A Study Comparing Haploidentical Hematopoietic Stem Cell Transplantations (HSCTs) From Young Non-first-degree and Older First-degree Donors in Hematological Malignancies

Study Overview
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Brief Summary
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An open, multi-center, randomized trial comparing haploidentical HSCTs from young non-first-degree and older first-degree donors in hematological malignancies

Detailed Description
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This is an open, multi-center, randomized trial comparing the clinical outcomes of haploidentical HSCTs from young non-first-degree and older first-degree donors in hematological malignancies. This study is indicated for patients with hematological malignancies including ALL, AML, MDS and NHL who are eligible to haploidentical HSCTs. 2 groups of patients will be enrolled with 80 in each group. The clinical criteria including survival, relapse, transplantation-related mortality will be monitored.

Official Title
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An Open, Multi-center, Randomized Trial Comparing Haploidentical HSCTs From Young Non-first-degree and Older First-degree Donors in Hematological Malignancies

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Me-CCNU
* Drug: Rabbit antithymocyte globulin
* Procedure: Allogeneic HSCT
* Drug: Cyclosporin A
* Drug: Mycophenolate Mofetil
* Drug: MTX


Participation Criteria
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Eligibility Criteria
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Patient Inclusion Criteria: Patient age 14-60 years Absence of a suitable HLA identical related or unrelated hematopoietic stem cell donor Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor aged between 18 and 50 Presence of both HLA haploidentical young non-first-degree (age ≤ 40) and older first-degree (age >50) donors Eligible diagnoses: AML（excluding APL） with at least one of the following: median- or high- risk according to the WHO prognostic stratification system failure to achieve CR after 2 cycles of induction chemotherapy AML arising from MDS or a myeloproliferative disorder, or secondary AML patients in CR2 or beyond, with <5% bone marrow blasts before HSCT ALL in remission, defined as <5% bone marrow blasts morphologically MDS with at least one of the following: IPSS score of INT-2 or greater IPSS score of INT-1 with life-threatening cytopenias, including those generally requiring greater than weekly transfusions NHLs (including diffuse large B-cell lymphoma, lymphoblastic lymphoma, Burkitt lymphoma, peripheral T-cell lymphoma, and NK or NK-T cell lymphoma) which are relapsed/refractory OR in CR2 or beyond Adequate end-organ function ECOG performance status < 2 No other contraindications for HSCT Signature of the informed consent Patient Exclusion Criteria: Availability of suitable HLA identical related or unrelated hematopoietic stem cell donors Availability of suitable partially HLA-mismatched (haploidentical), first-degree related donor aged between 18 and 50 Presence of uncontrolled bacterial, viral, or fungal infection Patients with severe heart, lung, liver and kidney insufficiency HIV-positive patients Women of childbearing potential who are pregnant (β-HCG+) or breast feeding Patients with a psychiatric history ECOG performance status ≥ 3 Patients with malignancies other than the primary disease Refusal to sign the informed consent Donor Inclusion Criteria: The donor and recipient must be HLA haploidentical Meets institutional selection criteria and medically fit to donate Lack of recipient anti-donor HLA antibody Donor Exclusion Criteria: The donor and recipient are HLA identical Has not donated blood products to recipient

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 60 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 |
| --- | --- |
| Active Comparator: Non-first-degree donor<br>Each patient receive graft from a non-first degree donor aged ≤40 | Drug: Cytarabine<br>* 4 mg/m2/day administered IV day -10 through -9.<br>Drug: Busulfan<br>* 3.2 mg/kg/day administered IV day -8 through -6.<br>Drug: Cyclophosphamide<br>* 1.8 g/m2/day administered IV day -5 through -4.<br>Drug: Me-CCNU<br>* 250mg/m2 once administered orally on day -3.<br>Drug: Rabbit antithymocyte globulin<br>* 1.5mg/kg/day administered IV day -5 through -2.<br>Procedure: Allogeneic HSCT<br>* Day 0<br>Drug: Cyclosporin A<br>* 2.5 mg/kg/day administered intravenously from day -7, target: 200-300ng/mL. Usually tapered during the second month, and ended in complete withdrawal during the ninth month after transplantation.<br>Drug: Mycophenolate Mofetil<br>* 500 mg/day administered intravenously from day -9, ended in complete withdrawal on day +100.<br>Drug: MTX<br>* 15 mg/m2 administered intravenously on day +1, 10mg/m2 on day +3, +6, and +9.<br>|
| Active Comparator: First-degree donor<br>Each patients receive graft from a first-degree donor aged >50 | Drug: Cytarabine<br>* 4 mg/m2/day administered IV day -10 through -9.<br>Drug: Busulfan<br>* 3.2 mg/kg/day administered IV day -8 through -6.<br>Drug: Cyclophosphamide<br>* 1.8 g/m2/day administered IV day -5 through -4.<br>Drug: Me-CCNU<br>* 250mg/m2 once administered orally on day -3.<br>Drug: Rabbit antithymocyte globulin<br>* 1.5mg/kg/day administered IV day -5 through -2.<br>Procedure: Allogeneic HSCT<br>* Day 0<br>Drug: Cyclosporin A<br>* 2.5 mg/kg/day administered intravenously from day -7, target: 200-300ng/mL. Usually tapered during the second month, and ended in complete withdrawal during the ninth month after transplantation.<br>Drug: Mycophenolate Mofetil<br>* 500 mg/day administered intravenously from day -9, ended in complete withdrawal on day +100.<br>Drug: MTX<br>* 15 mg/m2 administered intravenously on day +1, 10mg/m2 on day +3, +6, and +9.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of transplant-related nonrelapse mortality (NRM) | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. | 2 years | 
| Progression-free survival (PFS) | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. | 2 years | 
| Cumulative incidence of disease relapse or progression | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. | 2 years | 
| GVHD-free, relapse-free survival (GRFS) | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. GRFS is defined as survival with no evidence of relapse/progression, grade III to IV aGVHD, and systemic therapy-requiring cGVHD. | 2 years | 
| Cumulative incidence of acute grade II-IV GVHD | Date of symptom onset, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher acute GVHD and grade III-IV acute GVHD will be recorded. | 2 years | 
| Cumulative incidence of chronic GVHD | Date of symptom onset, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of chronic GVHD and severe chronic GVHD will be recorded. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematopoietic stem cell transplantation