Post-transplantation Cyclophosphamide as GVHD Prophylaxis After HSCT

Study Overview
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Brief Summary
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This study evaluates the efficacy of high-dose post-transplantation cyclophosphomide as graft-versus-host disease (GVHD) prophylaxis after allogeneic stem cell transplantation in patients with different risk of GVHD. The risk-adapted strategy involves using single-agent cyclophosphomide in recipients of matched bone marrow graft, and combining cyclophosphomide with tacrolimus and mycophenolate mofetil in recipients of matched peripheral blood stem cells and mismatched bone marrow.

Official Title
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High-dose Post-transplantation Cyclophosphamide as Graft Versus-host Disease Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Acute Myeloid Leukemia, Lymphoma, Acute Lymphoid Leukemia, Myelodysplastic Syndromes, Chronic Lymphocytic Leukemia, Immune System Diseases

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Busulfan
* Drug: Fludarabine monophosphate
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil
* Procedure: Allogeneic hematopoietic stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have an indication for allogeneic hematopoietic stem cell transplantation Signed informed consent Patients with a donor available. The donor and recipient must be identical at at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is required for related donor. A minimum match of 8/10 is required for unrelated donor. No second tumors No severe concurrent illness Exclusion Criteria: Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50% Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted Respiratory distress >grade I Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits Creatinine clearance < 60 mL/min Uncontrolled bacterial or fungal infection at the time of enrollment Requirement for vasopressor support at the time of enrollment Karnofsky index <30% Pregnancy Somatic or psychiatric disorder making the patient unable to sign informed consent

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Matched bone marrow graft<br>Days -8 through -4: Busulfan 1 mg/kg po qid x 4 days Days -3 through -2: Cyclophosphamide 50mg/kg/day iv x 2 days Or Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv | Drug: Cyclophosphamide<br> <br> Drug: Busulfan<br> <br> Drug: Fludarabine monophosphate<br> <br> Procedure: Allogeneic hematopoietic stem cell transplantation<br> <br> |
| Experimental: Matched peripheral blood stem cells graft<br>Days -8 through -4: Busulfan 1 mg/kg po qid x 4 days Days -3 through -2: Cyclophosphamide 50mg/kg/day iv x 2 days Or Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 2 g/day, iv or po x 30 days Days +5 through +120: Tacrolimus 0.03 mg/kg/day with further correction by concentration | Drug: Cyclophosphamide<br> <br> Drug: Busulfan<br> <br> Drug: Fludarabine monophosphate<br> <br> Drug: Tacrolimus<br> <br> Drug: Mycophenolate mofetil<br> <br> Procedure: Allogeneic hematopoietic stem cell transplantation<br> <br> |
| Experimental: Mismatched peripheral blood stem cells or bone marrow graft<br>Days -8 through -4: Busulfan 1 mg/kg po qid x 4 days Days -3 through -2: Cyclophosphamide 50mg/kg/day iv x 2 days Or Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv Days +5 through +35: Mycophenolate mofetil 45 mg/kg/day, maximum 3 g/day, iv or po x 30 days Days +5 through +120: Tacrolimus 0.03 mg/kg/day with further correction by concentration | Drug: Cyclophosphamide<br> <br> Drug: Busulfan<br> <br> Drug: Fludarabine monophosphate<br> <br> Drug: Tacrolimus<br> <br> Drug: Mycophenolate mofetil<br> <br> Procedure: Allogeneic hematopoietic stem cell transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute and chronic GVHD, requiring treatment |  | 365 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of primary graft failure |  | 60 days | 
| Non-relapse mortality analysis |  | 365 days | 
| Overall survival analysis |  | 365 days | 
| Event-free survival analysis |  | 365 days | 
| Relapse rate analysis |  | 365 days | 
| Toxicity based NCI CTC grades |  | 100 days | 
| Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence |  | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cyclophosphamide, Chronic Lymphocytic Leukemia, Immunosuppressive Agents, Tacrolimus, Mycophenolate mofetil, Antineoplastic Agents, Alkylating, Leukemia, Lymphoma, Myelodysplastic Syndromes, Immune System Diseases, Busulfan, Fludarabine, Myeloablative Agonists, Hematopoietic Stem Cell Transplantation, Allogeneic