Outcome Of Patients With IPSS Intermediate (int) Or High Risk Myelodysplastic Syndrome (MDS) According To Donor Availability: A Multicenter Prospective Non Interventional Study For The SFGM-TC and GFM
Authors: Robin Marie , Porcher Raphael , Ades Lionel , Raffoux Emmanuel , Michallet Mauricette , Francois Sylvie , Cahn Jean-Yves , Delmer Alain , Vigouroux Stephane , Bay Jacques-Olivier , Cornillon Jérôme , Huynh Anne , Nguyen Stephanie , Vincent Laure , Maillard Natacha , Reman Oumedaly , De Latour Regis Peffault , Dombret Herve , Fenaux Pierre , Socié Gérard 
Published: October 2019

Abstract

Background
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for MDS patients (pts). Due to transplant-related mortality, only pts with short life expectancy are referred to HSCT, usually those with IPSS int-2 or high risk. The aim of this prospective study was to compare outcome in candidates for HSCT according to donor availability: no donor, HLA-matched sibling donor, 10/10 HLA-matched unrelated donor and 9/10 HLA-mismatched unrelated donor.

Method
SFGM-TC and GFM centers that had agreed on general recommendations concerning the management of MDS pts participated to the study (16 centers). Transplant indications were int-2 or high IPSS, int-1 with refractory thrombocytopenia or proliferative CMML. Pts were registered in this study if older than 50 years, when they acquired an indication for HSCT and in the absence of comorbidity contraindicating HSCT. A donor research was initiated at registration including HLA-matched sibling donor, HLA-matched unrelated donor (10/10) or mismatched donor for one allele. Other alternative donors (mismatched unrelated cord blood or > 1 mismatched donor) were not accepted. Transplantation was scheduled upfront if bone marrow blasts < 10% at inclusion or after treatment with AML like anthracycline-aracytine chemotherapy (CT) or azacitidine (AZA) if marrow blasts > 10% ideally within 6 months if a donor was identified. Recommended reduced intensity conditioning regimen consisted in fludarabine, busulfan and anti-thymoglobulin with peripheral stem cells (PB) as source of stem cells. Characteristics of pts and disease were compared within 3 groups: no donor, HLA-matched donor (sibling or 10/10), HLA-one mismatched donor (9/10). Overall and disease free survivals (OS, DFS) were compared using Kaplan Meier estimates. Cumulative incidences of complete remission and disease-related mortality were compared using Gray-test.

Results
From April 2007 to January 2013, 163 pts were included: 34 (21%) pts had no donor; 115 (71%) pts had an HLA-matched donor (34% sibling and 37% unrelated) and 14 (9%) pts had an HLA mismatched donor. Groups were well-balanced for age, gender, time from diagnosis to inclusion, WHO classification, bone marrow blasts at time of inclusion, cytogenetic (IPSS) and IPSS classification. WHO classification at time of inclusion was: AML post MDS in 12, RAEB1 in 29, RAEB2 in 82, CMML1 or 2 in 20, RCMD in 14 and other MDS in 6 pts. Cytogenetics were favorable in 49 (30%), intermediate in 37 (23%) and poor in 74 (45%) pts. IPSS was int-1 for 8%, int-2 for 69% and high for 23% of pts.
Median follow-up was 38 months. 117 pts were treated by AZA and 40 by CT. Bone marrow blasts < 10% were achieved in 68% and 57% for pts without and with donor, respectively. 69% of pts with HLA-identical donor and 57% of those with HLA-mismatched donor were transplanted. Some pts with donors were not transplantation because of excess of marrow blasts in most pts (> 10% in 3, > 20% in 20 pts), comorbidities contraindicating the transplantation acquired after inclusion (9 pts), early deaths (7 pts) and other causes in 3 pts. Four other pts scheduled for transplantation have not been transplanted yet. Probability of complete remission 12 months after inclusion was: 39% (95% CI: 22-55), 49% (95%CI: 40-58) and 46% (95%CI: 17-71) for pts without a donor, with an HLA-compatible donor and with HLA-mismatched donor. Disease-related mortality at 48 months was not significantly different in the 3 groups: 50 % (95%CI: 29-68), 38% (95%CI: 27-49), 51% (95%CI: 17-77). DFS was also not different in 3 groups: 18% (95%CI: 7-44), 25% (95%CI: 16-37) and 9% (95%CI: 1-57). In contrast, OS at 48 months was better in pts with HLA-compatible donor than in pts without donor or those with HLA-mismatched donor: 35% (26-49), 17% (6-43) and 8% (1-55), respectively, p=0.011 (Figure 1). The poor survival observed in pts transplanted with an HLA-mismatched donor may be due to their small number and requires further analysis in a larger cohort. Outcome was not different in pts receiving PB from HLA-matched sibling or from HLA 10/10 matched unrelated donor.

Conclusion
In a prospective study, we observed that int-2 or high risk MDS pts with a HLA-matched donor have an improved life expectancy as compared to pts without donor. This study confirmed that they should be referred to the transplantation before acquisition of comorbidity contraindicating HSCT.

Disclosures:
No relevant conflicts of interest to declare.