Leukemia, Myelodysplasia, Transplantation

Ibrutinib (Imbruvica)

Photo courtesy of Janssen

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).

Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).

NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.

This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.

Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF

or similar program.

Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.

New recommendation

NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the

price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.

The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).

The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.

NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.

Ibrutinib (Imbruvica)

Photo courtesy of Janssen

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).

Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).

NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.

This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.

Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF

or similar program.

Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.

New recommendation

NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the

price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.

The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).

The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.

NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.

Ibrutinib (Imbruvica)

Photo courtesy of Janssen

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).

Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).

NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.

This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.

Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF

or similar program.

Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.

New recommendation

NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the

price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.

The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).

The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.

NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.

Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.

“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.

To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.

“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”

In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.

Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).

Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.

“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.

Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.

“As a result of further analysis of these studies, there’s a new safety label indication,” he said.

Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.

“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.

More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.

Age was found in the study to be a significant risk factor for early hepatotoxicity.

“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”

Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.

Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.

Preclinical data from mouse models supports this mechanism.

“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.

Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.

sworcester@frontlinemedcom.com

NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.

Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.

“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.

To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.

“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”

In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.

Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).

Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.

“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.

Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.

“As a result of further analysis of these studies, there’s a new safety label indication,” he said.

Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.

“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.

More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.

Age was found in the study to be a significant risk factor for early hepatotoxicity.

“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”

Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.

Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.

Preclinical data from mouse models supports this mechanism.

“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.

Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.

sworcester@frontlinemedcom.com

NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.

Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.

“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.

To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.

“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”

In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.

Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).

Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.

“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.

Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.

“As a result of further analysis of these studies, there’s a new safety label indication,” he said.

Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.

“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.

More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.

Age was found in the study to be a significant risk factor for early hepatotoxicity.

“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”

Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.

Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.

Preclinical data from mouse models supports this mechanism.

“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.

Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.

sworcester@frontlinemedcom.com

Philadelphia chromosome–like acute lymphoblastic leukemia, a high-risk subtype of childhood ALL, accounts for more than 24% of ALL in adults and is associated with poor outcome, according to gene-expression profiling in nearly 800 adults with B-cell ALL.

In the 798 subjects aged 21-86 years, Philadelphia chromosome–like (Ph-like) ALL accounted for 27.9% of ALL cases in those aged 21-39 years, 20.4% of cases in those aged 40-59 years, and 24% of cases in those aged 60-86 years. The overall 5-year event-free survival rate was inferior in those with Ph-like ALL vs. non–Ph-like ALL (22.5% vs. 49.3%), as was the 5-year overall survival (23.8% vs. 52.4%). Increasing age also was associated with inferior outcomes: 5-year event-free survival was 40.4%, 29.8%, and 18.9% in the age groups, respectively, and 5-year overall survival was 45.2%, 35.1%, and 28.4% in the groups, respectively, Kathryn G. Roberts, Ph.D., of St. Jude Children’s Research Hospital in Memphis and her colleagues reported online ahead of print (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.69.0073).

sworcester@frontlinemedcom.com

Philadelphia chromosome–like acute lymphoblastic leukemia, a high-risk subtype of childhood ALL, accounts for more than 24% of ALL in adults and is associated with poor outcome, according to gene-expression profiling in nearly 800 adults with B-cell ALL.

In the 798 subjects aged 21-86 years, Philadelphia chromosome–like (Ph-like) ALL accounted for 27.9% of ALL cases in those aged 21-39 years, 20.4% of cases in those aged 40-59 years, and 24% of cases in those aged 60-86 years. The overall 5-year event-free survival rate was inferior in those with Ph-like ALL vs. non–Ph-like ALL (22.5% vs. 49.3%), as was the 5-year overall survival (23.8% vs. 52.4%). Increasing age also was associated with inferior outcomes: 5-year event-free survival was 40.4%, 29.8%, and 18.9% in the age groups, respectively, and 5-year overall survival was 45.2%, 35.1%, and 28.4% in the groups, respectively, Kathryn G. Roberts, Ph.D., of St. Jude Children’s Research Hospital in Memphis and her colleagues reported online ahead of print (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.69.0073).

sworcester@frontlinemedcom.com

Philadelphia chromosome–like acute lymphoblastic leukemia, a high-risk subtype of childhood ALL, accounts for more than 24% of ALL in adults and is associated with poor outcome, according to gene-expression profiling in nearly 800 adults with B-cell ALL.

In the 798 subjects aged 21-86 years, Philadelphia chromosome–like (Ph-like) ALL accounted for 27.9% of ALL cases in those aged 21-39 years, 20.4% of cases in those aged 40-59 years, and 24% of cases in those aged 60-86 years. The overall 5-year event-free survival rate was inferior in those with Ph-like ALL vs. non–Ph-like ALL (22.5% vs. 49.3%), as was the 5-year overall survival (23.8% vs. 52.4%). Increasing age also was associated with inferior outcomes: 5-year event-free survival was 40.4%, 29.8%, and 18.9% in the age groups, respectively, and 5-year overall survival was 45.2%, 35.1%, and 28.4% in the groups, respectively, Kathryn G. Roberts, Ph.D., of St. Jude Children’s Research Hospital in Memphis and her colleagues reported online ahead of print (J Clin Oncol. 2016 Nov 21. doi: 10.1200/JCO.2016.69.0073).

sworcester@frontlinemedcom.com

Micrograph showing APL

Image courtesy of the Armed

Forces Institute of Pathology

The European Commission (EC) has extended the approved indication for arsenic trioxide (Trisenox®) in patients with acute promyelocytic leukemia (APL).

The drug is now approved for use in combination with all-trans-retinoic acid (ATRA) to induce remission and for consolidation in adults with newly diagnosed low- to intermediate-risk APL (white blood cell count, ≤ 10 x 10³/μL) characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene.

Arsenic trioxide was previously approved by the EC to induce remission and as consolidation in adults with relapsed/refractory APL, which is characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene, whose previous treatment included a retinoid and chemotherapy.

“This [expanded] approval by the European Commission is good news for APL patients, as we now have access to a cure for an acute leukemia without using chemotherapy,” said Francesco Lo-Coco, MD, of University of Rome Tor Vergata in Italy.

“Moreover, this decision is a very positive endorsement by the European Commission, as it was made based solely on published academic research and studies.”

Arsenic trioxide is marketed by Teva Pharmaceutical Industries Ltd.

Phase 3 study results

The EC’s expanded approval of arsenic trioxide is based on results from the APL0406 Intergroup GIMEMA-AMLSG-SAL study. Previous results from this phase 3 study were published in NEJM in 2013.

Updated results include 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.

A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).

After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).

At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).

After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.

In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.

Micrograph showing APL

Image courtesy of the Armed

Forces Institute of Pathology

The European Commission (EC) has extended the approved indication for arsenic trioxide (Trisenox®) in patients with acute promyelocytic leukemia (APL).

The drug is now approved for use in combination with all-trans-retinoic acid (ATRA) to induce remission and for consolidation in adults with newly diagnosed low- to intermediate-risk APL (white blood cell count, ≤ 10 x 10³/μL) characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene.

Arsenic trioxide was previously approved by the EC to induce remission and as consolidation in adults with relapsed/refractory APL, which is characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene, whose previous treatment included a retinoid and chemotherapy.

“This [expanded] approval by the European Commission is good news for APL patients, as we now have access to a cure for an acute leukemia without using chemotherapy,” said Francesco Lo-Coco, MD, of University of Rome Tor Vergata in Italy.

“Moreover, this decision is a very positive endorsement by the European Commission, as it was made based solely on published academic research and studies.”

Arsenic trioxide is marketed by Teva Pharmaceutical Industries Ltd.

Phase 3 study results

The EC’s expanded approval of arsenic trioxide is based on results from the APL0406 Intergroup GIMEMA-AMLSG-SAL study. Previous results from this phase 3 study were published in NEJM in 2013.

Updated results include 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.

A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).

After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).

At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).

After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.

In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.

Micrograph showing APL

Image courtesy of the Armed

Forces Institute of Pathology

The European Commission (EC) has extended the approved indication for arsenic trioxide (Trisenox®) in patients with acute promyelocytic leukemia (APL).

The drug is now approved for use in combination with all-trans-retinoic acid (ATRA) to induce remission and for consolidation in adults with newly diagnosed low- to intermediate-risk APL (white blood cell count, ≤ 10 x 10³/μL) characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene.

Arsenic trioxide was previously approved by the EC to induce remission and as consolidation in adults with relapsed/refractory APL, which is characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene, whose previous treatment included a retinoid and chemotherapy.

“This [expanded] approval by the European Commission is good news for APL patients, as we now have access to a cure for an acute leukemia without using chemotherapy,” said Francesco Lo-Coco, MD, of University of Rome Tor Vergata in Italy.

“Moreover, this decision is a very positive endorsement by the European Commission, as it was made based solely on published academic research and studies.”

Arsenic trioxide is marketed by Teva Pharmaceutical Industries Ltd.

Phase 3 study results

The EC’s expanded approval of arsenic trioxide is based on results from the APL0406 Intergroup GIMEMA-AMLSG-SAL study. Previous results from this phase 3 study were published in NEJM in 2013.

Updated results include 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.

A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).

After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).

At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).

After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.

In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.

Acute myeloid leukemia (AML) is characterized by clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular components.¹ Acute promyeloctic leukemia (APL; previously called AML-M3), a subtype of AML, is further characterized by a balanced translocation t(15;17) (q24.1;q21.1). It is an interesting model in cancer research because it responds to the differentiation and apoptosis induction therapy using arsenic trioxide (ATO) and all-trans retinoic acid (ATRA).²

Click on the PDF icon at the top of this introduction to read the full article.

Acute myeloid leukemia (AML) is characterized by clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular components.¹ Acute promyeloctic leukemia (APL; previously called AML-M3), a subtype of AML, is further characterized by a balanced translocation t(15;17) (q24.1;q21.1). It is an interesting model in cancer research because it responds to the differentiation and apoptosis induction therapy using arsenic trioxide (ATO) and all-trans retinoic acid (ATRA).²

Click on the PDF icon at the top of this introduction to read the full article.

Acute myeloid leukemia (AML) is characterized by clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular components.¹ Acute promyeloctic leukemia (APL; previously called AML-M3), a subtype of AML, is further characterized by a balanced translocation t(15;17) (q24.1;q21.1). It is an interesting model in cancer research because it responds to the differentiation and apoptosis induction therapy using arsenic trioxide (ATO) and all-trans retinoic acid (ATRA).²

Click on the PDF icon at the top of this introduction to read the full article.