Litzow, Mark R.

Background The relative benefits of haploidentical HCT using PTCy compared to traditional matched-sibling donor, traditional unrelated donor and umbilical cord blood (UCB) allogeneic HCT for adult acute lymphoblastic leukemia (ALL) is still being defined. Methods We performed a retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database comparing post-HCT outcomes of haploidentical donors with PTCy to HLA-identical sibling donors, 8/8 HLA-MUDs, 7/8 HLA-MUDs, and UCB. Outcomes were overall survival (OS) leukemia-free survival (LFS), relapse, non-relapse mortality (NRM), grade 2-4 and grade 3-4 acute graft-versus-host disease (aGVHD), and chronic GVHD (cGVHD). Eligible patients were adults with ALL in complete remission (CR1, CR2, or CR3) undergoing first allogeneic HCT from 2013 to 2017. Key exclusion included not receiving PTCy for haploidentical HCT and ex vivo T-cell depleted or CD34-selected grafts. Cox proportional hazards multivariable regression analysis was used to compare the treatment groups. Results 4201 patients were studied: 393 haploidentical donor (92 centers), 1627 HLA-identical sibling donor (206 centers), 1646 8/8 HLA-MUD (181 centers), 230 7/8 HLA-MUD (90 centers), and 305 UCB (79 centers). Groups were well matched, however, notable differences between included race, time from diagnosis to HCT (CR1 only), conditioning regimen intensity, donor age, graft source for non-cord (peripheral blood or bone marrow), GVHD prophylaxis modality, and the use of in vivo T-cell depletion. Compared to other groups, haploidentical HCT had the lowest percentage of non-Hispanic white patients (43% vs. 49-74%), was more likely to use reduced-intensity conditioning (42% vs 17-25%), and was more likely to use bone marrow (41% vs. 14-29%). In multivariate analysis comparing haploidentical to matched-sibling donor HCT, no differences were observed in OS, LFS, NRM, relapse, or aGVHD. Compared to haploidentical HCT, the risk of cGVHD was significantly higher with matched-sibling donor HCT (D/R sex match F/M, HR 2.59, P<0.001, D/R sex match, other, HR 1.37, P=0.003). Comparing haploidentical to 8/8 HLA-MUD HCT, no differences were seen in OS, LFS, relapse, or Grade 2-4 aGVHD but 8/8 HLA-MUD HCT was associated with increased incidences of NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD (HR D/R sex match F/M, HR 2.91, P<0.001, D/R sex match, other, HR 1.38, P=0.001). Comparing haploidentical to 7/8 HLA-MUD HCT, no differences were seen in LFS or relapse but 7/8 HLA-MUD HCT was associated with worse OS (HR 1.38, P=0.01) and increased incidences of NRM (HR 2.13, P=<0.001), grade 2-4 aGVHD (HR 1.33, P=0.04) , grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Comparing haploidentical to UCB HCT, no differences were seen in late OS (>18 months), late LFS, relapse, or cGVHD. Compared to haploidentical HCT, UCB HCT was associated with worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001), grade 2-4 aGVHD (HR 1.83, P<0.001), and grade 3-4 aGVHD (HR 1.97, P<0.001). Similar outcomes were observed in sensitivity analyses restricting cohorts to (1) MA conditioning with peripheral blood stem cells and (2) calcineurin inhibitor-based GVHD prophylaxis for matched-sibling, unrelated donor, and UCB HCT. Conclusions For OS and LFS, haploidentical HCT using PTCy for adult ALL was superior to traditional HCT using 7/8 HLA-MUDs and UCB but equivalent to traditional HCT using matched-sibling donors and 8/8 HLA-MUDs. Results were consistent across all subgroups. Haploidentical HCT had a lower incidence of aGVHD compared to 8/8 HLA-MUD, 7/8 HLA-MUD, and UCB HCT and a lower incidence of cGVHD compared to matched-sibling donor, 8/8 HLA-MUD, and 7/8 HLA-MUD HCT. Based on these data, haploidentical HCT with PTCy results in similar survival with less GVHD compared to traditional matched-sibling and 8/8 HLA-matched donor HCT and is the superior alternative donor option for adult patients with ALL needing allogeneic HCT in CR. Figure Disclosures Wieduwilt: Leadiant: Research Funding; Shire: Research Funding; Merck: Research Funding; Macrogeneics: Research Funding; Amgen: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. de Lima:Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board. Kebriaei:Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Jazz: Consultancy. Hourigan:Merck: Other: Research Support (CRADA); Sellas: Other: Research Support (CRADA). Weisdorf:FATE Therapeutics: Consultancy; Incyte: Research Funding.

Background: Gilteritinib is approved for the treatment of relapsed/refractory (R/R) AML and FLT3-mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) enrolled prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or post-transplant FLT3inhibitor (FLT3i) maintenance. Some mechanisms of drug resistance can be shared across FLT3i's, suggesting response to gilteritinib might differ in patients treated with frontline FLT3i. A better understanding of how prior therapy modulates response to gilteritinib is necessary to clarify this novel agent's role in the current FLT3-mutated AML treatment algorithm. Methods: This is an ongoing multi-institutional analysis from 13 US centers identifying patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. Patients who received gilteritinib as a part of an ongoing trial were excluded. Response criteria were identical to the ADMIRAL trial. For patients with available data and a composite complete remission (CRc), we defined clinically measurable residual disease (cMRD) negative status by bone marrow flow cytometry using a cutoff of <1 x 10x105 cells as well as polymerase chain reaction (PCR) for FLT3 mutation with a minimum sensitivity of 5%. Survival from the time of gilteritinib initiation was recorded. Multivariate analysis included all variables collected to determine interaction with patient outcome (CR and survival data). Kaplan-Meier curves and log rank test were used for survival analysis after gilteritinib initiation. Results: 72 patients treated with prior FLT3i exposure received gilteritinib for treatment of R/R FLT3mut+ AML. Patient characteristics are presented in table-1 with 46 (64%) previously receiving midostaurin, 19 (26%) sorafenib, and 7 (10%) other FLT3i. 8 (11%) received more than one prior TKI. NGS at diagnosis were available in 66 patients (92%) and co-mutations in DNMT3A, NPM1 and NRAS were observed in more than 10% of patients. Average duration of gilteritinib therapy was 5.7 months (range: 0.2-25 months). 27 (37.5%) received stem cell transplant (SCT) before gilteritinib and 15 (21%) underwent SCT after gilteritinib. The composite CR rate (CRc, defined as CR + CRi + CRp) was 51.4% (n= 37 patients). With regard to specific FLT3i's, we found no significant difference in median survival (7.1 months and 6.4 months for midostaurin and sorafenib, respectively) or remission rates (CRc 54% and 47% for prior midostaurin and sorafenib, respectively). The CRc rate for patients who received only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. A trend toward higher CRc rate was noted in patients treated with gilteritinib in combination regimens rather than as a single agent (64% vs 43%, respectively, p=0.09 using Chi-square test). No survival advantage for combination therapy was seen over single agent. Survival was longest in patients who obtained a CR, particularly a cMRD negative response; this remained significant after censoring at the time of SCT (figures 1&2). Patients who received SCT after gilteritinib had significantly longer survival than non-transplanted patients (9.3 months vs 5.6 months, respectively, HR 0.44, 95% CI 0.2-0.8)(figure-3). Patients with concurrent mutations of NPM1/DNMT3A had a trend toward a higher CRc compared to FLT3 mutation alone (71% vs 50%, p= 0.2) but similar survival. With regard to mutations associated with drug resistance to other FLT3i's, patients with both FLT3-ITD and FLT3-D835 mutation had similar response and survival to FLT3-ITD alone. However, patients with MAPK pathway activating mutations (e.g. NRAS and PTPN11) had lower CRc (37.5% vs 59.5%) and poorer median survival than other patients (3.3 months vs 7.5 months) (HR 2.2- 95% CI 1.1-4.4) p value <0.01(figure-4). Conclusions: In this multi-center, retrospective analysis, gilteritinib remains a clinically active agent after treatment failure of prior FLT3i's (midostaurin or sorafenib). Mutations activating MAPK pathway have been implicated in secondary gilteritinib resistance but are seldom co-mutated at initial FLT3mut+ AML diagnosis. While further study is required, we hypothesize that their detection after frontline FLT3i therapy may represent treatment-emergent clones with propensity for pan-FLT3i resistance. Disclosures Zeidan: Cardiff Oncology: Consultancy, Honoraria, Other; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; MedImmune/Astrazeneca: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Daver:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perl:Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Biomed Valley Discoveries: Research Funding; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Syndax: Consultancy, Honoraria; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Bayer HealthCare Pharmaceuticals: Research Funding; New Link Genetics: Honoraria, Other; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; Leukemia & Lymphoma Society, Beat AML: Consultancy; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; Takeda: Honoraria, Other: Travel costs for meeting. Altman:Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Theradex: Other: Advisory Board; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; PeerView: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; Fujifilm: Research Funding. OffLabel Disclosure: Some of the patients we are reporting on received gilteritinib in combination with other agents which is off-label use.

Introduction Clonal cytopenias of undetermined significance (CCUS) is defined by the presence of somatic driver mutations/copy number variations in hematopoietic cells in patients with low blood counts, in the absence of morphological evidence for myeloid neoplasms. Patients with CCUS are often symptomatic and can be transfusion dependent (TD), with high rates of progression to myeloid neoplasms, especially myelodysplastic syndromes (MDS). In addition, similar to MDS, there are reports of CCUS patients responding to hypomethylating agents. Due to the lack of a formal diagnosis/morphological dysplasia, CCUS patients are often denied therapies or clinical trial enrollment. We carried out this study to validate our hypothesis that CCUS shares similar clinical and survival characteristics with lower risk MDS (LR-MDS). Methods CCUS patients were prospectively identified from the clonal hematopoiesis clinic, whereas LR-MDS patients were retrospectively identified from our institutional database. LR-MDS was defined as very low, low and intermediate risk MDS based on the R-IPSS categorization. Baseline demographics, blood counts, bone marrow (BM) morphology, cytogenetics, and NGS results were abstracted. Transfusion dependency was defined as requiring at least one unit of red cell or platelets every 4 weeks. The Mann-Whitney-U and Fischer's exact test were used to compare quantitative and qualitative data in subgroups. Kaplan-Meier overall survival (OS) estimates were used for survival analysis and compared using the log-rank test. Results 186 patients were included in the study; 74 (40%) with CCUS and 112 (60%) with LR-MDS, median age 66 years, with 63% being male (Table 1). In the CCUS group, 93% had one or more mutations (67% >1 mutation) detected by NGS, while 7% had clonal cytogenetic abnormalities. Common mutations in CCUS included TET2 (30%), SRSF2 (20%), DNMT3A (13%) and ASXL1 (11%); with 28% of patients being red cell TD and 15% being platelet TD. On application of the R-IPSS stratification, 40%, 45%, 12% and 3% were in the very low, low, intermediate and high risk categories, respectively. LR-MDS subtypes included MDS-RS (50%), MDS-MLD (21%), MDS-EB (10%), MDS del5q (7%), and MDS-U (12%). SF3B1 mutations were seen in 67% (95% of MDS-RS), while TET2 and DNMT3A mutations were seen in 29% and 21%, respectively. 60% of LR-MDS patients had >1 mutation. 44% were red cell TD, while 10% were platelet TD. In comparison to patients with CCUS, LR-MDS patients were more likely to have higher white blood cell counts (p=0.002), higher neutrophil counts (p=0.009), higher platelet counts (p<0.001), be red cell TD (p=0.031), have BM ring sideroblasts (p<0.001), have higher BM blast% (p=0.004) and carry SF3B1 mutations (p<0.001); whereas CCUS patients were more likely to have higher monocyte counts (p=0.009) and more likely to carry IDH1 (p=0.005), ZRSR2 (p=0.005) and ATM (p=0.012) mutations. Importantly there were no differences with regards to R-IPSS cytogenetic risk groups, R-IPSS prognostic categories, platelet TD, and mutations involving TET2, DNMT3A, SRSF2 and ASXL1 and TP53. Notably signal pathway mutations and mutations involving tumor suppressor genes were infrequent (<5%) in both groups. The LR-MDS patients had a longer median follow up (53 vs 15 months) and at last follow up 72 (64%) and 11 (15%) deaths had been documented in the LR-MDS and CCUS groups respectively. 13 (18%) CCUS patients progressed to MDS (10) and AML (3) over a median of 15 months, while 9 (8%) LR-MDS patients progressed to higher grade MDS (1) and AML (8), respectively (median follow up 53 months). There was no difference in the median survival between CCUS (median OS not reached) versus LR-MDS (median OS 8.3 years) (p=0.372, Figure 1). Conclusion In spite of subtle phenotypic/molecular differences between LR-MDS and CCUS, both entities had similar prognostication, distribution of high risk mutations and survival outcomes. Within a short follow-up, 18% of CCUS patients progressed to MDS/AML, indicating that regardless of the absence of dysplasia these entities are a continuum of myeloid neoplasms. In order to improve access to treatments and clinical trial opportunities, we recommend that close consideration be given to consider CCUS as a MDS subtype. Disclosures Shah: Dren Bio: Consultancy.

Background Clonal cytopenia of undetermined significance (CCUS) is a newly described entity with a high probability to progress into myeloid disorders upon follow-up (Malcovati et al, Blood 2017). Little data is known on how to effectively treat patients with CCUS. We hereby describe a single institution experience in managing symptomatic CCUS patients. Methods Patients who had CCUS and underwent active treatment were identified after receiving IRB approval. CCUS diagnosis was rendered if patients had non-diagnostic bone marrow biopsy evaluation combined with evidence of pathogenic myeloid somatic mutation using our institution next generation sequencing (NGS) panel (OncoHeme, Mayo Clinic). "Symptomatic patients" is determined by patients who need therapy beyond blood transfusion. Treatment type is based on physicians' choice. Clinical and lab results were collected. Response and progression were graded based on the MDS IWG 2006 criteria. The date of treatment initiation was used for overall survival (OS) and progression (either to myeloid neoplasm or worsening cytopenias) free survival (PFS) calculation. Stata 14.1(StatCorp) was used for data analysis. Results 1) Cohort characteristics: Between 2015 and 2020, 24 patients met inclusion criteria with median age of 72 years (range: 24-87). Twenty (83%) were men. 15 (63%) were white, 1 (4%) African American, 1 (4%) Native American and 7 unknown (33%). Eighty percent had ECOG PS≤1. Four (17%) patients had prior other hematology disorders and 3 (13%) had solid tumor. Two (8%) patients had previous radiation therapy, 2 (8%) received chemotherapy and 1 (4%) received allogeneic stem cell transplantation. At the time of treatment, the median of hemoglobin was 8.9 (range 6.8-13.7) g/dL, white blood cell 2.9 (range 1.4-12.3) *109/L, and platelet 76 (range 8-407) *109/L. Red blood cell (RBC) and platelet transfusion dependency rate were 54% and 29%, respectively. We identified 23 different mutations. Most common mutations occurred in SRSF2 (N=5, 21%), TET2 (N=5, 21%), U2AF1 (N=5, 21%), and TP53 (N=4, 17%). Ten (42%) patients had 1 mutation, and 14 (58%) had ≥2 mutations. Treatment included hypomethylating agents (HMA) (N=10, 42%), growth factors (N=11, 46%), steroid (N=4, 17%), testosterone (N=2, 8%), cyclosporine (N=2, 8%), rituximab (N=1, 4%), immunoglobulin (N=1, 4%), vitamin B12 and iron (N=1, 4%). Seven (29%) patients received ≥2 treatments. Median follow up duration was 17.5 months (range 8.9-26.1). Median time from the diagnosis to treatment was 2.1 months (range 0-26.8). 2) Molecular correlation with response The overall response rate (RR) was 50% (hematological or symptomatic improvement). Most responders (67%) were treated with HMA (p=0.013). HMA treatment effect was not significantly associated with DNA methylation genes (DNMT3A, IDH1, IDH2 and TET2, all p>0.05). The RR was 100% for the three patients with IDH1 mutation (treated with HMA, steroid and erythropoietin stimulating agent (ESA), respectively). The RR was 100% for the 3 patients with ZRSR2 mutation (2 HMA, 1 testosterone). The RR was 0% for 3 patients with SF3B1 mutation (1 testosterone and ESA, 1 vitamin B12 and iron, and 1 HMA). The number of mutations had no impact on RR (p=0.41). Table demonstrates the RR for each treatment. 3) Survival and progression outcome At the last day of follow up, RBC and platelet transfusion dependency rate were 38% and 25%, respectively. The median PFS was 16.9 months (95% CI: 7.5-65.3). Six patients (25%) progressed to myeloid malignancy with 4 myelodysplastic syndrome (MDS) and 2 acute myeloid leukemia (AML). Five patients progressed with worsening cytopenias. Among the 4 MDS patients, they had SF3B1, TET2, and ASXL1 mutations at the diagnosis of CCUS. Within the 2 AML pts, 1 had RUNX1 mutation, 1 had BCOR, DNMT3A, PHF6, RUNX1, SF3B1, STAG2, and TET2 mutations at the diagnosis of CCUS. The median OS was not reached with an estimated 2 year OS 77%. Three (13%) patients progressed with cytopenia and died. Their NGS at CCUS diagnosis showed ASXL1, TP53 and U2AF1 mutations, respectively. Conclusion Patients with CCUS responded to available treatments used for myeloid diseases. HMA were effective in this cohort. Mutation profile may have an impact on treatment response. Studies of larger cohorts are needed to validate our findings. Additionally, development of response and progression criteria would be helpful for such patients for reporting treatment outcomes. Disclosures Shah: Dren Bio: Consultancy.

Background: Chronic myeloid leukemia (CML) is driven by the activity of the oncogenic BCR-ABL tyrosine kinase, which can be effectively inhibited by tyrosine kinase inhibitors (TKIs) leading to prolonged overall and disease-free survival. Despite their effectiveness, disease can progress on TKI therapy, and lifelong treatment with TKI can have substantial negative effects on quality of life and financial health. Studies assessing the safety of TKI discontinuation in CML patients in molecular remission showed that TKIs can be discontinued in up to 45% of patients without disease recurrence. Programmed death receptor-1 (PD-1) is an inhibitory immune checkpoint receptor expressed by T-cells that can be inhibited by the anti-PD-1 monoclonal antibody pembrolizumab. Preclinical data have shown that PD-1 is highly expressed on CML-specific cytotoxic T-cells and PD-1 ligand (PD-L1) is present on CML cells. In murine CML models, the administration of anti-PD-L1 antibodies prolonged survival. As these studies suggest that disease relapse might be due to PD-1/PD-L1 mediated immune escape by CML cells, we designed the BLAST MRD CML 1 trial to study whether adding pembrolizumab to TKI is safe, increases the rate of conversion to undetectable minimal residual disease (UMRD) and allows a higher rate of TKI discontinuation. Methods: The primary endpoint of this ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial is to assess the proportion of CML patients on stable-dose TKI who convert to UMRD during or within 2 years of initiating pembrolizumab therapy (NCT#03516279). Secondary endpoints are (I) the proportion of CML patients who maintain UMRD for 6 months and 12 months, (II) the proportion of CML patients who discontinue TKI after achieving UMRD, (III) the proportion of patients who maintain UMRD off TKI at 2 years after first determined UMRD, and (IV) the incidence of grade 3 or 4 immune related adverse events related to pembrolizumab treatment during the first 2 years after registration. UMRD state is defined as an undetectable BCR-ABL using the central RQ-PCR assay with a sensitivity of 4.5 [MR4.5] on 2 consecutive occasions separated by at least 4 weeks with the date of achievement of UMRD constituting the date of first test. Immune related and other adverse events will be assessed according to CTCAE v 5.0 terminology and grading. Adult (≥18 years) patients with pathologically-confirmed CML and who have achieved major molecular response (MR3) but not UMRD at time of screening are eligible. Eligibility was recently expanded to allow third line TKI. Therefore, currently eligible patients must have been on first, second, or third line TKI therapy with either dasatinib, imatinib, nilotinib, or bosutinib for at least 2 years prior to enrolment. Patients with accelerated or blast phase CML or who have received prior allogeneic hematopoietic stem cell transplant or anti-PD-1/PD-L1 therapy are excluded. Patients will continue a standard dose of TKI therapy and receive pembrolizumab at 200 mg IV every 21 days (Figure 1). MRD status will be assessed centrally every 4 cycles. Patients who achieve UMRD at or prior to cycle 17 will discontinue TKI and pembrolizumab. If MRD remains positive prior to cycle 17, TKI and pembrolizumab will be continued for an additional 18 cycles. If MRD is still detectable after the second year of combined therapy, patients will come off study. If patients are in an UMRD state by the end of year 1 or 2 of pembrolizumab therapy, pembrolizumab will be discontinued. Patients who remain in UMRD status for one year after the first UMRD result will discontinue TKI therapy. Once TKI is discontinued, BCR-ABL will monitored q4 weeks for the first six months post TKI discontinuation, then q8 weeks for the subsequent six months, then q12 weeks for another year. Assuming that the addition of pembrolizumab to TKI will increase the conversion rate to UMRD from 20% to 40%, enrollment of 36 patients (40 patients to allow for 10% drop-out) would give this trial 91% power with a one-sided type-I error of 0.089. The combination therapy will be considered promising if 11 or more patients meet the criteria for TKI discontinuation. Toxicity will be monitored and reviewed every six months. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cardinal Health: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Taiho: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; CCITLA: Other; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; ADC Therapeutics: Research Funding. Radich:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Bhatt:Incyte: Consultancy, Research Funding; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Research Funding; Partnership for health analytic research: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Hoffman La Roche: Research Funding; Ariad: Research Funding; Biosight: Research Funding.

Background: Allogeneic HCT continues to be the optimal consolidation strategy for many patients with AML. Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes. We tested the prognostic ability of a modified (mELN) classification system based on available CIBMTR genetic data, to predict post-transplant outcomes. Methods: Adult patients with a diagnosis of AML in first complete remission (CR1) with available pre-transplant cytogenetic and molecular mutational data, receiving a first allogeneic HCT from 2013-2017, were included. Patients were stratified according to mELN genetic classification in three distinct groups: favorable (Fav), intermediate (IM) and adverse (Adv). Clinical outcomes following HCT were compared among groups after adjusting for significant patient, disease, and transplant-related variables. The primary endpoint was disease free survival (DFS). Secondary endpoints were overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse, acute GVHD, and chronic GVHD. Cox proportional hazard models were used to compare endpoints among mELN risk groups, age groups and genetic subsets within the adverse-risk group. Results: Demographic characteristics are summarized in Table 1. 2289 patients (Fav, n=181; IM n=1185; and Adv n=923) met the inclusion criteria. Median follow-up for survivors was 35 months. Importantly, 41% of transplant recipients (n=936) were >60 years, 76% (n=1743) had de novo AML and 48% (n=1111) received a myeloablative conditioning regimen. Univariate analysis (UVA) demonstrated significant differences in 2-year OS (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p<0.001); DFS (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p<0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p<0.001) There were no significant differences in NRM (p=0.467) or the incidence of acute (p=0.423) and chronic GVHD (p=0.442) among mELN groups. Initial multivariate analysis (MVA) of mELN risk groups indicated that there was no significant difference in clinical outcomes between the Fav and IM risk groups. Thus, these groups were combined for subsequent analyses. Adv risk (vs. Fav/IM) led to significantly worse OS (HR 1.39 [1.24-1.57] p=<0.001), DFS (HR 1.32 [1.18-1.48] p=<0.001), and relapse (HR 1.42 [1.23-1.63] p=<0.001) (Table 2). This mELN classification effectively stratified both younger (<60 y/o) and older (>60 y/o) patients for OS (Adv vs. Fav/IM HR for <60: 1.43 [1.21-1.69] p<0.001; >60: 1.44 [1.21-1.72] p<0.001), DFS (Adv HR for <60: 1.31 [1.12-1.53] p<0.001; >60: 1.41 [1.19-1.66] p<0.001) and relapse (Adv HR for <60: 1.44 [1.20-1.74] p<0.001, >60: 1.42 [1.15-1.76] p=0.001). NRM was higher for older patients (>60 y/o) in both the Fav/IM (HR 1.40 [1.10-1.78] p=0.007) and Adv-risk cohorts (HR 1.59 [1.18-2.13] p=0.002). Genetic subset comparisons within the adverse-risk group showed that patients carrying monosomy 5, del(5q) or monosomy 7 had inferior 2-year OS (42.6%, p<0.001) and DFS (35.2%, p<0.001), as well as higher rates of relapse (45%, p= 0.002) when compared to other patients within the Adv-risk cohort (OS 60%, DFS 50.8%, relapse 33.5%). Conclusion: Stratification using mELN criteria resulted in clear prognostic separation of OS, DFS and relapse in this large cohort of AML patients undergoing allogeneic HCT. While Fav and IM groups had similar OS, DFS and relapse rates; patients in the Adv risk group had the highest risk of relapse and inferior DFS/OS. However, the majority of patients in all cohorts had favorable outcomes for HCT in CR1. Our findings confirm the value of a combined genetic prognostic model in the AML HCT setting and justify the use of this stratification system in future HCT trials. Correlation of genetic subtypes with other important transplant variables, such as conditioning intensity and pre-transplant MRD status deserves further evaluation. There remains a subset of Adv-risk patients for which post-transplant outcomes continue to be poor, even when transplanted in CR1. Novel peri-transplant pre-emptive/therapeutic strategies are urgently needed for this high-risk cohort. Disclosures de Lima: Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board. Komanduri:Kiadis: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kebriaei:Ziopharm: Other: Research Support; Jazz: Consultancy; Kite: Other: Served on advisory board; Amgen: Other: Research Support; Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board. Bhatt:National Marrow Donor Program: Research Funding; Rigel Pharmaceuticals: Other; Jazz: Research Funding; Agios: Other: Personal Fees; Incyte: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees; Partner Therapeutics: Other: Personal Fees; Pfizer: Other, Research Funding; CSL Behring: Other; Tolero Pharmaceuticals: Research Funding; Oncoceutics: Other: Drug support for a trial; Partnership for health analytic research, LLC: Other: Personal Fees; Omeros: Other: Personal Fees; Abbvie: Other: Personal Fees, Research Funding. Saad:Orcabio: Other: research support; Kadmon: Other: research support; Amgen: Other: research support; Incyte Pharmaceuticals: Other: Personal Fees; Magenta Therapeutics: Other: Personal Fees. Copelan:Amgen: Membership on an entity's Board of Directors or advisory committees. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy.

Background: Patients ≥55 years of age with high-risk acute myeloid leukemia (AML) may benefit from an allogeneic hematopoietic cell transplantation (HCT), which is often the only potentially curative therapy available. However, complete remission (CR) is usually a pre-requisite for most centers to perform HCT, as CR predicts an optimal outcome. Many older patients with relapsed/refractory (R/R) AML are not transplanted as they do not achieve the required CR. In addition, due to their advanced age, they are unable to tolerate the myeloablative conditioning required for eradication of disease, while the more tolerable reduced intensity conditioning often exhibits high rates of relapse. The SIERRA trial is a prospective, randomized, phase 3 trial for older patients with R/R AML to address this unmet need. We hypothesized that a targeted delivery of radiation to the marrow, achieved with a limit of 24 Gray (Gy) radiation dose to the liver, via an infusion of a therapeutic dose of Iomab-B enables successful engraftment despite active disease in the marrow. Methods: Eligible patients were ≥55 years with active R/R AML (≥5% blasts), adequate organ function, and related/unrelated 8/8 HLA-matched donors. Patients were randomized (1:1) to the Iomab-B or Conventional Care (CC) arm. Patients randomized to Iomab-B received an outpatient dosimetric dose of Iomab-B followed by nuclear medicine imaging to determine the personalized therapeutic dose that would deliver radiation to the marrow while limiting the delivery of radiation to the liver to 24 Gy. HCT is performed 12-14 days following the infusion of a therapeutic dose of Iomab-B, and a non-myeloablative conditioning backbone of fludarabine (30 mg/m2 x 3) and low-dose Total Body Irradiation (TBI 2 Gy x 1 dose). Patients on the CC arm received investigator's choice of salvage therapy, including newly approved targeted agents, and could proceed to physician's choice of conditioning and HCT if they achieved CR. If CC patients did not achieve CR, the study allowed them to cross-over and receive Iomab-B-based conditioning followed by allogeneic HCT. Results: Preliminary data were available from 106 patients (Table 1). 53 patients (median age 64) were randomized to Iomab-B and received allogeneic transplant. All Iomab-B patients engrafted, despite a pre-therapy median of 26% marrow blasts. After randomization, 83% (44/53) CC patients failed salvage therapy, including 45% (24/53) who received targeted agents. 26 of 44 (60%) CC patients, with a median 33% marrow blasts, crossed over and received Iomab-B followed by allogeneic HCT. Patient age, donor type (MRD, MUD), bone marrow cellularity, blast percentage, type of donor, stem cell dose, administered Iomab-B activity (mCi), and absorbed radiation dose to the marrow (Gy), were analyzed for time to engraftment among each group. Median time to neutrophil and platelet engraftment were 14 days (range 9-22) and 17 days (range 4-39) respectively, with 91% of evaluable patients achieving full donor chimerism (>95% by day 100, Table 1). Neither the radiation dose delivered to the marrow (median 14.7 Gy; range, 4.6-32 Gy; Table 1) nor the total administered activity (median 632 mCi; range, 354-1027 mCi) showed correlation with the time to either neutrophil (p value=0.525) or platelet engraftment (p value=0.952). Regression analyses, considering all of the variables individually, did not indicate a statistically significant correlation (p > 0.1) between days to engraftment and radiation dose delivered to the marrow. These results were consistent for the Iomab-B cross-over group as well. Furthermore, the marrow absorbed dose did not show a significant correlation with % chimerism at day 28 in patients on the Iomab-B arm or in cross-over patients. Conclusion: Dosimetry to determine a patient-specific therapeutic dose of Iomab-B of 24 Gy to the liver provided absorbed marrow radiation doses that allowed for reliable engraftment after allogeneic HCT in older patients with R/R AML, despite a heavy leukemia burden with median bone marrow blasts of 26% prior to HCT (Iomab-B arm). There was no relationship between total administered activity or radiation dose delivered to the marrow with the speed of engraftment. The SIERRA trial is currently enrolling patients (www.sierratrial.com or clinicaltrials.gov NCT02665065). Disclosures Gyurkocza: Actinium: Research Funding. Nath:Daiichi Sankyo: Consultancy, Honoraria; Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Delta-Fly: Research Funding; Amgen: Research Funding. Hari:Takeda: Consultancy; BMS: Consultancy; GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy. Al-Kadhimi:Actinium Pharmaceuticals Inc.: Research Funding; Genzyme: Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Gilead Science: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Novavax: Current equity holder in publicly-traded company. Abboud:BMS: Current equity holder in publicly-traded company; AbbVie Inc: Current equity holder in publicly-traded company; Forty Seven Inc: Research Funding; Abbott Labs: Current equity holder in publicly-traded company; AlloVir: Research Funding; Ryvu: Research Funding; Actinium Pharmaceuticals Inc.: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Pfizer: Research Funding. Magalhaes-Silverman:Incyte: Research Funding; Kadmon Holdings: Research Funding; Actinium Pharmaceuticals: Research Funding. Foran:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; Revolution Medicine: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Schuster:Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board. Levy:Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment. Giralt:ACTINUUM: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding. Liang:Actinium Pharmaceuticals: Current Employment. Berger:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Reddy:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company.

Introduction: Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT) while full engraftment remains a challenge in some recipients. Therapeutic approaches, such as recombinant hematopoietic growth factors, salvage only a minority of patients leaving affected patients at risk for recurrent infections and multiple blood products transfusions. PLX-R18 cells have been shown to mitigate bone marrow failure in rodent and non-human primate models. Further, these human placenta-derived mesenchymal-like adherent stromal cells secrete many cytokines after intramuscular (IM) injection that have been shown to stimulate growth and migration of bone marrow cells in vitro, e.g. MCP-1, IL-6, and IL-8. The initial results of the first cohort of this phase I trial were previously reported (ASH 2018 abstract 3379). Methods: Enrollment for this multi-center, open label, dose-escalation, phase I trial (ClinicalTrials.gov: NCT03002519) began in October 2017. Eligibility criteria included patients age ≥18 years who underwent either autologous (auto) or allogeneic (allo) HCT but suffered from incomplete hematopoietic recovery at least 3 months post-transplant, defined as failure to maintain either hemoglobin (Hb) >8g/dL and/or neutrophil count (ANC) >1,000/μL and/or platelet (PLT) count >50,000/μL. Other eligibility criteria included no evidence of underlying malignancy at time of enrollment, no active infection and no evidence of grade 3-4 acute or severe chronic GvHD. Subjects were enrolled into 3 dose-escalating cohorts: low-dose at 1M cells/kg (n=3), intermediate-dose at 2M cells/kg (n=6), and high-dose at 4M cells/kg (n=10). The specified dose of PLX-R18 cells was injected IM in multiple locations and given twice, 1 week apart. Cohorts were recruited sequentially, and progression to the next cohort was based on the safety assessment of its predecessor. Adverse event grading used the NCI CTCAE criteria. As of July 2020, all patients in cohorts 1 and 2 (3 & 6 patients, respectively) and 10 patients in cohort 3 were treated. Data were analyzed using the lmerTest package (ver. 3.1.0) in R (ver. 3.6.1) to produce baseline-adjusted least square means. As study is in progress and data collection ongoing, not all subjects have data on all parameters for all time points. Results: Data on 19 subjects (29-75 yrs) with either allo (n=17) or auto (n=2) HCT are reported herein. Not all patients reached the 9 month time point. Four patients died while on study and 2 withdrew consent within the 1 year follow up period. All deaths and other severe adverse events (SAEs) occurred due to progression of primary disease and were assessed as not related by investigators and sponsor. Most frequent related AEs were injection-site reactions. The table summarizes number of patients who improved from below the critical level, as defined above, at day 0 to above the critical level for a sustained period. Only those patients that were below the critical blood levels at day 0 are shown. To date, the majority of such patients improved to above the critical level after treatment. For example, 9 patients had ANC <1000/μL at day 0. Of the 4 patients for which data currently exists, all improved to ≥1000/μL at 9 months. The plots show changes in Hb, ANC and PLT up to 9 months following treatment. The dashed lines represent respective critical levels. Overall, there was improvement in the 3 parameters, with the greatest improvement observed in patients receiving the predicted optimal dose of 4M cells/kg. In this cohort, Hb levels increased from 9.29±0.5 to 13.19±1.2 (p=0.0019), ANC increased from 1.09±0.6 to 5.13±1.7 (p=0.018) and PLT increased from 45.7±10 to 175.9±28 (p=0.000012). Conclusions: Treatment with PLX-R18 is safe, well-tolerated and clearly effective in some patients. The most frequent AEs were reversible injection site reactions, all without sequelae. An overall improvement was observed in most patients, and among the high-dose cohort clinically impressive improvements in Hb, ANC and PLT were observed. The trial continues to follow up on patients. Upon completion, a large phase II trial, using the optimal dose, is considered for the same indication. Other attractive clinical areas for PLX-R18 therapy include acute radiation syndrome, bone marrow failure, aplastic anemia, myelofibrosis and with HCT as a "pan" cytokine to enhance rapid count recovery in all cells lines. Figure Disclosures Lazarus: Pluristem ltd: Consultancy. McGuirk:Astellas: Research Funding; Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Rowley:AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Ofir:Pluristem: Current Employment. Shani:Pluristem ltd: Current Employment. Rowe:Pluristem ltd: Consultancy.

Introduction Germline predisposition syndromes (GPS) are inherited disorders associated with germinal aberrations that increase the risk of malignancies. While aberrations in certain genes increase the risk for all types of malignancies (Tp53, ATM, CDKN2A, CHEK2), there is a growing list of genes associated specifically with hematological malignancies (GATA2, RUNX1, DDX41, ETV6, ANKRD26). At our institution, we have established a hematology GPS clinic to diagnose and manage GPS and with this report, detail our experience with 130 patients. Methods GPS were investigated in pediatric and adult patients with one or more first degree relatives with hematological/visceral malignancies or in those with antecedent thrombocytopenia (ANKRD26, RUNX1, ETV6), or with specific syndromic features (short telomere syndromes/STS, GATA2 haploinsufficiency, Fanconi anemia/FA, Shwachman-Diamond syndrome/SDS). Depending on the phenotype, specific functional assays such as flow-FISH for telomere length assessment and chromosomal breakage assays were ordered. After informed consent and genetic counselling, germline testing was carried out on peripheral blood mononuclear cell, skin fibroblast, or hair follicle-derived DNA. A custom-designed marrow failure NGS panel (200 genes) was used in most cases and interrogation of variants, in silico studies, and functional assays were carried out as previously described (Mangaonkar et al MC Proc 2019). Copy number variations were identified by aCGH. At the time of progression/worsening cytopenias, bone marrow/lymph node biopsies and NGS (next generation sequencing) were carried out where indicated. Results 130 patients with germline predisposition have been identified to date. The spectrum of disorders seen include STS 29 (22%), FA 17 (13%), GATA2 16 (12%), Diamond Blackfan anemia/DBA 13 (10%), RUNX1-FPD 12 (9%), ATM deletions/mutations 11 (8%), ANKRD26 6 (5%), SDS 5 (4%), DDX41 4 (3%), MPL 3 (2%), CHEK2, MECOM, Tp53 mutations 2 (2%) each, and CBL, CEPBA, ELANE, NF1, CDKN2A, CSF3R, ETV6, and GATA1 mutations, 1 (1%) each. Evidence for clonal evolution (CCUS) and hematological malignancies were seen in 51 (39%) patients, involving all the aforementioned genes/syndromes with the exception of DBA, CBL, ETV6, MPL, CSF3R, and GATA1. Seven (64%) of 11 patients with germline ATM deletions/mutations developed lymphoid malignancies; homozygous ATM (Follicular NHL-1, Burkitt lymphoma-1, T-ALL-1, T-LPD-1) and heterozygous ATM (T-PLL-1, DLBCL-1, CLL-1). Clonal evolution occurred in 11 (69%) of 16 GATA2 haploinsufficient patients (CCUS-2, MDS-3, CMML-1, AML-5) and in 7 (58%) of 12 RUNX1-FPD patients (CCUS-1, MDS-1, MDS/MPN-3, AML-2). Five of 29 (17%) STS patients had clonal progression (CCUS-2, MDS-2, AML-1), and 5 (29%) of 17 FA patients progressed to MDS-2 or AML-3. JMML was seen in one patient with a germline NF1 mutation, while 1 (20%) of 5 SDS patients progressed to AML. NGS data at progression was available in 24 (55%) of 44 myeloid/CCUS progressions, with somatic truncating ASXL1 mutations being most frequent (29%), followed by RAS pathway mutations (15%). AML/MDS progressions in STS, FA, and SDS were universally associated with complex/monosomal karyotypes, translating to refractory disease. Seventeen (39%) of 44 patients with myeloid predisposition underwent allogenic HCT (GATA2-7, FA-3, RUNX1-FPD-3, STS-2, NF1-1, Tp53-1), with 10 (59%) being alive at last follow up (Table 1). Conclusion We demonstrate the spectrum of germline aberrations associated with predisposition to hematological malignancies and outline the phenotypic heterogeneity of clonal transformation. The advent of NGS allows identification of clonal progression earlier than morphological changes, with mutations in ASXL1 and RAS pathway genes being commonly implicated. This study supports the universal development of dedicated germline predisposition clinics. Disclosures Pruthi: CSL Behring: Honoraria; Genentech Inc.: Honoraria; Bayer Healthcare: Honoraria; HEMA Biologics: Honoraria; Instrumentation Laboratory: Honoraria; Merck: Honoraria.

Background: Chronic myelomonocytic leukemia (CMML) is a rare chronic myeloid malignancy with a poor prognosis. There are few epidemiologic studies on CMML. We studied population-based outcomes in CMML using the Surveillance, Epidemiology, and End Results (SEER) and the National Cancer Database (NCDB). Methods: The SEER 18 registries and NCDB Participant User File were used to identify patients with ICD-O-3 diagnosis code 9945/3 from 2004-2015. Incidence was identified using SEER and age-adjusted to the U.S. 2000 standard population. Causes of death were obtained and CMML-related death was defined as death from any myeloid disorder (CMML, acute monocytic leukemia, acute myeloid leukemia [AML], chronic myeloid leukemia, other myeloid/monocytic leukemia, and aleukemic, subleukemic, and NOS) to avoid misattribution. Relative survival (RS) was defined as the ratio of the proportion of observed survivors in a cohort of CMML patients to the proportion of expected survivors in a comparable set of individuals that did not have CMML, adjusting for the general survival of the US population for race, sex, age, and time when the diagnosis was established. Time to AML was calculated using the left-truncated life tables session and a 3 month latency period was used to prevent misattribution. Per the NCDB's system on classifying treatment, hydroxyurea, decitabine, and azacitidine are considered chemotherapy. The Kaplan-Meier method was used to calculate overall survival (OS), and Cox regression model was used to identify predictors of survival. Variables significant in univariate analysis (age, Charlson Deyo score [CDS], insurance type, and treatment facility type) were included in a multivariate analysis. Statistical analyses were performed using SAS version 9.0. Results: In the SEER database (n=4437), the median age at diagnosis was 76 years (interquartile range [IQR] 68-83) and 2,783 patients (63%) were male. Incidence rates (1 case/1,000,000 individuals) were as follows: overall 4.4, male 6.6, female 2.9, Non-Hispanic White 4.9, and Non-Hispanic Black 3.3. The incidence did not significantly change from 2004 to 2015. With a median follow up of 5.8 years (95% CI: 5.5-6.3), the median OS was 1.3 years (95% CI: 1.3-1.4). 3635 patients (82%) died. Among those who died, 2016 patients (55%) deaths were CMML-related. When comparing CMML patients to the US general population, 3,156 patients were matched to the expected survival tables. In the general U.S. population, the expected survival for 12, 24, 36, 48 and 60 months was 95.6%, 91.3%, 87.1%, 83.1%, and 79.2%, respectively. In contrast, the RS for patients with CMML at the same time points was 63.6%, 46.2%, 35.2%, 28.8%, and 23.1% (Figure 1). 229 patients (5.2%) progressed to AML. The median time to AML was 1.2 years (IQR 0.6-2.3). In NCDB (n=6403), the median age at diagnosis was 74 years (IQR 66-82). With the median follow up of 6 years (95% CI 3.5-9), the median OS was 1.3 years (95% CI 0.4-3.3). The distribution of CDS score 0, 1, and >1 was 4518 (71%), 1193 (18%), and 692 (11%) respectively. 4687 (77%) had government insurance, while 1399 (23%) had private insurance. 3750 (60%) were treated at a non-academic center. The year of diagnosis was associated with improved OS (HR 0.99, 95% CI: 0.98-0.99). Patients who were diagnosed in 2012-2015 had improved OS compared to patients diagnosed in 2004-2007 (HR 0.89, 95% CI 0.83-0.95) with OS at 1- and 5- years being 60% and 16% (2012-2015) vs. 56% and 17% (2008-2011) vs. 53% and 15% (2004-2007) respectively. 3029 (48%) patients received chemotherapy, while 270 (4%) patients received stem cell transplant as the first-line therapy. The median time to chemotherapy from diagnosis was 19 days (IQR 6-43). OS at 1-, 5-, and 10-years was 57%, 18%, and 4% (no chemotherapy), 56%, 14%, and 7% (received chemotherapy), 79%, 44%, and 38% (received stem cell transplant), and 56%, 15%, 5% (no stem cell transplant). OS curves are shown in Figure 2. Factors independently predicting inferior OS were age ≥ 65 years at the time of diagnosis (p<0.001), CDS ≥ 1 (p<0.001), government insurance (p<0.001), and treatment at a non-academic center (p<0.001) (Table). Conclusion: Despite an improvement in survival over the years, CMML continues to be a cause of significant morbidity and mortality. Older age, CDS ≥ 1, government insurance, and treatment at non-academic facilities were predictive of inferior survival. Disclosures Shah: Dren Bio: Consultancy.