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

Assistance Publique - Hôpitaux de Paris

Status and phase: Unknown; Phase 3

Conditions: Myeloproliferative Syndromes; Acute Lymphoblastic Leukemia; Myelodysplastic Syndromes; Acute Myeloid Leukemia

Treatments: Other: HLA 10/10 MUD stem cell transplantation; Other: Haplo donor stem cell transplantation

Study type: Interventional

Funder types: Other

Identifiers

NCT03655145

AOM 17030

Details and patient eligibility

About

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.

Full 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.

Enrollment: 344 estimated patients

Sex: All

Ages: 15 to 55 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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344 participants in 2 patient groups

Haploidentical donor stem cell transplantation

Experimental group

Description:

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.

Treatment:

Other: Haplo donor stem cell transplantation

HLA 10/10 MUD stem cell transplantation

Active Comparator group

Description:

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.

Treatment:

Other: HLA 10/10 MUD stem cell transplantation