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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Haploidentical donor stem cell transplantation | Experimental | 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. |
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| HLA 10/10 MUD stem cell transplantation | Active Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Haplo donor stem cell transplantation | Other | 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. |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
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)
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Régis Peffault de Latour | Contact | +33142385073 | regis.peffaultdelatour@aphp.fr | |
| Sylvie Chevret | Contact | +33142499742 | sylvie.chevret@paris7.jussieu.fr |
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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
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|
| HLA 10/10 MUD stem cell transplantation | Other | HLA 10/10 matched unrelated donor myeloablative transplantation |
|
| 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 |
| 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 |
| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| D009190 | Myelodysplastic Syndromes |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007945 | Leukemia, Lymphoid |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D001855 | Bone Marrow Diseases |
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