Long-Term Outcomes of Acute Myeloid Leukemia Following Allogeneic Stem-Cell Transplantation after Decitabine and Venetoclax: Subgroup Analysis of a Phase II Trial

Abstract

Introduction: Venetoclax (VEN)-based lower intensity regimens are the current standard for older/unfit patients with newly diagnosed acute myeloid (AML). Such regimens are increasingly used in the salvage setting as well. Allogeneic stem-cell transplantation (SCT) following VEN-based regimens has been shown to be safe and feasible in pts with AML (Mukherjee et al. J Clin Oncol 2019; Pratz et al. Blood 2019). We herein describe long-term outcomes after SCT following treatment on a prospective clinical trial of 10-day decitabine and venetoclax (DEC10-VEN) for treatment-naïve and previously treated AML (NCT03404193). Methods: In this phase II trial, pts received decitabine 20 mg/m2 for 10 days during induction and 5 days during consolidation. VEN was administered 400 mg daily on D1-28 during cycle 1 but was held on day 21 if bone marrow evaluation showed blasts ≤5%. During subsequent cycles VEN duration could be reduced in pts with myelosuppression. This trial enrolled pts with ECOG PS ≤3 with adequate organ function. Pts with favorable risk cytogenetics were excluded. Pts with newly diagnosed AML were either unfit for intensive therapy, or older than 60 yrs. Pts in relapsed/refractory cohort were ineligible if they had received prior BCL2 inhibitor. Eligible pts with an available donor could proceed to SCT at any time following achievement of response. Response, overall survival (OS) and relapse-free survival were defined per ELN2017. Survival outcomes were not censored at SCT. Data cut-off date was July 26, 2022. Results: Between January 2018 and June 2022 we enrolled 230 pts with AML, high-risk or relapsed/refractory myelodysplastic syndrome or chronic myelomonocytic leukemia, and blastic plasmacytoid dendritic cell neoplasm. Among 201 pts with AML, CR/CRi/MLFS response was achieved in 146 pts (73%) and 40 pts (20%) were able to proceed to SCT; including 21 pts with treatment-naïve AML and 19 pts with either R/R AML or AML following treatment for antecedent hematological disorder (AHD) including MDS-EB (n=2) and CMML (n=1), considered "previously treated AML". The median age of pts undergoing SCT was 66 yrs (range 18-77); 10 pts (25%) were older than 70 yrs, 16 pts (40%) pts had R/R AML, 19 pts (45%) had ELN adverse risk disease and 4 pts had received prior SCT (Table 1). Fourteen pts in each group received additional concomitant therapy with FLT3 inhibitors including gilteritinib and sorafenib (Table 1). All pts proceeding to SCT were in CR/CRi except in the previously treated group where 4 pts had non-CR/CRi responses including MLFS/aplasia. 28 pts (70%) had achieved negative measurable residual disease (MRD) by flow cytometry (sensitivity 0.1-0.01%) prior to proceeding to SCT while 8/40 pts (20%) had persistent MRD. Remaining 4 pts either had inadequate sample or were not evaluated for MRD. Conditioning regimens and donor types are summarized in Table 1. Median no. of cycles of DEC10-VEN administered was 2 (range 1-12) and the median time to SCT was 3.5 mo from start of DEC10-VEN (range 1.1-16.2). The median follow-up duration was 29.1 mo. Among pts with AML who proceeded to SCT, the 100-day post-SCT mortality was 8% (n=3). The median OS for treatment-naïve pts was 35.1 mo and for previously treated pts was 16.7 mo. Median RFS for treatment naïve pts was 23.5 mo and for previously treated pts was 12.9 mo. Landmark analysis of pts achieving CR/CRi/MLFS and alive at 3.5 mo showed that pts with treatment-naïve AML who were eligible to proceed to SCT (n=21) derived significant benefit in OS with median OS 35.1 vs 15.7 mo in pts who did not / were ineligible (n=60) (HR 0.47, 95% CI 0.24, 0.76, p=.01, Fig. 1). Similarly, pts with previously treated AML who proceeded to SCT in CR/CRi/MLFS (n=18) had median OS of 19.3 vs 12.0 mo for pts who could not (n=36) (HR 0.53, 95% CI 0.28, 1.01, p=.07). Both analyses were limited by confounding factors. At data cut-off, 19 pts (48%) are alive, 8 pts (20%) died in remission, and 13 pts (33%) pts died after disease progression (Table 1). Conclusion: In this prospective trial of DEC10-VEN enrolling older/unfit pts with newly diagnosed AML, secondary AML, and younger or older pts with R/R AML, 20% of pts were able to proceed to SCT. DEC10-VEN served as bridge to SCT for responding pts with newly diagnosed as well as previously treated AML, with low 100-day post-SCT mortality. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal