Indication of HSCT in Patients With Refractory/Relapse AA After First-line Standard Immunosuppressive Therapy Aged More Than 40 Years

Phase 2

Not yet recruiting

• Conditions: Aplastic Anemia
• Interventions: Biological: Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow

• Registration Number: NCT06646497
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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".

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Status Verified: 2024-08
• Study First Submitted: 2024-09-13
• Study First Submitted QC: 2024-10-16
• Last Update Submitted: 2024-10-16
• Study First Posted: 2024-10-17
• Last Update Posted: 2024-10-17
• Study Start: 2024-11-01
• Primary Completion: 2029-11-01
• Study Completion: 2029-11-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 52

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow	Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow	-

Primary Outcome Measures

Name	Time	Method
GRFS (Graft Versus Host Disease (GvHD) and Relapse/rejection-Free Survival)	2 years after transplantation	GRFS is a composite right-censored endpoint, defined as the time from HSCT to the first of the following events: * primary graft failure, defined as the absence of engraftment from aplasia at day 60 after graft (D0) (i.e., persistence of neutrophils\< 500 AND platelets \< 20 Giga/L); * secondary graft failure, defined as the reoccurrence of aplasia after engraftment (defined as both occurrence of neutrophils\< 500 for 3 days and platelets \< 20 Giga/L for 7 consecutive days); * grade 3-4 acute GVHD, according to the MAGIC CONSORTIUM 2016; * severe chronic GVHD, according to the NIH classification; * death, whatever the cause

Secondary Outcome Measures

Name	Time	Method
Neutrophil engraftment	At day 100	Neutrophils engraftment will be defined as first day of 3 consecutive days with neutrophils \>0.5 G/L.; With donor chimerism\> 85% on the total blood.
Platelets engraftment	At day 100	Platelets engraftment will be defined as first day of 7 consecutive days with platelets \>20 G/L.; With donor chimerism\> 85% on the total blood.
Absolute number of neutrophils	At day of last platelet and red blood cell transfusions (up to 24 months)
Absolute number of platelets	At day of last platelet and red blood cell transfusions (up to 24 months)
Acute GvHD incidence grade 2-4	At 3 months
Chronic GvHD incidence	At 24 months
Severe chronic GvHD	At 24 months
Secondary graft failure	At 24 months
Severe infections	At 24 months	CTCAE grade 3-4
Incidence of cardiac toxicities	At 12 months
Incidence of Epstein Barr Virus (EBV) infection	At 12 months
Incidence of CytoMegaloVirus (CMV) infection	At 12 months
Mortality	At 24 months
Overall survival	At 24 months
Quality Of Life questionnaire	At 24 months	Quality of life will be evaluated using PedsQL questionnaire. Scores varies from 0 to100, with higher scores associated with better health-related quality of life
Chimerism	At 24 months	Proportion of patients with a donor chimerism of 85% or more
Immune reconstitution	At 24 months	Immune reconstitution will be done by analyzing T, B, NK, regulatory T cell levels in the peripheral blood. All have the same unit measure namely absolute numbers/microL.

Trial Locations

Locations (1)

Saint Louis hospital; 🇫🇷 Paris, France