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AFib risk with cancer drugs underestimated
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atorvastatin cut anthracycline cardiac dysfunction in lymphoma
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
AT ACC 2023
ZUMA-5: Axi-cel yields high response rate in indolent NHL
, according to phase 2 study results presented at the annual meeting of the American Society of Hematology, held virtually this year.
The overall response rate exceeded 90% in the ZUMA-5 study, which included patients with multiply relapsed follicular lymphoma (FL) or marginal zone lymphoma (MZL) who were treated with this anti-CD19 chimeric antigen receptor (CAR) T cell therapy.
“Although longer follow-up is needed, these responses appear to be durable,” said investigator Caron Jacobson, MD, of Dana-Farber Cancer Institute in Boston.
Complete responses (CRs) after axi-cel treatment were seen in about three-quarters of patients, and most of those patients were still in response with a median follow-up that approached 1.5 years as of this report at the ASH meeting.
In her presentation, Dr. Jacobson said the safety profile of axi-cel in ZUMA-5 was manageable and “at least similar” to what was previously seen in aggressive relapsed lymphomas, referring to the ZUMA-1 study that led to 2017 approval by the Food and Drug Administration of the treatment for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.
The FL patient cohort in ZUMA-5 appeared to have lower rates of cytokine release syndrome (CRS) and high-grade neurotoxicity, compared with the MZL cohort in the study, she added.
Catherine Bollard, MD, of Children’s National Research Institute in Washington, said these results suggest axi-cel may be a “viable treatment option” for some patients with indolent lymphomas who have not responded to other therapies.
“What the field does need is long-term follow-up in the real-world setting to see what the true progression-free and disease-free survival is for these patients,” said Dr. Bollard, who moderated a media briefing that included the ZUMA-5 study.
“It’s really exciting to see this data in the [indolent] lymphoma setting, and I actually would like to see it moved further up in the treatment of patients, earlier in their disease process, if that’s going to be possible,” she added.
Promising results
The report on ZUMA-5, presented by Dr. Jacobson, involved 146 patients with relapsed/refractory indolent NHL: 124 patients with FL and an exploratory cohort of 22 patients with MZL. All patients had received at least two prior lines of therapy.
Following a fludarabine/cyclophosphamide conditioning regimen, patients received axi-cel at the FDA-approved dose of 2 x 106 CAR-positive T cells per kg of body weight. The primary endpoint of the study was overall response rate (ORR).
For 104 patients evaluable for efficacy, the ORR was 92% (96 patients), including CR in 76% (79 patients), data show. Among 84 FL patients evaluable for efficacy, ORR and CR were 94% (79 patients) and 80% (67 patients), respectively, while among 20 evaluable patients in the exploratory MZL cohort, ORR and CR were 60% (12 patients) and 25% (5 patients), respectively.
Sixty-four percent of patients with FL had an ongoing response at a median follow-up of 17.5 months, according to Dr. Jacobson, who added that median duration of response (DOR) had not been reached, while the 12-month DOR rate approached 72%.
The 12-month progression-free survival and overall survival rates were 73.7% and 92.9%, respectively, with medians not yet reached for either survival outcome, according to reported data.
Adverse effects
The incidence of grade 3 or greater neurologic events was lower in FL patients (15%), compared with MZL patients (41%), according to Dr. Jacobson.
While CRS occurred in 82% of patients, rates of grade 3 or greater CRS occurred in just 6% of FL patients and 9% of MZL patients, the investigator said.
There were no grade 5 neurologic events, and one grade 5 CRS was observed, she noted in her presentation.
The median time to onset of CRS was 4 days, compared with 2 days in the ZUMA-1 trial. “This may have implications for the possibility of outpatient therapy,” she said.
A study is planned to look at outpatient administration of axi-cel in patients with indolent NHL, she added.
Dr. Jacobson said she had no conflicts of interest to declare. Coauthors reported disclosures related to Kite, a Gilead Company; Genentech; Epizyme; Verastem; Novartis; and Pfizer, among others.
Correction, 12/7/20: An earlier version of this article misattributed some aspects of the ZUMA-5 trial to ZUMA-1.
SOURCE: Jacobson CA et al. ASH 2020, Abstract 700.
, according to phase 2 study results presented at the annual meeting of the American Society of Hematology, held virtually this year.
The overall response rate exceeded 90% in the ZUMA-5 study, which included patients with multiply relapsed follicular lymphoma (FL) or marginal zone lymphoma (MZL) who were treated with this anti-CD19 chimeric antigen receptor (CAR) T cell therapy.
“Although longer follow-up is needed, these responses appear to be durable,” said investigator Caron Jacobson, MD, of Dana-Farber Cancer Institute in Boston.
Complete responses (CRs) after axi-cel treatment were seen in about three-quarters of patients, and most of those patients were still in response with a median follow-up that approached 1.5 years as of this report at the ASH meeting.
In her presentation, Dr. Jacobson said the safety profile of axi-cel in ZUMA-5 was manageable and “at least similar” to what was previously seen in aggressive relapsed lymphomas, referring to the ZUMA-1 study that led to 2017 approval by the Food and Drug Administration of the treatment for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.
The FL patient cohort in ZUMA-5 appeared to have lower rates of cytokine release syndrome (CRS) and high-grade neurotoxicity, compared with the MZL cohort in the study, she added.
Catherine Bollard, MD, of Children’s National Research Institute in Washington, said these results suggest axi-cel may be a “viable treatment option” for some patients with indolent lymphomas who have not responded to other therapies.
“What the field does need is long-term follow-up in the real-world setting to see what the true progression-free and disease-free survival is for these patients,” said Dr. Bollard, who moderated a media briefing that included the ZUMA-5 study.
“It’s really exciting to see this data in the [indolent] lymphoma setting, and I actually would like to see it moved further up in the treatment of patients, earlier in their disease process, if that’s going to be possible,” she added.
Promising results
The report on ZUMA-5, presented by Dr. Jacobson, involved 146 patients with relapsed/refractory indolent NHL: 124 patients with FL and an exploratory cohort of 22 patients with MZL. All patients had received at least two prior lines of therapy.
Following a fludarabine/cyclophosphamide conditioning regimen, patients received axi-cel at the FDA-approved dose of 2 x 106 CAR-positive T cells per kg of body weight. The primary endpoint of the study was overall response rate (ORR).
For 104 patients evaluable for efficacy, the ORR was 92% (96 patients), including CR in 76% (79 patients), data show. Among 84 FL patients evaluable for efficacy, ORR and CR were 94% (79 patients) and 80% (67 patients), respectively, while among 20 evaluable patients in the exploratory MZL cohort, ORR and CR were 60% (12 patients) and 25% (5 patients), respectively.
Sixty-four percent of patients with FL had an ongoing response at a median follow-up of 17.5 months, according to Dr. Jacobson, who added that median duration of response (DOR) had not been reached, while the 12-month DOR rate approached 72%.
The 12-month progression-free survival and overall survival rates were 73.7% and 92.9%, respectively, with medians not yet reached for either survival outcome, according to reported data.
Adverse effects
The incidence of grade 3 or greater neurologic events was lower in FL patients (15%), compared with MZL patients (41%), according to Dr. Jacobson.
While CRS occurred in 82% of patients, rates of grade 3 or greater CRS occurred in just 6% of FL patients and 9% of MZL patients, the investigator said.
There were no grade 5 neurologic events, and one grade 5 CRS was observed, she noted in her presentation.
The median time to onset of CRS was 4 days, compared with 2 days in the ZUMA-1 trial. “This may have implications for the possibility of outpatient therapy,” she said.
A study is planned to look at outpatient administration of axi-cel in patients with indolent NHL, she added.
Dr. Jacobson said she had no conflicts of interest to declare. Coauthors reported disclosures related to Kite, a Gilead Company; Genentech; Epizyme; Verastem; Novartis; and Pfizer, among others.
Correction, 12/7/20: An earlier version of this article misattributed some aspects of the ZUMA-5 trial to ZUMA-1.
SOURCE: Jacobson CA et al. ASH 2020, Abstract 700.
, according to phase 2 study results presented at the annual meeting of the American Society of Hematology, held virtually this year.
The overall response rate exceeded 90% in the ZUMA-5 study, which included patients with multiply relapsed follicular lymphoma (FL) or marginal zone lymphoma (MZL) who were treated with this anti-CD19 chimeric antigen receptor (CAR) T cell therapy.
“Although longer follow-up is needed, these responses appear to be durable,” said investigator Caron Jacobson, MD, of Dana-Farber Cancer Institute in Boston.
Complete responses (CRs) after axi-cel treatment were seen in about three-quarters of patients, and most of those patients were still in response with a median follow-up that approached 1.5 years as of this report at the ASH meeting.
In her presentation, Dr. Jacobson said the safety profile of axi-cel in ZUMA-5 was manageable and “at least similar” to what was previously seen in aggressive relapsed lymphomas, referring to the ZUMA-1 study that led to 2017 approval by the Food and Drug Administration of the treatment for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.
The FL patient cohort in ZUMA-5 appeared to have lower rates of cytokine release syndrome (CRS) and high-grade neurotoxicity, compared with the MZL cohort in the study, she added.
Catherine Bollard, MD, of Children’s National Research Institute in Washington, said these results suggest axi-cel may be a “viable treatment option” for some patients with indolent lymphomas who have not responded to other therapies.
“What the field does need is long-term follow-up in the real-world setting to see what the true progression-free and disease-free survival is for these patients,” said Dr. Bollard, who moderated a media briefing that included the ZUMA-5 study.
“It’s really exciting to see this data in the [indolent] lymphoma setting, and I actually would like to see it moved further up in the treatment of patients, earlier in their disease process, if that’s going to be possible,” she added.
Promising results
The report on ZUMA-5, presented by Dr. Jacobson, involved 146 patients with relapsed/refractory indolent NHL: 124 patients with FL and an exploratory cohort of 22 patients with MZL. All patients had received at least two prior lines of therapy.
Following a fludarabine/cyclophosphamide conditioning regimen, patients received axi-cel at the FDA-approved dose of 2 x 106 CAR-positive T cells per kg of body weight. The primary endpoint of the study was overall response rate (ORR).
For 104 patients evaluable for efficacy, the ORR was 92% (96 patients), including CR in 76% (79 patients), data show. Among 84 FL patients evaluable for efficacy, ORR and CR were 94% (79 patients) and 80% (67 patients), respectively, while among 20 evaluable patients in the exploratory MZL cohort, ORR and CR were 60% (12 patients) and 25% (5 patients), respectively.
Sixty-four percent of patients with FL had an ongoing response at a median follow-up of 17.5 months, according to Dr. Jacobson, who added that median duration of response (DOR) had not been reached, while the 12-month DOR rate approached 72%.
The 12-month progression-free survival and overall survival rates were 73.7% and 92.9%, respectively, with medians not yet reached for either survival outcome, according to reported data.
Adverse effects
The incidence of grade 3 or greater neurologic events was lower in FL patients (15%), compared with MZL patients (41%), according to Dr. Jacobson.
While CRS occurred in 82% of patients, rates of grade 3 or greater CRS occurred in just 6% of FL patients and 9% of MZL patients, the investigator said.
There were no grade 5 neurologic events, and one grade 5 CRS was observed, she noted in her presentation.
The median time to onset of CRS was 4 days, compared with 2 days in the ZUMA-1 trial. “This may have implications for the possibility of outpatient therapy,” she said.
A study is planned to look at outpatient administration of axi-cel in patients with indolent NHL, she added.
Dr. Jacobson said she had no conflicts of interest to declare. Coauthors reported disclosures related to Kite, a Gilead Company; Genentech; Epizyme; Verastem; Novartis; and Pfizer, among others.
Correction, 12/7/20: An earlier version of this article misattributed some aspects of the ZUMA-5 trial to ZUMA-1.
SOURCE: Jacobson CA et al. ASH 2020, Abstract 700.
FROM ASH 2020
COVID-19–related outcomes poor for patients with hematologic disease in ASH registry
Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.
Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.
However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.
The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.
Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.
“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.
ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.
However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.
“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
Comorbidities and more
Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.
Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.
To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.
More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.
All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.
The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.
The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.
At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.
Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.
Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).
“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.
Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.
SOURCE: Wood WA et al. ASH 2020, Abstract 215.
Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.
Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.
However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.
The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.
Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.
“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.
ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.
However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.
“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
Comorbidities and more
Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.
Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.
To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.
More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.
All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.
The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.
The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.
At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.
Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.
Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).
“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.
Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.
SOURCE: Wood WA et al. ASH 2020, Abstract 215.
Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.
Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.
However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.
The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.
Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.
“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.
ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.
However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.
“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
Comorbidities and more
Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.
Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.
To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.
More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.
All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.
The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.
The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.
At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.
Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.
Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).
“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.
Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.
SOURCE: Wood WA et al. ASH 2020, Abstract 215.
FROM ASH 2020
Care coordination, equity can eliminate disparities for nonwhite patients with DLBCL
ORLANDO – Patients with diffuse large B-cell lymphoma (DLBCL) who are members of an ethnic or racial minority do not have worse outcomes than whites when they receive appropriate treatment and institutional support, a study on disparities in cancer care shows.
Although previous studies have shown that minorities with DLBCL have worse outcomes than do whites, results of a study comparing outcomes from 155 patients of white heritage with those of 41 patients from black, Hispanic, or other minority backgrounds found no significant differences in either progression-free survival (PFS) or overall survival in 2 years over follow-up, reported Nilanjan Ghosh, MD, PhD, from the Levine Cancer Institute, Atrium Health, in Charlotte, N.C.
He attributes the results to his center’s robust nurse navigation program, equal access among all patients – regardless of ability to pay – to standard treatments, and to the availability of clinical trial participation and stem cell transplantation.
“I think a key message is that if you are able to offer the same treatment and clinical trials to people irrespective of their race or socioeconomic status and can provide support, you can get equal outcomes as long as the biology is the same in both groups,” he said at a briefing prior to presentation of data in an oral abstract session at the annual meeting of the American Society of Hematology.
Dr. Ghosh pointed to four separate studies that showed that minority populations with DLBCL have worse outcomes than did whites, and noted that both uninsured and Medicaid-insured patients have also been shown to have poorer results, suggesting a role of socioeconomic factors in determining who gets optimum care and who does not.
The investigators compared PFS and OS among white and nonwhite patients with DLBCL treated in their institution, which has a safety-net cancer center. They also looked at the frequencies of clinical trial participation and stem cell transplantation between the groups.
The study included all patients with de novo DLBCL who presented to their center during January 2016–January 2019. They used patient-reported descriptors of race/ethnicity to create one of two cohorts: either self-identified whites (155 patients) or nonwhites (41), a group that included black patients, Hispanic patients, Asian Americans, and Native Americans.
The authors collected data on demographics, disease characteristics (including revised International Prognostic Index and double-hit status), insurance data, treatment, trial enrollment, progression, and death.
They found that nonwhites were significantly younger at diagnosis (median 56 vs. 64 years; P = .007), with an even distribution between the sexes in each group.
Two-thirds of both white and nonwhite patients had government insurance (Medicare or Medicaid). Of the remaining patients, 33% of white had private insurance, compared with 27% of nonwhites. No whites were uninsured, but 3 of the 41 nonwhites (7%) had no insurance.
Of the 155 white patients, 121 (86%) received nurse navigation services, as did 33 of 41 (81%) of nonwhites. The services include lodging assistance for homeless patients, transportation services for patients without cars, and care coordination among primary care physicians, oncologists, and other specialists. The services are part of the center’s standard practice, with excess costs, if any, folded into the budget, Dr. Ghosh said.
Looking at disease characteristics and treatment, the investigators found that risk profiles were similar between the groups. A higher percentage of whites had double-hit lymphoma (11% vs. 7%), but this difference was not statistically significant.
The investigators also found that in their program race was not a barrier to optimum therapy, with 96% of whites and 98% of nonwhites receiving frontline therapy with an anthracycline and rituximab-based regimen, and 4% and 2%, respectively received a non–anthracycline based regimen.
In each group, 39% of patients had disease that either relapsed or was refractory to frontline therapy.
In all, 11% of whites and 12% of nonwhites enrolled in clinical trials, 11% and 19%, respectively, underwent stem cell transplantation.
For patients with relapsed/refractory disease, the 2-year PFS rates were 60% for whites, and 63% for nonwhites, and the 2-year OS rates were 74% and 81%, respectively.
Dr. Ghosh and colleagues concluded that “our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants, and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported.”
The study was internally funded. Dr. Ghosh reported consulting fees, research funding, speakers bureau activity, and/or honoraria from multiple companies.
SOURCE: Hu B et al. ASH 2019. Abstract 425.
ORLANDO – Patients with diffuse large B-cell lymphoma (DLBCL) who are members of an ethnic or racial minority do not have worse outcomes than whites when they receive appropriate treatment and institutional support, a study on disparities in cancer care shows.
Although previous studies have shown that minorities with DLBCL have worse outcomes than do whites, results of a study comparing outcomes from 155 patients of white heritage with those of 41 patients from black, Hispanic, or other minority backgrounds found no significant differences in either progression-free survival (PFS) or overall survival in 2 years over follow-up, reported Nilanjan Ghosh, MD, PhD, from the Levine Cancer Institute, Atrium Health, in Charlotte, N.C.
He attributes the results to his center’s robust nurse navigation program, equal access among all patients – regardless of ability to pay – to standard treatments, and to the availability of clinical trial participation and stem cell transplantation.
“I think a key message is that if you are able to offer the same treatment and clinical trials to people irrespective of their race or socioeconomic status and can provide support, you can get equal outcomes as long as the biology is the same in both groups,” he said at a briefing prior to presentation of data in an oral abstract session at the annual meeting of the American Society of Hematology.
Dr. Ghosh pointed to four separate studies that showed that minority populations with DLBCL have worse outcomes than did whites, and noted that both uninsured and Medicaid-insured patients have also been shown to have poorer results, suggesting a role of socioeconomic factors in determining who gets optimum care and who does not.
The investigators compared PFS and OS among white and nonwhite patients with DLBCL treated in their institution, which has a safety-net cancer center. They also looked at the frequencies of clinical trial participation and stem cell transplantation between the groups.
The study included all patients with de novo DLBCL who presented to their center during January 2016–January 2019. They used patient-reported descriptors of race/ethnicity to create one of two cohorts: either self-identified whites (155 patients) or nonwhites (41), a group that included black patients, Hispanic patients, Asian Americans, and Native Americans.
The authors collected data on demographics, disease characteristics (including revised International Prognostic Index and double-hit status), insurance data, treatment, trial enrollment, progression, and death.
They found that nonwhites were significantly younger at diagnosis (median 56 vs. 64 years; P = .007), with an even distribution between the sexes in each group.
Two-thirds of both white and nonwhite patients had government insurance (Medicare or Medicaid). Of the remaining patients, 33% of white had private insurance, compared with 27% of nonwhites. No whites were uninsured, but 3 of the 41 nonwhites (7%) had no insurance.
Of the 155 white patients, 121 (86%) received nurse navigation services, as did 33 of 41 (81%) of nonwhites. The services include lodging assistance for homeless patients, transportation services for patients without cars, and care coordination among primary care physicians, oncologists, and other specialists. The services are part of the center’s standard practice, with excess costs, if any, folded into the budget, Dr. Ghosh said.
Looking at disease characteristics and treatment, the investigators found that risk profiles were similar between the groups. A higher percentage of whites had double-hit lymphoma (11% vs. 7%), but this difference was not statistically significant.
The investigators also found that in their program race was not a barrier to optimum therapy, with 96% of whites and 98% of nonwhites receiving frontline therapy with an anthracycline and rituximab-based regimen, and 4% and 2%, respectively received a non–anthracycline based regimen.
In each group, 39% of patients had disease that either relapsed or was refractory to frontline therapy.
In all, 11% of whites and 12% of nonwhites enrolled in clinical trials, 11% and 19%, respectively, underwent stem cell transplantation.
For patients with relapsed/refractory disease, the 2-year PFS rates were 60% for whites, and 63% for nonwhites, and the 2-year OS rates were 74% and 81%, respectively.
Dr. Ghosh and colleagues concluded that “our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants, and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported.”
The study was internally funded. Dr. Ghosh reported consulting fees, research funding, speakers bureau activity, and/or honoraria from multiple companies.
SOURCE: Hu B et al. ASH 2019. Abstract 425.
ORLANDO – Patients with diffuse large B-cell lymphoma (DLBCL) who are members of an ethnic or racial minority do not have worse outcomes than whites when they receive appropriate treatment and institutional support, a study on disparities in cancer care shows.
Although previous studies have shown that minorities with DLBCL have worse outcomes than do whites, results of a study comparing outcomes from 155 patients of white heritage with those of 41 patients from black, Hispanic, or other minority backgrounds found no significant differences in either progression-free survival (PFS) or overall survival in 2 years over follow-up, reported Nilanjan Ghosh, MD, PhD, from the Levine Cancer Institute, Atrium Health, in Charlotte, N.C.
He attributes the results to his center’s robust nurse navigation program, equal access among all patients – regardless of ability to pay – to standard treatments, and to the availability of clinical trial participation and stem cell transplantation.
“I think a key message is that if you are able to offer the same treatment and clinical trials to people irrespective of their race or socioeconomic status and can provide support, you can get equal outcomes as long as the biology is the same in both groups,” he said at a briefing prior to presentation of data in an oral abstract session at the annual meeting of the American Society of Hematology.
Dr. Ghosh pointed to four separate studies that showed that minority populations with DLBCL have worse outcomes than did whites, and noted that both uninsured and Medicaid-insured patients have also been shown to have poorer results, suggesting a role of socioeconomic factors in determining who gets optimum care and who does not.
The investigators compared PFS and OS among white and nonwhite patients with DLBCL treated in their institution, which has a safety-net cancer center. They also looked at the frequencies of clinical trial participation and stem cell transplantation between the groups.
The study included all patients with de novo DLBCL who presented to their center during January 2016–January 2019. They used patient-reported descriptors of race/ethnicity to create one of two cohorts: either self-identified whites (155 patients) or nonwhites (41), a group that included black patients, Hispanic patients, Asian Americans, and Native Americans.
The authors collected data on demographics, disease characteristics (including revised International Prognostic Index and double-hit status), insurance data, treatment, trial enrollment, progression, and death.
They found that nonwhites were significantly younger at diagnosis (median 56 vs. 64 years; P = .007), with an even distribution between the sexes in each group.
Two-thirds of both white and nonwhite patients had government insurance (Medicare or Medicaid). Of the remaining patients, 33% of white had private insurance, compared with 27% of nonwhites. No whites were uninsured, but 3 of the 41 nonwhites (7%) had no insurance.
Of the 155 white patients, 121 (86%) received nurse navigation services, as did 33 of 41 (81%) of nonwhites. The services include lodging assistance for homeless patients, transportation services for patients without cars, and care coordination among primary care physicians, oncologists, and other specialists. The services are part of the center’s standard practice, with excess costs, if any, folded into the budget, Dr. Ghosh said.
Looking at disease characteristics and treatment, the investigators found that risk profiles were similar between the groups. A higher percentage of whites had double-hit lymphoma (11% vs. 7%), but this difference was not statistically significant.
The investigators also found that in their program race was not a barrier to optimum therapy, with 96% of whites and 98% of nonwhites receiving frontline therapy with an anthracycline and rituximab-based regimen, and 4% and 2%, respectively received a non–anthracycline based regimen.
In each group, 39% of patients had disease that either relapsed or was refractory to frontline therapy.
In all, 11% of whites and 12% of nonwhites enrolled in clinical trials, 11% and 19%, respectively, underwent stem cell transplantation.
For patients with relapsed/refractory disease, the 2-year PFS rates were 60% for whites, and 63% for nonwhites, and the 2-year OS rates were 74% and 81%, respectively.
Dr. Ghosh and colleagues concluded that “our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants, and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported.”
The study was internally funded. Dr. Ghosh reported consulting fees, research funding, speakers bureau activity, and/or honoraria from multiple companies.
SOURCE: Hu B et al. ASH 2019. Abstract 425.
REPORTING FROM ASH 2019
ASCO to award $50,000 young investigator grant to study MCL
Early-career researchers who are interested in studying
The young investigator grant is for a 1-year period and the award is used to fund a project focused on clinical or translational research on the clinical biology, natural history, prevention, screening, diagnosis, therapy, or epidemiology of MCL.
The purpose of this annual award, according to ASCO, is to fund physicians during the transition from a fellowship program to a faculty appointment.
Eligible applicants must be physicians currently in the last 2 years of final subspecialty training and within 10 years of having obtained his or her medical degree. Additionally, applicants must be planning a research career in clinical oncology, with a focus on MCL.
The grant selection committee’s primary criteria include the significance and originality of the proposed study and hypothesis, the feasibility of the experiment and methodology, whether it has an appropriate and detailed statistical analysis plan, and if the research is patient oriented.
The application deadline is Jan. 7, 2020, and the award term is July 1, 2020–June 30, 2021.
Application instructions are available on the ASCO website.
Early-career researchers who are interested in studying
The young investigator grant is for a 1-year period and the award is used to fund a project focused on clinical or translational research on the clinical biology, natural history, prevention, screening, diagnosis, therapy, or epidemiology of MCL.
The purpose of this annual award, according to ASCO, is to fund physicians during the transition from a fellowship program to a faculty appointment.
Eligible applicants must be physicians currently in the last 2 years of final subspecialty training and within 10 years of having obtained his or her medical degree. Additionally, applicants must be planning a research career in clinical oncology, with a focus on MCL.
The grant selection committee’s primary criteria include the significance and originality of the proposed study and hypothesis, the feasibility of the experiment and methodology, whether it has an appropriate and detailed statistical analysis plan, and if the research is patient oriented.
The application deadline is Jan. 7, 2020, and the award term is July 1, 2020–June 30, 2021.
Application instructions are available on the ASCO website.
Early-career researchers who are interested in studying
The young investigator grant is for a 1-year period and the award is used to fund a project focused on clinical or translational research on the clinical biology, natural history, prevention, screening, diagnosis, therapy, or epidemiology of MCL.
The purpose of this annual award, according to ASCO, is to fund physicians during the transition from a fellowship program to a faculty appointment.
Eligible applicants must be physicians currently in the last 2 years of final subspecialty training and within 10 years of having obtained his or her medical degree. Additionally, applicants must be planning a research career in clinical oncology, with a focus on MCL.
The grant selection committee’s primary criteria include the significance and originality of the proposed study and hypothesis, the feasibility of the experiment and methodology, whether it has an appropriate and detailed statistical analysis plan, and if the research is patient oriented.
The application deadline is Jan. 7, 2020, and the award term is July 1, 2020–June 30, 2021.
Application instructions are available on the ASCO website.
Group proposes new grading systems for CRS, neurotoxicity
A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.
The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.
The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.
Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.
CRS
The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:
- Hypotension
- Capillary leak (hypoxia)
- End organ dysfunction.
The ASBMT consensus for grading CRS is as follows:
- Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
- Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
- Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
- Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
- Grade 5—Death due to CRS when there is no other “principle factor” leading to death.
Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.
The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”
Neurotoxicity
Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”
The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
Symptoms of ICANS may include:
- Aphasia
- Altered level of consciousness
- Impairment of cognitive skills
- Motor weakness
- Seizures
- Cerebral edema.
The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:
- Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
- Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
- Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).
The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:
- Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
- Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
- Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors reported relationships with a range of companies.
A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.
The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.
The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.
Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.
CRS
The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:
- Hypotension
- Capillary leak (hypoxia)
- End organ dysfunction.
The ASBMT consensus for grading CRS is as follows:
- Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
- Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
- Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
- Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
- Grade 5—Death due to CRS when there is no other “principle factor” leading to death.
Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.
The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”
Neurotoxicity
Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”
The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
Symptoms of ICANS may include:
- Aphasia
- Altered level of consciousness
- Impairment of cognitive skills
- Motor weakness
- Seizures
- Cerebral edema.
The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:
- Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
- Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
- Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).
The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:
- Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
- Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
- Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors reported relationships with a range of companies.
A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.
The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.
The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.
Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.
CRS
The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:
- Hypotension
- Capillary leak (hypoxia)
- End organ dysfunction.
The ASBMT consensus for grading CRS is as follows:
- Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
- Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
- Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
- Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
- Grade 5—Death due to CRS when there is no other “principle factor” leading to death.
Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.
The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”
Neurotoxicity
Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”
The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
Symptoms of ICANS may include:
- Aphasia
- Altered level of consciousness
- Impairment of cognitive skills
- Motor weakness
- Seizures
- Cerebral edema.
The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:
- Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
- Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
- Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).
The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:
- Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
- Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
- Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors reported relationships with a range of companies.
Combo bests standard care in younger CLL patients
SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).
Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).
“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.
In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.
He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).
The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).
IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m2 on day 1 of cycle 2, at 325 mg/m2 on day 2 of cycle 2, and at 500 mg/m2 on day 1 for cycles 3 to 7.
From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.
Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.
He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.
PFS
In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).
In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).
In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.
PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).
Overall survival
In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).
In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).
Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.
Safety and cost
Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).
Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).
AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).
Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.
“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.
The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.
*Data in the abstract differ from the presentation.
SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).
Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).
“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.
In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.
He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).
The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).
IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m2 on day 1 of cycle 2, at 325 mg/m2 on day 2 of cycle 2, and at 500 mg/m2 on day 1 for cycles 3 to 7.
From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.
Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.
He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.
PFS
In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).
In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).
In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.
PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).
Overall survival
In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).
In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).
Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.
Safety and cost
Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).
Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).
AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).
Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.
“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.
The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.
*Data in the abstract differ from the presentation.
SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).
Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).
“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.
In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.
He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).
The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).
IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m2 on day 1 of cycle 2, at 325 mg/m2 on day 2 of cycle 2, and at 500 mg/m2 on day 1 for cycles 3 to 7.
From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.
Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.
He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.
PFS
In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).
In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).
In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.
PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).
Overall survival
In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).
In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).
Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.
Safety and cost
Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).
Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).
AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).
Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.
“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.
The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.
*Data in the abstract differ from the presentation.
Fludarabine deemed important for CD30.CAR T-cell therapy
SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.
A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.
However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.
Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*
This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.
Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.
The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).
Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).
In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.
Bendamustine alone
Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m2. Three of these patients received CD30.CAR T-cell therapy at 1×108 cells/m2, and all three progressed.
Of the five patients who received CAR T-cell therapy at a dose of 2×108 cells/m2, one progressed, one had stable disease, and three had a complete response (CR).
However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.
“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”
When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.
Bendamustine plus fludarabine
Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m2 and fludarabine at 30 mg/m2.
All 16 patients received CAR T cells at 2×108 cells/m2, which was the recommended phase 2 dose.
“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.
Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.
Two patients had a partial response, one had stable disease, and one progressed.
PFS and toxicity
Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.
The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).
There was no neurotoxicity in this trial.
Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.
Eight patients had a mild rash, one of whom had a rash at baseline.
“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.
“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”
This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.
*Data in the abstract differ from the presentation.
SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.
A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.
However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.
Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*
This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.
Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.
The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).
Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).
In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.
Bendamustine alone
Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m2. Three of these patients received CD30.CAR T-cell therapy at 1×108 cells/m2, and all three progressed.
Of the five patients who received CAR T-cell therapy at a dose of 2×108 cells/m2, one progressed, one had stable disease, and three had a complete response (CR).
However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.
“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”
When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.
Bendamustine plus fludarabine
Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m2 and fludarabine at 30 mg/m2.
All 16 patients received CAR T cells at 2×108 cells/m2, which was the recommended phase 2 dose.
“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.
Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.
Two patients had a partial response, one had stable disease, and one progressed.
PFS and toxicity
Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.
The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).
There was no neurotoxicity in this trial.
Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.
Eight patients had a mild rash, one of whom had a rash at baseline.
“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.
“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”
This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.
*Data in the abstract differ from the presentation.
SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.
A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.
However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.
Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*
This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.
Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.
The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).
Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).
In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.
Bendamustine alone
Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m2. Three of these patients received CD30.CAR T-cell therapy at 1×108 cells/m2, and all three progressed.
Of the five patients who received CAR T-cell therapy at a dose of 2×108 cells/m2, one progressed, one had stable disease, and three had a complete response (CR).
However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.
“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”
When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.
Bendamustine plus fludarabine
Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m2 and fludarabine at 30 mg/m2.
All 16 patients received CAR T cells at 2×108 cells/m2, which was the recommended phase 2 dose.
“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.
Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.
Two patients had a partial response, one had stable disease, and one progressed.
PFS and toxicity
Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.
The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).
There was no neurotoxicity in this trial.
Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.
Eight patients had a mild rash, one of whom had a rash at baseline.
“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.
“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”
This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.
*Data in the abstract differ from the presentation.
Mutation confers resistance to venetoclax in CLL
SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.
A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.
The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.
Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.
SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.
A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.
The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.
Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.
SAN DIEGO—A recurrent mutation in BCL2, the therapeutic target of venetoclax, appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, according to Piers Blombery, MBBS, of the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said during the late-breaking abstracts session at the 2018 ASH Annual Meeting.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” Dr. Blombery added.
A paper on the mutation was published in Cancer Discovery to coincide with the presentation at ASH (abstract LBA-7).
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven patients, the investigators identified a novel mutation that showed up at the time of progression but was absent from the pre-venetoclax samples.
The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies.
Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, the investigators determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and, in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage compared with wild-type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
He added that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
Dr. Blombery reported having no relevant disclosures. The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation.