Abstract
Background: Acute myeloid leukemia (AML) is an aggressive malignancy associated with poor long-term outcomes. This malignancy arises in the context of an immunosuppressive milieu, which fosters immune escape and tumor growth. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature myeloid cells with immunosuppressive activity, the most potent of which are the monocytic MDSCs (mMDSCs). The presence of mMDSCs within the bone marrow microenvironment of patients with AML, along with their impact on disease relapse and overall survival has yet to be fully characterized. Therefore, we sought to address this unanswered question through a retrospective analysis of a cohort of AML patients (pts) at Roswell Park Comprehensive Cancer Center.
Methods: Medical records were retrospectively reviewed under an IRB approved protocol in order to identify pts aged 18-70 years old with normal karyotype (NK) AML treated with standard cytarabine and anthracycline based chemotherapy with refractory or subsequent relapsed disease. Demographics, disease-specific variables, baseline clinical characteristics, treatment response, and adverse events were analyzed using descriptive statistics. Overall survival and relapse-free survival were estimated utilizing Kaplan-Meier (KM) analysis. Detailed analysis of previously collected clinical multiparameter flow cytometric data was performed utilizing WinList software to identify mMDSCs at serial clinical time points (diagnosis, after induction chemotherapy, and relapse). A mononuclear gate was created utilizing CD45 vs. SSC (blasts excluded), followed by FSC vs. SSC to eliminate dead cells and aggregates. Based on the scientific literature, mMDSCs were defined as the subset of marrow cells co-expressing CD14+ and HLA-DR dim, and was reported as the percentage of total monocytes in the marrow aspirate sample.
Results: Six pts with NK-AML who received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE) were identified. Mean age was 56 years (range 35 - 67), with 3/6 male pts (50%) (Table 1). NPM1 was mutated in 2/6 pts at diagnosis, with no FLT3-ITD mutations identified. In addition, 2 pts had an elevated WBC at presentation. Following induction therapy, 2 pts had primary refractory disease with four achieving complete remission (CR). Furthermore, each of the 6 pts relapsed. All 6 pts had marrow aspirate samples containing detectable mMDSCs by flow cytometry at multiple time points. Of note, 5 of 6 pts had elevated mMDSCs (average 76.2%; range 72.8% - 82.6% of total marrow monocytes) detected at time of response assessment following induction. Median relapse-free survival was 48 months (Figure 1). Overall survival not yet been reached. Mean duration of follow up was 85 months (range 61 - 119 months).
Conclusions: This retrospective analysis suggests that high numbers of marrow mMDSCs (>72%) are associated with relapsed/refractory AML in a small patient cohort. Of note, other risk factors for refractory/relapsed disease (i.e. elevated WBC at presentation and FLT3 mutation) were not consistently present in our cohort, thus supporting a potential role of mMDSCs in promoting disease recurrence. Additional studies to further quantify and delineate the biological role of mMDSCs in a larger pt cohort are needed to corroborate these findings and determine the potential role of these immune cells in therapy resistant AML.
Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.
