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For leukemias, COVID-19 death risks tied to poor prognoses, ICU deferrals
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
FROM ASH 2021
Customizing pre-CAR T chemotherapy could improve ALL patient outcomes
The findings, if validated in a prospective study, could help cut the rate of relapses after initial response to CAR T-cell therapy, which currently approaches 50%, the investigators noted.
In 152 pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) who underwent CD-19-directed CAR T-cell therapy after cyclophosphamide/fludarabine lymphodepleting chemotherapy, estimated fludarabine exposure was associated with cumulative incidence of relapse (CIR) and a composite endpoint that included loss of B-cell aplasia (BCA) or relapse, Vanessa Fabrizio, MD, and colleagues found.
Dr. Fabrizio, a pediatric hematologist and oncologist at Children’s Hospital Colorado and the University of Colorado Cancer Center in Aurora, was a fellow at Memorial Sloan Kettering (MSK) Cancer Center during the study.
Optimal fludarabine exposure was identified by the investigators as an area under the curve (AUC) of at least 13.8 mg*hr/L. The fludarabine exposure AUC was calculated for each patient by using a validated pharmacokinetics population model.
Multivariable analyses controlling for baseline patient factors and fludarabine exposure showed that patients without optimal exposure had a 2.5-fold higher CIR (hazard ratio, 2.45), and a twofold higher risk of relapse or loss of BCA (HR, 1.96), compared with those who had optimal fludarabine exposure, they reported.
High pre-infusion disease burden was associated with an increased risk of relapse and death (HRs, 2.66 and 4.77, respectively), they said.
The study was published online Nov. 17 in Blood Advances.
“We know that [with] fludarabine ... everyone’s body clears it differently,” principal investigator Kevin J. Curran, MD, said in an interview.
Factors affecting clearance include kidney function and weight, and it is simple to determine the optimal dose based on these factors and apply that in practice, said Dr. Curran, a pediatric oncologist and assistant attending physician specializing in cellular therapy at MSK Kids.
In fact, in prior studies, optimal fludarabine exposure in patients undergoing allogeneic hematopoietic cell transplantation has been shown to “decrease nonrelapse mortality due to improved immune reconstitution and subsequently improve survival,” he and his colleagues wrote, explaining the rationale for the study.
The participants, who were part of the Pediatric Real-World CAR Consortium (PRWCC), had a median age of 12.5 years, and 131 of 152 (86%) responded to CAR T-cell therapy. The 12-month OS was 75.1%, the 12-month CIR was 36.4%, and 67% of patients had optimal fludarabine exposure, the authors said.
The findings indeed suggest that one way to improve outcomes without changing the actual cell therapy is to tailor the lymphodepleting therapy prior to CAR T-cell therapy, said Dr. Curran.
“That’s what this does. It’s exciting because cell therapy is very effective [in terms of] initial response, but what we don’t like is the durability of the response,” he said “The next step is to prove it in a prospective study.”
A phase 2 study looking at personalized dosing, as opposed to the standard 30 mg/m2 that most patients receive, is planned for 2022, he noted.
The study was supported by a St Baldrick’s/Stand Up 2 Cancer Pediatric Dream Team Translational Cancer Research Grant, the Virginia and D.K. Ludwig Fund for Cancer Research, and a National Cancer Institute Cancer Center Support Grant. Dr. Curran has served as a consultant for Novartis and Mesoblast, and received research funding from Novartis and Celgene. Dr. Fabrizio reported having no disclosures.
The findings, if validated in a prospective study, could help cut the rate of relapses after initial response to CAR T-cell therapy, which currently approaches 50%, the investigators noted.
In 152 pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) who underwent CD-19-directed CAR T-cell therapy after cyclophosphamide/fludarabine lymphodepleting chemotherapy, estimated fludarabine exposure was associated with cumulative incidence of relapse (CIR) and a composite endpoint that included loss of B-cell aplasia (BCA) or relapse, Vanessa Fabrizio, MD, and colleagues found.
Dr. Fabrizio, a pediatric hematologist and oncologist at Children’s Hospital Colorado and the University of Colorado Cancer Center in Aurora, was a fellow at Memorial Sloan Kettering (MSK) Cancer Center during the study.
Optimal fludarabine exposure was identified by the investigators as an area under the curve (AUC) of at least 13.8 mg*hr/L. The fludarabine exposure AUC was calculated for each patient by using a validated pharmacokinetics population model.
Multivariable analyses controlling for baseline patient factors and fludarabine exposure showed that patients without optimal exposure had a 2.5-fold higher CIR (hazard ratio, 2.45), and a twofold higher risk of relapse or loss of BCA (HR, 1.96), compared with those who had optimal fludarabine exposure, they reported.
High pre-infusion disease burden was associated with an increased risk of relapse and death (HRs, 2.66 and 4.77, respectively), they said.
The study was published online Nov. 17 in Blood Advances.
“We know that [with] fludarabine ... everyone’s body clears it differently,” principal investigator Kevin J. Curran, MD, said in an interview.
Factors affecting clearance include kidney function and weight, and it is simple to determine the optimal dose based on these factors and apply that in practice, said Dr. Curran, a pediatric oncologist and assistant attending physician specializing in cellular therapy at MSK Kids.
In fact, in prior studies, optimal fludarabine exposure in patients undergoing allogeneic hematopoietic cell transplantation has been shown to “decrease nonrelapse mortality due to improved immune reconstitution and subsequently improve survival,” he and his colleagues wrote, explaining the rationale for the study.
The participants, who were part of the Pediatric Real-World CAR Consortium (PRWCC), had a median age of 12.5 years, and 131 of 152 (86%) responded to CAR T-cell therapy. The 12-month OS was 75.1%, the 12-month CIR was 36.4%, and 67% of patients had optimal fludarabine exposure, the authors said.
The findings indeed suggest that one way to improve outcomes without changing the actual cell therapy is to tailor the lymphodepleting therapy prior to CAR T-cell therapy, said Dr. Curran.
“That’s what this does. It’s exciting because cell therapy is very effective [in terms of] initial response, but what we don’t like is the durability of the response,” he said “The next step is to prove it in a prospective study.”
A phase 2 study looking at personalized dosing, as opposed to the standard 30 mg/m2 that most patients receive, is planned for 2022, he noted.
The study was supported by a St Baldrick’s/Stand Up 2 Cancer Pediatric Dream Team Translational Cancer Research Grant, the Virginia and D.K. Ludwig Fund for Cancer Research, and a National Cancer Institute Cancer Center Support Grant. Dr. Curran has served as a consultant for Novartis and Mesoblast, and received research funding from Novartis and Celgene. Dr. Fabrizio reported having no disclosures.
The findings, if validated in a prospective study, could help cut the rate of relapses after initial response to CAR T-cell therapy, which currently approaches 50%, the investigators noted.
In 152 pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) who underwent CD-19-directed CAR T-cell therapy after cyclophosphamide/fludarabine lymphodepleting chemotherapy, estimated fludarabine exposure was associated with cumulative incidence of relapse (CIR) and a composite endpoint that included loss of B-cell aplasia (BCA) or relapse, Vanessa Fabrizio, MD, and colleagues found.
Dr. Fabrizio, a pediatric hematologist and oncologist at Children’s Hospital Colorado and the University of Colorado Cancer Center in Aurora, was a fellow at Memorial Sloan Kettering (MSK) Cancer Center during the study.
Optimal fludarabine exposure was identified by the investigators as an area under the curve (AUC) of at least 13.8 mg*hr/L. The fludarabine exposure AUC was calculated for each patient by using a validated pharmacokinetics population model.
Multivariable analyses controlling for baseline patient factors and fludarabine exposure showed that patients without optimal exposure had a 2.5-fold higher CIR (hazard ratio, 2.45), and a twofold higher risk of relapse or loss of BCA (HR, 1.96), compared with those who had optimal fludarabine exposure, they reported.
High pre-infusion disease burden was associated with an increased risk of relapse and death (HRs, 2.66 and 4.77, respectively), they said.
The study was published online Nov. 17 in Blood Advances.
“We know that [with] fludarabine ... everyone’s body clears it differently,” principal investigator Kevin J. Curran, MD, said in an interview.
Factors affecting clearance include kidney function and weight, and it is simple to determine the optimal dose based on these factors and apply that in practice, said Dr. Curran, a pediatric oncologist and assistant attending physician specializing in cellular therapy at MSK Kids.
In fact, in prior studies, optimal fludarabine exposure in patients undergoing allogeneic hematopoietic cell transplantation has been shown to “decrease nonrelapse mortality due to improved immune reconstitution and subsequently improve survival,” he and his colleagues wrote, explaining the rationale for the study.
The participants, who were part of the Pediatric Real-World CAR Consortium (PRWCC), had a median age of 12.5 years, and 131 of 152 (86%) responded to CAR T-cell therapy. The 12-month OS was 75.1%, the 12-month CIR was 36.4%, and 67% of patients had optimal fludarabine exposure, the authors said.
The findings indeed suggest that one way to improve outcomes without changing the actual cell therapy is to tailor the lymphodepleting therapy prior to CAR T-cell therapy, said Dr. Curran.
“That’s what this does. It’s exciting because cell therapy is very effective [in terms of] initial response, but what we don’t like is the durability of the response,” he said “The next step is to prove it in a prospective study.”
A phase 2 study looking at personalized dosing, as opposed to the standard 30 mg/m2 that most patients receive, is planned for 2022, he noted.
The study was supported by a St Baldrick’s/Stand Up 2 Cancer Pediatric Dream Team Translational Cancer Research Grant, the Virginia and D.K. Ludwig Fund for Cancer Research, and a National Cancer Institute Cancer Center Support Grant. Dr. Curran has served as a consultant for Novartis and Mesoblast, and received research funding from Novartis and Celgene. Dr. Fabrizio reported having no disclosures.
FROM BLOOD ADVANCES
Treating ALL: Asparaginase enzyme levels linked to toxicities
Key toxicities related to treating acute lymphoblastic leukemia (ALL) with asparaginase, specifically pancreatitis and osteonecrosis, are associated with increases in asparaginase enzyme activity, suggesting that patients at risk for those toxicities would benefit from therapeutic drug monitoring, according to new research.
In the study, published Oct. 8 in Blood Advances, increased asparaginase enzyme activity was not significantly associated with overall asparaginase toxicity. However,“ the authors concluded.
“The [findings are] new, and we have included patients from a quite big cohort, which is unique,” coauthor Birgitte Klug Albertsen, MD, PhD, associate clinical professor with Aarhus (Denmark) University Hospital, told this news organization.
Therapeutic drug monitoring already is widely used during treatment with asparaginase, the standard of care treatment for ALL; however, the focus of this monitoring has typically been on clinical effectiveness, as levels of asparaginase enzyme activity can indicate hypersensitivity reactions, while the absence of such activity can suggest inferior outcomes.
Meanwhile, drug monitoring is not normally used to assess the risk of treatment-related toxicities. This has been due to a lack of evidence regarding asparaginase enzyme activity and toxicity risk, which, if severe enough, can prevent further treatment.
To investigate the relationship with toxicities, Dr. Albertsen and colleagues evaluated data from seven countries in Europe on 1,155 children between the ages of 1 and 17.9 who were diagnosed with ALL and treated with asparaginase, according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between July 2008 and March 2016.
Blood samples drawn approximately 14 days after asparaginase administration showed that some level of asparaginase enzyme activity was measurable in 955 patients (82.7%), while 200 patients (17.3%) had asparaginase inactivation. Overall, there were 159 asparaginase-associated toxicities of pancreatitis, thromboembolism, or osteonecrosis among the 955 patients with measurable asparaginase enzyme activity.
There were no significant differences in median asparaginase enzyme activity levels between those who did and did not experience toxicities (224 IU/L vs. 221 IU/L, respectively; P = .1), and the results did not change after adjustment for age and sex. However, the risk of pancreatitis was found to increase with a hazard ratio (HR) of 1.40 for each 100 IU/L increase in the median asparaginase enzyme activity level (P = .002).
Likewise, an increase in risk was observed for osteonecrosis (HR 1.36; P = .02) per 100 IU/L increase in median asparaginase enzyme activity. However, the HR for the risk of thromboembolism, the most common of asparaginase-related toxicities, was not significant (HR 0.99; P = .96).
Dr. Albertsen said the etiology behind the occurrence of osteonecrosis is not well understood.
“We know that steroids, especially dexamethasone, are a risk factor,” she said. “We believe that asparaginase may play a role too, but a clear association has not been demonstrated.”
In the NOPHO ALL2008 protocol used in the study, dexamethasone is used in the same time periods as PEG-asparaginase treatment for patients receiving 15 doses.
The finding of only a nonsignificant trend between asparaginase enzyme activity with overall toxicities may have reflected the low dose that was used, Dr. Albertsen added.
“In the NOPHO ALL2008 protocol, we used quite a low dose of PEG-asparaginase, and the risk may be higher in protocols using higher doses,” she said.
Relapse reduction
Notably, the study showed that asparaginase enzyme elevations were, in fact, not significantly associated with a reduction in the risk of leukemic relapse (HR .88 per 100 IU/L increase; P = .35).
Those findings suggest that measurable asparaginase enzyme activity levels, and thus asparaginase depletion, “may be sufficient to ensure an antileukemic effect,” the authors noted.
“Therapeutic drug monitoring of asparaginase enzyme activity is indicated mainly to detect inactivation, but [it] may be further explored for dose reduction to reduce some specific toxicities,” they concluded.
Dr. Albertsen disclosed being sponsor of the investigator-initiatied NOR-GRASPALL 2016 trial.
Key toxicities related to treating acute lymphoblastic leukemia (ALL) with asparaginase, specifically pancreatitis and osteonecrosis, are associated with increases in asparaginase enzyme activity, suggesting that patients at risk for those toxicities would benefit from therapeutic drug monitoring, according to new research.
In the study, published Oct. 8 in Blood Advances, increased asparaginase enzyme activity was not significantly associated with overall asparaginase toxicity. However,“ the authors concluded.
“The [findings are] new, and we have included patients from a quite big cohort, which is unique,” coauthor Birgitte Klug Albertsen, MD, PhD, associate clinical professor with Aarhus (Denmark) University Hospital, told this news organization.
Therapeutic drug monitoring already is widely used during treatment with asparaginase, the standard of care treatment for ALL; however, the focus of this monitoring has typically been on clinical effectiveness, as levels of asparaginase enzyme activity can indicate hypersensitivity reactions, while the absence of such activity can suggest inferior outcomes.
Meanwhile, drug monitoring is not normally used to assess the risk of treatment-related toxicities. This has been due to a lack of evidence regarding asparaginase enzyme activity and toxicity risk, which, if severe enough, can prevent further treatment.
To investigate the relationship with toxicities, Dr. Albertsen and colleagues evaluated data from seven countries in Europe on 1,155 children between the ages of 1 and 17.9 who were diagnosed with ALL and treated with asparaginase, according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between July 2008 and March 2016.
Blood samples drawn approximately 14 days after asparaginase administration showed that some level of asparaginase enzyme activity was measurable in 955 patients (82.7%), while 200 patients (17.3%) had asparaginase inactivation. Overall, there were 159 asparaginase-associated toxicities of pancreatitis, thromboembolism, or osteonecrosis among the 955 patients with measurable asparaginase enzyme activity.
There were no significant differences in median asparaginase enzyme activity levels between those who did and did not experience toxicities (224 IU/L vs. 221 IU/L, respectively; P = .1), and the results did not change after adjustment for age and sex. However, the risk of pancreatitis was found to increase with a hazard ratio (HR) of 1.40 for each 100 IU/L increase in the median asparaginase enzyme activity level (P = .002).
Likewise, an increase in risk was observed for osteonecrosis (HR 1.36; P = .02) per 100 IU/L increase in median asparaginase enzyme activity. However, the HR for the risk of thromboembolism, the most common of asparaginase-related toxicities, was not significant (HR 0.99; P = .96).
Dr. Albertsen said the etiology behind the occurrence of osteonecrosis is not well understood.
“We know that steroids, especially dexamethasone, are a risk factor,” she said. “We believe that asparaginase may play a role too, but a clear association has not been demonstrated.”
In the NOPHO ALL2008 protocol used in the study, dexamethasone is used in the same time periods as PEG-asparaginase treatment for patients receiving 15 doses.
The finding of only a nonsignificant trend between asparaginase enzyme activity with overall toxicities may have reflected the low dose that was used, Dr. Albertsen added.
“In the NOPHO ALL2008 protocol, we used quite a low dose of PEG-asparaginase, and the risk may be higher in protocols using higher doses,” she said.
Relapse reduction
Notably, the study showed that asparaginase enzyme elevations were, in fact, not significantly associated with a reduction in the risk of leukemic relapse (HR .88 per 100 IU/L increase; P = .35).
Those findings suggest that measurable asparaginase enzyme activity levels, and thus asparaginase depletion, “may be sufficient to ensure an antileukemic effect,” the authors noted.
“Therapeutic drug monitoring of asparaginase enzyme activity is indicated mainly to detect inactivation, but [it] may be further explored for dose reduction to reduce some specific toxicities,” they concluded.
Dr. Albertsen disclosed being sponsor of the investigator-initiatied NOR-GRASPALL 2016 trial.
Key toxicities related to treating acute lymphoblastic leukemia (ALL) with asparaginase, specifically pancreatitis and osteonecrosis, are associated with increases in asparaginase enzyme activity, suggesting that patients at risk for those toxicities would benefit from therapeutic drug monitoring, according to new research.
In the study, published Oct. 8 in Blood Advances, increased asparaginase enzyme activity was not significantly associated with overall asparaginase toxicity. However,“ the authors concluded.
“The [findings are] new, and we have included patients from a quite big cohort, which is unique,” coauthor Birgitte Klug Albertsen, MD, PhD, associate clinical professor with Aarhus (Denmark) University Hospital, told this news organization.
Therapeutic drug monitoring already is widely used during treatment with asparaginase, the standard of care treatment for ALL; however, the focus of this monitoring has typically been on clinical effectiveness, as levels of asparaginase enzyme activity can indicate hypersensitivity reactions, while the absence of such activity can suggest inferior outcomes.
Meanwhile, drug monitoring is not normally used to assess the risk of treatment-related toxicities. This has been due to a lack of evidence regarding asparaginase enzyme activity and toxicity risk, which, if severe enough, can prevent further treatment.
To investigate the relationship with toxicities, Dr. Albertsen and colleagues evaluated data from seven countries in Europe on 1,155 children between the ages of 1 and 17.9 who were diagnosed with ALL and treated with asparaginase, according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between July 2008 and March 2016.
Blood samples drawn approximately 14 days after asparaginase administration showed that some level of asparaginase enzyme activity was measurable in 955 patients (82.7%), while 200 patients (17.3%) had asparaginase inactivation. Overall, there were 159 asparaginase-associated toxicities of pancreatitis, thromboembolism, or osteonecrosis among the 955 patients with measurable asparaginase enzyme activity.
There were no significant differences in median asparaginase enzyme activity levels between those who did and did not experience toxicities (224 IU/L vs. 221 IU/L, respectively; P = .1), and the results did not change after adjustment for age and sex. However, the risk of pancreatitis was found to increase with a hazard ratio (HR) of 1.40 for each 100 IU/L increase in the median asparaginase enzyme activity level (P = .002).
Likewise, an increase in risk was observed for osteonecrosis (HR 1.36; P = .02) per 100 IU/L increase in median asparaginase enzyme activity. However, the HR for the risk of thromboembolism, the most common of asparaginase-related toxicities, was not significant (HR 0.99; P = .96).
Dr. Albertsen said the etiology behind the occurrence of osteonecrosis is not well understood.
“We know that steroids, especially dexamethasone, are a risk factor,” she said. “We believe that asparaginase may play a role too, but a clear association has not been demonstrated.”
In the NOPHO ALL2008 protocol used in the study, dexamethasone is used in the same time periods as PEG-asparaginase treatment for patients receiving 15 doses.
The finding of only a nonsignificant trend between asparaginase enzyme activity with overall toxicities may have reflected the low dose that was used, Dr. Albertsen added.
“In the NOPHO ALL2008 protocol, we used quite a low dose of PEG-asparaginase, and the risk may be higher in protocols using higher doses,” she said.
Relapse reduction
Notably, the study showed that asparaginase enzyme elevations were, in fact, not significantly associated with a reduction in the risk of leukemic relapse (HR .88 per 100 IU/L increase; P = .35).
Those findings suggest that measurable asparaginase enzyme activity levels, and thus asparaginase depletion, “may be sufficient to ensure an antileukemic effect,” the authors noted.
“Therapeutic drug monitoring of asparaginase enzyme activity is indicated mainly to detect inactivation, but [it] may be further explored for dose reduction to reduce some specific toxicities,” they concluded.
Dr. Albertsen disclosed being sponsor of the investigator-initiatied NOR-GRASPALL 2016 trial.
Immunotherapies for children with r/r ALL face off
It’s possible to compare apples and oranges – both are fruits, after all; likewise, in the absence of head-to-head trials, it’s possible to make an indirect comparison of two immunotherapy strategies for treating relapsed or refractory pediatric acute lymphoblastic leukemia (r/r ALL): chimeric antigen receptor (CAR) T-cell therapy with tisagenlecleucel (Kymriah), and immunotherapy with the bi-specific T-cell engager (BiTE) blinatumomab (Blincyto).
Michael Verneris, MD, of the University of Colorado Anschutz Medical Center in Aurora, and associates carried out the first such indirect, patient-level comparison of these two immunotherapies.
“The large differences in CR and OS outcomes across multiple differing assessments suggest that our findings describe a true treatment impact. Although the current analysis is retrospective and limited by cross-study comparison, these findings support the growing body of clinical trial and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with r/r ALL,” they wrote in an article published in Blood Advances.
However, as two pediatric leukemia experts uninvolved in the study noted, the comparison may be of limited use because the two immunotherapy agents can have different indications and applications, depending on the clinical situation.
Trial data compared
Dr. Verneris and colleagues looked at patient-level data from two clinical trials: the phase 2 single-arm ELIANA trial evaluating tisagenlecleucel in patients with relapsed and refractory B-cell lineage ALL (79 patients), and the efficacy phase of the MT103-205 trial assessing blinatumomab in a similar population (70 patients).
To account for differences between the studies, the investigators used five different statistical approaches, including propensity score weighting and adjustment for prognostic factors.
Regardless of the analytical method they used, results showed that patients treated with tisagenlecleucel were significantly more likely to have complete remissions than were patients treated with blinatumomab, with odds ratios favoring the CAR T-cell construct ranging from 6.71 to 9.76.
Similarly, treatment with tisagenlecleucel was associated with lower risk for death, with hazard ratios ranging from 68% to 74%.
The authors acknowledged that some prognostic variables such as bone marrow blast count, remission duration, and performance status were not recorded in the patient level data from the blinatumomab trial and therefore they could not be used in the analyses. They also conceded that selection bias could account for some of the differences in outcomes between the trials.
Patient characteristics drive choice
The comparison of the two agents “is something we as treating physicians often think about, because we are faced with a choice often of tisagenlecleucel or blinatumomab when we have a relapsed/refractory patient, ” Melinda Pauly, MD, medical director of oncology at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, said in an interview.
Dr. Pauly, who was not involved in the study, said that the choice of therapy is based primarily on patient characteristics and the specific clinical situation.
“For patients who have prior toxicity with bone marrow transplant or don’t have a good donor option for bone marrow transplant, those are certainly patients that we are looking for a therapy that would be more sustained, and that would definitely be the tisagenlecleucel,” she said.
CAR T-cell therapy may not be an immediate option for patients for whom time is critical, however, due to the requirements of apheresis for T-cell harvesting, cell transduction, expansion, and infusion, and for such patients who have disease refractory to chemotherapy, blinatumomab may be an option.
Blinatumomab may also serve as a bridge to transplant, she said.
Dr. Pauly, who has a special interest in the care of infants with ALL, noted that apheresis can be difficult to accomplish in very young patients and may not yield T-cells sufficient for CAR T therapy, and for these patients blinatumomab may be the better option.
Howard Weinstein, MD, unit chief of the division of pediatric hematology/oncology at Mass General Hospital for Children in Boston, noted that “there are all kinds of statistical methodologies to try to balance the two populations in the studies, and they did as best as you can at balancing the risk factors, such as the number of patients with relapses after prior bone marrow transplants.”
“But there are so many genetic subtypes of acute lymphoblastic leukemia that have differing prognoses, it’s hard to do this kind of retrospective analysis when it’s not a randomized head-to-head trial,” he said in an interview.
Novartis Pharmaceuticals, maker of tisagenlecleucel, sponsored the study. Dr. Verneris disclosed serving on advisory boards for Novartis, and five of the study coauthors are employees of the company. Dr. Pauly and Dr. Weinstein reported having no conflicts of interest.
It’s possible to compare apples and oranges – both are fruits, after all; likewise, in the absence of head-to-head trials, it’s possible to make an indirect comparison of two immunotherapy strategies for treating relapsed or refractory pediatric acute lymphoblastic leukemia (r/r ALL): chimeric antigen receptor (CAR) T-cell therapy with tisagenlecleucel (Kymriah), and immunotherapy with the bi-specific T-cell engager (BiTE) blinatumomab (Blincyto).
Michael Verneris, MD, of the University of Colorado Anschutz Medical Center in Aurora, and associates carried out the first such indirect, patient-level comparison of these two immunotherapies.
“The large differences in CR and OS outcomes across multiple differing assessments suggest that our findings describe a true treatment impact. Although the current analysis is retrospective and limited by cross-study comparison, these findings support the growing body of clinical trial and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with r/r ALL,” they wrote in an article published in Blood Advances.
However, as two pediatric leukemia experts uninvolved in the study noted, the comparison may be of limited use because the two immunotherapy agents can have different indications and applications, depending on the clinical situation.
Trial data compared
Dr. Verneris and colleagues looked at patient-level data from two clinical trials: the phase 2 single-arm ELIANA trial evaluating tisagenlecleucel in patients with relapsed and refractory B-cell lineage ALL (79 patients), and the efficacy phase of the MT103-205 trial assessing blinatumomab in a similar population (70 patients).
To account for differences between the studies, the investigators used five different statistical approaches, including propensity score weighting and adjustment for prognostic factors.
Regardless of the analytical method they used, results showed that patients treated with tisagenlecleucel were significantly more likely to have complete remissions than were patients treated with blinatumomab, with odds ratios favoring the CAR T-cell construct ranging from 6.71 to 9.76.
Similarly, treatment with tisagenlecleucel was associated with lower risk for death, with hazard ratios ranging from 68% to 74%.
The authors acknowledged that some prognostic variables such as bone marrow blast count, remission duration, and performance status were not recorded in the patient level data from the blinatumomab trial and therefore they could not be used in the analyses. They also conceded that selection bias could account for some of the differences in outcomes between the trials.
Patient characteristics drive choice
The comparison of the two agents “is something we as treating physicians often think about, because we are faced with a choice often of tisagenlecleucel or blinatumomab when we have a relapsed/refractory patient, ” Melinda Pauly, MD, medical director of oncology at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, said in an interview.
Dr. Pauly, who was not involved in the study, said that the choice of therapy is based primarily on patient characteristics and the specific clinical situation.
“For patients who have prior toxicity with bone marrow transplant or don’t have a good donor option for bone marrow transplant, those are certainly patients that we are looking for a therapy that would be more sustained, and that would definitely be the tisagenlecleucel,” she said.
CAR T-cell therapy may not be an immediate option for patients for whom time is critical, however, due to the requirements of apheresis for T-cell harvesting, cell transduction, expansion, and infusion, and for such patients who have disease refractory to chemotherapy, blinatumomab may be an option.
Blinatumomab may also serve as a bridge to transplant, she said.
Dr. Pauly, who has a special interest in the care of infants with ALL, noted that apheresis can be difficult to accomplish in very young patients and may not yield T-cells sufficient for CAR T therapy, and for these patients blinatumomab may be the better option.
Howard Weinstein, MD, unit chief of the division of pediatric hematology/oncology at Mass General Hospital for Children in Boston, noted that “there are all kinds of statistical methodologies to try to balance the two populations in the studies, and they did as best as you can at balancing the risk factors, such as the number of patients with relapses after prior bone marrow transplants.”
“But there are so many genetic subtypes of acute lymphoblastic leukemia that have differing prognoses, it’s hard to do this kind of retrospective analysis when it’s not a randomized head-to-head trial,” he said in an interview.
Novartis Pharmaceuticals, maker of tisagenlecleucel, sponsored the study. Dr. Verneris disclosed serving on advisory boards for Novartis, and five of the study coauthors are employees of the company. Dr. Pauly and Dr. Weinstein reported having no conflicts of interest.
It’s possible to compare apples and oranges – both are fruits, after all; likewise, in the absence of head-to-head trials, it’s possible to make an indirect comparison of two immunotherapy strategies for treating relapsed or refractory pediatric acute lymphoblastic leukemia (r/r ALL): chimeric antigen receptor (CAR) T-cell therapy with tisagenlecleucel (Kymriah), and immunotherapy with the bi-specific T-cell engager (BiTE) blinatumomab (Blincyto).
Michael Verneris, MD, of the University of Colorado Anschutz Medical Center in Aurora, and associates carried out the first such indirect, patient-level comparison of these two immunotherapies.
“The large differences in CR and OS outcomes across multiple differing assessments suggest that our findings describe a true treatment impact. Although the current analysis is retrospective and limited by cross-study comparison, these findings support the growing body of clinical trial and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with r/r ALL,” they wrote in an article published in Blood Advances.
However, as two pediatric leukemia experts uninvolved in the study noted, the comparison may be of limited use because the two immunotherapy agents can have different indications and applications, depending on the clinical situation.
Trial data compared
Dr. Verneris and colleagues looked at patient-level data from two clinical trials: the phase 2 single-arm ELIANA trial evaluating tisagenlecleucel in patients with relapsed and refractory B-cell lineage ALL (79 patients), and the efficacy phase of the MT103-205 trial assessing blinatumomab in a similar population (70 patients).
To account for differences between the studies, the investigators used five different statistical approaches, including propensity score weighting and adjustment for prognostic factors.
Regardless of the analytical method they used, results showed that patients treated with tisagenlecleucel were significantly more likely to have complete remissions than were patients treated with blinatumomab, with odds ratios favoring the CAR T-cell construct ranging from 6.71 to 9.76.
Similarly, treatment with tisagenlecleucel was associated with lower risk for death, with hazard ratios ranging from 68% to 74%.
The authors acknowledged that some prognostic variables such as bone marrow blast count, remission duration, and performance status were not recorded in the patient level data from the blinatumomab trial and therefore they could not be used in the analyses. They also conceded that selection bias could account for some of the differences in outcomes between the trials.
Patient characteristics drive choice
The comparison of the two agents “is something we as treating physicians often think about, because we are faced with a choice often of tisagenlecleucel or blinatumomab when we have a relapsed/refractory patient, ” Melinda Pauly, MD, medical director of oncology at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, said in an interview.
Dr. Pauly, who was not involved in the study, said that the choice of therapy is based primarily on patient characteristics and the specific clinical situation.
“For patients who have prior toxicity with bone marrow transplant or don’t have a good donor option for bone marrow transplant, those are certainly patients that we are looking for a therapy that would be more sustained, and that would definitely be the tisagenlecleucel,” she said.
CAR T-cell therapy may not be an immediate option for patients for whom time is critical, however, due to the requirements of apheresis for T-cell harvesting, cell transduction, expansion, and infusion, and for such patients who have disease refractory to chemotherapy, blinatumomab may be an option.
Blinatumomab may also serve as a bridge to transplant, she said.
Dr. Pauly, who has a special interest in the care of infants with ALL, noted that apheresis can be difficult to accomplish in very young patients and may not yield T-cells sufficient for CAR T therapy, and for these patients blinatumomab may be the better option.
Howard Weinstein, MD, unit chief of the division of pediatric hematology/oncology at Mass General Hospital for Children in Boston, noted that “there are all kinds of statistical methodologies to try to balance the two populations in the studies, and they did as best as you can at balancing the risk factors, such as the number of patients with relapses after prior bone marrow transplants.”
“But there are so many genetic subtypes of acute lymphoblastic leukemia that have differing prognoses, it’s hard to do this kind of retrospective analysis when it’s not a randomized head-to-head trial,” he said in an interview.
Novartis Pharmaceuticals, maker of tisagenlecleucel, sponsored the study. Dr. Verneris disclosed serving on advisory boards for Novartis, and five of the study coauthors are employees of the company. Dr. Pauly and Dr. Weinstein reported having no conflicts of interest.
FROM BLOOD ADVANCES
New trials in leukemia: Could your patient benefit?
A number of late-phase clinical trials in leukemia have opened in recent months. Maybe one of your patients could benefit from being enrolled.
Adults and children with acute or chronic leukemias
A phase 2 study partnering with the National Marrow Donor Program is seeking individuals aged 1-65 years with lymphoma or one of the following leukemias: “acute leukemia”, acute lymphoblastic (ALL), acute myelogenous (AML), mixed-phenotype acute, chronic myelogenous (CML), and chronic lymphocytic (CLL). Researchers hope to find a way to improve outcomes of hematopoietic-cell transplantation from mismatched, unrelated donors. Participants will receive the transplant and one of seven drug regimens and will be followed for a year. The trial plans to enroll 180 people and began recruiting on Sept. 30 in California, New York, and Virginia. The primary outcome is overall survival (OS). Quality of life (QoL) will not be measured.
Mast-cell leukemia (MCL)
Adults with MCL are sought for a phase 2 study of bezuclastinib, an experimental tyrosine-kinase inhibitor (TKI) called CGT9486. CGT9486 blocks the activity of a mutated version of tyrosine-kinase receptor KIT, called KIT D816V, which is known to cause systemic mastocytosis. Participants will receive oral CGT9486 daily for up to 18 months. The study opened in October, aiming for 140 participants with any advanced systemic mastocytoses (including MCL) at sites in California, Florida, Massachusetts, New York, Ohio, Texas, and Utah. OS and QoL will be tracked.
Previously Treated CLL/Small Lymphocytic Lymphoma (SLL)
Patients with CLL/SLL who have progressed on previous therapy can join a phase 3 study of another experimental oral TIK, pirtobrutinib, this time targeting Bruton’s tyrosine kinase (BTK). BTK plays a key role in the lifecycle of white blood cells. Participants will receive either “fixed-duration” pirtobrutinib plus venetoclax (Venclexta) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera) or the venetoclax-rituximab combo only, for up to 5 years. Investigators started recruiting in September, aiming for 600 participants across Florida, Louisiana, Missouri, New York, and Tennessee. Progression-free survival is the primary outcome; OS is a secondary outcome and QoL will not be tracked.
High-grade myeloid cancers with measurable residual disease
Patients with AML, myelodysplastic syndrome with excess blasts-2 or myeloid neoplasm, and whose original disease is still present, are eligible for a phase 2 study of CPX-351 (daunorubicin-cytarabine, Vyxeos). The intravenous chemotherapy was approved in 2017 for certain types of AML. The goal of this study is to determine if pretreatment with CPX-351 improves the outcome of donor stem-cell transplantation. Patients will either undergo immediate transplantation or receive CPX-351 for up to 10 days followed 60 days later by the transplant. The study, being conducted at the Fred Hutchinson Cancer Research Center in Seattle, started recruiting 130 patients in August. The primary outcome is OS; QoL will not be tracked.
Newly diagnosed Philadelphia-negative ALL
Patients aged 22 or older with Philadelphia-negative ALL who have not received chemotherapy or radiation therapy are invited to join a trial of calaspargase pegol (Asparlas). The therapy was approved in 2018 for ALL in children and young adults (1 month to 21 years). The aim of this study is to confirm the recommended doses and evaluate the drug’s safety and pharmacodynamics in adults over aged 21. Each participant will receive six 2-hour infusions of calaspargase pegol over several months. The primary outcomes are safety and drug activity; OS is a secondary outcome and QoL will not be measured. The study opened on July 7 and aims to recruit 122 participants in 11 states.
Untreated adults with TP53-mutant AML
Adult patients with previously untreated AML who have at least one TP53 gene mutation are sought for a phase 3 study of magrolimab, an investigational anti-CD47 monoclonal antibody. Participants will be treated for up to 27 months with either magrolimab plus azacytidine (Vidaza), venetoclax plus azacytidine (patients deemed “appropriate for nonintensive therapy”), or standard chemotherapy (those “appropriate for intensive therapy”). In patients who received nonintensive therapy, OS is the primary outcome; OS in all participants is a secondary outcome, and QoL won’t be assessed. The trial opened in July and aims to recruit 346 individuals in Hong Kong, Australia, and the United States (California, Missouri, Oklahoma, Pennsylvania, South Carolina, and Texas).
All trial information is from the U.S. National Library of Medicine, National Institutes of Health.
A version of this article first appeared on Medscape.com.
A number of late-phase clinical trials in leukemia have opened in recent months. Maybe one of your patients could benefit from being enrolled.
Adults and children with acute or chronic leukemias
A phase 2 study partnering with the National Marrow Donor Program is seeking individuals aged 1-65 years with lymphoma or one of the following leukemias: “acute leukemia”, acute lymphoblastic (ALL), acute myelogenous (AML), mixed-phenotype acute, chronic myelogenous (CML), and chronic lymphocytic (CLL). Researchers hope to find a way to improve outcomes of hematopoietic-cell transplantation from mismatched, unrelated donors. Participants will receive the transplant and one of seven drug regimens and will be followed for a year. The trial plans to enroll 180 people and began recruiting on Sept. 30 in California, New York, and Virginia. The primary outcome is overall survival (OS). Quality of life (QoL) will not be measured.
Mast-cell leukemia (MCL)
Adults with MCL are sought for a phase 2 study of bezuclastinib, an experimental tyrosine-kinase inhibitor (TKI) called CGT9486. CGT9486 blocks the activity of a mutated version of tyrosine-kinase receptor KIT, called KIT D816V, which is known to cause systemic mastocytosis. Participants will receive oral CGT9486 daily for up to 18 months. The study opened in October, aiming for 140 participants with any advanced systemic mastocytoses (including MCL) at sites in California, Florida, Massachusetts, New York, Ohio, Texas, and Utah. OS and QoL will be tracked.
Previously Treated CLL/Small Lymphocytic Lymphoma (SLL)
Patients with CLL/SLL who have progressed on previous therapy can join a phase 3 study of another experimental oral TIK, pirtobrutinib, this time targeting Bruton’s tyrosine kinase (BTK). BTK plays a key role in the lifecycle of white blood cells. Participants will receive either “fixed-duration” pirtobrutinib plus venetoclax (Venclexta) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera) or the venetoclax-rituximab combo only, for up to 5 years. Investigators started recruiting in September, aiming for 600 participants across Florida, Louisiana, Missouri, New York, and Tennessee. Progression-free survival is the primary outcome; OS is a secondary outcome and QoL will not be tracked.
High-grade myeloid cancers with measurable residual disease
Patients with AML, myelodysplastic syndrome with excess blasts-2 or myeloid neoplasm, and whose original disease is still present, are eligible for a phase 2 study of CPX-351 (daunorubicin-cytarabine, Vyxeos). The intravenous chemotherapy was approved in 2017 for certain types of AML. The goal of this study is to determine if pretreatment with CPX-351 improves the outcome of donor stem-cell transplantation. Patients will either undergo immediate transplantation or receive CPX-351 for up to 10 days followed 60 days later by the transplant. The study, being conducted at the Fred Hutchinson Cancer Research Center in Seattle, started recruiting 130 patients in August. The primary outcome is OS; QoL will not be tracked.
Newly diagnosed Philadelphia-negative ALL
Patients aged 22 or older with Philadelphia-negative ALL who have not received chemotherapy or radiation therapy are invited to join a trial of calaspargase pegol (Asparlas). The therapy was approved in 2018 for ALL in children and young adults (1 month to 21 years). The aim of this study is to confirm the recommended doses and evaluate the drug’s safety and pharmacodynamics in adults over aged 21. Each participant will receive six 2-hour infusions of calaspargase pegol over several months. The primary outcomes are safety and drug activity; OS is a secondary outcome and QoL will not be measured. The study opened on July 7 and aims to recruit 122 participants in 11 states.
Untreated adults with TP53-mutant AML
Adult patients with previously untreated AML who have at least one TP53 gene mutation are sought for a phase 3 study of magrolimab, an investigational anti-CD47 monoclonal antibody. Participants will be treated for up to 27 months with either magrolimab plus azacytidine (Vidaza), venetoclax plus azacytidine (patients deemed “appropriate for nonintensive therapy”), or standard chemotherapy (those “appropriate for intensive therapy”). In patients who received nonintensive therapy, OS is the primary outcome; OS in all participants is a secondary outcome, and QoL won’t be assessed. The trial opened in July and aims to recruit 346 individuals in Hong Kong, Australia, and the United States (California, Missouri, Oklahoma, Pennsylvania, South Carolina, and Texas).
All trial information is from the U.S. National Library of Medicine, National Institutes of Health.
A version of this article first appeared on Medscape.com.
A number of late-phase clinical trials in leukemia have opened in recent months. Maybe one of your patients could benefit from being enrolled.
Adults and children with acute or chronic leukemias
A phase 2 study partnering with the National Marrow Donor Program is seeking individuals aged 1-65 years with lymphoma or one of the following leukemias: “acute leukemia”, acute lymphoblastic (ALL), acute myelogenous (AML), mixed-phenotype acute, chronic myelogenous (CML), and chronic lymphocytic (CLL). Researchers hope to find a way to improve outcomes of hematopoietic-cell transplantation from mismatched, unrelated donors. Participants will receive the transplant and one of seven drug regimens and will be followed for a year. The trial plans to enroll 180 people and began recruiting on Sept. 30 in California, New York, and Virginia. The primary outcome is overall survival (OS). Quality of life (QoL) will not be measured.
Mast-cell leukemia (MCL)
Adults with MCL are sought for a phase 2 study of bezuclastinib, an experimental tyrosine-kinase inhibitor (TKI) called CGT9486. CGT9486 blocks the activity of a mutated version of tyrosine-kinase receptor KIT, called KIT D816V, which is known to cause systemic mastocytosis. Participants will receive oral CGT9486 daily for up to 18 months. The study opened in October, aiming for 140 participants with any advanced systemic mastocytoses (including MCL) at sites in California, Florida, Massachusetts, New York, Ohio, Texas, and Utah. OS and QoL will be tracked.
Previously Treated CLL/Small Lymphocytic Lymphoma (SLL)
Patients with CLL/SLL who have progressed on previous therapy can join a phase 3 study of another experimental oral TIK, pirtobrutinib, this time targeting Bruton’s tyrosine kinase (BTK). BTK plays a key role in the lifecycle of white blood cells. Participants will receive either “fixed-duration” pirtobrutinib plus venetoclax (Venclexta) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera) or the venetoclax-rituximab combo only, for up to 5 years. Investigators started recruiting in September, aiming for 600 participants across Florida, Louisiana, Missouri, New York, and Tennessee. Progression-free survival is the primary outcome; OS is a secondary outcome and QoL will not be tracked.
High-grade myeloid cancers with measurable residual disease
Patients with AML, myelodysplastic syndrome with excess blasts-2 or myeloid neoplasm, and whose original disease is still present, are eligible for a phase 2 study of CPX-351 (daunorubicin-cytarabine, Vyxeos). The intravenous chemotherapy was approved in 2017 for certain types of AML. The goal of this study is to determine if pretreatment with CPX-351 improves the outcome of donor stem-cell transplantation. Patients will either undergo immediate transplantation or receive CPX-351 for up to 10 days followed 60 days later by the transplant. The study, being conducted at the Fred Hutchinson Cancer Research Center in Seattle, started recruiting 130 patients in August. The primary outcome is OS; QoL will not be tracked.
Newly diagnosed Philadelphia-negative ALL
Patients aged 22 or older with Philadelphia-negative ALL who have not received chemotherapy or radiation therapy are invited to join a trial of calaspargase pegol (Asparlas). The therapy was approved in 2018 for ALL in children and young adults (1 month to 21 years). The aim of this study is to confirm the recommended doses and evaluate the drug’s safety and pharmacodynamics in adults over aged 21. Each participant will receive six 2-hour infusions of calaspargase pegol over several months. The primary outcomes are safety and drug activity; OS is a secondary outcome and QoL will not be measured. The study opened on July 7 and aims to recruit 122 participants in 11 states.
Untreated adults with TP53-mutant AML
Adult patients with previously untreated AML who have at least one TP53 gene mutation are sought for a phase 3 study of magrolimab, an investigational anti-CD47 monoclonal antibody. Participants will be treated for up to 27 months with either magrolimab plus azacytidine (Vidaza), venetoclax plus azacytidine (patients deemed “appropriate for nonintensive therapy”), or standard chemotherapy (those “appropriate for intensive therapy”). In patients who received nonintensive therapy, OS is the primary outcome; OS in all participants is a secondary outcome, and QoL won’t be assessed. The trial opened in July and aims to recruit 346 individuals in Hong Kong, Australia, and the United States (California, Missouri, Oklahoma, Pennsylvania, South Carolina, and Texas).
All trial information is from the U.S. National Library of Medicine, National Institutes of Health.
A version of this article first appeared on Medscape.com.
Tolerability doesn’t explain why kids do better than adults on ALL regimens
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
FROM BLOOD ADVANCES
CAR T for ALL: Areas that need optimizing
The success of chimeric antigen receptor T (CAR T)-cell therapy for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has garnered much attention, but the field is still in its infancy – with toxicity and relapse rates remaining unacceptably high.
in the use of the therapy in this setting, according to review authors Vanessa A. Fabrizio, MD, a fellow at Duke University, Durham, N.C., and Kevin J. Curran, MD, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
Based on their review of early pivotal clinical trials, relapse data, toxicities, and mechanisms to optimize CAR T-cell therapy, Dr. Fabrizio and Dr. Curran outlined several “practice points” and proposed a research agenda aimed at optimizing the use of CAR T-cell therapy for B-ALL (Best Pract Res Clin Haematol. 2021 Aug 27. doi: 10.1016/j.beha.2021.101305).
Practice points
CAR T-cell therapy has transformed the treatment of both pediatric and adult patients with relapsed/refractory (R/R) B-ALL, the authors said, adding that “[c]linical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients.”
Dr. Fabrizio and Dr. Curran specifically note that only one product (tisagenlecleucel) is currently approved for the treatment of R/R B-ALL in patients under age 26 years. Further, the successful application of this therapy is limited by high relapse rates, significant toxicity in some cases, and challenges related to collection and production issues.
They contend that areas in which optimization of CAR T-cell therapy can occur include apheresis, production, chemotherapy bridging, pretreatment disease burden management, toxicity management, disease monitoring after therapy, and use of consolidative allogeneic hematopoietic stem cell transplantation.
Research agenda
Key ways to heighten the success of CAR T-cell therapy for B-ALL are the development of off-the-shelf CAR T-cell products and the selection of optimal T cells to enhance apheresis and production, they said, adding that research is needed on the use of bridging chemotherapy to reduce tumor burden.
Bridging chemotherapy has been shown to impact outcomes while minimizing toxicity, but it remains undefined.
“Prospective trials are required to determine if the optimization of lymphodepleting chemotherapy can improve outcomes, and if consolidative therapy with transplantation should be considered in select patients,” they wrote. “Continued efforts to improve this technology for patients is ongoing while remaining questions are being investigated.”
The authors acknowledge that CAR T-cell therapy has transformed the treatment landscape for both pediatric and adult patients with R/R B-ALL, but this extensive review of all published data on the subject shows that “the incidence of relapse among responders is unacceptably high, demonstrating the need to improve this therapy.”
In conclusion, they wrote: “To be effective following infusion, CAR T cells must expand, persist, exhibit enduring anti-tumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal therapy,” noting that “[t]oxicity management and, ideally the prediction of toxicity in individualized patients, should continue to be a focus of ongoing efforts.”
Dr. Curran has received research support from Juno Therapeutics and Novartis, and has consulted, participated in advisory boards, or taken part in educational seminars for Juno Therapeutics, Novartis, and Mesoblast. Dr. Fabrizio reported having no conflict of interests.
The success of chimeric antigen receptor T (CAR T)-cell therapy for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has garnered much attention, but the field is still in its infancy – with toxicity and relapse rates remaining unacceptably high.
in the use of the therapy in this setting, according to review authors Vanessa A. Fabrizio, MD, a fellow at Duke University, Durham, N.C., and Kevin J. Curran, MD, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
Based on their review of early pivotal clinical trials, relapse data, toxicities, and mechanisms to optimize CAR T-cell therapy, Dr. Fabrizio and Dr. Curran outlined several “practice points” and proposed a research agenda aimed at optimizing the use of CAR T-cell therapy for B-ALL (Best Pract Res Clin Haematol. 2021 Aug 27. doi: 10.1016/j.beha.2021.101305).
Practice points
CAR T-cell therapy has transformed the treatment of both pediatric and adult patients with relapsed/refractory (R/R) B-ALL, the authors said, adding that “[c]linical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients.”
Dr. Fabrizio and Dr. Curran specifically note that only one product (tisagenlecleucel) is currently approved for the treatment of R/R B-ALL in patients under age 26 years. Further, the successful application of this therapy is limited by high relapse rates, significant toxicity in some cases, and challenges related to collection and production issues.
They contend that areas in which optimization of CAR T-cell therapy can occur include apheresis, production, chemotherapy bridging, pretreatment disease burden management, toxicity management, disease monitoring after therapy, and use of consolidative allogeneic hematopoietic stem cell transplantation.
Research agenda
Key ways to heighten the success of CAR T-cell therapy for B-ALL are the development of off-the-shelf CAR T-cell products and the selection of optimal T cells to enhance apheresis and production, they said, adding that research is needed on the use of bridging chemotherapy to reduce tumor burden.
Bridging chemotherapy has been shown to impact outcomes while minimizing toxicity, but it remains undefined.
“Prospective trials are required to determine if the optimization of lymphodepleting chemotherapy can improve outcomes, and if consolidative therapy with transplantation should be considered in select patients,” they wrote. “Continued efforts to improve this technology for patients is ongoing while remaining questions are being investigated.”
The authors acknowledge that CAR T-cell therapy has transformed the treatment landscape for both pediatric and adult patients with R/R B-ALL, but this extensive review of all published data on the subject shows that “the incidence of relapse among responders is unacceptably high, demonstrating the need to improve this therapy.”
In conclusion, they wrote: “To be effective following infusion, CAR T cells must expand, persist, exhibit enduring anti-tumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal therapy,” noting that “[t]oxicity management and, ideally the prediction of toxicity in individualized patients, should continue to be a focus of ongoing efforts.”
Dr. Curran has received research support from Juno Therapeutics and Novartis, and has consulted, participated in advisory boards, or taken part in educational seminars for Juno Therapeutics, Novartis, and Mesoblast. Dr. Fabrizio reported having no conflict of interests.
The success of chimeric antigen receptor T (CAR T)-cell therapy for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has garnered much attention, but the field is still in its infancy – with toxicity and relapse rates remaining unacceptably high.
in the use of the therapy in this setting, according to review authors Vanessa A. Fabrizio, MD, a fellow at Duke University, Durham, N.C., and Kevin J. Curran, MD, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
Based on their review of early pivotal clinical trials, relapse data, toxicities, and mechanisms to optimize CAR T-cell therapy, Dr. Fabrizio and Dr. Curran outlined several “practice points” and proposed a research agenda aimed at optimizing the use of CAR T-cell therapy for B-ALL (Best Pract Res Clin Haematol. 2021 Aug 27. doi: 10.1016/j.beha.2021.101305).
Practice points
CAR T-cell therapy has transformed the treatment of both pediatric and adult patients with relapsed/refractory (R/R) B-ALL, the authors said, adding that “[c]linical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients.”
Dr. Fabrizio and Dr. Curran specifically note that only one product (tisagenlecleucel) is currently approved for the treatment of R/R B-ALL in patients under age 26 years. Further, the successful application of this therapy is limited by high relapse rates, significant toxicity in some cases, and challenges related to collection and production issues.
They contend that areas in which optimization of CAR T-cell therapy can occur include apheresis, production, chemotherapy bridging, pretreatment disease burden management, toxicity management, disease monitoring after therapy, and use of consolidative allogeneic hematopoietic stem cell transplantation.
Research agenda
Key ways to heighten the success of CAR T-cell therapy for B-ALL are the development of off-the-shelf CAR T-cell products and the selection of optimal T cells to enhance apheresis and production, they said, adding that research is needed on the use of bridging chemotherapy to reduce tumor burden.
Bridging chemotherapy has been shown to impact outcomes while minimizing toxicity, but it remains undefined.
“Prospective trials are required to determine if the optimization of lymphodepleting chemotherapy can improve outcomes, and if consolidative therapy with transplantation should be considered in select patients,” they wrote. “Continued efforts to improve this technology for patients is ongoing while remaining questions are being investigated.”
The authors acknowledge that CAR T-cell therapy has transformed the treatment landscape for both pediatric and adult patients with R/R B-ALL, but this extensive review of all published data on the subject shows that “the incidence of relapse among responders is unacceptably high, demonstrating the need to improve this therapy.”
In conclusion, they wrote: “To be effective following infusion, CAR T cells must expand, persist, exhibit enduring anti-tumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal therapy,” noting that “[t]oxicity management and, ideally the prediction of toxicity in individualized patients, should continue to be a focus of ongoing efforts.”
Dr. Curran has received research support from Juno Therapeutics and Novartis, and has consulted, participated in advisory boards, or taken part in educational seminars for Juno Therapeutics, Novartis, and Mesoblast. Dr. Fabrizio reported having no conflict of interests.
FROM BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY
FDA approves first CAR T-cell for adult ALL: For patients with R/R B-cell disease
The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.
This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.
“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.
“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.
The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.
Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.
The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.
Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.
Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.
Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.
The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.
The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.
A version of this article first appeared on Medscape.com.
The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.
This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.
“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.
“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.
The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.
Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.
The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.
Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.
Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.
Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.
The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.
The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.
A version of this article first appeared on Medscape.com.
The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.
This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.
“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.
“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.
The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.
Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.
The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.
Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.
Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.
Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.
The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.
The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.
A version of this article first appeared on Medscape.com.
Methylation patterns correlate with prognosis in children with T-ALL
In childhood patients with T-cell acute lymphoblastic leukemia (T-ALL) the hypomethylation status of the arginine synthetase (ASNS) gene was significantly associated with poor therapeutic outcome, according to the results of a Japanese cohort study published online in Blood Advances.
Researchers Koshi Akahane, PHD, of the University of Yamanashi, Kofu, Japan, and colleagues conducted a comprehensive genetic analysis of diagnostic samples of 22 cell lines from childhood patients with T-ALL in Japan.
They also correlated known methylation status with outcomes in two large patient cohorts of Japanese children with T-ALL: the Tokyo Children’s Cancer Study Group (n = 57) and the Japan Association of Childhood Leukemia Study Group (n = 20).
Methylation results
For the 22 cell lines tested, sequencing technology revealed a stepwise allele-specific methylation of the ASNS gene. Mean ASNS gene expression level was significantly upregulated in 14 weakly methylated cell lines (P = .0001), but not significantly upregulated in 3 intermediately methylated cell lines (P = .25) or in 5 highly methylated cell lines (P = .063).
Among the 77 patient cohorts, 20 (26%) samples showed high methylation (> 66.7%), while 15 (19%) samples and 42 (55%) samples showed intermediate (33.3%-66.7%) and weak (< 33.3%) methylation status, respectively.
For the 75 patients where information was provided on outcomes, 25 patients (33%) showed induction failure or disease relapse. A highly methylated status of the ASNS gene was significantly more common in non-refractory/relapse cases (18/50 cases, 36%), while intermediately or weakly methylated status was more common in refractory/relapsed cases (23/25 cases, 92 %; P = .0001). In a log-rank test, the patients with weakly methylated status of the ASNS gene showed significantly shorter event-free survival and overall survival than the patients with an intermediate or highly methylated status (P = .00012 and P = .00016, respectively).
Asparaginase sensitivity
Asparaginase treatment is a key component of chemotherapy for patients with T-ALL, according to the researchers. Asparaginase depletes serum asparagine by deamination into aspartic acid. While normal hematopoietic cells can survive due to ASNS activity, leukemia cells are expected to undergo apoptosis due to silencing of the ASNS gene.
ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with the poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance, the researchers stated.
“ASNS methylation status may be a clinically useful biomarker to predict sensitivity to asparaginase therapy in T-ALL patients. Considering the severe complications of asparaginase therapy particularly in adolescents and adults, stratifying prospective asparaginase therapy according to ASNS methylation status may be beneficial for safer and more effective treatment of T-ALL patients,” the researchers concluded.
The authors reported that they had no conflicts of interest.
In childhood patients with T-cell acute lymphoblastic leukemia (T-ALL) the hypomethylation status of the arginine synthetase (ASNS) gene was significantly associated with poor therapeutic outcome, according to the results of a Japanese cohort study published online in Blood Advances.
Researchers Koshi Akahane, PHD, of the University of Yamanashi, Kofu, Japan, and colleagues conducted a comprehensive genetic analysis of diagnostic samples of 22 cell lines from childhood patients with T-ALL in Japan.
They also correlated known methylation status with outcomes in two large patient cohorts of Japanese children with T-ALL: the Tokyo Children’s Cancer Study Group (n = 57) and the Japan Association of Childhood Leukemia Study Group (n = 20).
Methylation results
For the 22 cell lines tested, sequencing technology revealed a stepwise allele-specific methylation of the ASNS gene. Mean ASNS gene expression level was significantly upregulated in 14 weakly methylated cell lines (P = .0001), but not significantly upregulated in 3 intermediately methylated cell lines (P = .25) or in 5 highly methylated cell lines (P = .063).
Among the 77 patient cohorts, 20 (26%) samples showed high methylation (> 66.7%), while 15 (19%) samples and 42 (55%) samples showed intermediate (33.3%-66.7%) and weak (< 33.3%) methylation status, respectively.
For the 75 patients where information was provided on outcomes, 25 patients (33%) showed induction failure or disease relapse. A highly methylated status of the ASNS gene was significantly more common in non-refractory/relapse cases (18/50 cases, 36%), while intermediately or weakly methylated status was more common in refractory/relapsed cases (23/25 cases, 92 %; P = .0001). In a log-rank test, the patients with weakly methylated status of the ASNS gene showed significantly shorter event-free survival and overall survival than the patients with an intermediate or highly methylated status (P = .00012 and P = .00016, respectively).
Asparaginase sensitivity
Asparaginase treatment is a key component of chemotherapy for patients with T-ALL, according to the researchers. Asparaginase depletes serum asparagine by deamination into aspartic acid. While normal hematopoietic cells can survive due to ASNS activity, leukemia cells are expected to undergo apoptosis due to silencing of the ASNS gene.
ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with the poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance, the researchers stated.
“ASNS methylation status may be a clinically useful biomarker to predict sensitivity to asparaginase therapy in T-ALL patients. Considering the severe complications of asparaginase therapy particularly in adolescents and adults, stratifying prospective asparaginase therapy according to ASNS methylation status may be beneficial for safer and more effective treatment of T-ALL patients,” the researchers concluded.
The authors reported that they had no conflicts of interest.
In childhood patients with T-cell acute lymphoblastic leukemia (T-ALL) the hypomethylation status of the arginine synthetase (ASNS) gene was significantly associated with poor therapeutic outcome, according to the results of a Japanese cohort study published online in Blood Advances.
Researchers Koshi Akahane, PHD, of the University of Yamanashi, Kofu, Japan, and colleagues conducted a comprehensive genetic analysis of diagnostic samples of 22 cell lines from childhood patients with T-ALL in Japan.
They also correlated known methylation status with outcomes in two large patient cohorts of Japanese children with T-ALL: the Tokyo Children’s Cancer Study Group (n = 57) and the Japan Association of Childhood Leukemia Study Group (n = 20).
Methylation results
For the 22 cell lines tested, sequencing technology revealed a stepwise allele-specific methylation of the ASNS gene. Mean ASNS gene expression level was significantly upregulated in 14 weakly methylated cell lines (P = .0001), but not significantly upregulated in 3 intermediately methylated cell lines (P = .25) or in 5 highly methylated cell lines (P = .063).
Among the 77 patient cohorts, 20 (26%) samples showed high methylation (> 66.7%), while 15 (19%) samples and 42 (55%) samples showed intermediate (33.3%-66.7%) and weak (< 33.3%) methylation status, respectively.
For the 75 patients where information was provided on outcomes, 25 patients (33%) showed induction failure or disease relapse. A highly methylated status of the ASNS gene was significantly more common in non-refractory/relapse cases (18/50 cases, 36%), while intermediately or weakly methylated status was more common in refractory/relapsed cases (23/25 cases, 92 %; P = .0001). In a log-rank test, the patients with weakly methylated status of the ASNS gene showed significantly shorter event-free survival and overall survival than the patients with an intermediate or highly methylated status (P = .00012 and P = .00016, respectively).
Asparaginase sensitivity
Asparaginase treatment is a key component of chemotherapy for patients with T-ALL, according to the researchers. Asparaginase depletes serum asparagine by deamination into aspartic acid. While normal hematopoietic cells can survive due to ASNS activity, leukemia cells are expected to undergo apoptosis due to silencing of the ASNS gene.
ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with the poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance, the researchers stated.
“ASNS methylation status may be a clinically useful biomarker to predict sensitivity to asparaginase therapy in T-ALL patients. Considering the severe complications of asparaginase therapy particularly in adolescents and adults, stratifying prospective asparaginase therapy according to ASNS methylation status may be beneficial for safer and more effective treatment of T-ALL patients,” the researchers concluded.
The authors reported that they had no conflicts of interest.
FROM BLOOD ADVANCES
Genetic shift increases susceptibility to childhood ALL
A genetically induced shift toward higher lymphocyte counts was found to increase susceptibility to childhood acute lymphoblastic leukemia, according to the results of a large genome-wide association study of 2,666 childhood patients with ALL as compared with 60,272 control individuals.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the department of epidemiology and biostatistics, University of California, San Francisco, and colleagues.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the Department of Epidemiology and Biostatistics, University of California San Francisco, and colleagues.
Previous research has shown that several childhood-ALL–risk regions have also been associated with variation in blood-cell traits and a recent phenome-wide association study of childhood ALL identified platelet count as the most enriched trait among known ALL-risk loci. To further explore this issue, the researchers conducted their comprehensive study of the role of blood-cell-trait variation in the etiology of childhood ALL.
The researchers identified 3,000 blood-cell-trait–associated variants, which accounted for 4.0% to 23.9% of trait variation and included 115 loci associated with blood-cell ratios: lymphocyte-to-monocyte ratio (LMR); neutrophil-to-lymphocyte ratio (NLR); and platelet-to-lymphocyte ratio (PLR), according to a report published online in The American Journal of Human Genetics.
Lymphocyte risk
The researchers found that ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, P = .0004) and PLR (rg = 0.072, P = .0017).
Using Mendelian randomization analyses, a genetically predicted increase in lymphocyte counts was found to be associated with increased ALL risk (odds ratio [OR] = 1.16, P = .031). This correlation was strengthened after the researchers accounted for other cell types (OR = 1.43, P = .0009).
The researchers observed positive associations with increasing LMR (OR = 1.22, P = .0017) as well as inverse effects for NLR (OR = 0.67, P = .0003) and PLR (OR = 0.80, P = .002).
“We identified the cell-type ratios LMR, NLR, and PLR as independent risk factors for ALL and found evidence that these ratios have distinct genetic mechanisms that are not captured by their component traits. In multivariable MR analyses that concurrently modeled the effects of lymphocyte, monocyte, neutrophil, and platelet counts on ALL, lymphocytes remained as the only independent risk factor and this association with ALL strengthened compared to univariate analyses,” the researchers stated.
They reported that they had no competing interests.
A genetically induced shift toward higher lymphocyte counts was found to increase susceptibility to childhood acute lymphoblastic leukemia, according to the results of a large genome-wide association study of 2,666 childhood patients with ALL as compared with 60,272 control individuals.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the department of epidemiology and biostatistics, University of California, San Francisco, and colleagues.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the Department of Epidemiology and Biostatistics, University of California San Francisco, and colleagues.
Previous research has shown that several childhood-ALL–risk regions have also been associated with variation in blood-cell traits and a recent phenome-wide association study of childhood ALL identified platelet count as the most enriched trait among known ALL-risk loci. To further explore this issue, the researchers conducted their comprehensive study of the role of blood-cell-trait variation in the etiology of childhood ALL.
The researchers identified 3,000 blood-cell-trait–associated variants, which accounted for 4.0% to 23.9% of trait variation and included 115 loci associated with blood-cell ratios: lymphocyte-to-monocyte ratio (LMR); neutrophil-to-lymphocyte ratio (NLR); and platelet-to-lymphocyte ratio (PLR), according to a report published online in The American Journal of Human Genetics.
Lymphocyte risk
The researchers found that ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, P = .0004) and PLR (rg = 0.072, P = .0017).
Using Mendelian randomization analyses, a genetically predicted increase in lymphocyte counts was found to be associated with increased ALL risk (odds ratio [OR] = 1.16, P = .031). This correlation was strengthened after the researchers accounted for other cell types (OR = 1.43, P = .0009).
The researchers observed positive associations with increasing LMR (OR = 1.22, P = .0017) as well as inverse effects for NLR (OR = 0.67, P = .0003) and PLR (OR = 0.80, P = .002).
“We identified the cell-type ratios LMR, NLR, and PLR as independent risk factors for ALL and found evidence that these ratios have distinct genetic mechanisms that are not captured by their component traits. In multivariable MR analyses that concurrently modeled the effects of lymphocyte, monocyte, neutrophil, and platelet counts on ALL, lymphocytes remained as the only independent risk factor and this association with ALL strengthened compared to univariate analyses,” the researchers stated.
They reported that they had no competing interests.
A genetically induced shift toward higher lymphocyte counts was found to increase susceptibility to childhood acute lymphoblastic leukemia, according to the results of a large genome-wide association study of 2,666 childhood patients with ALL as compared with 60,272 control individuals.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the department of epidemiology and biostatistics, University of California, San Francisco, and colleagues.
The development of ALL is thought to follow a two-hit model of leukemogenesis; in utero formation of a preleukemic clone and subsequent postnatal acquisition of secondary somatic mutations that leads to overt leukemia, according to Linda Kachuri, PhD, of the Department of Epidemiology and Biostatistics, University of California San Francisco, and colleagues.
Previous research has shown that several childhood-ALL–risk regions have also been associated with variation in blood-cell traits and a recent phenome-wide association study of childhood ALL identified platelet count as the most enriched trait among known ALL-risk loci. To further explore this issue, the researchers conducted their comprehensive study of the role of blood-cell-trait variation in the etiology of childhood ALL.
The researchers identified 3,000 blood-cell-trait–associated variants, which accounted for 4.0% to 23.9% of trait variation and included 115 loci associated with blood-cell ratios: lymphocyte-to-monocyte ratio (LMR); neutrophil-to-lymphocyte ratio (NLR); and platelet-to-lymphocyte ratio (PLR), according to a report published online in The American Journal of Human Genetics.
Lymphocyte risk
The researchers found that ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, P = .0004) and PLR (rg = 0.072, P = .0017).
Using Mendelian randomization analyses, a genetically predicted increase in lymphocyte counts was found to be associated with increased ALL risk (odds ratio [OR] = 1.16, P = .031). This correlation was strengthened after the researchers accounted for other cell types (OR = 1.43, P = .0009).
The researchers observed positive associations with increasing LMR (OR = 1.22, P = .0017) as well as inverse effects for NLR (OR = 0.67, P = .0003) and PLR (OR = 0.80, P = .002).
“We identified the cell-type ratios LMR, NLR, and PLR as independent risk factors for ALL and found evidence that these ratios have distinct genetic mechanisms that are not captured by their component traits. In multivariable MR analyses that concurrently modeled the effects of lymphocyte, monocyte, neutrophil, and platelet counts on ALL, lymphocytes remained as the only independent risk factor and this association with ALL strengthened compared to univariate analyses,” the researchers stated.
They reported that they had no competing interests.
FROM THE AMERICAN JOURNAL OF HUMAN GENETICS