Abeykoon, Jithma P.

Background: Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder that is now recognized as a neoplasm by the World Health Organization. It is generally classified based on the site and extent of disease involvement (single system or multisystem). Pulmonary LCH (pLCH), an uncommon interstitial lung disease associated with smoking, often presents as isolated pulmonary disease. It is unclear whether patients with clinically isolated pLCH have extra-pulmonary lesions at diagnosis or during the course of their disease. The role of [18F] fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) in the staging of pLCH remains unclear. Our study aims to better characterize the utility of radiographic staging studies at time of diagnosis and prevalence of extrapulmonary disease at follow up in pLCH. Methods: We conducted a retrospective study of patients presenting with clinical findings consistent with isolated pLCH seen at the Mayo Clinic from January 2000 to January 2020. All patients had a diagnosis of pLCH determined by chest imaging studies [computed tomography (CT) or high-resolution CT (HRCT)] or by histopathologic findings from surgical or transbronchial lung biopsy. Histopathologic findings for the diagnosis of pLCH required the presence of Langerhans cells (S100+/CD1a+/Langerin+). Patients were excluded if they had clinically apparent extra-pulmonary organ involvement at the time of diagnosis. BRAF V600E mutation was determined by immunohistochemistry (IHC) or cell-free DNA (cfDNA). Staging was defined as FDG-PET-CT or whole body CT imaging obtained within 3 months of diagnosis of pLCH. Extra-pulmonary LCH involvement was determined by imaging characteristics or by histopathologic findings. Descriptive statistics and overall survival (OS) were analyzed with JMP software, version 14 (SAS Institute Inc., Cary, NC). Results: A total of 112 patients with clinically isolated pLCH were identified. The median age at diagnosis was 45 years (range 21-73), and 48 (43%) were male. The majority (n=110, 99%) were former or current smokers with a median pack year of 25 (range 1-57). Three (3%) patients were noted to have occupational industrial exposure. Nine patients had a history of another cancer prior to their diagnosis and staging of pLCH [lung (n=4), breast (n=2), neuroendocrine (n=2), thyroid (n=1)]. Presenting symptoms included dyspnea on exertion 49 (44%), cough 18 (16%), chest pain 14 (13%), and 29 (28%) were incidentally discovered on imaging studies. On HRCT, the following characteristics were observed: 42 (38%) cystic, 32 (29%) cystic and nodular, 37 (33%) nodular, 1 (<1%) ground glass opacities. Seventy (63%) patients had lung biopsy confirmation, of which 11 (16%) patients underwent BRAF V600Emutation testing (7 by IHC, 4 by cfDNA). Six (55%) of these 11 patients were positive for BRAF V600E mutation. 34 (30%) patients underwent radiographic staging studies within 3 months of diagnosis of pLCH (25 FDG-PET-CT and 9 whole-body CT), and none of these imaging studies showed evidence of extra-pulmonary disease. Of the patients who had at least one year of follow-up (n=52), one (2%) developed extra-pulmonary disease. This patient did not undergo initial staging studies, developed headaches and was found to have a large calvarial lytic lesion within 2 months of pLCH diagnosis (BRAF V600E+). Among those who did not undergo staging at diagnosis (n=78), long term (>5 years) follow up data were available for 23 (29%), and none developed extra-pulmonary disease as determined by clinical notes or imaging studies. No patient had evidence of new extra-pulmonary involvement or second malignancy at the time of last known follow-up. After a median follow-up duration of 2.4 years (95% CI: 1.5-3.6, range: 0.1-17) ten (9%) patients died, of which 5 died of pLCH related complications. The median OS for entire cohort was 15 years (95% CI 9.1-not reached, Figure 1). Conclusion: Our study shows that adult patients with clinically isolated pLCH rarely present with extra-pulmonary manifestations at diagnosis or at follow up. These findings suggest a limited role of routine radiographic staging studies in pLCH unless clinically indicated. Studies on longer follow up of this cohort would provide further insights into the natural history of pLCH and are underway. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding. Shah:Dren Bio: Consultancy.

SummaryMeasurable residual disease (MRD) assessment by marrow‐based next‐generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false‐negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MASS‐FIX). Of all 61 complete responders who were NGF‐negative for MRD, around day‐100 post ASCT, 59% were MASS‐FIX‐positive. At median follow‐up of 26 months, 69% of MASS‐FIX(+)/NGF(−) patients were alive and progression‐free versus 96% of MASS‐FIX(‐)/NGF(−) patients, P = 0·02. MASS‐FIX, a simple peripheral blood‐based assay complements marrow‐based NGF to accurately prognosticate patients with myeloma.

SummaryIbrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression‐free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 81% and 57% respectively (P = 0·009). In the validation cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38;P = 0·01] and validation cohorts (HR 0·18;P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

Introduction Due to the higher metabolic demand, malignant cells have an increased dependency on the nucleocytoplasmic trafficking of proteins, as compared to normal cells. Chromosome region maintenance protein 1 (CRM1), encoded by the XPO1 gene, is the main protein receptor which facilitates export of molecules, including tumor suppressor proteins, from the nucleus to the cytoplasm thereby making them inactive. Expression of CRM1 in tumor tissue has been shown to be an independent prognostic marker in several solid tumors and in acute myeloid leukemia; high CRM1 expression by immunohistochemistry (IHC) was associated with more aggressive disease and shorter survival. Importantly, selinexor, a first in class small molecule inhibitor of CRM1, was recently approved for the treatment of relapsed diffuse large B-cell lymphoma (DLBCL). The expression of CRM1 on tumor cells and the assessment of its prognostic impact have not been studied in patients (pts) with DLBCL or primary mediastinal B-cell lymphomas (PMBCL). Methods Paraffin embedded tumor tissue from pts with DLBCL or PMBCL treated with immunochemotherapy was assessed for CRM1 expression through IHC on tissue microarray (TMA). CRM1 anti-rabbit monoclonal antibody (Cell Signaling, catalog-no: 46249) was used at 1:100 dilution. Tumor cell grading was based on CRM1 staining in tumor cells compared to background non-malignant lymphocytes and non-malignant lymphocytes in spleen and tonsillar tissue controls. Renal cell carcinoma (RCC) was used as a positive control [known high levels of CRM1 staining (Inoue et al, J Urol, 2012)]. Two expert hematopathologists (RLK & AJW) independently scored CRM1 nuclear staining and assigned a grade of 0-3; 0 (no definitive nuclear staining, equal to background lymphocytes), 1 (dim nuclear staining), 2 (consistent nuclear staining, nuclear detail still visible behind the stain) and 3 (strong nuclear staining obscuring most nuclear detail, staining equivalent to RCC control). The average CRM1 score per case across all available cores on the TMA was calculated. Low CRM1 expression for a case was arbitrarily defined as a score of 0-2.0; high CRM1 expression was score 2.1-3.0. Scoring reliability between reviewers and between cores was assessed using intra-class correlation coefficient; score 0.75-0.90 was considered as a good scoring reliability. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death. The association of CRM1 expression and risk of failing to achieve EFS at 24 months after diagnosis (EFS24) was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models, while the association of CRM1 expression with continuous EFS and overall survival (OS) was estimated using Kaplan-Meier curves and hazard ratios (HR) and 95% CI from Cox regression models. Results Tumor tissue from 282 pts was studied for CRM1 staining, including 275 pts with DLBCL and 7 pts with PMBCL. Median age of the study population was 61 years (range: 18-93) and 59% were male. The median follow-up for the entire cohort was 88.6 months. The first-line treatment regimens and baseline patient characteristics at diagnosis are outlined in Figure 1A. Of the 282 pts, 200 (71%) had high level of CRM1 expression and 82 (29%) had low CRM1 expression [only 4 (1.4%) had no or 0 staining]. Intra-class correlation coefficient to measure scoring reliability was 0.8. There was no difference in International Prognostic Index (IPI), ECOG performance score, lactate dehydrogenase or age at diagnosis among the groups with high CRM1 expression compared to low CRM1 expression (Figure 1A). The EFS24 failure was 29% for pts with low CRM1 expression while 26% in pts who had high CRM1 expression, OR=1.16, 95% CI 0.63-2.07; p=0.63. Null associations were also observed for EFS (HR=1.21, 95% CI 0.80-1.83; p=0.38) and OS (HR=1.02, 95% CI 0.61-1.69; p=0.95), (Figure 1B, C). Results were similar when adjusted for gender and IPI. Conclusion CRM1 expression by IHC on paraffin embedded tumor tissue is feasible in DLBCL and PMBCL. These data demonstrate that the CRM1 protein, the target for selinexor, is indeed expressed in the vast majority of these tumors; only 1.4% had no staining. However, CRM1 expression by IHC is not a prognostic marker for EFS24, EFS or OS. Whether CRM1 staining predicts selinexor response has not been studied but should be included in any new studies using CRM1 inhibitors. Disclosures Maurer: Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Witzig:Acerta: Research Funding; Immune Design: Research Funding; Incyte: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding; Spectrum: Consultancy; Karyopharm Therapeutics: Research Funding; AbbVie: Consultancy.

Magnesium is an essential element that is involved in the regulation of cell growth, division and differentiation. Epidemiologic studies have demonstrated that a diet poor in magnesium is associated with an increased risk of developing cancer. There are few studies investigating whether magnesium deficiency is associated with a poor prognosis in lymphomas. The recent discovery of X-linked immunodeficiency with magnesium defect, Epstein-Barr virus, and neoplasia (XMEN) disease, suggests a role of magnesium in the development of hematologic malignancies and lymphocyte function. Furthermore, a recently published study found that hypomagnesemia prior to chemotherapy is associated with inferior overall survival (OS) in patients with Burkitt Lymphoma. We hypothesized that low magnesium levels prior to autologous hematopoietic stem cell transplant (AHSCT) may lead to inferior outcomes via impaired lymphocyte recovery. We evaluated whether low serum magnesium levels were associated with inferior survival in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who underwent autologous hematopoietic stem cell transplant (AHSCT) between January 1998 and May 2020 using a retrospective study design. We cross-referenced our search with patients who had a magnesium level as part of their pre-transplant workup between 7 and 28 days prior to their first transplant. Two-sided Wilcoxon rank sum test and Chi square/Fischer's exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier and log-rank tests were used to perform all time to event analysis. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Our study included 581 patients of which 82 (14.1%) had hypomagnesemia (magnesium < 1.7 mg/dL) prior to AHSCT. Our study found that hypomagnesemia was associated with inferior OS and event-free survival (EFS) defined as re-transplant, relapse or death, compared to those with a normal magnesium level; median OS: 7.3 years (95% CI: 2.91 - upper limit not estimable) versus 9.7 years (95% CI: 6.92 - 12.3 years), p=0.0041; and median EFS: 3.9 years (95% CI: 1.63 - 8.98 years) versus 6.29 years (95% CI: 4.73 - 8.95 years), p = 0.016 respectively(B). Higher serum magnesium (HR 0.199 per doubling, 95% CI 0.078 - 0.503; p<0.001) and higher albumin (HR 0.090 per doubling, 95% CI 0.021 - 0.394; p=0.001) were associated with lower mortality rates, and higher creatinine (HR 1.669 per doubling, 95% CI 1.03 - 2.52; p=0.04) was associated with greater mortality up to 1 year post-transplantation. In a multivariate Cox regression excluding albumin, hypomagnesemia (p < 0.001) and elevated creatinine (p = 0.038) were independent predictors of poor overall survival(A). There was no significant difference between day 15 absolute lymphocyte count between patients with normal magnesium levels and low serum magnesium levels prior to their conditioning regimen. Although we hypothesized that we would find a significant difference between 15 day absolute lymphocyte count recovery and hypomagnesemia, this was not apparent. However, magnesium is an important nutrient for immune function and immune recovery is important after the bone marrow is restored post ablative therapy. Thus, low serum magnesium levels may lead to impaired OS and EFS via impaired lymphocyte function. In vitro studies will be necessary to understand this mechanism further. Magnesium may simply be a marker of illness and replacement of magnesium may not improve outcomes. However, further investigations are needed to determine whether outcomes would improve with replacement of magnesium in patients with hypomagnesemia, which our study did not address. Overall, our preliminary data suggests that hypomagnesemia is an independent prognostic factor and predictor of inferior OS and EFS in this cohort of patients. Figure Disclosures Ansell: ADC Therapeutics:Research Funding;AI Therapeutics:Research Funding;Trillium:Research Funding;Affimed:Research Funding;Regeneron:Research Funding;Seattle Genetics:Research Funding;Bristol Myers Squibb:Research Funding;Takeda:Research Funding.Witzig:Spectrum:Consultancy;Celgene:Consultancy, Research Funding;Immune Design:Research Funding;Karyopharm Therapeutics:Research Funding;Acerta:Research Funding;Incyte:Consultancy;AbbVie:Consultancy;MorphSys:Consultancy.

Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (selinexor), a first in class CRM1 inhibitor recently approved for multiple myeloma and diffuse large B-cell lymphoma (DLBCL), has been limited by substantial adverse effects (AEs). To address this clinical problem, we focused on identifying novel strategies to boost the potency, reduce toxicity, and broaden the applicability of CRM1 inhibitors to a wider range of malignancies. We discovered that salicylates could markedly enhance the anti-tumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. KPT-330 was chosen as the prototypical CRM1 inhibitor given its current FDA approval status and characterized pharmacokinetics; and choline salicylate (CS) was chosen as the prototypical salicylate given its favorable pharmacokinetics and reduced antiplatelet, renal, neurological and gastrointestinal AEs in humans compared to other salicylates. By using cell lines belonging to different hematologic malignancies and solid tumors, we demonstrated ex vivo that the combination of KPT-330 and CS (K+CS) could induce unique and significant antitumor effect at much lower dose of KPT-330 (at 25% of the dose used in the clinic), thereby potentially mitigating prohibitive clinical AEs (Figure 1a-d, and e-g). This significant synergetic antitumor effect observed with K+CS ex vivo was also validated in vivo by using an NSG mouse model of mantle cell lymphoma (Figure 1h). Moreover, the K+CS combination did not show this potent toxic effect on non-malignant cells in vivo and was safe without inducing toxicity to normal organs in NSG mice. Mechanistically, protein profiling through mass spectroscopy revealed that K+CS uniquely affects the cellular pathways of DNA damage repair, DNA synthesis and cell cycle progression. Studies involving immunoblotting, cell cycle analysis, immunofluorescence microscopy assessing nucleocytoplasmic molecular export and DNA damage, reporter assay to assess homologous recombination repair proficiency and immunohistochemistry showed that, compared to KPT-330 treatment alone, K+CS decreased the expression of CRM1, Rad51 and thymidylate synthase proteins in vitro and in vivo, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, and importantly a unique cell cycle arrest in S-phase, thus leading to cell apoptosis. These effects on cellular proteins and pathways were unique to K+CS treatment and were not observed with KPT-330 or CS single agent treatment. Pathway analyses through RNA sequencing also paralleled the findings of proteomic studies thus further validating the unique effect of K+CS treatment on the aforementioned cellular pathways. Importantly, K+CS treatment exerted unique and significant antitumor effect ex vivo on primary malignant cells obtained from patient's with high-risk hematologic malignancies such as double hit DLBCL, BTK and BCL2 inhibitor resistant mantle cell lymphoma, TP53 deleted/mutated chronic lymphocytic leukemia and high-risk multiple myeloma thus signifying its broader applicability as a treatment option for these aggressive hematologic malignancies where there is a dire need to find new treatment strategies (Figure 1i). In summary, we describe a unique all-oral drug combination with a novel constellation of mechanisms of action on cellular pathways that are exploited by cancer cells. K+CS represents a new class of therapy for multiple cancer types and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for therapy of blood cancers. Disclosures Witzig: Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; MorphSys: Consultancy; Immune Design: Research Funding; Spectrum: Consultancy.

Background: Patients with Waldenström Macroglobulinemia (WM) tend to present at an older age. Frailty, resulting from comorbidities and reduced organ function, poses unique challenges to the management of WM in the elderly. Age above 65 years, is an established unfavorable prognostic factor in WM. However, data specifically pertaining to the very elderly patient population are scant. The impact of advanced age (≥75 years at diagnosis) on the clinical features and outcomes of patients with symptomatic/active WM were studied. Methods: Patients with active WM, evaluated at Mayo Clinic, Rochester between January 1996 and December 2018 were included in the study. The characteristics and laboratory parameters at presentation of the cohort of patients with the age ≥75 years were compared to those of the younger (age <75 years) cohort. The median follow-up and overall survival (OS) were assessed from active disease to last follow-up or death using the Kaplan Meier method. Because older age is a confounding factor for deaths from unrelated causes, the cause-specific survival (CSS) was calculated. Deaths were deemed WM-related if patients died from progressive disease, transformation with antecedent WM, concomitant light chain (AL) amyloidosis, infection associated with WM or anti-WM therapy related toxicity, while patients who died from other causes were considered to have a WM-unrelated death. The patients who died from causes unrelated to WM were censored at death for CSS analysis. The OS of the cohort of the very elderly patients was compared to that of a cohort of the general US population, matched for age, sex as well as follow-up from the calendar-year of diagnosis, to assess the degree to which WM impacts survival. Results: Among 949 consecutive patients, with a median follow-up of 8.4 years [95% Confidence Interval (CI): 7.7-9.3 years] from active disease, the median age at diagnosis was 65 years (range: 31-93 years). Of 177 patients (19%) who were ≥75 years of age at the onset of active WM, 173 (98%) received anti-WM therapy. The baseline characteristics of the 2 cohorts (patients ≥75 years of age versus <75 years) are outlined in Table 1. The patients in the age ≥75 years cohort were noted to have lower IgM levels and serum albumin, and higher serum LDH and serum β-2 microglobulin compared to the age <75 years cohort. A higher proportion of patients in the age <75 years cohort had coexisting AL amyloidosis at diagnosis. The frequency of MYD88L265P mutation was similar between the 2 cohorts (p=0.2). During the 23-year period, there was an increase in the proportion of patients ≥75 years who were diagnosed with active WM (12% during the 1996-2003 period, 18% during 2004-2010, 25% during 2011-2018; P<0.0001). In the elderly WM cohort, the most frequently used frontline treatment was rituximab monotherapy (36%), followed by rituximab-alkylating agent-based regimen (31%). Of 177 patients with age ≥75 years, 89 (50%) patients were deceased at the time of last follow-up and 58% (52/89) of all deaths in age ≥75 years were attributable to WM. By contrast, 303 (39%) out of the 772 patients in the age <75 years cohort were deceased at last follow-up, with 73% (224/303) deaths attributable to WM. The CSS for patients with age ≥75 years was 10.9 years (95% CI: 7.3-11.7 years) versus 14.7 years (95% CI: 13.2-15.7 years) for age <75 years [Risk ratio 2.1(95% CI: 1.5-2.8); p<0.0001]. At the 1 and 2 year follow-up, WM-related mortality was 6.8% and 11.9%, respectively, for patients with age ≥75 years versus 2.6% and 4.9%, respectively, for the younger cohort. The median OS of patients with age ≥75 years from the diagnosis of active WM was 5.9 years (95% CI: 4.2-7.3 years) compared to the OS of 8.3 years for an age, sex and calendar-year-matched cohort, derived from the general US population (p<0.001), Figure 1. Conclusion: Patients who are ≥75 years of age at the time of diagnosis of active WM present with certain poor prognostic features, including higher serum LDH and β-2 microglobulin and lower serum albumin compared to their younger counterparts. The impact of advanced age is underscored by a poorer WM-specific survival for the subset of patients with the age ≥75 years compared to the younger cohort. Furthermore, although active/symptomatic WM is typically an indolent malignancy, it adversely affects OS of the very elderly patients as suggested by the comparison with an age, sex and calendar-year matched cohort of the general US population. Disclosures Ansell: Bristol Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding. Gertz:Ionis/Akcea: Other: personal fee; Alnylam: Other: personal fee; Prothena: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Annexon: Other: personal fee; Appellis: Other: personal fee; Amgen: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Physicians Education Resource: Other: personal fee; Abbvie: Other; Celgene: Other; Research to Practice: Other; Sanofi: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Proclara: Other; Springer Publishing: Patents & Royalties; Aurora Bio: Other; Janssen: Other: personal fee. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; MorphSys: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Dispenzieri:Pfizer: Research Funding; Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Dingli:Sanofi-Genzyme: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Alexion: Consultancy; Millenium: Consultancy. Kumar:Sanofi: Research Funding; Kite Pharma: Consultancy, Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; MedImmune: Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; BMS: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria.

Abstract Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Abstract Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm. To date, there is a lack of U.S. Food and Drug Administration–approved treatments in adult LCH to establish optimal first-line therapy. We conducted a retrospective, single-center case series evaluating the use of BRAF inhibitors in adult patients with BRAFV600E- LCH proven by biopsy. Our case series is the first to report the use of BRAF inhibitors as first-line therapy in adults with LCH. We also report the efficacy with single-agent dabrafenib in adult LCH. All but one of our patients had favorable response to targeted therapy.