Efficacy of Cladribine, Low-Dose Cytarabine, and Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia in a High-Risk Ethnically Diverse Cohort

Hypomethylating agents (HMAs) in combination with Venetoclax (Ven), are currently the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) above 75 or unfit for chemotherapy. While effective, this regimen is not a cure for most AML patients that succumb to their disease upon relapse. Cladribine (CLAD) has been shown to selectively kill monocytic leukemia stem cells and synergizes well with both Ven and low dose cytarabine (LDAC). A Phase II study in 93 patients with newly diagnosed AML were treated with a combination of CLAD/LDAC/Ven as a frontline treatment demonstrated a composite complete remission (CRc) rate of 92% with estimated 12- survival of 75.7%. However, there is a lack of data regarding this regimen's use in the relapsed/refractory (R/R) setting. We sought to evaluate the outcomes of R/R AML patients treated with CLAD/LDAC/Ven at a tertiary academic center with an ethnically diverse patient population in Bronx, NY.

We retrospectively reviewed all R/R patients treated with CLAD/LDAC/Ven at our center between July 2022 and February 2024. Patients with secondary AML who had failed prior treatment with HMAs and progressed to AML were also included in the analysis. All patients had cytogenetics and genomic analyses. Overall survival (OS) was defined as the duration from the start of salvage treatment to the time of death, with patients alive at the time of evaluation censored. Event-free survival (EFS) was defined as the time from treatment initiation to treatment failure, relapse, or death, with patients experiencing treatment failure assigned an EFS of 0 days. Additional outcomes measured included CRc, which includes CR and CR with incomplete count recovery (CRi).

Our analysis included nine patients with R/R AML and two myelodysplastic syndrome (MDS) patients with HMA-failure and progression to AML. The median age at treatment start was 66 years (range 29-83). Five patients (45.5%) were male. Six patients (54.5%) self-identified as Non-Hispanic white, three (27.3%) as Hispanic, and two (18.2%) as Non-Hispanic black. Eight patients (72.3%) had secondary AML, with six having a prior history of MDS. Three patients had therapy-related AML (25.3%). A majority (9) of patients (81.8%) had prior Ven exposure. Five patients (45.6%) received prior transplant. Median number of prior regimens was 2 (range 1-5).

Nine patients (81.8%) had abnormal cytogenetics, three of which (33.3%) were complex. Common mutations included ASXL1 (n=2, 18.2%), N/KRAS (n=4, 36.4%), and TET2 (n=3, 27.3%). One patient had a TP53 mutation. Ten patients (90.9%) were classified as adverse risk by European LeukemiaNet 2022, and one patient was intermediate risk. Seven patients had an ECOG performance status of 0 or 1 and four patients were performance status 2 or 3.

All patients received one cycle CLAD/LDAC/Ven. Patients received CLAD at a dose of 2.5 - 7.5 mg/m2/kg for 5 days, LDAC at 20mg every 12 hours for 10 days, and duration of Ven exposure varied from 3 to 16 days (median, 7 days) per treating physician discretion. The CRc rate after one cycle of treatment was 36.6%, with one patient achieving CR and three patients achieving CRi. Of the nine Ven-exposed patients, three achieved either CR or CRi, while one of two Ven-naive patients achieved CRi. No patients achieved minimal residual disease negative status.

In this heavily pretreated patient population, five (45.5%) patients died within 30 days of treatment start, all from infectious complications including sepsis, pneumonia, and bowel perforation with sepsis. Among the patients who achieved CR or CRi, two died during admission for induction treatment, one relapsed 78 days after achieving remission, and one remained disease-free at a six-month follow-up. One patient received a transplant after achieving remission. The median EFS was 47 days and median OS was 56 days.

In this retrospective analysis of R/R AML patients treated with CLAD/LDAC/Ven, our cohort demonstrated acceptable composite CR rates but poor long-term outcomes with high induction mortality. Our cohort was comprised of high risk heavily pre-treated patients, many of which had prior exposure to Ven. These results underscore limited utility of this regimen in the setting of Ven failure. Further studies are needed to evaluate efficacy in earlier salvage patients unexposed to Ven, with appropriate inclusion of minority population.

Verma:prelude: Research Funding; BMS: Research Funding; Incyte: Research Funding; Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Honoraria; Janssen: Honoraria; Bakx: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company. Feldman:Stelexis: Consultancy. Shastri:Gilead, Rigel, Kymera: Consultancy; Jassen: Consultancy; NACE & PeerView: Honoraria; Kymera: Research Funding; Ryvu therapeutics: Research Funding; Geron: Speakers Bureau. Konopleva:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; AstraZeneca: Consultancy, Other: clinical trials, Research Funding; Allogene: Research Funding; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Cellectis: Other: Clinical Trials; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Janssen: Consultancy, Other: clinical trials; Legend Biotech: Consultancy; MEI Pharma: Consultancy, Research Funding; Pfizer: Other: clinical trials; Precision Biosciences: Research Funding; Rafael Pharmaceutical: Research Funding; Reata Pharmaceutical: Other: IP; Redona: Consultancy; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; Sellas: Consultancy; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees.