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Introduction: DH/THL also classified as high-grade B cell lymphomas (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements have higher risk of progression after initial treatment and poor response to salvage therapies compared to diffuse large B cell lymphoma (DLBCL), NOS. Recently, CART cell therapy has shown encouraging responses in treatment of relapsed refractory (R/R) DLBCL. In this retrospective study, we evaluated whether survival of (R/R) DH/THL is improved in the CART era. Methods: In this multicenter retrospective study, adult pts (pts) with R/R DH/THL after anthracycline-based therapy were included. Demographic and clinical variables were obtained from electronic health records. Study objectives was overall survival (OS) at 2 year landmark. We utilized full propensity score matching to compare progression free survival (PFS) and OS of CART with 2 nd line chemoimmunotherapy. Results: 278 DH/THL pts treated between 2010-2020 were included. Median age was 63 years (range 52-74), 163 (58%) were male, 119 (43%) were classified as DLBCL and 116 (42%) as HGBCL; 40 (14%) were transformed from follicular lymphoma. 225 (82%) had advanced stage, 161 (67%) had elevated LDH, 85 (33%) had bulky disease, 74 (59%) had B symptoms. 105 (38%) pts treated for relapsed disease before 2018 were included in the pre-CART era cohort. 168 (60%) pts treated from 2018 onwards were included in the CART era cohort. 102 (60%) pts in CART cell era received CART cells, 40 (14%) received polatuzumab vedotin (pola), 10 (3.5%) received loncastuximab tesirine, tafasitamab and bispecific antibody each. Characteristics at relapse were similar in both groups. Median follow up was 8.9 (0.2-146) months. 2-year OS estimate was 36% (CI 95: 30-42%) in entire population. Patients treated in CART cell era had significantly higher OS (2 yr OS: 43% [CI 95: 35-53]) compared to pts treated in pre-CART cells era (2-year OS: 24% [CI 95: 16-34], p=0.0006) (Figure 1). In multivariable analyses, increasing age (HR = 1.02 (CI 95: 1.01, 1.04), p=0.003), extranodal disease (HR = 1.41 (CI 95: 1.00, 1.99), p<0.001), elevated LDH (HR = 1.57 (CI 95: 1.11, 2.24), p=0.01) were associated with inferior OS. Increasing time to relapse (HR = 0.98 (CI 95: 0.97, 0.99), p<0.001) was associated with superior OS. BCL6 rearrangement did not affect OS. When adjusted for these factors, treatment with CART cells was associated with higher 2 yr OS (HR = 0.33 (CI 95: 0.22, 0.49), p<0.001). Treatment with polatuzumab (HR = 1.07 (CI 95: 0.71, 1.6), p=0.07) was not significantly associated with OS in univariable analysis. 102 pts underwent CART cell therapy at any point for relapse; 94 (93%) were refractory to prior chemotherapy. 62 (60%) responded and 52 (50%) had CR after CART cells. 2-year PFS and OS after CART cell therapy were 28% (CI 95: 19-40) and 40% (CI 95: 30-53), respectively. Increasing time to CART was associated with inferior OS (HR: 1.02 (CI 95: 1.0-1.03, p=0.03) but not PFS (HR: 1.02 (CI 95: 0.99-1.04), p=0.2). 219 (79%) pts received curative intent salvage chemotherapy for 2 nd line. 2-year PFS and OS were 15% (CI 95: 11-20) and 38% (CI 95: 31-45), respectively. 21 pts received CART cell therapy for 2 nd line. 2 year PFS and OS in this small number of pts were 52% (CI 95: 35-79) and 70% (CI 95: 52-94), respectively. Due in part to the small number of pts who received CART cells in 2 nd line, we utilized full propensity score matched analysis to compare each patient in CART cell group to all possible matched controls in salvage chemotherapy group. Variables matched were age, LDH, extra nodal disease and time to relapse. In propensity score matched analysis, pts who received CART cells had significantly higher 2 year PFS (HR: 10.5 (CI 95: 3.4-17.5), p=002) and 2 year OS (HR: 7.5 (CI 95: 1.4-13), p=0.01). Conclusions: Survival of r/r DH/THL appears to have improved in the era of CART cell therapy. About 2/3 of pts refractory to chemotherapy respond to CART cells, and in multivariable analysis, receipt of CART cells was associated with improved OS. Increasing time to CART cells was associated with inferior survival. In a propensity score matched analysis utilizing full matching, CART cell therapy in 2 nd line was associated with significantly higher 2 year PFS and OS compared to curative intent salvage therapy. Other CD 19 and CD 20 targeting agents approved after CART cell therapy might contribute to favorable survival, effect of these agents could not be assessed because of small numbers.

Purpose: Advances in targeted therapeutics for histiocytic neoplasms have led to a growing survivor population, especially for Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD). This growing population is at risk of adverse health-related quality of life (HRQoL) as a result of the disease or treatments received. Patient-reported outcomes in this population remain understudied, and we aim to define their HRQoL using a validated tool. Methods: We enrolled patients from 2 histiocytosis centers and an international conference from Aug 2022-April 2023 to complete the PROMIS © (Patient-Reported Outcomes [PROs] Measurement Information System) 29+2 profile v2.1, which captures 8 domains of physical/mental health and functioning. Domains are reported as T-scores, with 50 being the general population mean. We calculated summary T-scores for Physical Health (PH) and Mental Health (MH), and differences of 3 from general population were considered clinically meaningful. We then used these T-scores to calculate each patient's PROMIS-Preference (PROPr) score, which is a health-utility score that measures overall HRQoL. A mean PROPr score difference of 0.4 from the US population mean of 0.52 was considered meaningful. We ran independent-samples t-tests to examine differences in PH/MH summary scores and PROPr between sub-cohorts. Finally, we performed a multinomial logistic regression analysis to identify factors associated with worse scores, and calculated odds ratios (OR) for each factor. Results: We included a total of 77 participants. Specific diagnoses included ECD (n=33, 42.9%), LCH (n=21, 27.3%), RDD (n=19, 24.7%), and other/unknown (n=4, 5.2%). Median age at diagnosis was 50y (9-79) and at survey was 54y (18-82), with a median 4 year difference between diagnosis and survey completion. Racial demographics included white (n=64, 83.1%), Black (n=12, 15.6%), and Asian (n=1, 1.3%). 4 patients (5.2%) identified as having a Hispanic ethnicity. Disease extent included unifocal (n=13, 16.9%), single system multifocal (ss-M, n=8, 10.4%), single system lung LCH (ss-L, n=3, 3.9%), or multisystem (n=53, 68.8%) disease. The most commonly involved organs included bone (n=44, 57.1%), kidney (n=24, 31.2%), skin (n=24, 31.2%), CNS (n=24, 31.2%), and pituitary (n=19, 24.7%). PH and MH summary scores were lower in various diagnostic categories as compared with the US population, and PROPr scores were reduced in all diagnostic categories. Bone involvement was associated with worse PH (-6.16, 95%CI -10.81, -1.52, [p=0.005]), MH (-7.96, 95%CI -12.48, -3.44, [p=<0.001]), and PROPr (-0.184, 95%CI -0.313, -0.056, [p=0.003]) scores. CNS involvement was associated with worse PH (-4.78, 95%CI -9.14, -0.42, [p=0.016]). We initially constructed a multinomial regression model using diagnosis, race, age at survey completion, and CNS and bone involvement. This model was not statistically significant, and in particular, diagnosis and age did not significantly contribute to the model. We then removed diagnosis and age and constructed a new model using the remaining variables, which was statistically significant for all 3 scores (p<0.05). We found that factors associated with worse PH score were disease involvement of bone (OR=6.19, 95%CI 1.88, 20.43 [p=0.003]) and CNS (OR=10.36, 95%CI 2.01, 53.39 [p=0.005] Figure 2). Factors associated with worse MH scores included female sex (OR=4.12, 95%CI 1.24, 13.66 [p=0.021]) and CNS involvement (OR=10.74, 95%CI 2.47, 46.79 [p=0.002]). Having race/ethnic group other than white/Non-Hispanic or Black was associated with improved MH. However, as this group had only 4 members, the significance of this is uncertain. Finally, CNS involvement was found to be associated with worse odds of having a low PROPr score (OR=10.46, 95%CI 2.17, 50.37 [p=0.003]). Conclusions: Several PROs were worse in patients with histiocytic neoplasms as compared with the general population. We further found that CNS involvement was independently associated with worse HRQoL, regardless of the diagnosis type. Additionally, female sex was associated with worse MH scores, and bone involvement with worse PH scores. PROPr score was particularly low among patients with ECD. Future research is warranted to assess the impact of treatments on HRQoL, as well as the economic loss resulting from loss of productivity as highlighted by low PROPr scores.

Introduction The treatment of Erdheim-Chester disease (ECD) has been revolutionized by the discovery of MAPK/ERK pathway mutations, most common being BRAF-V600E (50%). The US-FDA approved single-agent vemurafenib for BRAF-V600-mutated ECD in 2017 based on a phase II trial that included 22 patients with ECD and 4 with Langerhans cell histiocytosis (LCH), resulting in 100% overall response rate (ORR) by FDG-PET criteria (Diamond et al. JAMA Onc 2018). However, adverse events (AEs) to vemurafenib led to treatment interruption and/or dose modification in all patients, and drug discontinuation in 8 (31%) patients. Long-term outcomes and tolerability of BRAF-inhibitor (BRAFi) monotherapy in real world setting are unknown. In this study, we aimed to address these questions utilizing a large cohort of patients with ECD. Methods Registry-based ( NCT03329274) study of patients with ECD who received BRAFi (vemurafenib or dabrafenib) as any line of treatment. The registry captures detailed longitudinal clinical, treatment, and outcomes data through medical record abstraction. For this study, we focused on the events of discontinuation, dose reductions, and AEs to BRAFi therapy. Time-to-event analyses were conducted using Kaplan-Meier method from the date of initiation of BRAFi. Primary endpoint of the study was event-free survival (EFS), defined as time to progression of disease, discontinuation or alteration of therapy due to any cause (including addition of a MEK inhibitor), or death. Secondary endpoints included progression-free survival (PFS), defined as time to progression of disease or death, and overall survival (OS). Results We included 64 patients with ECD (including 7 with mixed ECD/LCH) in this study. Median age at diagnosis was 56y (range, 26-77) and at initiation of BRAFi was 57y (range, 26-77). Of these, 59 (92%) were BRAF-V600E, 2 (3.1%) were BRAF-wildtype, 1 had BRAF-V471F, 1 had BRAF-PICALM fusion, and 1 had unknown BRAF status. The distribution of organ involvement was bone (91%), neurologic (78%), brain parenchyma (62%), cardiovascular (58%), retroperitoneum (58%), skin (25%), and pulmonary (19%). BRAFi therapy was used as first-line in 38 (59.3%) and as subsequent line in the rest (median 1, range 1-7). The most common initial BRAFi used was vemurafenib (80%) followed by dabrafenib (20%). The median starting dose of vemurafenib was 720 mg bid (range 480-960) and end dose was 480mg bid (range, 240-480). The median start dose of dabrafenib was 100mg bid (range 50-150) and end dose was 50mg bid (range 50-100). Initial dose reduction of BRAFi was required due to AEs in 28 of 52 cases (54%) with final dose data available, encompassing cutaneous (43%), generalized symptoms or fatigue (18%), >1 system affected (14%), lab abnormalities (11%), musculoskeletal (7%), and other (7%) toxicities. Of 60 patients with response data, a response was seen in 51 patients or 85% (42 partial response, 9 complete response, 8 stable disease, and 1 progressive disease). The median follow-up duration was 3.9 years (range 0.2-8.8). Single-agent BRAFi therapy was discontinued in 38 (59%) patients who received it initially (vemurafenib 63% vs. dabrafenib 46%, p=0.28). Reasons for discontinuation included AEs (n=20, 53%), addition of MEK-inhibitor (18%) for reducing cutaneous toxicities (n=5) or augment CNS response (n=2), disease progression (n=4, 11%), death (n=3, 8%), or others (n=4, 11%). 17 patients were rechallenged with a BRAFi after initial discontinuation, and 6 (35%) discontinued it again. The median EFS for the entire cohort from first BRAFi treatment was 2.99y (95% CI 1.6-4.8) and from second BRAFi was 2.82y (95% CI 1.19- not reached). The median PFS and OS were not reached, and 4 patients died at last follow-up (3 from ECD). Conclusions Almost 5 years after the FDA approval of vemurafenib for ECD, our real-world study from long-term follow-up of a large cohort of patients highlights high response rates, but at the cost of adverse events leading to dose reductions and treatment discontinuation in a large subset. Our results also highlight the entity of disease progression on BRAFi therapy. Our results underscore the importance of developing therapies that are efficacious and well-tolerated in this incurable disease.

Abstract In the pre–novel agent era, the median postprogression overall survival (PPS) of patients with classic Hodgkin lymphoma (cHL) who progress after autologous stem cell transplant (ASCT) was 2 to 3 years. Recently, checkpoint inhibitors (CPI) and brentuximab vedotin (BV) have improved the depth and durability of response in this population. Here, we report the estimate of PPS in patients with relapsed cHL after ASCT in the era of CPI and BV. In this multicenter retrospective study of 15 participating institutions, adult patients with relapsed cHL after ASCT were included. Study objective was postprogression overall survival (PPS), defined as the time from posttransplant progression to death or last follow-up. Of 1158 patients who underwent ASCT, 367 had progressive disease. Median age was 34 years (range, 27-46) and 192 were male. Median PPS was 114.57 months (95% confidence interval [CI], 91-not achieved) or 9.5 years. In multivariate analysis, increasing age, progression within 6 months, and pre-ASCT positive positron emission tomography scan were associated with inferior PPS. When adjusted for these features, patients who received CPI, but not BV, as first treatment for post-ASCT progression had significantly higher PPS than the no CPI/no BV group (hazard ratio, 3.5; 95% CI, 1.6-7.8; P = .001). Receipt of allogeneic SCT (Allo-SCT) did not improve PPS. In the era of novel agents, progressive cHL after ASCT had long survival that compares favorably with previous reports. Patients who receive CPI as first treatment for progression had higher PPS. Receipt to Allo-SCT was not associated with PPS in this population.

Abstract Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

Abstract In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.