Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Rescuing Patients With Graft Failure
- Conditions
- Allogeneic Hematopoietic Stem Cell TransplantationHematologic DiseasesGraft Failure
- Interventions
- Other: haplo-SCT with PTCy
- Registration Number
- NCT05126186
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 35
-
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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description haplo-SCT with PTCy haplo-SCT with PTCy 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)
- Primary Outcome Measures
Name Time Method Overall Survival at one year
- Secondary Outcome Measures
Name Time Method Platelets engraftment at day 100 7 consecutive days with platelets \>20 G/L
Absolute number of platelets through study completion, an average of 6 months Incidence of CMV infection at 12 months Severity of veino-occlusive disease (VOD) at 3 months Quality of life for minors at 24 months 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
Graft failure incidence at 3 months Neutrophils engraftment at day 100 3 consecutive days with neutrophiles \>0.5 G/L
Chronic GvHD incidence at 24 months Absolute numbers of neutrophils 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 Relapse incidence at 24 months Progression free survival at 24 months Incidence of EBV infection at 12 months Incidence of severe infections at 24 months Severe infections are defined as CTAE grade of 3 or 4
Non-relapse mortality at 24 months Incidence of veino-occlusive disease (VOD) at 3 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 at 24 months 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.
Proportion of patients with a donor chimerism of 90% or more at 12 months Immune reconstitution at 24 months post-transplantation Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood
Iron overload estimation at 24 months