Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide in Patients With Acquired Refractory Aplastic Anemia or in Relapse After Immunosuppression

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Refractory Idiopathic Aplastic Anemia, Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Other: Allogenic transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Haploidentical allogeneic hematopoietic stem cell transplantation.<br>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) Stem cell source Bone Marrow 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. 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. | Other: Allogenic transplantation<br>* 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) Stem cell source Bone Marrow 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. 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate |  | at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft failure incidence |  | at 2 years | 
| Neutrophils engraftment | 3 consecutive days with neutrophiles >0.5 G/L | at day 100 | 
| Platelets engraftment | 7 consecutive days with platelets >20 G/L | at day 100 | 
| Absolute numbers of neutrophils |  | at 1 month | 
| Absolute numbers of neutrophils |  | at 2 months | 
| Absolute numbers of neutrophils |  | at 3 months | 
| Absolute numbers of neutrophils |  | at 6 months | 
| Absolute numbers of neutrophils |  | at 12 months | 
| Absolute numbers of neutrophils |  | through study completion, an average of 6 months | 
| Absolute numbers of platelets |  | at 1 month | 
| Absolute numbers of platelets |  | at 2 months | 
| Absolute numbers of platelets |  | at 3 months | 
| Absolute numbers of platelets |  | at 6 months | 
| Absolute numbers of platelets |  | at 12 months | 
| Absolute numbers of platelets |  | through study completion, an average of 6 months | 
| Incidence of use of growth factors for poor hematopoietic reconstitution |  | up to one year | 
| Acute graft-versus-host disease (GvHD) incidence |  | at 3 months | 
| Chronic graft-versus-host disease (GvHD) incidence |  | at 24 months | 
| Relapse incidence |  | at 12 months | 
| Relapse incidence |  | at 24 months | 
| Progression free survival |  | at 12 months | 
| Progression free survival |  | at 24 months | 
| Incidence of cytomegalovirus (CMV) infection |  | at 12 months | 
| Incidence of Epstein-Barr virus (EBV) infection |  | at 12 months | 
| Severe infections (CTAE grade 3-4) |  | at 3 months | 
| Severe infections (CTAE grade 3-4) |  | at 6 months | 
| Severe infections (CTAE grade 3-4) |  | at 12 months | 
| Severe infections (CTAE grade 3-4) |  | at 24 months | 
| Non-relapse mortality |  | at 24 months | 
| Incidence of cardiac toxicities |  | at 12 months | 
| Overall survival |  | at 12 months | 
| Quality of life questionnaire for adults | Quality of life will be assessed for adult using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)  EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | at 3 months | 
| Quality of life questionnaire for minors | Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning. | at 3 months | 
| Quality of life questionnaire for adults | Quality of life will be assessed for adult using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | at 6 months | 
| Quality of life questionnaire for minors | Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning. | at 6 months | 
| Quality of life questionnaire for adults | Quality of life will be assessed for adults using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | at 12 months | 
| Quality of life questionnaire for minors | Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning. | at 12 months | 
| Quality of life questionnaire for adults | Quality of life will be assessed for adult using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | at 24 months | 
| Quality of life questionnaire for minors | Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning. | at 24 months | 
| Proportion of patients with a donor chimerism of 90% or more |  | at 1 months | 
| Proportion of patients with a donor chimerism of 90% or more |  | at 3 months | 
| Proportion of patients with a donor chimerism of 90% or more |  | at 6 months | 
| Proportion of patients with a donor chimerism of 90% or more |  | at 12 months | 
| Proportion of patients with a donor chimerism of 90% or more |  | at 24 months | 
| Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood |  | at 3 months | 
| Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood |  | at 6 months | 
| Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood |  | at 12 months | 
| Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood |  | at 24 months | 
| Ferritin levels |  | at 3 months | 
| Ferritin levels |  | at 6 months | 
| Ferritin levels |  | at 12 months | 
| Ferritin levels |  | at 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acquired refractory idiopathic aplastic anemia, Haplo identical hematopoietic stem cell transplantation, Post-transplantation cyclophosphamide