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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Venetoclax; Drug: Fludarabine Phosphate; Drug: Busulfan; Drug: Cladribine; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 116
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (busulfan days -13 and -12 before PBSCT); 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; 2CDA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: Allogeneic; Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic
Experimental: Arm II (busulfan days -20 and -13 before PBSCT); 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; 2CDA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: Allogeneic; Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Uday R Popat, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2014
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): October 31, 2027

Study Registration Dates

• First Submitted: September 24, 2014
• First Submitted That Met QC Criteria: September 24, 2014
• First Posted (Estimated): September 26, 2014

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Therapeutics; Surgical Procedures, Operative; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons, Acyclic; Hydrocarbons; Transplantation; Purines; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Nucleosides; Ribonucleosides; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Deoxyribonucleosides; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Deoxyadenosines; Hematopoietic Stem Cell Transplantation; Busulfan; Cladribine; venetoclax; fludarabine phosphate; Stem Cell Transplantation; Peripheral Blood Stem Cell Transplantation
• Other Study ID Numbers: 2014-0431 (Other Identifier: M D Anderson Cancer Center); NCI-2014-02324 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No