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

NCT ID: NCT06646497

Last Updated: 2024-10-17

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-11-01
• Study Completion Date: 2029-11-01

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".

Conditions

Aplastic Anemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow

Group Type: EXPERIMENTAL

Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow

Intervention Type: BIOLOGICAL

1. Conditioning regimen Thymoglobulin (0.5/mg/kg à D-9, 2 mg /kg at D-8 and 2.5 mg/kg à D-7), Fludarabine (30mg/m2/day i.v: day -6 to day -2), pre-transplant, Cyclophosphamide (14.5 mg/kg/day i.v: day -6 and day -5), and Total Body Irradiation (2 Gray on day -1).

2. Stem cell source Bone Marrow only. Target of 4 × 10^8 nucleated cells/kg recipient body weight. Granulocyte colony stimulating factor is given subcutaneously starting on day +5 at 5 mg/ kg/day until the absolute neutrophil count is greater than 1.5 × 10^9/L for 3 days.

3. GVHD prophylaxis Cyclophosphamide 50 mg/Kg/day at D+3 and D+4. Tacrolimus (0,2 à 0,3 mg/kg/day per os divided into 2 doses or 0.05 to 0.1 mg/kg/d IVSE) and mycophenolate (MMF) will begin from D+5. In absence of GvHD, MMF will be stopped between D35 and D45 and Tacrolimus at day 365.

4. Prevention of EBV reactivation Rituximab 150mg/m2 intravenously at Day+5 post HSCT (except patients and their donor with EBV serology and EBV PCR negative).

Interventions

Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow

1. Conditioning regimen Thymoglobulin (0.5/mg/kg à D-9, 2 mg /kg at D-8 and 2.5 mg/kg à D-7), Fludarabine (30mg/m2/day i.v: day -6 to day -2), pre-transplant, Cyclophosphamide (14.5 mg/kg/day i.v: day -6 and day -5), and Total Body Irradiation (2 Gray on day -1).

2. Stem cell source Bone Marrow only. Target of 4 × 10^8 nucleated cells/kg recipient body weight. Granulocyte colony stimulating factor is given subcutaneously starting on day +5 at 5 mg/ kg/day until the absolute neutrophil count is greater than 1.5 × 10^9/L for 3 days.

3. GVHD prophylaxis Cyclophosphamide 50 mg/Kg/day at D+3 and D+4. Tacrolimus (0,2 à 0,3 mg/kg/day per os divided into 2 doses or 0.05 to 0.1 mg/kg/d IVSE) and mycophenolate (MMF) will begin from D+5. In absence of GvHD, MMF will be stopped between D35 and D45 and Tacrolimus at day 365.

4. Prevention of EBV reactivation Rituximab 150mg/m2 intravenously at Day+5 post HSCT (except patients and their donor with EBV serology and EBV PCR negative).

Intervention Type: BIOLOGICAL

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.

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

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Saint Louis hospital

Paris, , France

Countries

France

Central Contacts

Régis Peffault de Latour, MD PhD

Role: CONTACT

regis.peffaultdelatour@aphp.fr

142385073 ext. +33

Jérôme Lambert, MD PhD

Role: CONTACT

jerome.lambert@u-paris.fr

142499742 ext. +33

Facility Contacts

Régis Peffault de La Tour, MD PhD

Role: primary

+33142385073

Other Identifiers

APHP230832

Identifier Type: -

Identifier Source: org_study_id