GvHD Prophylaxis in Unrelated Donor HCT: Randomized Trial Comparing PTCY Versus ATG

Study Overview
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Brief Summary
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Post-transplantation cyclophosphamide (PTCY) has become increasingly popular in the haploidentical HCT setting because it overcomes the HLA-mismatch barrier and levels GVHD risk. This advantage may also prove useful in the context of unrelated donor (UD) transplantation. GVHD prophylaxis for matched unrelated donor hematopoietic cell transplantation (alloHCT) in Europe is mainly conducted with ATG. Still, the burden of acute and chronic GVHD and especially of relapse remains high with both approaches for GVHD prevention. PTCY has not been tested against the current standard ATG for GvHD prophylaxis in large randomized trials. The goal of this trial is to compare the outcomes of PTCY and ATG for patients receiving unrelated donor PBSCT. PTCY-based prophylaxis promises to have beneficial net effects on immune reconstitution, GVHD and disease control, and thus might impact on patient survival.

Official Title
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Graft vs Host Disease Prophylaxis in Unrelated Donor Transplantation: a Randomized Clinical Trial Comparing PTCY vs ATG (GRAPPA)

Conditions
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AML, MDS, Graft Vs Host Disease, Peripheral Blood Stem Cell Transplantation, MDS/MPN, CMML

Intervention / Treatment
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* Drug: Cyclophosphamide
* Biological: ATG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written Informed Consent and able to understand the nature of the trial and the trial related procedures and to comply with them. Age ≥ 18 years. One of the following eligible diagnoses: AML in CR1 with intermediate or adverse risk genetic abnormalities (according to the ELN 2017 guidelines), or undefined risk. AML of any ELN risk category after hematological or molecular relapse, or with primary refractory disease. AML arising from myelodysplastic syndrome (MDS) or a myeloproliferative neoplasia, except if favourable genetic abnormalities (according to ELN 2017 guidelines) are present. Therapy-related myeloid neoplasia (t-MN), except if favourable genetic abnormalities (according to ELN 2017 guidelines) are present. MDS with intermediate risk, high risk or very high risk disease (according to the IPSS-R Score) regardless of treatment status. MDS/MPN and CMML-1/CMML-2 regardless of treatment status. The left ventricular ejection fraction (LVEF) was assessed ≥40% at last echocardiography. Transplantation with Peripheral Blood Stem Cells (PBSC) scheduled to be performed 4 to 14 days after date of randomization. The scheduled donor is unrelated to the patient, and matched or partially matched (with not more than one allele or antigen mismatch) at HLA-A, -B, -C, or -DRB1. Absence of pregnancy confirmed by highly sensitive pregnancy test for WOCBP. Test must not date back more than 3 days prior to randomization, or more than 3 days prior to start of conditioning, if it started before randomization. Exclusion Criteria: Anamnestic intravenous or subcutaneous exposure to rabbit immunoglobin-preparations (e.g. Grafalon or Thymoglobulin) Known hypersensitivity to ATG-Grafalon or its excipients. Known hypersensitivity to cyclophosphamide, its metabolites or excipients. Prior allogeneic hematopoietic transplantation. Patients who receive supplementary continuous oxygen at the time of randomization. Symptomatic heart failure (NYHA ≥2) at the time of randomization. Uncontrolled viral, bacterial or fungal infection with progression or no clinical improvement at the time of randomization. Symptomatic cystitis or known obstruction of urine flow at the time of randomization. Breast-feeding women. WOCBP and fertile male patients unable or unwilling to follow highly effective contraception methods from enrollment to minimum six months after the last dose of the IMP. Simultaneous participation in another interventional clinical trial with an investigational medicinal product.

Ages Eligible for Study
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Minimum Age: 18 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: Cyclophosphamide<br>Cyclophosphamide 50 mg/kg (AIBW) i.v. d+3, d+4 post transplant | Drug: Cyclophosphamide<br>* 50 mg/kg (AIBW) i.v. d+3, d+4 post transplant<br>* Other names: all brands;|
| Active Comparator: ATG<br>ATG Grafalon 10 mg/kg i.v. d-3, d-2, d-1 pre-transplant | Biological: ATG<br>* 10 mg/kg i.v. d-3, d-2, d-1 pre-transplant<br>* Other names: ATG Grafalon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival from HCT |  | 1 year | 
| Relapse- and Immunosuppression-free Survival (RIFS) |  | 1 year after HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GVHD-and relapse-free survival (GRFS) |  | 1 year | 
| Cumulative incidence of relapse |  | 1 year | 
| Cumulative incidence of non-relapse mortality |  | 1 year | 
| Cumulative incidences of acute and chronic GVHD |  | 180 days and 2 years after HCT | 
| Event-free survival |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft vs Host Disease, Peripheral Blood Stem Cell Transplantation, Cyclophsophamide, Anti-thymocyte globulin (rabbit)