Venetoclax-Augmented RIC Allogeneic HCT With PTCy-Based GVHD Prophylaxis and Venetoclax/Azacitidine Maintenance for Poor Risk MDS and AML

Relapse remains the main cause of death following allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk myeloid malignancies. Post-transplant maintenance therapy may reduce relapse risk and improve outcomes. We previously showed that post-transplant azacitidine azacitidine: It works by reducing the amount of methylation in the body. Methylation is a process that acts like a switch to turn off or “silence” genes in certain cells. When these genes (called tumor suppressor genes) are turned off, MDS cells and cancer cells can grow freely. Azacitidine is approved by the U… + venetoclax venetoclax: Venetoclax is used to treat chronic lymphocytic leukemia or small lymphocytic leukemia in adults. Venetoclax is used alone or in combination with other cancer medicines to treat these conditions. (ven/aza) maintenance after reduced intensity conditioning (RIC) HCT with tacrolimus tacrolimus: Tacrolimus is in a class of medications called immunosuppressants. It works by decreasing the activity of the immune system. Tacrolimus can be prescribed to treat and prevent graft vs host disease (GVHD). It can also be used as part of combination therapy to treat aplastic anemia in place of… /methotrexate (Tac/MTX) graft-versus-host disease (GVHD) graft-versus-host disease (GVHD): Also called GVHD, it is a common complication of bone marrow/stem cell transplantation. It is caused when the donor's immune cells, now in the patient, begin to see the the patient's body as foreign and mount an immune response. GVHD most commonly effects the recipient's skin, intestines, or liver… prophylaxis is feasible, safe, and associated with encouraging outcomes. The ability to deliver prophylactic prophylactic: Something that prevents or protects. Blood thinners may be given as a prophylactic to prevent blood clots in high risk patients. maintenance after modified RIC conditioning including post-transplant cyclophosphamide cyclophosphamide: Cyclophosphamide is in a class of medications called alkylating agents. When used to treat cancer, it works by slowing or stopping the growth of cancer cells in your body. When cyclophosphamide is used to treat bone marrow failure, it works by suppressing your body's immune system. /tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) GVHD prophylaxis has not yet been shown. We sought to determine the extent to which PTCy/Tac/MMF GVHD prophylaxis affected the safety, tolerability, and preliminary efficacy of venetoclax/FluBu2 RIC HCT followed by ven/aza maintenance in patients with high-risk MDS and AML. Venetoclax was administered at 400 mg daily dose on days -8 to -2, overlapping with FluBu2. Eligible patients included those with adverse risk AML (by ELN 2017/2022 or therapy-related AML) or adverse risk MDS (IPSS Intermediate-2/High or MDS with high-risk mutations). We compared clinical outcomes with our previously published venetoclax/FluBu2 RIC HCT Tac/MTX cohort. This phase 1 trial was registered at clinicaltrials.gov/NCT03613532. Twenty-three patients enrolled in the PTCy cohort including 13/23 (57%) whose disease harbored TP53 mutations (12/13 multi-hit). At pretransplant screening (within 28 days of day -8), multi-parameter flow cytometry flow cytometry: (sy-TOM-uh-tree) A laboratory test that gives information about cells, such as size, shape, and percentage of live cells. Flow cytometry is the test doctors use to see if there are any proteins missing from the surface of blood cells. It is the standard test for confirming a diagnosis of paroxysmal… -measurable residual disease was detected in 11/20 (55%) patients in CR. With this study regimen, neutrophils engrafted at a median of 15 days and platelets engrafted at a median of 22 days from transplant. 100-day nonrelapse mortality (NRM) was 0%, 6-month grade II-IV acute GVHD rate was 4.4% (95% confidence interval [CI] .30 to 18.8) and 1-year chronic GVHD was 9.1% (95% CI: 1.4 to 26.1). 100-day event-free survival (EFS) was 59.1% (95% CI: 41.7 to 83.7). With median 14.9 months follow-up (range: 7.34 to 21.6), 1 year overall survival (OS) was 59.1% (95% CI: 41.6 to 84.0), progression-free survival (PFS) was 47% (95% CI: 30.2 to 73.1), relapse was 48.7% (95% CI: 26.4 to 67.8), and GVHD-free relapse free survival (GRFS) was 37.7% (95% CI: 21.9 to 64.7). We further compared safety and efficacy with another prospective cohort enrolled with identical inclusion criteria who underwent ven/FluBu2 HCT with Tac/MTX GVHD prophylaxis (n = 27). No differences were observed in 100-day cumulative incidence of grade ≥2 infections, though the PTCy cohort had numerically increased bacterial (26% versus 15%) and viral (17% versus 7%) infections. We did not identify differences in OS (P = .33), PFS (P = .55), relapse (P = .76), NRM (P = .28), GRFS (P = .97), EFS (P = .6), acute GVHD (P = .12), or chronic GVHD (P = .41). Furthermore, no significant differences were detected in FACT-BMT quality of life scores when comparing longitudinal changes between pretransplant and post-transplant/premaintenance timepoints by GVHD prophylaxis cohort. We demonstrate acceptable safety and encouraging efficacy of ven/FluBu2 with PTCy in an exceedingly high risk cohort and equivalent outcomes in comparison with Tac/MTX GVHD prophylaxis. Subtle differences in tolerability however highlight the need for additional studies to confirm the optimal backbone for poor-risk MDS/AML cases.