Bennani, N. Nora

Abstract Background The benefit of high-dose chemotherapy and autologous stem cell transplantation (ASCT) as a consolidation strategy after initial chemotherapy in peripheral T-cell lymphoma (PTCL) is currently unclear, and a randomized trial (EA4232/PTCL-STAT) to answer this question is currently underway. Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive subtype of nodal PTCL with poor prognosis and unique features. Here, we report a large-scale, real-world evidence on the role of ASCT in frontline AITL management. Methods We analyzed a national cohort of 5,827 patients diagnosed with AITL between 2004 and 2020 from the National Cancer Database (NCDB). Baseline demographic, clinical, and socioeconomic characteristics were assessed. Treatment modalities included chemotherapy alone, chemotherapy with ASCT, and no treatment. Overall survival (OS) was evaluated using Kaplan-Meier method and multivariable Cox proportional hazards regression. Propensity score matching (PSM) was performed to validate ASCT's treatment effect. Results Among patients with complete treatment information (n = 5,224), the median age at diagnosis was 68 years (range 20–90). Frontline treatments included chemotherapy alone (68.6%, n = 3,584), chemotherapy with ASCT (14.6%, n = 761), and no treatment (16.8%, n = 879). Compared with patients who did not receive ASCT, those who underwent ASCT were significantly younger (median 60.0 vs 68.0 years), more frequently treated at academic centers (81.5% vs 57.9%, p < 0.001), and more likely to reside in areas with higher educational attainment (p < 0.001). They exhibited lower Charlson-Deyo comorbidity scores (CDS), with a higher proportion having a score of 0 (82.8% vs 73.6%, p < 0.001), and were more likely to have advanced-stage disease (93.0% vs 86.9%, p < 0.001). Furthermore, a higher proportion of patients who received ASCT were diagnosed in more recent years (p < 0.001). Sex, race, and IPI score distribution showed no significant baseline differences. Median follow-up time was 81.1 months (95% CI: 77.4–84.9), and the median OS was 23.3 months (95% CI: 21.3–25.2) for the entire cohort. For patients receiving chemotherapy with ASCT, the median OS was 139.2 months (95% CI: 104.2–174.2). In comparison, chemotherapy alone yielded a median OS of 23.6 months (95% CI: 21.4–25.8), while patients who received no treatment had a median OS of 4.0 months (95% CI: 2.7–5.2); overall p < 0.001. Median OS also significantly improved with more recent diagnosis eras: 20.1 months for patients diagnosed in 2004–2009 (95% CI: 16.8–23.4), 23.9 months for those diagnosed in 2010–2015 (95% CI: 21.0–26.7), and 26.7 months for patients diagnosed in 2016–2020 (95% CI: 23.1–30.4) (p < 0.001). Analyses consistently demonstrated longer median OS in female patients (27.5 vs. 20.7 months in males, p <0.001), and in patients treated at academic centers (27.5 vs. 16.4 months at non-academic centers, p < 0.001). Median OS varied by race (White: 24.0 months vs. Black: 15.2 months vs. Others: 30.3 months; p = 0.017). Patients with higher household income and higher educational attainment experienced significantly improved survival (p = 0.005 and p = 0.017, respectively). Patients with early-stage disease, lower IPI scores, and lower CDS also showed significantly longer survival (p < 0.001 for all comparisons). Multivariate Cox regression showed that chemotherapy with ASCT significantly reduced mortality risk compared to chemotherapy alone (HR = 0.438, 95% CI: 0.364–0.527, p < 0.001). No treatment significantly increased mortality risk (HR = 1.941, 95% CI: 1.634–2.305, p < 0.001). PSM analysis further validated that chemotherapy with ASCT significantly lowered mortality risk compared to chemotherapy alone (HR = 0.608, 95% CI: 0.503–0.736, p < 0.001), after matching for age at diagnosis, sex, race, income, education level, academic center, stage, CDS, and diagnosis era. Conclusion This large-scale, real-world analysis suggests that chemotherapy followed by ASCT is associated with significantly improved overall survival in patients with AITL, supported by unadjusted Kaplan-Meier analysis, adjusted multivariate Cox regression, as well as PSM analysis. These data support ASCT as an important consolidation strategy for AITL in real-world practice.

Abstract Background: Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis with median overall survival of ~3-12 months with current therapies, highlighting an urgent unmet need for novel therapeutics. PTCL is uniquely sensitive to epigenetic modifiers. We have shown that DNMT3 inhibitors like 5-azacytidine have potent immunomodulatory effects, including upregulation of cancer testis antigens, in pre-clinical models of T-cell lymphoma. Similarly, we have shown that pralatrexate (PTX) is potentially synergistic with drugs targeting epigenetic regulation. These data suggest a role for combining the immune checkpoint inhibitor pembrolizumab (pembro) with epigenetic agents in patients with PTCL. Methods: PTCL-002 is a multicenter, multi-arm phase Ib study designed to evaluate the safety and efficacy of pembro in combination with PTX and/or decitabine (DAC) in patients with R/R PTCL and CTCL. The study included three arms: arm A (pembro+PTX), arm B (pembro+PTX+DAC), and arm C (pembro+DAC). All patients received pembro 200 mg by IV infusion every 21 days. Dose selection for DAC and PTX in arms A and C, respectively, was based on a continual reassessment method (CRM) while arm B used a partial order CRM. Primary endpoints included MTD, RP2D, dose-limiting toxicities (DLT) and clinical efficacy as assessed by overall response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and overall survival. Select pharmacokinetic and pharmacodynamic endpoints were also included in order to assess immune modulation and identify potential predictors of response. Results: We enrolled 26 patients, including 9 patients in arm A, 7 in arm B, and 10 in arm C. Median age was 61 (range 27-77) with 13 males and 13 females. Racial demographics were as follows: White 62%, Black 23%, Asian 3%, and Hispanic 1%. Median number of prior treatments was 3 (range 1-6). Histologic subtypes included ATLL (n=1), AITL (n=4), PTCL-NOS (n=10), SS (n=1), MF (n=6), PCALCL (n=1), MEITL (n=1), PCAECTL (n=1), and TFh-PTCL (n=1). Twenty-four of 26 patients received at least one dose of study drug and were evaluable for toxicity. Twenty-one of 26 of patients received at least one full cycle of therapy and were evaluable for response. Reasons for early discontinuation included consent withdrawal (n=1), rapid disease progression during cycle 1 (n=2), adverse event (n=1), and investigator decision (n=1). One DLT was observed each in arms A and B for prolonged grade 3 thrombocytopenia and febrile neutropenia, respectively. Three DLTs were observed in arm C including one patient with grade 3 hyponatremia and rash; one patient with grade 4 thrombocytopenia, neutropenia, and anemia; and one patient with grade 4 neutropenia. There were no treatment related deaths. Based on the observed DLTs, the RP2D for DAC in combination with pembro is 20 mg/m2on days 1-3; the RP2D for PTX in combination with pembro is 30 mg/m2on days 1, 8, and 15; for the triplet combination, the RP2D for DAC is 10 mg/m2given on days 1-5 and the RP2D for PTX is 20 mg/m2given on days 1, 8, and 15. Among 21 evaluable patients, responses were as follows: ORR 19% (4/21), CR 10% (2/21), PR 10% (2/21), and disease control rate (defined as proportion of patients with stable disease or better) 38% (8/21). ORR among evaluable patients in arms A, B, and C were 40% (2/5), 29% (2/7), and 0% (0/9), respectively. Analysis of serum cytokine levels in select patients (4 in Arm A, 4 in Arm B, and 5 in Arm C) revealed significant changes in 5 cytokines when compared to healthy age- and sex-matched controls. Of the 5 cytokines, 3 pro-inflammatory cytokines, TNFα, MIP-3α and IL-10, measured at day 1 pre-treatment were significantly higher in trial patients (p= 0.0001, 0.0008 and 0.003 respectively) than in healthy controls. Trial patients who responded to treatment (PR/CR) in any arms demonstrated a decline in serum levels of TNFα and IL-10 by day 15 of cycle 1, whereas non-responders (PD/SD) showed stable to increased levels of both TNFα and IL-10. Conclusion: We successfully identified the RP2D for DAC and/or PTX in combination with pembro in patients with R/R PTCL and CTCL. We demonstrated that an epigenetic platform incorporating the immune checkpoint inhibitor pembrolizumab is safe in heavily pretreated disease. More work on changes in cytokine profiles is needed before drawing any conclusions on their relationship to response.

Abstract Erdheim-Chester disease (ECD) is a rare systemic histiocytic neoplasm, with cardiac morbidities, including cardiovascular (CV) risk factors and cardiac conditions, playing a significant yet poorly understood role in the disease burden. This study evaluated the prevalence, characteristics, and prognosis of ECD in patients with (ECD-C) and without cardiac involvement (ECD-noC) and compared the burden of cardiac morbidities with matched controls. Patients diagnosed with ECD between 1990 and 2021 at a tertiary center were included, with cardiac involvement centrally assessed using radiographic studies. Cardiac morbidities were compared with a control group without ECD, matched for age, sex, body mass index, and smoking history. Among 104 patients with ECD, 39 (37%) had cardiac involvement. Patients with ECD-C had higher rates of hypertension (67% vs 46%), hyperlipidemia (67% vs 40%), heart failure (36% vs 8%), and pericardial effusion (28% vs 2%) than those with ECD-noC. Compared with the matched non-ECD cohort, patients with ECD had higher prevalence of coronary artery disease (20% vs 7%), heart failure (18% vs 4%), and antihypertensive drug use (55% vs 40%). Notably, patients with ECD-C had inferior progression-free survival (PFS) from frontline therapy compared with patients with ECD-noC (5-year PFS, 28.3% vs 70.5%). These findings highlight the burden of CV risk factors and cardiac conditions in ECD, even without a clinical diagnosis of ECD-C. Importantly, this cardiac morbidity burden is substantial for patients with ECD-C compared with ECD-noC. Our findings highlight the need for comprehensive cardiac risk assessment and management strategies to improve patient outcomes.

Introduction Malignant histiocytoses (MH), encompassing histiocytic sarcoma (HS), interdigitating dendritic cell sarcoma (IDCS), and Langerhans cell sarcoma (LCS), are a group of rare, hematologic neoplasms with diverse clinical presentations and poor outcomes. There are no established or effective treatments for patients with MH. The discovery of MAPK/ERK pathway mutations in non-malignant histiocytoses have revolutionized the treatment paradigm, but it is unknown whether novel treatments are efficacious for MH. This study aimed to assess the efficacy of targeted agents (TA) and immune checkpoint inhibitors (ICI) in MH. Methods We conducted a retrospective chart review of MH patients seen at our two institutions. Only patients treated with TA and/or ICI were included. We captured the mutational status by next generation sequencing and PD-L1 expression level by immunohistochemistry, where available. We also conducted a systematic literature review using PubMed to identify additional cases of MH patients treated with TA and/or ICI. Responses were reported as complete (CR), partial (PR), or none (NR) using previously published criteria for histiocytic disorders. Results From our institutions, we identified 12 MH patients (7 HS; 4 LCS; 1 IDCS) who received 14 instances of these treatments including TA (n=9) and/or ICI (n=5). The median age at diagnosis was 55 years (range, 33-70) and 50% were males. TAs included BRAF inhibitor (vemurafenib [1]), MEK inhibitors (binimetinib [1], cobimetinib [2], trametinib [2]) and others (dasatinib [1], pazopanib [1], pexidartinib [1]), while ICIs were exclusively pembrolizumab (5). The median number of prior treatments for those who received TAs and ICIs were 4 and 2, respectively. Responses were observed in 44.4% (1 CR, 3 PRs, 5 NR) and 40% (2 CRs, 3 NRs) of patients who received TA and ICI, respectively. Only 1 patient (20%) treated with MEK inhibitor responded [DOCK8-BRAF; PR 5+ mos]. Other responders received dasatinib [PDFGRA-V608I; PR 2 mos], pexidartinib [PTPN11-A72T; PR 5 mos], and vemurafenib [BRAF-V600E; CR 10+ mos]. Two patients (40%) who received pembrolizumab responded (both CRs 12+ [10% PD-L1] and 44+ mos [40% PD-L1]). We identified 29 MH patients in the literature (27 HS; 2 LCS) treated with TAs (22) and/or ICIs (10). TAs included BRAF inhibitor only (vemurafenib [3], dabrafenib [3]), MEK inhibitor only (trametinib [5]), BRAF + MEK inhibitors (2), and others (apatinib, anlotimib, bevacizumab, daratumumab, dasatinib, imatinib, pazopanib, sorafenib, or combinations [9]), while ICIs included pembrolizumab (4), nivolumab (4), tislelizumab (1), and sintilimab (1). Responses were observed in 77% (7 CRs, 10 PRs, 5 NRs) and 100% (2 CRs, 8 PRs) of patients who received targeted agents and ICI, respectively. Most patients carrying BRAF (7/8; V600E, G596R, D594G, TRIM::BRAF) or MAP2K1 (3/3; C121S, F53I) mutations responded to treatments, irrespective of the number of mutations present. The median durations of response for ICI and targeted agents were 10.5 months (range: 1-36+) and 12+ months (range: 3-44+), respectively. After combining the datasets from our institutions and literature review, we analyzed the association between the extent of PD-L1 expression and response to ICI. Those who responded to ICI had higher PDL-1 expression (median 75% [range, 10-75] vs 25% [range, 1-30]; P=0.0097). Conclusion TAs and ICIs can be considered in the management of MH. The responses to ICI therapy may be associated with the degree of PDL1 expression

Introduction. Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) belong to a group of histiocytic neoplasms often driven by mutations in the mitogen activated protein kinase (MAPK) pathway, most commonly in BRAF, MAP2K1 and K/NRAS. Currently, there are 2 drugs approved by the US Food and Drug Administration for the treatment of histiocytic neoplasms, cobimetinib and vemurafenib, both small molecule kinase inhibitors (SMKI) targeting mitogen-activated extracellular signal-regulated kinase (MEK) and BRAF, respectively. BRAF mutations are functionally classified as RAS-independent - either monomers (class I) or dimers (class II) - and RAS-dependent (class III). MAP2K1 mutations are functionally classified as RAF-independent, RAF-regulated, or RAF-dependent. Preclinical studies suggest class I, but not classes II-III, BRAF mutations are sensitive to RAF monomer inhibitors (dabrafenib, encorafenib, vemurafenib) while classes I-II, but not class III, BRAF mutations are sensitive to MEK inhibitors (Yaeger R, Cancer Discovery 2019). In contrast, RAF-regulated MAP2K1 mutants have variable sensitivities to allosteric MEK inhibitors (binimetinib, cobimetinib, selumetinib, trametinib) while RAF-dependent and RAF-independent MAP2K1 mutations are resistant. KRAS mutations are generally resistant to MEK inhibitors (Johnson C, Cancer Discovery 2022). Our study described the clinical efficacy of commercially available SMKIs in patients with histiocytic neoplasms harboring non-BRAFV600E mutations and compared the findings with preclinical data. Methods. We conducted a retrospective chart review of patients with histiocytic neoplasms who were treated with SMKI at Mayo Clinic. Only those who had adequate genomic testing and non-BRAFV600E mutations were included. Responses were categorized as complete (CR), partial (PR), or none (NR) based on established criteria. Results. We identified 31 non-BRAFV600E patients treated with SMKI (2 LCH; 20 ECD; 9 RDD). The median age at diagnosis was 61 years (range: 16-76) and 52% were females. The distribution of BRAF mutations was: class I (V600delinsRE [1]), class II (V495A [1], V471F [1], N486_P490del [2], GAB2-BRAF [1], UBR2-BRAF [1], RNF11-BRAF [1], UBTD2-BRAF [1]), and class III (G466E [1], D594A [1]). The only patient with class I mutation received cobimetinib and had PR. Among those with BRAF class II mutations, 2 received vemurafenib and had NR, while 9 received MEK inhibitors (binimetinib, cobimetinib, trametinib) and most responded (3 CRs, 5 PRs). The patient who had NR required dose reductions due to side effects. Both patients with class III mutation did not respond to cobimetinib. The median duration of responses was 19 months (range: 3+ to 45+) and 3 patients progressed subsequently. The distribution of MAP2K1 mutations was: RAF-independent (E102_103del [2]), RAF-regulated (I103N [1], K57T [1], Q56P [3], F53L [1], K57N [1]) and RAF-dependent (Y130C [1], D67N [1]). Both patients with RAF-independent mutations treated with cobimetinib had PRs. All patients with RAF-regulated mutations treated with allosteric MEK inhibitors responded (3 CRs, 5 PRs). Both patients with RAF-dependent mutations treated with cobimetinib responded (1 CR, 1 PR). The median duration of responses was 15 months (2 to 29+) with 3 patients progressing after treatment cessation due to intolerance. The distribution of RAS mutations was: NRAS (Q16R [1]) and KRAS (K117N [3], A146T [1], T581 [1], G13C [1], G12D [1]). Most patients treated with allosteric MEK inhibitors responded (3 CR, 4 PR, 1 NR). The median duration of response was 15 months (5 to 41) and 2 patients subsequently progressed, one of them after treatment cessation. Conclusions. Among patients with histiocytic neoplasms with non-BRAFV600E mutations receiving SMKI, our study found mixed patterns of concordance between pre-clinical predictions and clinical responses. There was concordance of efficacy in the setting of BRAF classes I-III and MAP2K1 RAF-regulated mutations. However, we found discordant findings in patients harboring RAF-dependent and RAF-independent MAP2K1 mutations as well as KRAS mutations as most responded to allosteric MEK inhibitors.

Background: Management of cytokine release syndrome (CRS) with chimeric antigen receptor T cell therapy (CAR-T) has evolved in the last decade. First line treatment tocilizumab (toci) was initially given for grade 2 or higher CRS in clinical trials (Toci/CRS≥2). Earlier use of toci in grade 1 CRS was found to be safe without negative impact on clinical response in cohort 4 of ZUMA-1 study for axicabtagene ciloleucel (axi-cel) for B-cell non-Hodgkin lymphoma (NHL; Toci/CRS1). This practice was also adopted for other CAR-T therapies for other disease indications. Subsequently, FDA also updated the package insert for axi-cel in 2021 to include the use of prophylactic dexamethasone (ppx dex) to be given on days 0, 1, 2 of CAR-T infusion based on the results from cohort 6 of ZUMA-1. We examined CRS and ICANS (immune effector cell associated neurologic syndrome) outcome of patients who received FDA approved axi-cel in standard-of-care (SOC) practice with these evolving practices. Of note, adoption of ppx dex has been variable across CAR-T treatment centers in the US (Khurana et al, Blood 2022). At Mayo Clinic Rochester, patients considered high-risk for severe CRS/ICANS (those who received bridging therapy and had LDH above upper limit of normal and/or with secondary CNS involvement or other CNS pathologies) would be considered for ppx dex. Methods: Medical records of patients who received axi-cel in SOC between 2018 and 2023 at Mayo Clinic Rochester were reviewed. ASTCT guideline was used for CRS and ICANS grading. Categorical variables were compared using Chi-squared test and continuous variables were compared using Kruskal-Wallis test. Results: Among 187 pts receiving SOC axi-cel, the median age was 60 years and 121 (65%) were males, 152 (81%) had CRS, of which 73 (39%) were grade ≥2; 97 (52%) had ICANS, of which 65 (35%) were grade ≥2. Of the 152 CRS pts, 54/152 (36%) pts never received toci or ppx/dex. Of the pts who received Toci, 35/152 (23%) received Toci when CRS is at least grade 2 (Toci/CRS≥2), 49/152 (32%) received Toci/CRS1 without ppx dex (Toci/CRS1), and 14 (9%) received ppx dex with Toci given in CRS1 when pts developed CRS (PPX DEX). Baseline demographics were comparable except age (Toci/CRS≥2: 58y; Toci/ CRS1: 63y; ppx dex: 50y; p=0.001) and pre-LD CRP (Toci/CRS≥2: 34mg/L; Toci/ CRS1: 6mg/L; ppx dex: 16mg/L; p=0.002). Pre-LD LDH and ferritin were also comparable. PPX DEX or Toci/CRS1 had significantly lower rate of maximum grade CRS≥2 (PPX DEX: 4 (29%); Toci/ CRS1: 20 (41%); 35 (100%); p<0.001) and duration of CRS (PPX DEX: 2.5d; Toci/ CRS1: 3d; Toci/CRS≥2: 5d; p<0.001). Time to onset of CRS was not statistically different between the 3 groups. Not surprisingly, Toci/CRS1 group had higher overall rate of toci use, compared to . Interestingly, use rate of ≥2 doses of Toci or siltuximab was significantly higher in Toci/CRS1 or PPX DEX (PPX DEX: 8 (57%); Toci/ CRS1: 26 (53%); 9 (26%); p=0.02). Pt who received PPX DEX or Toci/CRS1 had a significantly lower rate of ICANS (PPX DEX: 6 (43%); Toci/ CRS1: 33 (67%); 32 (91%); p=0.001) and rate of max grade ICANS ≥2 (PPX DEX: 3 (21%); Toci/ CRS1: 23 (47%); 27 (77%); p<0.001). The time to onset and duration of ICANS was not different among the 3 groups. Conclusion: Our real-world study shows that earlier use of Toci in grade 1, compared to its first use in grade 2, can result in lower overall incidence of more severe CRS, duration of CRS, incidence of ICANS and more severe ICANS. While we selected patients at higher risk for having more severe CRS in our PPX DEX cohort, experience to date suggests that these patients, compared to toci/CRS>=2 cohort, could also have reduced severity of CRS and ICANS with this updated management.

Background: In the ZUMA2 study, a higher peak chimeric antigen receptor (CAR) T cell expansion correlated with better outcomes in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving brexucabtagene autoleucel (brexu-cel). However, in clinical practice, peak CAR T cell expansion is not routinely assessed for. Since patients receive lymphodepleting agents prior to CAR T cell infusion, it is hypothesized that peak absolute lymphocyte count (ALC), which can be easily measured, in the first two weeks after CAR T cell infusion represents peak CAR T cell expansion. Our group previously showed that peak ALC was associated with response durability and outcomes in patients with R/R large B-cell lymphoma receiving axicabtagene ciloleucel. In this retrospective study, we assessed the association of peak ALC with clinical outcomes after brexu-cel infusion in patients with R/R MCL. Methods: Patients with R/R MCL who received brexu-cel between March 2020-March 2024 at Mayo Clinic were included in this analysis. Peak ALC was defined as maximum ALC value in the first 14 days after CAR T cell infusion. Progression-free survival (PFS) was defined as time from CAR T cell infusion to lymphoma relapse, progression, or death, and overall survival (OS) was defined as time from to CAR T cell infusion to death. The optimal cutoff point for peak ALC that correlated with PFS was determined by the log-rank method using the Cutoff Finder application, a computational method which fits Cox proportional hazard models to the dichotomized variable and survival. The optimal cutoff was the point with the most significant PFS split by log-rank test. Results: A total of 43 patients were identified. The median age at time of CAR T cell infusion was 68 years (IQR 58, 73). 34 (79%) were male, 28 (74%) had Ki-67 >30%, 14 (33%) had blastoid or pleomorphic histology, and 19 (44%) had TP53 mutation or deletion. Median number of prior lines of therapy was 3 (IQR 2, 4) and 13 (30%) received prior autologous stem cell transplant. 32 (74%) received bridging therapy prior to CAR T cell infusion. All patients received fludarabine plus cyclophosphamide for lymphodepletion. The best overall response rate was 88%, with a complete response rate of 84%. After a median follow-up of 25.6 months (95% CI 14.4-31.4), the median PFS and OS were 16.6 (95% CI 8.6-NE) and 35.1 (95% CI 24.5-NE) months, respectively. The incidence of cytokine release syndrome (CRS) was 95% (4.7% grade ≥3). The median time to initial CRS and maximum grade CRS onset was 4.5 days (IQR 1, 6.25) and 5.5 days (IQR 2.75, 7), respectively. The incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) was 65% (18% grade ≥ 3). The median time to initial and maximum grade ICANS onset was 9 days (IQR 6, 11) and 10.5 days (IQR 7, 12), respectively. The median ALC at time of CAR T cell infusion was 0.03 x109/L (IQR 0.02, 0.05). Among 37 patients with identifiable ALC peaks, the median ALC peak was 0.84 (IQR 0.41, 2.45) and the median time to peak ALC was 12 days (IQR 9, 12). 6 patients had no identifiable peak ALC due to no frequent CBC differentials post CAR T cell infusion. A peak ALC of ≥0.45 × 109/L correlated significantly with PFS, with median PFS not reached for the group with peak ALC of ≥0.45 × 109/L (n=27) compared to 9.3 months for the group with peak ALC of <0.45 × 109/L (n=10) and a 1-year PFS rate of 68% vs 33% (p=0.02). OS was also significantly higher in patients with a peak ALC of ≥0.45 × 109/L (median OS not reached vs 11 months, 1-year OS rate of 84% vs 44%, p=0.01). The incidence of ICANS was significantly higher (74% vs 30%, p=0.02) in patients with a peak ALC of ≥0.45 × 109/L. Numerically, the group with peak ALC of ≥0.45 × 109/L had a later onset of initial and maximum grade ICANS, but the difference was not statistically significant. Peak ALC was not associated with ICANS severity. There was a trend towards higher incidence of CRS (100% vs 80%, p=0.07) and earlier CRS onset (3 vs 5 days, p=0.07) in the high peak ALC group. There was no difference in CRS severity. Conclusion: Peak ALC after CAR T cell infusion was significantly associated with better PFS and OS and higher incidence of ICANS in patients with R/R MCL receiving brexu-cel. Peak ALC may serve as a surrogate measure for peak CAR T cell expansion in routine practice, but confirmatory studies are needed. Larger studies are warranted to confirm the association of peak ALC with PFS, OS and toxicities in patients with R/R MCL receiving brexu-cel.

Background: Erdheim-Chester disease (ECD) manifests as multi-organ infiltration of clonal histiocytes with mutations primarily in the mitogen-activated protein kinase (MAPK) pathway. The revised classification of histiocytosis (2016) categorizes ECD with typical bilateral, symmetric osteosclerosis of the lower extremity long bones as classical (C) and as non-classical (NC) if otherwise. The clinical and biological significance of this classification is unclear. This study compared the clinical and genotypic findings of the 2 subtypes within a large cohort of ECD patients. Methods: We included patients seen at our institution since 1990 meeting the following criteria: A) had an ECD diagnosis based on the revised criteria by Haroche J, et al. (Blood 2020;135:1311-1318); B) completed whole-body imaging studies including long bones of the legs. Classification as C-ECD required symmetric osteosclerosis of the distal femur and/or proximal tibia/fibula. Results: A total of 145 patients were enrolled, comprising a male-to-female ratio of 2:1 (66.2% male). C-ECD was diagnosed in 77.2% of cases, and NC-ECD in 22.8%. The median age at diagnosis was similar with 58.5 years (range, 18-82) in C-ECD and 55 years (range, 20-81) in NC-ECD, (p=0.65). The most frequently affected systems included skeletal (81.4%), renal (60.0%), vascular (45.5%), cardiac (40.0%), central nervous (38.6%), sinus (37.2%), pulmonary (36.6%), and adrenal (32.4%). The numbers of organs involved were significantly higher in C-ECD compared to NC-ECD (median 5 vs 3, p<0.01). Higher rates of skeletal (100% vs. 18.2%, p<0.01), adrenal gland (37.5% vs. 15.2%, p=0.02), and sinus (44.6% vs. 12.1%, p<0.01) involvement were observed in C-ECD. Arginine vasopressin deficiency (AVP-D) was exclusively observed in C-ECD (20.7% vs. 0%, p<0.01). NC-ECD had a higher rate of cardiac involvement (69.7% vs. 31.3%, p<0.01). No significant differences were found in other systems. The overall median time between onset of the first symptoms/signs to diagnosis was 15 months with no significant difference between C-ECD and NC-ECD (17.5 vs. 12 months, p=0.18). The median time to diagnosis of ECD in patients with AVP-D was 38.5 months, compared to 12 months without AVP-D (p=0.09). Genetic testing was conducted in 86.2% of patients and B-Raf proto-oncogene (BRAF) alterations were identified in 59.2% of the tested cases. BRAFV600E was more prevalent in C-ECD (61.3% vs. 21.9%, p<0.01), whereas non-V600 mutations were more commonly found in NC-ECD (12.5% vs. 1.1%, p<0.01). There was no significant difference in the frequency of BRAF fusions. NC-ECD patients exhibited a higher rate of MAP2K1 mutations (25.0% vs. 5.4%, p<0.01). Other frequently mutated genes included KRAS (4.0%), NRAS (2.4%), and CSF1R (2.4%), although no significant difference was observed in their frequency between C-ECD and NC-ECD. Testicular involvement appeared to be more common in patients with MAP2K1 mutations (23.1% vs. 8%, p=0.08). Two patients with pathogenic CSF1R mutations both had central nervous system (CNS) involvement. Among C-ECD patients, BRAFV600E conferred a higher rate of CNS involvement (50.9% vs. 25%, p=0.01). No significant difference was observed in NC-ECD patients (71.4% vs 36%, p=0.09). Among NC-ECD cases, MAP2K1 mutations conferred a reduced risk of cardiac involvement (37.5% vs. 79.2%, p=0.03) and no such difference was observed in patients with C-ECD (40% vs 34.1%, p=0.79). The median numbers of organs involved in patients with BRAF, MAP2K1, and KRAS/NRAS mutations were 5, 3, and 3, respectively, with no significant difference. Conclusions: C-ECD affects more organs and more frequently involves bones, adrenal glands, and sinuses. AVP-D was exclusively observed in C-ECD. Conversely, NC-ECD showed a higher prevalence of cardiac involvement. BRAFV600E was more commonly identified in C-ECD, whereas non-V600 mutations and MAP2K1 mutations were more prevalent in NC-ECD. Among C-ECD patients, BRAFV600E was correlated with a greater likelihood of CNS involvement. Conversely, NC-ECD patients with MAP2K1 mutations had a reduced risk of cardiac involvement. This study highlights the distinct clinical and molecular features of C-ECD and NC-ECD, underscoring the importance of subclassifying ECD into classical and non-classical forms. Further studies are needed to explore differences in the clinical outcomes between the 2 forms.

Background and Methods: IEC-HS is a hyperinflammatory state with high morbidity and mortality. Effective interventions to reverse the process early in the clinical course may be critical to improve outcomes. We previously examined cytokine differences between IEC-HS and other secondary hemophagocytic lymphohistiocytosis, and found significant differences in the patterns and outcomes.(1) This study examines cytokine profiles (CP) of patients treated with CAR-T from 9/2019 to 3/2024 who developed CRS, MAS-L and IEC-HS. Demographics and lab results were compared among the three groups and correlated with outcomes. Results: CP was tested in 113 of 366 CAR-T patients: 74 with CRS, 19 with MAS-L, and 20 with IEC-HS. The racial distribution was 93% White/Caucasian, 2% Black or African American, 1% Asian, 1% Native American and 3% other or unavailable. No differences were seen in demographics between groups except a higher percentage of patients with ECOG performance status ≥2 in IEC-HS (p=0.037). Incidence of IEC-HS by disease: 3.6% (7/193) in lymphoma, 5% (8/159) myeloma and 28.5% (4/14) B-acute lymphoblastic leukemia (p=0.0002). Incidence of IEC-HS by CAR-T product: 3% (4/150) in Axi-cel, 23% (6/26) in Brexu-cel, 8% (1/13) in Tisa-cel, 5% each (3/60) in Cilta-cel and Ide-cel, and 0/17 in Liso-cel (p=0.001). Prior to lymphodepletion, labs were already different among the CRS, MAS-L, and IEC-HS groups: hemoglobin (g/dL: 11.1, 9.6, 8.45); platelets (x109/L: 168, 116, 52.5); ferritin (µg/L: 115, 946, 1944). CP was started when patients needed a second dose of tocilizumab or concern for developing MAS-L/IEC-HS, and continued daily until clinical improvement or resolution of inflammatory state. Tocilizumab and dexamethasone use were similar across groups. Other therapies used were vasopressors (3%, 10.5%, 45%; p<0.0001), Methylprednisolone (20%, 31.6%, 50%; p=0.027), Anakinra (12%, 63%, 85%; p<0.0001), Siltuximab (9.5%, 16%, 30%; p=0.06), Basiliximab (30% of IEC-HS), and continuous veno-venous hemofiltration (30% of IEC-HS). Among the first CP, the CRS group had lower levels of cytokines (in pg/mL) compared to MAS-L and IEC-HS groups: TNF (31, 62.9, 47.7), IL-10 (29.3, 97.7, 169), IL-18 (794, 1353, 2011), IFN-gamma (74, 281, 250), MCP-1 (689, 2722, 2485.5), MIP-1 alpha (220, 234, 247.5), IL-6 (>315: 45%, 79%, 70%), soluble IL-2R alpha (>4000: 45%, 84%, 70%). The percentage of patients who received anakinra before CP1 were 4% (CRS), 21% (MAS-L) and 25% (IEC-HS) (p=0.007). IL-1 beta was below threshold among all patients who received anakinra in CRS and MAS-L and 75% in IEC-HS, suggesting rapid and effective IL-1 suppression by anakinra except in IEC-HS. Cytokines trends 24 hours and 48 hours after the first CP differed between MAS-L and IEC-HS. MAS-L had decreased TNF (62.9, 40.4, 18.5) and MCP-1 (2722, 355, 104) while these cytokines remained elevated or increased in IEC-HS (TNF: 47.7, 105.5, 62.6; MCP-1: 2486, 2276, 1585). IL-18 was minimally elevated in MAS-L (1353, 1955, 3068) and significantly increased in IEC-HS (2011, 2420, 4048). Notably, CP2 and CP3 levels of these cytokines in IEC-HS were statistically significantly higher than corresponding CPs among CRS and MAS-L. In addition, patients who died with persistent E. faecium bacteremia had higher IL-18 on CP3. Infections occurred in 43%, 58%, and 85% respectively (p=0.002), including E. faecium bacteremia (3%, 5%, 35%; p=0.0004), CMV viremia (30% of IEC-HS patients vs. 11% of non-IEC-HS; p=0.025), and invasive fungal infections (15% of IEC-HS patients; p=0.0001). Between the IEC-HS and non-IEC-HS groups, day 100 non-relapse mortality was 35% vs. 0 (p<0.0001), day 100 all-cause mortality was 45% vs. 3% (p<0.0001), and E. faecium bacteremia-related deaths were 50% vs. 1% (p<0.0001). Conclusions: CRS, MAS-L andIEC-HS are known complications of CAR-T. Cytokine-directed therapy can modify the cytokine milieu and control the inflammatory process. However, excess immunosuppression may result in life-threatening infections. Further studies are needed to identify optimal biomarker-guided immunosuppressive strategies to control the inflammatory cascade, while avoiding excess immunosuppression. References: 1. Leung, Nelson, et al. “Outcomes of patients who received CAR T cell therapy and developed IEC-HS treated with cytokine directed therapy.” (2024): 7516-7516.