PRIMARY OBJECTIVES:~I. To determine the complete response rate (CR) of cladribine in combination with idarubicin and cytarabine (araC) in patients with acute myeloid leukemia (AML), high risk (HR) myelodysplastic syndrome (MDS), or myeloid blast phase of chronic myeloid leukemia (CML).~SECONDARY OBJECTIVES:~I. To determine the overall response rate (ORR) of cladribine in combination with idarubicin and araC in patients with AML, HR MDS, or myeloid blast phase of CML.~II. To assess overall survival (OS) and event free survival (EFS) of patients treated with cladribine, idarubicin, and araC (cytarabine).~III. To assess the duration of response to the combination in patients with AML, HR MDS, or myeloid blast phase of CML.~IV. To determine the safety and tolerability of the combination in patients with AML, HR MDS, or myeloid blast phase of CML.~EXPLORATORY OBJECTIVES:~I. To study and describe the relationship between pretreatment patient/disease characteristics (including AML-associated molecular abnormalities) and outcome.~II. To identify molecular biomarkers predictive of response to therapy. III. To study and describe the relationship between patient/disease characteristics, use of intrathecal prophylaxis, and incidence of leptomeningeal disease.~IV. To study the trajectories of leukemia mutations and molecular minimal residual disease (MRD) during the therapy.~OUTLINE:~INDUCTION: Patients receive cladribine intravenously (IV) and cytarabine IV over 1-2 hours on days 1-5 and idarubicin IV over 30-60 minutes on days 1-3. Patients with untreated AML and MDS also receive venetoclax orally (PO) on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO twice daily (BID) on days 6-19 or gilteritinib PO once daily (QD) on days 1-14. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.~CONSOLIDATION: Patients receive cladribine IV and cytarabine IV over 1-2 hours on days 1-3 and idarubicin IV over 30-60 minutes on days 1-2. Patients with untreated AML and MDS also receive venetoclax PO on days 2-8. AML patients with known FLT3-ITD or FLT3 kinase domain mutations may receive midostaurin PO BID on days 6-19 or gilteritinib PO QD. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up every 6-12 months.
This phase II trial studies how well cladribine, idarubicin, cytarabine, and venetoclax work in patients with acute myeloid leukemia, high-risk myelodysplastic syndrome, or blastic phase chronic myeloid leukemia. Drugs used in chemotherapy, such as cladribine, idarubicin, cytarabine, and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.