General AML,   IDH1/2,  FLT3

Targeted treatment of AML – Oral abstract session at the 22nd congress of the EHA

During the 22nd Congress of the European Hematology Association (EHA) Congress, Madrid, Spain, the AGP attended a captivating oral session focused on targeted therapies for Acute Myeloid Leukemia (AML). The session was co-chaired by Professor Arnold Ganzer from the  Medizinische Hochschule Hannover, Germany, and Professor Farhad Ravandi-Kashani, M.D., from The University of Texas, MD Anderson Cancer Center, Houston, USA.

Abstract S471

The first talk during this session was presented by Eytan M. Stein, from the Memorial Sloan Kettering Cancer Center. The speaker presented results from a phase I/II dose escalation and expansion study (NCT01915498), which evaluated the safety, clinical activity, maximum tolerated dose, and pharmacodynamic profile of enasidenib (AG-221), an oral, selective inhibitor of mutations in isocitrate dehydrogenase 2 (mIDH2), in patients with advanced hematologic malignancies, specifically Relapsed or Refractory (R/R) AML. The results of the study were reported here.

Eytan M. Stein concluded his talk by stating that “enasidenib was well tolerated, induced durable CRs, and was associated with OS of > 8 months” in R/R AML patients. Additionally, differentiation of myeloblasts drives the clinical efficacy of enasidenib. 

Assistant Professor Amir Fathi, Harvard Medical School, spoke to the AGP on the differentiation syndrome seen in a “minority” of patients treated with enasidenib, which could be “life threatening” if not recognized early and managed properly. He added that enasidenib was effective in IDH2 mutated AML and “does not need to be permanently discontinued” as long as this differentiation syndrome is recognized and managed properly in patients.  

Abstract S472

The next talk during this session was given by Assistant Professor Keith W. Pratz, M.D., from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA.

The speaker presented preliminary results from the phase Ib dose-escalation and expansion study (NCT02203773), which assessed the efficacy and safety of venetoclax (VEN), an oral, selective BCL-2 inhibitor, combined with the Hypomethylating Agents (HMAs) decitabine (DEC) or azacitidine (AZA) in newly diagnosed elderly AML patients. The preliminary analysis compared two doses (400 mg vs 800 mg) of VEN in the expansion phase of this trial.

In total, one hundred de novo AML patients (median age = 72.5 years) were enrolled in this study as of 12/09/16. Patients were administered either a continuous 400 mg dose of once daily oral VEN in combination with DEC (arm D1 [n =25]) or AZA (arm E1 [n = 25]) or an interrupted 800 mg dose of once-daily oral VEN in combination with DEC (arm D2 [n = 25]) or AZA (arm E2 [n = 25]).

The key results of the study were:
  • Treatment-related Adverse Events (AEs) were similar between the arms and included nausea, diarrhea, febrile neutropenia, constipation, fatigue, neutropenia, and thrombocytopenia
  • Overall Response Rate (ORR) in Arms D1, E1, D2, and E2 were 76%, 72%, 68%, and 56%, respectively
  • ORR in all patients was 68%

  • Estimated 6-month Overall Survival (OS) was 79% and median OS has not been reached at the time of evaluation

Assistant Professor Keith W. Pratz concluded his talk by highlighting that the safety of VEN at either dose combined with DEC or AZA was “tolerable” in elderly AML patients. Additionally, high ORRs were observed with the lower 400 mg dose compared to 800 mg dose of VEN. A phase III study (NCT02993523) of venetoclax in combination with AZA is currently ongoing.

The findings of this study were further elaborated in an interview by Assistant Professor Keith W. Pratz.

Abstract S473

The next talk was presented by the chair of our Rest of the World Steering Committee, Associate Professor Andrew Wei from  Alfred Hospital, Monash University, Melbourne, Australia.

Previous results obtained from a phase I study, which evaluated the safety, pharmacokinetic profile, and efficacy of VEN in combination with Low-Dose cytarabine (LDAC) in newly diagnosed AML patients have shown that this combination is tolerable and durable in elderly AML patients. Additionally, the Recommended Phase 2 dose (RP2D) of VEN in combination with LDAC was found to be 600 mg.

The speaker presented updated results from this study, which aimed to evaluate the safety and preliminary efficacy of LDAC in combination with VEN at the RP2D.

Overall, sixty-one AML patients (median age = 74 years) were treated with 600 mg VEN in combination with LDAC.

The key results of the study were:
  • Grade 3–4 AEs occurred in ≥ 10% of patients including febrile neutropenia (36%), thrombocytopenia (44%), hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%)
  • ORR in all patients was 62%

  • Patients who achieved an objective response to VEN plus LDAC (n = 37) had longer survival than non-responders (n = 24)
  • 30-day and 60-day early mortality rates were 3% and 15%, respectively

Associate Professor Andrew Wei concluded his talk by highlighting that 600 mg venetoclax in combination with LDAC was “tolerable” and exhibited “durable efficacy” in elderly untreated AML patients. Furthermore, ORR correlated with better survival in patients.

Associate Professor Andrew Wei spoke to the AGP about the findings of this study. He highlighted that the combination was “extremely well tolerated” and “the treatment results were quite remarkable”. He added that the long term survival rate was also “very promising”.

Abstract S474

Assistant Professor Naval Daver, M.D., from The University of Texas, MD Anderson Cancer Center gave the next talk discussing results from the phase Ib/II study, which assessed the safety and efficacy of nivolumab in combination with AZA in patients with relapsed AML.

In this study, the authors investigated a novel combination of two agents; AZA and nivolumab, a PD-1 inhibitor. The rationale behind this study was to evaluate a mode of augmenting the anti-tumor and immunogenic effects of PD-1 inhibitors whilst combatting the problem of resistance in HMA therapy.

In total, seventy R/R AML patients (median age = 70 years) were enrolled and were evaluable for a response. The key results were:

  • ORR in all patients was 32%
  • Fifteen patients (22%) achieved Complete Remission (CR)/Complete Remission with Insufficient Recovery Counts (CRi)
  • Seven patients had Hematologic Improvement (HI) and had ≥ 50% Bone Marrow (BM) blast reduction

  • Median OS in CR/CRi patients was 15.3 months

  • Median OS of all patients treated with AZA + nivolumab compared favorably to historical survival with AZA-based salvage protocol

  • Patients who responded better to treatment had higher CD3 cells (P = 0.10), CD8+ T-cells (P = 0.02), and lower CD4+FoxP3+PD1+ T-regulatory (T-reg) cells (P = 0.01) at baseline, compared to non-responders

The AGP interviewed Assistant Professor Naval Daver on the findings of this study. He highlighted that the combination compared favorably to historical survival with AZA-based salvage protocols in similar patients treated at MDACC. Additionally, AZA and nivolumab combination were tolerable and produced promising and durable response rates in relapsed AML patients with poor risk features.

Abstract S475

The final talk of this session was presented by Professor Robert Hills from Cardiff University, Wales, UK.

Previous results from the phase II AC220-002 study, which evaluated the safety and efficacy of quizartinib (FLT3 inhibitor) monotherapy in R/R AML patients, showed that quizartinib conferred a median OS of 22.9 weeks and a remission rate of 46%.

During this talk, the speaker presented results from a study which aimed to compare the Stem Cell Transplantation (SCT) rates and outcomes of patients from the AC220-002 study with a historical cohort of 1,388 AML patients with confirmed FLT3-ITD mutations in the UK National Cancer Research Institute database.

In total, fifty-eight FLT3-ITD positive patients who were relapsed (n = 53) or refractory to salvage therapy prior to entry into the AC220-002 study were included in this analysis. Conversely, 118 R/R FLT3-ITD patients who were R/R following salvage chemotherapy were identified from the NCRI database and included in this study.

The key results of the study were:
  • Patients in the AC220-002 cohort had higher remission rates than patients in the NCRI cohort; 40% vs 3%, Odds Ratio(OR) = 0.05, P < 0.0001
  • Patients in the AC220-002 cohort had longer median OS than NCRI patients; 140 vs 54 days, HR = 0.38, P < 0.0001

  • The transplant rates of patients in the AC220-002 cohort was higher than patients in the NCRI cohort; 40% vs 8%, OR = 7.48, P = 0.0001
  • 18-month OS was longer in patients that underwent SCT than patients that did not undergo SCT; 29% vs 7%, HR = 0.37, P = 0.0005

The speaker concluded by stating that quizartinib when compared with historical cohort was associated with “greater remission rate” and “prolonged survival”. Additionally, patients treated with quizartinib have a greater opportunity to receive SCT in patients who relapsed after salvage therapy.

 

References
  1. Stein E. M. et al. Enasidenib (AG-221) in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase 1 dose-esclation sand expansion study. Abstract S471. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  2. Pratz K. et al. Safety and efficacy of venetoclax (VEN) in combination with decitabine or azacitidine in treatment-naïve, elderly patients (≥ 65 years) with acute myeloid leukemia (AML). Abstract S472. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  3. Wei A. et al. Updated safety and efficacy results of phase 1/2 study of venetoclax plus low-dose cytarabine in treatment-naïve acute myeloid leukemia patients aged ≥ 65 years and unfit for standard induction therapy. Abstract S473. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  4. Daver N. et al. Phase Ib/II study of nivolumab in combination with azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia. Abstract S474. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  5. Hills R. et al. Quizartinib and bridge to transplant in FLT3-ITD AML patients after failure of salvage chemotherapy: A historical comparison with UK National Cancer Research Institute (NCRI) data. Abstract S475. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
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