HLA 10/10 Matched Unrelated Donor vs Haploidentical Allogenic Hematopoietic Stem Cell Transplantation

Study Overview
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Brief Summary
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The MAC-HAPLO-MUD trial is a randomized prospective phase III trial comparing HLA 10/10 matched unrelated donor and haploidentical allogeneic hematopoietic stem cell transplantation after myeloablative conditioning regimen in patients, age 15 years or older, with Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) or Myeloproliferative Syndrome (SMP) or Myelodysplastic Syndromes (SMD) and requiring allogeneic hematopoietic stem cell transplantation. Primary endpoint is the 1-year progression free survival without acute grade II-IV GvHD and without moderate and severe chronic GvHD.

Detailed Description
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An unrelated adult donor who is HLA-matched to the recipient at the allele-level (at HLA-A, -B, -C, -DQB1 and -DRB1) is considered the best choice in the absence of an HLA-matched sibling for patients needing hematopoietic stem cell transplantation (SCT). However, using matched unrelated donors (MUD) is limited by (1) a prolonged time to identify and schedule donation for some MUD allowing some patients to relapse before transplantation can be performed, and (2) limited availability of fully HLA-MUD for the non-Caucasian population. Alternative donors are used for transplantation in patients without a fully-MUD including single HLA mismatched unrelated donor, unrelated umbilical cord blood and grafts from haploidentical related donors but are associated with higher non-relapse mortality and delayed immune reconstitution. A more recent strategy for haploidentical (haplo) related donor SCT (haplo-SCT) has improved dramatically outcomes using T-cell replete grafts with administration of post-transplantation cyclophosphamide (PTCy). From retrospective studies, haplo-SCT with PTCy are associated with similar overall and progression-free survivals as with MUD stem cell transplantation (MUD-SCT), but with lower rates of toxicity and graft versus host disease (GvHD), and thus potentially better results than MUD-SCT after reduced intensity conditioning (RIC) regimen. Haplo-SCT with PTCy is thus highly discussed nowadays motivating prospective trials to confirm the benefit of this procedure. In the setting of a myeloablative conditioning (MAC) regimen in adults with high risk hematological malignancies, few retrospective non-controlled registry studies recently suggest that outcomes after haplo-SCT using PTCy approach might also be superior in terms of GVHD free survival to that after MUD stem cell transplantation (MUD-SCT). The investigators propose to address this question, in a randomized prospective phase III clinical trial comparing HLA 10/10 MUD and haplo-SCT after MAC regimen. The stem cell source will be bone marrow for haploidentical SCT and peripheral blood stem cell (PBSC) for HLA-matched unrelated transplantation. The primary endpoint is the 1-year progression free survival without acute grade II-IV GvHD and without moderate and severe chronic GvHD.

Official Title
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Randomized Prospective Phase III Clinical Trial Comparing HLA 10/10 Matched Unrelated Donor and Haploidentical Allogenic Hematopoietic Stem Cell Transplantation After Myeloablative Conditioning Regimen

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myeloproliferative Syndromes, Myelodysplastic Syndromes

Intervention / Treatment
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* Other: Haplo donor stem cell transplantation
* Other: HLA 10/10 MUD stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: With AML/ALL/SMD/SMP requiring allogeneic stem cell transplantation In complete response (CR) for AML/ALL or in CR, or partial response (PR) or non pre-treated for SMD/SMP * Without a HLA matched related donor available With a good probability to have a HLA-10/10 matched donor available (the patient needs to have at least 5 MUD identified within the book BMDW (Bone Marrow Donors Worldwide) With identification of a haploidentical donor (brother, sister, parents, adult children or cousin) Absence of donor specific antibody (DSA) detected in the patient with a MFI ≥ 2000 (antibodies directed towards the distinct haplotype between donor and recipient) With usual criteria for hematopoietic stem cell transplant (HSCT): Eastern Cooperative Oncology Group (ECOG) ≤ 2 No severe and uncontrolled infection Cardiac function compatible with high dose of cyclophosphamide Adequate organ function: aspartate transaminase (ASAT) and alanine aminotransferase (ALAT) ≤ 2N, total bilirubin ≤ 1.5N, creatinine clearance ≥30ml/min (except if those abnormalities are linked to the hematological disease) With health insurance coverage Understand informed consent or optimal treatment and follow-up Contraception methods must be prescribed during all the duration of the research and using effective contraceptive methods during treatment and within 12 months for women and 6 months for men after the last dose of cyclophosphamide Having signed a written informed consent (2 parents for patients aged less than 18) Exclusion Criteria: Presence of donor specific antibody (DSA) with a MFI ≥ 2000 detected in the patient History of Cancer in the last 5 years (except basal cell carcinoma of the skin or in situ carcinoma of the cervix) Uncontrolled infection Seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive polymerase chain reaction (PCR) hepatitis B virus (HBV) or hepatitis C virus (HCV) and hepatic cytolysis due to HBV Yellow fever vaccine within 2 months before transplantation Uncontrolled coronary insufficiency, recent myocardial infarction <6 month, current manifestations of heart failure, uncontrolled cardiac rhythm disorders, ventricular ejection fraction <50% Heart failure according to New York Heart Association (NYHA) (II or more) Urinary tract obstruction Contraindications to treatments used during the research Preexisting acute hemorrhagic cystitis Renal failure with creatinine clearance <30ml / min Pregnancy ( β- human chorionic gonadotropin (β-HCG positive)) or breast-feeding Any debilitating medical or psychiatric illness which would preclude the realization of the SCT or the understanding of the protocol Under protection by law (tutorship or curatorship) Unwilling or unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 55 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
Interventional Model Description: Randomized prospective Phase III clinical trial comparing HLA 10/10 matched unrelated donor (standard arm) and haploidentical allogeneic hematopoietic stem cell transplantation (experimental arm) after myeloablative conditioning regimen
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Haploidentical donor stem cell transplantation<br>The stem cell source will be bone marrow for haploidentical transplantation.The bone marrow collection is carried out according to the practice of each centre with a minimal target dose of 3x108 TNC/kg. | Other: Haplo donor stem cell transplantation<br>* The algorithm for selection of haploidentical donor has been defined by the french society for stem cell transplantation The stem cell source will be bone marrow for haploidentical transplantation.The bone marrow collection is carried out according to the practice of each centre with a minimal target dose of 3x108 TNC/kg.<br>|
| Active Comparator: HLA 10/10 MUD stem cell transplantation<br>The stem cell source will be peripheral blood stem cell for HLA-matched unrelated transplantation.Peripheral blood stem cell (PBSC) for HLA-matched unrelated SCT will be mobilized by G-CSF (Neupogen®) administered to the donor from Day-4 to Day-1 subcutaneously (10µg/kg/day) with the minimal target dose of 4.106 CD34+ cells/kg. | Other: HLA 10/10 MUD stem cell transplantation<br>* HLA 10/10 matched unrelated donor myeloablative transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival, without acute grade II-IV GvHD and without moderate and severe chronic GvHD. | One year progression free survival, without acute grade II-IV GvHD and without moderate and severe chronic GvHD. -Relapse evaluation: For myeloid malignancies, the relapse will be defined by the reappearance of leukemic cells after SCT. For ALL, the relapse will be defined by: the reappearance of leukemic cells after SCT and/or an increase of at least 50 % of the smallest measure of any lymphnode considered abnormal in the pre-transplantation period for patients in partial response and in non-responders and/or the appearance of any new lesion in comparison with the pre-transplantation period evaluation. - GvHD evaluation: Grading of acute GVHD will be performed according to the classification of Glusckberg. Grading of chronic GVHD will be performed according to the NIH classification. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life at 6 months: EORTC QLQ-C30- v3 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300. | 6 months | 
| Quality of life at 12 months: EORTC QLQ-C30- v3 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300. | 12 months | 
| Quality of life at 24 months: EORTC QLQ-C30- v3 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300. | 24 months | 
| Number of new days of hospitalization after the hospitalization for transplantation |  | at 24 months | 
| Time interval between indication of stem cell transplantation (SCT) and transplant |  | 24 months | 
| Engraftment | Engraftment: at least 3 consecutive days with neutrophils > 0.5 G/L, with platelets > 20 G/L | at 24 months | 
| Numbers of neutrophils | Absolute numbers of neutrophils | at 1 month | 
| Numbers of platelets | Absolute numbers of platelets | at 1 month | 
| Numbers of neutrophils | Absolute numbers of neutrophils | at 2 months | 
| Numbers of platelets | Absolute numbers of platelets | at 2 months | 
| Numbers of neutrophils | Absolute numbers of neutrophils | at 3 months | 
| Numbers of platelets | Absolute numbers of platelets | at 3 months | 
| Numbers of neutrophils | Absolute numbers of neutrophils | at 6 months | 
| Numbers of platelets | Absolute numbers of platelets | at 6 months | 
| Numbers of neutrophils | Absolute numbers of neutrophils | at 12 months | 
| Numbers of platelets | Absolute numbers of platelets | at 12 months | 
| Numbers of neutrophils | Absolute numbers of neutrophils | at 24 months | 
| Numbers of platelets | Absolute numbers of platelets | at 24 months | 
| Use of growth factors | Use of growth factors for poor hematopoietic reconstitution | at 12 months | 
| Immune reconstitution | Immune reconstitution by analyzing T, B, Natural Killer (NK), regulatory T cell levels in the peripheral blood | at 1 month post transplantation | 
| Immune reconstitution | Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 3 months post transplantation | 
| Immune reconstitution | Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 6 months post transplantation | 
| Immune reconstitution | Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 12 months post transplantation | 
| Immune reconstitution | Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 24 months post transplantation | 
| Iron overload estimation |  | at 1 month | 
| Iron overload estimation |  | at 3 months | 
| Iron overload estimation |  | at 6 months | 
| Iron overload estimation |  | at 12 months | 
| Iron overload estimation |  | at 24 months | 
| Chimerism |  | at 1 month | 
| Chimerism |  | at 3 months | 
| Chimerism |  | at 6 months | 
| Chimerism |  | at 12 months | 
| Acute GvHD | Incidence of acute GvHD | at 24 months | 
| First line treatment |  | 24 months | 
| Response to steroids |  | 24 months | 
| Treatment courses for refractory aGVHD |  | 24 months | 
| Relapse | Incidence of relapse | 24 months | 
| Progression free survival |  | 24 months | 
| Severe infections (CTAE grade 3-4) |  | 12 months | 
| Cytomegalovirus (CMV) | Incidence of CMV | 12 months | 
| Epstein-Barr virus (EBV) | Incidence of EBV reactivation | 12 months | 
| Veno-occlusive disease (VOD) | Incidence of veno-occlusive disease | 3 months | 
| Severity of veno-occlusive disease (VOD) | Severity of veno-occlusive disease. VOD severity will be assessed using new EBMT criteria (Mohty et al., 2016). EBMT criteria for grading VOD severity in adult patients are based on the level of bilirubin and its rate of change, liver function (transaminase), weight increase, renal function and the kinetic of their onset (Mohty et al., 2016). This grading system is divided into five categories as following: mild, moderate; severe, very severe; and death. Mohty M., Malard F., Abecassis M., Aerts E., Alaskar AS. et al. (2016). Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplantation 51,906-912. | 3 months | 
| Cardiac toxicities | Incidence of cardiac toxicities | 12 months | 
| Non-relapse mortality |  | 12 months | 
| Overall survival | Time between death and inclusion | 24 months | 
| Quality of life post transplantation: EORTC QLQ-C30- v3 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300. | 1 week post-transplantation | 
| Quality of life at 3 months: EORTC QLQ-C30- v3 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30- v3). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. EORTC QLQ-C30 Scoring Manual. Fayers PM et al. on behalf of the EORTC Quality of Life Group. EORTC, 2001. ISBN: 2-9300. | 3 months |