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

Phase 2

Not yet recruiting

• Conditions: Myelodysplastic Syndromes
• Interventions: Biological: Hematopoietic stem-cell transplantation

• Registration Number: NCT06235398
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief 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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2023-08
• Study First Submitted: 2024-01-23
• Study First Submitted QC: 2024-01-23
• Last Update Submitted: 2024-01-23
• Study First Posted: 2024-01-31
• Last Update Posted: 2024-01-31
• Study Start: 2024-02-01
• Primary Completion: 2028-02-01
• Study Completion: 2028-02-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 55

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Adults with Myelodysplasic Syndrome diagnosis	Hematopoietic stem-cell transplantation	Adults (Age ≥ 50 and ≤ 70 years) patients with MDS diagnosis for whom transplantation is indicated from a related donor identified.

Primary Outcome Measures

Name	Time	Method
Disease-free survival	2 years after transplantation

Secondary Outcome Measures

Name	Time	Method
Cumulative incidence of transformation into acute myeloid leukemia from inclusion	2 years after inclusion
Percentage of engraftment	3 months after transplantation	Engraftment is defined by hematological recovery and donor chimerism \> 95%
Overall survival	2 years after transplantation
Non-relapse mortality	2 years after transplantation
Incidence of acute Graft versus Host Disease (GvHD) and grading	100 days after transplantation
Incidence of chronic GvHD and grading	2 years after transplantation
Percentage of graft failure	2 years after transplantation	Graft failure is defined by acute or late rejection and non-engraftment
Incidence of severe infections	24 months after transplantation	Severe infections are defined by Common Terminology of Adverse Events grade 3-4
Incidence of cardiac events	3 months after transplantation	CTAE grade 2-4