Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Karnofsky Performance Status Score Equal or Lower Than 80%. a Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Thanks to the recent developments in transplant procedures, an increasing number of patients with acute myeloid leukemia (AML) with a poor Karnofsky Performance Status (KPS) score are currently offered an allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, little data is available about outcome of this fragile population.

We report here the results of a retrospective study designed to evaluate outcome of patients with AML undergoing allo-HCT with KPS score ≤80%. The analysis included patients with AML aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score at the time of transplant between 50% and 80%. Patients who received manipulated grafts or had incomplete data about cytogenetics were excluded. Conditioning intensity was defined according to EBMT definitions.

A total of 2,963 patients were identified. Median age at transplant was 55 years (18-77 years). Median year of transplant was 2014. The KPS score was =80% in 85% of the patients and <80% in 15% of the patients. Cytogenetic risk was good, intermediate or poor in 6%, 68% and 26% of the patients, respectively. Donor type was sibling (MSD), matched (10/10 UD), mismatched (9/10 UD) unrelated, haploidentical (haplo) or cord blood (CB) in 47%, 35%, 8%, 6% and 4% of patients, respectively. Conditioning was myeloablative (MAC) or reduced-intensity (RIC) in 42% and 58% of patients. Stem cell source was PBSC or BM in 84% and 14% of the patients. Anti-thymocyte globulin (ATG) was administered to 55% of the patients.

Cumulative incidence of grade II-IV and III-IV acute GVHD (aGvHD) was 26% and 8%, respectively. The 2-year cumulative incidence of chronic GVHD (cGvHD) and severe cGVHD was 38% and 18%. Non-relapse mortality (NRM) and relapse incidence (RI) at 2 years were 19% and 27%, respectively. Notably, in the subgroup of patients with KPS <80% NRM rate was as high as 27%. At 2 years, leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) rates were 54%, 59% and 41%, respectively.

On multivariate analysis, transplant from a MSD was associated with a reduced risk of aGvHD (10/10 UD HR 1.8, 9/10 UD HR 2.4, haplo HR 1.9, CB HR 3.4, p<10^-4, MSD as reference) and NRM (10/10 UD HR 1.4, 9/10 UD HR 2.4, haplo HR 1.8, CB HR 2, p<10^-3, MSD as reference) as compared to all other donor types (Table 1). Transplant from 10/10 UD was associated with lower GRFS (HR 1.2, p=0.03), while 9/10 UD predicted inferior LFS, OS and GRFS (HR 1.6, 1.7, and 1.5, respectively, p<0.001) as compared to MSD. Patients with KPS score of 80% had significantly lower NRM and improved survival as compared to patients with KPS score <80% (NRM: HR 0.6, p<10^-4; OS: HR 0.7, p<10^-4). Other factors independently associated with improved OS were younger age, female sex, good or intermediate risk cytogenetics and de-novo AML. Notably, administration of ATG was associated with reduced risk of developing grade II-IV aGVHD (HR 0.7, p<10^-4), cGVHD (HR 0.6, p<10^-4), severe cGVHD (HR 0.5, p<10^-4) and predicted improved GRFS (HR 0.8, p<0.01).

In order to compare outcome following MAC and RIC conditioning the analysis was restricted to patients receiving transplant from MSD or UD. Patients with a KPS score =80% or <80% were analyzed separately. In the group of patients with a KPS score of 80%, a RIC regimen was associated with higher RI (HR 1.4, p<0.01), higher incidence of severe cGVHD (HR 1.6, p<0.001), and inferior GRFS (HR 1.3, p<0.001) as compared to MAC. NRM was not significantly different following RIC or MAC in this population. In contrast, in patients with a KPS score <80%, RIC was associated with lower NRM (HR 0.3, p<0.0001) and better LFS (HR 0.6, p<0.01), OS (HR 0.5, p<0.0001) and GRFS (HR 0.6, p<0.01) as compared to MAC.

In conclusion, allo-HCT is feasible in patients with acute myeloid leukemia in first remission and KPS score <80%, with acceptable NRM and survival rates. As for the conditioning regimen, in patients with a KPS score of 80% a MAC regimen was associated with lower relapse rate, similar NRM and better GRFS as compared to RIC, while in patients with a KPS score lower than 80% RIC was associated with reduced NRM and improved OS as compared to MAC. In addition, transplant from a MSD predicted a reduced risk of NRM and aGVHD as compared to other donor types. Notably, 9/10 UD was associated with significantly inferior survival as compared to MSD. Finally, administration of ATG correlated with reduced acute and chronic GVHD and improved GRFS.

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