Chen, Dong

7059 Background: TP53-mutated ( TP53mut) myeloid neoplasms (MN) are aggressive leukemia with poor survival. A subset of TP53mut MN is preceded by TP53mut CCUS that is conventionally considered to be high-risk premalignant condition, though evidence supporting the notion is lacking. We studied outcomes of TP53mut CCUS compared to TP53 wild-type ( TP53wt) CCUS. Methods: Mayo Clinic Molecular Hematology Database (N=7593) was queried to identify patients (pts) harboring pathogenic variant(s) in exons 4-11 of the TP53 gene with ≥2% variance allele frequency (VAF). CCUS was defined using the 5th edition of the WHO Classification for MN. Results: Of 457 pts with TP53mut, 29 (5.9%) had TP53mut CCUS. The median age at diagnosis was 67 years, 17 (59%) were female, and 20 (69%) had received cytotoxic therapies. One and ≥2 TP53mut were seen in 26 (89.6%) and 3 (10.3%) pts, respectively. Median TP53mut VAF was 9% (range 3-42), 3 had TP53mut VAF ≥20%, and 4 (14%) had non-MDS defining cytogenetic anomalies. Of 16 pts with available follow up evaluation (median interval 22 months, Table), 3 (10.3%) progressed to TP53mut MN at 5, 13, and 14 months from diagnosis. We next compared outcomes of TP53mut CCUS to TP53wt CCUS (n=138). The proportion of pts developing MN was not different between TP53wt and TP53mut CCUS (18.1 vs 10.3%, P= .42). Progression free survival of TP53mut CCUS was comparable to TP53wt CCUS at 1- (77 vs 83%), 2- (67 vs 67%), and 5-years (67 vs 59%, P=.9). Similarly, overall survival of TP53mut vs TP53wt CCUS at 1- (81 vs 89%), 2- (76 vs 76%), and 5-years (76 vs 67%) was comparable ( P= .94). Conclusions: In contrast to the prevalent notion, TP53mut was not associated with a higher risk of MN progression or mortality compared to TP53wt CCUS. Majority of TP53mut clones showed remarkable stability over years. [Table: see text]

Introduction: Patients who develop therapy-related myeloid neoplasms (t-MN) have dismal outcomes. Previous studies reported the incidence and risk factors associated with t-MN development. Lenalidomide, in the setting of oral, but not intravenous, melphalan is associated with a higher risk of t-MN (Palumbo et. al, Lancet Oncology, 2014). We carried out this study to evaluate the clinical and pathologic features of t-MN, therapies employed, and factors that predict long-term survival after diagnosis. Patients and methods: We identified patients who received the first ASCT 1998-2016 at our institution. t-MN was defined per the WHO 2016 classification. Median overall survival (OS) was calculated from the time of t-MN diagnosis to last follow-up or death. Statistical analyses were performed using SAS (JMP v14.1) or GraphPad Prism (v7). Results: Out of 2115 patients that underwent at least one ASCT, 53 (2.5%) developed t-MN. Thirty-five of 53 (66%) patients who developed t-MN had received lenalidomide. Among 2062 patients that did not develop t-MN, 916 (44.4%) patients received lenalidomide. Lenalidomide exposure was associated with development of t-MN (χ2 with Yate's correction 8.9, p=0.003). Ten patients were excluded from further analyses due to lack of follow up. Clinical characteristics are shown in Table 1a (N=43). Median age at t-MN diagnosis was 70 years (range 44-79). Median time from ASCT to t-MN was 5 years (range 1-15). After a median follow-up of 70 months (95% CI, 38-134), the median OS was 12 months (95% CI, 9-17, Figure). Primary causes of death were t-MN (71%), MM (12%), both (6%), and other including infection, GVHD, and unknown (12%). Seven (16%) had t-AML and 36(84%) had t-MDS. Three (42%) of 7 patients with t-AML had pure erythroid phenotype. At the time of last follow-up, 9 (21%) were alive. Seven (17%) underwent two ASCT, 16 (36%) received more than 2 years cumulative dose of lenalidomide. Median number of cycles of alkylator therapy including high-dose melphalan (HDM) used for ASCT was 2 (range 1-6). On univariate analysis, factors predicting OS from t-MN diagnosis were ≥ 2 alkylator vs. < 2 cycles (11 vs. 27 months, p=0.02), ≥10% vs. <10% blast at the time of t-MN diagnosis (5.5 vs. 17 months, p=0.01), and the presence of complex karyotype (CK) vs. not (11 vs. 17 months, p=0.03). There was no difference in survival among t-MDS patients who transformed to t-AML vs. those who did not, those who received 1 vs. 2 ASCT, and those with lenalidomide duration ≥ 2 vs. <2 years. On multivariate analysis, the number of alkylator therapies and CK, but not % blasts predicted OS from t-MN diagnosis (Figure). Eight (19%) patients proceeded to receive an autologous (n=4) or allogeneic (n=4) transplant for t-MN (Table 1b). There was no survival advantage for patients who underwent SCT for t-MN, compared to those who did not (17 vs. 10 months, p=0.3). Similarly, there was no survival advantage for patients who received allo SCT compared to auto SCT (21 vs. 16 months, p=0.7). Survival for t-MDS and t-AML was also not different (15 vs. 6 months, p=0.2). There is only one long-term survivor in the transplant group (s/p allogeneic SCT). Four of seven (57%) patients died of progressive t-MN, 1 died of progressive MM, progressive MM and t-MN, and TRM each. Conclusions: Lenalidomide, in the setting of HDM, is associated with an increased risk of t-MN. Increased exposure to alkylators, a higher tumor burden, and the presence of CK predict poor survival in t-MN. As HDM/ASCT followed by lenalidomide maintenance remains the standard of care for eligible patients, minimizing exposure to other alkylator regimens may be prudent. While considered the standard, only a minority undergo transplant; and post-transplant outcomes remain poor. Studies to identify prognostic genetic and epigenetic risk factors are ongoing. Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: CD123 (alpha chain of the interleukin-3 receptor [IL-3RA]) heterodimerizes with CD131 (βc, common beta chain) to constitute the high-affinity receptor for IL-3. CD123 is not expressed on hematopoietic stem/progenitor cells from normal bone marrow (BM). In contrast, CD123 is highly expressed in CD34+/CD38- cells from acute myeloid leukemia (AML) patients, which recapitulate the leukemic phenotype in NOD/SCID mice; CD123, therefore, is a marker for leukemic stem cells in AML (Jordan CT et al., Leukemia 2000). CD123 is also highly expressed on CD4+/56+ leukemic cells in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematodermic neoplasm. The validity of CD123 as a rational therapeutic target was illustrated by clinical efficacy data for SL-401, a biologic target therapy directed to IL-3R, in patients with BPDCN and AML, respectively (Frankel AE et al., Blood 2014 andFrankel AE et al., J Clin Oncol 31, 2013 (suppl; abstr 7029)). Objectives: To study CD123 expression as a potential therapeutic target in myeloproliferative neoplasms (MPN). Methods: The study was approved by our institutional review board and patients provided written consent for sample collection. MPN diagnosis was based on WHO 2008 criteria. Surface antigen expression on hematopoietic cells of various lineages was interrogated using the 4-color multiparametric flow cytometer, FACSCaliber TM (BD Biosciences, San Jose, CA). Data analysis was performed using CellQuest Pro Software (BD Biosciences). Results: We studied a total of 21 MPN patients and 3 normal controls. Of the former, 14 patients had systemic mastocytosis (SM) (indolent SM=9, SM with associated myeloid neoplasm=4 and aggressive SM=1), 6 had primary myelofibrosis (PMF) and 1 had eosinophilic leukemia transformed to AML. Normal controls: Three normal BM samples were studied; the number of CD123 positive cells in the total population was <1%. Rare CD34+/CD38- cells were uniformly CD123-. Of the CD123+ cells, only a minor subset (<10%) coexpressed myeloid/granulocyte lineage (CD13+, CD15+ or CD16+) or monocyte/macrophage lineage (CD14+ or CD11b+) markers. Systemic mastocytosis: The data were informative for 6 patients (3 with peripheral blood [PB], 1 with BM, and 2 with paired PB and BM samples) for whom a sufficient number of mast cells (MC) were identified for immunophenotyping. Neoplastic MC were defined as CD117 hi/SSC hi/CD45 hi/CD34-/CD25+/FcεRI+. CD123 expression was seen in the majority of MC for 4 patients (#1-4, CD123 percentage positive, PB/BM): 91%/n.a. (#1), 75%/81% (#2), 84%/n.a. (#3), and 88%/n.a. (#4). In contrast, one patient (#5) had a minority of CD123+ MC (33%/28%). Clonal eosinophilia: PB was studied; the WBC differential count showed 41% leukemic blasts and 57% eosinophils (both confirmed to be clonally related based on FISH studies). Both cell populations were predominantly CD123+ (≥90%). Primary myelofibrosis: We studied PB samples from 6 PMF patients. Approximately 1-2% of circulating cells marked as CD123+; of these, expression was notable on CD34-/CD38+ cells (median 54%; range 41-74% positive). We found a larger proportion (30-50%) of CD123+ cells that coexpressed CD13+, CD16+ or CD11b+ representing monocytes, immature myeloid cells and granulocytes, as compared to normal BM controls. Studies on BM samples from PMF patients are ongoing. Conclusions: CD123 (IL-3RA) is expressed on relevant primary cells of interest in select MPNs, namely neoplastic mast cells in SM patients and eosinophils in clonal eosinophilia patients. In PMF, a minor population of circulating cells was CD123+ with a biased distribution on myeloid lineage cells as compared to normal BM samples. We are currently studying CD123 expression in additional MPN patients, and also analyzing CD123 expression on BM trephine biopsies by immunohistochemistry. In addition, the cytotoxicity assessment of SL-401 against MPN cell lines and primary cells is ongoing. Overall, the aforementioned data support the clinical development of SL-401 in patients with MPNs and clinical trials are currently being planned. Disclosures Brooks: Stemline Therapeutics: Employment, Equity Ownership. Pardanani:Stemline Therapeutics Inc.: Research Funding.