Reduced Intensity (RIC) Conditioning And Transplantation of HLA-Haplo-HCT

Study Overview
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Brief Summary
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This is a single institution phase II study of a reduced intensity conditioning (RIC) followed by a haploidentical hematopoietic cell transplant (haplo-HCT) in persons with diagnosis of hematologic malignancy. Conditioning will consists of fludarabine, cyclophosphamide, melphalan and total body irradiation (TBI) preparative regimen with a melphalan dose reduction for patients ≥55 years old and those with HCT Comorbidity Index (CI) >3. This study uses a two-stage phase II design with accrual goal of 84 patients, using 28 patients separately for arms A, C and D

Official Title
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Reduced Intensity (RIC) Conditioning And Transplantation of HLA-Haploidentical Related Hematopoietic Cells (Haplo-HCT) For Patients With Hematologic Malignancies

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Biological: Haplo HCT <55 years old
* Biological: Haplo HCT ≥55 years old
* Drug: GVHD Prophylaxis
* Biological: Haplo HCT ≥55 and < 65 years old
* Biological: Haplo HCT ≥65 and ≤75 years old


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Karnofsky performance status of ≥70% or Lansky play score ≥ 70% A related haploidentical bone marrow donor with up to 2 or 3 HLA locus-mismatches The donor and recipient must be HLA identical for at least one haplotype (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Adequate liver and renal function Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction ≥ 40% Diffusion capacity corrected (DLCOcorr) > 40% predicted, and absence of O2 requirements > 6 months after prior autologous transplant (if applicable) Agrees to use contraception during study treatment Voluntary written consent (adult or parent/guardian with presentation of the minor information sheet, if appropriate) Patients who are HIV+ must have undetectable viral load. All HIV+ patients must be evaluated by Infectious Disease (ID) and a HIV management plan establish prior to transplantation Exclusion Criteria: < 70 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor Pregnancy or breastfeeding Current active and uncontrolled serious infection Acute leukemia in morphologic relapse/persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers (e.g. Auer rods). CML in blast crisis Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on salvage therapy. stable non-bulky disease is acceptable. Active central nervous system malignancy Criteria For Donor Selection: Donors must be HLA-haploidentical relatives of the patient, defined as having a shared HLA haplotype between donor and patient at HLA-A, -B, -C, and -DRB1. Eligible donors (14-70 years old) include biological children, siblings or half siblings, or parents, able and willing to undergo bone marrow harvesting. For donors <18 years, the maximum recipient weight (actual body weight) should not exceed 1.25 times the donor weight (actual body weight)1 In addition, bone marrow product volume should be limited to 20 ml/kg donor weight for donors <18 years.

Ages Eligible for Study
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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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Haplo-HCT <55 years old<br>Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients <55 years old with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≤2 | Biological: Haplo HCT <55 years old<br>* Fludarabine (Flu) Cyclophosphamide (Cy) Melphalan (Mel) Total body irradiation (TBI) Non-T-cell depleted donor bone marrow stem cell infusion Day 0<br>* Other names: HLA-haploidentical related hematopoietic cells transplant;Drug: GVHD Prophylaxis<br>* Cyclophosphamide (Cy) Tacrolimus (Tac) Mycophenolate mofetil (MMF)<br>|
| Experimental: CLOSED Arm B: Haplo-HCT ≥55 years old<br>Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients ≥55 years old or younger with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≥3. | Biological: Haplo HCT ≥55 years old<br>* Fludarabine (Flu) Cyclophosphamide (Cy) Melphalan (Mel): Dose reduction by 30% Total body irradiation (TBI) Non-T-cell depleted donor bone marrow stem cell infusion<br>* Other names: HLA-haploidentical related hematopoietic cells transplant;Drug: GVHD Prophylaxis<br>* Cyclophosphamide (Cy) Tacrolimus (Tac) Mycophenolate mofetil (MMF)<br>|
| Experimental: Arm C: Haplo-HCT HCT-CI ≤2 aged ≥55 and < 65yo<br>Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≤2 aged ≥55 and < 65 years old. | Drug: GVHD Prophylaxis<br>* Cyclophosphamide (Cy) Tacrolimus (Tac) Mycophenolate mofetil (MMF)<br>Biological: Haplo HCT ≥55 and < 65 years old<br>* Fludarabine (Flu) Cyclophosphamide (Cy) Melphalan (Mel) Total body irradiation (TBI) non-T-cell depleted donor bone marrow stem cells<br>* Other names: HLA-haploidentical related hematopoietic cells transplant;|
| Experimental: Arm D: Haplo-HCT aged ≥65 and ≤75yo OR any age HCT-CI ≥3<br>Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients patients ≥65 and ≤75 years old OR any age group with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≥3. | Drug: GVHD Prophylaxis<br>* Cyclophosphamide (Cy) Tacrolimus (Tac) Mycophenolate mofetil (MMF)<br>Biological: Haplo HCT ≥65 and ≤75 years old<br>* Fludarabine (Flu) Cyclophosphamide (Cy) Total body irradiation (TBI)<br>* Other names: HLA-haploidentical related hematopoietic cells transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) | estimate disease-free survival (DFS) at 1 year post-transplant | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade II-IV and grade III-IV acute graft versus-host-disease (GVHD) |  | day 100 | 
| Treatment related mortality (TRM) |  | 6 month, 1 and 2 year | 
| Relapse incidence |  | 1 and 2 year | 
| Incidence of serious fungal and viral infection | post-HCT | at day 100 and 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Leukemias, Acute myeloid leukemia (AML), Acute lymphoblastic leukemia (ALL)/lymphoma, Biphenotypic/Undifferentiated/Prolymphocytic Leukemias, Myelodysplastic syndrome, Chronic myelogenous leukemia, Minimal Residual Disease (MRD) positive leukemia, Leukemia or Myelodysplastic Syndromes (MDS) in aplasia, Myeloproliferative neoplasms/myelofibrosis, Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma, Burkitt's lymphoma, Relapsed T-cell lymphoma, Natural Killer cell malignancies, Relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, Lymphoplasmacytic lymphoma, Relapsed multiple myeloma, Bone marrow failure syndromes