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Background. Clonal hematopoiesis (CH) is an aging associated phenomenon with potential to transform to overt myeloid disease at a rate of 1% per year. CH is hypothesized to represent a precursor state for leukemogenesis. CH is detected in 10% of healthy, elderly (>70 years) individuals at variant allele frequencies (VAFs) above 2%, but prevalence is higher in patients (pts) with malignancies (~25%). We recently demonstrated in a large population database study that recent changes in therapy for melanoma and non-small lung cancer (NSCLC) are associated with a decreased incidence of therapy-related myeloid neoplasms (tMNs).1 This trend may reflect declining utilization of chemo-radiotherapies or even regression of CH clones in the context of immune checkpoint inhibitor therapy (ICI). To improve our understanding of the evolving clonal architecture in patients with CH receiving ICI we analyzed blood samples from pts with melanoma and NSCLC at baseline and after exposure to ICIs. We aimed to characterize (i) baseline prevalence of CH in pts with melanoma and NSCLC (ii) alterations in clonal architecture associated with ICI treatment in serial blood samples from these pts. Methods. In this retrospective analysis, stored blood samples from pts with melanoma (N=32) and NSCLC (N= 109) treated with ICIs were analyzed. To detect CH, genomic DNA collected before treatment initiation and serially on ICI were analyzed using a custom panel targeting 93 genes. A 1% VAF cutoff was used to define CH. Relationships among clinical, laboratory and mutational variables were examined using chi-square test, at a significance level of 0.05. Results. We present preliminary results on 25 pts with melanoma (Table 1). Median age was 61 years. 52% (13/25) were men. One/25 pts had previously received chemotherapy and 4/25 had prior radiation therapy exposure. 64% (16/25) had stage IV disease and 36% (9/25) had stage III disease. 20% (5/25) had a history of autoimmune disease. CH was present in 32% of cohort, consistent with prior reports in solid tumor pts. Mutations in DNMT3A (36%) were most common, followed by TET2 (18%). Mutations in PPM1D, ARID1A, SF3B1, LPA and TGFBR2 accounted for 46% of the mutations (Figure 1). The mutational pattern was similar to prior reports in other cancer cohorts. DNMT3A mutations were most common in this cohort, with only one patient harboring a mutation in the R882 AML/MDS hotspot, previously described in CH. Most common mutation type was single nucleotide variants (55%), followed by frameshift (27%), and splice site mutations and truncations. The mean VAF for somatic mutations was 9%, much higher than the usual VAF cutoff for CH. Mutations were more common in smokers (40% vs 26.7%), and in individuals older than 60 years (37.5% vs 22%). Pts with autoimmune disease did not demonstrate CH mutations (0/5), whereas 40% (8/20) of pts without autoimmune diseases harbored mutations, (p=0.08). Conclusions. Our findings demonstrate a high baseline prevalence of putative CH mutations and high mean VAFs in a cohort of melanoma patients, even in the setting of minimal prior chemotherapy and radiation exposure. Despite this high CH prevalence, risk of tMN development after melanoma is declining with the use of newer therapies, suggesting a possible immune clearance or halt in progression of clonal hematopoiesis with newer therapies (ICI). Lack of CH mutations in individuals with autoimmune disease is an interesting finding and warrants further investigation. Ongoing serial sample analysis of the melanoma cohort after exposure to ICI will provide insight into the impact of ICI on the underlying clonal architecture. These findings are also being tested in the NSCLC validation cohort. References Singh A, Mrad C, Faber MG, et al. Evolving risk of therapy-related myelodysplastic syndromes and acute myeloid leukemia (tMDS/AML) following modern cancer therapies. Journal of Clinical Oncology. 2020;38(15_suppl):7516-7516. Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource. Disclosures Griffiths: Persimmune: Research Funding; Boston Biomedical: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; AbbVie Inc: Honoraria; Novartis: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; SeqRx: Honoraria. Wang:Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy.

Background. Clonal hematopoiesis (CH) prevalence increases with age. Elderly (>70 years) healthy individuals have a 10% incidence of CH. Cancer cohorts are at increased risk of harboring CH mutations (~25%). Specific tumor types such as thyroid, ovarian, and bladder, have previously been shown to be at the highest risk of CH due to increased exposure to radionuclide and chemo-radiotherapies. Radionuclide therapies in particular are associated with a high incidence of subsequent myeloid disorders. Exposure to peptide receptor radionuclide therapy (PRRT, Lu 177 dotatate) leads to an increased risk (~2-5%) of therapy related myeloid neoplasms (MNs). It is not known if baseline CH architecture of neuroendocrine tumors (NETs) contributes to the increased risk or the protracted course of NETs or exposure to leukemogenic therapies. With a broader view to understand emergence of therapy induced myeloid neoplasms in various malignancies, we aimed to characterize baseline rates of CH in patients (pts) with NETs and assess clonal evolution in serial blood samples procured prior to and after exposure to PRRT. Methods. The NET Biobank housed at Roswell Park Comprehensive Cancer Center contains banked serial samples for pts receiving PRRT since its FDA approval in 2018. In this retrospective analysis, we identified pre-PRRT blood samples from 13 pts with NET treated at our institute from 2018-19. Serial samples (post PRRT exposure) were available for 6 of 13 pts. Genomic DNA collected from pts before and after PRRT treatment initiation was analyzed for CH mutations using a custom panel targeting 93 genes. A VAF cut off of 1% was used to define putative CH mutations. Relationships among clinical, laboratory and mutational variables were examined using chi-square test, at a significance level of 0.05. Results. Pt characteristics (n=13) are shown in Table 1. Median age was 58 years. 70% were men. Only 1/13 pt had prior chemotherapy exposure, and 3/13 had prior RT exposure. The primary location of NETs was small bowel (46%) followed by pancreas (23%) and others (cecal, rectal or unknown - 31%). All pts had stage IV disease. Over half (54%) harbored CH mutations, despite their relatively young age. This prevalence is much higher than previously reported CH prevalence of 25.1% in pts with other solid tumors.1TET2 (25%) was the most commonly mutated gene, followed by ASXL1 (12.5%), CHEK (12.5%), PPM1D (12.5%) and TP53 (12.5%) which together accounted for 50% of all mutations. Other mutations (DNMT3A, JAK2, DDX41, SRCAP) were less common (Figure 1). DNMT3A mutations (usually most prevalent mutation in cancer cohorts) were uncommon in this cohort and did not occur in the R882 AML/MDS hotspot, previously described in CH. Frameshift mutations and truncations comprised 53.3% of all mutations, and these mutations had higher mean VAFs (6.14%) than single nucleotide variants (1.93%; p = 0.001). This may suggest that frameshift mutations and truncations provide survival advantage to the affected clone. Mutations were more common in smokers than in non-smokers (100% vs 40%, p = 0.067). As expected, mutations were more common in individuals age 61 and above (75% harbored 1 or more mutation) vs only 20% mutation occurrence was noted in age 60 or below (p=0.05). Conclusion. CH with a distinct mutation profile occurs in NET patients, and in higher prevalence (54%) than observed in other solid tumors (25%). High baseline prevalence of putative CH mutations in NET patients may be an important contributor to heightened risk of MN development after PRRT exposure. Ongoing serial sample evaluation will provide further insights into clonal evolution of the above detected CH mutations after exposure to PRRT. The results regarding clonal evolution may have implications in predicting risk of MN associated with PRRT therapy and influence treatment selection in pts planned for PRRT. References Coombs CC, Zehir A, Devlin SM, et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell. 2017;21(3):374-382.e374. Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource. Disclosures Iyer: Advanced Accelerator Applications: Consultancy. Guzman:SeqRx: Honoraria; Cellectis: Research Funding. Wang:Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Astellas: Consultancy; Macrogenics: Consultancy; Pfizer: Speakers Bureau; Bristol Meyers Squibb (Celgene): Consultancy.

Several therapeutic approvals in recent years have resulted in a change in the paradigm for standard treatment of patients with newly diagnosed and relapsed/refractory (r/r) AML. Gemtuzumab ozogamicin (GO) was resurrected in 2017 for CD33+ newly diagnosed or relapsed/refractory AML using a safer fractionated dosing regimen. Since its re-approval it has been incorporated in combination with standard 7+3 (cytarabine 100mg/m2 + daunorubicin 60mg/m2; Castaigne S et al, Lancet 2012) as upfront therapy for good and intermediate risk AML patients (pts) treated at institutions with access to rapid risk stratification (molecular/cytogenetic results) including ours (Roswell Park; RP). In the five randomized studies of GO combinations for newly diagnosed AML, varied doses of cytarabine and anthracyclines were used (Lancet Oncol, 2014). In these, cytarabine doses ranged from (100-200 mg/m2), daunorubicin doses ranged from 45-60 mg/m2. These studies did not intensify daunorubicin beyond 60mg/m2 and did not incorporate FLT3 inhibitors. Previous work has demonstrated that anthracycline dose intensification (90mg/m2) provides a recognized survival advantage for younger AML pts (Luskin MR et al, 2016.), particularly those with mutations in FLT3. Optimal combination approach(s) including GO for the management of patient with AML are unclear. Adaptation of GO in combination with 7+3 for upfront AML management has led to the evolution of institutional standards to optimize early identification of good/intermediate risk AML pts. Unfortunately, there is limited data on the safety and efficacy of higher doses of daunorubicin in combination with GO and/or FLT3 inhibitors. Here we present outcomes and adverse events (AEs) using varied upfront treatment regimens in combination with GO at RP. We additionally present a cohort of r/rAML pts treated with GO alone or in combinations under an expanded access protocol (NCT02312037) at RP prior to re-approval in 2017. R/R AML pts treated on expanded access had AEs collected prospectively, all other cases were identified by retrospective chart review in accordance to IRB approval. 218 patients with a diagnosis of AML and a median age of 66.5 years were seen at RP since GO approval. Of these all good risk and 45% of intermediate risk AML underwent induction chemotherapy. During 2015-2017 r/rAML patients were treated with GO based therapy (N=32) on NCT02312037 trial. Since FDA approval another 48 pts have been treated with GO at our institution. Of the 80 patients in this cohort, N=25 underwent GO based induction therapy (Table 1). The most frequently used other combinations were: (i) daunorubicin 60mg/m2 and cytarabine 200mg/m2 (N=17), (ii) daunorubicin 90mg/m2 + cytarabine 100mg/m2, N=4), (iii) FLAG-GO (used in patients with cardiac comorbidities; N=2) and hypomethylating agents combined with GO (N=10), monotherapy was used in 45 pts. The ORR (CR+Cri) for patients treated with GO based induction was 88%. The overall (OS) and event free survival (EFS) were 48 and 17 months for induction-treated pts respectively. The most common AEs were febrile neutropenia (60%), infusion reactions (30%), transaminitis (20%), cytopenias beyond 30 days from induction (10%). The most common reason for change of therapy was disease progression. Toxicity was not higher in those patients receiving higher doses (>60mg/m2) of daunorubicin or cytarabine (200mg/m2). Two patients received GO+7+3+FLT3 inhibitors; this was well- tolerated in a very small sample. In the R/R cohort, pts received a median of 2 cycles of therapy, the ORR was 18%. GO had no activity in those treated with >2 prior regimens for relapsed disease. In conclusion, anthracycline intensification as part of a 7+3 combination with GO was not associated with increased toxicity. Although the number was small, FLT3 inhibitors following 7+3+GO were also well tolerated. These data require confirmation in a larger cohort. Our results confirm the EFS reported in the literature (18 months in ALFA 0701 study), and suggest a higher mean OS of 40 months compared with conventional 7+3 induction. The response rate for GO monotherapy in r/rAML is low and was exceedingly poor for heavily pretreated pts. Disclosures Thota: Incyte, Inc.: Speakers Bureau. Griffiths:Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Abbvie, Inc.: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding. Wang:Agios: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Amgen: Other: Advisory role; Daiichi: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau.

BACKGROUND: After many decades of stagnation, several promising novel therapies have recently been approved for the management of patients (pts) with Acute Myeloid Leukemia (AML). Many of these target pts in specific clinical and molecular subsets such as midostaurin/gilteritinib for FLT3-mutated AML, liposomal daunorubicin-cytarabine for secondary AML, and fractionated gemtuzumab ozogamicin (GO) for good risk AML. To address the dismal outlook for elderly AML patients, we now have venetoclax or glasdegib combinations. Single agent FLT3 inhibitors (resulting in ~4 m improvement in overall survival (OS)) and IDH inhibitors (response rate 40%, doubled OS in responders) have shown to be superior to traditional approaches in the relapsed setting. Although these agents are exciting, a majority of pts with AML present with intermediate and high-risk disease and only a small subset will have actionable mutations. In order to determine the impact of these newer therapies on outcome for our pts, we investigated AML outcomes for pts diagnosed and treated since 2017 and compared these with survival for similar pts treated in the prior two years (y). METHODS: We performed a retrospective chart review to identify newly diagnosed pts treated with chemotherapy over a 2y period (2015-17) prior to the first FDA approval of Midostaurin in April, 2017 (old AML era or group 1) and the 2y since approval (2017-19; new AML era or group 2). We reviewed charts of 138 AML pts meeting these criteria at our institution: 79 in group 1 and 59 in group 2. Demographics, disease-specific variables, as well as outcomes of interest (overall survival (OS), overall response rate (CR/CRi)) were collected on an IRB-approved protocol. Responses were defined according to the 2003 International Working Group (IWG) criteria. Demographics, baseline characteristics, and treatment responses were analyzed using descriptive statistics. Overall survival was estimated utilizing Kaplan-Meier (KM) survival analysis. RESULTS: Clinical characteristics were comparable in both groups. Median age was 65y with slight differences in gender distribution (Table 1). ELN risk categories (Döhner, Blood. 2017) across the groups were similarly distributed; a majority of pts had intermediate and adverse risk characteristics. As expected, more pts received newer therapies in group 2. 6 pts (7.6%) in group 1 received new drugs (as part of clinical trials), while 31 (52%) received newer therapies in group 2. Newer therapies were mostly GO (28%), midostaurin (11%) and venetoclax (11%) with lesser percentages of the more specific targeted therapies. Median follow-up was 10m for group 1 and 8m for group 2. Median OS was 13m for group 1 and 20m for group 2, but the difference was not statistically significant (p=0.29) [Figure 1]. OS was significantly better in the subgroup of older AML pts (age ≥ 60y); median OS was 7m vs. 11m in groups 1 and 2 respectively (p=0.01).Rates of CR from induction therapy were comparable in both groups (68% in group 1 versus 65% in group 2). A larger number of pts (especially older pts) in group 2 went on to allogeneic bone marrow transplant (allo-HCT). This was perhaps due to increased recognition of performance status over age in selection of pts for allo-HCT and increased utilization of reduced intensity and non-myeloablative conditioning regimens. CONCLUSIONS: Our results indicate a positive impact on survival for pts diagnosed in the era of novel therapies in a real world setting, specifically for pts presenting at older ages. A larger cohort analysis to further evaluate these findings is currently underway. The expansion of the therapeutic armamentarium as well as expanded transplant options is encouraging and offers new hope for pts diagnosed with AML Disclosures Griffiths: Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy. Wang:Kite: Other: Advisory role; Jazz: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role; Abbvie: Other: Advisory role; Daiichi: Other: Advisory role; Stemline: Other: Advisory role, Speakers Bureau; Pfizer: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau. Thota:Incyte, Inc.: Speakers Bureau.

BACKGROUND: Healthy adults with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of death from vascular disease. CHIP-associated genetic mutations such as ASXL1, TET2 and DNMT3A have been linked to the pathogenesis of atherosclerosis (Jaiswal et al, 2017). MDS and CHIP share common genetics events; in fact, certain MDS cases are believed to arise from preexisting clonal hematopoiesis. A recent SEER study demonstrated that 60 months from diagnosis, patients (pts) with low-risk MDS are at higher risk of death from cardiovascular causes than from MDS itself (Brunner et al, 2017). As the relationship between vascular disease and clonal hematopoiesis is delineated, management of vascular disease in patients with MDS is becoming increasingly important. Here we performed a retrospective analysis of MDS pts from Roswell Park to evaluate whether MDS-related factors such as morphologic subtype, treatment, cytopenias, iron status, blast percentage and karyotype modify atherosclerosis risk when molecular events are taken into account. METHODS: Over the past decade, 850 pts were diagnosed with MDS were seen and treated at Roswell Park. For the purpose of this study, 192 pts with a confirmed diagnosis of MDS seen between 2012- 2017 were investigated for cardiac events, blood counts, iron or inflammatory status as ferritin, MDS-related morphology, molecular profile and treatment. Cases were comprehensively annotated for the presence of vascular events, (defined as imaging or procedure verified coronary artery disease, cerebrovascular accident, or peripheral vascular disease) by review of the medical record. Conventional karyotype information was present in 98% of the cohort and NGS based multi-gene sequencing results through FoundationOne Heme was evaluated in 30% of the cohort. Numeric variables were summarized using simple descriptive statistics. A logistic regression model was used to investigate the association between vascular events and a set of explanatory variables for multivariate analysis. RESULTS: The median age at diagnosis for this cohort is 69 (range: 21-91) years; 60% were male and 57% had MDS with excess blasts. By IPSS-R, 25% had very low/low risk MDS, 22% had intermediate risk MDS and 46% had high risk MDS. The most common karyotypic abnormalities were normal (42%), complex (17%), trisomy 8 (10%) and del 7/7q (10%). Of the 59 patients with molecular data, the most common recurrent somatic mutations were in ASXL1 (47%), TET2 (30%), SRSF2 (27%), RAS pathway (22%) SF3B1 (22%), RUNX1 (20%) and TP53 (17%). The overall incidence of vascular events in this cohort was 27%. Vascular disease was noted at similar frequencies for pts with low grade and high grade MDS (based on subtype of MDS), 23% vs. 30% (p=0.33) respectively. Women with MDS were significantly less likely to develop to vascular events than were men, 16% vs. 34% (p=0.007) and the mean age of pts with vascular disease was significantly higher, 71 vs. 65 years (p=0.005). Traditional risk factors such as hypertension and hyperlipidemia were more prevalent in MDS pts with vascular disease. Baseline hemoglobin, transfusion requirements and blast % levels were comparable in MDS patients with or without vascular disease. MDS pts with vascular disease had higher median ferritin levels, 432 vs. 301 ng/ml (p=0.093). When stratified by the IPSS-R, pts with very low risk MDS had a non-significant lower incidence of cardiac events, 14% vs. 25% (p=0.30), compared to other groups. Treatment with erythropoietin, lenalidomide or hypomethylating agents was not associated with vascular events. MDS pts with mutations in ASXL1 and SRSF2 had a higher incidence of vascular disease, 43% vs. 13% (p=0.01) and 38% vs 20% (p=0.18) respectively. On multivariable analysis, older age and male gender were most strongly predictive for vascular events. CONCLUSION: Here we retrospectively examined the potential factors associated with cardiovascular events in MDS pts treated at our institute over a 5-year time span. Male gender and older age were positively associated. Treatment regimen (erythropoietin injections or lenalidomide) and IPSS-R were not associated with an increased risk for vascular events. Factors independent of traditional cardiac risk factors, such as somatic mutations in ASXL1, iron overload and/or an inflammatory milieu i.e, ferritin, may contribute to atherosclerotic vascular disease in pts with MDS. Disclosures Baron: Pfizer Pharmaceuticals: Other: Previously served as a consult on the Advisory Boards (May 2017).. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: 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. Griffiths:Pfizer, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Alexion Inc.: Honoraria, Research Funding. Thota:Incyte: Speakers Bureau.