Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Rescuing Patients With Graft Failure

Study Overview
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Brief Summary
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Prognosis of patients with graft failure is dismal, and re-transplantation is the sole option for long-term survival. Currently, there is no consensus concerning therapeutic options in patients with primary or secondary (within the 60 days post-transplantation) graft failure and finding a new donor within an acceptable delay is challenging. Literature is poor on the subject while the overall survival of such patients is about 30% at 1 year. This situation thus represents today a very challenging unmet medical need. Recently, 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, which targets alloreactive T cells generated early after an HLA-mismatched transplant, sparing regulatory T cells and leaving unaffected the non-dividing hematopoietic stem cells) and standard post-transplant immune suppression with a calcineurin inhibitor (CNI) and mycophenolate mofetil. Our group re-transplanted a patient who experienced two consecutive graft failures and was successfully managed through a third haplo-SCT from her son using PTCy. We then retrospectively collected and analyzed data from 26 primary graft failure patients transplanted between 2011 and 2017 in 15 centers on behalf of French Society for Stem Cell Transplantation and Cell Therapy (SFGM-TC). The study population consisted mainly of patients with primary or secondary (within the 60 days post-transplantation) graft failure who underwent haplo-SCT and received PTCy as graft-versus-host-disease prophylaxis. The 1-year overall survival was about 60% suggesting that this approach might be a valid option in this particular poor clinical situation but now need validation through a phase II multicenter, national, prospective cohort study.

Official Title
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Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Rescuing Patients With Graft Failure: a Phase II Study

Conditions
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Hematologic Diseases, Graft Failure, Allogeneic Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Other: haplo-SCT with PTCy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged from 3 to 70 years All hematological diseases Suffering from primary or secondary (within the 60 days post-transplantation) graft failure after a 1st allo-SCT With usual criteria for allo-SCT: ECOG ≤ 2 No severe and uncontrolled infection Cardiac function compatible with high dose of cyclophosphamide Adequate organ function: ASAT and ALAT ≤ 2.5N, total bilirubin ≤ 2N, creatinine clearance ≥30ml / min With identification of a haploidentical donor (brother, sister, parents, adult children or cousin) Absence of donor specific antibody (DSA) detected in the patient with a MFI ≥ 1500 (antibodies directed towards the distinct haplotype between donor and recipient) With health insurance coverage (bénéficiaire ou ayant droit). Understand informed consent or optimal treatment and follow-up. 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: Aged< 3 years old and >70 years old With uncontrolled infection With Seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive PCR HBV or HCV and associated hepatic cytolysis Yellow fever vaccine within 2 months before transplantation Cancer in the last 5 years (except basal cell carcinoma of the skin or in situ carcinoma of the cervix) Uncontrolled coronary insufficiency, recent myocardial infarction <6 month, current manifestations of heart failure, uncontrolled cardiac rhythm disorders, ventricular ejection fraction <50% Heart failure according to NYHA (II or more) Preexisting acute hemorrhagic cystitis Renal failure with creatinine clearance < 30ml / min Urinary tract obstruction Pregnant (β-HCG positive) or breast-feeding Who have any debilitating medical or psychiatric illness, which preclude understanding the inform consent as well as optimal treatment and follow-up COVID vaccination or recent COVID disease <3 months Tutorship or curatorship Contraindications to treatments used during the research

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 70 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: haplo-SCT with PTCy<br>haploidentical (haplo) related donor Stem Cell Transplantation (haplo-SCT) with administration of post-transplantation cyclophosphamide (PTCy, which targets alloreactive T cells generated early after an HLA-mismatched transplant, sparing regulatory T cells and leaving unaffected the non-dividing hematopoietic stem cells) | Other: haplo-SCT with PTCy<br>* Conditioning regimen Fludarabine (30mg/m2/day from day -6 to day -4), Cyclophosphamide (14.5 mg/kg/day at day -6 and day -5) except for patients who received a total dose of Cyclophosphamide >100mg/Kg during the first Bone Marrow Transplantation Total Body Irradiation (2 Gray on day -1). Source of stem cell source Peripheral blood stem cell Minimal target dose of 4.106 CD34+ cells/kg of recipient GvHD prophylaxis Cyclophosphamide 50 mg/Kg/day at D+3 and D+4 Ciclosporine from day+5 (residual 200 à 300ng/l) Mycophenolate mofetyl at 15mg/Kg x2/day from day+5 Prevention of EBV reactivation Rituximab : 150mg/m2 intravenously at Day+5 post Haplo-SCT Each infusion of Rituximab will be preceded by administration of anti-pyretic and an antihistaminic.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | at one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft failure incidence |  | at 3 months | 
| 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 number of platelets |  | at one month | 
| Absolute number of platelets |  | at 2 months | 
| 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 |  | through study completion, an average of 6 months | 
| Incidence of use of growth factors for poor hematopoietic reconstitution |  | at 3 months | 
| Acute GvHD incidence |  | at 3 months | 
| Chronic 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 CMV infection |  | at 12 months | 
| Incidence of EBV infection |  | at 12 months | 
| Incidence of severe infections | Severe infections are defined as CTAE grade of 3 or 4 | at 3 months | 
| Incidence of severe infections | Severe infections are defined as CTAE grade of 3 or 4 | at 6 months | 
| Incidence of severe infections | Severe infections are defined as CTAE grade of 3 or 4 | at 12 months | 
| Incidence of severe infections | Severe infections are defined as CTAE grade of 3 or 4 | at 24 months | 
| Incidence of veino-occlusive disease (VOD) |  | at 3 months | 
| Severity of veino-occlusive disease (VOD) |  | at 3 months | 
| Non-relapse mortality |  | at 24 months | 
| Incidence of cardiac toxicities |  | at 12 months | 
| Overall survival |  | at 24 months | 
| Interval between first allo-SCT and rescue haplo-SCT |  | at 60 days | 
| Quality of life 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 3 months | 
| Quality of life 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 6 months | 
| Quality of life 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 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 24 months | 
| Quality of life 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 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 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 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 month | 
| 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 | 
| Immune reconstitution | Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 3 months post-transplantation | 
| Immune reconstitution | Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 6 months post-transplantation | 
| Immune reconstitution | Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 12 months post-transplantation | 
| Immune reconstitution | Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood | at 24 months post-transplantation | 
| Iron overload estimation |  | at 3 months | 
| Iron overload estimation |  | at 6 months | 
| Iron overload estimation |  | at 12 months | 
| Iron overload estimation |  | at 24 months |