Clinical trial NCT05126849: Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide in Patients With Acquired Refractory Aplastic Anemia or in Relapse After Immunosuppression
Official title: Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide in Patients With Acquired Refractory Aplastic Anemia or in Relapse After Immunosuppression: a Nationwide Phase II Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Refractory Idiopathic Aplastic Anemia
Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation
Keywords: Acquired refractory idiopathic aplastic anemia
Haplo identical hematopoietic stem cell transplantation
Post-transplantation cyclophosphamide
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2021-11-19
Enrollment: 31
Sex: ALL
Minimum age (years): 3
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility criteria: Inclusion Criteria:

* 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)

Exclusion Criteria :

* 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

Primary outcomes:
measure: Overall survival rate
timeFrame: at 2 years
Secondary outcomes:
measure: Graft failure incidence
timeFrame: at 2 years
measure: Neutrophils engraftment
timeFrame: at day 100
measure: Platelets engraftment
timeFrame: at day 100
measure: Absolute numbers of neutrophils
timeFrame: at 1 month
measure: Absolute numbers of neutrophils
timeFrame: at 2 months
measure: Absolute numbers of neutrophils
timeFrame: at 3 months
measure: Absolute numbers of neutrophils
timeFrame: at 6 months
measure: Absolute numbers of neutrophils
timeFrame: at 12 months
measure: Absolute numbers of neutrophils
timeFrame: through study completion, an average of 6 months
measure: Absolute numbers of platelets
timeFrame: at 1 month
measure: Absolute numbers of platelets
timeFrame: at 2 months
measure: Absolute numbers of platelets
timeFrame: at 3 months
measure: Absolute numbers of platelets
timeFrame: at 6 months
measure: Absolute numbers of platelets
timeFrame: at 12 months
measure: Absolute numbers of platelets
timeFrame: through study completion, an average of 6 months
measure: Incidence of use of growth factors for poor hematopoietic reconstitution
timeFrame: up to one year
measure: Acute graft-versus-host disease (GvHD) incidence
timeFrame: at 3 months
measure: Chronic graft-versus-host disease (GvHD) incidence
timeFrame: at 24 months
measure: Relapse incidence
timeFrame: at 12 months
measure: Relapse incidence
timeFrame: at 24 months
measure: Progression free survival
timeFrame: at 12 months
measure: Progression free survival
timeFrame: at 24 months
measure: Incidence of cytomegalovirus (CMV) infection
timeFrame: at 12 months
measure: Incidence of Epstein-Barr virus (EBV) infection
timeFrame: at 12 months
measure: Severe infections (CTAE grade 3-4)
timeFrame: at 3 months
measure: Severe infections (CTAE grade 3-4)
timeFrame: at 6 months
measure: Severe infections (CTAE grade 3-4)
timeFrame: at 12 months
measure: Severe infections (CTAE grade 3-4)
timeFrame: at 24 months
measure: Non-relapse mortality
timeFrame: at 24 months
measure: Incidence of cardiac toxicities
timeFrame: at 12 months
measure: Overall survival
timeFrame: at 12 months
measure: Quality of life questionnaire for adults
timeFrame: at 3 months
measure: Quality of life questionnaire for minors
timeFrame: at 3 months
measure: Quality of life questionnaire for adults
timeFrame: at 6 months
measure: Quality of life questionnaire for minors
timeFrame: at 6 months
measure: Quality of life questionnaire for adults
timeFrame: at 12 months
measure: Quality of life questionnaire for minors
timeFrame: at 12 months
measure: Quality of life questionnaire for adults
timeFrame: at 24 months
measure: Quality of life questionnaire for minors
timeFrame: at 24 months
measure: Proportion of patients with a donor chimerism of 90% or more
timeFrame: at 1 months
measure: Proportion of patients with a donor chimerism of 90% or more
timeFrame: at 3 months
measure: Proportion of patients with a donor chimerism of 90% or more
timeFrame: at 6 months
measure: Proportion of patients with a donor chimerism of 90% or more
timeFrame: at 12 months
measure: Proportion of patients with a donor chimerism of 90% or more
timeFrame: at 24 months
measure: Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood
timeFrame: at 3 months
measure: Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood
timeFrame: at 6 months
measure: Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood
timeFrame: at 12 months
measure: Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood
timeFrame: at 24 months
measure: Ferritin levels
timeFrame: at 3 months
measure: Ferritin levels
timeFrame: at 6 months
measure: Ferritin levels
timeFrame: at 12 months
measure: Ferritin levels
timeFrame: at 24 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: CHU Angers
city: Besançon
country: France
facility: CHU Besancon
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Bordeaux
country: France
facility: Hôpital du Haut-Lévêque
city: Caen
country: France
facility: CHU Caen
city: Clamart
country: France
facility: Hopital Percy
city: Clermont-Ferrand
country: France
facility: CHU Clermont
city: Clermont-Ferrand
country: France
facility: CHU-Estaing_Clermont Ferrand
city: Créteil
country: France
facility: Henri Mondor
city: Grenoble
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: CHU Lille
city: Lille
country: France
facility: CHU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: CHU Lyon Sud
city: Lyon
country: France
facility: IHOP, CHU Lyon
city: Marseille
country: France
facility: Hopital La Timone
city: Montpellier
country: France
facility: CHU Montpellier
city: Montpellier
country: France
facility: CHU Montpellier
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Paris
country: France
facility: Hopital Necker
city: Paris
country: France
facility: Hopital Robert Debré
city: Paris
country: France
facility: Hôpital de La Pitié Salpetriere
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpital Saint Louis
city: Poitiers
country: France
facility: CHU Poitiers
city: Rennes
country: France
facility: CHU Rennes
city: Rennes
country: France
facility: CHU Rennes
city: Rouen
country: France
facility: Crlcc Henri Becquerel Rouen
city: Saint-Priest-en-Jarez
country: France
facility: ICLN_Saint Priest En Jarez
city: Strasbourg
country: France
facility: CHRU Strasbourg
city: Toulouse
country: France
facility: CHU Toulouse
Study officials:
References: