Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML

Abstract

We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532.

Graphical abstract

Figure 1.

Study design and baseline disease and mutational profiles. (A) Pretransplant screening and enrollment of patients were conducted in the 28-day period before day −8. Schematic and timeline of events for the phase 1 trial of Ven plus Ven/FluBu2 conditioning chemotherapy, including reviewing criteria to initiate maintenance (after day +28), and starting maintenance therapy with Ven and Aza between days +42 to +90. SC, subcutaneously; DL1, 42-day cycles; DL2, 28-day cycles. (B) Comutation plot of diagnostic mutations amenable to MRD tracking. Columns represent individual patients by study identifier (ID) and rows represent clinical variables or the presence of mutation(s) identified at diagnosis or mutations at screening with VAF of ≥1%. This VAF cutoff is suggestive of a diagnostic mutation, which was not confirmed at diagnosis because of lack of diagnostic sample or technical assay differences. Secondary AML (sAML)-associated genes include the following SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR/L1, and STAG2. MAPK signaling genes included were NRAS, KRAS, FLT3, and PTPN11. "Other" includes mutations in the following genes: JAK2, SETBP1, WT1, MYC, EP300, PRPF8, PPM1D, BRAF, CSF3R, PHF6, and GATA2.

Figure 2.

Neutrophil and platelet counts on venetoclax and azacitidine maintenance. Peripheral blood counts for patients on DL1 (42-day cycles with 8 planned cycles) and DL2 (28-day cycles with 12 planned cycles) and maintenance Ven/Aza on days 1, 8, 15, and 22 of cycle 1, and then days 1 and 15 each of each subsequent cycle. (A) Median ANC (K/μL) (± standard deviation [SD]) with dashed line at grade 4 neutrophil level (<0.5 x 10³/μL). (B) Median platelet counts (K/μL) (± SD) with dashed line representing grade 3 platelet level (<50 x10³/μL). The bars in all plots represent median values with error bars representing the interquartile range between the 25% and 75% quartiles. Details for each time point are shown in supplemental Tables 3-4.

Figure 3.

Outcomes after Ven plus FluBu2 allo-SCT followed by Ven/Aza maintenance. (A) Swimmer plot for the intent-to-treat cohort (N = 27) and time to death or last known alive. Shown with accompanying heat map for disease status over time (D0, D28, D100, 6M, and 12M), maintenance receipt, and survival status. D0, day 0; D28, day +28 after transplant; D100, day +100 after transplant; 6M, 6 months after transplant; and 12M, 12 months after transplant. Relapse indicated by red-filled triangle. (B) Kaplan-Meier estimate and log-rank test of OS (blue line), PFS (red line), and relapse (green line) in the intent-to-treat cohort (top, N = 27) and in the cohort that ultimately received maintenance Ven/Aza (bottom, N = 22). 95% CIs are reported for each outcome.

Figure 4.

Serial molecular MRD surveillance before and after transplant. (A) Molecular MRD swimmer plot. Each bar represents a patient, with the length of gray bars indicating follow-up time. Patients arranged by follow-up time and labeled by patient/study ID number. Recommended window for maintenance initiation indicated (day +42 to day +90). Symbols indicate molecular status (defined as detection of pre-allo-SCT mutation) at serial time points, relapse, and death; asterisk indicates those that did not receive maintenance (n = 5), and blue- or green-filled circles indicate TP53 mutation status. Notably, ID 40 had molecular MRD positive clone detected at 1 year (RUNX1 p.L175fs at VAF of 0.19%) but did not relapse at time of data cutoff. (B) Plot of mutational burden by VAF over time early in the transplant course. Line presents median. VAF > 0.01 (1%) at day +100 identifies cases that are most likely to relapse. One exception to this is a 4.8% VAF TP53-mutated clone identified at day +100 that was not detected at subsequent time points.

Figure 5.

Assessment of peripheral blood for immune reconstitution. Flow cytometry immune monitoring was performed on peripheral blood samples collected from patients on Ven/Aza maintenance and matched controls at 1 (n = 51, including 26 study patients and 25 controls), 2 (n = 41, including 24 study patients and 17 controls), 3 (n = 47, including 24 study patients and 23 controls), 6 (n = 38, including 18 study patients and 20 controls), and 12 (n = 34, including 13 study patients and 21 controls) months after transplant. (A) T-cell populations were measured at serial time points after transplant to evaluate for impaired immune cell expansion. Three major T-cell populations, regulatory CD4⁺ T (CD4Treg), conventional CD4⁺ T (CD4Tcon), and CD8⁺ T cells, were defined as CD3⁺CD4⁺CD8⁻CD25⁺CD127⁻ cells, CD3⁺CD4⁺CD8⁻CD25^−/lowCD127^+/− cells, and CD3⁺CD4⁻CD8⁺, respectively. (B) Natural killer (NK) cells were defined as CD3⁻CD56⁺ lymphocytes. NK T cells were defined as CD3⁺CD56⁺ lymphocytes. B cells were defined as CD45⁺CD19⁺ lymphocytes. Details of gating strategy are shown in supplemental Figure 5. Data are median (thick black line), and box plots indicate the interquartile range.