Clinical trial NCT03655145: HLA 10/10 Matched Unrelated Donor vs Haploidentical Allogenic Hematopoietic Stem Cell Transplantation
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Myeloproliferative Syndromes
Myelodysplastic Syndromes
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-08-31
Enrollment: 344
Sex: ALL
Minimum age (years): 15
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression free survival, without acute grade II-IV GvHD and without moderate and severe chronic GvHD.
timeFrame: 12 months
Secondary outcomes:
measure: Time interval between indication of stem cell transplantation (SCT) and transplant
timeFrame: 24 months
measure: Engraftment
timeFrame: at 24 months
measure: Numbers of neutrophils
timeFrame: at 1 month
measure: Numbers of platelets
timeFrame: at 1 month
measure: Numbers of neutrophils
timeFrame: at 2 months
measure: Numbers of platelets
timeFrame: at 2 months
measure: Numbers of neutrophils
timeFrame: at 3 months
measure: Numbers of platelets
timeFrame: at 3 months
measure: Numbers of neutrophils
timeFrame: at 6 months
measure: Numbers of platelets
timeFrame: at 6 months
measure: Numbers of neutrophils
timeFrame: at 12 months
measure: Numbers of platelets
timeFrame: at 12 months
measure: Numbers of neutrophils
timeFrame: at 24 months
measure: Numbers of platelets
timeFrame: at 24 months
measure: Use of growth factors
timeFrame: at 12 months
measure: Immune reconstitution
timeFrame: at 1 month post transplantation
measure: Immune reconstitution
timeFrame: at 3 months post transplantation
measure: Immune reconstitution
timeFrame: at 6 months post transplantation
measure: Immune reconstitution
timeFrame: at 12 months post transplantation
measure: Immune reconstitution
timeFrame: at 24 months post transplantation
measure: Iron overload estimation
timeFrame: at 1 month
measure: Iron overload estimation
timeFrame: at 3 months
measure: Iron overload estimation
timeFrame: at 6 months
measure: Iron overload estimation
timeFrame: at 12 months
measure: Iron overload estimation
timeFrame: at 24 months
measure: Chimerism
timeFrame: at 1 month
measure: Chimerism
timeFrame: at 3 months
measure: Chimerism
timeFrame: at 6 months
measure: Chimerism
timeFrame: at 12 months
measure: Acute GvHD
timeFrame: at 24 months
measure: First line treatment
timeFrame: 24 months
measure: Response to steroids
timeFrame: 24 months
measure: Treatment courses for refractory aGVHD
timeFrame: 24 months
measure: Relapse
timeFrame: 24 months
measure: Progression free survival
timeFrame: 24 months
measure: Severe infections (CTAE grade 3-4)
timeFrame: 12 months
measure: Cytomegalovirus (CMV)
timeFrame: 12 months
measure: Epstein-Barr virus (EBV)
timeFrame: 12 months
measure: Veno-occlusive disease (VOD)
timeFrame: 3 months
measure: Severity of veno-occlusive disease (VOD)
timeFrame: 3 months
measure: Cardiac toxicities
timeFrame: 12 months
measure: Non-relapse mortality
timeFrame: 12 months
measure: Overall survival
timeFrame: 24 months
measure: Quality of life post transplantation: EORTC QLQ-C30- v3
timeFrame: 1 week post-transplantation
measure: Quality of life at 3 months: EORTC QLQ-C30- v3
timeFrame: 3 months
measure: Quality of life at 6 months: EORTC QLQ-C30- v3
timeFrame: 6 months
measure: Quality of life at 12 months: EORTC QLQ-C30- v3
timeFrame: 12 months
measure: Quality of life at 24 months: EORTC QLQ-C30- v3
timeFrame: 24 months
measure: Number of new days of hospitalization after the hospitalization for transplantation
timeFrame: at 24 months
Other outcomes:
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