Expression of CD25 on Acute Myeloid Leukemia (AML) Blasts Is An Independent Risk Factor Associated with Refractory Disease, Which May Be Overcome by Stem Cell Transplantation (SCT),
Authors: Cerny Jan , Woods Lesley , Yu Hongbo , Ramanathan Muthalagu , Raffel Glen D , Walsh William V , Petrillo-Deluca Laura J , Tarrasky Natasha M , O'Rourke Elizabeth , Bednarik Jayde L , Woda Bruce , Hutchinson Lloyd , Kroll Aimee , Barton Bruce , Rosmarin Alan G. , Nath Rajneesh 
Published: October 2019

Abstract
Abstract 3560

Introduction:
Acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). LSCs are chemotherapy resistant and responsible for disease recurrence. AML containing a high percentage of LSCs displays aggressive biology in animal models. Using humanized mice Saito et al (Sci Transl Med 2010; 2: 1–11) have recently shown that xenografted CD25+ LSCs initiate AML and are chemotherapy resistant. Confirmation with clinical data from human AML is needed.

Methods:
In order to determine the prognostic impact of CD25 expression on AML outcome we have retrospectively investigated CD25 expression in 56 patients (pts) diagnosed and treated for AML at our institution between 02/2008 to 05/2011. 46 pts who had non-APL morphology, were treated with induction chemotherapy and had an adequate specimen for CD25 assessment were included in further analysis. CD25 expression was assessed in each specimen by flow cytometry and immunohistochemistry and correlated with clinical outcome.

Patients:
Median age was 61 years (22–84), 18 (39%) pts were older than 65; F:M ratio was 19:27, 3 (7%) patients had good risk (core binding factor leukemias), 26 intermediate (diploid karyotype and no good or high risk; 57%) and 17 (37%) high risk cytogenetics (complex, anbormality of 3q26, monosomy 7 and 5). 6 (13%) pts had NPM1mut/FLT3-ITDwt, 6 (13%) pts had NPM1wt/FLT3-ITDmut and 9 (13%) pts had NPM1mut/FLT3-ITDmut. As induction high dose cytarabine/anthracycline based regimen was used in 36 (78%) pts, 7 pts received 7+3 (15%) and 3 (7%) pts received hypomethylating agent. 24 (53%) pts received stem cell transplantation (SCT; 16 [35%] allogeneic and 8 [17%] autologous). The median follow up of the surviving pts was 11.2 months (1.1–38.7).

Results:
CD25 was detected in 17 pts (37%; 16 at diagnosis and 1 at relapse). Six CD25+ pts experienced relapse (3 pts with 3 or more relapses) heralded by increase in the percentage of CD25+ blasts. 65% of pts with CD25+ AML also had FLT3-ITDmut (p=0,0012). When comparing CD25+ and CD25- pts there was no statistical difference in distribution of the following characteristics: sex, age (65+), cytogenetics risk, presence of NPM1mut, type of induction, SCT. Fifteen (88%) of CD25+ pts experienced relapse compared to 8 (28%) of CD25- pts (p= 0.00007), 8 (47%) CD25+ pts died and 9 (31%) CD25- pts died (p=ns). The median relapse free survival (RFS) of all pts was 10.8 months with the median overall survival (OS) 12.2 months. The estimated 6-month RFS was significantly decreased in CD25+ pts compared to CD25- pts (26% vs 79%, p= 0.0003). This did not translate into a difference in OS between both groups (1-year OS: CD25+ 43% vs CD25- 65%, p=ns). In univariate analysis CD25 positivity was a stronger predictor for relapse (HR 5.28 [2.21–12.62], p=0.0002) than FLT3-ITDmut (HR 4.72 [2.04–10.92]; p= 0.0003). In multivariate analysis CD25 positivity was also a stronger predictor for relapse (HR 6.54 [1.34–9.15], p=0.01) than FLT3-ITDmut (HR 4.72 [2.04–10.92], p= 0.03). Pts undergoing SCT had significantly longer 1-year OS (66%) compared to pts without SCT (21%; p=0.0004). In multivariate analysis SCT was a predictor for improved OS (HR 0.2 [0.07–0.57], p=0.0002). CD25+ pts who received SCT had also significantly longer 1-year OS (63%) compared to CD25+ pts who did not receive SCT (0%; p=0.0098). SCT did not impact RFS in either group.

Conclusion:
CD25 represents a novel prognostic factor in AML. The increase in CD25+ blasts at relapse is associated with increased relapsed rate and refractory AML supporting the LSCs hypothesis. The detection of CD25 serves not only as a prognostic marker, but may be valuable for minimal residual disease assessment in patients who lack a molecular marker. In our experience treatment inclusive of stem cell transplantation abrogated the negative impact of CD25 expression on OS. Exploration of CD25 as a therapeutic target in AML is warranted.

Disclosures:
No relevant conflicts of interest to declare.