Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active

Abstract

Adding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity and thereby reduce the risk of posttransplant relapse. This phase 1 study investigated the recommended phase 2 dose (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day -8 for 6-7 doses) in combination with fludarabine 30 mg/m2 per day for 4 doses and busulfan 0.8 mg/kg twice daily for 8 doses on day -5 to day -2 (FluBu2). Transplant related-toxicity was evaluated from the first venetoclax dose on day -8 to day 28. Twenty-two patients were treated. At study entry, 5 patients with MDS and MDS/MPN had 5% to 10% marrow blasts, and 18 (82%) of 22 had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea, and liver transaminitis (n = 3 each). Neutrophil/platelet recovery and acute/chronic graft-versus-host-disease rates were similar to those of standard FluBu2. No dose-limiting toxicities were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (range, 8.6-24.8 months), median overall survival was not reached, and progression-free survival was 12.2 months (95% confidence interval, 6.0-not estimable). In patients with high-risk AML, MDS, and MDS/MPN, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is ongoing. This study was registered at clinicaltrials.gov as #NCT03613532.

© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Baseline disease and genetic profiles of study patients. Comutation plot of diagnostic mutations amenable to MRD tracking. Columns represent individual patients, and rows represent clinical variables or the presence of mutation(s) identified at diagnosis or mutations at screening with VAF ≥2%. This VAF cutoff is suggestive of a diagnostic mutation that was not confirmed at diagnosis due to lack of diagnostic sample or technical assay differences. Asterisk represents a BCR-ABL–mutated case (detected by reverse transcriptase polymerase chain reaction).

Figure 2.

Engraftment, donor chimerism, and GVHD rate after venetoclax plus FluBu2 allo-HCT. (A) No evidence for impairment in neutrophil (red) and platelet (blue) engraftment. (B) CD3 T-cell donor chimerism was evaluated at days 28 and 100. In the T-cell chimerism plot, individual patients’ chimerism are connected by lines at days 28 and 100. The black solid line connects 2 medians at days 28 and 100 (P = .0015). (C) Risk for acute (blue) and chronic (red) GVHD were plotted. No grade IV acute GVHD (aGVHD) events occurred. cGVHD, chronic GVHD; D, day; mod/sev, moderate/severe.

Figure 3.

Outcomes after venetoclax plus FluBu2 allo-HCT. Kaplan-Meier estimate and log-rank test of probability of OS (blue) and PFS (red) (A) and probability of NRM (blue) and relapse (red) (B). 95% CIs are reported for each outcome. Probability of OS (C) and PFS (D) in relation to ECOG PS of 0 to 1 (blue) vs ECOG PS of 2 (red).

Figure 4.

Serial genetic MRD monitoring before and after transplant. (A) NGS swimmer plot. Each bar represents a patient, with the length of the gray bars indicating follow-up time. Symbols indicate NGS status at serial time points, relapse, and death. Patients arranged according to NGS status at days 28/100, and then by follow-up time. Mutation VAF, relapse, and post-relapse course in patients 1 and 5 are shown. (B) Patient 1 had a baseline mutation in TP53, relapsed >6 months’ posttransplant, and acquired new mutations in NF1, CSF3R, and KRAS. (C) Patient 5 was another TP53-mutated patient who relapsed but later achieved durable CR2 after salvage therapy (decitabine and venetoclax) followed by donor lymphocyte infusion. TP53 VAF and read level support indicated at time points leading up to and including relapse. CR2 indicates timepoint of second complete remission achieved after two cycles of decitabine and venetoclax.