Introduction: Therapy related-MDS (tMDS), a known sequalae of genotoxic therapies, is a highly aggressive form of MDS accounting for 10–20% of newly diagnosed cases (Venugopal S et al, Semin Hematol 2024) with a dismal prognosis. Hypomethylating agents (HMAs) are the current standard of care, but their efficacy is limited in patients (pts) with complex cytogenetics and adverse-risk mutations enriched in tMDS; with a CR rate of 14% reported in a prior study (Klimek V et al, Leuk Res 2012). The phase 3 VERONA trial did not show a survival benefit with azacitidine and venetoclax (Aza/Ven) in high-risk MDS pts, however, t-MDS pts were excluded from this study. Here, we report the interim results of the safety and efficacy of Aza/Ven in newly diagnosed tMDS pts from a multi-center, phase 2 study (NCT05379166)

Methods: In this single arm, multi-center, open-label, phase II study, pts aged ≥18, ECOG </= 2 with newly diagnosed tMDS and IPSS-R score of ≥ 3.5 and <20% BM blasts were enrolled. Aza was administered at 75 mg/m2 for 7 days with Ven 400 mg QD on days 1-14 of each 28-day cycle (C). Bone marrow (BM) aspirate and biopsy were performed at the end of C 1,2,4. The primary endpoint was complete remission (CR) rate by the end of C4 or earlier as per the 2023 IWG criteria. Key secondary endpoints include the rate of treatment-emergent adverse events (TEAEs), overall response rate (ORR), duration of response (DoR), hematologic improvement (HI), rate of progression to AML, transition to allogeneic stem cell transplant (allo-SCT), progression-free (PFS) and overall survival (OS). Patient characteristics were summarized using median and range for continuous variables and frequency and proportion for categorical variables. The response outcomes were analyzed using proportions. OS, PFS, and DOR were analyzed using the Kaplan-Meier method.

Results: We analyzed the first 23 pts in a planned interim analysis. The majority were men (70%) with a median age of 67y (range, 30-88); 19/23 (83%) had TP53 mutations including 13 pts with biallelic TP53 status, 17/23 (81%) had a complex karyotype, 19/23 (83%) belonged to high/very-high risk IPSS-R category, and 12/23 (52%) had ≥5% BM blasts (median= 9.5; range 5-17) at baseline.

The ORR is 56.5% (13/23) including 7 pts who achieved CR with limited count recovery (CRL; CRbi= 5 and CRuni= 2) and one with CR with partial hematological recovery (CRh). With the median follow-up of 16 months (mo), the median duration of response is 12.7 mo. Pts received a median of 3 (range, 1-7) cycles of therapy with a median cycle length of 42 days (range, 28-73). HI was noted in 12/23 (52%) pts including 11 (48%) with platelet response, 6 (26%) with erythroid response and 3 with neutrophil response (13%). The study met its planned interim analysis endpoint with a CR rate of 21.7% (5/23; 4=CR and 1=CR equivalent) as per IWG 2023 criteria in stage 1 and is currently in stage 2 with a planned enrollment of 53 total pts. All pts with CR had biallelic TP53 mutations and persistent MRD by NGS; 2/5 pts in CR achieved the lowest TP53 VAF of 1-2% after 4 cycles of therapy and one patient was bridged to allo-SCT.

Nine pts (39%) progressed to AML with a median PFS of 6.7 mo. Median OS is 10 mo for all pts and 14.75 mo for responders, with a 1 yr OS of 48% and 73%; respectively. Seven pts (30%) proceeded to receive allo-SCT after a median of 3 cycles (range, 2-4) of therapy.

Most pts (21/23; 91%) experienced ≥1 TEAE, with all 21 experiencing grade 3 or higher AEs. Most common grade ≥ 3 TEAEs were hematological with anemia (52%), neutropenia (52%) and thrombocytopenia (34.7%) often occurring in the context of persistent disease. Febrile neutropenia was reported in 11 pts (48%) including 2 (9%) pts with bacteremia and 3 (13%) with sepsis. Only 1 patient discontinued study treatment due to AEs. Five pts remain on active treatment.

Conclusion: Combination of Aza/Ven was effective in inducing responses in >50% of tMDS pts including biallelic TP53 and complex karyotype with no new safety signals. While Aza/Ven did not confer a survival benefit in high-risk MDS over Aza alone in the phase 3 VERONA trial, the combination approach may be a feasible strategy to employ as a bridge to transplant in the exceptionally high-risk group of tMDS pts with no other standard of care options.

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2025
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