Clinical trial NCT06235398: Upfront Related Donor Transplantation in Patients With Myelodisplatic Syndrome : a Phase 2 Trial
Official title: Upfront Related Donor Transplantation in Patients With Myelodisplatic Syndrome : a Phase 2 Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-01-31
Enrollment: 55
Sex: ALL
Minimum age (years): 50
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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)

Primary outcomes:
measure: Disease-free survival
timeFrame: 2 years after transplantation
Secondary outcomes:
measure: Overall survival
timeFrame: 2 years after transplantation
measure: Non-relapse mortality
timeFrame: 2 years after transplantation
measure: Cumulative incidence of transformation into acute myeloid leukemia from inclusion
timeFrame: 2 years after inclusion
measure: Incidence of acute Graft versus Host Disease (GvHD) and grading
timeFrame: 100 days after transplantation
measure: Incidence of chronic GvHD and grading
timeFrame: 2 years after transplantation
measure: Percentage of engraftment
timeFrame: 3 months after transplantation
measure: Percentage of graft failure
timeFrame: 2 years after transplantation
measure: Incidence of severe infections
timeFrame: 3 months after transplantation
measure: Incidence of severe infections
timeFrame: 6 months after transplantation
measure: Incidence of severe infections
timeFrame: 12 months after transplantation
measure: Incidence of severe infections
timeFrame: 24 months after transplantation
measure: Incidence of cardiac events
timeFrame: 1 month after transplantation
measure: Incidence of cardiac events
timeFrame: 3 months after transplantation
Other outcomes:
Locations:
Study officials:
References: