Cladribine based salvage chemotherapy in AML patients with persistent or recurrent disease after venetoclax/HMA

Abstract INTRODUCTION In adults with acute myeloid leukemia (AML), the combination of venetoclax (ven) and a hypomethylating agent (HMA) represents a standard frontline option, often utilized in adverse risk AML regardless of fitness, and also as subsequent line therapy. With this, increasingly, pts fit for intensive chemotherapy (IC) are receive ven/HMA. Little is known about the utility of challenging these pts with intensive salvage chemotherapy if disease relapses or is refractory (R/R) to ven/HMA. Overall, multiple studies report survival in the range of 2-4 months after ven/HMA, however these analyses largely include pts ineligible for intensive therapies. Therefore, to better distinguish outcomes in fit patients after Ven/HMA, and also to report outcomes after a cladribine based salvage regimen, which represents a common salvage approach in R/R AML, we report the outcomes of this approach in pts treated at our institution. METHODS We performed a retrospective study of pts with AML receiving either CLAG-M (cladribine 5mg/m2 D1-5, cytarabine 2G/m2 D1-5, G-CSF D1-5, mitoxantrone 10mg/m2 D1-3) or Cladribine-LDAC (cladribine 5mg/m2 D1-5 cytarabine 40mg SQ D1-10) after receiving treatment with Ven/HMA. Response was defined using ELN 2022 criteria, and when able, measurable residual disease (MRD) was determined by flow cytometry. KM estimator was used for OS. RESULTS Between 2019-2024, we identified 33 pts with R/R AML who received a cladribine combination after Ven/HMA (CLAG-M = 27, Cladribine-LDAC = 6). Median age was 65y (range: 34-78y), 15 (45%) were female, 26(78%) had ELN adverse risk AML, including 8(24%) with a TP53 alteration. Median number of prior therapies was 2 (range: 1-5), 14 (42%) received Ven/HMA as frontline therapy. Among cladribine-LDAC recipients, 0 pts achieved a response, and median OS was 2 months. Among CLAG-M recipients, 5(19%) achieved CR/CRi, 6(22%) achieved MLFS yielding an overall response rate (ORR) of 41%. Among CLAG-M recipients as first salvage after ven/HMA, 3/6(50%) achieved CR/CRi. MRD was assessed in 7 pts, 1(12%) achieved an MRD(-) response. Median OS was 3.6 mo. 7 pts were successfully bridged to allogeneic HCT, median OS among these pts was 8.8 mo. CONCLUSION Among fit AML pts receiving ven/HMA in a prior line, salvage chemotherapy with CLAG-M is reasonable, particularly if a pt requires bridging therapy for possible allogeneic HCT. Outcomes with CLAG-M salvage overall remains suboptimal, necessitating the development of novel salvage therapies in patients previously exposed to ven/HMA.