Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donor After Flu-Mel-PTCy Versus Flu-Mel-ATG Reduced-intensity Conditioning

Study Overview
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Brief Summary
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The present project aims at comparing two conditioning regimens (FM-PTCy vs FM-ATG). The hypothesis is that one or the two regimens will lead to a 2-year cGRFS rate improvement from 30% (the cGRFS rate with FM without ATG/PTCy) to 45% (Pick-a-winner phase 2 randomized study).

Detailed Description
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This study is a multicenter, randomized, open-label, phase II study pick-a-winner study, comparing 2 conditioning regimens. A total of 114 eligible patients with HLA-matched donors will be randomized 1:1 between the FM-PTCy arm and the FM-ATG arm, with stratification for donor type (related or unrelated). The recruitment period is 3 years with a 5-year follow-up plus a 10-year additional long-term follow-up (for GVHD status, disease status, second malignancy and QOL). The whole study will be completed within 18 years.

Official Title
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Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donor After Flu-Mel-PTCy Versus Flu-Mel-ATG Reduced-intensity Conditioning: a Phase II Randomized Study From the Belgian Hematology Society (BHS)

Conditions
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Acute Myeloid Leukemia in Remission, Myelodysplastic Syndromes, Chronic Myeloid Leukemia in Remission, Myeloproliferative Syndrome, Myeloproliferative Disorder, Acute Lymphoid Leukemia in Remission, Multiple Myeloma, Chronic Lymphoid Leukemia, Non Hodgkin Lymphoma, Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Thymoglobulin
* Drug: Melphalan
* Drug: Fludarabine
* Drug: Cyclophosphamid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients V.1.1. Diseases Hematological malignancies confirmed histologically: AML in morphological CR or not in morphological CR but not rapidly progressing (i.e. no need to give treatments such as hydroxyurea to maintain WBC count < 10 000 x109/mL); MDS; CML in CP or AP; MPD not in blast crisis, MDS/MPD overlap, ALL in CR; Multiple myeloma; CLL; Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease); Hodgkin's disease with chemosensitive disease or responding to checkpoint inhibitors. * Clinical situations • Theoretical indication for a standard allo-transplant, but not feasible because: Age > 50 yrs; Unacceptable end organ performance; The physician's decision; The patient's decision Underlying 'lower risk' disease, for which Reduced Intensity Conditioning is preferred (eg CLL, MCL) * Other inclusion criteria Male or female; fertile patients must use a reliable contraception method; Age 18-75 yrs (children of any age are not allowed in the protocol); Informed consent given by patient or his/her guardian if indicated. Donors Male or female; Any age; Human Leukocyte Antigen (HLA)-identical sibling donor or 10 of 10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele matched unrelated donor; Weight > 15 Kg (because of leukapheresis); Fulfills criteria for allogeneic Peripheral Blood Stem Cell (PBSC) donation according to standard procedures; Informed consent given by donor or his/her guardian if indicated, as per donor center standard procedures. Exclusion Criteria: Patients Any condition not fulfilling inclusion criteria; Human Immunodeficiency Virus positive; Non-hematological malignancy(ies) (except non-melanoma skin cancer) active < 3 years before Hematopoietic Cell Transplantation (HCT). Life expectancy severely limited by disease other than malignancy; Central Nervous System involvement with disease refractory to intrathecal chemotherapy. Terminal organ failure, except for renal failure (dialysis acceptable) Cardiac: Symptomatic coronary artery disease; ejection fraction <40%; uncontrolled arrhythmia, uncontrolled hypertension; Pulmonary: Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)< 40% and/or receiving supplementary continuous oxygen, Forced Expiratory Volume in 1 Second (FEV1)< 40%; Hepatic: Fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin >3 mg/dL, and symptomatic biliary disease; Uncontrolled infection; Karnofsky Performance Score <70%; Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment; Patient is a female who is pregnant or breastfeeding; Any condition precluding the use of melphalan or Thymoglobulin; Donors Any condition not fulfilling inclusion criteria; Unable to undergo leukapheresis because of poor vein access or other reasons.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine-Melphalan-Cyclophosphamide<br>FM-PTCy conditioning will consist in IV fludarabine 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2), melphalan given at the dose of 100 mg/m2 on day -2, and cyclophosphamide 50 mg/kg on days +3 and +4. | Drug: Melphalan<br>* 100mg/m² on day -2<br>* Other names: alkeran;Drug: Fludarabine<br>* 30mg/m² on days -6, -5, -4, -3, and -2<br>Drug: Cyclophosphamid<br>* 50 mg/kg on days +3 and +4.<br>* Other names: PTCy;|
| Experimental: Fludarabine-Melphalan-thymoglobulin<br>FM-ATG conditioning will consist in IV fludarabine 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2), melphalan given at the dose of 100 mg/m2 on day -2, and ATG (Thymoglobulin®, Genzyme), at a dose of 2.5 mg/kg/d on days -2 and -1. | Drug: Thymoglobulin<br>* ATG: 2.5 mg /kg/day on day -2 and -1 (day 0 is allogenic transplantation)<br>* Other names: ATG;Drug: Melphalan<br>* 100mg/m² on day -2<br>* Other names: alkeran;Drug: Fludarabine<br>* 30mg/m² on days -6, -5, -4, -3, and -2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Current GVHD-free, relapse-free survival (cGRFS) | To assess the current GVHD-free, relapse-free survival (cGRFS) for patients in the 2 arms | 15 years (the primary endpoint will be first assessed after 191 events have been reached) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cGRFS according donor | To assess cGRFS for patients conditioned with FM-PTCy or FM-ATG separately in those transplanted with a related or an unrelated donor | 15 years | 
| Relapse/progression rate | To assess the relapse/progression rate for patients conditioned with FM-PTCy or FM-ATG | 15 years | 
| Rate aGVHD | To assess rate of grade II-IV and III-IV acute GVHD (Graft-versus-host disease) in patients conditioned with FM or FM-ATG. | 6 months | 
| Rate cGVHD | To assess rate of grade of moderate-severe chronic GVHD in patients conditioned with FM or FM-ATG. | 24 months | 
| Rate of Nonrelapse Mortality (NRM) | To assess rate of Nonrelapse Mortality in patients conditioned with FM-PTCy or FM-ATG. | 15 years | 
| Rate of Leukemia Free Survival (LFS) | To assess rate of Leukemia Free Survival in patients conditioned with FM-PTCy or FM-ATG. | 15 years | 
| Rate of Overall Survival (OS) | To assess rate of Overall Survival in patients conditioned with FM-PTCy or FM-ATG. | 15 years | 
| Proportion of patients alive | To assess the proportion of patients alive without active disease and without systemic immunosuppression | 15 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematological malignancies, Graft versus host disease, GVHD, Progression free survival, Allogeneic hematopoeitic cell transplantation, HLA-matched donor, reduced intensity conditioning, Overall survival, ATG PK, Immunosuppressive regimen, Prophylaxis