General AML,   DNMT3A,  IDH1/2,  NPM1,  FLT3

Molecular response to FLT3 inhibitor, enasidenib in mutant-IDH2, and the correlation between somatic mutation clearance and clinical outcomes in AML patients – oral abstracts at the 2017 ASCO Annual Meeting

On Tuesday 6th June 2017, during the 2017 American Society of Clinical Oncology (ASCO) annual meeting, an oral abstract session took place. The session was jointly chaired by Tapan M. Kadia, M.D. from The University of Texas MD Anderson Cancer Center and Alice S. Mims, M.D., from the Ohio State University.

Three oral abstracts were presented on Acute Myeloid Leukemia (AML):

Abstract 7003

Jessica K. Altman, M.D, from the Northwestern University, Chicago, IL, presented results from their exploratory analysis of the molecular response to gilteritinib, a potent, oral, Fms Like Tyrosine 3 (FLT3)/AXL inhibitor, in a sub-group of patients enrolled in the phase I/II CHRYSALIS study (NCT02014558). The CHRYSALIS study examined the tolerability and anti-leukemic effects of once-daily gilteritinib in a FLT3-ITD-enriched R/R AML patients.

Previous results from CHRYSALIS study have revealed that gilteritinib was well tolerated and showed potent FLT3 inhibition at doses ≥80 mg/day.

Minimal Residual Disease (MRD) may predict relapse in AML patients and there is a paucity of studies that have assessed MRD in patients treated with FLT3 inhibitor, hence the rationale for this study.

Using Next Generation Sequencing (NGS), Jessica K. Altman and her colleagues assessed the molecular response of FLT3 Mutated Positive (FLT3mut+) AML patients at baseline and also after therapy with gilteritinib. FLT3-ITD and total FLT3 alleles were quantified in FLT3mut+ AML patients who were enrolled in the 120 mg/day and 200 mg/day gilteritinib dose cohorts of the CHRYSALIS study. A molecular response was defined as ITD signal ratio (FLT3-ITD:FLT3 total) of ≤ 10−2. A Major Molecular Response (MMR) was defined as ITD signal ratio of ≤ 10−3 and negative MRD was defined as ITD signal ratio of ≤ 10-4. The key results of evaluable patients (n = 80, median age = 61 years) included in this study were:

  • 25% of patients had a molecular response
  • MMR was observed in eighteen patients
  • 16% of patients had MRD negative status
  • Median Overall Survival (OS) in patients that had achieved a molecular response (n = 20) and patients that did not achieve a molecular response (n = 60); 49.6 vs 28.4 weeks, P = 0.001
  • Median Overall Survival (OS) in patients that had achieved MRD negative status (n = 13) and patients that did not achieve MRD negative status (n = 67); 59.6 vs 30.4 weeks, P = 0.002

Jessica K. Altman highlighted that their study is the first to demonstrate a “molecular response to a FLT3 inhibitor in AML”.  She further added that molecular response may predict durable clinical benefit from gilteritinib therapy.

The AML Global Portal interviewed Professor Jessica Altman on the molecular response to gilteritinib. She highlighted that the median OS in patients that had achieved a molecular response to gilteritinib was significantly longer than patients that did not achieve a molecular response.

Abstract 7004

Eytan M. Stein, from the Memorial Sloan Kettering Cancer Center, presented results from a phase I/II dose escalation and expansion study (NCT01915498), which evaluated the safety, clinical activity, maximum tolerated dose, and pharmodynamic profile of enasidenib (AG-221), an oral, selective inhibitor of mutations in isocitrate dehydrogenase 2 (mIDH2), in patients with advanced hematologic malignancies.

After the dose escalation part of this study, it was then expanded into four cohorts including two cohorts with patients with R/R AML patients. The results obtained from the cohorts of R/R AML patients were presented during this talk.

In total, 176 R/R AML patients received enasidenib with 100 patients receiving 100 mg/day doses.  

  • Overall Response Rate (ORR) in all R/R AML patients (n = 176); 40.3%
  • Median OS in all R/R AML patients; 9.3 months
  • Median OS in R/R AML patients that achieved Complete Remission and patients that did not achieve CR; 19.7 vs 7.0 months
  • Grade 3–4 drug-related investigator reported AEs included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%)

Eytan M. Stein summarized his talk by stating that “enasidenib was well tolerated, induced durable CRs, and was associated with OS of >9 months” in R/R AML patients.

 Abstract 7005

In patients with AML in CR, the persistence of somatic mutations can lead to poor survival. Koichi Takahasi from The University of Texas MD Anderson Cancer Center presented results from his group’s study, which aimed to determine the prognostic impact of mutation clearance after chemotherapy in AML and also evaluate the variable effect of chemotherapy on clearance of various mutations.  

Takashi et al. sequenced pretreatment Bone Marrow (BM) samples and CR samples from ninety-five AML patients (median age = 53 years) who were treated with induction chemotherapy. Overall, 295 mutations were detected in 78 genes, with the most frequently identified mutations in NPM1, DNMT3A, and FLT3. Three levels of Mutation Clearance (MC) were detected based on the Variant Allele Frequency (VAF); persistent mutation with VAF < 2.5% (MC2.5), persistent mutation with VAF < 1% (MC1.0), and Complete Mutation Clearance (CMC).

The key results of the study are:
  • CR samples, 62 (10%) and 82 (14%) mutations persisted at VAF ≥ 2.5% and ≥ 1%, respectively, which corresponded to 43 (49%), 34 (39%), and 30 (34%) patients achieving MC2.5, MC1.0, and CMC, respectively
  • Low rate of MC was seen in mutations associated with Clonal Hematopoiesis of Indeterminate Potential (CHIP), DNA methylation, and splicing pathways
  • High rate of MC was seen in mutations associated transcription factors or Receptor Tyrosine Kinase (RTK)
  • Median Relapse Free Survival (RFS) was significantly longer in patients that achieved MC1.0 (P = 0.04) or CMC (P = 0.049) compared to patients that achieved MC2.5

In summation, somatic mutations associated with DNA methylation, CHIP, and splicing were frequent in CR samples from AML patients, thus indicating these mutations have pre-leukemic activity. Additionally, patients with deeper MC had significantly longer RFS. Koichi Takahasi concluded by suggesting that somatic mutation clearance may aid predicting risk in AML but further suggested that larger studies are required to understand the complex association between pretreatment mutation and clearance.

We interviewed Koichi Takahasi on the correlation between mutation clearance and clinical response in elderly patients with AML.

Additionally, one of the co-chairs of this oral session was interviewed to provide his key highlights from this captivating session.

References
  1. Altman J .K. et al. Deep molecular response to gilteritinib to improve survival in FLT3 mutation-positive relapsed/refractory acute myeloid leukemia. J Clin Oncol 35, 2017 (suppl; abstr #7003). 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, 2017 June 2–6; Chicago, IL, USA.
  2. Stein E. M. et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study. J Clin Oncol 35, 2017 (suppl; abstr #7004). 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, 2017 June 2–6; Chicago, IL, USA.
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