Venetoclax, Busulfan and Fludarabine in Treating Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Myelodysplastic / Myeloproliferative Neoplasm Overlap Syndromes Undergoing Donor Stem Cell Transplantation

Status: Active


This phase I trial studies the best dose and side effects of venetoclax when given together with busulfan and fludarabine in treating patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, or myelodysplastic syndrome / myeloproliferative neoplasm undergoing donor hematopoietic stem cell transplantation. Drugs used in chemotherapy, such as venetoclax, busulfan and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Eligibility Criteria

Inclusion Criteria

  • Patients must have a prior diagnosis of one of the following: (Note: Mutational and cytogenetic studies performed at sites other than Dana-Farber Cancer Institute or Brigham and Women’s Hospital will require review of the outside cytogenetic and/or molecular pathology reports by the overall principal investigator [PI]) * High-risk MDS, which is defined as International Prognostic Scoring System (IPSS) Intermediate-2, IPSS high, or the presence of a mutation in TP53, or those in the RAS pathway including NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT) * High-risk AML, which is defined as one of the following subsets: ** AML with adverse risk disease according to European LeukemiaNet (ELN) guidelines including one of the following features: *** A history of mutation in TP53, RUNX1, or ASXL1 *** t(6;9)(p23;q34.1); DEK-NUP214 *** t(v;11q23.3); KMT2A rearranged *** t(9;22)(q34.1;q11.2); BCR-ABL1 *** inv(3)(q21.3q26.2) or t(3;3)(q21.3;26.2); GATA2,MECOM(EVI1) *** -5 or del(5q) *** -7 *** -17/abn(17p) *** Complex karyotype *** Monosomal karyotype *** Wild-type NPM1 and FLT3-ITD^high ** Secondary AML, which is defined as a history of antecedent hematologic disorder (an MPN or MDS), a diagnosis of therapy-related myeloid neoplasm including therapy-related (t)-MDS and t-AML, or AML with myelodysplasia-related changes, OR ** “Secondary-type” AML, which is defined by the presence of a mutation in any of the following eight genes with high specificity for the presence of antecedent myelodysplastic syndrome including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 * High-risk chronic myelomonocytic leukemia (CMML) or MDS/MPN unclassifiable (MDS/MPN-U), which is defined by the presence of trisomy 8, chromosome 7 abnormalities or complex karyotype (3 or more abnormalities); or by the presence of a mutation in ASXL1
  • Measurable disease is not required for eligibility
  • Patient is determined to be a suitable candidate for an allo-HCT using a reduced intensity conditioning (RIC) regimen using peripheral blood stem cell as stem cell source
  • Patient must have a matched related or an 8/8 unrelated donor option for his/her allo-HCT
  • Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • There are no limitations or minimum on the amount of prior therapy for patient’s advanced myeloid malignancy. Prior exposure to venetoclax is allowed
  • Total bilirubin =< 2.0 x institutional upper limit of normal. (In patients with Gilbert’s syndrome, total bilirubin >= 2.0 is permitted)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
  • Creatinine clearance >= 30 mL/min using Cockcroft Gault formula
  • The effects of venetoclax on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of venetoclax administration. For women who are of child-bearing potential, they must have a negative serum beta-HCG (human chorionic gonadotropin) test to be eligible
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Patients with > 10% blasts on bone marrow biopsy
  • Patients recommended to receive a myeloablative conditioning regimen prior to transplantation (since there is a known survival advantage for AML using higher intensity)
  • Patients who have a history of prior allogeneic stem cell transplantation
  • Patients who have had chemotherapy (with the exception of hydroxyurea and/or dexamethasone) or radiotherapy or investigational therapy within 14 days prior to starting treatment on study. Exceptions: Patients already on venetoclax therapy prior to transplant need a three day wash out prior to first treatment dose on study. Patients on BCR-ABL, IDH and FLT3 small molecule inhibitors can stay on this treatment up until 5 days prior to first treatment dose on study
  • Symptomatic or untreated known central nervous system (CNS) involvement of disease
  • Patients with active heart disease (New York Heart Association class 3-4 as assessed by history and physical exam, or a critical event including unstable angina/stroke/myocardial infarction within the last 6 months prior to first dose on study)
  • Patients who receive either coumadin or a medication that is a strong or moderate CYP3A inhibitor or inducer within 7 days prior to the first dose of study drug. Note: Patients may receive these CYP3A agents starting 3 days after the last dose of venetoclax on study if clinically necessary
  • Malabsorption syndrome or other clinically significant condition that would preclude enteral administration
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
  • Patients with known active hepatitis B virus (HBV) infection should be excluded because of potential effects on immune function and/or drug interactions. However, if a patient has HBV history with an undetectable HBV load by polymerase chain reaction (PCR), no liver-related complications, and is on definitive HBV therapy that is not contraindicated on this study, then he/she would be eligible for study
  • Patients with known active hepatitis C virus (HCV) infection. However, if a patient with a history of HCV infection has received definitive therapy (and is now HCV viral load negative), or if a patient has a reactive HCV antibody test but has an undetectable viral load by PCR, then he/she would be eligible
  • Patients with known active human immunodeficiency virus (HIV) infection out of concern for the drug-drug interaction with venetoclax and highly active antiretroviral therapy (HAART) therapy

Locations & Contacts


Brigham and Women's Hospital
Status: Active
Contact: Jacqueline Suen Garcia
Phone: 617-632-1906
Dana-Farber Cancer Institute
Status: Active
Contact: Jacqueline Suen Garcia
Phone: 617-632-1906

Trial Objectives and Outline


I. To determine a safe dose and schedule of venetoclax that can be added to a reduced intensity conditioning regimen consisting of busulfan and fludarabine for patients with clonal myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and MDS/myeloproliferative neoplasm (MPN) overlap syndromes who are undergoing allogeneic (allo)-hematopoietic cell transplantation (HCT).


I. To estimate the overall survival at 12 months.

II. To estimate the progression free survival at 12 months.

III. To estimate the best overall response rate (complete remission [CR] and CR with incomplete count recovery [CRi]) for subjects that enter the study with less than a CR or CRi.

IV. To estimate the remission duration from study entry.

V. To estimate the cumulative incidence of disease relapse at 12 months.

VI. To estimate the cumulative incidence of non-relapse mortality at 12 months.

VII. To estimate the cumulative incidence including grading and severity of acute graft versus host disease (GVHD) and chronic GVHD following allo-HCT at 12 months.

VIII. To assess donor granulocyte chimerism at day +28, +100 and at 12 months.


I. To assess for biological activity with venetoclax when combined with a fludarabine and busulfan conditioning regimen in the peri-transplantation setting with a series of exploratory assays:

Ia. Characterize the leukemia stem cell and progenitor compartments for anti-apoptotic protein expression in patients with clonal myeloid malignancies.

Ib. Evaluate if dynamic BH3 profiling (DBP) is a predictor of response (reduce risk of relapse) by evaluating how primed the leukemia stem cell and progenitor compartments are to apoptosis in patients with clonal myeloid malignancies who will receive venetoclax plus reduced intensity conditioning (RIC) prior to allo-HCT.

Ic. Evaluate the transcriptome of tumor infiltrates at baseline for critical factors that may impact response in patients with clonal myeloid malignancies who receive venetoclax plus RIC prior to allo-HCT.

Id. Assess for minimal residual disease clearance using deep sequencing techniques for patients who achieve morphologic CR prior to or after allo-HCT.

OUTLINE: This is a dose-escalation study of venetoclax.

Patients receive venetoclax orally (PO) on days -8 to -3 or -2, and fludarabine phosphate intravenously (IV) over 30 minutes once daily (QD) and busulfan IV over 3 hours twice daily (BID) on days -5 to -2. Patients also receive tacrolimus PO BID beginning on day -3 for 6-9 months, then undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed up at 30-45, 46-61, 62-77, and 100 days, and at 6 and 12 months.

Trial Phase & Type

Trial Phase

Phase I

Trial Type


Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Jacqueline Suen Garcia

Trial IDs

Primary ID 18-283
Secondary IDs NCI-2018-02454 ID NCT03613532