A Review of Selected Presentations From the 2017 American Society of Hematology Annual Meeting and Exposition • December 9-12, 2017 • Atlanta, Georgia
Continuing Enasidenib Treatment for Patients With Mutant-IDH2 Relapsed or Refractory Acute Myeloid Leukemia With Stable Disease May Result in Improved Survival and Responses Over Time
The AG-221-C-001 trial was a phase 1 dose-escalation and dose-expansion study that evaluated enasidenib, a first-in-class, oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes, in patients with mutant-IDH2 advanced myeloid malignancies.1 In the dose-escalation phase, doses ranged from 50 mg/day to 650 mg/day, and a maximum tolerated dose was not reached. A dose of 100 mg/day was selected for the expansion phase. An analysis of patients with relapsed or refractory acute myeloid leukemia (AML) showed an overall response rate (ORR) of 40.3%, with a median response duration of 5.8 months. The median overall survival was 9.3 months. Among patients with a complete response (CR; 19.3%), overall survival was 19.7 months.
Dr Eytan Stein and colleagues evaluated response and survival outcomes in the AG-221-C-001 study among patients with relapsed/refractory AML and a mutated IDH2 who maintained stable disease during early enasidenib treatment cycles.2 Stable disease was defined per the 2017 criteria from European LeukemiaNet (ELN).3 The patients in this post hoc analysis had no formal hematologic response (as defined by the International Working Group) and no evidence of progressive disease for at least 90 days.4 The 89 patients who met these criteria were divided into 3 subgroups: stable disease late responders (n=24), who went on to attain a hematologic response after day 90; patients with stable disease only (n=40), who continued to maintain persistent stable disease after day 90; and patients with progressive disease after day 90 (n=25).2
Among all 89 patients with stable disease, the median overall survival was 9.0 months (95% CI, 8.2-11.4). Variations were seen among the patient subgroups (Figure 1). Median overall survival was 26.7 months (95% CI, 10.7-26.7) in patients with stable disease and a late response, 8.8 months (95% CI, 7.7-11.6) in patients with stable disease only, and 5.8 months (95% CI, 5.4-8.3) in patients with progressive disease after day 90. The corresponding estimated 1-year survival rates were 61.3% (95% CI, 37.9-84.7), 26.0% (95% CI, 8.1-43.9), and 0%, respectively. In patients with stable disease and a late response, the risk of death was significantly reduced by 61% compared with patients with stable disease only (hazard ratio [HR], 0.39; 95% CI, 0.18-0.85) and by 84% compared with patients with progressive disease after day 90 (HR, 0.16; 95% CI, 0.07-0.39). In patients with stable disease only, the risk of death was significantly reduced by 57% compared with patients with progressive disease after day 90 (HR, 0.43; 95% CI, 0.23-0.80).2 The need for transfusions with red blood cells or platelets also varied across these subgroups (Figure 2).
In this population of patients with relapsed/refractory AML and the IDH2 mutation, 42% maintained stable disease during the first 90 days of treatment with enasidenib. Of these, approximately 1 in 4 patients achieved a response after day 90, with a median time to first response of approximately 4 months from the initiation of enasidenib. For those patients with stable disease who went on to achieve a response after day 90, overall survival was significantly prolonged compared with patients who maintained stable disease and patients who developed progressive disease. Therefore, stable disease during early treatment with enasidenib is not an indication of treatment failure, and patients who maintain stable disease may benefit from continued enasidenib therapy.
The authors of this post hoc analysis speculated that stable disease may be associated with a more controlled state of leukemic blast proliferation, as well as slower cell differentiation, which can lead to a later response. The authors noted that no baseline factor was significantly predictive of a response after day 90, but an ongoing longitudinal molecular and translational study may provide more insight.2
References
1. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
2. Stein EM, Stone RM, Pollyea DA, et al. Continuing enasidenib treatment for patients with mutant-IDH2 (mIDH2) relapsed or refractory acute myeloid leukemia (R/R AML) with stable disease may result in improved survival and responses over time [ASH abstract 1299]. Blood. 2017;130(suppl 1).
3. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
4. Cheson BD, Bennett JM, Kopecky KJ, et al; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-4649.
Phase 2 Study of the Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients With Newly Diagnosed Acute Myeloid Leukemia
In a preclinical animal model, inhibition of the programmed death 1 (PD-1)/PD ligand 1 (PD-L1) checkpoint pathway enhanced the cytotoxic response to traditional chemotherapeutic agents.1 This enhanced response was attributed to increased CD8-positive T-cell activity. Patients with AML express a high number of PD-1–positive, CD8-positive T cells, prompting evaluation of this pathway as a potential target in AML.2 Inhibition of PD-1 demonstrated some activity in a pilot study of patients with hematologic malignancies, including AML.3 Dr Farhad Ravandi-Kashani and colleagues presented results from the phase 2 portion of a phase 1/2 study that evaluated the addition of nivolumab, an antibody inhibitor of PD-1, to standard frontline therapy in patients with newly diagnosed AML.4
The study enrolled 35 patients with AML (diagnosed according to criteria from the World Health Organization) or high-risk myelodysplastic syndrome, with at least 10% or more blast cells. The study focused on younger patients, who were between the ages of 18 and 60 years. However, patients older than 60 years were permitted to enroll if they were very fit. Other enrollment criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and adequate cardiac, renal, and hepatic function.4
All patients received induction therapy consisting of cytarabine (1.5 g/m2 on days 1 to 4 [days 1-3 for patients >60 years]) and idarubicin (12 mg/m2 once daily for 3 days), plus nivolumab (3 mg/kg every 2 weeks). Nivolumab was initiated on day 24 (±2 days), and continued as maintenance therapy for up to 1 year. Among the 35 enrolled patients, the first 3 were treated with nivolumab at 1 mg/kg in a run-in phase. There was no evidence of drug-related toxicity. Thereafter, the remaining 32 patients received 3 mg/kg.4
After the induction phase, patients with a CR or a CR with incomplete blood count recovery (CRi) were then treated with up to 5 cycles of consolidation chemotherapy (administered at approximately monthly intervals) consisting of an attenuated dose of cytarabine (0.75 g/m2 once daily for 3 days) and idarubicin (8 mg/m2 once daily for 3 days). Eligible patients could undergo an allogeneic stem cell transplant at any time during or after the consolidation phase.4
The patients’ median age was 54 years (range, 26 to 65 years), and 43% were male. Most patients had de novo AML (74%). The remaining patients had secondary AML (11%), therapy-related AML (9%), or high-risk myelodysplastic syndrome (6%). Risk (according to ELN criteria) was intermediate in 46% and adverse in 40%.5 The most commonly observed mutations at baseline were TP53 (23%), IDH2 (23%), NPM1 (17%), DNMT3A (17%), and KRAS/NRAS (14%). FLT3-ITD and FLT3 0835 mutations occurred at a frequency of 9% each.4
The primary endpoint of the phase 2 portion of the study was event-free survival. After a median follow-up of 8.4 months (range, 0.7-21.1 months), the median event-free survival was 8.3 months (range, 0.5-18.0). The median relapse-free survival was 17.3 months (range, 0.6-17.3), and the median overall survival was 15.8 months (range, 0.5-21.1; Figure 3).4
Among 34 evaluable patients, the ORR was 79%. The CR rate was 62%, and the CRi plus CR with incomplete platelet recovery (CRp) rate was 14%. Among the 26 patients who achieved a CR or CRp/CRi, 12 had no signs of minimal residual disease (MRD) at the time of their response. Among the remaining 14 patients who were either MRD-positive or MRD-indeterminate at the time of their response, 9 converted to MRD-negative status after an additional 1 to 3 months of follow-up (during which time, they received nivolumab).4
A total of 26 patients were able to proceed to allogeneic stem cell transplant. Among 9 patients with available follow-up (for a median of 6.7 months), 5 patients were in a continuous CR and 1 patient had relapsed. Three patients died.
The risk of severe graft-versus-host disease was not increased with the study treatment.4 The most frequently reported grade 3/4 adverse events (AEs) were febrile neutropenia (38%) and diarrhea (14%). Some of the grade 3/4 AEs, such as rash (6%), colitis (6%), pancreatitis (3%), and cholecystitis (3%), were considered immune-mediated. These suspected immune-mediated events were reversible.4
Multicolor flow cytometry studies were conducted on bone marrow aspirate and peripheral blood specimens to assess the T-cell repertoire and expression of costimulatory receptors and ligands on T-cell subsets and leukemic blasts, respectively. Specimens were obtained at baseline (before the first dose of nivolumab) and during treatment. The bone marrow was evaluated at baseline in 24 patients, including 19 patients with a CR and 5 nonresponders. The percentage of live CD3-positive total T-cell infiltrate in the bone marrow aspirate at baseline was higher among responders vs nonresponders. Additionally, flow cytometry revealed a reduction in the frequency of D34-positive/CD123-positive AML progenitor cells over time with treatment.4
At baseline, the bone marrow aspirate of nonresponders had a significantly higher percentage of CD4-positive T effector cells expressing the inhibitor marker TIM3 (P=.01). Additionally, nonresponder bone marrow aspirate also had a significantly higher percentage of CD4-positive T-effector cells co-expressing the inhibitory markers PD1 and TIM3 (P=.04).4 Co-expression of TIM3 on PD1-positive T cells is associated with an exhausted immune phenotype in AML. T-cell exhaustion is a type of T-cell dysfunction linked to diminished cytokine production, impaired killing of cancer cells, and hypoproliferation.6
References
1. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114(8):1545-1552.
2. Daver N, Ravandi F. Enhancing cytotoxicity of immunotoxins in AML. Blood. 2016;127(23):2787-2788.
3. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044-3051.
4. Ravandi F, Daver N, Manero G, et al. Phase 2 study of combination of cytarabine, idarubicin, and nivolumab for initial therapy of patients with newly diagnosed acute myeloid leukemia [ASH abstract 578]. Blood. 2017;130(suppl 1).
5. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
6. Zhou Q, Munger ME, Veenstra RG, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501-4510.
Mutant Isocitrate Dehydrogenase Inhibitors, Enasidenib or Ivosidenib, in Combination With Azacitidine: Preliminary Results of a Phase 1b/2 Study in Patients With Newly Diagnosed Acute Myeloid Leukemia
Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are found in approximately 20% of patients with AML, with an increasing prevalence among older patients.1 IDH1/2 mutations lead to accumulation of the oncometabolite 2-hydroxyglutarate, which in turn may contribute to inhibition of cell differentiation, a decreased threshold for apoptosis, and an altered hypoxic response.2,3 Two oral small molecule inhibitors of mutated IDH have been evaluated in AML. Ivosidenib is an inhibitor of IDH1, and enasidenib is an inhibitor of IDH2. Both agents have shown activity in early studies of relapsed/refractory AML.4,5 In preclinical models, the combination of mutated IDH inhibitors and azacitidine showed synergistic efficacy. Dr Courtney DiNardo and coworkers reported preliminary results from the phase 1b portion of a clinical trial investigating each of these mutated IDH inhibitors in combination with azacitidine in patients with newly diagnosed AML.6
Enrolled patients were 18 years or older. They had newly diagnosed AML and an IDH1/2 mutation, and were ineligible for intensive chemotherapy. The study permitted enrollment of patients with antecedent hematologic disorders (such as myelodysplastic syndrome), but prior treatment with hypomethylating agents was exclusionary.6
The study followed a 3-plus-3 dose-finding/expansion design. During the phase 1b portion of the study, patients were grouped into 2 cohorts based on whether their mutation was in IDH1 or IDH2. Those with an IDH1 mutation were recruited to a dose-finding phase (n=7) followed by a dose-expansion phase (n=4) in which they received ivosidenib (500 mg daily) plus subcutaneous azacitidine (75 mg/m2 daily for 7 days of a 28-day cycle). Patients with an IDH2 mutation were enrolled into a dose-finding phase (n=6) and treated with enasidenib (either 100 mg or 200 mg daily), plus the same subcutaneous dose of azacitidine.7
The primary endpoints of the phase 1b portion were safety and identification of recommended doses of the mutated IDH inhibitors. Key secondary endpoints were ORR, pharmacokinetic and pharmacodynamic parameters, and quality-of-life outcomes.6
This preliminary report provided data for 17 patients. Six patients were treated with enasidenib (either 100 mg or 200 mg) plus azacitidine, and 11 patients were treated with ivosidenib plus azacitidine. At the time of the data cut-off (September 1, 2017), 11 patients remained in the study (3 in the enasidenib group and 8 in the ivosidenib group).6
Among the 6 patients treated with enasidenib plus azacitidine, the median age was 68 years (range, 64-79 years), and all but 1 patient was age 65 years or older. Four patients were female. Patients had an ECOG performance status of 0 (n=1) or 1 (n=5). Four patients had the IDH2 R140 mutation, and the other 2 patients had the IDH2 R172 mutation. FLT3-ITD/FLT3-TKD was identified in 3 patients and NPM1 in 1 patient. All 6 patients had intermediate-risk cytogenetic features.7
The median number of enasidenib treatment cycles was 9 (range, 1-13). The most frequent treatment-emergent AEs of any grade were nausea (n=4) and hyperbilirubinemia (n=4). IDH differentiation syndrome occurred in 1 patient, who was treated with 200 mg/day of enasidenib. Grade 3/4 hematologic treatment-emergent AEs all occurred in patients treated with the 200 mg/day dose of enasidenib. These events included neutropenia (n=2, with 1 event considered treatment-related); thrombocytopenia, febrile neutropenia, and anemia (n=1 for each, all considered treatment-related); and decreases in lymphocyte count and white blood cell count (n=1 for each, none considered treatment-related). Nonhematologic grade 3/4 treatment-emergent AEs considered related to the study treatment included hyperbilirubinemia (n=1) and embolism (n=1). The study authors speculated that hyperbilirubinemia might be caused by off-target inhibition of the UGT1A1 enzyme.6
Among the 6 patients treated with enasidenib, 4 achieved a response (either a CR, CRi/CRp, partial res-ponse, or morphologic leukemia-free state; Figure 4). Among the 3 patients treated with 100 mg/day of enasidenib plus azacitidine, 2 patients achieved a CR. Among the 3 patients treated with 200 mg/day of enasidenib plus azacitidine, 1 patient achieved a partial response, and 1 patient experienced a morphologic leukemia-free state.6
Among the 11 patients with mutated IDH1 who were treated with ivosidenib plus azacitidine, the median age was 76 years (range, 72-88 years), and all patients were ages 65 years or older. Five patients were male. Nine patients had an ECOG performance status of 1; the other 2 patients had a performance status of 0. One patient had an NPM1 co-mutation. No FLT3-ITD or FLT3-TKD co-mutations were identified. Risk was intermediate in 7 patients and poor in 3.6 (In 1 patient, risk was undetermined.)
These patients received a median of 3 treatment cycles (range, 1-13). The most common any-grade treatment-emergent AEs were nausea (n=8), constipation (n=6), fatigue (n=5), and diarrhea (n=4). The most common treatment-emergent AEs related to the study treatment were nausea (n=6) and fatigue (n=4). IDH differentiation syndrome occurred in 1 patient. Grade 3/4 hematologic treatment-emergent AEs included anemia (n=2, with 1 case considered treatment-related), febrile neutropenia (n=2, with no cases related to study treatment), and neutropenia and thrombocytopenia (n=1 for each, with both cases considered related to study treatment). The treatment-related grade 3/4 nonhematologic treatment-emergent AEs included constipation, increase in blood creatinine, and IDH differentiation syndrome (n=1 for each). One patient died during the study, from pneumonia. This death was considered unrelated to study treatment.6
In the 11 patients treated with ivosidenib plus azacitidine, a total of 8 patients achieved a response. A CR was reported in 4 patients, a CRi in 1, a partial response in 1, and a morphologic leukemia-free state in 2. The remaining 3 patients had stable disease.6
Based on these preliminary data, the study authors concluded that enasidenib or ivosidenib plus azacitidine were well-tolerated regimens among patients with newly diagnosed AML. The most frequent treatment-emergent AEs were grade 1 or 2 gastrointestinal events. The authors found the initial efficacy results encouraging, with responses seen in 4 of the 6 patients treated with enasidenib and in 8 of the 11 patients treated with ivosidenib. The recommended doses for further study in combination with azacitidine was 100 mg/day for enasidenib and 500 mg/day for ivosidenib. Enrollment has been completed for the ivosidenib-plus-azacitidine arm of the randomized phase 2 portion of the study.6
References
1. Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28(9):1774-1783.
2. Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178-184.
3. Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood. 2013;122(16):2877-2887.
4. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
5. DiNardo CD, de Botton S, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study [ASH abstract 725]. Blood. 2017;130(suppl 1).
6. DiNardo CD, Stein AS, Fathi AT, et al. Mutant isocitrate dehydrogenase (mIDH) inhibitors, enasidenib or ivosidenib, in combination with azacitidine (AZA): preliminary results of a phase 1b/2 study in patients with newly diagnosed acute myeloid leukemia (AML) [ASH abstract 639]. Blood. 2017;130(suppl 1).
Prognostic Impact of NPM1/FLT3-ITD Genotypes From Randomized Patients With Acute Myeloid Leukemia Treated Within the International RATIFY Study
The double-blind, randomized phase 3 Cancer and Leukemia Group B (CALGB) 10603 RATIFY study (A Randomized Phase III Study of Induction [Daunorubicin/Cytarabine] and Consolidation [High-Dose Cytarabine] Chemotherapy Combined With Midostaurin or Placebo in Treatment-Naive Patients With FLT3 Mutated AML) evaluated the efficacy and safety of the small-molecule FLT3 inhibitor midostaurin vs placebo in combination with standard chemotherapy in patients with FLT3-mutated AML. Results of the study, published in 2017 in The New England Journal of Medicine, showed that the addition of midostaurin to standard chemotherapy significantly increased median overall survival (the primary endpoint) as compared with placebo (74.7 months vs 25.6 months; HR, 0.78; 95% CI, 0.63-0.96; 1-sided P=.009).1 These results led the US Food and Drug Administration (FDA) to approve midostaurin, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation, for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation–positive (as detected by an FDA-approved test).2
All patients in the RATIFY study had newly diagnosed AML. Before patients were randomly assigned to treatment, they were tested to confirm the presence of the FLT3 mutation.1 A post hoc analysis of the RATIFY study, reported by Dr Konstanze Döhner and colleagues, evaluated the prognostic impact of distinct NPM1 and FLT3-ITD ELN genotypes among patients treated in the study.3 The analysis also examined the potential effect of midostaurin among patients within these genotypes.2
This post hoc analysis included data for 428 patients (from a total of 717 patients randomly assigned to treatment in the overall study). Among these patients, 264 (62%) underwent a stem cell transplant during the study (with 183 [43%] undergoing transplant during their first CR). The overall median follow-up for the post hoc analysis subgroup was 59 months (range, 42 to 81 months).
The distinct genotypes identified included NPM1mut/FLT3-ITDlow (favorable risk, n=85), NPM1mut/FLT3-ITDhigh (intermediate risk, n=159), NPM1wt/FLT3-ITDlow (intermediate risk, n=75), and NPM1wt/FLT3-ITDhigh (adverse risk, n=109). The patients’ median age ranged from 45 years to 50 years. Among patients with the NPM1mut genotype, approximately 65% were women. Patients with the NPM1wt genotype were slightly more likely to be male (53%). This difference was statistically significant (P=.003). Also significant were the median percentages of blasts present in the bone marrow, which were 72.0% among patients with NPM1mut/FLT3-ITDlow, 80.0% among those with NPM1mut/FLT3-ITDhigh, 71.5% among those with NPM1wt/FLT3-ITDlow, and 77.0% among those with NPM1wt/FLT3-ITDhigh (P=.001).
The rates of CR for patients randomly assigned to midostaurin vs placebo were 71% vs 66% for those with NPM1mut/FLT3-ITDlow (P=.309), 70% vs 68% for those with NPM1mut/FLT3-ITDhigh (P=.387), 62% vs 43% for those with NPM1wt/FLT3-ITDlow (P=.058), and 55% vs 49% for those with NPM1wt/FLT3-ITDhigh (P=.267). In a multivariate analysis for CR, the ELN subgroup had a significant 2-sided P value (P=.009). Other variables tested were not significant, including treatment (P=.209), bone marrow blasts (P=.513), age (P=.090), white blood cell count (P=.122), and sex (P=.082).
There was a significant effect on overall survival according to the ELN subgroup (Figure 5), regardless of whether the analysis was censored at the time of hematopoietic stem cell transplant. In a multivariate analysis, the ELN subgroup (NPM1/FLT3-ITD; P<.001), allogeneic hematopoietic stem cell transplant (P<.001), and white blood cell count (≥ vs <50 × 109/L; P=.028) were significant for overall survival. Midostaurin improved survival compared with placebo in most genetic subtypes (Figure 6). Rates of event-free survival were highest among patients with NPM1mut/FLT3-ITDlow treated with midostaurin and lowest among patients with NPM1wt/FLT3-ITDhigh who received placebo.
The study authors concluded that the combination of NPM1 and FLT3-ITD genotypes has prognostic value in patients with AML. Accordingly, these genotypes also impact the 2017 ELN risk stratification criteria, which include FLT3-ITD allelic burden. Patients with a favorable-risk genotype, as indicated by the ELN category (NPM1mut/FLT3-ITDlow), had
a positive long-term outcome with midostaurin, but they may not benefit from allogeneic hematopoietic stem cell transplant. Patients with an ELN adverse-risk genotype may benefit from midostaurin together with allogeneic hematopoietic stem cell transplant.
References
1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464.
2. Midostaurin. US Food and Drug Administration. April 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555756.htm. Accessed February 27, 2018.
3. Döhner K, Thiede C, Larson RA, et al. Prognostic impact of NPM1/FLT3-ITD genotypes from randomized patients with acute myeloid leukemia (AML) treated within the international RATIFY study [ASH abstract 467]. Blood. 2017;130(suppl 1).
Ivosidenib or Enasidenib Combined With Standard Induction Chemotherapy Is Well Tolerated and Active in Patients With Newly Diagnosed AML With an IDH1 or IDH2 Mutation: Initial Results From a Phase 1 Trial
A phase 1 study investigated ivosidenib or enasidenib in the frontline setting among patients with newly diagnosed AML that was positive for the IDH1/2 mutation. The aim of this study was to determine the safety and efficacy of regimens combining ivosidenib or enasidenib with the standard 7-plus-3 induction chemotherapy and consolidation treatment. Dr Eytan Stein and colleagues presented the initial results.1
This open-label, dose-escalation and dose-expansion trial enrolled adult patients with previously untreated AML. All patients had a documented IDH1 or IDH2 mutation. Those with an IDH1 mutation (n=32) received 1 to 2 cycles of standard induction therapy consisting of daunorubicin (60 mg/m2 per day) or idarubicin (12 mg/m2 per day) for 3 days plus cytarabine (200 mg/m2 per day for 7 days) in combination with ivosidenib (500 mg once daily). Patients with an IDH2 mutation (n=56) received the same standard induction regimen, with the addition of enasidenib (100 mg once daily).1
Patients with a CR or a CRi/CRp after induction therapy could receive up to 4 cycles of consolidation treatment with either 500 mg/day of ivosidenib (for the IDH1 mutation group) or 100 mg/day of enasidenib (for the IDH2 mutation group), both in combination with cytarabine. Patients who maintained a CR or CRi/CRp following consolidation then went on to receive either single-agent ivosidenib at 500 mg/day or enasidenib at 100 mg/day for up to 2 years (from day 1 of induction treatment). Patients who discontinued consolidation treatment to undergo stem cell transplant were not permitted to restart the study treatment.1
Among the 32 patients with an IDH1 mutation who were treated with ivosidenib plus chemotherapy, the median age was 60.5 years (range, 24 to 76 years). More than half were male (56%), and most patients (69%) had de novo AML. The primary type of IDH1 mutation identified was R132 (94%). Risk was favorable in 25%, intermediate in 41%, and poor in 34%. The most common co-mutation was in the NPM1 gene (41%).1
No dose-limiting toxicities were reported in the ivosidenib cohort. The 60-day mortality rate was 6%; none of the deaths were related to ivosidenib. Overall, 94% of patients experienced at least 1 grade 3 or higher nonhematologic treatment-emergent AE, most commonly febrile neutropenia (60%). Grade 3 or higher increases in blood bilirubin, alanine aminotransferase, and aspartate aminotransferase, as well as hypertension and colitis, each occurred in 9% of patients.1
The pharmacokinetic and pharmacodynamic profiles of ivosidenib were not affected by coadministration of daunorubicin vs idarubicin. By day 14 of the first induction cycle, plasma trough concentrations for ivosidenib had reached steady-state, and plasma 2-hydroxyglutarate concentrations decreased by up to 99%.1
The median time to absolute neutrophil count recovery (to >500/mm3) among the 20 patients treated with ivosidenib was 28.5 days (95% CI, 27-34). This duration was longer among the 5 patients with secondary AML (median, 35 days) vs the 15 patients with de novo AML (median, 28 days). The median time to platelet recovery (to >50,000/mm3) was also 28 days (95% CI, 26-34). The duration was 38 days in the 5 patients with secondary AML and 27 days in the 15 patients with de novo AML.1
Overall, 77% of patients in the ivosidenib-treated cohort achieved either a CR or CRi/CRp (Table 1). Among the 21 patients with de novo AML, 19 achieved a CR or CRi/CRp (91%). Among the 9 patients with secondary AML, 4 achieved a CR or CRi/CRp (44%). An additional 2 patients (1 with de novo AML and 1 with secondary AML) achieved a partial response, and 1 patient with secondary AML achieved a morphologic leukemia-free state.1
Among the 56 patients with an IDH2 mutation who received enasidenib plus chemotherapy, the median age was 63 years (range, 32-76 years). More than half were male (55%), and 57% had de novo AML. IDH2 mutations consisted of either R140 (70%) or R172 (30%). Risk was favorable in 7%, intermediate in 45%, and poor in 36%. (Risk was unknown in the remaining 13%.) The most common co-mutations reported were FLT3-ITD and NPM1 (13% each).1
One dose-limiting toxicity was reported in the enasidenib cohort. This patient received enasidenib in combination with daunorubicin and cytarabine and showed persistent grade 4 thrombocytopenia on day 42 of induction therapy. The 60-day mortality rate was 7%; no deaths were related to enasidenib. Most patients (91%) experienced at least 1 grade 3 or higher nonhematologic treatment-emergent AE. The most frequent of these events was febrile neutropenia (63%), followed by an increase in blood bilirubin, hypertension, and bacteremia (9% each).1
The pharmacokinetics and pharmacodynamics of enasidenib were not affected by coadministration with daunorubicin vs idarubicin. Similar to what was observed with ivosidenib, by day 14 of the first induction cycle, plasma trough concentrations of enasidenib had reached steady-state, and plasma 2-hydroxyglutarate concentrations decreased by up to 99%.1
The median time to absolute neutrophil count recovery (defined as >500/mm3) among enasidenib-treated patients (n=29) was 34 days (95% CI, 29-35). This duration was similar among the 15 patients with secondary AML (median, 34 days) and the 14 patients with de novo AML (median, 32.5 days). The median time to platelet recovery (to >50,000/mm3) was 33 days (95% CI, 29-50), and was longer in the 15 patients with secondary AML (50 days) than in the 14 patients with de novo AML (29 days).1
In the enasidenib-treated cohort, 62% of patients achieved either a CR or CRi/CRp. Among the 27 patients with de novo AML, 18 achieved a CR or CRi/CRp (67%). Of the 23 patients with secondary AML, 13 achieved a CR or CRi/CRp (57%). No partial responses were reported, but an additional 10 patients (4 with de novo AML and 6 with secondary AML) achieved a morphologic leukemia-free state.1
The study authors concluded that both ivosidenib and enasidenib were safe and well-tolerated when combined with standard 7-plus-3 induction therapy in patients with newly diagnosed AML. They noted that the response rates observed were consistent with what was expected in this population of patients with mutated IDH. Delays in hematologic recovery following induction therapy were observed in patients with secondary AML, but they could be addressed with an alternative dosing schedule.
Based on the activity observed in this and other studies with ivosidenib and enasidenib, phase 2 and 3 trials are planned to assess these agents in combination with standard induction chemotherapy for the treatment of patients with newly diagnosed AML and the IDH mutation.2,3
References
1. Stein EM, DiNardo CD, Mims AS, et al. Ivosidenib or enasidenib combined with standard induction chemotherapy is well tolerated and active in patients with newly diagnosed AML with an IDH1 or IDH2 mutation: initial results from a phase 1 trial [ASH abstract 726]. Blood. 2017;130(suppl 1).
2. ClinicalTrials.gov. Safety study of AG-120 or AG-221 in combination with induction and consolidation therapy in patients with newly diagnosed acute myeloid leukemia with an IDH1 and/or IDH2 mutation. https://clinicaltrials.gov/ct2/show/NCT02632708. Identifier: NCT02632708. Accessed March 6, 2018.
3. ClinicalTrials.gov. Study of AG-120 (ivosidenib) vs. placebo in combination with azacitidine in patients with previously untreated acute myeloid leukemia with an IDH1 mutation (AGILE). https://clinicaltrials.gov/ct2/show/NCT03173248. Identifier: NCT03173248. Accessed February 27, 2018.
Enasidenib Monotherapy Is Effective and Well-Tolerated in Patients With Previously Untreated Mutant-IDH2 Acute Myeloid Leukemia
Dr Daniel Pollyea and colleagues reported on clinical outcomes among older patients with newly diagnosed AML who had received single-agent enasidenib in the AG-221-C-001 phase 1 dose-escalation and dose-expansion study.1,2 This study included patients ages 60 years or older (median age, 77.0 years; range, 58-87 years) who were not considered candidates for standard induction/consolidation treatment. All patients had an ECOG performance status of 0, 1, or 2. Within the dose-escalation phase, enasidenib was administered at doses ranging from 50 mg/day to 650 mg/day. A dose of 100 mg/day was selected for the dose-expansion portion of the study.2
A total of 37 patients with previously untreated AML and an IDH2 mutation were treated. At the data cut-off (on October 14, 2016), 4 patients (11%) remained on-study: 3 patients in CR, and 1 patient with stable disease at cycle 13.2
An ORR was seen in 14 patients (37.8% [95% CI, 22.5-55.2]). Among these patients, 7 had a CR, 5 had a partial response, and 2 experienced a morphologic leukemia-free state (Table 2). The median time to CR was 5.6 months (range, 3.4-12.9). The median duration of CR was not reached (95% CI, 3.7 to not reached), and the median duration of any response was 12.2 months (95% CI, 2.9 to not reached). Three patients were able to proceed to transplant. At the time of data cut-off, all of these patients remained in a CR.2
The median overall survival was 10.4 months (95% CI, 5.7-15.1), and the median event-free survival was 11.3 months (95% CI, 3.9 to not reached). As expected, patients with a response survived longer. The median overall survival among patients with a response was 19.8 months (95% CI, 10.4 to not reached) vs 5.4 months (95% CI, 2.8-12.4) among nonresponders.2
The most frequent all-grade treatment-emergent AEs were fatigue (43%), nausea (41%), and decreased appetite (41%). The most commonly occurring treatment-related treatment-emergent AEs were hyperbilirubinemia (30%) and nausea (22%). Serious treatment-related treatment-emergent AEs reported for more than 1 patient were IDH differentiation syndrome (n=3) and tumor lysis syndrome (n=2). Dose modifications were required in 3 patients (8%) and dose interruptions in 7 patients (19%). One patient discontinued the study drug.2
The study investigators concluded that enasidenib was active in these patients. Enasidenib was associated with durable responses, and treatment prolonged survival among patients who achieved a response. The frequency of treatment-emergent AEs considered related to the study treatment was low, requiring few dose modifications or discontinuations. Ongoing trials are evaluating this approach. The Beat AML Master Trial (Master Protocol for Biomarker-Based Treatment of AML) is recruiting older patients with previously untreated AML with the IDH2 mutation to further assess enasidenib in this population.3
References
1. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
2. Pollyea DA, Tallman MS, de Botton S, et al. Enasidenib monotherapy is effective and well-tolerated in patients with previously untreated mutant-IDH2 (mIDH2) acute myeloid leukemia (AML) [ASH abstract 638]. Blood. 2017;130(suppl 1).
3. ClinicalTrials.gov. Study of biomarker-based treatment of acute myeloid leukemia. https://clinicaltrials.gov/ct2/show/NCT03013998. Identifier: NCT03013998. Accessed February 27, 2018.
Ivosidenib in Mutant IDH1 AML and Advanced Hematologic Malignancies: Results of a Phase 1 Dose Escalation and Expansion Study
D
r Courtney DiNardo and colleagues reported results from a single-arm, open-label study that evaluated single-agent ivosidenib in a dose-escalation and dose-expansion phase 1 design. In the dose-escalation portion of this study, ivosidenib was administered at doses ranging from 100 mg twice daily to 1200 mg once daily. During the dose-expansion phase, in which ivosidenib was administered at a dose of
500 mg/day, patients were enrolled into 4 cohorts. Cohort 1 included patients with AML that was relapsed or refractory after at least 2 courses of therapy, who had relapsed after stem cell transplant or within 1 year of treatment, or who were refractory to induction or reinduction. Cohort 2 consisted of patients with newly diagnosed AML who were ineligible for standard induction therapy. Cohort 3 included patients with other non-AML relapsed/refractory hem-atologic malignancies that were positive for the IDH1 mutation. Cohort 4 included patients with relapsed/refractory AML who did not qualify for inclusion in cohort 1.1
This report focused on data from patients considered to be the primary relapsed/refractory AML analysis set. This group included the first 125 patients who were treated during the dose-expansion phase (n=92) and eligible patients from the dose-escalation phase who had been treated with 500 mg/day of ivosidenib and who had been enrolled at least 6 months before the primary analysis cutoff date (n=33).1
The median age of patients in the primary relapsed/refractory AML analysis set was 67.0 years (range, 18-87 years), and 60% were female. Most patients had an ECOG performance status of either 0 (21.6%) or 1 (51.2%), and approximately two-thirds of patients had de novo AML (66.4%). The median number of prior therapies was 2 (range, 1-6). No patients were considered to have favorable risk. Risk was intermediate in 52.8% and poor in 30.4%. (Risk was unknown in 16.8% of patients.) The most frequent co-mutations were NPM1 (19.4%), FLT3-TKD (5.6%), and FLT3-ITD (2.4%).1
In this group of 125 patients, the median duration of treatment was 3.9 months (range, 0.1-25.8 months). Among patients who discontinued treatment, the most common reason was disease progression (52.8%). Other reasons included AEs (13.6%), treatment with stem cell transplant (9.6%), and death (6.4%).1
The primary efficacy endpoint of the study was the rate of CR plus CR with partial hematologic recovery (CRh). This rate was 30.4% (95% CI, 22.5-39.3) in the primary relapsed/refractory AML analysis set. The median time to CR/CRh was 2.7 months (range, 0.9-5.6), and the median duration of CR/CRh was 8.2 months (95% CI, 5.5-12.0). A total of 32.4% maintained either a CR or CRh for 12 or more months. The ORR (consisting of a CR, CRh, partial response, and morphologic leukemia-free state) was 41.6% (95% CI, 32.9-50.8). The median duration of ORR was 6.5 months (95% CI, 4.6-9.3), and 24.6% were still responding at 12 months.1
Responses were particularly high among patients with untreated disease who were not eligible for standard therapies. Among these patients, the ORR was 55.9% (95% CI, 37.9-72.8) in 34 patients with untreated AML, and 91.7% (95% CI, 61.5-99.8) in 12 patients with untreated myelodysplastic syndrome.1
After a median follow-up of 14.8 months, the median overall survival among all patients in the primary relapsed/refractory AML analysis set was 8.8 months (95% CI, 6.7-10.2; Figure 7). Achievement of a response markedly impacted survival, as the median overall survival was not reached among patients who had achieved either a CR or CRh (95% CI, 13.8 to not estimable), 9.3 months (95% CI, 3.7-10.8) in patients with a non-CR/CRh response, and 3.9 months (95% CI, 2.8-5.8) in patients with no response.1
Transfusion independence was achieved across all response categories, and was highest among patients with the deepest responses (Figure 8). For example, the rates of red blood cell transfusion independence (n=68) were 84.6%, 75.0%, 50.0%, and 15.4%, respectively, for patients who achieved a CR, CRh, partial response, and no response. Similarly, the rates of platelet transfusion independence (n=69) were 100%, 71.4%, 58.3%, and 16.7%, respectively.1
In a baseline mutation analysis substudy, no single gene mutation predicted response or resistance to ivosidenib treatment. Receptor tyrosine kinase pathway mutations were associated with a lack of response. A longitudinal analysis of mutated IDH1 found that treatment with ivosidenib was associated with a reduced mutated IDH1 allele burden in both bone marrow mononuclear cells and neutrophils among patients with relapsed/refractory AML who achieved a CR or CRh.2
The safety analysis population consisted of all 258 treated patients. In this population, the most frequent all-grade AEs (regardless of causality) included diarrhea (33.3%), leukocytosis (30.2%), nausea (29.5%), fatigue (28.7%), and febrile neutropenia (25.2%). The most common grade 3 or higher AEs were hematologic, and included febrile neutropenia (24.8%), anemia (19.0%), and thrombocytopenia (13.6%).1
The study authors identified 3 AEs of interest in the primary relapsed/refractory AML analysis. Grade 3 or higher leukocytosis occurred in 10 patients (8%), and was managed with hydroxyurea. None of these events were fatal. Grade 3 electrocardiogram QT prolongation occurred in 10 patients (8%), and led to a dose reduction in 1 patient. Interestingly, the incidence of febrile neutropenia in this analysis set appeared to be affected by the patients’ response. Although the incidence of all-grade febrile neutropenia was 6.9%, it reached 14.2% among nonresponders and decreased to 2.6% among patients who achieved a CR.1
All-grade IDH differentiation syndrome was reported in 12 patients (9.6%). Four of these patients experienced concurrent leukocytosis. IDH differentiation syndrome was well-managed with corticosteroids and diuretics (accompanied by hydroxyurea in cases of concurrent leukocytosis).1
Based on these data, the study investigators concluded that ivosidenib was well-tolerated and active in patients with relapsed/refractory AML. They noted that many responses were observed in heavily pretreated patients, and that responses were durable and clinically meaningful, with associated transfusion independence.1
References
1. DiNardo CD, de Botton S, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study [ASH abstract 725]. Blood. 2017;130(suppl 1).
2. Stone RM, Choe S, Zhang V, et al. Genetic profiling and deep IDH1 mutation clearance to ≤0.04% in ivosidenib (AG-120)-treated patients with mutant IDH1 relapsed or refractory and untreated AML [ASH abstract 2684]. Blood. 2017;130(suppl 1).
Highlights in Acute Myeloid Leukemia From the 2017 American Society of Hematology Annual Meeting and Exposition: Commentary
Courtney DiNardo, MD
Assistant Professor
Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas
Presentations in acute myeloid leukemia (AML) at the 2017 American Society of Hematology (ASH) Annual Meeting provided new data and updated analyses that may impact clinical care. Several important studies evaluated molecularly-based therapies targeting FLT3 and isocitrate dehydrogenase (IDH) mutations, and others presented exciting data on new chemotherapy combination regimens.
FLT3 Inhibitors
Dr Konstanze Döhner presented a subanalysis of the RATIFY study (A Randomized Phase III Study of Induction [Daunorubicin/Cytarabine] and Consolidation [High-Dose Cytarabine] Chemotherapy Combined With Midostaurin or Placebo in Treatment-Naive Patients With FLT3 Mutated AML).1 The RATIFY trial evaluated standard induction chemotherapy with a 7-plus-3 regimen in combination with the FLT3 inhibitor midostaurin in more than 700 patients with FLT3-mutated AML. This study was the first to show a clear benefit in overall survival with the addition of an FLT3 inhibitor to standard therapy.2 The presentation by Dr Döhner focused on specific genotypes within the RATIFY study, including NPM1 mutations, which represent a more favorable molecular phenotype. The study identified 428 patients with known NPM1 status. Overall survival varied according to the presence of the NPM1 mutation and low vs high FLT3-ITD burden. The rates of overall survival varied from not reached among patients with NPM1mut/FLT3-ITDlow to 17 months in patients with NPM1wt/FLT3-ITDhigh. This study was important because molecular stratification is emerging as a way to define different patient groups with different expectations for therapy.
A study presented by Dr Keith Pratz evaluated gilteritinib, a potent FLT3-ITD inhibitor, in combination with a 7-plus-3 induction chemotherapy backbone.3 Gilteritinib was given with induction on days 4 through 17 to 50 enrolled patients. The rate of complete response (CR)/CR with incomplete blood count recovery (CRi) was more than 70%, and the median overall survival was not met in this early analysis. An interesting aspect of the trial was enrollment of patients without FLT3 mutations. The most benefit was seen in patients with FLT3-ITD mutations, with a response rate of 91% vs 56% in those without these mutations. In contrast to midostaurin and sorafenib, gilteritinib is a more potent and selective inhibitor that specifically targets FLT3, and thus it makes sense to prioritize gilteritinib for use in patients with FLT3 mutations.
The IDH Inhibitors
At the 2017 ASH meeting, several studies provided data for IDH1- or IDH2-targeted therapies. The IDH2 inhibitor enasidenib was recently approved as a single agent by the US Food and Drug Administration in August 2017 for relapsed/refractory AML.4 In addition, there are now combination studies evaluating the IDH1 inhibitor ivosidenib (formerly known as AG-120) or enasidenib in combination with standard therapy. Dr Eytan Stein presented an early analysis of ivosidenib or enasidenib in combination with 7-plus-3 induction chemotherapy.5 The analysis provided data for approximately 80 patients. The rates of 30-day and 60-day mortality were as expected, at 5% vs 7% with enasidenib and 6% at both time points with ivosidenib. The rate of CR/CRi ranged from 60% to 80%, also as expected. There was a hint of prolonged platelet count recovery in the IDH2 arm, which may be confounded by the fact that almost half of these patients had therapy-related myelodysplastic syndrome or secondary AML, in contrast to the de novo patient populations in similar studies. More follow-up time and more patients will help confirm the optimal combination strategy.
I presented an update of the AG120-001 study of the IDH1 inhibitor ivosidenib as monotherapy in patients with relapsed/refractory AML.6 This large study has treated 258 patients, who had received a median of 2 prior treatments. The primary relapsed/refractory AML analysis focused on the 125 patients who were treated with ivosidenib at 500 mg, which is the phase 2 recommended dose level. Among these patients, the overall response was more than 40%. The rate of true CRs exceeded 20%, with a remission duration of 9 months. The median overall survival was 9 months or higher. These results significantly improve upon the historical control rates seen for these patients.
Another study I presented combined azacitidine with ivosidenib or enasidenib for up-front treatment of newly diagnosed AML among an unfit population.7 Data from the first 6 patients in the IDH2 arm and 11 in the IDH1 arm were presented. This early analysis provided results for response (but not survival). A response was seen in 4 of 6 patients with the IDH2 mutation and in 8 of 11 patients with the IDH1 mutation. These results are higher than those expected for azacitidine alone, which is associated with a response in approximately 30% to 40% of patients.8 Additional patients and follow-up time will be needed to further evaluate these combinations.
Dr Daniel Pollyea presented subset results of the enasidenib monotherapy AG-221-C-001 study for newly diagnosed patients with AML.9 Previously, data were presented for the AG-221-C-001 for patients with relapsed/refractory AML, showing an overall response rate of 40.3% and a median overall survival of 9.3 months.10 The newly diagnosed AML cohort included 38 patients. Most patients were elderly, with a median age of 77 years, and they were not candidates for intensive induction therapy. The rates of CR and overall response were favorable and consistent with those in the relapsed/refractory setting. The CR rate was approximately 18%, and the overall response rate was 32%. The median survival was 11 months. Monotherapy with the IDH2 inhibitors therefore appears to be a valid treatment strategy in this very high-risk population, providing an option for patients who are not able to receive intensive cytotoxic agents.
New Chemotherapy Regimens
Checkpoint inhibitors have generated excitement in nearly all cancers. Dr Farhad Ravandi-Kashani presented an early look at intensive chemotherapy combined with the programmed death inhibitor nivolumab.11 This study is one of the first to evaluate combinations of checkpoint inhibitors and chemotherapy in AML. This early analysis provided data for the first 35 patients. The CR/CRi rate was 76%. The 8-week mortality was 9%—which is consistent with historical experience with AML induction/consolidation—and the median overall survival was 15 months. Interpretation of these data is limited owing to the early analysis time point. It will be exciting to see if checkpoint inhibitors can be added to the treatment armamentarium for AML. The study reported some immune-related adverse events, but all were reversible with early corticosteroid use. If checkpoint inhibitors become a treatment option for patients with AML, it will be important to remain alert for these adverse events.
Dr Andrew Wei presented results from a study evaluating venetoclax in combination with low-dose ara-C in patients with AML who were ages 65 years or older.12 Many physicians who treat AML (including myself) have been reluctant to prescribe regimens with low-dose ara-C because the responses are suboptimal. Instead, hypomethylating agents are the unofficial standard therapy for the older or unfit AML population. The results from this new study presented by Dr Wei may change this approach. The study enrolled 61 patients, with a median age of 74 years. Notably, many patients had received prior treatment with a hypomethylating agent for an antecedent hematologic disorder. A 600-mg dose of venetoclax was given with low-dose ara-C. The response rate was higher than 60%, with a median overall survival of approximately 11 months. This outcome is vastly superior to that seen with low-dose ara-C alone.13 This important study has evolved into a randomized phase 3 trial, which is ongoing.14
I presented results from a phase 1/2 study evaluating venetoclax with a hypomethylating agent, either azacitidine or decitabine, as frontline therapy for a similar newly diagnosed, unfit patient population.15 This larger study enrolled 145 elderly patients. Based on phase 2 data for this combination, the recommended dose of venetoclax with hypomethylating therapy is 400 mg. This analysis showed a CR/CRi rate of approximately 70%, an overall response rate of 83%, and a median overall survival (so far) of 17.5 months. These results are dramatic, representing the first time that overall survival has exceeded 12 months with a frontline therapy in elderly patients with AML. An ongoing phase 3 randomized trial is evaluating the combination of venetoclax plus azacitidine vs azacitidine alone.16 Results will be of great interest to the AML community.
Finally, Dr Geert Huls presented an analysis of results of azacitidine as maintenance therapy from the HOVON97 trial (Hemato-Oncologie voor Volwassenen Nederland 97).17 Whether maintenance therapy has a role in AML remains unknown; rigorously performed studies have failed to demonstrate an improvement in survival with the use of maintenance treatment in the management of AML patients who receive intensive therapy. This phase 3 trial enrolled patients ages 60 years or older who had received 2 courses of intensive chemotherapy. Patients were randomly assigned to observation or 12 cycles of azacitidine. The study showed a significant improvement in disease-free survival with the addition of maintenance azacitidine. At 12 months, the disease-free survival was 63% with maintenance azacitidine vs 39% in the observation arm. This important study suggests that there could be a role for maintenance therapy with a hypomethylating agent in older patients with AML who have undergone a short course of intensive chemotherapy. Future studies will be needed to confirm and extend upon these findings.
Disclosure
Dr DiNardo is an advisor for Agios, Celgene, Novartis, and Bayer.
References
1. Döhner K, Thiede C, Larson RA, et al. Prognostic impact of NPM1/FLT3-ITD genotypes from randomized patients with acute myeloid leukemia (AML) treated within the international RATIFY study [ASH abstract 467]. Blood. 2017;130(suppl 1).
2. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464.
3. Pratz K, Cherry M, Altman JK, et al. Preliminary results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia [ASH abstract 722]. Blood. 2017;130(suppl 1).
4. FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML. US Food & Drug Administration. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569482.htm. Updated August 1, 2017. Accessed March 4, 2018.
5. Stein EM, DiNardo CD, Mims AS, et al. Ivosidenib or enasidenib combined with standard induction chemotherapy is well tolerated and active in patients with newly diagnosed AML with an IDH1 or IDH2 mutation: initial results from a phase 1 trial [ASH abstract 726]. Blood. 2017;130(suppl 1).
6. DiNardo CD, de Botton S, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study [ASH abstract 725]. Blood. 2017;130(suppl 1).
7. DiNardo CD, Stein AS, Fathi AT, et al. Mutant isocitrate dehydrogenase (mIDH) inhibitors, enasidenib or ivosidenib, in combination with azacitidine (AZA): preliminary results of a phase 1b/2 study in patients with newly diagnosed acute myeloid leukemia (AML) [ASH abstract 639]. Blood. 2017;130(suppl 1).
8. Khan C, Pathe N, Fazal S, Lister J, Rossetti JM. Azacitidine in the management of patients with myelodysplastic syndromes. Ther Adv Hematol. 2012;3(6):355-373.
9. Pollyea DA, Tallman MS, de Botton S, et al. Enasidenib monotherapy is effective and well-tolerated in patients with previously untreated mutant-IDH2 (mIDH2) acute myeloid leukemia (AML) [ASH abstract 638]. Blood. 2017;130(suppl 1).
10. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
11. Ravandi F, Daver N, Manero G, et al. Phase 2 study of combination of cytarabine, idarubicin, and nivolumab for initial therapy of patients with newly diagnosed acute myeloid leukemia [ASH abstract 578]. Blood. 2017;130(suppl 1).
12. Wei A, Strickland SA, Roboz GJ, et al. Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes [ASH abstract 890]. Blood. 2017;130(suppl 1).
13. Heiblig M, Elhamri M, Tigaud I, et al. Treatment with low-dose cytarabine in elderly patients (age 70 years or older) with acute myeloid leukemia: a single institution experience. Mediterr J Hematol Infect Dis. 2016;8(1):e2016009. doi:10.4084/MJHID.2016.009.
14. ClinicalTrials.gov. A study of venetoclax in combination with low dose cytarabine versus low dose cytarabine alone in treatment naïve patients with acute myeloid leukemia who are ineligible for intensive chemotherapy. ttps://clinicaltrials.gov/ct2/show/NCT03069352. Identifier: NCT03069352. Accessed March 5, 2018.
15. DiNardo C, Pollyea DA, Jonas BA, et al. Updated safety and efficacy of venetoclax with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia [ASH abstract 2628]. Blood. 2017;130(suppl 1).
16. ClinicalTrials.gov. A study of venetoclax in combination with azacitidine versus azacitidine in treatment naïve subjects with acute myeloid leukemia who are ineligible for standard induction therapy. https://clinicaltrials.gov/ct2/show/NCT02993523. Identifier: NCT02993523. Accessed March 4, 2018.
17. Huls G, Chitu D, Havelange V, et al. Randomized maintenance therapy with azacitidine (Vidaza) in older patients (≥60 years of age) with acute myeloid leukemia and refractory anemia with excess of blasts (RAEB, RAEB-t). Results of the HOVON97 phase III randomized multicentre study (EudraCT 2008-001290-15) [ASH abstract 463]. Blood. 2017;130(suppl 1).