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

Myelodysplastic Syndromes Clinical Trial

— FIRST ALLO MDS  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06235398
• Other study ID #: APHP221273
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: February 1, 2024
• Est. completion date: February 1, 2028

Study information

• Verified date: August 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Marie Robin, Dr
• Phone: +33142499639
• Email: marie.robin[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 55
• Est. completion date: February 1, 2028
• Est. primary completion date: February 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 70 Years

Eligibility

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 (ß-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)

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Syndrome

Intervention

Biological:
• Hematopoietic stem-cell transplantation
Upfront related donor transplantation

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free survival		2 years after transplantation
Secondary	Overall survival		2 years after transplantation
Secondary	Non-relapse mortality		2 years after transplantation
Secondary	Cumulative incidence of transformation into acute myeloid leukemia from inclusion		2 years after inclusion
Secondary	Incidence of acute Graft versus Host Disease (GvHD) and grading		100 days after transplantation
Secondary	Incidence of chronic GvHD and grading		2 years after transplantation
Secondary	Percentage of engraftment	Engraftment is defined by hematological recovery and donor chimerism > 95%	3 months after transplantation
Secondary	Percentage of graft failure	Graft failure is defined by acute or late rejection and non-engraftment	2 years after transplantation
Secondary	Incidence of severe infections	Severe infections are defined by Common Terminology of Adverse Events (CTAE) grade 3-4	3 months after transplantation
Secondary	Incidence of severe infections	Severe infections are defined by Common Terminology of Adverse Events grade 3-4	6 months after transplantation
Secondary	Incidence of severe infections	Severe infections are defined by Common Terminology of Adverse Events grade 3-4	12 months after transplantation
Secondary	Incidence of severe infections	Severe infections are defined by Common Terminology of Adverse Events grade 3-4	24 months after transplantation
Secondary	Incidence of cardiac events	CTAE grade 2-4	1 month after transplantation
Secondary	Incidence of cardiac events	CTAE grade 2-4	3 months after transplantation