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Abstract INTRODUCTION Rosai-Dorfman disease (RDD) is a rare histiocytic disorder associated with histiocytes expressing high level of macrophage colony stimulating factor receptor (c-fms). Mutations in mitogen-activated protein kinase (MAPK) pathway have been reported in RDD, indicating an underlying clonal process in some patients. Aberrant activation of MAPK pathway can occur due to mutations or high c-fms expression. Data on the use of MAPK/extracellular-signal-related kinase (ERK)-inhibitor therapy in RDD are very limited. Cobimetinib is a MEK inhibitor, which is listed in the National Comprehensive Cancer Network Compendium ® for the treatment of RDD. We present our retrospective experience of cobimetinib treatment in a large series of patients with RDD. METHODS Following approval of the institutional reviewed board, patients (pts) with RDD who were consecutively seen at Mayo Clinic and treated with cobimetinib between 2013-2021 were included. Response was assessed as described by Goyal et al (Haematologica 2020;105:2). Cobimetinib was given 20-60 mg once a day by mouth for 21 days in a 28-day cycle. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria v5.0. Time-to-event analyses were calculated from the time of treatment initiation, while duration of response was calculated from the time of 1 st response. Tumor genomic profile was analyzed using Tempus-xT ® assay (Chicago, IL), which includes targeted DNA sequencing (648 oncogenes) and whole transcriptome sequencing. RESULTS Of the 54 pts with RDD, ten were treated with cobimetinib and included in this study. The median follow-up was 16 months (m) [95% confidence interval (CI): 13-not reached (NR)] and most (n=8; 80%) were females. The median age at the time of treatment was 63 years (range: 36-74). Cobimetinib was used as first line therapy in four pts. Overall response rate was 70%, with 30% and 40% achieving complete (CR) and partial (PR) responses, respectively. One had stable disease (SD) and two had progressive disease (PD) (Table 1). The median progression-free-survival was 6.4 m (95%CI: 4.9-NR) and at 6 and 12 m, 67% and 50% of pts remained free from disease progression or death, respectively (Figure 1). The median duration of response was 7.6 m (95%CI: 3.1-NR). At the time of last follow-up, nine (90%) pts were alive. One pt died due to myelodysplastic syndrome with excessive blasts. She had multiple chemotherapy treatments before initiation of cobimetinib. Cobimetinib was discontinued in this pt due to grade 3 anemia and skin toxicity after 6 m of therapy and had SD as the best response. Median duration of treatment for the entire cohort was 6 m (range: 2-14). In the seven pts who responded, the median duration of treatment was 7 m (range: 2-14). Cobimetinib was discontinued in seven pts: disease progression (n=3; one disease progression after achieving PR and two PD while on therapy), grade 3 left ventricular systolic dysfunction (n=1), grade 3 diarrhea (n=1), grade 3 anemia (n=1), and grade 2 creatinine elevation (n=1). Five (50%) pts were started at a reduced dose of cobimetinib at the discretion of treating physician [20 mg (n=4) and 40mg, (n=1)]. Two pts were started at 60 mg and dose reduced to 20 mg after one cycle of treatment due to grade 2 skin toxicity in one and grade 2 skin toxicity and diarrhea in the other. Both pts achieved a PR but progressed after four and six cycles, respectively. One pt started at 40 mg and reduced to 20 mg due to grade 2 skin toxicity after two cycles achieving a PR. The response was sustained in this pt for at least 9 months, until the time of last follow-up (Table 1). Tissue molecular testing showed five pts with MAPK pathway alterations and all of them responded to therapy (CR=3 and PR=2). Of the other five pts who either did not have a MAPK pathway alteration (n=4) or had test failure (n=1), responses were observed in two (40%) pts, both PR (Table 1). CONCLUSION Our study suggests that cobimetinib is an effective treatment in RDD, with responses observed in all pts having MAPK pathway alterations. Less than half of pts without a MAPK pathway alteration achieved a response. However, treatment discontinuations due to AEs were common despite dose reductions. Patients who were treated at low doses of cobimetinib also had remarkable clinical response. Further studies are needed in evaluating other MAPK pathway inhibitors with better toxicity profile to improve adherence and outcomes. Figure 1 Figure 1. Disclosures Tobin: National Institutes of Health: Research Funding; Mayo Clinic Center for MS and Autoimmune Neurology: Research Funding; Mallinckrodt Pharmaceuticals: Research Funding. Bennani: Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Kymera: Other: Advisory Board. Vassallo: Pfizer: Research Funding; Bristol-Myers-Squibb: Research Funding; Sun Pharma.: Research Funding.

Abstract Background Primary bone diffuse large B cell lymphoma (DLBCL) is a variant of extranodal non-Hodgkin lymphoma (NHL) that is relatively rare, accounting for 3-15% of extranodal NHL and less than 1% of all NHL. Patients often present with pain and swelling or pathologic fracture of the affected area of the skeleton, and B symptoms are often less prevalent. Many cases are limited stage at presentation. Patients are usually treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or similar induction therapy. Based on older studies showing improved outcomes associated with the addition of radiation (many completed prior to the rituximab era), patients often still receive combined-modality therapy today. However, it remains unknown whether consolidative radiation therapy (RT) confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction. We sought to address this question in a multicenter retrospective study. Methods We conducted a retrospective analysis of outcomes in a modern cohort of patients who underwent treatment for primary bone DLBCL using chemotherapy regimens in the rituximab era either with or without consolidative RT. Data was collected from 13 academic medical centers in the U.S., with patients treated between 2005 and 2019. Patients were identified using each institution's hematologic malignancy registries. Analysis was limited to patients with primary bone DLBCL, with stage I-II disease (primary site +/- locoregional lymph nodes) that could be encompassed in a radiation field. Patients who received CIT alone or CIT followed by RT were included. Treatment selection was at the treating physician's discretion. Electronic medical records were reviewed for: demographics, chemotherapy regimens, radiation treatments, and PET scan data. Local IRB approval was obtained at sites. All data was distributed in a de-identified fashion. The primary outcomes were overall survival (OS), and relapse-free survival (RFS). Secondary outcomes included: response after induction CIT induction and the need for additional therapies. Chi-square test analysis was used to compare categorical variables and the Wilcoxon rank-sum test was used for continuous and ordinal measures. Survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. Multi-variable analysis (MVA) for OS and RFS was performed using RT vs no RT, PET status post CIT (negative vs positive) and rituximab in induction (Y/N) as variables. Results A total of 127 patients were included: 91 who received CIT and radiation (RT group), and 36 who received CIT alone (no RT group). The median age of patients at diagnosis in the RT group and no RT group was 58.5 and 57.0, respectively. For CIT, the majority of patients received R-CHOP (84%). Despite focusing on 2005-2019, a small percentage of patients (5 - 14%) in each group (RT and no RT) did not receive rituximab with their induction therapy. The OS at 10 years was 74.5% in the RT group and 86.5% in the no RT group (p = 0.29). The RFS at 10 years was 70.9% in the RT group and 78.2% in the no RT group (p = 0.85). Among the 91 patients who received RT, 67 (77.0%) received a dose of 36 Gy or higher. There was no difference in OS (p = 0.63) or RFS (p = 0.90) in patients who received > 36 Gy vs < 36 Gy of radiation. On MVA for OS, RT was not associated with improved OS, although rituximab as part of induction was (p = 0.048). On MVA for RFS, neither RT nor rituximab were associated with improved RFS. For rituximab the trend was in the direction of rituximab benefit (p = 0.11). Conclusion Our results demonstrate that, in the rituximab era, patients with limited stage primary bone DLBCL have excellent outcomes overall. In this study, neither RFS or OS appeared to be improved with the addition of consolidative RT. Rituximab, however, was associated with improved OS on MVA. Outcomes do not appear to differ based on the dose of RT (> 36 Gy vs < 36 Gy). Our data suggests that RT may have less benefit for primary bone DLBCL in the rituximab era, although it is possible that a subset of patients may benefit from consolidative radiation therapy. A larger data set would likely be needed to evaluate this. We plan to present data regarding PET responses at the meeting. Figure 1 Figure 1. Disclosures Lunning: Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Kyowa Kirin: Consultancy; Verastem: Consultancy; Kite, a Gilead Company: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Spectrum: Consultancy; Daiichi-Sankyo: Consultancy; Beigene: Consultancy; Legend: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Bartlett: Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Caimi: XaTek: Patents & Royalties: Royalties from patents (wife); Amgen Therapeutics.: Consultancy; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; TG Therapeutics: Honoraria; Seattle Genetics: Consultancy; Verastem: Consultancy; Kite Pharmaceuticals: Consultancy. Rodgers: MJH Lifesciences: Consultancy. Barr: Morphosys: Consultancy; Gilead: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Abbvie/Pharmacyclics: Consultancy. Epperla: Verastem: Speakers Bureau; Beigene: Speakers Bureau; Karyopharm: Other: Ad Board; Genzyme: Honoraria. Hill: AstraZenica: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Epizyme: Consultancy; Karyopharm: Consultancy; Janssen/Pharmacyclics: Consultancy; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; EUSA: Consultancy; Takeda: Research Funding; Genentech: Consultancy; Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Portell: Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Aptitude Health: Honoraria; Morphosys: Honoraria; Targeted Oncology: Honoraria; SeaGen: Research Funding; BeiGene: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Pharmacyclics: Honoraria; Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Genentech: Research Funding; VelosBio: Research Funding. Fenske: Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; Servier Pharmaceuticals: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau; Biogen: Consultancy; ADC Therapeutics: Consultancy; Kite (Gilead): Speakers Bureau; Beigene: Consultancy; AbbVie: Consultancy.

Abstract Introduction: Clinical trials of novel salvage therapies (ST) have encouraging outcomes for relapsed/refractory classic Hodgkin lymphoma (R/R cHL) after autologous stem cell transplant (ASCT); yet studies comparing novel ST with conventional salvage chemotherapy are lacking. In a single center cohort, we demonstrated that bendamustine/brentuximab (BBV) had higher overall response rates (ORR) and complete response (CR) rates in ASCT-eligible R/R cHL (Desai et al JCO, 2021). Herein we report comparative outcomes of novel and conventional ST in R/R cHL who undergo ASCT, in a large multicenter retrospective cohort. Methods: Consecutive R/R cHL pts who underwent ASCT at 12 institutions across United States were included. Demographics and clinical variables at relapse including age, sex, B symptoms, stage, bulky disease (BD, single mass > 6 cm) extra nodal disease (END), primary refractory disease (PRD) and early relapse (ER, within 1 year) were recorded by electronic health records review. Study objectives were ORR, CR to first ST, post-ASCT PFS and OS by final ST. Time to event endpoints were defined from date of ASCT. Results: From 12 participating institutions, 853 pts of R/R cHL who underwent ASCT were eligible for this study. Median age was 33 (14-72) years, 457 (54%) were male, 446 (52%) had BD, 257 (30%) had advanced stage, 271 (32%) had END, 369 (43%) had B symptoms, 142 (17%) had PRD and 307 (36%) had ER. All 853 received at least 1 ST, 245 received 2 ST, 71 received 3 ST and 26 received 4 ST. Seven groups of ST were identified: 1. Conventional platinum-based chemotherapy (PBC) group including ICE, DHAP and ESHAP 2. BBV 3. Brentuximab Vedotin and nivolumab (BV/Nivo) 4. BV alone (BV) 5. gemcitabine-based chemotherapy (Gem) 6. checkpoint inhibitors (CPI) and 7. other miscellaneous agents (Misc). 1st ST was as follows: 553 had PBC; 69 had BBV; 48 had BV/Nivo; 65 had BV; 49 had Gem; 4 had CPI and 63 had Misc. There was no significant difference in the baseline characteristics by type of 1 st ST (data not shown). BBV had significantly higher ORR (92% vs 79%, p<0.001) and CR rate (80% vs 49%, p <0.001) compared to PBC. BV/Nivo had significantly higher CR rate (67% vs 49%, p <0.001) and a trend towards higher ORR (86% vs 79%, p = 0.1) compared to PBC. BV had significantly lower ORR (62% vs 79%, p <0.001) and CR rate (34% vs 49%, p <0.001) compared to PBC. There was no difference in ORR and CR rate of PBC, Gem, CPI and Misc agents. Final ST prior to ASCT was PBC in 451, BBV in 76, BV/Nivo in 48, BV in 87, CPI in 24, Gem in 90 and Misc in 64. Table 1 lists K-M estimates of 2-year survival probabilities for different Final ST groups. Median follow up was 3 (range 0.1-13) years. BV/Nivo group had significantly higher proportion of patients with PRD and BD than PBC, no other differences in baseline characteristics were identified amongst ST groups (data not shown). BV/Nivo (HR: 0.1 (CI 95:0.02-0.4), p<0.01) and CPI (HR: 0.12 (CI 95:0.03-0.5), p<0.01) had significantly higher PFS than PBC. There was no significant difference in PFS between other ST groups (Figure 1a). Type of ST was not significantly associated with difference in OS (Figure 1b). 536 pts underwent ASCT in CR, 273 underwent ASCT in partial response (PR) and 31 underwent ASCT with progressive disease (PD). Pre-ASCT PR (HR 1.6 (CI 95:1.3-2.6), p<0.001) and PD (HR: 4.1 (CI 95: 2.5-6.8), p<0.001) predicted significantly lower PFS compared to CR (Figure 2a). OS was also significantly lower in pts with pre-ASCT PR (HR 1.7 (CI 95: 1.2-1.6), p<0.001) and PD (HR 5.3 (CI 95: 2.8-10), p<0.001) (Figure 2b). Higher number of pre-ASCT ST predicted lower PFS (HR 1.3 (CI 95: 1.1-1.6), p<0.001) and OS (HR 1.5 (CI 95: 1.2-1.8), p<0.001). In pts with pre-ASCT CR, all 36 who had pre-ASCT CR after BV/Nivo were alive and relapse free for follow up of 0.1-5 yrs. BV/Nivo was associated with significantly higher PFS (HR 0.1 (CI 95: 0.01-0.7), p <0.05) but not OS compared to PBC in this subgroup. Increasing number of pre-ASCT ST predicted worse PFS (HR 1.5 (CI 95: 1.2-2.0), p<0.01) and OS (HR 2.2 (CI 95: 1.4-3.4), p<0.001) in this subgroup as well. Conclusions: BV/Nivo has a higher CR rate and better post-ASCT PFS compared to conventional chemotherapy and can lead to durable remissions in pts with pre-ASCT CR. BBV had a higher response rate and similar post-ASCT survival to conventional chemotherapy. BV had lower response rates compared to chemotherapy. Novel ST such as BV/Nivo and BBV may be preferable to conventional chemotherapy in R/R cHL. Figure 1 Figure 1. Disclosures Spinner: Notable Labs: Honoraria. Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dorritie: SITC presentation: Honoraria; Genmab: Research Funding; University of Pittsburgh/UPMC Hillman Cancer Center: Current Employment; Janssen: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Juno/BMS: Research Funding; Kite, a Gilead Company: Research Funding; OncLive/Institutional Perspectives on Cancer presentation: Honoraria. Arai: Magenta Therapeutics: Research Funding. Maurer: Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diefenbach: Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; IMab: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; AbbVie: Research Funding; IGM Biosciences: Research Funding; Incyte: Research Funding; Trillium: Research Funding; Gilead: Current equity holder in publicly-traded company; MEI: Consultancy, Research Funding. Nowakowski: Kyte Pharma: Consultancy; Ryvu Therapeutics: Consultancy; Selvita: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy; Bantham Pharmaceutical: Consultancy; Daiichi Sankyo: Consultancy; Zai Labolatory: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: 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; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees.

SummaryErdheim–Chester disease (ECD) is a rare histiocytic neoplasm with frequent multiorgan involvement. An accurate diagnosis of ECD requires the correlation of clinical features, histopathologic and radiologic findings. We describe a case series of patients with a referral diagnosis of ECD, whereby the diagnosis was changed to non‐histiocytic diseases after comprehensive review at a tertiary care center. This accurate revision of the referral diagnosis of ECD enabled initiation of proper disease‐directed therapy in a timely manner for these patients and avoided unnecessary exposure to systemic cytotoxic chemotherapy or targeted agents. Our study highlights the value of a multidisciplinary team of histiocytosis experts in confirming the diagnosis of ECD and also brings attention to other conditions to consider that can mimic ECD, including osteopoikilosis, tenosynovial giant cell tumour, IgG4‐related disease, fibrous dysplasia and chronic recurrent multifocal osteomyelitis.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation (“watch and wait”) may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

AbstractLangerhans cell histiocytosis (LCH) is a histiocytic neoplasm that can involve the lungs as single system (LCH‐SSL) or multisystem disease (LCH‐MSL). The role of full‐body radiographic staging to determine whether patients have LCH‐SSL or LCH‐MSL is unclear. Long‐term outcomes of LCH‐SSL versus LCH‐MSL and multisystem without lung involvement (LCH‐MSNL) are unknown. A retrospective study of adult LCH patients seen at our center from January 2000 to 2020 was performed. In Part 1, we addressed utility of whole‐body staging imaging among those presenting with isolated pulmonary signs or symptoms. Staging was defined as fluorodeoxyglucose positron emission tomography‐computed tomography (CT) or whole‐body CT obtained within 3 months of diagnosis. In Part 2, we examined the frequency of developing extra‐pulmonary disease over time and mortality in patients with LCH‐SSL. In Part 3, we compared the overall survival of LCH‐SSL, LCH‐MSL, and LCH‐MSNL. Part 1: 240 patients with LCH were identified. A total of 112 (47%) had pulmonary signs or symptoms at presentation. Thirty‐four (30%) underwent radiographic staging and only one showed evidence of extra‐pulmonary disease. Part 2: 108 (45%) were LCH‐SSL. Median follow‐up duration of 4.5 years (95% confidence interval [CI]: 2.9–6.0). None developed extra‐pulmonary disease. Part 3: 5‐year survival: 94% (95% CI: 84%–98%) for LCH‐SSL, 78% (95% CI: 59%–90%) for LCH‐MSL, and 75% (95% CI: 53%–89%) for LCH‐MSNL. LCH patients presenting with isolated pulmonary signs or symptoms rarely have extra‐pulmonary involvement at the time of diagnosis and generally do not develop extra‐pulmonary progression. LCH‐SSL has the best overall survival, while LCH‐MSL and LCH‐MSNL have similar clinical outcomes.

7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]

7049 Background: Langerhans cell histiocytosis (LCH) can manifest as single system (SS) disease, multisystem (MS) disease, or pulmonary LCH (smoking-related). There is a paucity of data on prognostic factors including risk organ (RO) involvement (liver, spleen, and bone marrow) in adult LCH, which we sought to address in this study. Methods: Single-center retrospective study of patients ≥18y diagnosed with LCH from 1998 to 2020. Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were conducted using age, sex, organ involvement, LCH subtype, year of diagnosis, BRAF V600E status, and treatments. Results: We included 219 patients with LCH; median age 43y (range 19-88), females 51%, SS unifocal (23%), SS multifocal (6%), pulmonary (31%) and MS (40%). Commonly involved organs included lung (53%), bone (42%), skin (24%), pituitary (16%), and CNS (12%). BRAF V600E was positive in 40/88 (46%). Median follow-up duration was 6.1y (95% CI, 5.1- 7.1). On univariate analysis, factors associated with worse PFS were bone LCH, RO involvement, multifocal/MS LCH, and radiation therapy alone; those with worse OS included RO involvement, MS disease, BRAF V600E+, and age ≥45y at diagnosis. In multivariate analysis, BRAF V600E and age ≥45y at diagnosis were associated with worse mortality (Table). Median PFS was not reached (NR-NR) for SS unifocal LCH, 5mo (0-12.7) for SS multifocal LCH, 110mo (84.7-135.3) for pulmonary LCH, and 27mo (17.2-36.8) for MS LCH. 5-year OS was 97.4% for SS unifocal LCH, 100% for SS multifocal LCH, 96.1% for pulmonary LCH, and 79.9% for MS LCH. 41 (18.7%) developed a second primary malignancy (SPM), of which 11 were hematologic neoplasms. There was a trend towards a higher prevalence of SPMs in patients with BRAF V600E (28% vs. 17%; p = 0.22). Conclusions: In our large single-center study, PFS for multifocal and MS LCH was worse than SS unifocal or pulmonary LCH. RO involvement was not associated with outcomes in multivariate analysis. Overall prognosis was excellent for all subtypes except MS LCH. BRAF V600E and older age were associated with worse OS. The prevalence of SPMs was very high and needs to be explored further.[Table: see text]

Background: Primary myelofibrosis (PMF) has the worst prognosis of the classical BCR-ABL1 negative myeloproliferative neoplasms, with a median overall survival of six years. Factors affecting survival include age, symptom burden, cytopenias, mutation profile, and development of second malignancies including transformation to acute myeloid leukemia (AML). Ruxolitinib, a selective JAK1 and JAK2 inhibitor, was granted approval by the United States (US) Food and Drug Administration for treatment of intermediate and high-risk PMF in November 2011 based on reduction in spleen volume and demonstration of symptom improvement. The impact of ruxolitinib on PMF survival is unknown. In this study, we aimed to evaluate whether there has been a change in survival and patterns of second primary malignancies (SPMs) including AML transformation among PMF population in US after ruxolitinib approval. Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 survival and Multiple Primary Standardized Incidence Ratio (MP-SIR) registries, we conducted a retrospective study with patients diagnosed with PMF between the years of 2007 and 2016. We divided these patients into two five-year cohorts, pre-ruxolitinib approval (2007-2011) and post-ruxolitinib approval (2012-2016), and compared relative survival rates (RSRs) and standardized incidence ratios (SIRs) of SPMs between the cohorts. SIRs were calculated as the ratio of observed to expected malignancy cases over the specified time periods. Median follow-up duration was five years for each cohort. RSRs and SIRs were compared between cohorts using two-proportion Z-tests. Results: We included 2164 patients diagnosed with PMF between 2007 and 2016 with data available in the SEER-18 survival and MP-SIR registries. Of these, 1051 (49%) patients were included in the pre-ruxolitinib cohort and 1113 (51%) patients were included in the post-ruxolitinib cohort. There was no significant difference in the four-year RSRs between the pre-ruxolitinib and post-ruxolitinib cohorts (55% vs. 56%, p = 0.719). A higher proportion of SPMs occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (60% vs. 40%, p < 0.001). Hematologic malignancies comprised a majority of all SPMs (AML 39% and non-Hodgkin lymphoma 16%). A higher incidence of AML transformation occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 121.48 vs. 72.22, p = 0.037). Non-hematologic malignancies were also more common in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 1.09 vs. 0.94, p < 0.001). The most common non-hematologic malignancies were cancers of the respiratory tract, urinary tract, and prostate gland, though their SIRs were not significant in either cohort. Conclusions: Our study results suggest that despite improvements in prognostication and the approval of ruxolitinib, the prognosis of PMF remains poor in the US. These results may be due to low uptake of ruxolitinib in practice or a lack of benefit from the drug itself. Additionally, for reasons that are unclear, SPM incidence has increased in the five years following the approval of this drug. Further studies should be conducted to determine the cause of these findings. Figure Disclosures Shah: Dren Bio: Consultancy. Vachhani:astellas: Speakers Bureau; agios, blueprint medicines, jazz pharmaceuticals, daiichi sankyo: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.