Randomized Prospective Phase III Clinical Trial Comparing HLA 10/10 Matched Unrelated Donor and Haploidentical Allogenic Hematopoietic Stem Cell Transplantation After Myeloablative Conditioning Regimen
试验速览
- 阶段
- 3 期
- 入组人数
- 344
- 主要终点
- Progression free survival, without acute grade II-IV GvHD and without moderate and severe chronic GvHD.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 15 Years 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
Haploidentical donor 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.
干预措施: Haplo donor stem cell transplantation (Other)
HLA 10/10 MUD stem cell transplantation
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.
干预措施: HLA 10/10 MUD stem cell transplantation (Other)
结局指标
主要结局
Progression free survival, without acute grade II-IV GvHD and without moderate and severe chronic GvHD.
时间窗: 12 months
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.
次要结局
- Acute GvHD(at 24 months)
- First line treatment(24 months)
- Epstein-Barr virus (EBV)(12 months)
- Veno-occlusive disease (VOD)(3 months)
- Numbers of neutrophils(at 24 months)
- Numbers of platelets(at 24 months)
- Use of growth factors(at 12 months)
- Immune reconstitution(at 24 months post transplantation)
- Time interval between indication of stem cell transplantation (SCT) and transplant(24 months)
- Engraftment(at 24 months)
- Iron overload estimation(at 24 months)
- Chimerism(at 12 months)
- Relapse(24 months)
- Progression free survival(24 months)
- Severe infections (CTAE grade 3-4)(12 months)
- Cytomegalovirus (CMV)(12 months)
- Response to steroids(24 months)
- Treatment courses for refractory aGVHD(24 months)
- Severity of veno-occlusive disease (VOD)(3 months)
- Cardiac toxicities(12 months)
- Non-relapse mortality(12 months)
- Overall survival(24 months)
- Quality of life post transplantation: EORTC QLQ-C30- v3(1 week post-transplantation)
- Quality of life at 3 months: EORTC QLQ-C30- v3(3 months)
- Quality of life at 6 months: EORTC QLQ-C30- v3(6 months)
- Quality of life at 12 months: EORTC QLQ-C30- v3(12 months)
- Quality of life at 24 months: EORTC QLQ-C30- v3(24 months)
- Number of new days of hospitalization after the hospitalization for transplantation(at 24 months)