upfront related donor transplantation in patients with myelodisplatic syndrome : a phase 2 trial

Conditions: Myelodysplastic Syndromes

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)