Study Testing Two Conditioning Regimen With a Single Prophylaxis of GVHD by Cyclophosphamide and Methotrexate Post-transplant in Patients Eligible for Matched-donor Allograft Transplantation

Phase 2RecruitingNCT06252870

Nantes University Hospital82 enrolled

Overview

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-CSH). Recently, in the context of semi-identical (=haploidentical) HLA donors, but also of compatible HLA donors, the use of cyclophosphamide (CY) administered in high doses at early post-transplant (PT) (=PTCY) (Days +3 and +4 or +5) has shown excellent control of acute and chronic GVH, even enabling the discontinuation of other immunosuppressive drugs administered after allo-CSH (ciclosporin, mycophenolate mofetyl (MMF) or Cellcept). This step has already been taken in the context of allo-CSH with myeloablative conditioning (MAC), which is a minoritary conditioning in adults. However, in the context of allo-CSH with reduced-intensity conditioning (RIC), which predominates in adults, this strategy seems insufficient to prevent the risk of GVHD. The idea of reducing the use of immunosuppressants in the context of RIC/HLA-compatible transplants seems, however, still relevant, in order to reduce their adverse effects, improve patients' quality of life and enhance the reconstitution of the post-transplant immune system.

For this reason, the investigators now wish to test the administration of a combination of a high dose of early post-transplant CY (PTCY) and methotrexate (MTX) on days (D) D+1, D+4, D+6, D+11 (doses already performed in MAC transplant prophylaxis), with anti-lymphocyte serum (ALS) with RIC conditioning, without ciclosporin or MMF. The investigators hypothesize that administration of this PTCY+MTX combination will enable immunosuppressive drugs to be discontinued as early as D+11 post-transplant, compared with the usual average of 3 to 4 months.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Interventions

MethotrexateDRUG

15 mg/m² on Day+1 after graft (=Day0) 10 mg/m² 3 days on Day+4/Day+6/Day+11 after graft (=Day0)

Post-Transplant CyclophosphamideDRUG

50 mg/kg intravenous 2 days on Day+3/Day+5 after graft (=Day0)

FludarabineDRUG

Conditioning regimen: 30 mg/m² Intravenous 5 days from Day-6 to Day-2 (Day-6/Day-5-/Day-4/Day-3/Day-2 before graft (=Day0)

CycophosphamideDRUG

Conditioning regimen: 14.5 mg/kg intravenous 2 days on Day-6/Day-5 before graft (=Day0)

Anti-ThymoglobulinDRUG

Conditioning regimen: 2.5 mg/kg intravenous on Day-2 before graft (=Day0)

total body irradiationRADIATION

2 grays on Day-1 before graft (=Day0)

hematopoietic stem cellsOTHER

High dose of hematopoietic stem cells derived from peripheral blood on transplantation day (=Day0 graft)

Graft nuclear cellsOTHER

Graft nuclear cells CD3+ cells if needed after transplantation

Donor Lymphocytes InjectionOTHER

DLI with CD3+ if relapse after transplantation or in prevention of relapse

ClofarabineDRUG

Conditioning regimen: 30 mg/m² Intravenous 5 days from Day-6 to Day-2 (Day-6/Day-5-/Day-4/Day-3/Day-2 before graft (=Day0)

ThiotepaDRUG

Conditioning regimen: 5 mg/kg Intravenous at Day-6 before graft (=Day0)

BusulfanDRUG

Conditioning regimen: 3.2 mg/kg Intravenous 2 days at Day-2 and Day-1 before graft (=Day0)

FludarabineDRUG

Conditioning regimen: 40 mg/m² intravenous 4 days on Day-5/Day-4/Day-3/Day-2 before graft (=Day0)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age: ≥ 18 and ≤ 70 years old * Patient with hematologic malignancy * Indication for HSC allograft with attenuated conditioning * Pluripotent stem cell (PSC) engraftment * Availability of a 10/10 familial or non-familial HLA compatible donor * Consent to the protocol * ECOG \<=2 * Woman of childbearing age with negative pregnancy test and on highly effective contraception during treatment and for a period of 12 months after stopping MTX and CY * Man of childbearing age with highly effective contraception during treatment and for a period of 6 months after stopping MTX and CY and a period of 12 months after stopping MTX and CY if TBF conditioning regimen arm * Negative Hepatitis B, C, HIV serologies * Social security affiliation Exclusion Criteria: * History of allograft * Patient eligible for myeloablative conditioning (MAC) * Bone marrow transplant * Other progressive cancerous disease, or antecedent of cancer in the last five years, with the exception of a carcinoma of the skin or a carcinoma in situ of the uterine cole treated and in remission. * Progressive psychiatric condition * Pregnant or breastfeeding woman, * Woman or man of childbearing age with lack of effective contraception * Serious and uncontrolled concomitant infection * Cardiac: systolic ejection fraction \< 50% by transthoracic ultrasound or by isotopic method (isotope gamma angiography), NYHA II, III or IV heart failure, active rhythmic, valvular or ischemic heart disease or anteriority * Respiratory with EFR: DLCOc \<40% of theoretical * Renal: creatinine clearance \< 50 ml/min (assessment with MDRD method) * Urological: active urinary tract infection, history of acute urothelial toxicity due to cytotoxic chemotherapy or radiotherapy, known obstruction of urinary flow, pre-existing hemorrhagic cystitis * Hepatic: transaminases greater than 5 times normal or bilirubin greater than 2 times normal * Person protected by law (major under guardianship, curatorship or legal protection) * Vaccination against yellow fever in the last year * Known or suspected hypersensitivity to rabbit proteins as well as to the active substance and excipients of all investigational and ancillary drugs administered during the study, * Contraindication to any of the investigational or adjuvant drugs administered during the study * Patient not speaking French

Outcomes

Primary Outcomes

Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF).

Estimation of the incidence of grade 3 and 4 acute GVHD following allo-CSH (excluding post-DLI\* acute GVHD) according to Mount Sinai criteria.

Time frame: Post-transplant through study completion, an average of 1 year

Secondary Outcomes

Incidence of engraftment

Engraftment assessed on hematological reconstitution (number of days of aplasia with PNN \<0.5 G/L and platelets \< 20 G/L, number of platelet and red cell concentrate transfusions)

Time frame: Month 1 post-transplant

Overall survival (OS)

survival between day 0 of transplantation and date of death or last follow-up

Time frame: Post-transplant through study completion, an average of 1 year

Disease-free survival (DFS)

survival between day 0 of transplantation and date of relapse, death or last follow-up

Time frame: Post-transplant through study completion, an average of 1 year

GVHD and relapse-free survival (GRFS)

relapse-free survival without grade 3-4 acute GVHD or chronic GVHD requiring systemic treatment

Time frame: Post-transplant through study completion, an average of 1 year

Incidence of acute GVHD grade 2-4

Acute GVH grade 2-4 according to Mount Sinai criteria

Time frame: Post-transplant through study completion, an average of 1 year

Incidence of chronic GVHD

Chronic GVHD according to NCI criteria

Time frame: From month 3 post-transplant through study completion, an average of 1 year

Incidence of corticoresistant acute GVHD

Acute corticoresistant GVHD according to the criteria of Mohty et al. defined by : * worsening/progression of disease after 3 days of 2mg/kg/day systemic corticosteroid therapy with methylprednisolone (or equivalent), * non-improvement of disease after 7 days of 2mg/kg/day systemic corticosteroid therapy with methylprednisolone (or equivalent), * disease progression to a new organ after treatment with 1mg/kg/day methylprednisolone (or equivalent) in the case of cutaneous or gastrointestinal GVHD or, * recurrence of acute GVHD during or after the corticosteroid reduction phase

Time frame: Post-transplant through study completion, an average of 1 year

Incidence of non-relapse mortality (NRM)

any death unrelated to relapse or disease progression

Time frame: Post-transplant through study completion, an average of 1 year

Incidence of relapse

any documented disease recurrence

Time frame: Post-transplant through study completion, an average of 1 year

Chimerism

Total donor or mixed chimerism. Total donor chimerism = result \>95% donor CD3+ cells. Mixed chimerism = result \>5% and \<95% donor CD3+ cells.

Time frame: At Month1, Month2, Month3, Month6, Month12 post-transplant

Immune reconstitution

T, NK, B lymphocytes and monocytes

Time frame: At Month3, Month6, Month9, Month12 post-transplant

Grade 3 and 4 post-transplant adverse events

Grade 3 and 4 post-transplant adverse events (dates of occurrence) (NCI CTCAE criteria, version number 5)

Time frame: Post-transplant through study completion, an average of 1 year

Incidence of viral, bacteriological, fungal and parasitic infections

Infections: viral (CMV, EBV, BKV, adenovirus), bacteriological, fungal and parasitic

Time frame: Post-transplant through study completion, an average of 1 year

Study Testing Two Conditioning Regimen With a Single Prophylaxis of GVHD by Cyclophosphamide and Methotrexate Post-transplant in Patients Eligible for Matched-donor Allograft Transplantation

Overview

Conditions

Interventions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts