Acute Leukemias of Ambiguous Lineage Have Durable Response to Hypomethylating Agents Plus Venetoclax in Older Patients

Background: The standard of care for frontline therapy of acute leukemias of ambiguous lineage (ALAL) remains controversial due to their rarity; however, outcomes are generally poor. Intensive chemotherapy (IC) regimens are standard, with evidence suggesting that acute lymphoblastic leukemia regimens are more effective than those used for acute myeloid leukemia (AML). Strategies for treating older or frail patients are limited. Although treatment with a hypomethylating agent plus venetoclax (HMA/Ven) is standard therapy for IC-ineligible AML patients, the role of HMA/Ven in ALAL remains poorly characterized. We performed a retrospective chart review of patients at our institution with Philadelphia-negative ALAL, comparing the outcomes of those treated with HMA/Ven and those who received IC. Method: Patients ≥ 18 years treated at Weill Cornell Medical Center with newly diagnosed, pathologically confirmed acute undifferentiated leukemia (AUL), T/myeloid, or Philadelphia chromosome-negative B- and B/T-myeloid leukemia were included. Frontline HMA/Ven was defined as Ven plus azacytydine, decitabine, or oral decitabine/cedazuridine (one patient had initial HMA monotherapy followed by HMA/Ven). Intensive chemotherapy included patients who received variations of standard ALL or AML IC regimens (hyper- or mini-hyper-CV[A]D, cytarabine plus daunorubicin or idarubicin, or cladribine plus idarubicin and cytarabine) with or without Ven. Tyrosine kinase inhibitors including midostaurin or gilteritinib were added for patients with fms-like tyrosine kinase 3 ( FLT3) mutations. Baseline and disease characteristics were collected as well as disease response, subsequent lines of therapy, whether the patient proceeded to allogeneic hematopoietic cell transplantation (HCT), rate of morphologic complete remission (CR), and overall survival (OS). Results: Of 16 patients, 7 received frontline HMA/Ven. B/myeloid was the most common disease type (n=8), followed by T/myeloid (n=4), AUL (n=3), and 1 patient with B/T/myeloid disease. The median age was 74 years (interquartile range [IQR] 62-80). Patients who received HMA/Ven were older than those who received IC, with median ages of 79 (IQR: 77-82) and 62 (IQR: 56-70; p = 0.01), respectively. Baseline white blood cell, hemoglobin, platelet counts, and lactate dehydrogenase, as well as blast percentages in both peripheral blood and bone marrow were similar between the groups. Although not validated in ALAL, markers of adverse myeloid