AML

Micrograph showing MDS

The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.

APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.

Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.

The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.

Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.

However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose  voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.

A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.

Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.

Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”

“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.

“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”

The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.

APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.

APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.

Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.

The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.

Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.

However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose  voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.

A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.

Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.

Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”

“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.

“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”

The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.

APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.

APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.

Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.

The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.

Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.

However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose  voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.

A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.

Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.

Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”

“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.

“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”

The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.

APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for glasdegib, an oral SMO inhibitor.

With this NDA, Pfizer is seeking approval for glasdegib in combination with low-dose cytarabine (LDAC) as a treatment for adults with previously untreated acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the NDA for glasdegib by December 2018.

The NDA is supported by results from the phase 2 BRIGHT 1003 study. Results from this trial were presented at the 2016 ASH Annual Meeting.

The trial was a comparison of glasdegib plus LDAC (n=88) to LDAC alone (n=44) in patients with previously untreated AML or high-risk myelodysplastic syndromes who were not eligible for intensive chemotherapy.

Results demonstrated a significant improvement in overall survival with glasdegib. The median overall survival was 8.8 months in the glasdegib arm and 4.9 months in the LDAC-alone arm.

This difference represented a 49.9% reduction in the risk of death for patients treated with glasdegib plus LDAC (hazard ratio=0.501; 95% CI: 0.334, 0.752; one-sided P-value=0.0003).

The most frequent adverse events—occurring in at least 30% of patients in the glasdegib arm and LDAC-alone arm, respectively—were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%), and thrombocytopenia (30% vs 27%).

The most frequently reported serious adverse events—occurring in at least 15%  of patients in the glasdegib and LDAC-alone arms, respectively—were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

A phase 3 trial of glasdegib in AML began enrolling earlier this year. In this trial (BRIGHT AML 1019; NCT03416179), researchers are evaluating glasdegib plus intensive or non-intensive chemotherapy in patients with newly diagnosed AML.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for glasdegib, an oral SMO inhibitor.

With this NDA, Pfizer is seeking approval for glasdegib in combination with low-dose cytarabine (LDAC) as a treatment for adults with previously untreated acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the NDA for glasdegib by December 2018.

The NDA is supported by results from the phase 2 BRIGHT 1003 study. Results from this trial were presented at the 2016 ASH Annual Meeting.

The trial was a comparison of glasdegib plus LDAC (n=88) to LDAC alone (n=44) in patients with previously untreated AML or high-risk myelodysplastic syndromes who were not eligible for intensive chemotherapy.

Results demonstrated a significant improvement in overall survival with glasdegib. The median overall survival was 8.8 months in the glasdegib arm and 4.9 months in the LDAC-alone arm.

This difference represented a 49.9% reduction in the risk of death for patients treated with glasdegib plus LDAC (hazard ratio=0.501; 95% CI: 0.334, 0.752; one-sided P-value=0.0003).

The most frequent adverse events—occurring in at least 30% of patients in the glasdegib arm and LDAC-alone arm, respectively—were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%), and thrombocytopenia (30% vs 27%).

The most frequently reported serious adverse events—occurring in at least 15%  of patients in the glasdegib and LDAC-alone arms, respectively—were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

A phase 3 trial of glasdegib in AML began enrolling earlier this year. In this trial (BRIGHT AML 1019; NCT03416179), researchers are evaluating glasdegib plus intensive or non-intensive chemotherapy in patients with newly diagnosed AML.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for glasdegib, an oral SMO inhibitor.

With this NDA, Pfizer is seeking approval for glasdegib in combination with low-dose cytarabine (LDAC) as a treatment for adults with previously untreated acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the NDA for glasdegib by December 2018.

The NDA is supported by results from the phase 2 BRIGHT 1003 study. Results from this trial were presented at the 2016 ASH Annual Meeting.

The trial was a comparison of glasdegib plus LDAC (n=88) to LDAC alone (n=44) in patients with previously untreated AML or high-risk myelodysplastic syndromes who were not eligible for intensive chemotherapy.

Results demonstrated a significant improvement in overall survival with glasdegib. The median overall survival was 8.8 months in the glasdegib arm and 4.9 months in the LDAC-alone arm.

This difference represented a 49.9% reduction in the risk of death for patients treated with glasdegib plus LDAC (hazard ratio=0.501; 95% CI: 0.334, 0.752; one-sided P-value=0.0003).

The most frequent adverse events—occurring in at least 30% of patients in the glasdegib arm and LDAC-alone arm, respectively—were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%), and thrombocytopenia (30% vs 27%).

The most frequently reported serious adverse events—occurring in at least 15%  of patients in the glasdegib and LDAC-alone arms, respectively—were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

A phase 3 trial of glasdegib in AML began enrolling earlier this year. In this trial (BRIGHT AML 1019; NCT03416179), researchers are evaluating glasdegib plus intensive or non-intensive chemotherapy in patients with newly diagnosed AML.

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

Question: What do you think about TET2 mutations being among the most frequent mutations in CH, but IDH being relatively rare?

Dr. Viny: Great question. Both are affecting demethylation and epigenetic instability. While I don’t think the answer is known, perhaps the IDH mutations have a more dominant effect on hematopoietic output. The majority of the CH data uses blood; maybe the marrow tells a different story.

Question: Can we cure clonal hematopoiesis with vitamin C?

Dr. Viny: You clearly know the recent work by Iannis Aifantis, PhD, showing the effects of vitamin C on TET enzyme activity, published here: Cell. 2017 Sep 7;170(6):1079-95. For CH patients with TET2 mutations, a high-dose vitamin C regimen sounds very exciting. There is also complementary work by Sean Morrison, PhD, published in Nature (2017 Sep 28;549[7673]:476-81).

Question: Is there a limit to the sequencing depth and variant allele fraction needed to identify clonal hematopoiesis? At what point is CH not CH?

Dr. Viny: So this is as much a technical question as it is a biological question. As of now we can reliably detect variant allele fraction in CH to 0.1%, at best. What is detectable and what is clinically relevant are questions that still need to be answered.

Question: There seems to be a lot of good research going on in CH. What are the big knowledge gaps that future studies should be targeting?

Dr. Viny: First, what are the functional and molecular consequences of the varying alleles in CH? Second, are there other clinical risks to CH beyond leukemia and cardiovascular disease? And third, does inflammation cause CH or does CH cause inflammation?

Dr. Viny is with the Memorial Sloan Kettering Cancer Center, New York, where he is a clinical instructor; is on the staff of the leukemia service; and is a clinical researcher in the Ross Levine Lab. Connect with him on Twitter at @TheDoctorIsVin.

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

Question: What do you think about TET2 mutations being among the most frequent mutations in CH, but IDH being relatively rare?

Dr. Viny: Great question. Both are affecting demethylation and epigenetic instability. While I don’t think the answer is known, perhaps the IDH mutations have a more dominant effect on hematopoietic output. The majority of the CH data uses blood; maybe the marrow tells a different story.

Question: Can we cure clonal hematopoiesis with vitamin C?

Dr. Viny: You clearly know the recent work by Iannis Aifantis, PhD, showing the effects of vitamin C on TET enzyme activity, published here: Cell. 2017 Sep 7;170(6):1079-95. For CH patients with TET2 mutations, a high-dose vitamin C regimen sounds very exciting. There is also complementary work by Sean Morrison, PhD, published in Nature (2017 Sep 28;549[7673]:476-81).

Question: Is there a limit to the sequencing depth and variant allele fraction needed to identify clonal hematopoiesis? At what point is CH not CH?

Dr. Viny: So this is as much a technical question as it is a biological question. As of now we can reliably detect variant allele fraction in CH to 0.1%, at best. What is detectable and what is clinically relevant are questions that still need to be answered.

Question: There seems to be a lot of good research going on in CH. What are the big knowledge gaps that future studies should be targeting?

Dr. Viny: First, what are the functional and molecular consequences of the varying alleles in CH? Second, are there other clinical risks to CH beyond leukemia and cardiovascular disease? And third, does inflammation cause CH or does CH cause inflammation?

Dr. Viny is with the Memorial Sloan Kettering Cancer Center, New York, where he is a clinical instructor; is on the staff of the leukemia service; and is a clinical researcher in the Ross Levine Lab. Connect with him on Twitter at @TheDoctorIsVin.

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

Question: What do you think about TET2 mutations being among the most frequent mutations in CH, but IDH being relatively rare?

Dr. Viny: Great question. Both are affecting demethylation and epigenetic instability. While I don’t think the answer is known, perhaps the IDH mutations have a more dominant effect on hematopoietic output. The majority of the CH data uses blood; maybe the marrow tells a different story.

Question: Can we cure clonal hematopoiesis with vitamin C?

Dr. Viny: You clearly know the recent work by Iannis Aifantis, PhD, showing the effects of vitamin C on TET enzyme activity, published here: Cell. 2017 Sep 7;170(6):1079-95. For CH patients with TET2 mutations, a high-dose vitamin C regimen sounds very exciting. There is also complementary work by Sean Morrison, PhD, published in Nature (2017 Sep 28;549[7673]:476-81).

Question: Is there a limit to the sequencing depth and variant allele fraction needed to identify clonal hematopoiesis? At what point is CH not CH?

Dr. Viny: So this is as much a technical question as it is a biological question. As of now we can reliably detect variant allele fraction in CH to 0.1%, at best. What is detectable and what is clinically relevant are questions that still need to be answered.

Question: There seems to be a lot of good research going on in CH. What are the big knowledge gaps that future studies should be targeting?

Dr. Viny: First, what are the functional and molecular consequences of the varying alleles in CH? Second, are there other clinical risks to CH beyond leukemia and cardiovascular disease? And third, does inflammation cause CH or does CH cause inflammation?

Dr. Viny is with the Memorial Sloan Kettering Cancer Center, New York, where he is a clinical instructor; is on the staff of the leukemia service; and is a clinical researcher in the Ross Levine Lab. Connect with him on Twitter at @TheDoctorIsVin.

STOCKHOLM – A novel compound chimeric antigen receptor (cCAR) T-cell construct directed against two different targets may one day serve as a standalone therapy, as a supplement to chemotherapy, or as a bridge to transplant for patients with refractory acute myeloid leukemia (AML), investigators asserted.

To date, however, only one patient – a man with treatment-refractory AML – has been treated with the cCAR T, which contains two independent complete units, one directed against CD33 to target bulky disease and the other targeted against CLL1 on leukemic stem cells.

Neil Osterweil/MDedge News

SOURCE: Liu F et al. EHA Congress, Abstract S149.

STOCKHOLM – A novel compound chimeric antigen receptor (cCAR) T-cell construct directed against two different targets may one day serve as a standalone therapy, as a supplement to chemotherapy, or as a bridge to transplant for patients with refractory acute myeloid leukemia (AML), investigators asserted.

To date, however, only one patient – a man with treatment-refractory AML – has been treated with the cCAR T, which contains two independent complete units, one directed against CD33 to target bulky disease and the other targeted against CLL1 on leukemic stem cells.

Neil Osterweil/MDedge News

SOURCE: Liu F et al. EHA Congress, Abstract S149.

STOCKHOLM – A novel compound chimeric antigen receptor (cCAR) T-cell construct directed against two different targets may one day serve as a standalone therapy, as a supplement to chemotherapy, or as a bridge to transplant for patients with refractory acute myeloid leukemia (AML), investigators asserted.

To date, however, only one patient – a man with treatment-refractory AML – has been treated with the cCAR T, which contains two independent complete units, one directed against CD33 to target bulky disease and the other targeted against CLL1 on leukemic stem cells.

Neil Osterweil/MDedge News

SOURCE: Liu F et al. EHA Congress, Abstract S149.

The 23rd Congress of the European Hematology Association

STOCKHOLM—Phase 3 results suggest the FLT3 inhibitor quizartinib can prolong overall survival (OS) in patients with relapsed/refractory, FLT3-ITD acute myeloid leukemia (AML).

In the QuANTUM-R study, patients who received single-agent quizartinib had a significantly longer median OS than patients who received salvage chemotherapy.

There was a trend toward improved event-free survival (EFS) with quizartinib as well.

“QuANTUM-R represents the first study that shows a significant improvement in overall survival for a single agent—a FLT3 inhibitor or any other targeted agent—in this population of FLT3-mutated AML patients with refractory or relapsed disease . . .,” said study investigator Jorge Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.

Dr Cortes presented results from QuANTUM-R at the 23rd Congress of the European Hematology Association (EHA). The research was selected as the best late-breaking abstract (LB2600).

The study was funded by Daiichi Sankyo, Inc., and Dr Cortes is a consultant for the company.

Patients and treatment

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission. They had received at least 1 cycle of an induction regimen containing standard-dose anthracycline or mitoxantrone.

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

Baseline characteristics were similar between the treatment arms. The median age was 55 (range, 19-81) for patients receiving quizartinib and 58 (range, 18-78) for those receiving chemotherapy.

Thirty-three percent of the quizartinib arm had refractory disease, and 67% had relapsed disease. Thirty-four percent of the chemotherapy arm had refractory disease, and 66% had relapsed disease.

The percentage of patients with a prior allogeneic HSCT was 25% in the quizartinib arm and 23% in the chemotherapy arm. Most patients in both arms had intermediate-risk cytogenetics—78% of the quizartinib arm and 66% of the chemotherapy arm.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

The median treatment duration was 4 cycles (range, 1-3) in the quizartinib arm and 1 cycle (range, 1-2) for patients who received LoDAC, MEC, and FLAG-IDA.

The most common reason for discontinuation of chemotherapy was lack of response/progression (n=49), followed by death (n=6). Twenty-four patients completed salvage chemotherapy.

In the quizarinib arm, the most common reasons for treatment discontinuation were HSCT (n=79), relapse (n=60), or lack of response/progression (n=47).

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Results

The median follow-up was 23.5 months. The efficacy results include all randomized patients, and the safety results include only those who received their assigned treatment.

The study’s primary endpoint was OS. The median OS was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year OS rate was 27% and 20%, respectively.

The median EFS was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071). Dr Cortes noted that patients who did not receive treatment were censored on day 1, and partial responses were counted as failures in the EFS analysis.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.

The composite complete response (CR) rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes the CR rate (4% and 1%, respectively), the rate of CR with incomplete platelet recovery (4% and 0%, respectively), and the rate of CR with incomplete hematologic recovery (40% and 26%, respectively). The rate of partial response was 21% and 3%, respectively.

Dr Cortes said rates of treatment-emergent adverse events (TEAEs) were similar between the treatment arms.

Grade 3 or higher hematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).

Grade 3 or higher nonhematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).

Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, but there were no grade 4 cases. Two patients discontinued quizartinib due to QTcF prolongation.

“The safety of this drug has remained constant across over 1600 patients that have been treated with quizartinib across a variety of studies,” Dr Cortes said.

He added that QuANTUM-R results open up the possibility that quizartinib could be used in other settings. Researchers are already testing standard chemotherapy with and without quizartinib in a phase 3 trial of patients with newly diagnosed, FLT-ITD AML (QuANTUM-First).

The 23rd Congress of the European Hematology Association

STOCKHOLM—Phase 3 results suggest the FLT3 inhibitor quizartinib can prolong overall survival (OS) in patients with relapsed/refractory, FLT3-ITD acute myeloid leukemia (AML).

In the QuANTUM-R study, patients who received single-agent quizartinib had a significantly longer median OS than patients who received salvage chemotherapy.

There was a trend toward improved event-free survival (EFS) with quizartinib as well.

“QuANTUM-R represents the first study that shows a significant improvement in overall survival for a single agent—a FLT3 inhibitor or any other targeted agent—in this population of FLT3-mutated AML patients with refractory or relapsed disease . . .,” said study investigator Jorge Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.

Dr Cortes presented results from QuANTUM-R at the 23rd Congress of the European Hematology Association (EHA). The research was selected as the best late-breaking abstract (LB2600).

The study was funded by Daiichi Sankyo, Inc., and Dr Cortes is a consultant for the company.

Patients and treatment

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission. They had received at least 1 cycle of an induction regimen containing standard-dose anthracycline or mitoxantrone.

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

Baseline characteristics were similar between the treatment arms. The median age was 55 (range, 19-81) for patients receiving quizartinib and 58 (range, 18-78) for those receiving chemotherapy.

Thirty-three percent of the quizartinib arm had refractory disease, and 67% had relapsed disease. Thirty-four percent of the chemotherapy arm had refractory disease, and 66% had relapsed disease.

The percentage of patients with a prior allogeneic HSCT was 25% in the quizartinib arm and 23% in the chemotherapy arm. Most patients in both arms had intermediate-risk cytogenetics—78% of the quizartinib arm and 66% of the chemotherapy arm.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

The median treatment duration was 4 cycles (range, 1-3) in the quizartinib arm and 1 cycle (range, 1-2) for patients who received LoDAC, MEC, and FLAG-IDA.

The most common reason for discontinuation of chemotherapy was lack of response/progression (n=49), followed by death (n=6). Twenty-four patients completed salvage chemotherapy.

In the quizarinib arm, the most common reasons for treatment discontinuation were HSCT (n=79), relapse (n=60), or lack of response/progression (n=47).

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Results

The median follow-up was 23.5 months. The efficacy results include all randomized patients, and the safety results include only those who received their assigned treatment.

The study’s primary endpoint was OS. The median OS was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year OS rate was 27% and 20%, respectively.

The median EFS was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071). Dr Cortes noted that patients who did not receive treatment were censored on day 1, and partial responses were counted as failures in the EFS analysis.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.

The composite complete response (CR) rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes the CR rate (4% and 1%, respectively), the rate of CR with incomplete platelet recovery (4% and 0%, respectively), and the rate of CR with incomplete hematologic recovery (40% and 26%, respectively). The rate of partial response was 21% and 3%, respectively.

Dr Cortes said rates of treatment-emergent adverse events (TEAEs) were similar between the treatment arms.

Grade 3 or higher hematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).

Grade 3 or higher nonhematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).

Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, but there were no grade 4 cases. Two patients discontinued quizartinib due to QTcF prolongation.

“The safety of this drug has remained constant across over 1600 patients that have been treated with quizartinib across a variety of studies,” Dr Cortes said.

He added that QuANTUM-R results open up the possibility that quizartinib could be used in other settings. Researchers are already testing standard chemotherapy with and without quizartinib in a phase 3 trial of patients with newly diagnosed, FLT-ITD AML (QuANTUM-First).

The 23rd Congress of the European Hematology Association

STOCKHOLM—Phase 3 results suggest the FLT3 inhibitor quizartinib can prolong overall survival (OS) in patients with relapsed/refractory, FLT3-ITD acute myeloid leukemia (AML).

In the QuANTUM-R study, patients who received single-agent quizartinib had a significantly longer median OS than patients who received salvage chemotherapy.

There was a trend toward improved event-free survival (EFS) with quizartinib as well.

“QuANTUM-R represents the first study that shows a significant improvement in overall survival for a single agent—a FLT3 inhibitor or any other targeted agent—in this population of FLT3-mutated AML patients with refractory or relapsed disease . . .,” said study investigator Jorge Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.

Dr Cortes presented results from QuANTUM-R at the 23rd Congress of the European Hematology Association (EHA). The research was selected as the best late-breaking abstract (LB2600).

The study was funded by Daiichi Sankyo, Inc., and Dr Cortes is a consultant for the company.

Patients and treatment

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission. They had received at least 1 cycle of an induction regimen containing standard-dose anthracycline or mitoxantrone.

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

Baseline characteristics were similar between the treatment arms. The median age was 55 (range, 19-81) for patients receiving quizartinib and 58 (range, 18-78) for those receiving chemotherapy.

Thirty-three percent of the quizartinib arm had refractory disease, and 67% had relapsed disease. Thirty-four percent of the chemotherapy arm had refractory disease, and 66% had relapsed disease.

The percentage of patients with a prior allogeneic HSCT was 25% in the quizartinib arm and 23% in the chemotherapy arm. Most patients in both arms had intermediate-risk cytogenetics—78% of the quizartinib arm and 66% of the chemotherapy arm.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

The median treatment duration was 4 cycles (range, 1-3) in the quizartinib arm and 1 cycle (range, 1-2) for patients who received LoDAC, MEC, and FLAG-IDA.

The most common reason for discontinuation of chemotherapy was lack of response/progression (n=49), followed by death (n=6). Twenty-four patients completed salvage chemotherapy.

In the quizarinib arm, the most common reasons for treatment discontinuation were HSCT (n=79), relapse (n=60), or lack of response/progression (n=47).

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Results

The median follow-up was 23.5 months. The efficacy results include all randomized patients, and the safety results include only those who received their assigned treatment.

The study’s primary endpoint was OS. The median OS was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year OS rate was 27% and 20%, respectively.

The median EFS was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071). Dr Cortes noted that patients who did not receive treatment were censored on day 1, and partial responses were counted as failures in the EFS analysis.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.

The composite complete response (CR) rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes the CR rate (4% and 1%, respectively), the rate of CR with incomplete platelet recovery (4% and 0%, respectively), and the rate of CR with incomplete hematologic recovery (40% and 26%, respectively). The rate of partial response was 21% and 3%, respectively.

Dr Cortes said rates of treatment-emergent adverse events (TEAEs) were similar between the treatment arms.

Grade 3 or higher hematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).

Grade 3 or higher nonhematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).

Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, but there were no grade 4 cases. Two patients discontinued quizartinib due to QTcF prolongation.

“The safety of this drug has remained constant across over 1600 patients that have been treated with quizartinib across a variety of studies,” Dr Cortes said.

He added that QuANTUM-R results open up the possibility that quizartinib could be used in other settings. Researchers are already testing standard chemotherapy with and without quizartinib in a phase 3 trial of patients with newly diagnosed, FLT-ITD AML (QuANTUM-First).

©ASCO/Scott Morgan 2018

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. 

©ASCO/Scott Morgan 2018

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. 

©ASCO/Scott Morgan 2018

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. 

©ASCO/Rodney White 2018

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.

©ASCO/Rodney White 2018

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.

©ASCO/Rodney White 2018

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 – 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).

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

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

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

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.

AML cells

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.

ADMIRAL trial (NCT02421939)

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.  

AML cells

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.

ADMIRAL trial (NCT02421939)

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.  

AML cells

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.

ADMIRAL trial (NCT02421939)

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.