the patients had at least 1 infectious event within a year of transplant, including 11 who had a severe infection.
Of the 57 infections that occurred post-transplant, 25 were due to bacteria, 22 to viruses, 6 to fungal organisms, 2 to protozoa, and 2 to other organisms. No patient developed Pneumocystis jiroveci pneumonia after transplant.
Nine patients experienced a total of 13 grade 3–5 adverse events. This included infection/sepsis (5 events), venous thromboembolism (2 events), and 1 event each for esophageal candidiasis, enteritis, hyperglycemia, hypernatremia, acute appendicitis, and acute coronary syndrome.
Sixteen patients had to be re-admitted to the hospital after the transplant, for a total of 34 readmissions. Infection (18) and fever (6) were the most common reasons for readmission.
Data comparison
The investigators compared the OS and PFS results to a control group identified through the Center for International Bone Marrow Transplant Research (CIBMTR).
One hundred fifty-one controls matched for age, performance status, primary disease, and disease status at transplant were identified for the 40 HIV-lymphoma cases.
The 1-year OS for the control group was 87.7%, and the 2-year PFS was 69.5%. This compared with the 87.3% and 79.8% for OS and PFS, respectively, for the HIV-lymphoma patients.
These results, the investigators wrote, were not significantly different from outcomes of CIBMTR controls, with a hazard ratio for overall mortality in the HIV-lymphoma patients of 0.67 (95% CI: 0.30–1.50, P=0.33) compared to controls.
And the hazard ratio for treatment failure in the HIV-lymphoma patients was 0.52 (95% CI: 0.2927–1.03, P=0.06) compared to controls.
The investigators concluded that HIV infection alone should not be considered a contraindication to ASCT for patients who otherwise meet transplant inclusion criteria. And ASCT should be considered the standard of care for patients with HIV-related lymphoma, provided that the HIV infection is treatment-responsive.
The team added that these patients should also be considered “appropriate potential participants” for future ASCT clinical trials.
cultured lymphocyte
Image courtesy of CDC
With the advent of effective anti-retroviral therapy, patients with HIV-related lymphoma receive standard therapeutic regimens and achieve outcomes comparable to those of non-HIV-infected individuals.
Based on results of a multicenter phase 2 study, this now extends to treatment with autologous stem cell transplant (ASCT).
Researchers found that outcomes were not significantly different between HIV-infected patients who received ASCT and matched controls.
“These findings are remarkably important for a group of patients who, up until now, have been inconsistently treated,” said lead study author Joseph C. Alvarnas, MD, of City of Hope National Medical Center in Duarte, California.
“Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection.”
To arrive at this recommendation, investigators enrolled 43 HIV-infected patients with relapsed or persistent non-Hodgkin lymphoma (NHL) or classical Hodgkin lymphoma (HL) onto the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AIDS Malignancy Consortium (AMC) 071 study.
They reported their findings in Blood.
Eligibility
Patients had to be 15 years or older, have documented evidence of HIV infection, and have a Karnofsky performance status of greater than 70%.
They had to have persistent or recurrent diffuse large B-cell lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, Burkitt lymphoma, Burkitt-like NHL, or classic HL.
Patients could have had no more than 3 prior treatment regimens or 2 or fewer salvage regimens.
They had to have adequate organ function, fewer than 10% blasts in their marrow, no prior autologous or allogeneic transplant, and adequate hematopoietic progenitor cell mobilization of more than 1.5 x 106 CD34+ cells/kg to be eligible.
Transplant regimen
Patients received the BEAM (carmustine, etoposide, cytarabine, and melphalan) transplant regimen on day 0. They did not receive antiretroviral therapy from the time of the start of BEAM until 7 days after completion of the preparative regimen.
Efavirenz was held for 2 weeks prior to BEAM initiation, and an alternative agent was substituted during this time period. Zidovudine was prohibited following transplant because of its myelosuppressive effects.
Patients received growth factor, transfusion, and antimicrobial supportive care according to institutional standards of the transplant center.
Patient characteristics
Of the original 43 patients enrolled, 3 patients experienced disease progression prior to the conditioning regimen and did not undergo transplant. Therefore, investigators did not include them in the study analysis.
Forty patients received ASCT at 16 different transplant centers. They were a median age of 46.9 (range, 22.5–62.2), and 35 were male.
All patients received peripheral blood stem cell grafts at a median dose of 3.9 x 106 CD34+ cells/kg (range, 1.6–11.0). And all patients were able to mobilize hematopoietic progenitor cells in a median of 2 apheresis collections (range, 1–5).
Most patients (n=32; 80%) had a pre-transplant HIV viral load that was undetectable. The median viral load for those 8 patients with detectable disease was 80 copies/mL (range, 50–17,455).
Patients had a median pre-transplant CD4+ T-cell count of 249.0 CD4+/μL (range, 39–797).
Investigators followed the patients for a median of 24.8 months (range, 2.8–27.2).
Response
Seven patients died during the follow-up period, 5 within 1 year of transplant. Four of the deaths within 1 year of transplant were due to relapse or disease progression.
One-year transplant-related mortality (TRM) was 5.2%.
The 1-year overall survival (OS) probability was 87.3%, and, at 2 years, it was 82%. The 2-year progression-free survival (PFS) was 79.8%, and the cumulative incidence of relapse/progression at 2 years was 12.5%.
The probabilities for OS and PFS at 2 years were comparable for both NHL and HL patients.
The median time to post-transplant neutrophil recovery was 11 days, and 97.5% of patients recovered their neutrophil counts by day 28.
The median time to platelet recovery was 18 days, and 92.5% of patients recovered their platelet counts by day 100.
At 100 days post-transplant, 28.9% of the evaluable patients (11/38) had recovered hematologic function. And at 1 year, 74.2% (23/31) had recovered hematologic function.
Adverse events
A little more than half (55%) the patients had at least 1 infectious event within a year of transplant, including 11 who had a severe infection.
Of the 57 infections that occurred post-transplant, 25 were due to bacteria, 22 to viruses, 6 to fungal organisms, 2 to protozoa, and 2 to other organisms. No patient developed Pneumocystis jiroveci pneumonia after transplant.
Nine patients experienced a total of 13 grade 3–5 adverse events. This included infection/sepsis (5 events), venous thromboembolism (2 events), and 1 event each for esophageal candidiasis, enteritis, hyperglycemia, hypernatremia, acute appendicitis, and acute coronary syndrome.
Sixteen patients had to be re-admitted to the hospital after the transplant, for a total of 34 readmissions. Infection (18) and fever (6) were the most common reasons for readmission.
Data comparison
The investigators compared the OS and PFS results to a control group identified through the Center for International Bone Marrow Transplant Research (CIBMTR).
One hundred fifty-one controls matched for age, performance status, primary disease, and disease status at transplant were identified for the 40 HIV-lymphoma cases.
The 1-year OS for the control group was 87.7%, and the 2-year PFS was 69.5%. This compared with the 87.3% and 79.8% for OS and PFS, respectively, for the HIV-lymphoma patients.
These results, the investigators wrote, were not significantly different from outcomes of CIBMTR controls, with a hazard ratio for overall mortality in the HIV-lymphoma patients of 0.67 (95% CI: 0.30–1.50, P=0.33) compared to controls.
And the hazard ratio for treatment failure in the HIV-lymphoma patients was 0.52 (95% CI: 0.2927–1.03, P=0.06) compared to controls.
The investigators concluded that HIV infection alone should not be considered a contraindication to ASCT for patients who otherwise meet transplant inclusion criteria. And ASCT should be considered the standard of care for patients with HIV-related lymphoma, provided that the HIV infection is treatment-responsive.
The team added that these patients should also be considered “appropriate potential participants” for future ASCT clinical trials.
Delaying therapy for HL/NHL likely safe for mom, baby
Photo credit: Vera Kratochvil
A single-center retrospective study of 39 pregnant women diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy indicates that delaying treatment until the second trimester is “likely safe and results in acceptable” outcomes for both mother and child.
Investigators also found that deferring therapy until after delivery did not adversely affect maternal outcomes.
In order to clarify the sometimes conflicting reports regarding management of lymphoma during pregnancy, investigators at MD Anderson Cancer Center in Houston, Texas, undertook the study to determine whether administering standard chemotherapy during the second and third trimesters has acceptable maternal and fetal outcomes.
Michelle A. Fanale, MD, and colleagues published their findings in JAMA Oncology.
Patient characteristics
Investigators identified 31 women with HL and 8 with NHL who were diagnosed between 1991 and 2014 and had sufficient pregnancy and follow-up data.
The women were a median age of 28 years (range 19-38). The patients with NHL were significantly older, P=0.004.
Approximately 20% of patients had B symptoms. Most were stage II disease (72%), and 80% were ECOG performance status 0 or 1.
About two thirds of patients had hemoglobin levels less than 12 g/dL.
Most patients did not have extranodal nonbone-marrow disease (82%), although there was a significant difference between those with HL (90%) and NHL (50%), P=0.03.
One third of patients had bulky disease, and 88% were in their second or third trimesters at diagnosis.
Three women electively terminated their pregnancies at diagnosis. Of the 36 remaining patients, 24 (61%) began antenatal therapy and 12 (31%) postponed therapy until after delivery.
Four patients received radiation therapy above the diaphragm at a median dose of 40.4 Gy.
Obstetric outcomes
Antenatal therapy was not associated with increased incidence of preterm delivery. Of the 24 women who received treatment during pregnancy, 7 (29%) gave birth prematurely compared with 5 of the 12 women (42%) who postponed treatment until after delivery, P=0.73.
The investigators noted that the miscarriage rate was approximately 10%, which was higher than previous studies.
Four patients had miscarriages, 2 during the first trimester and 2 during the second. Both patients who had miscarriages in the first trimester had received lymphoma treatment during that time.
And one of the patients who had antenatal therapy during the second trimester and had a miscarriage was critically ill, which the investigators believed was a contributing factor.
The second woman who miscarried after therapy in the second trimester had conceived twins through in vitro fertilization and miscarried at 23 weeks after ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy had been initiated at gestational week 15.
Investigators had fetal outcomes available for 31 of 32 patients who did not terminate or have a miscarriage. And these 31 infants had no anomalies at birth.
The investigators said that although the follow-up time is relatively short, they observed no malformations in the newborns.
Treatment responses and survival
The overall response rate (OR) was 91.7% and the complete response (CR) rate was 75.0% for the 24 patients who started treatment during pregnancy.
And for those 12 women who deferred therapy until delivery, both ORR and CR rates were 91.7%.
The 5-year progression-free survival (PFS) and OS were 74.7% and 82.4%, respectively, for all women. The median follow-up was 67.9 months (range 8.8 to 277.5).
For the 31 women with HL, the 5-year PFS and OS were 69.9% and 80%, respectively.
And for the 8 women with NHL, the 5-year PFS and OS were 85.7% and 83.3%, respectively.
Investigators found no difference in PFS or OS (P=0.84) based on undergoing antenatal lymphoma treatment among the 36 women who did not terminate their pregnancies at diagnosis.
The investigators conducted a univariate analysis and found that for the 36 women who did not electively terminate their pregnancies, the following were associated with increased risk of disease progression:
• Bulky disease—hazard ratio [HR] 3.6, P = 0.06
• Extranodal nonbone marrow involvement—HR 4.2, P = 0.04
• Poor ECOG performance status—HR 3.9, P = 0.005
Poor performance status was also associated with OS, HR 8.88, P = 0.004.
Multivariate analysis revealed significant associations in terms of OS and PFS for extranodal nonbone marrow involvement and performance status:
• Nonbone marrow involvement—OS HR, 73.5, P = 0.02; PFS HR 8.26, P = 0.01
• Performance status—OS HR, 26.7, P = 0.003; PFS HR, 4.89, P = 0.002
The investigators concluded that because they found no differences in PFS or OS according to whether patients received antenatal therapy, they believe that disease factors, rather than treatment-related factors, influence worse maternal outcomes.
They recommended delaying therapy until the second trimester if that can be accomplished without harm to the patient.
Photo credit: Vera Kratochvil
A single-center retrospective study of 39 pregnant women diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy indicates that delaying treatment until the second trimester is “likely safe and results in acceptable” outcomes for both mother and child.
Investigators also found that deferring therapy until after delivery did not adversely affect maternal outcomes.
In order to clarify the sometimes conflicting reports regarding management of lymphoma during pregnancy, investigators at MD Anderson Cancer Center in Houston, Texas, undertook the study to determine whether administering standard chemotherapy during the second and third trimesters has acceptable maternal and fetal outcomes.
Michelle A. Fanale, MD, and colleagues published their findings in JAMA Oncology.
Patient characteristics
Investigators identified 31 women with HL and 8 with NHL who were diagnosed between 1991 and 2014 and had sufficient pregnancy and follow-up data.
The women were a median age of 28 years (range 19-38). The patients with NHL were significantly older, P=0.004.
Approximately 20% of patients had B symptoms. Most were stage II disease (72%), and 80% were ECOG performance status 0 or 1.
About two thirds of patients had hemoglobin levels less than 12 g/dL.
Most patients did not have extranodal nonbone-marrow disease (82%), although there was a significant difference between those with HL (90%) and NHL (50%), P=0.03.
One third of patients had bulky disease, and 88% were in their second or third trimesters at diagnosis.
Three women electively terminated their pregnancies at diagnosis. Of the 36 remaining patients, 24 (61%) began antenatal therapy and 12 (31%) postponed therapy until after delivery.
Four patients received radiation therapy above the diaphragm at a median dose of 40.4 Gy.
Obstetric outcomes
Antenatal therapy was not associated with increased incidence of preterm delivery. Of the 24 women who received treatment during pregnancy, 7 (29%) gave birth prematurely compared with 5 of the 12 women (42%) who postponed treatment until after delivery, P=0.73.
The investigators noted that the miscarriage rate was approximately 10%, which was higher than previous studies.
Four patients had miscarriages, 2 during the first trimester and 2 during the second. Both patients who had miscarriages in the first trimester had received lymphoma treatment during that time.
And one of the patients who had antenatal therapy during the second trimester and had a miscarriage was critically ill, which the investigators believed was a contributing factor.
The second woman who miscarried after therapy in the second trimester had conceived twins through in vitro fertilization and miscarried at 23 weeks after ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy had been initiated at gestational week 15.
Investigators had fetal outcomes available for 31 of 32 patients who did not terminate or have a miscarriage. And these 31 infants had no anomalies at birth.
The investigators said that although the follow-up time is relatively short, they observed no malformations in the newborns.
Treatment responses and survival
The overall response rate (OR) was 91.7% and the complete response (CR) rate was 75.0% for the 24 patients who started treatment during pregnancy.
And for those 12 women who deferred therapy until delivery, both ORR and CR rates were 91.7%.
The 5-year progression-free survival (PFS) and OS were 74.7% and 82.4%, respectively, for all women. The median follow-up was 67.9 months (range 8.8 to 277.5).
For the 31 women with HL, the 5-year PFS and OS were 69.9% and 80%, respectively.
And for the 8 women with NHL, the 5-year PFS and OS were 85.7% and 83.3%, respectively.
Investigators found no difference in PFS or OS (P=0.84) based on undergoing antenatal lymphoma treatment among the 36 women who did not terminate their pregnancies at diagnosis.
The investigators conducted a univariate analysis and found that for the 36 women who did not electively terminate their pregnancies, the following were associated with increased risk of disease progression:
• Bulky disease—hazard ratio [HR] 3.6, P = 0.06
• Extranodal nonbone marrow involvement—HR 4.2, P = 0.04
• Poor ECOG performance status—HR 3.9, P = 0.005
Poor performance status was also associated with OS, HR 8.88, P = 0.004.
Multivariate analysis revealed significant associations in terms of OS and PFS for extranodal nonbone marrow involvement and performance status:
• Nonbone marrow involvement—OS HR, 73.5, P = 0.02; PFS HR 8.26, P = 0.01
• Performance status—OS HR, 26.7, P = 0.003; PFS HR, 4.89, P = 0.002
The investigators concluded that because they found no differences in PFS or OS according to whether patients received antenatal therapy, they believe that disease factors, rather than treatment-related factors, influence worse maternal outcomes.
They recommended delaying therapy until the second trimester if that can be accomplished without harm to the patient.
Photo credit: Vera Kratochvil
A single-center retrospective study of 39 pregnant women diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy indicates that delaying treatment until the second trimester is “likely safe and results in acceptable” outcomes for both mother and child.
Investigators also found that deferring therapy until after delivery did not adversely affect maternal outcomes.
In order to clarify the sometimes conflicting reports regarding management of lymphoma during pregnancy, investigators at MD Anderson Cancer Center in Houston, Texas, undertook the study to determine whether administering standard chemotherapy during the second and third trimesters has acceptable maternal and fetal outcomes.
Michelle A. Fanale, MD, and colleagues published their findings in JAMA Oncology.
Patient characteristics
Investigators identified 31 women with HL and 8 with NHL who were diagnosed between 1991 and 2014 and had sufficient pregnancy and follow-up data.
The women were a median age of 28 years (range 19-38). The patients with NHL were significantly older, P=0.004.
Approximately 20% of patients had B symptoms. Most were stage II disease (72%), and 80% were ECOG performance status 0 or 1.
About two thirds of patients had hemoglobin levels less than 12 g/dL.
Most patients did not have extranodal nonbone-marrow disease (82%), although there was a significant difference between those with HL (90%) and NHL (50%), P=0.03.
One third of patients had bulky disease, and 88% were in their second or third trimesters at diagnosis.
Three women electively terminated their pregnancies at diagnosis. Of the 36 remaining patients, 24 (61%) began antenatal therapy and 12 (31%) postponed therapy until after delivery.
Four patients received radiation therapy above the diaphragm at a median dose of 40.4 Gy.
Obstetric outcomes
Antenatal therapy was not associated with increased incidence of preterm delivery. Of the 24 women who received treatment during pregnancy, 7 (29%) gave birth prematurely compared with 5 of the 12 women (42%) who postponed treatment until after delivery, P=0.73.
The investigators noted that the miscarriage rate was approximately 10%, which was higher than previous studies.
Four patients had miscarriages, 2 during the first trimester and 2 during the second. Both patients who had miscarriages in the first trimester had received lymphoma treatment during that time.
And one of the patients who had antenatal therapy during the second trimester and had a miscarriage was critically ill, which the investigators believed was a contributing factor.
The second woman who miscarried after therapy in the second trimester had conceived twins through in vitro fertilization and miscarried at 23 weeks after ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy had been initiated at gestational week 15.
Investigators had fetal outcomes available for 31 of 32 patients who did not terminate or have a miscarriage. And these 31 infants had no anomalies at birth.
The investigators said that although the follow-up time is relatively short, they observed no malformations in the newborns.
Treatment responses and survival
The overall response rate (OR) was 91.7% and the complete response (CR) rate was 75.0% for the 24 patients who started treatment during pregnancy.
And for those 12 women who deferred therapy until delivery, both ORR and CR rates were 91.7%.
The 5-year progression-free survival (PFS) and OS were 74.7% and 82.4%, respectively, for all women. The median follow-up was 67.9 months (range 8.8 to 277.5).
For the 31 women with HL, the 5-year PFS and OS were 69.9% and 80%, respectively.
And for the 8 women with NHL, the 5-year PFS and OS were 85.7% and 83.3%, respectively.
Investigators found no difference in PFS or OS (P=0.84) based on undergoing antenatal lymphoma treatment among the 36 women who did not terminate their pregnancies at diagnosis.
The investigators conducted a univariate analysis and found that for the 36 women who did not electively terminate their pregnancies, the following were associated with increased risk of disease progression:
• Bulky disease—hazard ratio [HR] 3.6, P = 0.06
• Extranodal nonbone marrow involvement—HR 4.2, P = 0.04
• Poor ECOG performance status—HR 3.9, P = 0.005
Poor performance status was also associated with OS, HR 8.88, P = 0.004.
Multivariate analysis revealed significant associations in terms of OS and PFS for extranodal nonbone marrow involvement and performance status:
• Nonbone marrow involvement—OS HR, 73.5, P = 0.02; PFS HR 8.26, P = 0.01
• Performance status—OS HR, 26.7, P = 0.003; PFS HR, 4.89, P = 0.002
The investigators concluded that because they found no differences in PFS or OS according to whether patients received antenatal therapy, they believe that disease factors, rather than treatment-related factors, influence worse maternal outcomes.
They recommended delaying therapy until the second trimester if that can be accomplished without harm to the patient.