AML-351 Low-Dose Weekly Decitabine and Venetoclax in TP53-Mutated Myeloid Malignancies

Lauren Shapiro, Ioannis Mantzaris, Aditi Shastri, Alejandro Sica, Nishi Shah, Noah Kornblum, Kira Gritsman, Eric Feldman, Amit K. Verma, Ira Braunschweig, Yogen Saunthararajah, Mendel Goldfinger

Research output: Contribution to journalArticlepeer-review

Abstract

Background: TP53-mutated (TP53mut) AML and high-risk MDS are often treated with hypomethylating agents (HMAs) combined with venetoclax (Ven); however, myelosuppression often leads to dose-reductions and/or cycle delays. Administration of noncytotoxic doses of decitabine (Dec) 1x/week decreases HMA-mediated myelosuppression while maintaining S-phase–dependent DNMT1-targeting. In pre-clinical studies, single-dose Ven given prior to HMA administration inhibited de novo pyrimidine synthesis, countering a major mechanism of resistance to HMAs without suppressing normal myelopoiesis. Methods: We conducted a retrospective analysis of patients with TP53mut MDS/AML at our institution treated with 400 mg Ven on D1 and low-dose subcutaneous (subQ) Dec (0.2 mg/kg; ~5 mg/m2) on D2, administered weekly in 28-day cycles. We analyzed patient characteristics, response to therapy, and outcomes using standard descriptive statistics. Results: Six patients with TP53mut MDS or AML were treated. Two patients with high-risk MDS and 3 patients with adverse-risk AML (83%) received front-line treatment, all with poor performance status, and 1 patient (17%) had resistant/refractory (R/R) MDS transformed to adverse-risk AML refractory to both standard Aza/Ven and Vyxeos (daunorubicin and cytarabine). Median age was 79 years [41–82]. Median TP53mut variant allelic frequency was 48% [28%–79%]. All patients had complex cytogenetics. Median follow-up was 10.1 [2.9–16.3] months, and 83% of patients were transfusion-dependent prior to treatment. Overall response rate was 100%: 5/5 front-line patients had complete remissions (CR), and the R/R patient achieved a morphologic leukemia-free state. Median time to best response was 2.5 months, and 60% of patients became transfusion independent. The regimen was well tolerated, with no patients stopping therapy due to adverse effects and a median of 1.5 unplanned hospitalizations per patient during follow-up. Median duration of therapy was 13.8 [6.1–27.1] months, with 2 (33%) patients remaining on therapy and 2 (33%) patients with measurable relapse who have since died. One patient who achieved a CR underwent allogeneic stem cell transplantation. The R/R patient died after being lost to follow-up 2.9 months after therapy initiation. Conclusions: Weekly Ven with low-dose subQ Dec is well tolerated, yielding high response rates in TP53mut MDS/AML. We demonstrate proof-of-activity for cytotoxic DNMT1-targeting to a high-risk, chemorefractory population by allowing sustained drug exposure.

Original languageEnglish (US)
Pages (from-to)S241
JournalClinical Lymphoma, Myeloma and Leukemia
Volume22
DOIs
StatePublished - Oct 2022

Keywords

  • AML
  • decitabine
  • MDS
  • P53 mutant
  • venetoclax

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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