Allogeneic Hematopoietic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia- a Report from the Acute Leukemia Working Party of the EBMT
Authors: Savani Bipin N. , Labopin Myriam , Boumendil Ariane , Ehninger Gerhard , Ganser Arnold , Ayuk Francis , Stelljes Matthias , Finke Jürgen , Beelen Dietrich W. , Niederwieser Dietger , Stuhler Gernot , Glass Bertram , Arnold Renate , Polge Emmanuelle , Gorin Norbert Claude , Esteve Jordi , Ciceri Fabio , Baron Frederic , Schmid Christoph , Giebel Sebastian , Mohty Mohamad , Nagler Arnon 
Published: October 2019

Abstract
Secondary acute myeloid leukemia (sAML) is a very heterogeneous group of disease derived from myelodysplasia, chronic myeloproliferative disorders or after exposure to chemotherapy and or radiation therapy (therapy related AML) or due to exposure to environmental carcinogens. sAML has traditionally been considered a devastating disease with inferior outcomes compared to de novo AML, affecting a vulnerable population of heavily pretreated, especially older patients. Allogeneic hematopoietic stem cell transplantation (HCT) is the only potential curative therapy and usually considered in patients with low comorbidities and transplant related risk score. However, relapse is the most frequent cause of failure after HCT, occurring in more than 50% of the patients. No systematic large analysis of HCT for sAML is available to study the risk factors and outcome. Therefore, the EBMT Acute Leukemia Working Party has performed a retrospective registry study on patients with sAML (n=4256) undergoing HCT.
Patients who underwent HLA-identical sibling (n=2290) or unrelated donor (n=1966) peripheral blood (n=3781) or bone marrow transplantation (n=475) from 2000 to 2013 are included in the study. All unrelated donors were Human Leucocyte Antigens (HLA)-matched (10/10) (n=1532) or one locus mismatched (9/10) (n=434). 1901 (45%) patients received ablative (MAC) and 2355 (55%) reduced-intensity conditioning (RIC) regimen. Median age at transplant was 56 years, IQR 48-63 (MAC 51, IQR 42-58; RIC 60, IQR 54-64). Median time from diagnosis of sAML to HCT was 6.2 months, IQR 4.1-12.0 (MAC 5.6, IQR 3.8-9.7; RIC 7.0, IQR 4.4-14.12; p<0.0001). At time of transplant, 2313 (54%) patients were in CR1, 278 (7%) in ≥CR2 and active diseases in 1665 (39%) patients. 158 (4%) patients had prior autologous HCT (MAC 58 [3%], RIC 100 [4%], p=0.049). Median follow-up of surviving patients was 26 months (IQR 7 -56).
Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 33% (95% CI, 32-35%) and 25% (95% CI, 24-27%), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 2 years were 46% (95% CI, 44-48%) and 41% (95% CI, 39-43%), respectively. Acute GVHD (grade II-IV) occurred in 1043 (26%) patients. The 2-year cumulative incidence of chronic GVHD was 54% (95% CI, 51-56). Two year OS, LFS, RI and NRM of MAC and RIC groups were 48% (95% CI, 46-50) vs. 44% (95% CI, 42-47), p=0.06, 44% (95% CI, 41-46) vs. 39% (95% CI, 37-41), p=0.003, 30% (95% CI, 28-32) vs. 36% (95% CI, 34-38), p<0.0001, 26% (95% CI, 24-28) vs. 25% (95% CI, 24-27), p=0.273, respectively. Two year OS of patients in CR1, ≥CR2 and active disease before HCT was 54% (95% CI, 52-56), 45% (95% CI, 39-52) and 35% (95% CI, 33-38), respectively (p<0.0001).
In multivariate analysis adjusted for variable with different distribution between groups, the type of conditioning (RIC vs. MAC) had no impact on OS and LFS, however RIC group had higher RI (HR, 1.3, 95% CI 1.12-1.44, p=0.0001) and lower NRM (HR 0.8, 95% CI 0.72-0.96, p=0.01). Older age at HCT was an independent adverse prognostic factor for OS, LFS and NRM. Time from diagnosis to HCT had no impact on transplant outcome. Patients receiving PB grafts had superior OS (HR 0.84, 95% CI 0.73-0.97, p=0.01), LFS (HR 0.85, 95% CI 0.74-0.97, p=0.02) and lower RI (HR 0.83, 95% CI 0.70-0.99, p=0.049) compared with BM. Patients in remission and receiving HCT from HLA-identical siblings were independently associated better outcome.
In summary, our registry study in the largest cohort of patients studied so far receiving HCT for secondary AML, demonstrated that about 45% of patients with secondary AML can attain long term survival after HCT. Patients receiving ablative regimens were associated with lower relapse risk and patients in remission had superior survival. Patients receiving PB grafts were associated potent graft-versus leukemia effects with decreased relapse risk and improved survival. Post- transplant pre-emptive therapy to decrease relapse risk might improve outcome further in these high risk populations.

Disclosures
Niederwieser: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Schmid:Janssen Cilag: Other: Travel grand; Neovii: Consultancy.