Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide in Patients With Acquired Refractory Aplastic Anemia or in Relapse After Immunosuppression
HAPLO-EMPTY
1 other identifier
interventional
31
1 country
35
Brief Summary
Outcomes for patients with severe aplastic anemia (SAA) who are refractory to first-line immunosuppressive therapy (IST) and who lack a matched unrelated donor (MUD) remain poor. Recently, the use of eltrombopag (ELT) has shown blood count improvements in 40% of these patients. However, most refractory patients do not respond to ELT or other second-line treatment and are therefore exposed to life-threatening infections, and bleeding. During the past 2 decades, there has been a significant decrease in infection-related mortality in patients with SAA unresponsive to initial IST but clonal evolution including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) still occur in the long-term with a grim prognosis. Overall, the overall survival of such patients with acquired refractory SAA to ELT is about 60-70% at 2 years. Hematopoietic stem cell transplantation (HSCT) using alternative donor sources (i.e., mismatched unrelated donors, cord blood (CBT), and haplo-identical family donors) may be curative in patients with refractory SAA, despite carrying much higher rates of complications than in transplantations from matched related or unrelated donors. Recently, our group showed that CBT is a valuable curative option for young adults with refractory SAA. However, not all patients have available CB and CBT treatment related mortality is high in adult patients. Haploidentical (haplo) related donor Stem Cell Transplantation (haplo-SCT) have improved dramatically outcomes using T-cell replete grafts with administration of post-transplantation cyclophosphamide (PTCy). Preliminary results in a little number of patients with refractory SAA at Kings college (London, UK) and John Hopkins (Baltimore, USA) seem promising. The investigators retrospectively analyzed data from 36 patients (median age 42 years) transplanted between 2010 and 2017 in Europe on behalf of the SAA working party of the European Blood and Marrow Transplantation group. The 1-year overall survival was about 80% suggesting that this approach might be a valid option in this particular poor clinical situation. The main objective of this study is to demonstrate a benefit in term of the 2-year overall survival rate from 60% (historical rates in patients with acquired refractory idiopathic aplastic anemia) up to 80% using haplo-SCT with PTCy.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_2
Started Jan 2022
Longer than P75 for phase_2
35 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 15, 2021
CompletedFirst Posted
Study publicly available on registry
November 19, 2021
CompletedStudy Start
First participant enrolled
January 6, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 6, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
January 6, 2027
November 24, 2023
November 1, 2023
5 years
October 15, 2021
November 21, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Overall survival rate
at 2 years
Secondary Outcomes (52)
Graft failure incidence
at 2 years
Neutrophils engraftment
at day 100
Platelets engraftment
at day 100
Absolute numbers of neutrophils
at 1 month
Absolute numbers of neutrophils
at 2 months
- +47 more secondary outcomes
Study Arms (1)
Haploidentical allogeneic hematopoietic stem cell transplantation.
EXPERIMENTAL1. Conditioning regimen 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 3. GVHD Prophylaxis Rabbit ATG dosed at 0.5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, Cyclophosphamide 50 mg/Kg/day at D+3 and D+4, Tacrolimus (residual 8-12 microg/L) and mycophenolate (MMF) from D+5. In absence of GvHD, MMF will be stopped at D35 and tacrolimus at day 365. 4. Prevention of EBV reactivation Rituximab 150mg/m2 intravenously at Day+5 post HSCT, Each infusion of Rituximab will be preceded by administration of anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine.
Interventions
1. Conditioning regimen 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 3. GVHD Prophylaxis Rabbit ATG dosed at 0.5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, Cyclophosphamide 50 mg/Kg/day at D+3 and D+4, Tacrolimus (residual 8-12 microg/L) and mycophenolate (MMF) from D+5. In absence of GvHD, MMF will be stopped at D35 and tacrolimus at day 365. 4. Prevention of EBV reactivation Rituximab 150mg/m2 intravenously at Day+5 post HSCT, Each infusion of Rituximab will be preceded by administration of anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine.
Eligibility Criteria
You may qualify if:
- Aged from 3 to 35 years old
- Suffering from refractory acquired idiopathic aplastic anemia (at least one course of immunosuppression with anti-thymocyte globulin)
- Absence of geno-identical donor or 10/10 matched donor
- With identification of a haploidentical donor (brother, sister, parents, adult children or cousin)
- Absence of donor specific antibody detected in the patient with a MFI ≥ 1500 (antibodies directed towards the distinct haplotype between donor and recipient)
- With usual criteria for HSCT :
- ECOG(Eastern Cooperative Oncology Group) ≤ 2
- No severe and uncontrolled infection
- Cardiac function compatible with high dose of cyclophosphamide
- Adequate organ function: ASAT(aspartate transaminase) and ALAT (alanine aminotransferase) ≤ 2.5 N (the norm), total bilirubin ≤ 2N, creatinine \< 150 μmol/L
- With health insurance coverage
- Contraception methods must be prescribed during all the duration of the research. Women and men of childbearing age must use contraceptive methods within 12 months and 6 months after the last dose of cyclophosphamide, respectively.
- Having signed a written informed consent (2 parents for patients aged less than 18)
You may not qualify if:
- With morphologic evidence of clonal evolution (patients with isolated bone marrow cytogenetic abnormalities are also eligible excepted chromosome 7 abnormalities and complex karyotype)
- With uncontrolled infection
- With seropositivity for HIV or HTLV-1 (Human T cell Leukemia) or active hepatitis B or C defined by a positive PCR (polymerase chain reaction) HBV (hepatitis B virus) or HCV (hepatitis C virus) 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.
- Who received live attenuated vaccine within 2 months before transplantation and during the research
- Uncontrolled coronary insufficiency, recent myocardial infarction \<6 month, current manifestations of heart failure, uncontrolled cardiac rhythm disorders, ventricular ejection fraction \<50%
- With heart failure according to NYHA (New York Heart Association) (II or more)
- Preexisting acute hemorrhagic cystitis
- Renal failure with creatinine clearance \<30ml / min
- With urinary tract obstruction
- Who receive the following treatments Phenytoin, Pentostatin, inhibitor of adenoside)
- Who have any debilitating medical or psychiatric illness, which preclude understanding the inform consent as well as optimal treatment and follow-up
- Under tutorship or curatorship
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (35)
CHU Amiens
Amiens, France
CHU Angers
Angers, France
CHU Besancon
Besançon, France
CHU Bordeaux
Bordeaux, France
Hôpital du Haut-Lévêque
Bordeaux, France
CHU Caen
Caen, France
Hopital Percy
Clamart, France
CHU Clermont
Clermont-Ferrand, France
CHU-Estaing_Clermont Ferrand
Clermont-Ferrand, France
Henri Mondor
Créteil, France
CHU Grenoble
Grenoble, France
CHU Lille
Lille, France
CHU Lille
Lille, France
CHU Limoges
Limoges, France
CHU Lyon Sud
Lyon, France
IHOP, CHU Lyon
Lyon, France
Hopital La Timone
Marseille, France
CHU Montpellier
Montpellier, France
CHU Montpellier
Montpellier, France
CHU Nancy
Nancy, France
CHU Nantes
Nantes, France
CHU Nantes
Nantes, France
CHU Nice
Nice, France
Hopital Necker
Paris, France
Hopital Robert Debré
Paris, France
Hôpital de La Pitié Salpetriere
Paris, France
Hôpital Saint Antoine
Paris, France
Hôpital Saint Louis
Paris, France
CHU Poitiers
Poitiers, France
CHU Rennes
Rennes, France
CHU Rennes
Rennes, France
Crlcc Henri Becquerel Rouen
Rouen, France
ICLN_Saint Priest En Jarez
Saint-Priest-en-Jarez, France
CHRU Strasbourg
Strasbourg, France
CHU Toulouse
Toulouse, France
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NA
- Masking
- NONE
- Purpose
- OTHER
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 15, 2021
First Posted
November 19, 2021
Study Start
January 6, 2022
Primary Completion (Estimated)
January 6, 2027
Study Completion (Estimated)
January 6, 2027
Last Updated
November 24, 2023
Record last verified: 2023-11