Outcomes of therapy with venetoclax combined with a hypomethylating agent in favorable-risk acute myeloid leukemia.

Abstract

Favorable-risk acute myeloid leukemia (AML) includes core-binding factor (CBF) leukemia with either t(8;21) (q22;q22.1) RUNX1-RUNX1T1 or inv(16)(q13. 1q22) or t(16;16) (p13.1;q22) CBFB-MYH11 and AML with normal cytogenetics (CN-AML) with mutated nucleophosmin-1 (NPM1 mutated CN-AML) without FLT-3 ITD mutation; and CN-AML with bi-allelic CEBPA mutations.1, 2 Although observed more frequently in younger patients, favorable-risk alterations are also observed among older patients, often unfit for intensive regimens.3 Favorable-risk AML has better outcomes compared to other genetic subtypes of AML; when treated with standard frontline regimens (such as 7 + 3) followed by high-dose cytarabine consolidation. Nonetheless, for older patients with newly diagnosed (ND) favorable-risk AML, the administration of standard intensive induction regimens is usually limited due to poor performance status and comorbidities. Furthermore, even for older patients with favorable-risk AML who can tolerate intensive induction regimens, their outcomes remain unsatisfactory and appear inferior to their younger counterparts.3 A subset of patients with favorable-risk AML eventually relapse and become chemotherapy-refractory, especially those with t(8;21), and better salvage therapies are required to re-induce remission and improve their outcomes.4 Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has shown encouraging response rates for AML in treatment-naïve older or frail patients as well as relapsed/refractory (R/R) patients, and the regimen is well-tolerated with favorable toxicity profile and low treatment-related mortality. In the multicenter, phase 1b study, DiNardo et al., reported CR/CRi rate of 67% with VEN-HMA in treatment-naïve unfit patients with AML, however, this study did not include patients with favorable-risk genetics.5 Data on the activity of VEN-HMA in patients with favorable-risk AML is scarce, particularly in those with CBF alterations. To fill in the knowledge gap on the activity of VEN-HMA in favorable-risk AML, and determine what factors affect response, we performed this multicenter retrospective analysis focusing on this population of patients. We conducted a retrospective analysis on patients with favorable-risk AML who underwent therapy with VEN-HMA between March 2016 and June 2020 at four academic cancer centers in the United States. Analysis of NPM1, CEBPA, and other somatic mutations was performed utilizing PCR and next-generation sequencing panel. The study was approved by the Institutional Review Boards of each institution. The primary endpoint is either complete remission (CR) or CR with incomplete count recovery (CRi).1 Favorable-risk AML was defined based on the presence of either CBF [t(8;21) and inv(16) or t(16;16)], or normal cytogenetics with NPM1 mutation in the absence of FLT-3 ITD mutations; or bi-allelic CEBPA mutations.1 Minimal residual disease (MRD) was evaluated using multi-parameter color-flow cytometry with a sensitivity of at least 0.1%. The secondary end-point, overall survival (OS), was defined as the time from the start of the therapy with VEN-HMA to the death or censored if alive at the last follow-up. Leukemia-free survival (LFS) among patients with CR/CRi was defined as the time interval from the date of response to the relapse or death, whichever occurred first, and was censored at the last follow-up if still leukemia-free. In univariate analysis, all demographic, genetic or clinical covariates/outcome were summarized by descriptive statistics (mean, SD, median, range, count, proportion, and 95% C.I.) and stratified by AML setting: ND vs R/R. The association between these covariates and AML setting was assessed by Wilcoxon rank sum test for non-normal continuous endpoints, Pearson chi-square test or Fisher's exact test for categorical variables, Kaplan-Meier method and log-rank test for time-to-event (relapse/death) survival data. A P value of .05 or less was considered statistically significant. We identified 46 patients with favorable-risk AML who were treated with HMA-VEN. Their median age was 70 years (range; 27-82 years), and 54% were females. There were 26 (57%) patients with ND AML and 20 (43%) patients with R/R AML. The majority of patients had a de novo AML (56%). Twenty (44%) patients had secondary or therapy-related AML. Ten (22%) patients had CBF AML, 24 (52%) had NPM1 mutations (NPM1m), and 12 (26%) had bi-allelic CEBPA mutations (CEBPAm). The median number of prior lines of therapy was two (range:1-4) in patients with R/R AML, including six (30%) who had failed prior allogeneic hematopoietic cell transplant (HCT). Eleven (24%) patients had received HMA before HMA-VEN therapy, including one patient in the ND cohort for prior MDS. The majority of the cases (76%) received decitabine as HMA, including 15 patients who received 10-day decitabine and 20 patients who received 5-day decitabine during the first cycle (Table S1). Compared to the ND AML patients, R/R patients were younger in age (median: 56 vs 72 years, P = .003). Three patients with ND AML, <65 years, received upfront VEN-HMA because of comorbidities or poor functional status. Other patients <65 years received VEN-HMA in R/R setting. The CR/CRi rate among the whole cohort was 80% (n = 37), including 24 CR (52%) and 13 CRi (28%). The median number of cycles required to achieve the best CR/CRi was two (range: 1-5). Among the responders who had MRD assessment done (n = 27), 22 (81%) achieved MRD negativity by multicolor flow cytometry with VEN-HMA. The MRD negativity among the patients who had MRD analysis was 83% (15 out of 18) for the ND and 78% (seven out of nine) for R/R cases. The 30-day and 60-day mortality for the whole cohort was 0% and 9%, respectively. There was no statistically significant difference in CR/CRi rate between the ND and R/R AML patients (88% vs 70%, P = .15), Table 1. However, patients with a history of prior HMA exposure had a lower response rate compared to HMA-naïve patients (55% vs 88%, P = .025). No difference in response was observed based on the favorable genetic alteration subgroups (80% in CBF vs 88% in NPM1m vs 75% in CEBPAm, (P = .594), the presence of additional co-mutations (P = .713), patient age (P = .83), AML types (de novo vs secondary; P = .47), prior transplant (P = .999), or the type and schedule of HMA (P = .66). Following response to VEN-HMA, 13 (35%) patients underwent allogeneic transplant consolidation, including eight patients with ND AML and five with R/R AML. The median OS for the whole cohort was 18 months (12.5-not reached [NR]). Median LFS was 13.2 months (7-20.2) for all responders, 11.2 months (1.7-NR) for responders with ND AML, and 14.0 months (1-NR) for responders with R/R AML (P = .98). Factors affecting survival are summarized in Table S2. The role of VEN-HMA in older patients with AML or younger patients with comorbidities is well studied and now is accepted as a standard of care for those with intermediate-risk or poor-risk disease. However, there are limited available data on the activity of VEN-HMA in favorable-risk AML. In this multi-center retrospective analysis, we report the outcomes of VEN-HMA restricted to a cohort of patients with favorable-risk AML, and we showed very encouraging results with CR/CRi rate as high as 88% in ND patients with a median age of 72 years. Consistent with previous reports, VEN-HMA was well tolerated and associated with low rate of early mortality. Our CR rate appears comparable to what was reported before in fit older patients (≥60 years) with favorable-risk AML treated with intensive regimens on the CALGB protocols (CR rate = 83%), however, 3-year DFS and OS for these patients in the CALGB experience were disappointing with these regimen, 24% and 33%, respectively.3 The activity of VEN-HMA in untreated older AML patients with NPM1m was reported recently by Lachowiez et al. In their retrospective cohort study, when compared with a cohort of older patients with NPM1m AML treated with intensive induction therapy, VEN-HMA achieved a higher CR rate (88% vs 56%) and had significantly improved OS (not reached vs 0.9 years).6 Given a comparable remission rate with VEN-HMA in older favorable-risk patients, and unsatisfactory long-term outcomes with more intensive regimens, our study suggests that VEN-HMA therapy may represent a therapeutic alternative for older or unfit patients with favorable-risk disease. We also observed similar encouraging response in R/R favorable-risk AML treated with VEN-HMA, although the median prior lines of therapy were two (range:1-4), and the cohort included 13% and 24% patients who failed previous allogeneic HCT or an HMA, respectively. However, response rate with VEN-HMA was significantly lower for patients who had prior exposure to HMA. Among all responders, 13 patients successfully underwent subsequent allogeneic HCT consolidation, indicating that these responses were meaningful and VEN-HMA could serve as bridging therapy to subsequent curative therapies. Our analysis is limited by relatively small number of patients and the retrospective nature of the study design. Nevertheless, this is the first study that restricts analysis of the activity of VEN-HMA to favorable-risk AML, including cases of CBF AML. In summary, our multi-center study demonstrated promising therapeutic results from VEN-HMA in patients with favorable-risk AML both in ND and r/r disease, with high composite rates of remission and durable responses. The majority of responders were MRD negative, confirming the prevalence of deep responses with VEN-HMA in this setting. Given the safety profile and promising response, randomized prospective studies are warranted to compare VEN-HMA to standard intensive regimens in newly diagnosed, traditionally fit, older patients, who may be candidates for allogeneic HCT. None. A.S.S. serves on the speaker bureau for Stemline, Amgen and Celgene, and on advisory boards for Stemline and Amgen. G.M. is a member of the speakers' bureau for AbbVie and Novartis, and serves on advisory board with Janssen Pharm. V.P. has served on the advisory boards for AbbVie and Jazz Pharmaceuticals and is member of speakers' bureau for Jazz, Amgen, Novartis and AbbVie. G.Y. served on Advisory Boards for Novartis, Agios and Takeda, and speaker for Jazz Pharmaceutical, Takeda, Astellas, Alexion and BMS. V.R.B. served as consultant for Genentech, Rigel, Agios, Incyte, Omeros, Takeda, Jazz Pharmaceuticals and Partnership for health analytic research, and research funding from Abbvie, Pfizer, Incyte, Jazz, Tolero Pharmaceuticals, Inc., and National Marrow Donor Program, Oncoceutics, and Novartis. A.T.F. served as consultant for Boston Biomedical, PTC Therapeutics, Agios, Celgene/Bristol-Myers Squibb, Abbvie, Astellas, Novartis, Daiichi Sankyo, Trovagene, Seattle Genetics, Amgen, Pfizer, NewLink Genetics, Jazz, Takeda, Genentech, Blueprint, Kura Oncology, Kite, Amphivena, Trillium, Forty Seven/Gilead, and research support from Celgene/BMS, Seattle Genetics, Takeda, and Agios. I.A. has served on advisory boards with AbbVie, Amgen, KiTE pharmaceuticals, Agios, consultant for Autolus and Amgen, speaker for Jazz Pharmaceuticals. The remaining authors have no relevant conflict of interest to declare. S.A., G.Y., V.B., A.T.F. and V.P. designed research; all authors collected, assembled, analyzed, and interpreted data, J.Z. performed statistical analysis, S.A. and I.A. wrote the manuscript; and all authors approved the final version. Data available on request from the authors. The study was approved by the Institutional Review Boards of each institution. Table S1 Patients characteristics Table S2 Survival outcomes Table S3 Response outcomes 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.