Upfront Related Donor Transplantation in Patients With Myelodisplatic Syndrome : a Phase 2 Trial (FIRST ALLO MDS)

Assistance Publique - Hôpitaux de Paris

Status and phase

Not yet enrolling

Phase 2

Conditions

Myelodysplastic Syndromes

Treatments

Biological: Hematopoietic stem-cell transplantation

Study type

Interventional

Funder types

Other

Identifiers

NCT06235398

APHP221273

Details and patient eligibility

About

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.

Enrollment

55 estimated patients

Sex

All

Ages

50 to 70 years old

Volunteers

No Healthy Volunteers

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)