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

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

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".

Study Overview

• Status: Recruiting
• Conditions: Aplastic Anemia
• Intervention / Treatment: Biological: Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jérôme Lambert, MD PhD; Phone Number: +33 142499742; Email: jerome.lambert@u-paris.fr
• Study Contact Backup: Name: Régis Peffault de Latour, MD PhD; Phone Number: +33 142385073; Email: regis.peffaultdelatour@aphp.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • CHU Amiens
    • Contact: Magalie Joris; Phone Number: +33 +33 3 22 45 54 23; Email: joris.magalie@chu-amiens.fr
  • Angers, France
    • Recruiting
    • CHU Angers
    • Contact: Sylvie François; Phone Number: +33 +33 2 41 35 44 82; Email: syfrancois@chu-angers.fr
  • Besançon, France
    • Recruiting
    • CHU Besancon
    • Contact: Etienne Daguindau; Phone Number: +33 +33370632285; Email: edaguindau@chu-besancon.fr
  • Bordeaux, France
    • Recruiting
    • CHU Bordeaux
    • Contact: Edouard Forcade; Phone Number: +33 +33 5 57 65 65 11; Email: edouard.forcade@chu-bordeaux.fr
  • Caen, France
    • Not yet recruiting
    • CHU Caen
    • Contact: Sylvain Chantepie; Phone Number: +33231272073; Email: Chantepie-s@chu-caen.fr
  • Clamart, France
    • Recruiting
    • HNIA Percy
    • Contact: Johanna Konopacki; Phone Number: +33 +33 1 41 46 63 03; Email: johanna.konopacki@intradef.gouv.fr
  • Clermont-Ferrand, France
    • Recruiting
    • Hôpital d'Estaing
    • Contact: Aurélie Ravinet; Phone Number: +33 +33 4 73 75 00 65; Email: aravinet@chu-clermontferrant.fr
  • Créteil, France
    • Not yet recruiting
    • Hôpital Henri Mondor AP-HP
    • Contact: Sébastien Maury; Phone Number: +33 +33 1 49 81 45 26; Email: sebastien.maury@aphp.fr
  • Grenoble, France
    • Recruiting
    • CHU Grenoble Alpes
    • Contact: Claude-Eric Bulabois; Phone Number: +33 +33 4 76 76 92 09; Email: cebulabois@chu-grenoble.fr
  • Lille, France
    • Not yet recruiting
    • CHU Lille
    • Contact: Micha Srour; Email: Micha.SROUR@chu-lille.fr
    • Contact: Micha Srour; Phone Number: +33 +33 3 20 44 42 85; Email: Micha.SROUR@chu-lille.fr
  • Limoges, France
    • Recruiting
    • CHU Limoges
    • Contact: Pedro de Lima Prata; Phone Number: +33 +33 5 55 05 88 67; Email: Pedro.PRATA@chu-limoges.fr
  • Lyon, France
    • Recruiting
    • CHU Lyon Sud
    • Contact: Vincent Alcazer; Phone Number: +33 +33 4 78 86 22 59; Email: vincent.alcazer@chu-lyon.fr
  • Marseille, France
    • Not yet recruiting
    • Institut Paoli Calmettes
    • Contact: Raynier Devillier; Phone Number: +33 4 91 22 33 33; Email: DEVILLIERR@ipc.unicancer.fr
  • Montpellier, France
    • Recruiting
    • CHU Montpellier
    • Contact: Patrice Ceballos; Phone Number: +33 +33 4 67 33 32 68; Email: p-ceballos@chu-montpellier.fr
  • Nancy, France
    • Recruiting
    • CHRU Nancy
    • Contact: Simona Pagliuca; Phone Number: +33 +33383155259; Email: s.pagliuca@chru-nancy.fr
  • Nantes, France
    • Recruiting
    • CHU Nantes
    • Contact: Alice Garnier; Phone Number: +33 +33 2 40 08 42 28; Email: alice.garnier@chu-nantes.fr
  • Nice, France
    • Recruiting
    • CHU Nice
    • Contact: Michael Loschi; Phone Number: +33 +33 4 92 03 52 11; Email: loschi.m@chu-nice.fr
  • Paris, France
    • Recruiting
    • Hopital Necker - APHP
    • Contact: Felipe Suarez; Phone Number: +33 +331 44 49 51 88; Email: felipe.suarez@aphp.fr
  • Paris, France
    • Not yet recruiting
    • Hôpital La Pitié Salpêtrière AP-HP
    • Contact: Stéphanie Nguyen-Quoc; Phone Number: +33 +33 1 42 17 61 84; Email: stephanie.nguyen-quoc@aphp.fr
  • Poitiers, France
    • Recruiting
    • CHU Poitiers
    • Contact: Natacha Maillard; Phone Number: +33 5 16 60 43 29; Email: natacha.maillard@chu-poiters.fr
  • Rennes, France
    • Not yet recruiting
    • CHU Rennes
    • Contact: Jean-Baptiste Mear; Phone Number: +33 +33299284321; Email: jean-baptiste.mear@chu-rennes.fr
  • Rouen, France
    • Not yet recruiting
    • Henri Becquerel
    • Contact: Anne-Lise Menard; Phone Number: +33 +33 2.32.08.24.98; Email: anne-lise.menard@chb-unicancer.fr
  • Saint-Etienne, France
    • Recruiting
    • CHU Saint Etienne
    • Contact: Jérôme Cornillon; Phone Number: +33 +334 77 82 24 55; Email: Jerome.Cornillon@chu-st-etienne.fr
  • Strasbourg, France
    • Recruiting
    • CHU Strasbourg
    • Contact: Bruno Lioure; Phone Number: +33 +33 3 68 76 74 03; Email: bruno.lioure@chru-strasbourg.fr
  • Toulouse, France
    • Recruiting
    • CHU Toulouse
    • Contact: Anne Huynh; Phone Number: +33 +33 5 31 15 63 31; Email: huynh.anne@iuct-oncopole.fr
  • France
    • Paris, France, France, 75010
      • Recruiting
      • Saint Louis Hospital
      • Contact: Régis Peffault de La Tour, MD PhD; Phone Number: +33142385073

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow

Biological: Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow; 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).; 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.; 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.; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GRFS (Graft Versus Host Disease (GvHD) and Relapse/rejection-Free Survival)	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	2 years after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		At 24 months
Absolute number of platelets		At 1 month
Absolute number of platelets		At 3 months
Absolute number of platelets		At 6 months
Absolute number of platelets		At 12 months
Absolute number of platelets		At 24 months
Overall survival		At 12 months
Mortality		At 12 months
Neutrophil engraftment	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.	At day 100
Platelets engraftment	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.	At day 100
Absolute number of neutrophils		At 1 month
Absolute number of neutrophils		At 3 months
Absolute number of neutrophils		At 6 months
Absolute number of neutrophils		At 12 months
Absolute number of neutrophils		At 24 months
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 12 months
Secondary graft failure		At 24 months
Severe infections	CTCAE grade 3-4	At 1 month
Severe infections	CTCAE grade 3-4	At 3 months
Severe infections	CTCAE grade 3-4	At 6 months
Severe infections	CTCAE grade 3-4	At 12 months
Severe infections	CTCAE grade 3-4	At 24 months
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
Quality Of Life questionnaire	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	Before transplantation - at baseline day 0
Quality Of Life questionnaire	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	At 6 months
Quality Of Life questionnaire	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	At 12 months
Quality Of Life questionnaire	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	At 24 months
Chimerism	Proportion of patients with a donor chimerism of 85% or more	At 1 month
Chimerism	Proportion of patients with a donor chimerism of 85% or more	At 3 months
Chimerism	Proportion of patients with a donor chimerism of 85% or more	At 6 months
Chimerism	Proportion of patients with a donor chimerism of 85% or more	At 12 months
Chimerism	Proportion of patients with a donor chimerism of 85% or more	At 24 months
Immune reconstitution	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.	At 1 month
Immune reconstitution	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.	At 3 months
Immune reconstitution	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.	At 6 months
Immune reconstitution	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.	At 12 months
Immune reconstitution	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.	At 24 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2025
• Primary Completion (Estimated): January 24, 2030
• Study Completion (Estimated): January 24, 2030

Study Registration Dates

• First Submitted: September 13, 2024
• First Submitted That Met QC Criteria: October 16, 2024
• First Posted (Actual): October 17, 2024

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Hematopoietic stem cell transplantation; Post-transplantation cyclophosphamide; Refractory/relapse idiopathic anemia; Idiopathic aplastic anemia
• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Hematologic Diseases; Bone Marrow Diseases; Anemia; Hemic and Lymphatic Diseases; Anemia, Aplastic
• Other Study ID Numbers: APHP230832

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No