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Introduction Physically frail older adults with hematological malignancies experience greater treatment-related toxicity, higher rates of treatment non-completion, increased utilization of health care services, and shorter overall survival than younger and fitter patients. For frail adults, living in areas of high social vulnerability may also place them at disproportionately higher risk of experiencing poor health outcomes. Yet, the association between community-level social vulnerability and physical frailty among patients with hematological malignancies has not been previously described. Methods We used a previously developed frailty index [Carolina Frailty Index (CFI)] (Guerard et al., 2017) of accumulated health deficits, derived from geriatric assessment data of participants enrolled in the Carolina Senior Registry (CSR) (ClinicalTrials.gov identifier: NCT01137825) at the University of North Carolina at Chapel Hill or the Registry for Adults with Plasma Cell Disorders (ClinicalTrials.gov identifier: NCT03717844). In this cross-sectional study, we examined the association between county-level social vulnerability [Centers for Disease Control Social Vulnerability Index (CDC SVI)] (https://www.atsdr.cdc.gov/placeandhealth/svi/data_documentation_download.html. Accessed on July 1, 2021) and physical frailty in adults with hematological malignancies enrolled in the registries. In a cohort of 338 patients (CFI score range, 0-1), patients with a CFI score of 0.2 or above were considered frail. Social vulnerability was measured using participant residential zip codes and county locations linked to the overall SVI and each of the four domains: 1, socioeconomic status; 2, household composition & disability; 3, minority status & language, and 4, housing & transportation, that comprise the overall SVI (score range 0-1, with 1= most vulnerable). We used cut points of 0.2, 0.4, 0.6, and 0.8 to stratify the level of social vulnerability. Associations were made using Jonkherre-Terpstra tests for trends. All analyses were performed using SAS version 9.4 (SAS Institute, Inc). All tests were 2-sided, and p < 0.05 was considered statistically significant. Results Among 338 patients [51% male, 70% aged ≥ 70 years (median age 72.5 years) 84% White], multiple myeloma was the most common cancer type (45%), followed by lymphoma (30%) and leukemia (23%). Overall, 52% (n=177) of patients were considered frail. Just over half of the sample (53%, 179/338) lived in a county with an SVI Conclusion Among older adults with hematological malignancies, those residing in areas of high social vulnerability were more likely to be physically frail. These findings suggest that external, contextual factors significantly influence an individual's overall health and highlight the need for further work in this area. Future research should examine community social vulnerability as a risk factor for physical frailty development in adults; information could then be leveraged to identify those at greatest risk for functional losses and frailty onset. Through early identification of this subset of patients, preventative strategies and interventions could be developed, and resources allocated to help those considered most vulnerable. Figure 1 Figure 1. Disclosures Rubinstein: Sanofi: Consultancy; Roche: Consultancy. Wildes: Sanofi: Consultancy; Seattle Genetics: Consultancy; Carevive: Consultancy; Janssen: Consultancy. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy.

Background: Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients after cancer itself. Risk factors for CAT include tumor type/stage, body mass index (BMI), blood cell counts and chemotherapy exposure. These factors form the basis of prediction algorithms for CAT risk, including most notably the Khorana Risk Score. However, significant limitations exist with these currently-available risk prediction models. Emerging data suggest that a tumor's molecular profile can impact venous thromboembolism (VTE) risk. Mutations of ALK, EGFR, IDH1, ROS1, and KRAS for example have been shown to modulate the risk of CAT; however, these studies were limited by the number of mutations and specific tumor types analyzed. We hypothesized that extended molecular testing in a large patient cohort would allow for improved detection of molecular signatures associated with CAT. We analyzed deep-coverage targeted sequencing data (up to 341 genes) of tumor samples from 11,776 cancer patients to identify gene mutations associated with VTE. Methods: Adult patients with any solid tumor diagnosis who had their tumors sequenced using MSK-IMPACT from 1/2014 to 12/2016 were retrospectively assessed for CAT events using redundant algorithmic methods and individual chart reviews. The endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis (DVT). An episode of upper extremity DVT was considered a competing event. The observation period was limited to 365 days after IMPACT blood control sampling. Cause-specific Cox proportional hazards regression was used to test for an association between gene and CAT risk, adjusting for clinical covariates including age, cancer type, cytotoxic chemotherapy (time-dependent), anticoagulant use, stage (metastatic/non-metastatic) and prior history of VTE. Separate multivariate models evaluated the association for the 60 most frequently-mutated genes identified, along with ALK, MET, ROS1 which were included based on existing literature suggesting an effect on VTE risk. Final p-values were adjusted for false discovery using the Benjamini-Hochberg procedure, and the threshold for statistical significance was set at 0.10. Patients with multiple cancer diagnoses were excluded. Results: Out of 11,776 individuals we observed 727 CAT events (6.2% of cohort). The most commonly represented tumor types were lung (18%), breast (15%) and colorectal cancer (10%); see Figure for a breakdown of CAT incidence by tumor type. Most (72%) of patients were metastatic at time of IMPACT testing and 4% were on anticoagulation therapy. Statistically significant predictors of CAT included cytotoxic chemotherapy (HR 1.61 [1.37-1.9]; p Conclusions: This work is the first large-scale analysis to elucidate cancer-specific genomic determinants of CAT. Using a large patient cohort, we found that somatic tumor mutations in STK11, KRAS, IDH1, KEAP1, and MET modulate the risk of venous thromboembolism in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. We hope these findings will ultimately translate into improved risk stratification for patients at risk of CAT. Disclosures Mones: Janssen: Research Funding. Iyengar:Puma Biotechnology: Consultancy; Novartis: Consultancy. Hyman:AstraZeneca: Consultancy, Research Funding; Fount: Consultancy, Equity Ownership; Pfizer: Consultancy; Chugai Pharma: Consultancy; Loxo Oncology: Research Funding; Boehringer Ingelheim: Consultancy; Bayer Pharmaceuticals: Consultancy, Research Funding; Genentech / Roche: Consultancy; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Consultancy. Park:Merck: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Astellas: Research Funding; Ipsen: Consultancy. Khorana:Bayer: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy. Soff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mantha:Medical Case Management Group: Consultancy; MJH Live Events: Other: Give CME talk; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; Daboia Consulting LLC: Equity Ownership; Janssen: Research Funding.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present.

Background : Diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) are aggressive lymphomas that evolve rapidly and are fatal if untreated. Most treatment-related toxicities occur during the initial phase of therapy, particularly in the elderly and in patients with a high disease burden. Prephase therapy is used as a preventive strategy prior to definitive multiagent chemotherapy to ameliorate the development of toxicity, such as febrile neutropenia, tumor lysis syndrome, deterioration in performance status, and death. While this approach is often implemented, there are few data supporting when to initiate a prephase regimen, or whether this approach will be effective. We present data from our experience at the University of North Carolina Cancer Hospital. Methods : We conducted a retrospective analysis of patients (pts) diagnosed with DLBCL and BL between January 2016 and December 2017. Pts were divided into 'prephase' (PP) and 'non-prephase' (NPP) groups. The PP group received either prednisone (P) alone at 60 mg/kg oral daily from day -6 to day -1, or in combination with vincristine (V) 1 mg intravenously on day -6 (VP regimen), cyclophosphamide 200 mg/m2 on day -6 (CP regimen), or all three drugs (CVP regimen). Multiagent chemotherapy was given at day 0. Both groups were evaluated until day 30. ECOG performance status (PS), grade 3-4 cytopenias, absolute neutrophil count (ANC) and platelet nadirs, time to ANC and platelet recovery, episodes of febrile neutropenia, hospitalization and emergency (ER) visits, and next cycle dose reduction or delay, were compared in both groups. Results : Ninety-two pts (DLBCL n=82, and BL n=10) were identified. Clinical characteristics are shown in Table 1. Twenty-two pts received PP therapy (vs. NPP n=70). Median age at diagnosis was 59 years and 61 years for PP and NPP group, respectively. Female predominance was observed in both groups (PP 59% and NPP 54%). Poor baseline ECOG PS was significantly different between the PP and NPP group (median score 2 vs. 0, p Conclusions : Prephase therapy significantly improved PS by day 14 of definitive multiagent chemotherapy at first cycle. The overall improvement in PS was primarily caused by improvements in 2 groups: pts older than 60 years, and pts 60 years or younger with poor PS (ECOG PS 2 or more). This is consistent with who we would expect to benefit the most from prephase therapy. Patients who received prephase therapy had a significant reduction in the length of their ANC nadir, although, interestingly, the rate of febrile neutropenia was low in both arms. The length of the platelet nadir was also significantly reduced in the PP group. Conversely, the depth of platelet nadir was significantly lower in the PP group, which may be a reflection of more aggressive disease in this group. The prephase group trended towards a reduction in the number of hospital admissions, ER visits, and next cycle dose reduction or delays, but these did not reach statistical significance. Based on these results, we will implement a provider reminder to consider prephase therapy when using multiagent chemotherapy in pts with aggressive lymphomas older than 60 years, or pts Disclosures Grover: Seattle Genetics: Consultancy. Dittus:Seattle Genetics: Consultancy.

Genomic analyses of histiocytic neoplasms (including Langerhans Cell Histiocytosis (LCH) and the non-LCH Erdheim-Chester Disease (ECD)) have revolutionized our understanding of these disorders as clonal hematopoietic malignancies driven by MAPK signaling and led to FDA approval of vemurafenib for BRAFV600E-mutant ECD. Despite these advances, several questions about the pathogenesis of the histiocytoses remain unanswered. For example, the cell-of-origin of the histiocytoses is not definitively known. In addition, histiocytoses represent a spectrum of diseases, and genetic alterations across histiocytosis subtypes have not been comprehensively evaluated. Finally, although the histiocytoses most commonly occur as sporadic, non-hereditary disorders, familial clustering has been well documented and occurs most often in monozygotic twins. This has been taken to suggest a hereditary component of the disease, but germline genetic causes for histiocytoses are not known. Here we performed comprehensive genomic analyses of 218 patients with all subsets of histiocytoses, including monozygotic twins with histiocytosis. In so doing, we uncover a novel series of activating receptor tyrosine kinase (RTK) alterations in the histiocytoses, including the first example in any disease of recurrent, activating mutations in CSF1R, the RTK required for monocyte/macrophage development. We initially performed whole exome sequencing (WES) of skin lesions, blood, and fingernails from identical (monozygotic, dichorionic), one-year-old twins with systemic juvenile xanthogranuloma (JXG). This identified an identical in-frame deletion in CSF1R (CSF1RY546_K551del) in the skin lesions of both children. Recent data from murine models suggest that CSF1R-expressing yolk sac derived precursors of tissue-resident macrophages may be a cell-of-origin of the histiocytoses (Mass, et al. Nature 2017). Consistent with this hypothesis, the identical CSF1R mutation was shared across the histiocytosis lesions in both twins but was absent from blood or fingernails. We next sought to determine if similar mutations in CSF1R might exist in sporadic histiocytosis cases. We therefore sequenced 92 ECD (42%), 58 LCH (27%), 50 JXG (23%), 12 RDD (5%), and 6 histiocytic sarcoma (HS) (3%) lesions using WES, targeted DNA sequencing with a 585-gene panel, and targeted RNA-sequencing for fusions in 74 genes. This identified recurrent mutations in BRAFV600E, MAP2K1, N/KRAS, and ARAF, as well as BRAF, NTRK1, and ALK fusions as previously described in ECD and LCH (Fig. A-C). Interestingly, CSF1R mutations were also found in 8 cases, most commonly as CSF1RY546_K551del, and were predominantly in JXG (10%; n=5/50). Consistent with the recurrent nature of this mutation, expression of CSF1RY546_K551del, but not CSF1RWT, conferred robust cytokine-independent growth to cell lines normally dependent on cytokines (Ba/F3 and 32D cells; Fig. D). We also identified individuals with mutations in CSF3R, KIT, ALK, MET, JAK3, and CRAF, as well as a RET fusion. These studies additionally identified important differences in the spectrum of kinase alterations across histiocytoses subtypes. For example, the BRAFV600E mutation was the most common kinase alteration in LCH and ECD but was not identified in JXG or RDD. Furthermore, BRAF fusions were predominantly seen in LCH and JXG. Meanwhile, NTRK1 and ALK fusions were mainly identified in JXG and ECD, respectively. From a therapeutic perspective, CSF1R activating mutations sensitized cells to inhibition with the CSF1R-specific, small-molecule kinase inhibitors pexidartinib and BLZ945. In addition, in the course of this study, a patient bearing ALK-rearranged ECD required therapy, and we were able to evaluate response to the ALK inhibitor crizotinib. Crizotinib-treatment resulted in profound and sustained therapeutic improvements in this patient (Fig. E). Overall, the above data demonstrate the occurrence of activating CSF1R and other RTK alterations in patients with histiocytic neoplasms, many of which have direct therapeutic importance (such as the first demonstration of ALK inhibitor efficacy in ALK+ histiocytosis). In addition, the discovery of somatically acquired CSF1R activating mutations in identical twins with histiocytosis provides the first human evidence that tissue-resident macrophages may serve as a cell-of-origin of the histiocytoses. Figure Figure. Disclosures Arcila: Invivoscribe, Inc.: Consultancy, Honoraria.

To the editor: In a recent paper in Blood , Haroche et al reported dramatic efficacy of vemurafenib in 3 cases of multisystem and refractory Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis harboring the BRAF V600E mutation.[1][1] The findings of an ∼50% prevalence of BRAF

Chromosomal rearrangements involving the neurotrophic receptor tyrosine kinases NTRK1-3 produce oncogenic fusions in a wide variety of adult and pediatric cancers. Although the frequency of NTRK fusions in most cancers is 7,000 patients with hematologic malignancies and characterize their signal transduction, transforming properties, and response to larotrectinib in vitro and in an AML patient and corresponding patient-derived xenograft (PDX) in vivo . We performed targeted RNA sequencing using the Foundation One Heme sequencing panel across 7,311 cases of hematologic malignancies and discovered 8 patients (0.11%) harboring NTRK fusions. Fusions occurred in patients with histiocytic (LMNA-NTRK1, TFG-NTRK1) and dendritic cell (TPR-NTRK1) neoplasms (n=2/78), ALL (ETV6-NTRK3; n=1/659) as well as two with AML (n=2/1201). While previous case reports have reported ETV6-NTRK3 fusions in ALL and AML, our cohort also included an ETV6-NTRK2 fusion previously unreported in AML. In addition, we detected two multiple myeloma patients with NTRK3 fusions (UBE2R2-NTRK3 and HNRNPA2B1-NTRK3; n=2/1859) which represent the first description of NTRK fusions in myeloma. The fusion breakpoints are predicted to create in-frame fusions containing the tyrosine kinase domain of each of the NTRK genes and Sanger sequencing of RT-PCR on available tissues confirmed this. We next cloned 4 of these fusions and tested their transforming capacity in cytokine-dependent murine hematopoietic cells (Ba/F3 cells), which do not express endogenous Trk proteins. Despite equivalent levels of Trk expression, the transforming properties and auto-phosphorylation of each TRK fusion was distinct (A). The LMNA-NTRK1 and ETV6-NTRK2 fusions caused robust cytokine-independent growth. In contrast, additional NTRK fusions in which the 5' partner lacked classic oligomerization domains resulted in slower transformation (UBE2R2-NTRK3 fusion)or no transformation (HNRNPA2/B1-NTRK3). Consistent with these different growth properties, each fusion activated PI3K-AKT signaling to differing degrees after cytokine withdrawal (B) . Finally, the cells that gained cytokine-independence were exquisitely sensitive to treatment with larotrectinib. In contrast, Ba/F3 cells transformed by BRAF V600E mutation were unresponsive to Trk inhibition (C). The course of the above studies identified a patient with an ETV6-NTRK2 fusion AML. Using a PDX generated from this patient, we initiated treatment with larotrectinib (200mg/kg/day) after 8 weeks of transplantation when human myeloid leukemia engraftment reached a median of 15%. Larotrectinib treatment reduced human chimerism compared with mice receiving vehicle (although human myeloid leukemia cells persisted even with larotrectinib treatment- D). Consistent with the response of the AML PDX to Trk inhibition, treatment of the same patient with larotrectinib initiated under the FDA expanded access program resulted in clinical partial remission. This was due to eradication of the ETV6-NTRK2 mutant clone, which was sustained until outgrowth of a treatment refractory ETV6-MECOM clone resulted in progressive disease. FACS sorting and analysis of the AML revealed that each ETV6 fusion occurred in a distinct AML clone. Serial targeted RNA-seq analysis of bulk cells identified reduction of expression of the ETV6-NTRK2 fusion throughout the period of LOXO-101 treatment with concomitant increased expression of the ETV6-MECOM fusion (E). We herein describe that NTRK fusions occur across patients with a wide variety of hematologic malignancies and are amenable to Trk inhibition. Further studies to evaluate the clonality of NTRK fusions across cancers and whether this is predictive of therapeutic response to Trk inhibition will be critical based on the case here. Nonetheless, the clinical response here in a refractory patient argues for the need for systematic evaluation of NTRK fusions despite their rarity across hematologic neoplasms. Figure Figure. Disclosures Pavlick: Foundation Medicine: Employment. Watts: Jazz Pharmaceuticals: Consultancy, Speakers Bureau. Albacker: Foundation Medicine Inc.: Employment, Equity Ownership. Mughal: Foundation Medicine, Inc: Employment, Other: Stock. Ebata: LOXO Oncology: Employment. Tuch: LOXO Oncology: Employment. Ku: LOXO Oncology: Employment. Arcila: Archer: Honoraria; Raindance Tecnologies: Honoraria; Invivoscribe: Honoraria. Ali: Foundation Medicine, Inc: Employment, Other: Stock. Park: Amgen: Consultancy.

The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation.

Background: ECD and LCH are rare disorders for which no approved therapies are available. BRAFV600E mutations have been observed in 50% of patients with LCH and in 50-60% of patients with ECD. Here we present data from a planned Week 16 analysis of patients with ECD/LCH who were enrolled in the VE-BASKET study (ClinicalTrials.gov identifier NCT01524978). Methods: This open-label, Simon 2-stage adaptive-design, phase 2 study included patients with BRAFV600E-mutant ECD and LCH. Patients received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed response rate at Week 8; secondary endpoints included best overall response rate, clinical benefit rate, progression-free survival (PFS), and overall survival (OS). For a subset of patients (n=15), metabolic response by 18F-FDG-PET was assessed; five target lesions were selected and their maximal standardized uptake value (SUVmax), normalized for body weight (BW), was compared with background (liver) SUV. Data cut-off was 2 October 2015. Results: 26 patients (22 with ECD and 4 with LCH; median age 61y) were enrolled. Seven patients (27%) had one prior therapy, six (23%) had two prior therapies, four (15%) had ≥3 prior therapies, and nine (35%) had no prior systemic therapy. Six patients were in follow-up at data cut-off; 16 were on treatment. Best overall response (according to RECIST v1.1) in 25 patients with measurable disease at baseline was 60% (95% CI 38.7-78.9%) with complete response (CR) in two patients (8%) and partial response (PR) in 13 patients (52%) (Figure). Responses were seen in patients with ECD (1 CR, 10 PRs) and LCH (1 CR, 3 PRs). After a median treatment exposure of 14.2 months (range 4.2-22.5 months), median OS and PFS have not been reached. All of the 15 patients assessed by 18F-FDG-PET showed a response: 12 patients had a complete metabolic response (normalization of all lesions' SUVmax-BW to background SUV) and three had a partial metabolic response (>50% decrease in sum of baseline SUVmax of all target lesions) (Figure). Overall, safety data were consistent with prior studies of vemurafenib. Arthralgia (n=17; 65%), fatigue (n=15; 58%), rash macropapular (n=14; 54%), alopecia (n=14; 54%), skin papilloma (n=14; 54%), prolonged QT (n=12; 46%), and palmar-plantar erythrodysesthesia syndrome (n=12; 46%) were the most common all-grade adverse events (AEs). Seventeen patients had serious AEs, including 10 with squamous cell carcinoma of the skin. Seven patients discontinued vemurafenib due to AEs. Conclusion: These data, which represent the only prospective clinical trial data of BRAF inhibition in histiocytosis to date, reveal that vemurafenib has potent single-agent activity in patients with ECD/LCH. Moreover, vemurafenib treatment had remarkable durability of response in histiocytosis, such that no evidence of resistance has been encountered following a median of 14.2 months of treatment. These results are distinct from vemurafenib use in other solid or hematologic malignancies. Figure Figure. Disclosures Subbiah: Abbvie: Research Funding; Nanocarrier: Research Funding; GlaxoSmithKline: Research Funding; Roche/Genentech: Research Funding; Bayer: Research Funding; Novartis: Research Funding. Blay:F. Hoffmann-La Roche: Consultancy, Research Funding; MDS: Research Funding; Lilly: Research Funding; Bayer: Consultancy, Research Funding; Pharmamar: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Puzanov:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunocore: Consultancy. Wolf:F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Clovis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ulaner:GE Healthcare: Research Funding; Genentech: Research Funding; Blue Earth Diagnostics: Research Funding; Susan Komen Foundation: Research Funding; Department of Defense: Research Funding; National Institutes of Health: Research Funding; Zevacor: Honoraria. Lacouture:Quintiles: Consultancy; Boehringer Ingelheim: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Foamix: Consultancy; Infinity: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Berg: Research Funding; Bristol Myers Squibb: Research Funding. Robson:F. Hoffmann-La Roche Ltd: Employment. Makrutzki:F. Hoffmann-La Roche Ltd: Employment.

Background: Contemporary approaches to non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) incorporate chemo-immunotherapy, biologic combinations, and immune modulating agents; toxicities in elderly pts (³65 years) receiving these therapies are not well studied. Further, clinical and biologic factors predicting these toxicities in pts receiving biologic therapy remain undefined. Methods: We reviewed data on NHL and/or CLL pts treated prospectively on 14 studies by the Alliance for Clinical Trials in Oncology from 2004-2014 (Table 1). Toxicity was assessed per the NCI CTCAE at the time of trial enrollment, and the probabilities of experiencing grade 3 and grade 4 hematologic (hem) and non-hematologic (non-hem) toxicities were modeled as a function of age (³65 years vs. < 65), time on study, treatment (biologics only vs. biologic + chemotherapy), gender, race, LDH, performance status (PS), stage, and an age-by-treatment interaction using logistic regression. Results: A total of 1199 pts (409 age ³ 65; 790 age < 65; 736=CLL and 463=NHL) were included. Among these patients, 493 received only biologic therapy (166 age ³ 65; 327 age < 65; 104 CLL; 389 NHL), and 706 received biologic + chemotherapy (243 age ³ 65; 463 age < 65; 632 CLL; 74 NHL). Among CLL pts (259 pts ³ 65), the effect of age on the probability of experiencing a grade 3 heme toxicity differed by treatment type (age-by-treatment interaction p = 0.047). Specifically, the adjusted odds ratio (OR) (age ³ 65 vs. < 65) for pts receiving only biologic therapy was 3.075 (95% CI: 1,15-8.25), and that for pts receiving biologic + chemotherapy was 1.044 (95% CI: 0.69 - 1.57). Similar results were seen in CLL pts for grade 4 heme toxicities (age-by-treatment interaction p = 0.033; biologic OR 6.937, 95% CI: 1.76-27.35; biologic + chemo OR 1.484, 95% CI: 1.04-2.13). No such interactions were found in CLL pts for grade 3 and 4 non-hem toxicities; however, older pts had significantly higher odds of experiencing a grade 3 non-hem toxicity than younger pts (adjusted OR 1.40; p = 0.047; 95% CI: 1.004-1.96). No age group differences were found in CLL pts for grade 4 non-hem toxicity. Similar analyses were performed for NHL pts (150 pts ³ 65), but no significant age group differences were found. Among CLL pts, women had significantly higher odds of experiencing a grade 3 heme toxicity than men (OR 2.01; p = 0.0007); no difference in grade 3 non-hem or any grade 4 toxicity was noted. Non-Caucasian CLL pts had higher odds of experiencing a grade 4 non-hem toxicity than Caucasians (OR 2.892; p = 0.0029), but no other toxicity differences were found. Worse PS was associated with increased toxicities (OR 1.871; p = 0.0009: grade 3 heme; OR 1.647; p = 0.0025: grade 3 non-hem; OR 1.410; p = 0.0448: grade 4 heme, and OR 1.931; p = 0.0252: grade 4 non-hem). CLL pts with advanced stage disease had higher odds of experiencing a heme toxicity (grade 3: OR 1.95; p = 0.0007, grade 4: OR 1.451; p = 0.0329), but no stage associations were found for non-hem toxicities. Among NHL pts, men had significantly higher odds of experiencing a grade 4 hematologic toxicity than women (OR 4.351; p = 0.0169), but no other toxicity differences were found. An increase in LDH was associated with significantly higher odds of experiencing grade 3 non-hem and grade 4 heme toxicities (grade 3 non-heme: OR 1.633; p = 0.021, grade 4 heme: OR 2.039, p = 0.0182), but no such effect was found for grade 3 heme or grade 4 non-hem. Worse PS was associated with higher odds of experiencing grade 3 toxicities (heme: OR 2.025; p = 0.0344, non-hem: OR 2.458; p = 0.0013), but no such differences were found for grade 4 toxicities. No significant stage or race effects were found in NHL patients. Conclusion: In pts ³65 years who have CLL or NHL, we identified several clinical and disease-related factors as potential predictors of developing grade 3 and/or 4 heme and non-hem toxicities (Table 2). A prognostic model is being constructed to predict toxicities in these under-studied pts to guide management and monitoring. Further, the impact of these toxicities on outcomes is being analyzed and will be presented at the meeting. Disclosures Hurria: Celgene: Other: Research; Optum Health Care SOlutions: Consultancy, Other: Conference panel, research; Boehringer Ingelheim Pharmaceuticals: Consultancy; Sanofi: Consultancy; Carevive: Consultancy; Novartis: Other: Research; GTx, Inc: Consultancy. Bartlett:Gilead: Consultancy. Cheson:Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nabhan:Infinity: Consultancy; Abbvie: Consultancy; Cardinal Health: Consultancy; Seattle Genetics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Celgene Corporation: Consultancy, Research Funding.

Background: Clonal hematopoiesis (CH) as evidenced by recurrent somatic mutations in leukemia-associated genes has been demonstrated to predict increased risk for subsequent hematologic cancers and decreased overall survival (OS) in large, population-based studies. We examined the incidence and clinical implications of CH in a large cohort of patients with advanced, non-hematologic cancers to examine whether individual mutations carried unique phenotypes with respect to effect on hematologic parameters and association with prior toxic exposures. Methods: We analyzed deep coverage targeted next-generation sequencing data of 410 cancer genes in paired tumor and blood samples from 7,200 patients with non-hematologic cancers. We called mutations in the blood and genotyped them in the matched tumor and required them to be supported by at least 8 reads and present at twice the variant allele frequency (VAF) or greater in blood cells compared to the tumor. Mutations were scored as hematopoietic in origin if they were detected with a VAF greater than 2% for a selected panel of leukemia genes and 5% for other genes. When at least one mutation exceeded these thresholds, we reduced the VAF threshold in blood to 1% to detect subsequent events for leukemia genes and 3% for non-leukemia genes. Mutations where VAF in blood and tumor were both greater than 35% were excluded as likely germline events except in cases where the blood-associated variants were seen in the blood at >35% for mutations reported in COSMIC on at least 10 occasions.Common SNPs were excluded. We excluded patients with concurrent hematologic malignancies.We examined whether different mutations harbored unique phenotypes in regard to their effect on hematologic parameters and associations with prior toxic exposuresin a subset of 5,145 patients. Results: CH was identified in 23.4% of patients. CH was associated with increased age (p Of the 35 JAK2 mutations identified in entire cohort, 13 occurred in patients with a known diagnosis of hematologic malignancies and were excluded from our analyses. Median VAF of JAK2 mutations in patients with known malignancies was 26% compared the median VAF of 3.1% in patients without a known hematopoietic malignancy. All 13 patients with known hematologic malignancies harbored the V617F mutation; however, this mutation was observed only in 14 of the 22 patients without known hematologic malignancies. DNMT3A, TET2, ASXL1, and TP53 mutations were all associated with current/former tobacco use, consistent with an important role for smoking in selecting for mutation-driven CH. DNMT3A, TET2, ASXL1, ATM, were not significantly associated with prior chemotherapy or radiation therapy (RT). CHEK2 mutations were associated with prior chemotherapy but not with prior RT. PPM1D and TP53 mutations were both associated with prior chemotherapy and RT. We examined a subset of CH mutations in presumptive driver genes (CH-PD) occurring at VAF>10%. CH-PD led to an increased risk for subsequent hematologic cancers (p Conclusions: Individual CH mutations exhibit unique phenotypes in regard to their effect on hematologic parameters and associations with prior toxic exposures. JAK2 mutations were associated with increased platelet counts even after excluding patients with a known diagnosis of hematologic malignancies. TP53 and PPM1D mutations demonstrated the strongest association with prior chemotherapy and radiation exposure. CH-PD is associated with increased risk for subsequent hematologic cancers and inferior OS in patients 65 and older. Disclosures Levine: Qiagen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.

Retinoic acid (RA), a metabolite of vitamin A, modulates a variety of aspects of the immune system, primarily because of its diverse effects on a wide range of immune cells. Initiation of RA-mediated transcription requires the binding of RA to heterodimeric nuclear receptors composed of RA receptors (RARα, β, and γ) and retinoid X receptors (RXRα, β, and γ). Although RA signaling is tolerogenic under steady state conditions, previous studies, including ours, have shown that RA can enhance pro-inflammatory responses in acute graft-versus-host disease (aGVHD) (Blood. 2013; 122(12): 2125). In that study, we demonstrated that donor T cells expressing a dominant negative RARα (DNRARα) markedly impaired GVHD lethality capacity. This paradoxical function in aGVHD was attributed to excessive RA production caused by the upregulation of RA-synthesizing enzymes, retinaldehyde dehydrogenases (RALDH), in hematopoietic and non-hematopoietic cells. In the current study, we investigated genetic and translational approaches to ablate RA synthesis and signaling as a means to treat aGVHD. The 4 isoforms of the RALDH enzyme are differentially expressed in a variety of cell types. RALDH-2 is the predominant isoform in dendritic cells (DCs), whereas RALDH-1 levels were found to be higher in intestinal epithelial cells (IECs) during aGVHD. We hypothesized that conditional deletion of either RALDH-2 in host CD11c+ DCs, or RALDH-1 in host IECs using a Cre-Lox system would diminish RA synthesis and reduce aGVHD. Consistent with this hypothesis, ablation of RA synthesis by RALDH-2 in host CD11c+ DCs significantly reduced aGVHD (Figure 1A; p We further explored RA signaling in aGVHD using a translational approach. IRX4204 is a novel and highly specific RXR agonist currently in clinical trials for autoimmune diseases, which can sequester RXR receptors and phenocopies the genetic approach using DNRARα T cells and allowing translation into the clinic. We discovered that IRX4204 can enhance in vitro CD4+CD25+Foxp3+ Regulatory T cell (iTreg) generation from naïve CD4+Foxp3- precursors (Figure 1B), suggesting it might increase Treg in vivo, and therefore be therapeutically useful for aGVHD prevention. To determine the effects of IRX4204 in aGVHD, we used two fully MHC mismatched mouse models: (B6 (H-2b) into BALB/c (H-2d) and BALB/c (H-2d) into B6 (H-2b). Recipients treated with IRX4204 had significantly prolonged survival time (Figure 1C&D), reduced weight loss, and better clinical scores compared to vehicle-treated mice. IRX4204 also significantly reduced donor T cell proliferation, effector differentiation and a 2-4 fold reduced production of pro-inflammatory cytokine (IFN-γ, TNF-α). Despite up-regulating gut-homing receptors on donor T cells, intestinal (and liver) GVHD pathology was reduced, which was associated with higher IEC integrity, assessed by po FITC-dextran serum levels. Compared to controls, IRX4204-treated recipients had a higher frequency of Treg in the spleen, mesenteric lymph nodes (p Disclosures Chandraratna: Io Pharmaceuticals: Other: Employed by Io Pharmaceuticals and is a board member, holding the titles of title of President and Chief Scientific Officer, and has ownership interest in Io Pharmaceuticals. .

CD63 is a 53-Kd lysosomal membrane glycoprotein that has been identified as a platelet activation molecule. The current study presents evidence that CD63 and Pltgp40, a platelet membrane glycoprotein identified in this laboratory, are the same molecule and that CD63/Pltgp40 is identical to the well-characterized, stage- specific melanoma-associated antigen ME491. Identity of CD63 and Pltgp40 was demonstrated by immunoprecipitation and sequential immunodepletion studies, which showed that the anti-Pltgp40 monoclonal antibody (MoAb) H5C6 and an anti-CD63 MoAb CLB/Gran 12 recognized the same 40- to 55-Kd platelet glycoprotein. In addition, the anti-CD63 MoAb specifically recognized immunoaffinity-purified Pltgp40. Amino acid sequences obtained from NH2-terminal and tryptic fragment peptides of Pltgp40 were used to generate complementary DNA (cDNA) probes using the polymerase chain reaction (PCR) technique. A 386-bp cDNA probe partially encoding CD63/Pltgp40 and a full length cDNA probe were 100% identical to the corresponding sequence of ME491. Antibodies H5C6 and CLB/Gran12 immunoprecipitated a 30- to 60-Kd heterodisperse glycoprotein from G361 melanoma cells, as had previously been reported for antibodies recognizing ME491. These data, taken together with the extensive homology recently reported between ME491, the Schistosoma mansoni membrane antigen SM23, CD37, the tumor-associated antigen CO- 029, and the target of an antiproliferative antibody-1, suggest that CD63 is a member of a new family of related molecules.

CD63 is a 53-Kd lysosomal membrane glycoprotein that has been identified as a platelet activation molecule. The current study presents evidence that CD63 and Pltgp40, a platelet membrane glycoprotein identified in this laboratory, are the same molecule and that CD63/Pltgp40 is identical to the well-characterized, stage- specific melanoma-associated antigen ME491. Identity of CD63 and Pltgp40 was demonstrated by immunoprecipitation and sequential immunodepletion studies, which showed that the anti-Pltgp40 monoclonal antibody (MoAb) H5C6 and an anti-CD63 MoAb CLB/Gran 12 recognized the same 40- to 55-Kd platelet glycoprotein. In addition, the anti-CD63 MoAb specifically recognized immunoaffinity-purified Pltgp40. Amino acid sequences obtained from NH2-terminal and tryptic fragment peptides of Pltgp40 were used to generate complementary DNA (cDNA) probes using the polymerase chain reaction (PCR) technique. A 386-bp cDNA probe partially encoding CD63/Pltgp40 and a full length cDNA probe were 100% identical to the corresponding sequence of ME491. Antibodies H5C6 and CLB/Gran12 immunoprecipitated a 30- to 60-Kd heterodisperse glycoprotein from G361 melanoma cells, as had previously been reported for antibodies recognizing ME491. These data, taken together with the extensive homology recently reported between ME491, the Schistosoma mansoni membrane antigen SM23, CD37, the tumor-associated antigen CO- 029, and the target of an antiproliferative antibody-1, suggest that CD63 is a member of a new family of related molecules.