Comparing Post-Transplant Cyclophosphamide as GVHD Prophylaxis to Standard of Care for Acute Leukemia Patients

Study Overview
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Brief Summary
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This randomized clinical trial will evaluate two approaches of GvHD prophylaxis; the standard of care GVHD prophylaxis regimen (methotrexate/calcineurin inhibitors) and post-transplant cyclophosphamide with calcineurin inhibitors for their efficacy as a new GVHD prophylaxis strategy.

Detailed Description
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An open-label randomized clinical trial will be performed. Eligible patients are females and males, between 14 and 65 years undergoing allo-HCT for treatment of Acute Leukemia (AML or ALL). Patients must have a matching related peripheral blood stem cell donor. Patients from or referred to the KFSH&RC for allogeneic transplant consideration will be offered the opportunity to participate in this trial. Treatment Description: Patients will be randomized on one of the arms; an intervention or a standard of care arm.

Official Title
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Comparing Post-Transplant Cyclophosphamide With Calcineurin Inhibitors as A GVHD Prophylaxis to Standard Care of Methotrexate and Calcineurin Inhibitors for Acute Leukemia Incorporating Patient Pharmacogenomics Profiling

Conditions
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Acute Lymphoblastic Leukemia (ALL) in Complete Remission, Acute Myeloid Leukemia (AML) in Remission

Intervention / Treatment
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* Drug: Cyclophosphamide 50mg
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Acute Leukemias (AML, ALL) in morphologic complete remission with or without hematologic recovery Patients must have a fully matched (8/8) related donor willing to donate peripheral blood stem cells and must meet institutional criteria for donation Planned Myeloablative conditioning regimen Cardiac function: ejection fraction at rest ≥ 50% by MUGA or TTE Estimated creatinine clearance greater than 50 mL/minute Pulmonary function: DLCO ≥ 50% (adjusted for hemoglobin), and FVC and FEV1 ≥ 50% Liver function: total bilirubin < 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and ALT/AST < 2.5x the upper normal limit Signed informed consent Exclusion Criteria: Karnofsky or Lansky Performance Score < 70%. Active disease Patients with uncontrolled bacterial, viral, or fungal infections Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated Patients seropositive for HIV-1 or -2 Patients seropositive for HTLV-I or -II Patients with active Hepatitis B or C viral replication by PCR Women who are pregnant (positive serum or urine βHCG) or breastfeeding Females with childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation History of uncontrolled autoimmune disease or on active treatment Patients with prior malignancies, except resected non-melanoma skin cancer or treated cervical carcinoma in situ; cancer treated with curative intent ≥ 5 years previously will be allowed; cancer treated with curative intent < 5 years previously will not be allowed.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Intervention<br>Peripheral blood matched related donor HCT, using myeloablative conditioning regimen (IV Busulfan/IV Fludarabine for AML, IV VP16/TBI for ALL) HCT with cyclophosphamide, and oral tacrolimus (or another calcineurin inhibitor if intolerant for tacrolimus) for GVHD prophylaxis. Cyclophosphamide will be given at a dose of 50 mg/kg/day IV on Day +3 and Day +5 post stem cell infusion (only 2 doses). | Drug: Cyclophosphamide 50mg<br>* Cyclophosphamide as GVHD prophylaxis will be on day +3 and day +5<br>|
| Active Comparator: Arm 2: Standard of Care<br>Peripheral blood matched related donor HCT, using myeloablative conditioning regimen (IV Busulfan/IV Fludarabine for AML, IV VP16/TBI for ALL) HCT with methotrexate, and oral tacrolimus (or another calcineurin inhibitor if intolerant for tacrolimus) for GVHD prophylaxis | Drug: Methotrexate<br>* Methotrexate as GVHD prophylaxis will be on day +1, day +3, and day +6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GRFS (GVHD-free/relapse-free survival) | Defined as the non-occurrence of a grade 3-4 acute GVHD, or systemic therapy-requiring chronic GVHD, or relapse, or death during the first post-transplant year. | One-year post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Graft versus Host Disease (aGVHD) | The probabilities of grade II-IV and III-IV acute GVHD will be determined. Acute GVHD will be graded according to Glucksberg and NIH 2014 criteria. | 100 Day post transplant | 
| Chronic Graft versus Host Disease (cGVHD) | The cumulative incidence of systemic therapy-requiring chronic GVHD will be determined. Moderate and severe chronic GVHD will be defined per the NIH 2014 criteria. | One year Post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sibling Donor Transplant, Allogeneic hematopoietic cell transplantation, GvHD Prophylaxis, Myeloablative regimen