Venetoclax and Sequential Busulfan, Cladribine, and Fludarabine Phosphate Before Donor Stem Cell Transplant in Treating Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Study Overview
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Brief Summary
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This randomized phase II trial studies how well venetoclax and sequential busulfan, cladribine, and fludarabine phosphate before donor stem cell transplant work in treating patients with acute myelogenous leukemia or myelodysplastic syndrome. Giving chemotherapy before a donor peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare progression free survival of two schedules of venetoclax, timed sequential busulfan, cladribine and fludarabine conditioning regimen in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). SECONDARY OBJECTIVES: I. Compare overall survival between the two schedules. II. Compare non relapse mortality between the two schedules. III. Compare neutrophil and platelet engraftment between the two schedules. IV. Compare acute and chronic graft-versus-host disease (GVHD) between the two schedules. V. Compare cumulative incidence of relapse between the two schedules. VI. Compare grade III/IV toxicity between the two schedules. TERTIARY OBJECTIVES: I. To study chemotherapy resistance. II. To study deoxyribonucleic acid (DNA) damage. III. To study immune recovery and cytokines (both in plasma and cells). IV. To study BCL-2 family expression, stem cell surface markers and intracellular signaling markers in AML cells at the time of relapse. OUTLINE: PREPARATIVE REGIMEN: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive venetoclax orally (PO) once daily (QD) on days -22 to -3 and busulfan intravenously (IV) over 3 hours on days -13 and -12. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3. ARM II: Patients receive venetoclax PO QD on days -22 to -3 and busulfan IV over 3 hours on days -20 and -13. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3. TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0. After completion of study treatment, patients are followed up for 2.5 years.

Official Title
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Allogeneic Transplantation Using Venetoclax, Timed Sequential Busulfan,Cladribine, and Fludarabine Conditioning in Patients With AML and MDS

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Busulfan
* Drug: Cladribine
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Procedure: Peripheral Blood Stem Cell Transplantation
* Other: Pharmacological Study
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with biopsy-proven acute myeloid leukemia or myelodysplastic syndrome with persistent disease or in remission Human leukocyte antigen (HLA)-identical sibling or 8/8 matched unrelated donor transplant Patients age 18 to 70 years old; eligibility for pediatric patients will be determined in conjunction with an MD Anderson Cancer Center (MDACC) pediatrician; patients age 2-17 years may be enrolled after at least 10 adults (ages 18-70 years old) have been assessed for safety at day 30 Direct bilirubin < 1 mg/dl Alanine aminotransferase (ALT) < 3 times upper limit of normal Creatinine clearance > 50 ml/min (calculated creatinine clearance is permitted) Forced expiratory volume in 1 second (FEV1) >= 50% of expected corrected for hemoglobin and/or volume Forced vital capacity (FVC) >= 50% of expected corrected for hemoglobin and/or volume Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 50% of expected corrected for hemoglobin and/or volume Children unable to perform pulmonary function tests (e.g., less than 7 years old) pulse oximetry of >= 92% on room air Left ventricular ejection fraction (LVEF) >= 40% Patient, legally authorized representative (LAR), or parent able to sign informed consent; able to give assent for patients age 7-17 Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization; women of child bearing potential must be willing to use an effective contraceptive measure while on study Performance score of >= 70 by Karnofsky/Lansky or performance status (PS) 0 or 1 (Eastern Cooperative Oncology Group [ECOG] =< 1) Exclusion Criteria: Prior allogeneic or autologous transplantation Uncontrolled infections Human immunodeficiency virus (HIV) seropositivity Hematopoietic cell transplantation (HCT) co-morbidity index score > 3; the principal investigator is the final arbiter of eligibility for comorbidity score > 3 Patients with prior coronary artery disease

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (busulfan days -13 and -12 before PBSCT)<br>PREPARATIVE REGIMEN: Patients receive venetoclax PO QD on days -22 to -3 and busulfan IV over 3 hours on days -13 and -12. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Cladribine<br>* Given IV<br>* Other names: RWJ-26251;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|
| Experimental: Arm II (busulfan days -20 and -13 before PBSCT)<br>PREPARATIVE REGIMEN: Patients receive venetoclax PO QD on days -22 to -3 and busulfan IV over 3 hours on days -20 and -13. Patients then receive fludarabine phosphate IV over 1 hour, cladribine IV over 2 hours, and busulfan IV over 3 hours on days -6 to -3. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Cladribine<br>* Given IV<br>* Other names: RWJ-26251;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | The method of Kaplan and Meier will be used to estimate distribution of progression free survival. | At 6 months | 
| Disease free survival (DFS) | Will test whether there is strong evidence that DFS differs between the two arms using a stratified log-rank test. Will use the Lan-DeMets alpha spending approach with an O'Brien-Fleming stopping boundary to compare the two arms. | Up to 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity of these regimens |  | Up to 2.5 years | 
| Cumulative incidence of acute graft versus host disease (GVHD) | Will use the method of Gooley et al to estimate the cumulative incidence of acute GVHD. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes. | Up to 2.5 years | 
| Cumulative incidence of chronic GVHD | Will use the method of Gooley et al to estimate the cumulative incidence of chronic GVHD. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes. | Up to 2.5 years | 
| Overall survival | The method of Kaplan and Meier will be used to estimate the distribution of overall survival. Cox proportional hazards regression analysis will be used to model the association between overall survival and covariates of interest. | Up to 2.5 years | 
| Time to neutrophil engraftment | The method of Kaplan and Meier will be used to estimate time to neutrophil engraftment. | Up to 2.5 years | 
| Time to platelet engraftment | The method of Kaplan and Meier will be used to estimate time to platelet engraftment. | Up to 2.5 years | 
| Cumulative incidence of relapse | Will use the method of Gooley et al to estimate the cumulative incidence of relapse. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes. | Up to 2.5 years | 
| Non-relapse mortality | Will use the method of Gooley et al to estimate the cumulative incidence of non-relapse mortality. Will use the method of Fine and Gary to fit regression models to the cumulative incidence outcomes. Logistic regression will be used to model the association between 100-day NRM and clinical and demographic covariates of interest. | Up to 2.5 years |