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ImportanceRosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments.ObjectiveTo study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD.Design, Setting, and ParticipantsThis retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis.Main Outcomes and MeasuresMain outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD.ResultsA total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs.Conclusions and RelevanceIn this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.

Abstract IgM MGUS and Waldenstrom Macroglobulinemia (WM) represent a disease spectrum with highly dissimilar therapeutic management ranging from observation to chemoimmunotherapy. The current classification relies solely on clinical features and does not explain the heterogeneity that exists within each of these conditions. To shed light on the biology that may account for the clinical differences, we used bone marrow (BM) CD19+/CD138+ sorted cells and matched BM plasma from 32 patients (pts) (7 IgM MGUS, 25 WM) and 5 healthy controls to perform the first comprehensive multiomics approach including whole exome sequencing, RNA seq, proteomics and metabolomics. Applying principal component analysis to gene expression profiling, most of WM pts clustered together, while a small subset of them grouped separately with MGUS pts, suggesting a biologic dichotomy within WM. The healthy controls formed a distinct group from most WM and MGUS. We then applied a non-negative matrix factorization consensus clustering to the gene expression data and identified three robust clusters. Cluster 1 (C1) included only WM pts, cluster 2 (C2) included both WM and MGUS pts, and cluster 3 (C3) included all controls as well as a small number of WM and MGUS pts. When mutations commonly identified in WM were analyzed, there was no difference among the three groups (excluding controls) in mutation burden of MYD88 L265P and CXCR4. Interestingly, aberrant expression of TNFAIP3 seemed a distinct feature of C1 as deletion of 6q (which encodes for TNFAIP3) and TNFAIP3 mutations were each significantly enriched in C1 (47%) compared to C2 (0%) and C3 (20%; p=0.04). Individual clusters associated with specific transcriptional signature and clinical features. While C1 displayed enrichment of cell growth, downregulation of inflammatory pathways (eg IL6 and IL8 signaling) and aggressive behavior, C2 showed increased inflammatory signaling and cell survival with indolent behavior. C3 had an intermediate feature with combined proliferative and inflammatory signatures. In accordance with the transcriptomic data, the hallmark of C1 was upregulation of proliferation-associated proteins (eg AKT, MAPK) and downregulation of inflammatory proteins (eg IL4, IL10) while the opposite was observed in C2. Once more, C3 confirmed intermediate features with combined upregulation of proliferation and inflammatory proteins. The metabolism was rewired towards fatty acid catabolism in C1, glycolysis in C2 and anabolism in C3. Accordingly, C1 showed undetectable concentration of 3-hydroxybutyric acid as opposed to C2 which had increased levels of malic and lactic acids, as end products of fatty acid oxidation and glycolysis respectively. Those metabolites had intermediate levels in C3. In conclusion, we identified three molecular clusters with distinct clinical, proteomic and metabolomic features, suggesting a potential biologic classification that may have therapeutic implications. Citation Format: Patrizia Mondello, Jonas Paludo, Joseph Novak, Kerstin Wenzl, Shahrzad Jalali, Jordan Krull, Esteban Braggio, Surendra Dasari, Michelle Manske, Jithma Abeykoon, Asher Chanan-Khan, Robert Kyle, Morie Gertz, Zhi Zhang Yang, Anne Novak, Stephen Ansell. Molecular clusters and functional drivers of IgM monoclonal gammopathies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3487.

SummaryBelantamab mafodotin (BLMF) is a B‐cell maturation antigen‐directed antibody‐drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF‐induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity‐related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2–not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

e19562 Background: Considerable healthcare resource utilization and financial burden have been associated with the treatment of Waldenstrom Macroglobulinemia (WM); however, the impact of health insurance status on patient outcomes has not been explored. We aimed to assess the insurance-based outcome relationship in WM using the National Cancer Database (NCDB). Methods: We analyzed patient-level data obtained from the NCDB, a database representing more than 70% of newly diagnosed cancer cases nationwide. All newly diagnosed WM cases (n = 8540) between 2004 to 2017 were identified. Only patients who underwent treatment were included. Insurance status was recorded by assessing the primary payer at the time of diagnosis. Due to Medicare eligibility criteria, age-based (< 65 and ≥65 years) stratified analysis was conducted. Cox proportional hazards model was utilized to analyze survival. Time-to-event analysis was conducted based on date-of-diagnosis using the Kaplan-Meier method and log-rank test. Results: Analysis was conducted on 3878 patients after meeting inclusion criteria, with a median follow-up time of 54.6 months. Among patients < 65 years (n = 1249; median age: 58 years; male: 62.4%), those with non-private insurance had inferior survival on multivariate analysis (Table) after adjusting for patient demographics, comorbidities, income, education, treatment center characteristics, and treatment start time. Significant overall survival (OS) differences were seen in those < 65 years (log-rank p < 0.001), with 5-year OS highest among patients with private insurance 91.2%, compared to Medicaid 79.8%, uninsured 77.4%, and Medicare 70.2%. In patients < 65 years, compared to private insurance, uninsured patients were more likely to be of Black race, reside in lower income areas, and be treated at non-academic centers (all p < 0.05). Both Medicaid and Medicare patients < 65 years were more likely to have a higher Charlson-Deyo comorbidity index (> 1) and live in areas of lower educational attainment and household income compared to private insurance (all p < 0.05). In patients ≥65 years (n = 2629; median age: 75 years; 60.6% males), no insurance-based OS (log-rank p = 0.096) differences were seen. Conclusions: Based on our study, significant insurance-based disparities exist in WM, where patients < 65 years old who are uninsured, or non-privately insured are at a higher risk of mortality. While the root cause of these differences is not fully elucidated, efforts should focus on ensuring that all patients have equal access to care regardless of primary payer status.[Table: see text]

e19533 Background: Pneumocystis pneumonia (PJP) is a catastrophic infection seen in the context of low CD4 counts. Brentuximab vedotin (BV) is a drug antibody conjugate targeting CD30 and is used to treat patients with Hodgkin’s lymphoma (HL) and T-cell lymphoma (TCL). PJP prophylaxis is not currently recommended for patients receiving BV-based treatment despite co-expression of CD30 on CD4 cells. The frequency of PJP following BV remains poorly defined. Methods: We evaluated patients who received BV between January 1, 2011 and October 31, 2021 at Mayo Clinic for the development of PJP. Patient demographics and clinical characteristics including underlying disease, chemotherapy regimen, absolute lymphocyte count (ALC), and steroid exposure were collected. Patients who developed PJP more than 3 months after their last BV exposure were excluded. Results: Of 402 BV recipients identified, 63 received PJP prophylaxis and were omitted. Fourteen of the 339 (4.1%) not on prophylaxis developed PJP following BV. Those infected had a median age of 61 (22-87), 71% were male. The most common diagnoses were HL, TCL, and primary mediastinal B-cell lymphoma at rates of 57%, 21%, and 14% respectively. Therapy regimens included BV monotherapy, BV-CHP, and BV-AVD at rates of 43%, 21%, and 14% respectively. BV represented median 2nd line of therapy (1-10) and patients received median of 3 doses (1-10) prior to PJP diagnosis. Patients with PJP had median ALC of 620 (370-3500). 71.4% (10/14) had an ALC less than 750 and among those with ALC greater than 1000, 75% (3/4) had underlying diagnosis of HL. Three patients had CD4 count measured at time of PJP diagnosis with median value of 157 (5-175). 57.1% (8/14) had no steroid exposure beyond the treatment regimen. 14.3% (2/14) were on chronic doses of 5mg prednisone for autoimmune conditions. Short bursts of steroids (prednisone 40 mg) prior to PJP were seen in 21.4% (3/14) with median exposure of 8 days (7-10). One patient had prolonged steroid exposure but was weaned off 17 days prior to PJP diagnosis. 71.4% were older than 50 years at time of PJP. Conclusions: We observed rates of PJP above the commonly accepted threshold of 3.5% for recommending prophylaxis. Among patients with an ALC greater than 1000, 75% had HL raising the question of a qualitative defect in immunity. Close ALC monitoring is recommended for patients receiving BV with a low threshold to institute PJP prophylaxis, especially amongst those older than 50 or with a diagnosis of HL.[Table: see text]