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NCT06235398

PHASE2

Upfront Related Donor Transplantation in Patients With Myelodisplatic Syndrome : a Phase 2 Trial

Sponsor: Assistance Publique - Hôpitaux de Paris

View on ClinicalTrials.gov

Summary

Three recent prospective "transplant/no transplant" studies concluded to an advantage of OS with transplantation in patients with high or intermediate-2 IPSS risk (not significant in Kröger's study). No prospective randomized trial has assessed the pre-transplant therapy in MDS patients yet but some information can be extracted from these 3 recent studies. In the French study (n=162), 72% patients with a donor received HSCT, previously treated by hypomethylating agent (HMA) in 71% of them. There was a trend to a better survival in patients achieving a complete remission with pre-graft therapy (HR: 0.55, p=0.088) and higher risk of death in unresponsiveness patients transformed into AML (HR: 2.36, p=0.008). In Nakamura's study (n=384), 83% of patients with a donor were transplanted, previously treated by HMA in 68%2. The multivariable Cox model for Overall Survival (OS) and Leukemia-free survival showed an excess risk in patients treated by HMA. Moreover, responders still have a higher risk of mortality as compared to patients who did not receive any pre-graft therapy (HR: 2.417, p=0.0054). In the German study, the aim was to initiate azacytidine at inclusion and to transplant patients after 4 cycles if a donor was identified1. Among 170 registered patients, 162 initiated 5-aza but 36% of them were "lost during this pre-graft therapy" before allocation to "donor" or "no-donor" arm, for different reasons including death (n=12). After 4 cycles of 5-aza, 79/81 patients "donor arm" were transplanted. The multivariable analysis showed remission status did not influence OS. Those 3 previous clinical trials thus suggest that a substantial number of patients planned for transplantation are not transplanted nowadays while no evidence of HMA benefit before HSCT has been clearly identified. This phase 2 study aim to assess the feasibility of upfront HSCT in patients with high risk MDS in order to increase the probability to be transplanted and to achieve a subsequent remission and better survival.

Key Details

Gender

All

Age Range

50 Years - 70 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2024-02-01

Completion Date

2028-02-01

Last Updated

2024-01-31

Healthy Volunteers

Conditions

Myelodysplastic Syndromes

Interventions

BIOLOGICAL

Hematopoietic stem-cell transplantation

Upfront related donor transplantation

Inclusion Criteria: * Age ≥ 50 and ≤ 70 years * An HLA (Human Leukocyte Antigen) matched sibling donor or familial haplo-identical donor has been identified * The disease fulfills at least one of the following criteria: * Intermediate-2 or high risk according to classical International Prognostic Scoring System (IPSS) * Intermediate-1 risk if marrow fibrosis \> grade I or poor risk cytogenetics according to R IPSS or classified high or very high risk according to Revised International Prognostic Scoring System (R IPSS) or if the MDS is therapy-related neoplasm * Usual criteria for Hematopoietic Stem Cell Transplantation (HSCT): * Eastern Cooperative Oncology Group Score (ECOG) ≤ 2 * No severe and uncontrolled infection * Cardiac function compatible with high dose of cyclophosphamide Left Ventricular Function (LVF) \> 50% * Adequate organ function: ASAT and ALAT ≤ 2.5N, total bilirubin ≤ 2N, creatinine clearance ≥ 30 ml/min (according to Cockroft formula) * In case of transplantation with a haploidentical donor, absence of donor specific antibody (DSA) detected in the patient with a MFI \>1000 (antibodies directed towards the distinct haplotype between donor and recipient) * Contraception methods must be prescribed for women of childbearing age during all the study. If cyclophosphamide is used, effective contraceptive methods for men during all their participation in the study * With health insurance coverage * With a written informed consent signed Exclusion Criteria: * Marrow blast \> 15% at time of inclusion * MDS with excess blast \>10% and NPM1 mutation or a recurrent genetic abnormality related to Acute Myeloid Leukemia (AML) (WHO 2022) * Chemotherapy (AML like intensive chemotherapy or demethylating agent) to treat MDS at the current stage * Disponibility of an unrelated donor 10/10 (MUD) in absence of geno-identical donor * Patient with uncontrolled infection * Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix * Renal failure with creatinine clearance \<30ml / min (according to Cockroft formula) * With contraindications to treatments used 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 (II or more) * Patient with seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive PCR Hepatitis B Virus or Hepatitis C Virus * Yellow fever vaccine or any alive vaccine within 2 months before transplantation * Pregnancy (β-HCG positive) or breast-feeding * Who have any debilitating medical or psychiatric illness, which would preclude giving well understand informed consent or optimal treatment and follow-up * Under protection by law (tutorship or curatorship)