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Introduction: Myeloid neoplasms occurring after exposure to chemo- and/or radiotherapy, termed Therapy-related myeloid neoplasms (T-MN), are considered poor prognosis. This perception creates an inherent bias in treatment decision, resulting in either over- (allo-HSCT) or under-treatment (palliation) and exclusion from most clinical trials. The optimal T-MN treatment paradigm is unknown, partly because its mutational architecture is not well defined. Few small studies show mutations in only 50-60% (Ok, Leuk Res 2015; Lindsley, Blood 2015) of T-MN (compared to 80-90% in PMDS). This study compares the mutational architecture of T-MN and PMDS from the South Australian Myelodysplastic Syndrome registry. Methods: Demographic, clinical and laboratory data including cytogenetic profiles of 129 T-MN (95 T-MDS; 34 T-AML [≥20% blasts]) and 108 PMDS patients were analysed. Targeted Massively Parallel Sequencing of a custom panel of 43 myeloid neoplasms associated genes (all coding regions) was performed on diagnosis bone marrow samples. Mutations with VAF ≥3% were selected for further assessment. Overall survival (OS) was calculated from date of diagnosis to date of last follow-up or death and adjusted using time varying covariate to account for disease modifying therapy (DMT) exposure. Results: Compared to PMDS, T-MN patients were younger at diagnosis (71.1 vs 75.3 years, p Although the OS was poorer for T-MN than PMDS (10.6 vs 31.4 mo, p As expected, VL or Low risk T-MN patients were different from T-MN with intermediate, High or VH IPSS-R score (n=74) who showed higher frequency of high-risk karyotypes and poorer OS. Additionally, the mutation profile was also different between the two groups; TP53 mutations were less common while TET2, SF3B1, IDH2 mutations were significantly more frequent in low-risk T-MN. Conclusions: In our cohort, somatic mutations were seen in 93% of T-MN which is higher than published literature. TP53 and spliceosomal mutations were commonest in T-MN and PMDS, respectively. Although, the T-MN survival is poorer than PMDS, the subgroup with IPSS-R Very Low or Low risk mirrors clinical and genetic characteristics of PMDS and has similar outcome. Such patients should be managed at par with PMDS counterparts and, importantly, should not be excluded from appropriate clinical trials based on pre-MDS chemotherapy or radiotherapy exposure. Disclosures Hiwase: Novartis: Research Funding; Celgene: Research Funding.

Despite major breakthroughs in melanoma drug development, there remains a need for new drugs and novel approaches. Of the three forms of skin cancer, malignant melanoma has the most significant impact on human health carrying the highest risk of mortality from metastasis. An estimated 87,110 new cases of invasive melanoma will be diagnosed and 9,730 people will die of melanoma in the USA in 2017. Melanoma accounts for less than one percent of skin cancer cases, but the vast majority of skin cancer deaths. The vast majority of melanomas are caused by the sun. In fact, one UK study found that about 86 percent of melanomas can be attributed to exposure to ultraviolet (UV) radiation from the sun. The estimated 5-year survival rate for patients whose melanoma is detected early is about 98 percent in the USA, whereas, the survival rate falls to 62 percent when the disease reaches the lymph nodes, and 18 percent when the disease metastasizes to distant organs. Thus, novel effective therapies are urgently needed to treat this disease. The Isatin (1H-indole-2,3-dione) is found as an endogenous molecule in humans and other mammals and its analogs display diverse types of biological activities including anti-cancer activities. Earlier our group synthesized a novel series of 5,7-dibromoisatin analogs. Various melanoma cells were treated with several Isatin derivatives having functional groups like selenocyanate, thiocyanates, thiourea, and selenourea for 72 hours and the cell survival was estimated by MTS assay. Agents were treated with melanoma cell lines UACC 903, 1205 Lu or normal fibroblast cell line FF2441. Treatment with KS99, a thiocyanate analog and KS101, a selenourea analog of 5,7-dibromoisatin effectively killed melanoma cells after 72 h treatment. Overall, IC50 values of Isatin derivatives on melanoma cell lines were 3.0-5.7μM and 2.1-5.7μM, respectively. IC50 value on normal fibroblast cells with these Isatin derivatives was 5.4-20.7μM. KS101 was toxic to the xenograft mice at 1mg/kg body weight, animals developed vein inflammatic symptoms after 20 days of treatment. However, liposomal formulation of KS101 was safe up to 30mg/kg body weight in 1205 xenografted nude mice when treated alternate days by tail vein injection. The melanoma tumor burden was reduced by 47%. We will discuss structural activity relationship (SAR) of Isatin derivatives, and its in vitro and in vivo inhibitory effects against melanoma. Citation Format: Dhimant H. Desai, Raghvendra Gowda, Krishne Gowda, Saketh S. Dinavahi, Gavin P. Robertson, Shantu G. Amin. Inhibition of melanoma development by Isatin analogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2806.

Introduction: Therapy-related myeloid neoplasms (T-MN; inclusive of T-MDS and T-AML) are aggressive neoplasms occurring after exposure to chemo (CT) and/or radiotherapy (RT) and are characterized by poor prognosis. Unlike primaryMDS and AML, the mutational architecture of T-MN has not been well elucidated. Most published studies in T-MN are small in size with a restricted panel of genes tested. Here we compare the cytogenetic and mutation profile of T-MN and primary MDS patients from the South Australian Myelodysplastic Syndrome (SA-MDS) registry. Methods: Demographic, clinical and laboratory data including cytogenetic profile of 147 T-MN and 744 primary MDS patients were analysed. Targeted Massively Parallel Sequencing of a custom panel of 27 myeloid genes (all coding regions) was performed on bone marrow samples from 60 T-MN and 142primary MDS patient samples. Results: Median age of T-MN and primary MDS was 71 (20-91) and 73 years (19-98), respectively. In T-MN patients the most frequent primary neoplasms were lymphoproliferative neoplasms (n=56, 38%) and prostate cancer (n=22, 15%). Sixty-three (43%) patients had received CT only, 34 (23%) patients RT only, and 48 (33%) patients had received both CT and RT. The T-MN group consisted of 104 T-MDS (71%) and 43 T-AML (29%). Poor risk cytogenetics were more frequent in T-MN cases following CT than after RT alone, and more frequent than in primary MDS cases (52% vs 25% vs 13%; P Mutation profiling detected at least one mutation in 117/142(82%) of primary MDS cases (total 324 mutations), similar to previous reports. Contrary to the published literature (42-58%; Shih et al, Haematologica 2013 & Ok CY et al, Leuk Res 2015), a high proportion of T-MN (54/60; 90%) patients showed at least 1 mutation. Notably, 14/15 (93%) of normal karyotype T-MN cases harbored at least one mutation. Although frequency of mutation was similar between T-MN and primary MDS cases, mutation burden and pattern were different (Fig 2). Multiple mutations were detected in 75% of primary MDS compared to 48% of T-MN cases. Mutations in spliceosome complex genes were detected in 44% of primary MDS cases, with SF3B1 being most common, while only 7% of T-MN cases (4/60) harboured these mutations. Mutations in TET2, ASXL1, NOTCH1, and RUNX1 were less frequent in T-MN compared to primary MDS (Fig 2). Mutations in TP53 were detected in 17/60 T-MN cases (28%), were associated with del7q/complex/monosomal karyotypes (15/17; 88%) and with prior CT±RT exposure. We then compared mutation frequency between T-AML and T-MDS cases. The proportion of patients with at least one mutation (89% vs 93%) and the mean number of mutations per case (1.84 vs 1.57) were similar. The genes in which mutations occurred were different: DNMT3A was more frequent in T-AML (36% vs 15%), while NOTCH1 (17%), SF3B1 (7%), and EZH2 (11%) mutations were seen only in T-MDS. Multiple somatic mutations in the same gene were detected in 30% (42/142) and 18% (11/60) of primary MDS and T-MN cases, respectively; most often in TET2, ASXL1, KRAS, NRAS, and TP53. In 41% (13/32) primary MDS and 28% (2/7) of T-MN cases harboring multiple somatic TET2 mutations, the variant allele frequency was similar (40-50%) suggesting biallelic clonal origin. Conclusions: Contrary to published literature, mutation frequency in our study is higher in T-MN and is similar to primary MDS. Though frequency of mutation is similar in T-MN and primary MDS, mutation pattern was different. Unlike primary MDS, mutations in the spliceosome complex were rare in T-MN while TP53 mutations were detected in 28% of T-MN cases. Multiple somatic mutations in the same gene were detected in 30% primary MDS and 18% T-MN cases. In summary, this study highlights differences in cytogenetic and mutation profiling between primary MDS and T-MN, and provides insight into molecular pathogenesis of T-MN. Disclosures Ross: BMS: Honoraria; Novartis Pharmaceuticals: Honoraria, Research Funding.