Trial of GVHD Prophylasxis With PTCy or Thymoglobulin in Unrelated SCT

Study Overview
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Brief Summary
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Purpose There is a growing evidence of high efficacy of post-transplantation cyclophocphomide (PTCy)-based GVHD prophylaxis in haploidentical and matched related and unrelated bone marrow transplantation. There is limitted, but growing data on safety and efficacy of this prophylaxis in unrelated and peripheral blood stem cell transplantations. Use of PTCy in chronic myeloproliferative neoplasms and myelodisplatic syndrome is of particular interest. On the one hand, PTCy could reduce the incidence of chronic GVHD and long-term bormidity. On the other hand, there is a concern, that PTCy can increase the incidence of graft failures in this group of patients. Currently published data indicate that low-dose Thymoglobulin-based prophylaxis is the most promissing compatitor in terms of acute and chronic GVHD control. So there is a rationale to randomize Thymoglobulin and PTCy as GVHD prophilaxis. Pre-transplant assesment of moratlity (PAM)-index will be used as the strata for randomization, as it is the paramter that takes into account the most important factors effecting survival. The conditioning regimen and the other two components of GVHD prophylaxis (mycophenolate mofetil and tacrolimus) will be identical in the two arms of the study.

Official Title
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Randomized Trial of GVHD Prophylasxis With Post-transplantation Cyclophocphomide (PTCy) or Thymoglobulin in Unrelated SCT Recepients With Chronic Myeloproliferative Neoplasms and Myelodisplatic Syndrome

Conditions
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Leukemia, Chronic Myeloid, Myelodysplastic Syndromes, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative

Intervention / Treatment
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* Procedure: Unrelated allogeneic stem cell transplantation
* Drug: Busulfan
* Drug: Fludarabine monophosphate
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil
* Drug: Cyclophosphamide
* Drug: Thymoglobulin


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 Diagnosis: Chronic myeloid leukemia Myelodysplastic Syndromes Myeloprolipherative neoplsm unclassified Atypical chronic myelogenous leukemia Signed informed consent Patients with 10/10 HLA-matched unrelated donor available. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Mismatches in these loci are not allowed. Peripheral blood stem cells as graft source No second tumors No prior history of Thymoglobulin exposure or no history of anaphylactic shock after Thymoglobulin administration 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: 75 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: Thymoglobulin<br>Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -5 Busulfan 1 mg/kg po qid x 2 days Days -4 through -3 Thymoglobulin 2,5 mg/kg po qd x 2 days Days -1 through +30: Mycophenolate mofetil 30 mg/kg/day, maximum 2 g/day, iv or po x 30 days Days -1 through +150: Tacrolimus 0.03 mg/kg/day with further correction by concentration | Procedure: Unrelated allogeneic stem cell transplantation<br> <br> Drug: Busulfan<br> <br> Drug: Fludarabine monophosphate<br> <br> Drug: Tacrolimus<br> <br> Drug: Mycophenolate mofetil<br> <br> Drug: Thymoglobulin<br> <br> |
| Experimental: PTCy<br>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 | Procedure: Unrelated allogeneic stem cell transplantation<br> <br> Drug: Busulfan<br> <br> Drug: Fludarabine monophosphate<br> <br> Drug: Tacrolimus<br> <br> Drug: Mycophenolate mofetil<br> <br> Drug: Cyclophosphamide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of primary graft failure |  | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute GVHD, grades II-IV |  | 365 days | 
| Incidence of chronic GVHD, moderate and severe (NIH criteria) |  | 365 days | 
| Non-relapse mortality analysis |  | 365 days | 
| Event-free survival analysis |  | 365 days | 
| Overall survival analysis |  | 365 days | 
| Relapse rate analysis |  | 365 days | 
| Toxicity (NCI CTCAE 4.03) | Toxicity parameters based on NCI CTCAE 4.03 grades: hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), mucositis (attending physician assessment), hemorrhagic cystitis (attending physician assessment), cardiotoxicity (ECG, echocardiography). Additional toxicity parameters: incidence and severity of veno-occlusive disease, incidence of transplant-associated microangiopathy | 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, Thymoglobulin, Myelodysplastic Syndromes, Immunosuppressive Agents, Immune System Diseases, Busulfan, Fludarabine, Tacrolimus, Mycophenolate mofetil, Antineoplastic Agents, Alkylating, Myeloablative Agonists, Hematopoietic Stem Cell Transplantation, Allogeneic Transplantation, Leukemia, Chronic Myeloid, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative