A Study of Cladribine, Low Dose Cytarabine, and Venetoclax in Treatment of Relapsed/Refractory or Secondary Acute Myeloid Leukemia

A Phase II Study of Cladribine, Low Dose Cytarabine, and Venetoclax in Treatment of Relapsed/Refractory and Secondary Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a bone marrow cancer that is challenging to treat. It is the most common type of acute leukemia, particularly in adults. There are around 20,000 cases of acute myeloid leukemia diagnosed in the United States every year. Despite the recent significant progress in the understanding of acute myeloid leukemia leading to the development of new therapies, significant challenges remain. The initial treatment for acute myeloid leukemia involves using therapies aimed at reducing the disease burden in the bone marrow to the lowest possible level (a state known as disease remission). This is usually followed by consolidation treatment aimed at curing the disease. The initial treatment involves high intensity chemotherapy in younger adults who can tolerate these therapies and low intensity therapies for older adults or those with other medical conditions that prohibit them from receiving high intensity chemotherapy. The consolidation therapy involves either more chemotherapy or a bone marrow transplant. In the recent years, a treatment regimen consisting of two drugs; Azacytidine and Venetoclax has become the standard of care for low intensity therapy intended for older adults. Despite significant improvement in outcomes of acute myeloid leukemia in older adults after the introduction of Azacytidine/Venetoclax, yet 40% of patients who receive this treatment will either be refractory to it or relapse after an initial remission. Those whose leukemia relapses after Azacytidine/Venetoclax treatment are left with very few treatment options and have a dismal prognosis. Based on previous laboratory studies, certain subtypes of acute myeloid leukemia tend to not respond as well to Azacytidine/Venetoclax therapy and have a better chance of responding to the treatment regimen the investigators are proposing in this study. The study treatment regimen consists of 3 drugs; Cladribine, low dose Cytarabine and Venetoclax. Demonstrating efficacy of the study regimen in treatment of relapsed/refractory acute myeloid leukemia, after prior Venetoclax therapy, will provide another treatment option for those with a relapsed/refractory disease who wish to continue receiving therapy.

Among the main mechanisms implicated in acute myeloid leukemia (AML) relapse after treatment with Venetoclax is upregulation of myeloid cell leukemia 1 (MCL-1) in AML cells with their survival becoming less dependent on the Venetoclax target, B-cell leukemia/lymphoma 2 (BCL-2). Leukemic stem cells (LSCs) in AML with monocytic differentiation are significantly more resistant to treatment with azacytidine/venetoclax being less dependent on BCL-2 and demonstrating preferential reliance on MCL-1 for survival. Cladribine, combined with Venetoclax in preclinical studies have shown efficacy in overcoming resistance to Venetoclax by downregulating MCL-1, particularly in AML with monocytic features and/or rat sarcoma oncogene (RAS) mutations.

The investigators propose to use the cladribine, low-dose cytarabine and venetoclax (CAV) regimen in patients with relapsed/refractory or secondary AML (transformed from myelodysplastic syndrome [MDS], myeloproliferative neoplasm [MPN] or MDS/MPN overlap) who were previously treated with a venetoclax-containing regimen, whose disease lacks molecular targets with approved therapies. CAV is a medium intensity regimen that has demonstrated acceptable safety and tolerability in older patients with AML and/or those who are unfit for intensive therapies

Objective:

The primary objective is to estimate the rate of composite complete remission (CRc) in participants with relapsed/refractory or secondary AML who are treated with cladribine, low-dose cytarabine and venetoclax after prior treatment with a venetoclax-containing regimen.

• Inclusion Criteria

  • Participants with relapsed/refractory AML (according to European LeukemiaNet 2022 Criteria) after treatment with a Venetoclax-containing regimen.

  • Participants with MDS, MPN, or MDS/MPN overlap who develop secondary AML after treatment with a Venetoclax-containing regimen.

  • Prior therapy with hydroxyurea or emergency use of Cytarabine (up to 1 gm total dose) for cytoreduction is allowed.

  • Prior hematopoietic stem-cell transplant (HSCT) and/or donor lymphocyte infusion (DLI) are allowed if at the time of relapse ≥ 90 days have passed from the date of the last stem cell transplant (90-day duration not required for DLI).

  • Age ≥ 18 years old.

  • Eastern Oncology Group (ECOG) performance status of ≤ 2

  • Participants must agree to take the following reproductive precautions:

    • Negative urine pregnancy test within one week prior to starting the study therapy for all women of childbearing potential.
    • Participants who could become pregnant should use effective contraception during therapy and for 6 months after the last dose of study treatments. Participants with partners who could become pregnant should also use effective contraception during therapy and for 6 months after the last dose of study treatments.
    • Nursing women should discontinue breastfeeding during therapy and for 10 days after the last dose of study treatments.

  • Adequate organ function as follows:

    • liver function (bilirubin < 2mg/dL, AST and/or ALT <3 x ULN). Unless liver enzyme abnormalities are suspected by the treating investigator to be due to leukemic infiltration after discussion with the principal investigator (PI).
    • kidney function (creatinine < 1.5 x ULN)

  • Ability to understand the study procedures and requirements. A signed informed consent by the participant or an authorized legal representative is required.

• Exclusion Criteria

  • Pregnant or breastfeeding women
  • Uncontrolled active infections, i.e., signs of severe sepsis or hemodynamic instability
  • Concurrent diagnosis with another active malignancy (indolent or adequately treated malignancies are allowed after discussion with the PI.
  • Decompensated organ failure
  • Documented hypersensitivity to any of the study treatments
  • Participants with a diagnosis of acute promyelocytic leukemia (APL)
  • Recipients of previous HSCT who have > grade 1 graft versus host disease (GVHD) of the gastro-intestinal tract, liver, lung or skin.
  • Prior therapy with purine analogues (Fludarabine, Clofarabine or Cladribine) unless it was part of a prior HSCT conditioning regimen.