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Ivosidenib active in R/R IDH1-mutated AML patients
CHICAGO—The investigational drug ivosidenib, an inhibitor of the mutant IDH1 enzyme, achieved complete remission (CR) rates of 32% and an overall response rate of 42% in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML) and IDH1 mutation, according to investigators.
In addition, overall survival (OS) in patients who achieved CR more than doubled compared with those in the overall study population.
Fewer patients with CR had febrile neutropenia and infectious complications, and 25% of patients with CR were able to clear the IDH1 clone.
Duration of response was 6.5 months with the investigational drug.
Investigators reported the grade 3/4 toxicities could be managed with supportive care, were not fatal, and some patients still achieved responses.
IDH1 mutation, first identified almost 10 years ago with the sequencing of the first AML cancer genome, is a recurrent mutation in over 10% of patients with AML.
Mutated IDH1, reported in several malignancies, results in impaired cellular differentiation. Ivosidenib is a first-in-class oral therapy designed to inhibit the mutant IDH1 enzyme.
Phase 1 study (NCT02074839)
The phase 1 dose-escalation and dose expansion study specifically enrolled patients with R/RAML with mutated IDH1.
Daniel A. Pollyea, MD, of the Colorado University School of Medicine in Aurora, reported the data from 2 of the dose expansion cohorts as well as 35 patients from the dose escalation cohort at the 2018 ASCO Annual Meeting (abstract 7000).
All patients received ivosidenib 500 mg daily.
CR/CRh (CR with partial hematologic recovery; defined as morphologic remission with recovery of neutrophils to at least 500/mm3 and recovery of platelets to at least 50,000/µL) was the primary efficacy endpoint.
Of 179 patients in the primary efficacy cohort, 10% were still receiving treatment at the time of the presentation.
While most patients discontinued due to disease progression, 10% came off therapy for stem cell transplantation. Median duration of treatment was 4 months.
Patients were a median 67 years of age. Approximately 1/3 had secondary AML.
Patients had received a median of 2 prior therapies and approximately 1/4 had relapsed after transplantation.
Fifty-nine percent were refractory to induction or reinduction therapy.
Toxicity
Dr Pollyea considered adverse events to be as expected for a relapsed/refractory AML population.
However, he called out 3 for special mention—leukocytosis, ECG QT prolongation, and IDH differentiation syndrome—none of which was fatal.
Eight percent of patients had grade 3 or 4 leukocytosis, some of which were mechanistically induced from treatment.
About 10% of patients had grade 3 or 4 QT prolongation.
And grade 3 or 4 differentiation syndrome was reported for approximately 5% of patients.
In 19 patients with any grade differentiation syndrome, CR was reported for 5 patients. The message: patients experiencing this adverse event can be managed with supportive care, continue treatment, and still respond.
All adverse events were managed with supportive care measures, including concomitant medications, and ivosidenib dose modifications as required.
CR/CRh was 32% for the efficacy cohort; median time to response was 2 months and median time of response was 8.2 months. CR rate was 24%. Investigator-reported International Working Group categorized ORR was 42%.
The median OS was 9 months for the entire cohort and 18.8 months for patients who achieved CR/CRh.
Dr Pollyea reported that transfusion independence—defined as no need for transfusion for 56 days—was achieved in all CR patients, 75% of CRh patients, and even in a proportion of nonresponders.
Investigtors observed febrile neutropenia and grade 3 or 4 infectious complications in fewer patients who achieved CR/CRh.
Of note was the observation that 23% of patients who achieved CR/CRh were able to clear the mutant IDH1 clone. Patients who did not respond still harbored the IDH1 clone, Dr Pollyea reported.
These results reported at ASCO are an update from those simultaneously published in NEJM.
The study was supported by Agios Pharmaceuticals.
Ivosidenib is being evaluated alone and in combination in other clinical trials.
CHICAGO—The investigational drug ivosidenib, an inhibitor of the mutant IDH1 enzyme, achieved complete remission (CR) rates of 32% and an overall response rate of 42% in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML) and IDH1 mutation, according to investigators.
In addition, overall survival (OS) in patients who achieved CR more than doubled compared with those in the overall study population.
Fewer patients with CR had febrile neutropenia and infectious complications, and 25% of patients with CR were able to clear the IDH1 clone.
Duration of response was 6.5 months with the investigational drug.
Investigators reported the grade 3/4 toxicities could be managed with supportive care, were not fatal, and some patients still achieved responses.
IDH1 mutation, first identified almost 10 years ago with the sequencing of the first AML cancer genome, is a recurrent mutation in over 10% of patients with AML.
Mutated IDH1, reported in several malignancies, results in impaired cellular differentiation. Ivosidenib is a first-in-class oral therapy designed to inhibit the mutant IDH1 enzyme.
Phase 1 study (NCT02074839)
The phase 1 dose-escalation and dose expansion study specifically enrolled patients with R/RAML with mutated IDH1.
Daniel A. Pollyea, MD, of the Colorado University School of Medicine in Aurora, reported the data from 2 of the dose expansion cohorts as well as 35 patients from the dose escalation cohort at the 2018 ASCO Annual Meeting (abstract 7000).
All patients received ivosidenib 500 mg daily.
CR/CRh (CR with partial hematologic recovery; defined as morphologic remission with recovery of neutrophils to at least 500/mm3 and recovery of platelets to at least 50,000/µL) was the primary efficacy endpoint.
Of 179 patients in the primary efficacy cohort, 10% were still receiving treatment at the time of the presentation.
While most patients discontinued due to disease progression, 10% came off therapy for stem cell transplantation. Median duration of treatment was 4 months.
Patients were a median 67 years of age. Approximately 1/3 had secondary AML.
Patients had received a median of 2 prior therapies and approximately 1/4 had relapsed after transplantation.
Fifty-nine percent were refractory to induction or reinduction therapy.
Toxicity
Dr Pollyea considered adverse events to be as expected for a relapsed/refractory AML population.
However, he called out 3 for special mention—leukocytosis, ECG QT prolongation, and IDH differentiation syndrome—none of which was fatal.
Eight percent of patients had grade 3 or 4 leukocytosis, some of which were mechanistically induced from treatment.
About 10% of patients had grade 3 or 4 QT prolongation.
And grade 3 or 4 differentiation syndrome was reported for approximately 5% of patients.
In 19 patients with any grade differentiation syndrome, CR was reported for 5 patients. The message: patients experiencing this adverse event can be managed with supportive care, continue treatment, and still respond.
All adverse events were managed with supportive care measures, including concomitant medications, and ivosidenib dose modifications as required.
CR/CRh was 32% for the efficacy cohort; median time to response was 2 months and median time of response was 8.2 months. CR rate was 24%. Investigator-reported International Working Group categorized ORR was 42%.
The median OS was 9 months for the entire cohort and 18.8 months for patients who achieved CR/CRh.
Dr Pollyea reported that transfusion independence—defined as no need for transfusion for 56 days—was achieved in all CR patients, 75% of CRh patients, and even in a proportion of nonresponders.
Investigtors observed febrile neutropenia and grade 3 or 4 infectious complications in fewer patients who achieved CR/CRh.
Of note was the observation that 23% of patients who achieved CR/CRh were able to clear the mutant IDH1 clone. Patients who did not respond still harbored the IDH1 clone, Dr Pollyea reported.
These results reported at ASCO are an update from those simultaneously published in NEJM.
The study was supported by Agios Pharmaceuticals.
Ivosidenib is being evaluated alone and in combination in other clinical trials.
CHICAGO—The investigational drug ivosidenib, an inhibitor of the mutant IDH1 enzyme, achieved complete remission (CR) rates of 32% and an overall response rate of 42% in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML) and IDH1 mutation, according to investigators.
In addition, overall survival (OS) in patients who achieved CR more than doubled compared with those in the overall study population.
Fewer patients with CR had febrile neutropenia and infectious complications, and 25% of patients with CR were able to clear the IDH1 clone.
Duration of response was 6.5 months with the investigational drug.
Investigators reported the grade 3/4 toxicities could be managed with supportive care, were not fatal, and some patients still achieved responses.
IDH1 mutation, first identified almost 10 years ago with the sequencing of the first AML cancer genome, is a recurrent mutation in over 10% of patients with AML.
Mutated IDH1, reported in several malignancies, results in impaired cellular differentiation. Ivosidenib is a first-in-class oral therapy designed to inhibit the mutant IDH1 enzyme.
Phase 1 study (NCT02074839)
The phase 1 dose-escalation and dose expansion study specifically enrolled patients with R/RAML with mutated IDH1.
Daniel A. Pollyea, MD, of the Colorado University School of Medicine in Aurora, reported the data from 2 of the dose expansion cohorts as well as 35 patients from the dose escalation cohort at the 2018 ASCO Annual Meeting (abstract 7000).
All patients received ivosidenib 500 mg daily.
CR/CRh (CR with partial hematologic recovery; defined as morphologic remission with recovery of neutrophils to at least 500/mm3 and recovery of platelets to at least 50,000/µL) was the primary efficacy endpoint.
Of 179 patients in the primary efficacy cohort, 10% were still receiving treatment at the time of the presentation.
While most patients discontinued due to disease progression, 10% came off therapy for stem cell transplantation. Median duration of treatment was 4 months.
Patients were a median 67 years of age. Approximately 1/3 had secondary AML.
Patients had received a median of 2 prior therapies and approximately 1/4 had relapsed after transplantation.
Fifty-nine percent were refractory to induction or reinduction therapy.
Toxicity
Dr Pollyea considered adverse events to be as expected for a relapsed/refractory AML population.
However, he called out 3 for special mention—leukocytosis, ECG QT prolongation, and IDH differentiation syndrome—none of which was fatal.
Eight percent of patients had grade 3 or 4 leukocytosis, some of which were mechanistically induced from treatment.
About 10% of patients had grade 3 or 4 QT prolongation.
And grade 3 or 4 differentiation syndrome was reported for approximately 5% of patients.
In 19 patients with any grade differentiation syndrome, CR was reported for 5 patients. The message: patients experiencing this adverse event can be managed with supportive care, continue treatment, and still respond.
All adverse events were managed with supportive care measures, including concomitant medications, and ivosidenib dose modifications as required.
CR/CRh was 32% for the efficacy cohort; median time to response was 2 months and median time of response was 8.2 months. CR rate was 24%. Investigator-reported International Working Group categorized ORR was 42%.
The median OS was 9 months for the entire cohort and 18.8 months for patients who achieved CR/CRh.
Dr Pollyea reported that transfusion independence—defined as no need for transfusion for 56 days—was achieved in all CR patients, 75% of CRh patients, and even in a proportion of nonresponders.
Investigtors observed febrile neutropenia and grade 3 or 4 infectious complications in fewer patients who achieved CR/CRh.
Of note was the observation that 23% of patients who achieved CR/CRh were able to clear the mutant IDH1 clone. Patients who did not respond still harbored the IDH1 clone, Dr Pollyea reported.
These results reported at ASCO are an update from those simultaneously published in NEJM.
The study was supported by Agios Pharmaceuticals.
Ivosidenib is being evaluated alone and in combination in other clinical trials.
Two agents could take AML therapy in new directions
CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.
“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.
Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.
Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).
Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).
“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.
Mivebresib (NCT02391480)
Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.
Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.
The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.
Bemcentinib (NCT02488408)
Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).
For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.
In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.
Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.
Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.
“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said.
*Data presented at the meeting differ from the abstracts.
CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.
“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.
Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.
Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).
Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).
“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.
Mivebresib (NCT02391480)
Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.
Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.
The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.
Bemcentinib (NCT02488408)
Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).
For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.
In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.
Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.
Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.
“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said.
*Data presented at the meeting differ from the abstracts.
CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.
“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.
Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.
Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).
Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).
“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.
Mivebresib (NCT02391480)
Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.
Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.
The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.
Bemcentinib (NCT02488408)
Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).
For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.
In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.
Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.
Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.
“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said.
*Data presented at the meeting differ from the abstracts.
Ivosidenib leads to complete responses in 32% of IDH1-mutated relapsed/refractory AML
CHICAGO – The investigational drug ivosidenib was associated with durable responses, transfusion independence, and a low rate of serious adverse events in patients with IDH1-mutated relapsed/refractory acute myeloid leukemia (AML), based on results of a phase 1 study presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
Daily oral ivosidenib, which inhibits mutant IDH1 the gene that encodes for isocitrate dehydrogenase 1 and is present in 6%-10% of AML patients, was associated with a complete response rate of nearly 32%. In patients who achieved a complete response, median duration of response was 8.2 months and median overall survival was 18.8 months, Daniel A. Pollyea, MD, University of Colorado School of Medicine, Aurora, reported at the meeting.
A wide variety of study participants achieved transfusion independence, even patients who had lesser and no discernable responses, Dr. Pollyea said. “A significant minority of these patients (with lesser or no response) were able to achieve transfusion independence which is obviously a big achievement with respect to quality of life, and suggestive of the mechanism of action here with respect to differentiation.”
The conclusions of this study are “striking,” with response rates and tolerability “very similar” to results seen with the IDH2 inhibitor enasidenib, said Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y.
Ivosidenib is “likely to become the new standard of care treatment” for IDH1-mutant patients in the relapsed-refractory setting based on the data presented at ASCO, Dr. Wang said in a presentation commenting on the results.
“Given the development of ivosidenib and enasidenib, I think we should all carefully consider whether testing of IDH1 and IDH2 mutational status should also become standard of care in all relapsed and refractory patients, in order to offer them these novel and highly effective as well as well-tolerated targeted therapies,” she said.
Enasidenib was approved by the U.S. Food and Drug Administration (FDA) in 2017 for relapsed or refractory AML with an IDH2 mutation.
Here at ASCO, Dr. Pollyea reported results based on 179 patients with relapsed/refractory IDH1-mutant AML who received 500 mg of ivosidenib daily.
The overall response rate was 41.9% (75 patients), he said. The rate of complete remission (CR) or CR with partial hematologic recovery (CRh) was 31.8% (57 patients), with a median of 2.0 months to CR/CRh and a median duration of CR/CRh of 8.2 months, he said.
Grade 3 or greater leukocytosis was seen in 8% of patients, and grade 3 or greater QT prolongation was seen in 10% of patients, Dr. Pollyea reported.
IHD differentiation syndrome of any grade was seen in 19 patients (10.6%), and about half of those cases (5%) were grade 3 or greater. However, cases were managed with supportive care, and there were no dose reductions, permanent treatment discontinuations, or deaths due to the condition, Dr. Pollyea said.
Moreover, the majority of those patients (10 out of 19) went on to have a response. “Supportive care and continued treatment can allow for patients ultimately to respond who are experiencing differentiation syndrome,” Dr. Pollyea said.
Results of the phase 1 study were published simultaneously in the New England Journal of Medicine.The trial was sponsored by Agios. Dr. Pollyea reported disclosures related to Agios, as well as Abbvie, argenx, Celgene, Celyad, Curis, Pfizer, and Servier.
SOURCE: Pollyea DA, et al. J Clin Oncol36, 2018 (suppl; abstr 7000).
CHICAGO – The investigational drug ivosidenib was associated with durable responses, transfusion independence, and a low rate of serious adverse events in patients with IDH1-mutated relapsed/refractory acute myeloid leukemia (AML), based on results of a phase 1 study presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
Daily oral ivosidenib, which inhibits mutant IDH1 the gene that encodes for isocitrate dehydrogenase 1 and is present in 6%-10% of AML patients, was associated with a complete response rate of nearly 32%. In patients who achieved a complete response, median duration of response was 8.2 months and median overall survival was 18.8 months, Daniel A. Pollyea, MD, University of Colorado School of Medicine, Aurora, reported at the meeting.
A wide variety of study participants achieved transfusion independence, even patients who had lesser and no discernable responses, Dr. Pollyea said. “A significant minority of these patients (with lesser or no response) were able to achieve transfusion independence which is obviously a big achievement with respect to quality of life, and suggestive of the mechanism of action here with respect to differentiation.”
The conclusions of this study are “striking,” with response rates and tolerability “very similar” to results seen with the IDH2 inhibitor enasidenib, said Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y.
Ivosidenib is “likely to become the new standard of care treatment” for IDH1-mutant patients in the relapsed-refractory setting based on the data presented at ASCO, Dr. Wang said in a presentation commenting on the results.
“Given the development of ivosidenib and enasidenib, I think we should all carefully consider whether testing of IDH1 and IDH2 mutational status should also become standard of care in all relapsed and refractory patients, in order to offer them these novel and highly effective as well as well-tolerated targeted therapies,” she said.
Enasidenib was approved by the U.S. Food and Drug Administration (FDA) in 2017 for relapsed or refractory AML with an IDH2 mutation.
Here at ASCO, Dr. Pollyea reported results based on 179 patients with relapsed/refractory IDH1-mutant AML who received 500 mg of ivosidenib daily.
The overall response rate was 41.9% (75 patients), he said. The rate of complete remission (CR) or CR with partial hematologic recovery (CRh) was 31.8% (57 patients), with a median of 2.0 months to CR/CRh and a median duration of CR/CRh of 8.2 months, he said.
Grade 3 or greater leukocytosis was seen in 8% of patients, and grade 3 or greater QT prolongation was seen in 10% of patients, Dr. Pollyea reported.
IHD differentiation syndrome of any grade was seen in 19 patients (10.6%), and about half of those cases (5%) were grade 3 or greater. However, cases were managed with supportive care, and there were no dose reductions, permanent treatment discontinuations, or deaths due to the condition, Dr. Pollyea said.
Moreover, the majority of those patients (10 out of 19) went on to have a response. “Supportive care and continued treatment can allow for patients ultimately to respond who are experiencing differentiation syndrome,” Dr. Pollyea said.
Results of the phase 1 study were published simultaneously in the New England Journal of Medicine.The trial was sponsored by Agios. Dr. Pollyea reported disclosures related to Agios, as well as Abbvie, argenx, Celgene, Celyad, Curis, Pfizer, and Servier.
SOURCE: Pollyea DA, et al. J Clin Oncol36, 2018 (suppl; abstr 7000).
CHICAGO – The investigational drug ivosidenib was associated with durable responses, transfusion independence, and a low rate of serious adverse events in patients with IDH1-mutated relapsed/refractory acute myeloid leukemia (AML), based on results of a phase 1 study presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
Daily oral ivosidenib, which inhibits mutant IDH1 the gene that encodes for isocitrate dehydrogenase 1 and is present in 6%-10% of AML patients, was associated with a complete response rate of nearly 32%. In patients who achieved a complete response, median duration of response was 8.2 months and median overall survival was 18.8 months, Daniel A. Pollyea, MD, University of Colorado School of Medicine, Aurora, reported at the meeting.
A wide variety of study participants achieved transfusion independence, even patients who had lesser and no discernable responses, Dr. Pollyea said. “A significant minority of these patients (with lesser or no response) were able to achieve transfusion independence which is obviously a big achievement with respect to quality of life, and suggestive of the mechanism of action here with respect to differentiation.”
The conclusions of this study are “striking,” with response rates and tolerability “very similar” to results seen with the IDH2 inhibitor enasidenib, said Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y.
Ivosidenib is “likely to become the new standard of care treatment” for IDH1-mutant patients in the relapsed-refractory setting based on the data presented at ASCO, Dr. Wang said in a presentation commenting on the results.
“Given the development of ivosidenib and enasidenib, I think we should all carefully consider whether testing of IDH1 and IDH2 mutational status should also become standard of care in all relapsed and refractory patients, in order to offer them these novel and highly effective as well as well-tolerated targeted therapies,” she said.
Enasidenib was approved by the U.S. Food and Drug Administration (FDA) in 2017 for relapsed or refractory AML with an IDH2 mutation.
Here at ASCO, Dr. Pollyea reported results based on 179 patients with relapsed/refractory IDH1-mutant AML who received 500 mg of ivosidenib daily.
The overall response rate was 41.9% (75 patients), he said. The rate of complete remission (CR) or CR with partial hematologic recovery (CRh) was 31.8% (57 patients), with a median of 2.0 months to CR/CRh and a median duration of CR/CRh of 8.2 months, he said.
Grade 3 or greater leukocytosis was seen in 8% of patients, and grade 3 or greater QT prolongation was seen in 10% of patients, Dr. Pollyea reported.
IHD differentiation syndrome of any grade was seen in 19 patients (10.6%), and about half of those cases (5%) were grade 3 or greater. However, cases were managed with supportive care, and there were no dose reductions, permanent treatment discontinuations, or deaths due to the condition, Dr. Pollyea said.
Moreover, the majority of those patients (10 out of 19) went on to have a response. “Supportive care and continued treatment can allow for patients ultimately to respond who are experiencing differentiation syndrome,” Dr. Pollyea said.
Results of the phase 1 study were published simultaneously in the New England Journal of Medicine.The trial was sponsored by Agios. Dr. Pollyea reported disclosures related to Agios, as well as Abbvie, argenx, Celgene, Celyad, Curis, Pfizer, and Servier.
SOURCE: Pollyea DA, et al. J Clin Oncol36, 2018 (suppl; abstr 7000).
REPORTING FROM ASCO 2018
Key clinical point: Daily oral ivosidenib was associated with a complete response rate of nearly 32% and a low rate of serious adverse events in patients with IDH1-mutated relapsed/refractory acute myeloid leukemia (AML).
Major finding: Patients with complete responses had an 8.2-month duration of response, and a median overall survival of 18.8 months.
Study details: A phase 1 study including 179 patients who received 500 mg of ivosidenib daily.
Disclosures: Daniel A. Pollyea, MD, who presented the study, reported disclosures related to Abbvie, Agios, argenx, Celgene, Celyad, Curis, Pfizer, and Servier.
Source: Pollyea DA, et al. J Clin Oncol 36, 2018 (suppl; abstr 7000).
Under his IDH2: Epigenetic drivers of clonal hematopoiesis
The world has surely changed in recent years, leading television and Hollywood to recreate many former works of postapocalyptic fiction. Watching the recent Hulu drama “The Handmaid’s Tale” leads many to make modern-day comparisons, but to this hematologist the connection is bone deep.
Hematopoietic stem cells face a century of carefully regulated symmetric division. They are tasked with the mission to generate the heterogeneous and environmentally responsive progenitor populations that will undergo coordinated differentiation and maturation.1
Within this epic battle of Gilead, much like hematopoiesis, there is a hierarchy within the Sons of Jacob. At the top there are few who drive leukemogenicity and require no other co-conspirators. MLL fusions and core binding factor are the Commanders that can overthrow the regulated governance of normal marrow homeostasis. Other myeloid disease alleles are soldiers of Gilead (i.e. FLT3-ITD, IDH1, IDH2, NPM1c, Spliceosome/Cohesin). Their individual characteristics can influence the natural history of the disease and define its strengths and weaknesses, particularly as new targeted therapies are developed.
Recently, Jongen-Lavrencic et al. reported that all disease alleles that persist as minimal residual disease after induction have a negative influence on outcome, except for three – DNMT3A, TET2, and ASXL1.2 What do we make of the “DTA” mutations? Are they the “Eye” – spies embedded in the polyclonal background of the marrow – intrinsically wired with malevolent intent? Are they the innocent, abused Handmaids – reprogrammed by inflammatory “Aunts” at the marrow’s Red Center and forced to clonally procreate? Previous works have suggested the latter, that persistence of mutations in genes found in clonal hematopoiesis (CH) do not portend an equivalent risk of relapse.3,4
A more encompassing question remains as to the equivalency of CH in the absence of a hematopoietic tumor versus CH postleukemia therapy. Comparisons to small cell lymphomas after successful treatment of transformed disease are disingenuous; CH is not itself a malignant state.5 Forty months of median follow-up for post-AML CH is simply not enough time. Work presented at the 2017 annual meeting of the American Society of Hematology by Jaiswal et al. showed that the approximately 1% risk of transformation per year was consistent over a 20-year period of follow up in the Swedish Nurse’s Study.
The recent work in the New England Journal of Medicine adds to the growing understanding of CH, but requires the test of time to know if these cells are truly innocent Handmaids or the Eye in a red cloak. I’ll be exploring these issues and taking your questions during a live Twitter Q&A on June 14 at noon ET. Follow me at @TheDoctorIsVin and @HematologyNews1 for more details. Blessed be the fruit.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab.
References
1. Orkin SH and Zon L. Cell. 2008 Feb 22;132(4):631-44.
2. Jongen-Lavrencic M et al. N Engl J Med 2018; 378:1189-99.
3. Bhatnagar B et al. Br J Haematol. 2016 Oct;175(2):226-36.
4. Shlush LI et al. Nature. 2017;547:104-8.
5. Bowman RL et al. Cell Stem Cell. 2018 Feb 1;22(2):157-70.
The world has surely changed in recent years, leading television and Hollywood to recreate many former works of postapocalyptic fiction. Watching the recent Hulu drama “The Handmaid’s Tale” leads many to make modern-day comparisons, but to this hematologist the connection is bone deep.
Hematopoietic stem cells face a century of carefully regulated symmetric division. They are tasked with the mission to generate the heterogeneous and environmentally responsive progenitor populations that will undergo coordinated differentiation and maturation.1
Within this epic battle of Gilead, much like hematopoiesis, there is a hierarchy within the Sons of Jacob. At the top there are few who drive leukemogenicity and require no other co-conspirators. MLL fusions and core binding factor are the Commanders that can overthrow the regulated governance of normal marrow homeostasis. Other myeloid disease alleles are soldiers of Gilead (i.e. FLT3-ITD, IDH1, IDH2, NPM1c, Spliceosome/Cohesin). Their individual characteristics can influence the natural history of the disease and define its strengths and weaknesses, particularly as new targeted therapies are developed.
Recently, Jongen-Lavrencic et al. reported that all disease alleles that persist as minimal residual disease after induction have a negative influence on outcome, except for three – DNMT3A, TET2, and ASXL1.2 What do we make of the “DTA” mutations? Are they the “Eye” – spies embedded in the polyclonal background of the marrow – intrinsically wired with malevolent intent? Are they the innocent, abused Handmaids – reprogrammed by inflammatory “Aunts” at the marrow’s Red Center and forced to clonally procreate? Previous works have suggested the latter, that persistence of mutations in genes found in clonal hematopoiesis (CH) do not portend an equivalent risk of relapse.3,4
A more encompassing question remains as to the equivalency of CH in the absence of a hematopoietic tumor versus CH postleukemia therapy. Comparisons to small cell lymphomas after successful treatment of transformed disease are disingenuous; CH is not itself a malignant state.5 Forty months of median follow-up for post-AML CH is simply not enough time. Work presented at the 2017 annual meeting of the American Society of Hematology by Jaiswal et al. showed that the approximately 1% risk of transformation per year was consistent over a 20-year period of follow up in the Swedish Nurse’s Study.
The recent work in the New England Journal of Medicine adds to the growing understanding of CH, but requires the test of time to know if these cells are truly innocent Handmaids or the Eye in a red cloak. I’ll be exploring these issues and taking your questions during a live Twitter Q&A on June 14 at noon ET. Follow me at @TheDoctorIsVin and @HematologyNews1 for more details. Blessed be the fruit.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab.
References
1. Orkin SH and Zon L. Cell. 2008 Feb 22;132(4):631-44.
2. Jongen-Lavrencic M et al. N Engl J Med 2018; 378:1189-99.
3. Bhatnagar B et al. Br J Haematol. 2016 Oct;175(2):226-36.
4. Shlush LI et al. Nature. 2017;547:104-8.
5. Bowman RL et al. Cell Stem Cell. 2018 Feb 1;22(2):157-70.
The world has surely changed in recent years, leading television and Hollywood to recreate many former works of postapocalyptic fiction. Watching the recent Hulu drama “The Handmaid’s Tale” leads many to make modern-day comparisons, but to this hematologist the connection is bone deep.
Hematopoietic stem cells face a century of carefully regulated symmetric division. They are tasked with the mission to generate the heterogeneous and environmentally responsive progenitor populations that will undergo coordinated differentiation and maturation.1
Within this epic battle of Gilead, much like hematopoiesis, there is a hierarchy within the Sons of Jacob. At the top there are few who drive leukemogenicity and require no other co-conspirators. MLL fusions and core binding factor are the Commanders that can overthrow the regulated governance of normal marrow homeostasis. Other myeloid disease alleles are soldiers of Gilead (i.e. FLT3-ITD, IDH1, IDH2, NPM1c, Spliceosome/Cohesin). Their individual characteristics can influence the natural history of the disease and define its strengths and weaknesses, particularly as new targeted therapies are developed.
Recently, Jongen-Lavrencic et al. reported that all disease alleles that persist as minimal residual disease after induction have a negative influence on outcome, except for three – DNMT3A, TET2, and ASXL1.2 What do we make of the “DTA” mutations? Are they the “Eye” – spies embedded in the polyclonal background of the marrow – intrinsically wired with malevolent intent? Are they the innocent, abused Handmaids – reprogrammed by inflammatory “Aunts” at the marrow’s Red Center and forced to clonally procreate? Previous works have suggested the latter, that persistence of mutations in genes found in clonal hematopoiesis (CH) do not portend an equivalent risk of relapse.3,4
A more encompassing question remains as to the equivalency of CH in the absence of a hematopoietic tumor versus CH postleukemia therapy. Comparisons to small cell lymphomas after successful treatment of transformed disease are disingenuous; CH is not itself a malignant state.5 Forty months of median follow-up for post-AML CH is simply not enough time. Work presented at the 2017 annual meeting of the American Society of Hematology by Jaiswal et al. showed that the approximately 1% risk of transformation per year was consistent over a 20-year period of follow up in the Swedish Nurse’s Study.
The recent work in the New England Journal of Medicine adds to the growing understanding of CH, but requires the test of time to know if these cells are truly innocent Handmaids or the Eye in a red cloak. I’ll be exploring these issues and taking your questions during a live Twitter Q&A on June 14 at noon ET. Follow me at @TheDoctorIsVin and @HematologyNews1 for more details. Blessed be the fruit.
Dr. Viny is with the Memorial Sloan-Kettering Cancer Center, N.Y., where he is a clinical instructor, is on the staff of the leukemia service, and is a clinical researcher in the Ross Levine Lab.
References
1. Orkin SH and Zon L. Cell. 2008 Feb 22;132(4):631-44.
2. Jongen-Lavrencic M et al. N Engl J Med 2018; 378:1189-99.
3. Bhatnagar B et al. Br J Haematol. 2016 Oct;175(2):226-36.
4. Shlush LI et al. Nature. 2017;547:104-8.
5. Bowman RL et al. Cell Stem Cell. 2018 Feb 1;22(2):157-70.
FDA grants priority review to gilteritinib for R/R AML
The US Food and Drug Administration (FDA) has granted priority review to gilteritinib for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have a FLT3 mutation.
At present, no FLT3-targeting agents are approved for the treatment of R/R FLT3-mutation-positive AML, according to Astellas, the developer of the drug.
The FDA previously granted gilteritinib orphan drug designation and fast track designation.
The European Commission (EC) also granted gilteritinib orphan designation and the Japan Ministry of Health, Labor and Welfare (MHLW) did likewise.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT tyrosine kinase domain (TKD) mutation. These 2 FLT3 mutations are present in approximately 1/3 of AML patients.
The priority review for the new drug application is based on the ongoing phase 3 ADMIRAL trial.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The goal date for a decision by the FDA is the end of November.
This open-label multicenter randomized study compares gilteritinib with salvage chemotherapy in adult patients with FLT3 mutations who are refractory to or have relapsed after first-line AML therapy.
The study has enrolled 371 patients with FLT3 mutations present in bone marrow or whole blood, as determined by a central lab.
Patients were randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy.
Salvage chemotherapy could consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, cytarabine) induction chemotherapy, or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin) induction chemotherapy.
The primary endpoints of the study are overall survival and complete remission or complete remission with partial hematologic recovery.
Secondary endpoints include event-free survival, complete remission rate, leukemia-free survival, duration of remission, transplantation rate, fatigue inventory, among other outcomes.
The study is estimated to be completed in October for its primary endpoint and February 2020 for the entire study.
The US Food and Drug Administration (FDA) has granted priority review to gilteritinib for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have a FLT3 mutation.
At present, no FLT3-targeting agents are approved for the treatment of R/R FLT3-mutation-positive AML, according to Astellas, the developer of the drug.
The FDA previously granted gilteritinib orphan drug designation and fast track designation.
The European Commission (EC) also granted gilteritinib orphan designation and the Japan Ministry of Health, Labor and Welfare (MHLW) did likewise.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT tyrosine kinase domain (TKD) mutation. These 2 FLT3 mutations are present in approximately 1/3 of AML patients.
The priority review for the new drug application is based on the ongoing phase 3 ADMIRAL trial.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The goal date for a decision by the FDA is the end of November.
This open-label multicenter randomized study compares gilteritinib with salvage chemotherapy in adult patients with FLT3 mutations who are refractory to or have relapsed after first-line AML therapy.
The study has enrolled 371 patients with FLT3 mutations present in bone marrow or whole blood, as determined by a central lab.
Patients were randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy.
Salvage chemotherapy could consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, cytarabine) induction chemotherapy, or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin) induction chemotherapy.
The primary endpoints of the study are overall survival and complete remission or complete remission with partial hematologic recovery.
Secondary endpoints include event-free survival, complete remission rate, leukemia-free survival, duration of remission, transplantation rate, fatigue inventory, among other outcomes.
The study is estimated to be completed in October for its primary endpoint and February 2020 for the entire study.
The US Food and Drug Administration (FDA) has granted priority review to gilteritinib for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have a FLT3 mutation.
At present, no FLT3-targeting agents are approved for the treatment of R/R FLT3-mutation-positive AML, according to Astellas, the developer of the drug.
The FDA previously granted gilteritinib orphan drug designation and fast track designation.
The European Commission (EC) also granted gilteritinib orphan designation and the Japan Ministry of Health, Labor and Welfare (MHLW) did likewise.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT tyrosine kinase domain (TKD) mutation. These 2 FLT3 mutations are present in approximately 1/3 of AML patients.
The priority review for the new drug application is based on the ongoing phase 3 ADMIRAL trial.
The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The agency grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The goal date for a decision by the FDA is the end of November.
This open-label multicenter randomized study compares gilteritinib with salvage chemotherapy in adult patients with FLT3 mutations who are refractory to or have relapsed after first-line AML therapy.
The study has enrolled 371 patients with FLT3 mutations present in bone marrow or whole blood, as determined by a central lab.
Patients were randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy.
Salvage chemotherapy could consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, cytarabine) induction chemotherapy, or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin) induction chemotherapy.
The primary endpoints of the study are overall survival and complete remission or complete remission with partial hematologic recovery.
Secondary endpoints include event-free survival, complete remission rate, leukemia-free survival, duration of remission, transplantation rate, fatigue inventory, among other outcomes.
The study is estimated to be completed in October for its primary endpoint and February 2020 for the entire study.
FDA to review FLT3 agent for refractory AML
The Food and Drug Administration has granted priority review to an FMS-like tyrosine kinase 3 (FLT3)–targeting agent for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML).
If approved, it would be the first FLT3 inhibitor available for this indication.
The application is based on the ongoing ADMIRAL trial, a phase 3, open-label, randomized study of gilteritinib versus salvage chemotherapy. The trial is designed to enroll 369 patients with FLT3 mutations present in bone marrow or whole blood who are refractory or have relapsed on first-line therapy. The primary endpoints are overall survival and rates of complete remission and complete remission with partial hematologic recovery.
The FDA has set Nov. 29 as a target date for reaching a decision on approval of the drug.
The Food and Drug Administration has granted priority review to an FMS-like tyrosine kinase 3 (FLT3)–targeting agent for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML).
If approved, it would be the first FLT3 inhibitor available for this indication.
The application is based on the ongoing ADMIRAL trial, a phase 3, open-label, randomized study of gilteritinib versus salvage chemotherapy. The trial is designed to enroll 369 patients with FLT3 mutations present in bone marrow or whole blood who are refractory or have relapsed on first-line therapy. The primary endpoints are overall survival and rates of complete remission and complete remission with partial hematologic recovery.
The FDA has set Nov. 29 as a target date for reaching a decision on approval of the drug.
The Food and Drug Administration has granted priority review to an FMS-like tyrosine kinase 3 (FLT3)–targeting agent for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML).
If approved, it would be the first FLT3 inhibitor available for this indication.
The application is based on the ongoing ADMIRAL trial, a phase 3, open-label, randomized study of gilteritinib versus salvage chemotherapy. The trial is designed to enroll 369 patients with FLT3 mutations present in bone marrow or whole blood who are refractory or have relapsed on first-line therapy. The primary endpoints are overall survival and rates of complete remission and complete remission with partial hematologic recovery.
The FDA has set Nov. 29 as a target date for reaching a decision on approval of the drug.
Protein may be therapeutic target for AML
A signaling protein may be a “potent” therapeutic target for acute myeloid leukemia (AML), according to a paper published in the Journal of Experimental Medicine.
The protein, interleukin-1 receptor accessory protein (IL1RAP), is often highly expressed on the surface of leukemic stem cells (LSCs) but largely absent from normal hematopoietic stem cells.
Despite this, it wasn’t known whether LSCs require IL1RAP to survive and proliferate and whether inhibiting IL1RAP could be a successful way to treat AML.
Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues conducted research to find out.
The team found that targeting IL1RAP via RNA interference, genetic deletion, or antibodies induced the death of AML cells, including LSCs, in vitro. These effects were seen in the absence of immune effector cells, indicating that AML cells intrinsically depend on IL1RAP.
In contrast, antibodies targeting IL1RAP had no effect on the growth and survival of normal hematopoietic cells.
In mice, IL1RAP antibody treatment inhibited the proliferation of AML cells without causing any negative side effects.
The researchers also found that IL1RAP’s role in AML is not restricted to the IL-1 receptor pathway.
The team found that IL1RAP enhances the activity of 2 other membrane receptor proteins, FLT3 and c-KIT, which are known to stimulate the proliferation of LSCs when activated by their ligands. IL1RAP antibodies inhibited the ability of these ligands to induce proliferation in AML cells.
“Our findings show that IL1RAP can amplify multiple key pathways in AML, demonstrating a much broader role for this protein in disease pathogenesis than previously appreciated,” Dr Steidl noted.
“Importantly, as IL1RAP is also overexpressed in the stem cells of chronic myeloid leukemia and high-risk myelodysplastic syndromes, there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies.”
A signaling protein may be a “potent” therapeutic target for acute myeloid leukemia (AML), according to a paper published in the Journal of Experimental Medicine.
The protein, interleukin-1 receptor accessory protein (IL1RAP), is often highly expressed on the surface of leukemic stem cells (LSCs) but largely absent from normal hematopoietic stem cells.
Despite this, it wasn’t known whether LSCs require IL1RAP to survive and proliferate and whether inhibiting IL1RAP could be a successful way to treat AML.
Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues conducted research to find out.
The team found that targeting IL1RAP via RNA interference, genetic deletion, or antibodies induced the death of AML cells, including LSCs, in vitro. These effects were seen in the absence of immune effector cells, indicating that AML cells intrinsically depend on IL1RAP.
In contrast, antibodies targeting IL1RAP had no effect on the growth and survival of normal hematopoietic cells.
In mice, IL1RAP antibody treatment inhibited the proliferation of AML cells without causing any negative side effects.
The researchers also found that IL1RAP’s role in AML is not restricted to the IL-1 receptor pathway.
The team found that IL1RAP enhances the activity of 2 other membrane receptor proteins, FLT3 and c-KIT, which are known to stimulate the proliferation of LSCs when activated by their ligands. IL1RAP antibodies inhibited the ability of these ligands to induce proliferation in AML cells.
“Our findings show that IL1RAP can amplify multiple key pathways in AML, demonstrating a much broader role for this protein in disease pathogenesis than previously appreciated,” Dr Steidl noted.
“Importantly, as IL1RAP is also overexpressed in the stem cells of chronic myeloid leukemia and high-risk myelodysplastic syndromes, there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies.”
A signaling protein may be a “potent” therapeutic target for acute myeloid leukemia (AML), according to a paper published in the Journal of Experimental Medicine.
The protein, interleukin-1 receptor accessory protein (IL1RAP), is often highly expressed on the surface of leukemic stem cells (LSCs) but largely absent from normal hematopoietic stem cells.
Despite this, it wasn’t known whether LSCs require IL1RAP to survive and proliferate and whether inhibiting IL1RAP could be a successful way to treat AML.
Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues conducted research to find out.
The team found that targeting IL1RAP via RNA interference, genetic deletion, or antibodies induced the death of AML cells, including LSCs, in vitro. These effects were seen in the absence of immune effector cells, indicating that AML cells intrinsically depend on IL1RAP.
In contrast, antibodies targeting IL1RAP had no effect on the growth and survival of normal hematopoietic cells.
In mice, IL1RAP antibody treatment inhibited the proliferation of AML cells without causing any negative side effects.
The researchers also found that IL1RAP’s role in AML is not restricted to the IL-1 receptor pathway.
The team found that IL1RAP enhances the activity of 2 other membrane receptor proteins, FLT3 and c-KIT, which are known to stimulate the proliferation of LSCs when activated by their ligands. IL1RAP antibodies inhibited the ability of these ligands to induce proliferation in AML cells.
“Our findings show that IL1RAP can amplify multiple key pathways in AML, demonstrating a much broader role for this protein in disease pathogenesis than previously appreciated,” Dr Steidl noted.
“Importantly, as IL1RAP is also overexpressed in the stem cells of chronic myeloid leukemia and high-risk myelodysplastic syndromes, there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies.”
NCCN releases guidelines for AML patients
The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).
The guidelines are intended to help patients make better informed decision about their care.
The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.
The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.
“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.
“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”
The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.
NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.
There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.
*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML
(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML
(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML
(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.
The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).
The guidelines are intended to help patients make better informed decision about their care.
The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.
The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.
“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.
“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”
The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.
NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.
There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.
*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML
(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML
(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML
(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.
The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).
The guidelines are intended to help patients make better informed decision about their care.
The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.
The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.
“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.
“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”
The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.
NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.
There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.
*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML
(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML
(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML
(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.
CAR T-cell therapy bridges to HSCT in AML patient
A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).
The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.
This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.
Investigators reported no adverse events related to CYAD-01.
This report was published in haematologica.
The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.
According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.
The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.
The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.
The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.
At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 108 cells every 2 weeks for 3 administrations.
The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.
The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.
The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.
“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.
“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.”
A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).
The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.
This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.
Investigators reported no adverse events related to CYAD-01.
This report was published in haematologica.
The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.
According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.
The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.
The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.
The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.
At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 108 cells every 2 weeks for 3 administrations.
The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.
The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.
The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.
“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.
“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.”
A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).
The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.
This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.
Investigators reported no adverse events related to CYAD-01.
This report was published in haematologica.
The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.
According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.
The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.
The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.
The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.
At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 108 cells every 2 weeks for 3 administrations.
The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.
The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.
The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.
“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.
“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.”
Y chromosome gene protects against AML
Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.
The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).
However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.
The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.
“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.
“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.
In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.
They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.
Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.
“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.
“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.
The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).
However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.
The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.
“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.
“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.
In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.
They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.
Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.
“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.
“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.
The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).
However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.
The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.
“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.
“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.
In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.
They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.
Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.
“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.
“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”