Unmanipulated Graft Haploindentical Allogeneic Stem Cell Transplantation (Haplo-SCT) In Acute Leukemia: A Long-Term Follow-Up Survey On Behalf Of The Acute Leukemia Working Party (ALWP) Of The European Group For Blood and Marrow Transplantation (EBMT)
Authors: Piemontese Simona , Ciceri Fabio , Labopin Myriam , Gorin Norbert Claude , Huang He , Di Bartolomeo Paolo , Wu Depei , Beelen Dietrich , Koc Yener , Afanasyev Boris V , Bacigalupo Andrea , Tischer Johanna , Arcese William , Mohty Mohamad 
Published: October 2019

Abstract
on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Background
The use of an unmanipulated graft is increasingly adopted in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) from haploidentical family donors.

Methods
This survey aimed to assess the outcome of adult patients with de novo acute leukemia (AL) who were reported to the EBMT registry, and who received an unmanipulated peripheral blood (PB) and/or bone marrow (BM) graft from a haploidentical family donor between 2007 and 2011. 106 patients with consolidated follow-up and fully audited data were selected for the purpose of this analysis.

Results
The median folllow-up was 36.2 months (range, 1.3-66.1). 74 pts received a haplo-SCT for acute myeloid leukemia (AML, 70%), 31 pts for acute lymphoblastic leukemia (ALL, 28%) and 1 pt for acute biphenotypic leukemia (1%). The haplo-SCT was the first allogeneic transplant for all the patients. However, 17 pts had previously received an autologous SCT (16%). 26 pts were transplanted in CR1 (24%), 27 pts in CR2 or higher CR (26%) and 53 pts in more advanced disease (50%). The number of HLA mismatches was 2 in 16 pts (15%), 3 in 14 pts (13%), 4 in 27 pts (26%) and 5 in 44 pts (46%). Median age at time of haplo-SCT was 46 years (range, 18-66). 81 pts out of 106 received a reduced-intensity conditioning regimen (RIC, 76%). 92 pts received anti-thymocyte globulins (87%) as part of the conditioning regimen and 5 pts received alemtuzumab (4.7%). Stem cell source was bone marrow (BM) for 37 pts (35%) and peripheral blood (PB) for 69 pts (65%). Median dose of infused CD34+ cells was 2x10e6/kg (range, 0.85-5.3) for BM and 8x10e6/kg (1.72-13,19) for PB. Donor median age was 38 years (range, 19-71). 26 male pts received a graft from a female donor (24%). CMV donor/host serostatus was as follow: neg/neg for 13 pts (12%), pos/neg for 9 pts (9%), neg/pos for 25 pts (24%) and pos/pos for 57 pts (55%), missing for 2 pts. Finally, the Karnofsky Performance Status (KPS) at time of haplo-SCT was >80% for 74 pts (71%), < or = 80% for 30 pts (29%) and missing for 2 pts. 98 out of 106 pts engrafted (96.1%), with a median time for reaching ANC >0.5x10e9/L of 17.5 days (range, 11-63). The cumulative incidence of grade II or higher acute GvHD was 30±4%. The 2-years incidence of chronic GvHD was 39±5% (n=41: 23 limited, 18 extensive). At 3 years, the estimates of leukemia-free survival (LFS) for pts transplanted in CR1, CR2 or in advanced disease were 54±10%, 37±9%, 12±5%, respectively. The estimates of overall survival (OS) were 67±10%, 48±10% and 11±5%, respectively. The cumulative incidences of relapse (RI) were 37±10%, 26±9% and 59±7%, respectively. Non-relapse mortality (NRM) incidences were 8±6%, 37±9% and 29±6%.
In a multivariate analysis including all relevant factors for LFS, disease status at transplant was found to be significant (HR=2.89; 95%CI:1.73-4.83; p=0.0001) in conjunction with the number of HLA mismatches >3 (HR=1.69; 95%CI: 1-2.86; p=0.05). Disease status and number of HLA mismatches (>3) were also significant risk factors for OS: (HR=3.79; 95%CI:2.24-6.39; p<10-3) and (HR=1.87; 95%CI: 1.06-3.30; p=0.03,), respectively. For RI, 2 factors were identified: disease status (HR=3.94; 95%CI: 2.10-7.39; p<10-3) and patient age (≥35y) (HR=2.57; 95%CI: 1.13-5.85; p=0.02). Finally, the number of HLA mismatches (>3) was the only significant parameter associated with NRM (HR=3.06; 95%CI: 1.05-8.93; p=0.04).

Conclusion
These data suggest that unmanipulated graft haplo-SCT is a valid treatment option in acute leukemia. We are currently completing this EBMT survey to include all patients reported to the registry (> 350 patients). The current LFS and NRM rates support the use of such transplant approach as part of the treatment algorithms for adult acute leukemia patients with an indication to allogeneic SCT but lacking an HLA-identical sibling or matched-unrelated donor.

Disclosures:
No relevant conflicts of interest to declare.