Citations

Abstract Introduction: Selinexor is a novel, oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks exportin 1 (XPO1). Selinexor treatment results in nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and translational suppression of several oncoprotein mRNAs (e.g., c-myc, cyclin D).Multiple myeloma (MM) remains incurable, and most patients (pts) eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 mAbs and others. The increased use of combinations in MM treatment, (PIs/IMiDs/mAbs), has led to a growing number of pts with penta-refractory MM (pts that have been treated with bortezomib (bort), carfilzomib (carfil), lenalidomide (len), pomalidomide (pom) and daratumumab (dara)). Active novel therapies with different mechanisms of actions are needed to address this unmet medical need. Part 1 of STORM enrolled pts with both quad- (bort, carfil, len, pom, treated MM) or penta-refractory MM and demonstrated an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Based on these findings, the Pivotal Part 2 of STORM was initiated, enrolling an additional cohort of 122 patients with penta-refractory MM. Methods: Pts with penta-refractory MM were treated with 80 mg selinexor plus 20 mg dexamethasone (Sd) twice weekly. Pts must have received an alkylator, bort, carfil, len, pom and dara, and had MM refractory to ≥1 PI, ≥1 IMiD, dara, a glucocorticoid, and their last therapy. Pts must have a total ANC ≥1000 mm3,platelets ≥50k/mm3 (or ≥75k if marrow plasma cells <50%), and creatinine clearance ≥20 mL/min. The primary endpoint was ORR. Secondary endpoints: duration of response (DOR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Efficacy was assessed by an Independent Review Committee (IRC) based on IMWG criteria. OS was also compared to a cohort of pts with PI, IMiD, dara refractory MM from the Flatiron Health Analytic Database (FHAD), (ref: ASH 2018 abs ID: 116493),who met all the inclusion criteria for STORM. Results: As of 1-Jun-2018, 122 pts (71 M/ 51 F) were enrolled in 38 sites (US and EU). Pt characteristics were [medians (range)]: age 65 yrs (40-85); 7 (3 - 18) prior treatment regimens, 6.6 yrs (<1 - 23.4) from initial MM diagnosis.65 pts (53%) had high risk cytogenetics, 86 pts (70%) had prior dara in combination, 102 pts (84%) had prior stem cell transplantation, 2 pts had prior CAR-T therapy. All pts enrolled with progressive disease (PD), 72% of pts had increases (3% - 792%) in MM markers from screening to C1D1 (median 11 days). Frequently reported Sd treatment related adverse events (AEs) included (all grades, grades 3/4): thrombocytopenia (67%, 53%), nausea (67%, 10%), fatigue (68%, 21%), anorexia (50%, 2%), anemia (46%, 28%), and weight loss (46%, 0%). Eight pts remain on study and 114 pts discontinued treatment (most commonly for PD). There were 4 deaths on treatment: sepsis, respiratory failure, pulmonary embolism, and an unrelated, unspecified cardiac event. IRC determined ORR (≥PR) was 26.2%, with 6.5% ≥ very good partial response, including 2 stringent complete responses (sCRs; MRD negative at 1:10-6 and at 1:10-4sensitivity). Both pts who relapsed after CAR-T achieved PRs. The CBR (≥minimal response, [MR]) was 39.3%, and 79% of pts achieved ≥stable disease (SD). Responses typically occurred within the first month. Medians: DOR 4.4 months (mo) (range <1 - 10 mo), PFS 3.7 mo, and OS 8.0 mo. Pts with ≥MR had significantly longer OS than pts with PD/NE (median not reached vs 1.9 mo, p=<0.0001). Compared to the FHAD cohort, STORM cohort had longer OS (Figure 1, HR 0.41, p=0.0001). Conclusions: Results of the pivotal STORM Part 2 in penta (PI, IMiD, dara)-refractory MM demonstrated that oral selinexor plus low-dose dexamethasone (Sd) was highly active with an ORR of 26.2%. Importantly, responses were rapid and deep with 2 patients achieving sCRs (both MRD negative) in these heavily pre-treated penta-refractory MM pts (median 7 prior regimens, 53% high risk). AEs are a function of dose/schedule/disease severity and can be managed with dose modifications and supportive care. No major organ toxicity was observed and AEs were typically transient and reversible. Sd is an all-oral, first in class mechanism with novel MOA and represents a potential therapeutic option to the growing number of pts with penta-refractory MM who have exhausted approved therapies. Disclosures Chari: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Celgene: 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; Pharmacyclics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy. Vogl:Karyopharm Therapeutics: Consultancy. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene and Janssen: Research Funding; Amgen, Celgene, Janssen and Takeda: Consultancy. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Mohty:Amgen: Consultancy, Honoraria; Molmed: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Bristol Myers: Consultancy, Research Funding. Sylvain:Gilead: Other: scientific advisor board. Costa:Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; BMS: Research Funding. Shah:Karyopharm Therapeutics: Employment. Picklesimer:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Li:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Novartis: Consultancy; Merck: Consultancy.

Abstract Introduction Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have significantly improved survival in patients with multiple myeloma (MM). Refractoriness to PIs and IMiDs results in poor outcomes with a median survival of about 13 months.Daratumumab and isatuximab are CD38-targeting monoclonal antibodies (MoABs) with remarkable activity in relapsed and refractory MM. The outcome of MM patients in US clinical practice who becomes refractory to CD38 MoABs is unknown. The aim of this multicenter, retrospective study is to investigate the natural history of patients with MM who become refractory to CD38 MoABs (Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure: MAMMOTH study). Methods We identified patients from 14 academic institutions in the US with diagnosis of active MM and refractory to daratumumab or isatuximab, administered alone or in combination. Patients were considered refractory to CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. The time when patients met the above criteria of progression was defined as time zero (T0). Data including patient-disease characteristics and all therapies administered before and after T0 were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. For survival outcome analysis, patients were classified into three groups: "Penta-refractory" (refractory to 1 CD38 MoAB + 2 PIs + 2 IMiDs), "Triple-refractory and quad-refractory" (refractory to 1 CD38 MoAB + 1 PI + 1/2 IMiDs, or 1 CD38 MoAB + 1/2 PIs + 1 IMiD), and "Not triple-refractory" (refractory to 1 CD38 MoAB, and not both of a PI and an IMiD). Responses were evaluated using the IMWG criteria. Results Two hundred and seventy-five patients were included in this study; median age at T0 was 65 years (range 27-90). Fifty five percent of patients were males, 52% had IgG isotype, 29% had ISS stage III disease, and 29% had high-risk cytogenetics at diagnosis. Median interval from diagnosis of MM to T0 was 50.1 months (mo) (range 2.5-230.1). Patients received a median of 4 lines of treatment (1-16) prior to the CD38 MoAB-containing regimen; 72% underwent prior autologous transplant. Daratumumab-refractory patients formed a majority (256, 93.1%) of this cohort. Most of the patients were refractory to lenalidomide (77%), pomalidomide (65%), bortezomib (68%), and carfilzomib (47%). Seventy patients (25.5%) were "penta-refractory" and 148 (53.8%) were "triple-refractory and quad-refractory". Median follow-up from T0 for survivors was 10.6 mo (range 1.9-42.3 mo). The median overall survival (OS) from T0 for the entire cohort was 8.6 mo (95% C.I. 7.2-9.9); OS for the groups based on refractoriness to prior treatments are shown (Figure). Two hundred and forty-nine patients (90.5%) received at least one line of treatment after T0, (median 2, range 1-10). The response rates and depth of responses to each line of treatment post T0 are shown (Table). Among patients who received ≥ 1 subsequent treatment, the median PFS and OS from T0 were 3.4 (95% C.I. 2.8-4.0) mo and 9.3 (95% C.I. 8.1-10.6) mo, respectively; the median OS for the 26 patients who received no further treatment was only 1.3 (95% C.I. 0.6-1.9) mo. By multivariate analysis, penta-refractoriness (HR 2.4, p <0.001), high-risk cytogenetics (HR 1.5, p=0.01), elevated LDH (HR 2, p<0.001) and creatinine > 2 (HR 2.4, p=0.01) at the onset of CD38-based therapy predicted inferior OS. Conclusions Patients with MM who become refractory to CD38 MoAB are increasingly less responsive to subsequent therapies. While survival is particularly dismal for penta-refractory patients, the outcomes are poor even for patients who are not refractory to other mainstream MM agents. The MAMMOTH study defines a MM population in urgent need for new therapies, and provides benchmark OS, PFS and response data for subsequent investigational therapies in this setting. Disclosures Malek: Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Paul:Bristol Myer Squibb: Other: Stock and pension plan (past employee). Neppalli:Amgen: Consultancy; Celgene: Consultancy. Liedtke:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; BlueBirdBio: Research Funding; celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen Inc.: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Vij:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa:Karyopharm: Research Funding; Sanofi: Honoraria; Janssen: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Abstract Background: Conventional AlloTx for MM is associated with TRM exceeding 20%. Non-myeloablative AlloTx (NST) utilizes the known graft-vs-myeloma (GVM) effect in an attempt to eradicate minimal residual disease. Preliminary studies of NST in MM demonstrated significant CR and low 100 day post-NST TRM (Badros et al Blood97:2574, 2001). However, even though response rates were high, the vast majority of pts with significant MM disease at the time of transplant, relapsed within the first year. To provide maximal tumor cytoreduction to allow for a subsequent GVM effect, the ECOG designed a Phase II trial of AHSCT for maximal tumor cytoreduction followed by a matched sibling NST to allow for a GVM effect. Methods: The study was designed as a two-stage process based upon early transplant mortality in the first 100 days. Eligibility included pts treated as part of induction therapy or salvage therapy. Chemotherapy responsive disease was not required. Only matched sibling donors were allowed. Pts must have had adequate PS and physiologic organ function. After stem cell mobilization, pts received melphalan 200 mg/m2 with AHSCT. Pts underwent NST 100–182 d post-AHSCT following fludarabine 30 mg/m2 daily × 5 and cyclophosphamide 1 g/m2 for 2 days. GVHD prophylaxis included cyclosporine and corticosteroids. For pts with acute GVHD, Zenapax 1 mg/kg for 5 doses q 3 d was recommended. GM-CSF was incorporated post-AHSCT and NST. The primary endpoints were day 100 TRM, early graft failure, extent of acute GVHD, toxicities, DFS and OS. The study was suspended for 6 mo after the first 19 pts to evaluate early TRM-no early TRM was observed and the study was re-opened. Results: From 5/3/01 to 1/14/05, 32 pts from 10 institutions were enrolled on the study. 23 patients, median age 51 (range 32–64) completed both transplants (28% drop-out rate): 7 (30%) CR (2 in CCR), 11 (48%) PR and 2 (9%) NR and 3 (13%) NE as the best overall response. Of the 32 pts who completed AHSCT, there were 12 grade 4 toxicities pre-NST; 11/23 pts had grade 4 toxicities post-NST. Acute grade III/IV GVHD was observed in 4 (17%); chronic GVHD was observed in 9 pts (39%): 5 limited; 4 extensive resulting in 3 CR (33%), 1 CCR, and 3 PR (33%). 1 pt (4%) had graft-failure. Two pts (8.7%; 95% CI 1.6%, 24.9%) had TRM prior to day + 100 post-NST. With a median follow up of 3.5 years from registration, the median PFS was 4.4 years and the 2-year survival rate was 78% (95% CI: 61% ∼ 95%) for the 23 pts who completed both transplants. Conclusions: AHSCT followed by NST is feasible in a Cooperative Group setting with a low early TRM. The PFS and OS were superior to historical reports for single and tandem AHSCT. AHSCT-NST tandem transplants resulted in a 78% overall response, including 30% CR (2/7 CCR) - similar to other reports for AHSCT-NST. 3/9 pts with chronic GVHD achieved CR demonstrating the GVM effect. However, a plateau in PFS or OS was not observed indicating that the GVM effect is not sufficient to produce long- term disease control and is unlikely curative using this treatment schema. Future studies should include novel therapies to induce better responses pre-transplant and consideration for post-NST maintenance to further eradicate MRD while allowing for GVM.

Abstract Four patients with macroglobulinemia demonstrated an impaired ability to produce IgM antibody when stimulated with a relatively weak antigen, sheep cell stroma, but not with a more potent antigen, Brucellin. The explanation of this defect is unknown. It may be in part the cause of the greater-than-normal infection rate seen in patients with macroglobulinemia.

Abstract Abstract 2686 Background: DLBCL is the most commonly occurring form of non-Hodgkin lymphoma and is a highly curable disease, but one that is universally fatal if untreated or improperly treated. In a series of studies, we have reported racial disparities in the clinical presentation and the treatment outcomes for patients (pts) with DLBCL in the United States (Shenoy Cancer 2010; Flowers CEBP 2012). These studies showed that black pts with DLBCL are diagnosed at an age a decade younger than whites, are more likely to have advanced stage disease, and are less likely to survive 5 years. One explanation is that black patients in the US less often receive standard of care therapy (Flowers CEBP 2012). However, in a cohort study of 533 white and 144 black patients with DLBCL managed at Emory and University of Alabama-Birmingham (UAB) black race predicted worse overall survival (OS) even when black and white pts received the same therapy (CHOP; Hazard ratio [HR] 1.8, p<0.001) suggesting a biological basis for some disparities(Flowers Leuk Lymph 2012). To address these findings, we examined whether known prognostic biological variants within DLBCL [germinal center B-cell-like (GCB) and activated B-cell like (ABC)] occurred differentially between black and white pts. Methods: DLBCL pts within our Emory-UAB cohort study provided formalin fixed material available for construction of tissue microarrays (TMAs). All pts were diagnosed with DLBCL from 1990–2010 and met the following criteria: age ≥18 years at diagnosis and available information on demographics, race, gender, initial clinical features at presentation, treatment, and treatment outcomes. H&E slides from each block for each case were reviewed to identify the appropriate zone(s) for cores. Sections placed in TMAs underwent immunohistochemistry (IHC) staining with BCL6, GCET1, CD10, FOXP1, and LMO2 antibodies. The percentages of positive cells were scored in 10% increments for each antibody, and recorded for each case by 3 hematopathologists blinded to the clinical and demographic data. The Choi algorithm was used to classify all patients into ABC and GCB subsets; other IHC algorithms were used as a backup. Descriptive statistics for the baseline characteristics of black and white pts were compared using Chi-square tests. Kaplan–Meier estimation was used to evaluate OS for the two groups and compared with the log-rank test. To evaluate prognostic factors and the effects of treatment on OS, Cox proportional hazards models were used controlling for age, sex, stage, LDH, performance status, presence of B-symptoms, race, treatment (R-CHOP vs. other), and ABC subtype. Results: Tissues for 26 black pts and 63 white pts meeting all eligibility criteria were evaluated in the TMA. There were significant differences in baseline characteristics between the two groups; 23% of black pts vs. 46% of whites were > 60 years of age (p=0.04), 73% had stage III/IV disease vs. 56% (p=0.03), and 77% had an LDH>ULN vs. 51% (p=0.04). There were no significant differences between the two racial groups in terms of sex, ECOG PS, presence of B-symptoms (38% vs. 29%p=0.46), extranodal sites (50% vs. 78% ≤ 1, p=0.27), IPI risk, or treatment received (RCHOP 46% vs. 40% p=0.93). By the Hans, Natkunam, Tally, and Choi algorithms black patients more commonly presented with the poor-risk ABC/non-GCB subtype (by Choi black 64% ABC vs. white 37%; p= 0.01, Table). After controlling for clinical confounders including age, sex, stage, LDH, performance status, presence of B-symptoms, race, treatment (RCHOP vs. other), and ABC subtype, being >60 years of age [HR 3.1 95% CI 1.3–7.2], being black (HR 3.5 95% CI 1.5–8.2), and receiving treatment other than RCHOP (HR 12.8, 95% CI 3.2–50.6) were associated with inferior OS. Conclusions: The rate of ABC DLBCL is significantly higher in black pts compared to white pts in this university-based cohort from the Southern United States. Additional studies confirming these findings in larger populations and examining the mutations associated with these differences are underway to address biological differences intrinsic to DLBCL that may in part explain comparatively adverse features and outcomes for black pts with DLBCL. Disclosures: Flowers: Celgene, Spectrum, Millennium, Gilead, Janssen: Research Funding; Genentech/Roche (unpaid), Millennium (unpaid), Celgene: Consultancy. Bernal-Mizrachi:Empire Genomics (not related to current work): Patents & Royalties. Sinha:Celgene: Research Funding. Jaye:Millenium Pharmaceuticals (For single lecture on immunohistochemical subtyping of large B cell lymphomas): Honoraria.

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of the BRAF V600E mutation in ~50% of patients with LCH and the non-LCH Erdheim-Chester Disease (ECD) provided the first molecular target in these patients and novel insights into the pathogenesis of these disorders. However, recurrent mutations in the majority of the ~50% of BRAF V600E-wild type patients with non-LCH are unknown. Moreover, recurrent mutations outside of the MAP kinase pathway are undefined throughout histiocytic neoplasms. To address these issues, we performed whole exome sequencing (WES) of frozen biopsies from 24 patients with LCH (n=10) or ECD (n=14) paired with peripheral blood mononuclear cells. 13/24 patients also underwent RNA sequencing (RNA-seq). All mutations in activating kinases were validated by droplet-digital PCR, while targeted-capture next-generation sequencing validated all others. Both adult (n=18; n=2 with LCH) and pediatric cases (n=9; n=8 with LCH) were included. Using combined WES/RNA-seq, activating kinase alterations were identified in 100% of patients. In LCH, 60% and 40% had BRAF V600E and MAP2K1 mutations, respectively. In non-LCH 51%, 14%, 14%, and 7% were BRAFV600E, ARAF, MAP2K1, and NRAS mutant (Fig1A). Overall, a mean of 7 non-synonymous mutations per adult patient was identified (range 1-22) compared with 5 mutations per pediatric patient (range 4-9; p =ns). Mutations affecting diverse cellular processes were found to co-exist with kinase mutations including mutations in epigenetic modifiers and the p38/MAPK pathway. In addition to kinase point mutations, RNA-seq identified recurrent, in-frame kinase fusions-a first for these disorders. All identified fusions were validated using FISH and RT-PCR. This includes novel fusions in BRAF (RNF11-BRAF and CLIP2-BRAF), as well as therapeutically important fusions in ALK (2 separate KIF5B-ALK fusions) and NTRK1 (LMNA-NTRK1;Fig1B). Expression of each fusion in Ba/F3 cells conferred cytokine-independent growth. Importantly, the BRAF fusions were found to be sensitive to MEK inhibition but resistant to vemurafenib while the ALK fusions conferred sensitivity to the ALK inhibitors crizotinib or alectinib. We next interrogated a validation cohort of 37 BRAF V600E-wild type, non-LCH, formalin-fixed, paraffin-embedded tissue samples using targeted mutational profiling for MAP2K1, ARAF, NRAS, KRAS, and PIK3CA. This revealed activating mutations in MAP2K1 (32%; n=12), NRAS (16%; n=6), KRAS (11%; n=4), PIK3CA (8%; n=3), and ARAF (3%; n=1). Three of the investigated non-LCH patients with refractory disease and progressive organ dysfunction were treated with targeted therapies based on the discovery of novel kinase alterations described above. Treatment of 2 refractory MAP2K1- mutant, non-LCH patients with MEK inhibitors (trametinib or cobimetinib) resulted in dramatic clinical improvement (Fig1C). Both patients have been maintained on MEK inhibitor single-agent therapy with a sustained clinical response for >100 days. Further evidence of effective targeted inhibition was found in a refractory ECD patient carrying an ARAF S214A mutation. This patient failed to respond to 3 lines of prior therapies and suffered near blindness due to disease infiltration in the retina and optic nerves. Given a recent report of complete response to sorafenib in a lung cancer patient with an ARAF S214C mutation, we initiated sorafenib. Within 12 weeks, there was improvement in the patientÕs eyesight and decreased infiltrative disease, coinciding with >50% decrease in mutant ARAF DNA in plasma cell-free DNA. Whole exome and transcriptome sequencing identified activating kinase mutations or translocations in all patients with the common downstream effect of activating the MAPK pathway. The preliminary, dramatic, clinical efficacy observed with use of MEK and RAF inhibitors in MAP2K1 - and ARAF-mutated, non-LCH patients further supports the central role of targeting the MAPK pathway in these tumors. The discovery of the discussed mutations and fusions in diverse kinases provides critical new insights into the genetic events central to a spectrum of adult and pediatric histiocytic neoplasms. Figure 1. Figure 1. Disclosures Off Label Use: This abstract describes use of MEK inhibitors (both tremetinib and cobimetinib) as well as sorafenib for MEK1 and ARAF mutant histiocytosis. . Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership. Ross:Foundation Medicine Inc.: Employment. Ali:Foundation Medicine Inc.: Employment. Hyman:Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria.

INTRODUCTION: While esophagectomy is the standard treatment for submucosal (T1b) esophageal adenocarcinoma (EAC) and squamous cell cancer (SCC), many elderly patients -the age group that esophageal cancer tends to affect- are not candidates for surgery. Endoscopic submucosal dissection (ESD) is a minimally invasive procedure that allows for en-bloc resection of early esophageal cancer and allows for precise histopathologic staging of the tumor. ESD could be curative in submucosal cancer without lymph node metastasis, and it allows for precise histopathologic staging. To evaluate the long-term outcomes of ESD in patients with EUS-staged T1b esophageal cancer. METHODS: A retrospective multicenter study was performed at three academic hospitals in the U.S. Patients who underwent ESD with a pre-procedural or post-procedural histopathologic diagnosis of T1b N0 M0 EAC or SCC were included in the study. Data was collected on demographics, tumor and procedure characteristics, procedure pathology, and follow-up. Local recurrence was confirmed by endoscopic findings and pathological analysis. Metastasis was confirmed by cross-sectional imaging. The main outcome was a composite of rate of metastasis and local recurrence. Follow-up time was defined as months from initial procedure to recurrence or last follow-up visit if recurrence-free. A time-to-event analysis was performed to evaluate recurrence. RESULTS: Fifty-two patients underwent ESD (mean age 69.6 years +/-9; 35 males) (Table 1). Based on available comorbidity data, 42% patients were not fit for surgery, as determined by an age-adjusted Charlson Comorbidity Index > 6. Twenty tumors (62%) were found to be HGD or T1a on post-ESD specimen analysis, while one was staged as T2. Nineteen patients were staged as T1b after ESD. Immediately after ESD, 6 patients were referred for surgery, 3 underwent chemoradiation therapy, and 6 radiation alone (Table 2). Patients were followed for a median of 18 months, and the calculated 24-month recurrence rate was 13% (Figure 1). CONCLUSION: This multicenter trial showed that ESD for T1b esophageal cancer can be acceptable for patients who deemed not surgical candidates. However, close follow up is necessary. ESD can also serve as a staging procedure, as our data confirms inaccurate EUS-staging of T1b cancer, with 62% of tumors being down-staged to T1a, as has been previously reported.

INTRODUCTION: The difference in long-term outcomes of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for Barrett’s related superficial neoplasia remains unclear. We aimed to compare the rates of local and metachronous recurrence of ESD and EMR in patients with clinically staged BE-associated high-grade dysplasia (HGD) and T1a esophageal adenocarcinoma (EAC). METHODS: Multicenter study at six academic hospitals in the U.S. including patients who underwent ESD for BE-HGD or T1a EAC. Primary outcome was a composite of metastasis and local recurrence rate. A time-to-event analysis was performed to evaluate recurrence. A Kaplan-Meier plot was constructed, and a log-rank test was used to compare the groups. A Cox hazard ratio regression analysis was performed to identify predictors of recurrence. RESULTS: A total of 241 patients were included. 154 underwent EMR, while 84 underwent ESD (Table 1). ESD had higher en bloc (96% vs 33%, P < 0.0001), R0 (76% vs 54%, P = 0.0009) and curative resection rates (75% vs 32%, P < .0001) when compared to EMR. The 24-month local recurrence rate for EMR and ESD was 43% and 11%, respectively ( P = 0.0007) (Figure 1). Significantly more endoscopic resection procedures were required to treat recurrence after EMR compared to after ESD (Table 1). EMR, piecemeal resection, positive margins, and non-curative resection were identified as predictors of recurrence on univariate analysis. En bloc resection remained significant after multivariate analysis (Table 2). CONCLUSION: This multicenter study showed that ESD results in more definitive treatment of BE-associated early neoplasia than EMR, with significant lower recurrence rates and less need for repeat endoscopic therapeutic procedures than EMR.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

Distress is defined in the NCCN Guidelines for Distress Management as a multifactorial, unpleasant experience of a psychologic (ie, cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment. Early evaluation and screening for distress leads to early and timely management of psychologic distress, which in turn improves medical management. The panel for the Distress Management Guidelines recently added a new principles section including guidance on implementation of standards of psychosocial care for patients with cancer.