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In IDH-mutated AML, first-line IDH inhibitors plus chemo may boost remission
SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.
In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.
Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.
“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.
Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.
Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day for 3 days, plus cytarabine 200 mg/m2 per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.
After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.
The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.
The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.
A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.
All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.
Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).
Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.
The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.
Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.
Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.
In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).
The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.
The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.
The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
SOURCE: Stein EM et al. ASH 2018, Abstract 560.
SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.
In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.
Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.
“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.
Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.
Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day for 3 days, plus cytarabine 200 mg/m2 per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.
After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.
The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.
The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.
A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.
All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.
Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).
Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.
The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.
Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.
Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.
In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).
The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.
The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.
The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
SOURCE: Stein EM et al. ASH 2018, Abstract 560.
SAN DIEGO – In patients with newly diagnosed acute myeloid leukemia (AML) bearing IDH1 or IDH2 mutations, combinations of either ivosidenib (Tibsovo, for IDH1) or enasidenib (Idhifa, for IDH2) with standard induction and consolidation regimens are safe and well tolerated and are associated with encouraging remission rates, results of a phase 1 trial indicate.
In the open-label, phase 1 trial, ivosidenib plus chemotherapy was associated with elimination of minimal residual disease (MRD) by flow cytometry in 88% of treated patients and with IDH1-mutation clearance in 41% of patients.
Enasidenib plus chemotherapy was associated with elimination of MRD in 45% of patients and with IDH2-mutation clearance in 25% of patients, said Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York.
“The overall survival rates are robust, with greater than 75% 1-year survival in both ivosidenib- and enasidenib-treated patients,” he said at the annual meeting of the American Society of Hematology.
Both ivosidenib and enasidenib are approved in the United States for treatment of patients with relapsed or refractory AML bearing either IDH1 or IDH2 mutations, respectively. In this trial, the investigators explored the therapeutic potential of the IDH inhibitors in patients with previously untreated disease.
Dr. Stein and his colleagues investigated combining each of the agents with standard induction therapy with either daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day for 3 days, plus cytarabine 200 mg/m2 per day for 7 days. Patients with IDH1 mutations received ivosidenib 500 mg once daily, and those with IDH2 mutations received enasidenib 100 mg once daily.
After induction, patients with a complete remission (CR), CR with incomplete recovery of hematologic counts (CRi), or CR with incomplete recovery of platelets (CRp) could receive up to four cycles of consolidation therapy while continuing the IDH inhibitor. Patients who completed consolidation or were ineligible for consolidation could continue on maintenance therapy with their assigned drug until the end of the study.
The drugs were discontinued in patients who went on to hematopoietic stem cell transplant.
The most frequent co-occurring baseline mutations were DNMT3A, NPM1, and NRAS for patients with IDH1 mutations, and DNMT3A, SRSF2, and ASXL1 for patients with IDH2 mutations.
A total of 60 patients were assigned to ivosidenib and chemotherapy and 93 were assigned to enasidenib/chemotherapy. The median patient age was about 63 years in each arm.
All patients in each arm received a least one induction dose and about 48% in each arm received at least some consolidation dosing. In all, 18% of patients in the ivosidenib arm and 19% in the enasidenib arm went on to maintenance.
Treatment discontinuations occurred in 55% of patients in the ivosidenib group and 84% in the enasidenib group. The primary reason for discontinuation included HSCT, adverse events, progressive disease, and death (one and four patients in the respective arms).
Adverse events of interest, regardless of attribution, included the IDH differentiation syndrome in two patients on ivosidenib and one on enasidenib, leukocytosis, QT interval prolongation, and increased blood bilirubin.
The 30-day and 60-day mortality rates were 5% and 8% in the ivosidenib arm and 5% and 9% in the enasidenib arm, respectively.
Best overall response rates (CR+CRi+CRp) among all patients were 80% in the ivosidenib arm and 72% in the enasidenib arm. In each trial arm, the response rates were higher among patients with de novo AML, compared with secondary AML.
Of 12 ivosidenib-treated patients who had IDH1-mutation clearance, 10 had clearance at the end of induction therapy, and 2 achieved clearance during or after consolidation. Of 15 ivosidenib-treated patients who became MRD negative, 12 had achieved it by the end of induction, and 3 became MRD negative during consolidation.
In the enasidenib arm, 15 patients had IDH2 mutation clearance (11 after induction, 4 during consolidation) and 9 became MRD negative (7 after induction and 2 during or after consolidation).
The probability of surviving to 1 year after the start of induction among ivosidenib-treated patients was 79%; the median overall survival had not been reached and was not estimable at the time of data cutoff. The probability of surviving to 1 year among patients in the enasidenib arm was 75%. In this group, too, median overall survival had not been reached.
The clinical benefit of adding either IDH inhibitor to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML with IDH mutations will be further evaluated in a randomized, phase 3 trial, Dr. Stein said.
The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
SOURCE: Stein EM et al. ASH 2018, Abstract 560.
REPORTING FROM ASH 2018
Key clinical point: The IDH1 inhibitor ivosidenib and IDH2 inhibitor enasidenib combined with induction and consolidation therapy showed promising efficacy against newly diagnosed acute myeloid leukemia.
Major finding: The 1-year survival rates were greater than 75% for patients with previously untreated acute myeloid leukemia who received either of the IDH-mutated inhibitors.
Study details: An open-label, prospective trial in 153 patients with newly diagnosed acute myeloid leukemia.
Disclosures: The study was funded by Agios Pharmaceuticals and Celgene. Dr. Stein reported consulting with those companies and others.
Source: Stein EM et al. ASH 2018, Abstract 560.
ALL regimens clear disease in kids with MPAL
SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.
In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).
Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.
Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).
The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.
Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.
Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.
Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).
The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.
Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.
Survival
The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.
In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.
“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.
The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.
The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.
In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).
There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.
“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.
In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.
“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.
He disclosed no conflicts of interest.
* Data in the presentation differ from the abstract.
SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.
In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).
Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.
Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).
The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.
Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.
Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.
Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).
The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.
Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.
Survival
The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.
In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.
“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.
The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.
The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.
In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).
There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.
“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.
In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.
“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.
He disclosed no conflicts of interest.
* Data in the presentation differ from the abstract.
SAN DIEGO—Pediatric patients with mixed phenotype acute leukemia (MPAL) can achieve minimal residual disease (MRD) negativity with acute lymphoblastic leukemia (ALL)-directed chemotherapy, according to new research.
In a retrospective study, most pediatric MPAL patients who received ALL-directed chemotherapy achieved an MRD-negative complete response (CR).
Ninety-three percent of patients achieved a CR at the end of induction with an ALL regimen, 70% were MRD-negative at the end of induction, and 86% were MRD-negative at the end of induction or consolidation.
Etan Orgel, MD, of the University of Southern California, Los Angeles, presented these findings at the ASH 2018 Annual Meeting (abstract 558*).
The study included 94 patients aged 1-21 years who met World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions.
Most patients had B/Myeloid phenotype (89%, n=84), 10% (n=9) had T/Myeloid, and 1% (n=1) had B/T phenotype.
Eighty-seven patients (93%) received ALL induction, and 83 (89%) continued on ALL therapy after induction.
Ninety-three percent (81/87) of patients treated with an ALL induction regimen had a CR at the end of induction. One patient died during induction, and six had induction failures, defined as either disease progression (n=2) or MRD of 5% or greater (n=4).
The MRD-negative rates, defined as MRD less than 0.01%, were 70% (59/84) at the end of induction and 86% (68/79) at the end of induction or consolidation.
Twelve of 14 patients (86%) who were MRD-positive at the end of induction and continued on ALL therapy achieved MRD negativity at the end of consolidation.
Survival
The researchers assessed 5-year survival in patients who received an ALL regimen but did not go on to transplant.
In these patients, the 5-year event-free survival (EFS) was 75%, and the 5-year overall survival (OS) was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said.
“[T]his is very different from the approach used at many adult centers and many of the adult recommendations,” he added.
The 5-year EFS rate was 80% in patients who were MRD-negative at the end of induction and 52% in patients who were MRD-positive at the end of induction. Five-year OS rates were 91% and 84%, respectively.
The 5-year EFS rate was 77% in patients who were MRD-negative at the end of consolidation and was unavailable in the three patients who were MRD-positive. The 5-year OS rates were 89% and not available, respectively.
In a multivariable analysis, MRD was the strongest predictor of EFS (hazard ratio [HR]=3.5) and OS (HR=4.6).
There was a trend toward earlier failure and worse OS (HR=4.49, P=0.074) for T-lineage-containing MPAL.
“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” Dr. Orgel said.
In closing, he said this research suggests that ALL therapy without transplant may be sufficient to treat most patients with pediatric MPAL. However, he noted that clinical trials are necessary to prospectively validate MRD thresholds at end of induction and consolidation and to establish the threshold for favorable survival.
“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” Dr. Orgel said.
He disclosed no conflicts of interest.
* Data in the presentation differ from the abstract.
FLT3 inhibitor moves forward in newly diagnosed AML
SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3
The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.
The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.
“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.
Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.
Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.
“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.
Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.
SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3
The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.
The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.
“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.
Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.
Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.
“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.
Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.
SAN DIEGO – In an ongoing phase 1 study, the oral FMS-like tyrosine kinase 3
The dose escalation/expansion study coupled the oral agent with induction and consolidation chemotherapy and was aimed at establishing the dosing and safety of gilteritinib.
The findings – reported at the annual meeting of the American Society of Hematology – mean that the FLT3 inhibitor will next be compared with the current standard of care, which has a 60%-65% remission rate, according to Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.
“The later-phase clinical studies that we will be doing with gilteritinib will look to compare midostaurin-based chemotherapy with gilteritinib and looking for outcomes, with hopes of improving upon this 60%-65% remission rate,” Dr. Pratz said in a video interview.
Gilteritinib was recently approved by the Food and Drug Administration for relapsed/refractory AML patients with FLT3 mutations.
Dr. Pratz said the approval will provide a needed new treatment option in that patient population, which has had a low response rate to conventional therapy, in the range of 10%-15%.
“There really wasn’t a standard approved therapy prior to this and this will be what is given to most patients who have a FLT3 mutation and relapse,” he said.
Dr. Pratz reported consultancy and research funding from Astellas, which markets gilteritinib, as well as other companies.
REPORTING FROM ASH 2018
Beat AML trial delivers genomic results in 7 days
SAN DIEGO – Investigators demonstrated the feasibility of delivering genomic results in 7 days in a population of older, newly diagnosed patients with acute myeloid leukemia (AML).
The Beat AML Master Trial is an ongoing umbrella study that harnesses cytogenetic information and next generation sequencing to match patients with targeted therapies across a number of substudies or outside of the trial’s multicenter network.
The researchers chose AML for this precision-medicine study because of its rapid onset and lethal nature, its heterogeneity, and the availability of more-targeted therapies, said Amy Burd, PhD, of the Leukemia & Lymphoma Society, which is sponsoring the study.
Initial data from the trial showed that more than 95% of patients were assigned to treatment in 7 days or less, based on their personalized genomic information.
Overall, 285 patients had usable genomic screening data and were assigned to treatment. Of those patients, 273 were assigned to a treatment within 7 days, Dr. Burd reported at the annual meeting of the American Society of Hematology.
The speed of delivering these results is critical, said Joseph Mikhael, MD, chief medical officer for the International Myeloma Foundation in Phoenix, who moderated a media briefing on personalized medicine.
“One of the greatest challenges we faced in the concept of personalized medicine is by the time you’ve determined what is best for that patient ... the horse is already out of the barn,” Dr. Mikhael said. “You have to have started the patient on treatment already or else their disease could have progressed quite rapidly.”
In the past, genomic results might come back a month after the patient started therapy. “It was really almost academic,” he said.
In the Beat AML study, more than half (146 patients) were treated based on their AML subtype. The remaining patients (139) were not treated: 2.5% of patients died within 7 days, 7% of patients chose an alternative treatment prior to assignment, 20% chose standard of care, 9.1% chose an alternative trial after assignment, 8.1% chose palliative care, and the remainder had a reason that was not specified.
“The treatment decisions are made for what’s best for the patient even if that means a study outside of Beat AML,” Dr. Burd said.
Currently, there are 11 substudies offering treatment to trial participants across 13 clinical sites. There has been promising efficacy in many of the treatment arms, Dr. Burd said.
In the future, the researchers are looking to expand the substudies to look into novel drug combinations for certain AML subtypes, specifically isocitrate dehydrogenase 2–mutated groups.
Dr. Burd is an employee of the Leukemia & Lymphoma Society. Other coinvestigators reported financial relationships with the pharmaceutical industry. Dr. Mikhael reported research funding from AbbVie, Celgene, Onyx Pharmaceuticals, and Sanofi.
SOURCE: Burd A et al. ASH 2018, Abstract 559.
SAN DIEGO – Investigators demonstrated the feasibility of delivering genomic results in 7 days in a population of older, newly diagnosed patients with acute myeloid leukemia (AML).
The Beat AML Master Trial is an ongoing umbrella study that harnesses cytogenetic information and next generation sequencing to match patients with targeted therapies across a number of substudies or outside of the trial’s multicenter network.
The researchers chose AML for this precision-medicine study because of its rapid onset and lethal nature, its heterogeneity, and the availability of more-targeted therapies, said Amy Burd, PhD, of the Leukemia & Lymphoma Society, which is sponsoring the study.
Initial data from the trial showed that more than 95% of patients were assigned to treatment in 7 days or less, based on their personalized genomic information.
Overall, 285 patients had usable genomic screening data and were assigned to treatment. Of those patients, 273 were assigned to a treatment within 7 days, Dr. Burd reported at the annual meeting of the American Society of Hematology.
The speed of delivering these results is critical, said Joseph Mikhael, MD, chief medical officer for the International Myeloma Foundation in Phoenix, who moderated a media briefing on personalized medicine.
“One of the greatest challenges we faced in the concept of personalized medicine is by the time you’ve determined what is best for that patient ... the horse is already out of the barn,” Dr. Mikhael said. “You have to have started the patient on treatment already or else their disease could have progressed quite rapidly.”
In the past, genomic results might come back a month after the patient started therapy. “It was really almost academic,” he said.
In the Beat AML study, more than half (146 patients) were treated based on their AML subtype. The remaining patients (139) were not treated: 2.5% of patients died within 7 days, 7% of patients chose an alternative treatment prior to assignment, 20% chose standard of care, 9.1% chose an alternative trial after assignment, 8.1% chose palliative care, and the remainder had a reason that was not specified.
“The treatment decisions are made for what’s best for the patient even if that means a study outside of Beat AML,” Dr. Burd said.
Currently, there are 11 substudies offering treatment to trial participants across 13 clinical sites. There has been promising efficacy in many of the treatment arms, Dr. Burd said.
In the future, the researchers are looking to expand the substudies to look into novel drug combinations for certain AML subtypes, specifically isocitrate dehydrogenase 2–mutated groups.
Dr. Burd is an employee of the Leukemia & Lymphoma Society. Other coinvestigators reported financial relationships with the pharmaceutical industry. Dr. Mikhael reported research funding from AbbVie, Celgene, Onyx Pharmaceuticals, and Sanofi.
SOURCE: Burd A et al. ASH 2018, Abstract 559.
SAN DIEGO – Investigators demonstrated the feasibility of delivering genomic results in 7 days in a population of older, newly diagnosed patients with acute myeloid leukemia (AML).
The Beat AML Master Trial is an ongoing umbrella study that harnesses cytogenetic information and next generation sequencing to match patients with targeted therapies across a number of substudies or outside of the trial’s multicenter network.
The researchers chose AML for this precision-medicine study because of its rapid onset and lethal nature, its heterogeneity, and the availability of more-targeted therapies, said Amy Burd, PhD, of the Leukemia & Lymphoma Society, which is sponsoring the study.
Initial data from the trial showed that more than 95% of patients were assigned to treatment in 7 days or less, based on their personalized genomic information.
Overall, 285 patients had usable genomic screening data and were assigned to treatment. Of those patients, 273 were assigned to a treatment within 7 days, Dr. Burd reported at the annual meeting of the American Society of Hematology.
The speed of delivering these results is critical, said Joseph Mikhael, MD, chief medical officer for the International Myeloma Foundation in Phoenix, who moderated a media briefing on personalized medicine.
“One of the greatest challenges we faced in the concept of personalized medicine is by the time you’ve determined what is best for that patient ... the horse is already out of the barn,” Dr. Mikhael said. “You have to have started the patient on treatment already or else their disease could have progressed quite rapidly.”
In the past, genomic results might come back a month after the patient started therapy. “It was really almost academic,” he said.
In the Beat AML study, more than half (146 patients) were treated based on their AML subtype. The remaining patients (139) were not treated: 2.5% of patients died within 7 days, 7% of patients chose an alternative treatment prior to assignment, 20% chose standard of care, 9.1% chose an alternative trial after assignment, 8.1% chose palliative care, and the remainder had a reason that was not specified.
“The treatment decisions are made for what’s best for the patient even if that means a study outside of Beat AML,” Dr. Burd said.
Currently, there are 11 substudies offering treatment to trial participants across 13 clinical sites. There has been promising efficacy in many of the treatment arms, Dr. Burd said.
In the future, the researchers are looking to expand the substudies to look into novel drug combinations for certain AML subtypes, specifically isocitrate dehydrogenase 2–mutated groups.
Dr. Burd is an employee of the Leukemia & Lymphoma Society. Other coinvestigators reported financial relationships with the pharmaceutical industry. Dr. Mikhael reported research funding from AbbVie, Celgene, Onyx Pharmaceuticals, and Sanofi.
SOURCE: Burd A et al. ASH 2018, Abstract 559.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: More than 95% of patients in the trial were assigned to treatment within 7 days based on results of their genomic screening.
Study details: An umbrella study of 285 patients aged 60 years and older with newly diagnosed acute myeloid leukemia.
Disclosures: The study is sponsored by the Leukemia & Lymphoma Society. Dr. Burd is an employee of the Society and other investigators reported funding from multiple pharmaceutical companies.
Source: Burd A et al. ASH 2018, Abstract 559.
Gut bacteria influence HCT outcomes
A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.
The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.
In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.
Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.
A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.
The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.
In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.
Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.
A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.
The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.
In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.
Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.
REPORTING FROM ASH 2018
ELIANA update: Tisagenlecleucel responses durable in r/r B-cell ALL
SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.
Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.
“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”
The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.
The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.
The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.
Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.
The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.
There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.
Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.
Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.
SOURCE: Grupp SA et al. ASH 2018, Abstract 895.
SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.
Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.
“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”
The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.
The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.
The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.
Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.
The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.
There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.
Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.
Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.
SOURCE: Grupp SA et al. ASH 2018, Abstract 895.
SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.
Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.
“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”
The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.
The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.
The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.
Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.
The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.
There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.
Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.
Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.
SOURCE: Grupp SA et al. ASH 2018, Abstract 895.
REPORTING FROM ASH 2018
Key clinical point: A single infusion of tisagenlecleucel continues to demonstrate high efficacy a year and a half later in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia.
Major finding: Among patients who had complete remission, 66% were still in remission at 18 months, while overall survival was 70% and median overall survival had not yet been reached.
Study details: A follow-up of the pivotal ELIANA trial, an international, single-arm, open-label, phase 2 study including 97 patients aged 3-24 years with relapsed or refractory B-cell acute lymphoblastic leukemia.
Disclosures: The study was supported by Novartis. Dr. Grupp reported disclosures with Novartis, Jazz Pharmaceuticals, Adaptimmune Therapeutics, and the University of Pennsylvania.
Source: Grupp SA et al. ASH 2018, Abstract 895.
Ibrutinib outperforms bendamustine and rituximab in older CLL patients
SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).
“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach of the Ohio State University, Columbus.
Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.
Participants in the international, multicenter trial – a project of the National Cancer Institute National Clinical Trials Network – were 547 adults aged 65 years or older (median, 71 years) with previously untreated, symptomatic CLL. They were enrolled from 219 sites across the United States and Canada between Dec. 9, 2013, and May 16, 2016.
The three arms were well matched with respect to baseline characteristics except for a slightly higher number of patients with complex karyotypes in the IR arm, Dr. Woyach said.
Treatment in the BR arm included bendamustine 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at a dose of 375 mg/m2 on day 0 of cycle 1 then 500 mg/m2 on day 1 of cycles 2-6. Patients in the ibrutinib arms received 420 mg daily until disease progression either with or without rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2 day 1 and then given on day 1 of cycles 3-6.
Grade 3-5 treatment-emergent hematologic adverse events (AEs) occurred in 61%, 41%, and 38% of patients in the BR, ibrutinib, and IR arms, respectively. Neutropenia and thrombocytopenia occurred more often in the BR than in the ibrutinib arms. Nonhematologic AEs occurred in 63%, 74%, and 74%, respectively, with an overall greater incidence in the ibrutinib arms. Infections and sudden deaths were numerically but not significantly higher in the ibrutinib arms.
“We undertook this study to determine the most effective therapy for older patients with CLL,” Dr. Woyach said, explaining that while older patients make up the majority of patients with CLL, they are typically underrepresented in trials.
At the start of the study, BR was widely used and the Bruton’s tyrosine kinase inhibitor ibrutinib was “just entering the clinic,” she noted.
“Despite now-widespread use in the [front-line setting] following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy has not previously been investigated,” she said.
Since adding rituximab has been shown to improve PFS and OS when added to chemotherapy in CLL, she and her colleagues also looked at whether this was the case with ibrutinib as well.
“This is the only phase 3 trial designed to answer this question,” she noted, adding that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.
David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing, agreed. “I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice.”
Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.
Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib
Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
SOURCE: Woyach JA et al. ASH 2018, Abstract 6.
SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).
“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach of the Ohio State University, Columbus.
Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.
Participants in the international, multicenter trial – a project of the National Cancer Institute National Clinical Trials Network – were 547 adults aged 65 years or older (median, 71 years) with previously untreated, symptomatic CLL. They were enrolled from 219 sites across the United States and Canada between Dec. 9, 2013, and May 16, 2016.
The three arms were well matched with respect to baseline characteristics except for a slightly higher number of patients with complex karyotypes in the IR arm, Dr. Woyach said.
Treatment in the BR arm included bendamustine 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at a dose of 375 mg/m2 on day 0 of cycle 1 then 500 mg/m2 on day 1 of cycles 2-6. Patients in the ibrutinib arms received 420 mg daily until disease progression either with or without rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2 day 1 and then given on day 1 of cycles 3-6.
Grade 3-5 treatment-emergent hematologic adverse events (AEs) occurred in 61%, 41%, and 38% of patients in the BR, ibrutinib, and IR arms, respectively. Neutropenia and thrombocytopenia occurred more often in the BR than in the ibrutinib arms. Nonhematologic AEs occurred in 63%, 74%, and 74%, respectively, with an overall greater incidence in the ibrutinib arms. Infections and sudden deaths were numerically but not significantly higher in the ibrutinib arms.
“We undertook this study to determine the most effective therapy for older patients with CLL,” Dr. Woyach said, explaining that while older patients make up the majority of patients with CLL, they are typically underrepresented in trials.
At the start of the study, BR was widely used and the Bruton’s tyrosine kinase inhibitor ibrutinib was “just entering the clinic,” she noted.
“Despite now-widespread use in the [front-line setting] following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy has not previously been investigated,” she said.
Since adding rituximab has been shown to improve PFS and OS when added to chemotherapy in CLL, she and her colleagues also looked at whether this was the case with ibrutinib as well.
“This is the only phase 3 trial designed to answer this question,” she noted, adding that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.
David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing, agreed. “I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice.”
Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.
Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib
Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
SOURCE: Woyach JA et al. ASH 2018, Abstract 6.
SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).
“There was no difference in progression-free survival between ibrutinib and ibrutinib plus rituximab,” said Dr. Woyach of the Ohio State University, Columbus.
Median PFS in this study was 43 months in the BR arm, and was not reached in either of the ibrutinib-containing arms, she said. No significant differences in overall survival (OS) were seen among the treatment arms, which may have been because of short follow-up and the fact that patients in the BR arm were allowed to cross over to ibrutinib if they progressed on treatment.
Participants in the international, multicenter trial – a project of the National Cancer Institute National Clinical Trials Network – were 547 adults aged 65 years or older (median, 71 years) with previously untreated, symptomatic CLL. They were enrolled from 219 sites across the United States and Canada between Dec. 9, 2013, and May 16, 2016.
The three arms were well matched with respect to baseline characteristics except for a slightly higher number of patients with complex karyotypes in the IR arm, Dr. Woyach said.
Treatment in the BR arm included bendamustine 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at a dose of 375 mg/m2 on day 0 of cycle 1 then 500 mg/m2 on day 1 of cycles 2-6. Patients in the ibrutinib arms received 420 mg daily until disease progression either with or without rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2 day 1 and then given on day 1 of cycles 3-6.
Grade 3-5 treatment-emergent hematologic adverse events (AEs) occurred in 61%, 41%, and 38% of patients in the BR, ibrutinib, and IR arms, respectively. Neutropenia and thrombocytopenia occurred more often in the BR than in the ibrutinib arms. Nonhematologic AEs occurred in 63%, 74%, and 74%, respectively, with an overall greater incidence in the ibrutinib arms. Infections and sudden deaths were numerically but not significantly higher in the ibrutinib arms.
“We undertook this study to determine the most effective therapy for older patients with CLL,” Dr. Woyach said, explaining that while older patients make up the majority of patients with CLL, they are typically underrepresented in trials.
At the start of the study, BR was widely used and the Bruton’s tyrosine kinase inhibitor ibrutinib was “just entering the clinic,” she noted.
“Despite now-widespread use in the [front-line setting] following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy has not previously been investigated,” she said.
Since adding rituximab has been shown to improve PFS and OS when added to chemotherapy in CLL, she and her colleagues also looked at whether this was the case with ibrutinib as well.
“This is the only phase 3 trial designed to answer this question,” she noted, adding that the findings justify the use of ibrutinib as a standard-of-care treatment for CLL patients aged 65 years and older.
David P. Steensma, MD, of Dana-Farber Cancer Institute in Boston, who moderated the press briefing, agreed. “I think this really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice.”
Dr. Woyach added, however, that while ibrutinib represents a major therapeutic advance, its cost and its toxicities in older patients are a concern that warrant close monitoring and development of strategies to reduce the need for long-term continuous treatment.
Additional phase 3 studies set to open soon will compare ibrutinib in combination with venetoclax and obinutuzumab with standard ibrutinib
Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
SOURCE: Woyach JA et al. ASH 2018, Abstract 6.
REPORTING FROM ASH 2018
Key clinical point: In chronic lymphocytic leukemia patients aged 65 years and older, progression-free survival is better with ibrutinib than with bendamustine and rituximab.
Major finding: The 2-year progression-free survival was 74%, 87%, and 88% with bendamustine and rituximab, ibrutinib, and ibrutinib and rituximab, respectively.
Study details: A randomized, phase 3 study of 547 previously untreated patients with CLL.
Disclosures: Dr. Woyach reported having no disclosures. Dr. Steensma reported receiving research funding from, and/or serving as a consultant, board member, or adviser for Takeda Pharmaceutical, Syros Pharmaceuticals, Otsuka Pharmaceutical, Onconova Therapeutics, Novartis, Kura Oncology, Janssen, H3 Biosciences, Celgene, Amphivena Therapeutics, and Acceleron Pharma.
Source: Woyach JA et al. ASH 2018, Abstract 6.
MEDALIST: Erythroid maturation agent reduced transfusion burden in MDS
SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.
Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.
“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.
The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.
In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.
Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.
The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).
A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.
A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).
There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.
The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.
That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.
Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.
“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.
Dr. List reported research funding from Celgene.
SOURCE: List AF et al. ASH 2018, Abstract 1.
SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.
Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.
“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.
The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.
In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.
Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.
The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).
A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.
A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).
There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.
The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.
That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.
Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.
“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.
Dr. List reported research funding from Celgene.
SOURCE: List AF et al. ASH 2018, Abstract 1.
SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.
Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.
“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.
The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.
In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.
Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.
The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).
A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.
A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).
There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.
The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.
That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.
Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.
“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.
Dr. List reported research funding from Celgene.
SOURCE: List AF et al. ASH 2018, Abstract 1.
REPORTING FROM ASH 2018
Key clinical point: Luspatercept, a novel erythroid maturation agent, significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes and ringed sideroblasts.
Major finding: The proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment was 37.9% for luspatercept and 13.2% for placebo (P less than .0001).
Study details: A randomized, phase 3 trial including 220 lower-risk myelodysplastic syndromes patients with ringed sideroblasts who were RBC transfusion–dependent.
Disclosures: Dr. List reported research funding from Celgene.
Source: List AF et al. ASH 2018, abstract 1.
Stem cell transplant after CAR T cells may reduce B-ALL relapse risk
SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.
Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.
Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.
However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.
In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.
Dr. Summers reported no disclosures related to her presentation.
SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.
Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.
Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.
However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.
In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.
Dr. Summers reported no disclosures related to her presentation.
SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.
Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.
Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.
However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.
In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.
Dr. Summers reported no disclosures related to her presentation.
REPORTING FROM ASH 2018
FDA warns of serious side effect of AML treatment
The (Idhifa).
Enasidenib is FDA approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation. The drug is known to be associated with differentiation syndrome, and the drug’s prescribing information contains a boxed warning about this life-threatening condition.
However, the FDA has found that patients and health care providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.
The FDA also is warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).
However, the agency has not provided many details on cases related to this drug, which is FDA approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.
The agency is advising health care providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.
Symptoms of differentiation syndrome include:
- Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen.
- Pulmonary infiltrates and pleural effusion.
- Fever.
- Lymphadenopathy.
- Bone pain.
- Peripheral edema with rapid weight gain.
- Pericardial effusion.
- Hepatic, renal, and multiorgan dysfunction.
The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.If health care providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA. Providers also should monitor hemodynamics until improvement and provide supportive care as necessary.
If patients continue to experience renal dysfunction or severe pulmonary symptoms that require intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.
Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon. The FDA notes that in the clinical trial that supported approval of enasidenib at least 14% of patients experienced differentiation syndrome.
The manufacturer’s latest safety report includes five deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.
Differentiation syndrome was listed as the only cause of death in two cases. In the other cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.
One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly.
Treatment details are not available for the remaining three patients who died, according to the FDA.
The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n = 214) or ivosidenib (n = 179).
With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in two of the ivosidenib-treated patients (6%) and two of the enasidenib-treated patients (5%).
Additional results from this analysis are scheduled to be presented at the annual meeting of the American Society of Hematology (Abstract 288).
The (Idhifa).
Enasidenib is FDA approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation. The drug is known to be associated with differentiation syndrome, and the drug’s prescribing information contains a boxed warning about this life-threatening condition.
However, the FDA has found that patients and health care providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.
The FDA also is warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).
However, the agency has not provided many details on cases related to this drug, which is FDA approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.
The agency is advising health care providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.
Symptoms of differentiation syndrome include:
- Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen.
- Pulmonary infiltrates and pleural effusion.
- Fever.
- Lymphadenopathy.
- Bone pain.
- Peripheral edema with rapid weight gain.
- Pericardial effusion.
- Hepatic, renal, and multiorgan dysfunction.
The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.If health care providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA. Providers also should monitor hemodynamics until improvement and provide supportive care as necessary.
If patients continue to experience renal dysfunction or severe pulmonary symptoms that require intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.
Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon. The FDA notes that in the clinical trial that supported approval of enasidenib at least 14% of patients experienced differentiation syndrome.
The manufacturer’s latest safety report includes five deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.
Differentiation syndrome was listed as the only cause of death in two cases. In the other cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.
One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly.
Treatment details are not available for the remaining three patients who died, according to the FDA.
The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n = 214) or ivosidenib (n = 179).
With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in two of the ivosidenib-treated patients (6%) and two of the enasidenib-treated patients (5%).
Additional results from this analysis are scheduled to be presented at the annual meeting of the American Society of Hematology (Abstract 288).
The (Idhifa).
Enasidenib is FDA approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation. The drug is known to be associated with differentiation syndrome, and the drug’s prescribing information contains a boxed warning about this life-threatening condition.
However, the FDA has found that patients and health care providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.
The FDA also is warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).
However, the agency has not provided many details on cases related to this drug, which is FDA approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.
The agency is advising health care providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.
Symptoms of differentiation syndrome include:
- Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen.
- Pulmonary infiltrates and pleural effusion.
- Fever.
- Lymphadenopathy.
- Bone pain.
- Peripheral edema with rapid weight gain.
- Pericardial effusion.
- Hepatic, renal, and multiorgan dysfunction.
The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.If health care providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA. Providers also should monitor hemodynamics until improvement and provide supportive care as necessary.
If patients continue to experience renal dysfunction or severe pulmonary symptoms that require intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.
Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon. The FDA notes that in the clinical trial that supported approval of enasidenib at least 14% of patients experienced differentiation syndrome.
The manufacturer’s latest safety report includes five deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.
Differentiation syndrome was listed as the only cause of death in two cases. In the other cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.
One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly.
Treatment details are not available for the remaining three patients who died, according to the FDA.
The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n = 214) or ivosidenib (n = 179).
With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in two of the ivosidenib-treated patients (6%) and two of the enasidenib-treated patients (5%).
Additional results from this analysis are scheduled to be presented at the annual meeting of the American Society of Hematology (Abstract 288).