Decitabine and venetoclax for <i> <scp>IDH1/2</scp> ‐ </i> mutated acute myeloid leukemia
Authors: Sangeetha Venugopal, Abhishek Maiti, Courtney D. DiNardo, Sanam Loghavi, Naval G. Daver, Tapan M. Kadia, Caitlin R. Rausch, Yesid Alvarado, Maro Ohanian, Koji Sasaki, Nicholas J. Short, Koichi Takahashi, Musa Yilmaz, Farhad Ravandi, Hagop M. Kantarjian, Marina Y. Konopleva
Journal: American Journal of Hematology (2021)

Isocitrate dehydrogenase (IDH) 1/2 mutations occur in approximately 20% of older patients with acute myeloid leukemia (AML). Ivosidenib, an IDH1 inhibitor, is approved for the treatment of relapsed/refractory (R/R) IDH1mut AML and newly diagnosed (ND) patients ineligible for standard therapy, and enasidenib, an IDH2 inhibitor in IDH2mut R/R AML. In ND IDH1mut AML, ivosidenib offers complete remission (CR) plus CR with partial hematologic recovery (CRh) rate of 42% and median overall survival (OS) of 12.6 months, and in the R/R setting, CR/CRh of 30% and median OS of 8.8 months.1 Comparably, enasidenib in ND IDH2mut AML patients showed a CR/CR with incomplete hematologic recovery (CRi) rate of 21% and median OS of 11.3 months, and in R/R patients, a CR/CRi of 26% and median OS of 8.8 months.2 Venetoclax with hypomethylating agent (HMA) is now standard for elderly patients ineligible for intensive therapy. Preclinical studies have shown that IDH1/2mut primary AML cells are highly sensitive to BCL-2 inhibition which was confirmed by clinical studies showing durable responses in IDH1/2mut patients receiving venetoclax monotherapy. In the recently published randomized placebo-controlled trial, venetoclax and azacitidine showed a CR/CRi rate of 75% of patients with ND IDH1/2mutAML with a median OS of 24.5 months.3 Herein, we describe the outcomes of patients with treatment naïve and previously treated IDH1/2mut AML, who were treated on a prospective phase 2 trial of 10-day decitabine with venetoclax (DEC10-VEN, NCT03404193).4 Older patients with ND patients (>60 years) and adult patients >18 years with secondary AML (sAML) from antecedent hematological disorder (AHD), with or without prior therapy for AHD, and R/R AML, with ECOG performance status ≤3 without prior BCL-2 inhibitor exposure were enrolled. In line with our prior report and due to differences in outcomes, we classified treatment-naïve AML as ND AML or sAML without prior therapy for AHD, and the previously treated group as patients with prior treatment for AHD or R/R AML. Patients received 10-day decitabine at 20 mg/m2/day for induction followed by 5-days for consolidation. Venetoclax dose was 400 mg PO daily or equivalent (with azole co-administration). Full protocol of the study have been published previously.4 Reduction in venetoclax duration to <21 days per cycle was allowed to mitigate any myelosuppression. Addition of IDH1/2 inhibitors was allowed. Responses, OS, and relapse-free survival (RFS) were graded per ELN2017 guidelines for AML. Measurable residual disease (MRD) was assessed on bone marrow specimens using multiparametric flow cytometry (FCM) validated to a sensitivity level of 0.01%-0.1%. IDH1/2mut testing was performed using a next-generation sequencing panel with an analytical sensitivity of 5% mutant reads in a background of wild-type reads; or separately using Sanger sequencing during follow-up (variant allele frequency sensitivity 20%). Between January 20, 2018 and March 19, 2020, we treated 10 and 25 patients with IDH1mut and IDH2mut AML, respectively (Table S1). No patients with IDH1mut received concurrent ivosidenib. Among patients with treatment naive IDH1mut AML (n = 7), the median age was 69 years (range, 65-77), and three (43%) patients had adverse risk AML per ELN 2017. ND IDH1mut AML cohort was enriched with DNMT3A (57%), NPM1, SRSF2 (43% each) mutations (Figure 1(F)). The overall response rate (ORR) was 100% (n = 7/7) with MRD negativity by FCM (MRDneg) achieved in 43% patients (n = 3/7) (Figure 1(A)). The 60-day mortality was 0%. After a median follow-up of 23.2 months three patients have relapsed (43%). The 1-year OS was 71% and 1-year RFS was 84% (Figure 1(B) and (C)). Three patients with previously treated IDH1mut AML had a median age of 77 years (range, 75-79) and had received a median of one prior therapy for AHD or AML (range, 1-2). This cohort was enriched with DNMT3A, K/NRAS, NPM1, PHF6, TP53 (33% each) (Figure 1(F)). Only one patient (33%) attained CR MRDneg; one patient (33%) was inevaluable and one patient (33%) was refractory. The 60-day mortality was 0%. After a median follow-up of 14.7 months, the 1-year OS was 66% and the 1-year RFS was 100% (Figure 1(B) and (C)). Among patients with IDH2mut AML, 14 patients had treatment-naive AML and 11 patients had previously treated AML. One treatment-naïve and one previously treated patient continued to receive decitabine and venetoclax with the addition of enasidenib from cycle 15 and six, respectively. The median age in the treatment-naïve group was 72 years (range, 65-80) and 36% patients (n = 5) had adverse risk AML. ND IDH2mut AML cohort was enriched with SRSF2 (57%), K/NRAS (29%), DNMT3A (28%) (Figure 1(F)). The ORR was 86% (n = 12/14) and MRDneg was achieved in 57% patients (n = 8/14) (Figure 1(A)). One patient (7%) had aplasia, one patient (7%) had refractory disease, and four patients (29%) relapsed. The 60-day mortality was 7% (n = 1/14) which was related to bacteremic sepsis. At a median follow up of 19.9 months, the 1-year OS was 79%, the median OS was 29.6 months (Figure 1(D)) and 1-year RFS was 74% (Figure 1(E)). Among 11 patients with previously treated IDH2mut AML, the median age was 62 years (range, 34-75), six patients (55%) had ELN adverse risk AML and had received a median of three prior therapies (range, 1-5). This cohort was enriched with DNMT3A (36%) and TP53 (27%) (Figure 1(F)). The ORR was 82% (n = 9/11) and MRDneg rate was 54% (n = 6/11). One patient was inevaluable (9%), one patient was refractory (9%) and four patients (36%) relapsed. The 60-day mortality was 9% (n = 1) which was related to traumatic intracranial hemorrhage. At a median follow up of 22.1 months, the 1-year OS was 59% and median OS was 14.7 months (Figure 1(D)). The 1-year RFS was 80% and median RFS was 15.6 months (Figure 1(E)). The most frequent new mutations emerged on NGS testing in 11 patients at the time of relapse included SRSF2 (n = 5/10), DNMT3A (n = 3), WT1 (n = 3), and K/NRAS (n = 3, Figure 1(F)). DEC10-VEN appeared effective in clearing IDH1/2mut clones in majority of patients and three patients (3/10) relapsed with undetectable IDH1/2mut. Co-mutations in tumor suppressor genes (TP53, WT1, PHF6) were more frequent at baseline or at relapse in patients with refractory disease or relapse compared to those with durable responses without relapse till data cut-off for this report (9/14 vs. 4/18, p = .02). After a median follow-up of 20.2 months in all patients, nine patients (26%) continue therapy and 21 patients (60%) are alive. The reasons for treatment discontinuation in 26 patients included relapse (n = 8, 23%), SCT (n = 6, 17%), death (n = 4, 11%), refractory disease (n = 3, 9%), patient choice (n = 2, 6%), toxicity (n = 2, 6%) and new lung cancer diagnosis (n = 1, 3%). Causes of death in 14 patients included infections (n = 4, 11%), death in hospice (n = 4, 11%), unknown reason (n = 3, 9%), intracranial hemorrhage (n = 2, 6%), and cardiac arrest (n = 1, 3%). With necessary caution for cross-trial comparisons and differences in patient populations, CR/CRi rates with DEC10-VEN in both treatment-naive and previously treated IDH1/2mut AML were numerically higher compared to IDH1/2 inhibitor monotherapy1, 2 and were comparable with available data on HMA + IDH inhibitors or HMA + venetoclax. In IDH1mut treatment-naive patients ineligible for intensive chemotherapy, CR/CRi rate of 86% with DEC10-VEN was modestly higher compared to CR/CRi of 70% with ivosidenib and azacitidine.5 Similarly, in treatment-naive patients with IDH2mut AML,CR/CRi of 70% with DEC10-VEN was comparable to CR/CRi of 63% with enasidenib and azacitidine.6 These responses rates of 70%-86% with DEC10-VEN were comparable to CR/CRi rate of 75% with azacitidine and venetoclax for IDH1/2mut AML.3 Although all AML patients with IDH1/2mut and/or NPM1mut treated with frontline venetoclax combination have been reported to have excellent outcomes in terms of sustained remission and survival benefit,3 durable remissions are possibly unique to IDH2/NPM1 co-mutated patients.7 In our cohort, outcomes in treatment naïve IDH1mut AML appeared favorable compared to IDH2mut AML, which may be due to the limited sample size, enrichment for NPM1 mutations in IDH1mut cohort (43% vs. 21%) and previously treated cohort having a median of one prior line of therapy in IDH1mut patients compared to three lines in IDH2mut cohort. Of note, the triplet combination of DEC10-VEN + enasidenib maintained and prolonged the duration of remission in two patients who experienced disease progression on DAC10 + VEN combination (for 11 and 8 months, respectively). The value and optimal regimen of venetoclax and IDHi doublets and triplets in IDH1/2mut AML need further clarification through larger datasets. One prospective trial evaluating ivosidenib with venetoclax ± HMA triplet combination is underway (NCT03471260). Although our study is limited by the lack of apriori post-hoc analysis and a small sample size, DEC10-VEN appears to be a possibly efficacious frontline option with high activity for older patients with IDH1/2mut ND AML, and additionally may be an effective strategy for R/R IDH1/2mut AML. Early referral for high-risk patients and post-SCT maintenance with IDH inhibitors, as well as ongoing evaluation of this and other clinical trials incorporating “triplet” therapy, may offer even enhanced future outcomes. This study was supported in part by the MD Anderson Cancer Center Support Grant CA016672 from the National Cancer Institute and the Research Project Grant Program (R01CA235622) from the National Institutes of Health. We thank the patients, their caregivers, and members of the study team involved in this trial. SV: None. AM: Research funding from Celgene Corporation. CDD: Personal fees from Abbvie, personal fees from Agios, personal fees from Novartis, personal fees from ImmuneOnc, personal fees from Daiichi Sankyo, personal fees from Celgene, personal fees from Jazz, personal fees from Notable Labs, outside the submitted work. SL: None. NGD: reports grant from Abbvie, Genentech, Astellas, Daiichi-Sankyo, Pfizer, BMS, Immunogen, Novimmune, Forty-seven; personal fees from Abbvie, Genentech, Astellas, Daiichi-Sankyo, Pfizer, BMS, Immunogen, Jazz pharmaceuticals, Trillium, Forty-seven, Gilead, Kite, Novartis. TMK: None. CRR: None. YA: None. MO: None. KS: None. NJS: reports grant from Takeda Oncology, Astellas; Personal fees from Takeda Oncology, AstraZeneca, Amgen. KT: has received personal fees for service on advisory boards of Symbio Pharmaceuticals, GSK, Celgene. MY: None. FR: None. HMK: grants and other from AbbVie, grants and other from Agios, grants and other from Amgen, grants from Ariad, grants from Astex, grants from BMS, from Cyclacel, grants from Daiichi-Sankyo, grants and other from Immunogen, grants from Jazz Pharma, grants from Novartis, grants and other from Pfizer, other from Actinium, other from Takeda, outside the submitted work. MYK: has received grants from NIH, NCI, Abbvie, Genentech, Stemline Therapeutics, Forty-Seven, Eli Lilly, Cellectis, Calithera, Ablynx, Astra Zeneca; Consulting/honorarium from AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; clinical trial support from Ascentage; stocks/royalties in Reata Pharmaceutical. Institutional review board approval and ethics committee clearance were obtained. The protocol has been published elsewhere. At this time, we will not be able to share individual patient-level data outside of our institution. Table S1. Baseline characteristics of patients with IDH1/2mut AML treated with venetoclax and 10-day decitabine Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.