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

Acute Myeloid Leukemia Clinical Trial

— MacHaploMud  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03655145
• Other study ID #: AOM 17030
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: August 2018
• Est. completion date: June 2023

Study information

• Verified date: May 2018
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Régis Peffault de Latour
• Phone: +33142385073
• Email: regis.peffaultdelatour[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 344
• Est. completion date: June 2023
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 55 Years

Eligibility

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 ( ß- human chorionic gonadotropin (ß-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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Myeloproliferative Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Syndrome

Intervention

Other:
• Haplo donor stem cell transplantation
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.
• HLA 10/10 MUD stem cell transplantation
HLA 10/10 matched unrelated donor myeloablative transplantation

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Time interval between indication of stem cell transplantation (SCT) and transplant		24 months
Secondary	Engraftment	Engraftment: at least 3 consecutive days with neutrophils > 0.5 G/L, with platelets > 20 G/L	at 24 months
Secondary	Numbers of neutrophils	Absolute numbers of neutrophils	at 1 month
Secondary	Numbers of platelets	Absolute numbers of platelets	at 1 month
Secondary	Numbers of neutrophils	Absolute numbers of neutrophils	at 2 months
Secondary	Numbers of platelets	Absolute numbers of platelets	at 2 months
Secondary	Numbers of neutrophils	Absolute numbers of neutrophils	at 3 months
Secondary	Numbers of platelets	Absolute numbers of platelets	at 3 months
Secondary	Numbers of neutrophils	Absolute numbers of neutrophils	at 6 months
Secondary	Numbers of platelets	Absolute numbers of platelets	at 6 months
Secondary	Numbers of neutrophils	Absolute numbers of neutrophils	at 12 months
Secondary	Numbers of platelets	Absolute numbers of platelets	at 12 months
Secondary	Numbers of neutrophils	Absolute numbers of neutrophils	at 24 months
Secondary	Numbers of platelets	Absolute numbers of platelets	at 24 months
Secondary	Use of growth factors	Use of growth factors for poor hematopoietic reconstitution	at 12 months
Secondary	Immune reconstitution	Immune reconstitution by analyzing T, B, Natural Killer (NK), regulatory T cell levels in the peripheral blood	at 1 month post transplantation
Secondary	Immune reconstitution	Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood	at 3 months post transplantation
Secondary	Immune reconstitution	Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood	at 6 months post transplantation
Secondary	Immune reconstitution	Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood	at 12 months post transplantation
Secondary	Immune reconstitution	Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood	at 24 months post transplantation
Secondary	Iron overload estimation		at 1 month
Secondary	Iron overload estimation		at 3 months
Secondary	Iron overload estimation		at 6 months
Secondary	Iron overload estimation		at 12 months
Secondary	Iron overload estimation		at 24 months
Secondary	Chimerism		at 1 month
Secondary	Chimerism		at 3 months
Secondary	Chimerism		at 6 months
Secondary	Chimerism		at 12 months
Secondary	Acute GvHD	Incidence of acute GvHD	at 24 months
Secondary	First line treatment		24 months
Secondary	Response to steroids		24 months
Secondary	Treatment courses for refractory aGVHD		24 months
Secondary	Relapse	Incidence of relapse	24 months
Secondary	Progression free survival		24 months
Secondary	Severe infections (CTAE grade 3-4)		12 months
Secondary	Cytomegalovirus (CMV)	Incidence of CMV	12 months
Secondary	Epstein-Barr virus (EBV)	Incidence of EBV reactivation	12 months
Secondary	Veno-occlusive disease (VOD)	Incidence of veno-occlusive disease	3 months
Secondary	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
Secondary	Cardiac toxicities	Incidence of cardiac toxicities	12 months
Secondary	Non-relapse mortality		12 months
Secondary	Overall survival	Time between death and inclusion	24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of new days of hospitalization after the hospitalization for transplantation		at 24 months