Clinical trial NCT06646497: Indication of HSCT in Patients With Refractory/Relapse AA After First-line Standard Immunosuppressive Therapy Aged More Than 40 Years
Official title: Evaluation of an Optimized Allogeneic Hematopoietic Stem Cell Transplantation Protocol With Post-transplant Cyclophosphamide in Patients Aged 40 to 60 Years Old With Acquired Aplastic Anemia Refractory or in Relapse After Immunosuppression
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Aplastic Anemia
Keywords: Refractory/relapse idiopathic anemia
Idiopathic aplastic anemia
Hematopoietic stem cell transplantation
Post-transplantation cyclophosphamide
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-10-17
Enrollment: 52
Sex: ALL
Minimum age (years): 40
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A phase II multicenter, national, prospective, single-arm trial
Primary purpose: TREATMENT

Brief summary: Outcomes for adult patients with Severe Aplastic Anemia (SAA) aged more than 40 years who are refractory or in relapse after first-line IST remain poor. Hematopoietic stem cell transplantation (HSCT) is the unic valid therapeutic option but results have always been disappointing in patients aged 40 years or older. The first cause of death after HSCT in those refractory/relapse SAA patients is still graft versus host disease (GvHD). Recently, new strategies to prevent GvHD, including T-cell replete grafts with administration of post-transplantation cyclophosphamide (PTCy), have revolutionized the field, notably in haplo-identical donor setting. Using marrow as source of stem cells and a PTCy strategy not only in haplo-identical donor setting but also in case of an available matched sibling or unrelated donor might prevent drastically GvHD and eventually be practice changing. Evaluating this new strategy is the main objectives of "APARR".


Eligibility criteria: Inclusion Criteria:

* Aged from 40 to 60 years old
* Suffering from acquired refractory severe idiopathic aplastic anemia after at least 6 months treatment with anti-thymocyte globulin, cyclosporine with Eltrombopag or in relapse
* Allograft validated in the National Multidisciplinary expertise meetings of the French reference centre for aplastic anemia
* With an available geno-identical donor or 10/10 matched donor or haploidentical donor
* With the absence of donor specific antibody detected in the patient with a MFI \< 1500 (antibodies to the distinct haplotype between donor and recipient)
* Usual criteria for HSCT:

  * ECOG ≤ 2
  * No severe and uncontrolled infection
  * Cardiac function compatible with high dose of cyclophosphamide
  * With an adequate organ function ASAT and ALAT ≤ 3N, conjugated bilirubin ≤ 2N (or total bilirubin ≤ 2N if not available), clearance creatinine ≥ 50ml / min
* With health insurance coverage
* Women of childbearing potential and men must use contraceptive methods during their participation to the research and for 12 months and 6 months after the last dose of cyclophosphamide, respectively.
* Having signed a written informed consent

NB: The authorized contraceptive methods are: For women of childbearing age and in absence of permanent sterilization:

* oral, intravaginal or transdermal combined hormonal contraception,
* oral, injectable or transdermal progestogen-only hormonal contraception,
* intrauterine hormonal-releasing system (IUS),
* sexual abstinence (need to be evaluated in relation to the duration of clinical trial and the preferred and usual lifestyle of the participants).

For men in absence of permanent sterilization: sexual abstinence, condoms.

Individuals must meet all of the inclusion criteria as verified at the screening / inclusion visit to be eligible to participate at the study.

Exclusion Criteria:

Patients:

* With morphologic evidence of clonal evolution (patients with isolated bone marrow cytogenetic abnormalities are also eligible excepted chromosome 7 abnormalities and complex karyotype).
* With seropositivity for HIV or HTLV-1-2 or active hepatitis B or C and associated hepatic cytolysis
* Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)
* Pregnant (βHCG positive) or breast-feeding
* Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation and during the research
* With uncontrolled coronary insufficiency, recent myocardial infarction \< 6-month, current manifestations of heart failure according to NYHA (II or more), ventricular ejection fraction \<50%
* With renal failure with creatinine clearance \<50ml /min
* Any contraindication mentioned in the SmPC and the Investigator's brochure of all medicinal products planned to be used in the trial including conditioning regimen, GVHD prophylaxis, prevention of EBV reactivation, infection prophylaxis
* Known allergy or intolerance to all medicinal products and/or excipients planned to be used in the trial including conditioning regimen, GVHD prophylaxis, prevention of EBV reactivation, infection prophylaxis, according to Investigator's brochure and SmPC.
* Who have any debilitating medical or psychiatric illness, which precludes understanding the inform consent as well as optimal treatment and follow-up
* Under legal protection (tutorship or curatorship)
* Under state medical aid
* Participation to another interventional trial on a medicinal product or cell therapy

Individuals meeting any of the exclusion criteria as verified at the screening / inclusion visit will be ineligible to participate at the study.

Primary outcomes:
measure: GRFS (Graft Versus Host Disease (GvHD) and Relapse/rejection-Free Survival)
timeFrame: 2 years after transplantation
Secondary outcomes:
measure: Neutrophil engraftment
timeFrame: At day 100
measure: Platelets engraftment
timeFrame: At day 100
measure: Absolute number of neutrophils
timeFrame: At 1 month
measure: Absolute number of neutrophils
timeFrame: At 3 months
measure: Absolute number of neutrophils
timeFrame: At 6 months
measure: Absolute number of neutrophils
timeFrame: At 12 months
measure: Absolute number of neutrophils
timeFrame: At 24 months
measure: Absolute number of neutrophils
timeFrame: At day of last platelet and red blood cell transfusions (up to 24 months)
measure: Absolute number of platelets
timeFrame: At 1 month
measure: Absolute number of platelets
timeFrame: At 3 months
measure: Absolute number of platelets
timeFrame: At 6 months
measure: Absolute number of platelets
timeFrame: At 12 months
measure: Absolute number of platelets
timeFrame: At 24 months
measure: Absolute number of platelets
timeFrame: At day of last platelet and red blood cell transfusions (up to 24 months)
measure: Acute GvHD incidence grade 2-4
timeFrame: At 3 months
measure: Chronic GvHD incidence
timeFrame: At 24 months
measure: Severe chronic GvHD
timeFrame: At 24 months
measure: Secondary graft failure
timeFrame: At 12 months
measure: Secondary graft failure
timeFrame: At 24 months
measure: Severe infections
timeFrame: At 1 month
measure: Severe infections
timeFrame: At 3 months
measure: Severe infections
timeFrame: At 6 months
measure: Severe infections
timeFrame: At 12 months
measure: Severe infections
timeFrame: At 24 months
measure: Incidence of cardiac toxicities
timeFrame: At 12 months
measure: Incidence of Epstein Barr Virus (EBV) infection
timeFrame: At 12 months
measure: Incidence of CytoMegaloVirus (CMV) infection
timeFrame: At 12 months
measure: Mortality
timeFrame: At 12 months
measure: Mortality
timeFrame: At 24 months
measure: Overall survival
timeFrame: At 12 months
measure: Overall survival
timeFrame: At 24 months
measure: Quality Of Life questionnaire
timeFrame: Before transplantation - at baseline day 0
measure: Quality Of Life questionnaire
timeFrame: At 6 months
measure: Quality Of Life questionnaire
timeFrame: At 12 months
measure: Quality Of Life questionnaire
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: Chimerism
timeFrame: At 24 months
measure: Immune reconstitution
timeFrame: At 1 month
measure: Immune reconstitution
timeFrame: At 3 months
measure: Immune reconstitution
timeFrame: At 6 months
measure: Immune reconstitution
timeFrame: At 12 months
measure: Immune reconstitution
timeFrame: At 24 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Saint Louis hospital
Study officials:
References: