Venetoclax, Busulfan, Fludarabine, and Azacitidine in Treating Patients with High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Myelodysplastic / Myeloproliferative Neoplasm Overlap Syndromes Undergoing Donor Stem Cell Transplantation
- 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 one of the following subsets: ** International Prognostic Scoring System (IPSS) Intermediate-2 ** Presence of a mutation in TP53 ** Presence of a mutation in the RAS pathway including NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT) OR ** Therapy-related MDS * 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)-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 ** Patients with AML with evidence of measurable residual disease by multiparameter flow cytometry (>= 0.1%) despite morphologic remission on the pre-transplant/screening bone marrow biopsy. Review required by overall principal investigator (PI) * 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
- Morphologic 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
- 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
- Patients with > 10% morphologic blasts on bone marrow biopsy if they have a diagnosis of MDS or MDS/MPN. Patients > 5% morphologic blasts on bone marrow biopsy if they have a diagnosis of AML
- 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
- 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 have consumed grapefruit, grapefruit products, Seville oranges or starfruit within 3 days prior to study treatment. Patients who a strong or moderate inducer within 7 days prior to the first dose of study drug
- 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
- Pregnant or breastfeeding women or those intending to become pregnant during the study or within 3 months after the final dose of study treatment are excluded from this study. Women of childbearing potential must have a negative serum pregnancy test resulted during screening and repeated within 7 days prior to study drug (local labs are allowed)
- Vaccination with live, attenuated vaccines within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study
- Patients with uncontrolled infection at time of first dose of treatment on study. Patients receiving anti-microbial agents including antibiotics, antiviral and antifungal therapies are allowed if hemodynamically stable
- Part 2 only: Patients recommended to receive FLT3 inhibitor therapy or any other anti-leukemic therapy for AML as maintenance post allo-HCT
I. To determine the safety 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 (acute myeloid leukemia [AML], myelodysplastic syndrome [MDS] and MDS/myeloproliferative neoplasm [MPN] overlap syndromes who are undergoing allogeneic (allo)-hematopoietic cell transplantation (HCT). (Part 1)
II. To determine the safety of venetoclax in combination with azacitidine administered post allo-HCT as maintenance therapy. (Part 2)
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]) for subjects that enter the study with less than a CR.
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 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.
IX. To determine the feasibility of administering the combination of venetoclax and azacitidine post allo-HCT as maintenance therapy.
X. To compare the cumulative incidence of relapse and non-relapse mortality, overall survival and progression-free survival between patients enrolled in Part 1 and Part 2.
I. To assess for biological activity with venetoclax when combined with a fludarabine and busulfan conditioning regimen and with azacitidine maintenance regiment in the peri-transplantation setting with a series of exploratory assays:
Ia. Measure baseline/pre-treatment and changes in the mitochondrial apoptotic priming level of residual morphologic myeloblasts before and after venetoclax therapy using the BH3 profiling assay.
Ib. Measure the changes in mitochondrial apoptotic priming level of immune cell subsets in the post-transplant setting using BH3 profiling.
Ic. Determine the immune cell subsets present (including natural killer [NK] cell and T cell subsets) in the post-transplant setting.
Id. Evaluate the transcriptome of tumor infiltrates at baseline for critical factors that may impact response in patients with clonal myeloid malignancies who receive venetoclax peri-transplant.
Ie. Assess for measurable residual disease clearance in bone marrow by deep sequencing alone in cases of MDS and MDS/MPN and paired with multi-parameter flow cytometry in cases of AML.
OUTLINE: This is a dose-escalation study of venetoclax.
PART I: 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.
PART II: Patients receive venetoclax PO on days -8 to -2, and fludarabine phosphate IV over 30 minutes QD and busulfan IV over 3 hours 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. Patients then move to maintenance therapy between days 42-90.
PART II, MAINTENANCE: Patients receive venetoclax PO on days 1-14 and azacitidine IV or subcutaneously (SC) on days 1-5. Treatment repeats every 28 or 42 days for up to 8 or 12 cycles, respectively, in the absence of disease progression or unacceptable toxicity.
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 Phase I
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Jacqueline Suen Garcia
- Primary ID 18-283
- Secondary IDs NCI-2018-02454
- Clinicaltrials.gov ID NCT03613532