Outcome Of Patients With Abnl(17p) Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Middeke Jan Moritz , Fang Min , Cornelissen Jan , Appelbaum Frederick R. , Mohr Brigitte , Stadler Michael , Sanz Miguel , Baurmann Herrad , Bug Gesine , Schäfer-Eckart Kerstin , Hegenbart Ute , Bochtler Tilmann , Stölzel Friedrich , Walter Roland B. , Ehninger Gerhard , Bornhäuser Martin , Löwenberg Bob , Schetelig Johannes 
Published: October 2019

Abstract

Purpose
Patients with acute myeloid leukemia (AML) and abnormalities (abnl) of the short arm of chromosome 17 (17p) are considered to be at high risk of treatment failure after conventional chemotherapy. Small studies have suggested that this abnormality may portend a poor prognosis even after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to assess the prognostic role of abnl(17p) in a larger cohort of patients with AML undergoing allogeneic HSCT, and to analyse the impact of disease status, conditioning regimen, and type of abnormality. Here, we present data on the outcome of 201 patients with abnl(17p) AML transplanted since 2000.

Patients and Methods
We performed a retrospective cohort analysis based on study-registries from two AML groups, HOVON and SAL, and transplant-registries of the Fred Hutchinson Cancer Research Center (FHCRC) and the German Cooperative Transplant Study Group (GCTSG). Inclusion criteria were AML diagnosed according to the current WHO criteria with 17p abnormalities and a first HSCT between January, 1, 2000 and January, 1, 2011. Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after HSCT are reported for the whole cohortand for patients receiving HSCT in first complete remission (CR1). We tested for center effects (FHCRC, HOVON, SAL, GCTSG) in a multivariate Cox regression model.

Results
Data from 201 patients with full information on the karyotype were analysed. The median age was 54 years with a range from 2 years to 75 years. Five patients were younger than 18 years. Sixty-one percent of the patients suffered from de novo AML, while 26% had secondary AML and 11% therapy-related myeloid neoplasm. Complex and monosomal karyotypes were present in 90% and 77% of patients, respectively. Eighty-four patients (42%) were in CR1 at the time of HSCT. Seventy patients (35%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining patients received reduced intensity conditioning (RIC). Donors were matched siblings in 34%, matched unrelated donors in 43% and partially matched or mismatched unrelated donors in 18% of the patients. Eight patients (4%) had a haploidentical donor.
At the time of analysis 30 patients were alive with a median follow-up of 30 months (range 1 to 121 months). At three years, the probabilities of OS and EFS were 15% (95% CI, 10% to 20%) and 12% (95% CI, 7% to 16%), respectively, whereas the CIR was 49%. For patients transplanted in CR1 the probability of OS at three years was 22% (95% CI, 13% to 32%) compared to 9% (95% CI, 3% to 15%) for those with advanced disease (p=<.001). The main cause of treatment failure was relapse. The CIR at three years was 57% in patients who were transplanted in CR1 compared to 42% in patients with more advanced disease (p=.0912). Notably, 70% of the observed relapses occurred within the first six months after HSCT. NRM was also high within the first six months, mainly among patients with advanced disease (40% NRM in advanced stages compared to 14% in CR1; p=<.001). In multivariate analysis only age (HR=1.02; p=.01) and disease status (HR=0.52; p=.007) had a significant influence on OS. No significant differences in outcomes were observed between the different types of abnormalities regarding OS, EFS, CIR and NRM, but patients with a monosomal karyotype had worse outcome compared to patients with a non-MK karyotype (3-year OS 11% versus 29%, p=.003).
The incidence of grade II to IV acute GvHD up to day 100 was 32% while grade III to IV occurred in 11% of the patients. Due to the high frequency of competing events (death or relapse before onset of GvHD) the cumulative incidence for chronic GvHD at one year was very low with 8%.

Conclusion
Patients with abnl(17p) AML have a poor outcome after HSCT. The observation of better outcome in patients with less advanced disease stages and without MK argues against primary resistance to allogeneic immune effects of 17p abnormalities. While transplantation in CR1 may still be considered the treatment of choice due to the lack of more promising alternatives, novel strategies to prevent relapse are highly warranted for this group of patients. For patients with abnl(17p) AML in more advanced stages experimental approaches should be considered.

Disclosures:
No relevant conflicts of interest to declare.