Paludo, Jonas

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.

Introduction: The primary analysis of the phase 3 ECHO trial (NCT02972840) demonstrated that acalabrutinib plus bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) vs placebo plus bendamustine-rituximab (PBR) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang et al. EHA 2024, Abstract #LB3439). Here we present additional efficacy and safety results from the ECHO trial. Methods: Pts aged ≥65 years (y) with previously untreated MCL and ECOG PS ≤2 were randomly assigned 1:1 to receive ABR or PBR. Acalabrutinib (100 mg twice daily) or placebo was administered until progressive disease (PD) or unacceptable toxicity. Induction with BR was administered for 6 cycles followed by rituximab maintenance (A±R maintenance, cycles 7-30) in pts achieving a partial or complete response (PR or CR). Pts progressing on PBR could cross over to receive acalabrutinib monotherapy. PFS (primary endpoint) was assessed by independent review committee. Minimal residual disease (MRD) negativity rate (10-5) was assessed in peripheral blood (every 24 weeks [wks], at CR, and at PD) and bone marrow (at CR) by NGS-based ClonoSEQ assay (Adaptive Biotechnologies). Results: Among the 598 pts randomized to ABR or PBR (299 in each arm), high-risk baseline characteristics included high-risk simplified MIPI score in 24.1% and 24.4%, blastoid histology in 8.7% and 6.7%, pleomorphic histology in 5.0% and 6.0%, centrally tested Ki-67 ≥30% in 46.5% and 49.2%, and known TP53 mutation in 7.4% and 9.7%, respectively. PFS hazard ratios (HRs) for subgroups were 0.78 (95% confidence interval [CI] 0.51-1.19) in pts with high-risk simplified MIPI score, 0.68 (95% CI 0.29-1.58) in pts with blastoid histology, 0.64 (95% CI 0.25-1.66) in pts with pleomorphic histology, 0.69 (95% CI 0.49-0.98) in pts with Ki-67 ≥30%, and 0.88 (95% CI 0.42-1.78) in pts with known TP53 mutation. In the ABR arm, median PFS was 22.2 months (mo) among pts who discontinued acalabrutinib during induction for reasons other than PD or death, 29.4 mo in pts who discontinued acalabrutinib during A±R maintenance (cycles 7-30) for reasons other than PD or death, and not reached in pts who received acalabrutinib for 31 cycles or more. Among evaluable patients who were MRD negative at the end of induction (24 wks), the rate of conversion to MRD positive during maintenance was lower in the ABR arm (5.85%; n=11/188) than in the PBR arm (15%; n=26/171). Conversely, among evaluable pts who were MRD positive at the end of induction (24 wks), 37.5% (n=3/8) in the ABR arm and 20% (n=3/15) in the PBR arm converted to MRD negative during maintenance. Overall rates of AEs were similar in each arm during induction, but were higher in ABR during A±R maintenance (cycles 7-30) and more so in the monotherapy phase (cycle 31+). Grade ≥3 TEAEs (ABR vs PBR) were 70.0% vs 68.7% during induction, 64.9% vs 62.9% during A±R maintenance (cycles 7-30), and 57.0% vs 45.3% during monotherapy (cycle 31+). Similarly, rates of TEAEs leading to discontinuation of acalabrutinib/placebo were 8.1% vs 8.8% during induction, 23.9% vs 19.0% during A±R maintenance (cycles 7-30), and 25.9% vs 13.7% during monotherapy (cycle 31+). Exposure-adjusted incidence rates per 100 person-years reduced the difference between ABR and PBR for clinically relevant TEAE rates (32.6 vs 29.3 for grade ≥3 serious TEAEs; 4.2 vs 4.0 for grade 5 TEAEs; 15.5 vs 12.4 for TEAEs leading to acalabrutinib/placebo discontinuation), possibly due to longer median exposure to acalabrutinib (28.6 vs 24.6 mo). Conclusion: Acalabrutinib in combination with BR provides a significant PFS benefit in pts with previously untreated MCL, including those with high-risk features. Furthermore, the addition of acalabrutinib to BR provided a greater PFS effect among pts in the ABR arm with the longest exposure to acalabrutinib. The PFS improvement may be partially driven by the contribution of acalabrutinib to sustained MRD-negative status and deepened responses after the end of induction. ABR provides this clinical benefit without excess toxicity as shown by attenuated differences between arms in exposure-adjusted incidence rates, suggesting that higher AE rates in the ABR arm are likely due in part to the longer duration of acalabrutinib treatment vs placebo. These data emphasize the benefits of acalabrutinib in frontline MCL treatment in high-risk pts and the additional benefit of continuous therapy.

Background: Continuous single-agent ibrutinib (Ibr) treatment has been associated with extended progression-free survival in patients with Waldenström macroglobulinemia (WM). Previous clinical studies have shown that Ibr dose reductions (DRs) improved or resolved adverse events (AEs) in most patients, while hematologic responses were sustained. However, real-world data on long-term outcomes for patients with WM undergoing Ibr DR in first-line (1L) settings remain limited. Methods: Medicare Fee-for-Service (FFS) medical and pharmacy records were used to identify patients diagnosed with WM who initiated 1L single-agent Ibr (420 mg/day) or 1L Ibr + rituximab from January 1, 2015, to September 30, 2022. Observed patients were enrolled in Medicare FFS ≥12 months before and after 1L treatment initiation and had ≥1 qualifying post-treatment initiation AE of special interest (AESI; both prevalent and incident AEs), as identified via ICD-9-CM or ICD-10-CM diagnosis codes. Ibr DR was defined as a reduction of the starting dose (420 mg/day) following the first AESI during 1L treatment. Patients without an Ibr DR were defined as those who had received Ibr at 420 mg/day during 1L treatment. Patients without an AESI post-Ibr initiation and prior to DR were excluded from the analysis. Demographics, clinical characteristics, time to AESI, duration of therapy (DOT), and time to treatment discontinuation (TTD) were assessed in cohorts with and without DRs. DOT was measured at the date of Ibr treatment initiation through treatment discontinuation (end of 1L treatment). Patients were considered to have discontinued treatment if they received a subsequent systemic therapy after the 1L regimen, had a gap of ≥120 days with no systemic therapy following the last administration, or died while on the 1L regimen. Patients without a discontinuation were censored at the earliest date of end of follow-up or disenrollment. TTD was analyzed using the Kaplan-Meier method. A Cox proportional hazards model adjusted for patient demographics and clinical characteristics was used to identify factors associated with treatment discontinuation. Results: A total of 407 patients with WM were included in the analysis (DR, n=55 [14%]; no DR, n=352 [86%]). Patients in the DR and no DR cohorts, respectively, had similar a median age (78 years vs 77 years), Charlson Comorbidity Index score (3 vs 4), and prevalence of the most common baseline comorbidities: hypertension (67% vs 68%) and cardiovascular conditions (31% vs 28%). The median time between treatment initiation and the occurrence of the first AESI was 89 days versus 76 days, and total Ibr DOT mean ± SD [median] was 786.1 ± 692.6 [661] days versus 454.8 ± 510.4 [279] days (P=0.001) for DR cohort versus no DR cohort. Following DR, patients remained on Ibr for mean ± SD [median] 336.0 ± 422.8 [179] days until the end of 1L therapy. After adjusting for variations in baseline characteristics, patients with a DR had significantly longer TTD post-treatment initiation than those without a DR (median TTD, DR vs no DR: 22.5 months vs 9.3 months; adjusted HR [95% CI], 0.52 [0.37-0.72]). Conclusion: This real-world evidence study suggests that implementing DRs to manage AEs can be a valuable strategy in supporting patients with WM to remain on 1L Ibr longer, thus maintaining beneficial clinical outcomes. These findings are consistent with previous studies, demonstrating that Ibr DRs help to improve tolerability while maintaining treatment efficacy.

Introduction: The optimal induction for younger fit patients (pts) with mantle cell lymphoma (MCL) is unknown; though intensive chemoimmunotherapy (CIT) containing high dose cytarabine has been shown to prolong remission. Achieving molecular remission is an independent predictor of outcomes post induction therapy in patients with MCL. Incorporating undetectable measurable residual disease (uMRD) status into the primary endpoint may be preferable to progression-free survival (PFS), particularly when approaches following induction are varied (e.g., ASCT, maintenance treatment, observation). Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton's tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439). In 2019, the US Intergroup activated EA4181 to explore the efficacy with the addition of fixed duration BTKi, to BR or BR/CR for patients with MCL ≤ 70 years old. Patients and methods: Patients were randomized 1:1:1 (stratified by MIPI risk status) to 6 cycles of BR/CR (control arm), BR/CR-A, or BR-A. Cytarabine was dosed at 2 g/m2 Q12 hours x 4, with dose reductions based on age and creatinine clearance. Acalabrutinib was dosed at 100 mg BID continuously on BR cycles with the BR/CR-A and BR-A arms and at 100 mg BID on days 1-7 and 22-28 with CR cycles on the BR/CR-A arm to mitigate hematologic toxicity. Consolidation approaches following induction were at the discretion of the treating physician. The primary endpoint was a composite of PET/CT CMR and peripheral blood uMRD rate (< 1 in 105). ClonoSEQ (Adaptive Biotechnologies) was performed at baseline and MRD testing was obtained at the end of induction. Secondary clinical objectives included PFS and overall survival (OS) at 36 months (mo), objective response rates (ORR), and toxicity rates. With 108 patients per arm expected, there was 86% power to detect an increase in PET/CT CMR/uMRD rate from 60% in the control arm to 75% in either BR/CR-A or BR-A arms using a Z-test with a 10% alpha (1-sided). Results: Between October 2019 and March 2023, 359 participants were randomized to BR/CR (n = 128), BR/CR-A (n = 129), and BR-A (n = 102). BR-A was closed to further accrual by the DSMC based on interim futility analysis for superiority in Fall 2022. The median (range) age was 61 (25, 70), 30% were ≥ 65 years, 77% were male, 89% were white, 89% were non-Hispanic, 18%/43%/39% were low/intermediate/high risk MIPI. Baseline clonal sequence was identified in 308/326 (95%) among samples received. 281/308 were eligible and treated and 260/281 had an end of treatment MRD test result (BR/CR = 85, BR/CR-A = 98, BR-A = 77). This subset (n = 260) is the focus of the primary analysis; sensitivity analysis included 281 eligible and treated pts with trackable clonal marker. In the primary analysis subset, 94%, 91%, and 90% in BR/CR, BR/CR-A, and BR-A arms, respectively, completed 6 cycles of protocol therapy. The PET/CT CMR/uMRD rates were 82% (BR/CR), 82% (BR/CR-A; p = 0.55 vs BR/CR), and 78% (BR-A; p = 0.76 vs BR/CR). In the sensitivity analysis set, PET/CT CMR/uMRD rates were 74% with BR/CR (n = 94), 76% (p = 0.44) with BR/CR-A (n = 106), and 74% (p = 0.52) with BR-A (n = 81). ORR (CMR) rates were 94% (91%), 99% (90%), and 94% (91%) with BR/CR, BR/CR-A, and BR-A, respectively. At a median follow-up of 27.9 mo, estimated 12-mo PFS/OS were 86%/94% (BR/CR), 89%/98% (BR/CR-A) and 87%/95% (BR-A). The proportion of treatment-related grade 3 or higher adverse events (AE) was 78%/88%/73%, with neutropenia in 52%/58%/27%, anemia in 23%/32%/3%, thrombocytopenia in 55%/66%/6%, and febrile neutropenia in 11%/12%/4%; treatment discontinuation due to AE occurred in 5%/7%/8% in BR/CR, BR/CR-A, and BR-A arms, respectively. Conclusion: High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles. BR-A was found not superior and closed early by the DSMC; however, it is the least toxic arm with similar efficacy, and represents an appealing option to avoid high dose cytarabine.

Background: Physical function (PF) is an important outcome that can inform cancer treatment tolerability from a clinical and regulatory perspective. PF can be assessed through different modalities: patient-reported (PRO), clinician-reported (ClinRo), performance tests (PerfO), and digital sensors (wearables). No standard approach for PF measurement has been defined, and each modality bears unique implementation challenges. The Integrating 4 Measures to Assess Physical Function study (In4M, NCT05214144) characterized the performance of these PF modalities in patients receiving cytotoxic chemotherapy, with a goal of guiding an assessment strategy in future cancer trials. Here we present feasibility results of the In4M study in patients with lymphoma. Methods: In4M is a prospective observational study with longitudinal PF assessment of PROs, ClinRo, PerfO, and wearable sensor data for over 9 months in patients initiating chemotherapy for lymphoma or breast cancer at Mayo Clinic and Yale University. Patient-reported PF was assessed using several validated ePRO instruments, ClinRo utilized clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status, PerfO was measured via 6-minute walk test (6MWT), and digital sensor data was obtained from a wearable (Fitbit) provided to all participants. We evaluated the feasibility of implementing these PF modalities through compliance outcomes and a study-specific exit survey. Descriptive statistics included medians and interquartile ranges (IQR) for continuous variables and frequencies for categorical variables. We used a mixed model to estimate mean number of Fitbit compliant days per week. Results: Among 66 patients with lymphoma in the study (median age was 57 years; 52% were male), 90% self-reported as White, 4.9% as Black, 1.6% as Asian, 1.6% as American Indian or Alaska Native, and 1.6% as multiple races. Ethnicity was reported as non-Hispanic/Latino by 93% of patients. Education status was reported as more than high school by 92% of patients, and 49% reported full-time employment at time of enrollment. The overall ePROs completion rate was 80.7% for the entire study period. Baseline ePRO completion rate was 93.9%. Completion rate while undergoing chemotherapy was 91.3% and 75.4% in the post-treatment follow-up. The median time to complete ePROs was 4.1 minutes (IQR 2.8-5.9), ranging from 3.1 minutes for surveys with 37 questions to 5.6 minutes for surveys with 55 questions (survey length varied by timepoint). The baseline 6MWT was completed by 91% of patients. The most common reasons for not completing the baseline 6MWT were: patient refusal (50%, 3/6), patient not physically present (33%, 2/6), and unable to complete due to fatigue (17%, 1/6). The 3-month 6MWT was completed by 66% (40/61) of patients, with the most common reasons for missingness being: patient not physically present (38%, 8/21) and unable to complete due to fatigue (14%, 3/21). When considering the days when Fitbit was used, the median wear time was 21.3 hours (IQR 18.9-22.5) per day. The proportion of compliant days (>10 hours of wear time during waking hours) was 53% (IQR 20-84). The median of participants' average compliant days per week was 5.4 (IQR 4.3-6.1) days/week after enrollment, with a slight downward trend over time (-0.017 compliant days per week [95% CI: -0.021, -0.012, p <0.001] over each consecutive week in the study). The exit survey was completed by 39 (59%) patients. Most participants (85%) indicated they did not find the ePRO surveys burdensome to complete. Using the Fitbit (charging and syncing) was found to be manageable by most patients (87% and 84%, respectively). 60.8% of patients did not find the wearable bothersome to use, while the main themes reported by the remaining patients were related to the operation of the wearable itself (functions, small text size, forgetting login information) or discomfort (band material, wearing at night). Conclusion: Multi-modal assessment of PF with PRO, ClinRo, PerfO and wearable sensor data in patients with lymphoma undergoing treatment is feasible. Designing lymphoma therapeutic trials that incorporate at least one PF assessment modality, or assessment with a parsimonious combination of modalities, is achievable and may yield valuable insights into treatment tolerability for clinical and regulatory purposes.

Introduction: Traditional home-call, or the practice of holding a pager at home overnight to manage questions regarding patient care and direct patient calls, is a common component of hematology fellowship. Depending on the institution and training program, the frequency and expectations of home-call may vary. Home-call in fellowship is often performed overnight between two days of work without a “post-call” day to recover. As a field, medicine has entered the digital era, accompanied by changes in patient interactions and expectations involving after-hours calls. Little is known about modern non-digital interactions with patients such as after-hours calls in hematology practices and their effects on trainees. This project aims to evaluate the home-call pager burden and subjective experience in fellows. Methods: We analyzed Hematology Pager (HP) data from 7/1/19 - 4/14/23. The HPs for Mayo Clinic Rochester are covered by hematology fellows, including the weekend and after hours (6PM - 7AM) pagers. Those of interest were the Consults Pager (CP; covers new inpatient consults if discussion initiated outside of electronic order) and the Outpatient Pager (OP; covers direct patient calls as well as critical result communications for weekends and after-hours). The frequency of home-call varies based on each rotation but can require home-call up to 3-4 times per week with the expectation to occasionally present to the hospital overnight in the setting of a hematologic emergency. An optional survey was distributed to the fellowship in May 2024 with the intent to support trainee wellness and assess perceptions and attitudes toward the home-call experience. We allowed for free-text responses and used a 5-point Likert scale for structured responses. Results: The CP received a total of 5,304 pages during the analyzed period for a mean of 3.8 pages per day. Of those, 975 pages (18%) occurred after-hours and 1,250 (24%) during weekends. The OP received a total of 3,964 pages during the analyzed period, definitionally during weekends and/or after-hours, for a mean of 2.9 pages per day. The OP had the highest relative activity on weekends, which ranged from 1-18 calls per day. The survey captured 19/33 (58%) hematology/oncology fellows, which were comprised of 58% males and 42% females representing all levels of training with 42% PGY4s, 26% PGY5s, and 32% PGY6s. Over 85% felt that holding the HP was not an educational experience and that they did not learn about hematology while managing it. Moreover, 85% of respondents felt that they did not help patients get time-sensitive care when holding the HP. Only 5% felt that the majority of care provided through the HP required a Medical Degree and 32% agreed that the majority of calls were due to an acute clinical status change warranting immediate medical attention. If immediate medical attention was possibly required, 95% of fellows reported a recommendation of evaluation in the nearest emergency room. Over 85% of fellows felt that the HP affected other individuals (e.g., significant other) in their households. No respondents (0%) agreed that they could maintain their exercise schedule while holding the HP and only 16% reported no effect on their social life. Nearly all fellows reported not feeling well rested after a home call shift, regardless of whether the level of pager activity was low (≤2 calls), average (3-5 calls), or high (≥6 calls). Up to 95% of fellows reported feeling anxiety when holding the pagers. The free responses outlined concerns about sleep deprivation from call multiple times per week, the impact of home-call on learning, and the desire for a process that triaged patient calls at night that did not require physician resource utilization. Conclusions: Home-call is a long-standing tradition that gives hospital teams and patients access to specialty care after standard business hours. However, home-call can impact wellness, contribute to fatigue, and affect learning. To our knowledge, this is the first analysis evaluating call pager volumes and hematology fellows' perceptions and attitudes toward the home-call experience. Hematology is a dynamic field that requires empathy, critical thinking, and physician wellness to provide the best possible care to patients. In the digital era, the current structure of this long-standing tradition may warrant reevaluation and optimization to prioritize a system beneficial for both patient care and physician wellness.

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 Mantle cell lymphoma (MCL) is more common in males, with a male to female ratio of approximately 3:1. However, it is unclear whether disease characteristics and survival outcomes differ by sex. Additionally, the impact of race and ethnicity in MCL is understudied due to underrepresentation of minorities in clinical studies and trials. In this study, we utilized the National Cancer Database (NCDB) to examine patient and disease characteristics and survival outcomes of MCL by sex, race and ethnicity. Methods Patients diagnosed with MCL in 2004-2020 were identified from NCDB. Patient and disease characteristics were compared between groups using Chi-squared tests. Overall survival (OS) analysis was performed using the Kaplan-Meier method and the Cox proportional hazards model. Results A total of 35,135 patients was included. The median follow-up was 83.0 months (95% CI 81.9-84.1). 24,980 (71.1%) patients were male and 10,155 (28.9%) were female. Females had more elderly (age ≥65: 65.9% vs 59.0%; p<0.001), lower Charlson-Deyo Score (CDS ≥2: 7.0% vs 8.6%; p<0.001) and fewer stage III-IV diagnoses (80.5% vs 82.6%; p<0.001). Females were less likely to receive upfront treatment (80.7% vs 85.3%; p<0.001), treatment at academic centers (36.8% vs 40.9%; p<0.001) or transplant (11.0% vs 13.7%; p<0.001). Compared to males, females were more likely to live in metropolitan areas (83.7% vs 81.6%; p<0.001), had similar incomes, had more Medicare (60.4% vs 53.1%) and fewer private insurance (33.2% vs 38.6%; p<0.001). Female patients had better OS, with a median OS of 76.0 (95% CI 72.4-79.6) vs 67.8 months (95% CI 65.9-69.6; p<0.001). In the multivariable Cox model adjusting for age, race, ethnicity, CDS, stage, upfront treatment (vs surveillance or no treatment), facility (academic vs nonacademic), transplant, residence (metropolitan vs urban or rural) and insurance, female sex remained associated with superior OS (HR 0.84, 95% CI 0.793-0.890; p<0.001). For race, 32,399 (92.2%) patients were White, 1,465 (4.2%) were Black, 942 (2.7%) were others and 329 (0.9%) were unknown. Compared to White patients, Black patients had fewer elderly (52.9% vs 61.7%; p<0.001), higher CDS (≥2: 11.4% vs 7.9%; p<0.001), similar stage III-IV (80.7% vs 82.1%; p=0.276) and upfront treatment (84.7% vs 84.0%; p=0.074), were more likely to be treated at academic centers (50.6% vs 38.9%; p<0.001), were less likely to receive transplant (11.1% vs 13.0%; p=0.042), were more likely to live in metropolitan areas (91.0% vs 81.5%; p<0.001), had lower income, had more uninsured (4.4% vs 2.0%) and Medicaid (9.8% vs 3.7%) and fewer Medicare (47.4% vs 56.0%; p<0.001). Black and White patients had similar OS, with a median of 67.9 (95% CI 57.5-78.2) vs 69.6 months (95% CI 67.8 vs 71.3; p=0.697). In the multivariable Cox model, Black vs White race was not associated with OS (HR 1.086, 95% CI 0.952-1.240; p=0.219). For ethnicity, 31,717 (90.3%) patients were non-Hispanic, 1,894 (5.4%) were Hispanic and 1,534 (4.3%) were unknown. Hispanics had fewer elderly (51.3% vs 61.5%; p<0.001), lower CDS (≥2: 6.4% vs 8.2%; p=0.018), similar stage III-IV (81.2% vs 82.1%; p=0.467), were more likely to receive upfront treatment (86.0% vs 83.9%; p<0.001), more likely to be treated at academic centers (49.9% vs 39.5%; p<0.001), equally likely to receive transplant (13.0% vs 13.1%; p=0.943), more likely to live in metropolitan areas (95.4% vs 81.6%; p<0.001), had lower income, had more uninsured (9.6% vs 1.8%) and Medicaid (15.2% vs 9.6%) and fewer Medicare (40.3% vs 55.9%; p<0.001). Hispanics had better OS, with a median OS of 84.4 (95% CI 71.7-97.1) vs 70.5 months (95% CI 68.7-72.2; p<0.001). However, in the multivariable Cox model, Hispanic ethnicity was not associated with OS (HR 0.952, 95% CI 0.839-1.080; p=0.448). Conclusion This study is the first of its scale to demonstrate that female MCL patients have superior survival outcomes compared to males. It also demonstrated that neither Black race nor Hispanic ethnicity appears to be associated with worse survival outcomes. Despite its size, the NCDB is limited in the treatment information and disease characteristics it provides, including MIPI score, Ki-67, blastoid/pleomorphic morphology, and TP53 status. Thus, additional real-world dataset studies are needed to gain a deeper understanding of potential differences in sex, race and ethnicity with regards to disease characteristics and survival outcomes.

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.

Introduction MYD88 L265P mutations (MUT) are found in 90% of patients with Waldenstrom macroglobulinemia (WM) and lead to the activation of pro-survival signaling. Limited literature has demonstrated that patients with MYD88 wild-type (WT) WM have poorer responses to conventional therapies and a higher likelihood of histological transformation. Increasingly the role of non-coding genomics in lymphomagenesis has demonstrated importance and currently, the epigenetic landscape of MYD88 WT WM remains underexplored. This study utilized a multi-omics approach to assess DNA methylation in MYD88 WT WM compared to MYD88 MUT patients and controls. Methods Bone marrow samples were prospectively collected from 20 subjects [3 MYD88 WT/CXCR4 WT WM, 12 MYD88 MUT WM and 5 normal controls] and positive selection for CD19+ and/or CD138+ B cells was performed. The analysis focused on the comparison between MYD88 WT WM to normal controls and MYD88-WT to MUT WM. Genome-wide DNA methylation analysis was performed, and CpG methylation ratios were segmented into 200-bp regions. Differentially methylated regions (DMRs) were determined using a Q-value <0.05 and absolute methylation difference ≥10%. Next, RNA-seq data was interrogated and differentially expressed genes (log2fold change>0.5 or <-0.5, false discovery rate<0.05) with corresponding promoter hypo- or hypermethylation were assessed. Ingenuity Pathway Analysis was used to determine potentially epigenetically regulated pathways using a corrected p<0.05. Results Comparing MYD88 WT WM samples to controls, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (29129 vs 6300), 3'untranslated region (UTR) (2068 vs 1551), 5'UTR (10169 vs 735), intron (30344 vs 24511), exon (2224 vs 6855), CpG island (30372 vs 1240) and CpG shore (14477 vs 5872) (all p<0.001). Next, mRNA analysis demonstrated that 214 genes were differentially up-/downregulated with concordant promoter hypo-/hypermethylation. On the assessment of promoter-methylation-based pathways, multiple pathways involved in cell signaling, proliferation, gene regulation, cytokine and immune signaling and metabolism were found to be deregulated. Most pathways were found to be negatively enriched in MYD88 WT patients compared to controls including several members of interleukin (IL) signaling (IL-2, IL-3, IL,7) and regulators of cell proliferation and signaling including mTOR, PI3K/AKT, and p53. Positive enrichment of the PTEN, FGFR3 and ERK/MAPK pathways were observed. Underlying multiple pathways was promoter hypermethylation with corresponding mRNA downregulation of AKT3 and PIK3CA. Furthermore, promoter hypomethylation with transcript upregulation of PTEN was observed. Next, in comparison of MYD88 WT to MUT samples, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (24829 vs 2544), 3'UTR (3534 vs 378), 5'UTR (6111 vs 605), intron (52292 vs 5360), exon (21066 vs 2187), CpG island (18334 vs 1551) and CpG shore (16351 vs 1957) (all p<0.001). Assessing mRNA expression, 354 genes were up-/downregulated with concordant promoter hypo-/hypermethylation. Pathway analysis revealed positive enrichment of the mitotic G1 phase to G1/S transition pathway with upregulation of the CDK4, LYN, and PSMA6 transcripts in MYD88 WT compared to MUT samples. Further, negative enrichment of cell signaling regulators including the RHO GTPase family, IL pathways (IL-4, IL-8, IL-13, IL-17) and integrin signaling were found in MYD88 WT compared to MUT samples. Underlying multiple pathways were downregulation with promoter hypermethylation of BCL2, an important regulator of apoptosis. Conclusion Genome-wide methylation analysis of MYD88 WT WM revealed a unique DNA methylation profile, with potential epigenetic alteration of key oncogenic transcripts and pathways. The negative enrichment of cell signaling and cytokine/inflammatory pathways in MYD88 WT samples compared to controls and MYD88 MUT WM suggests an epigenetic mechanism for immune evasion and potentially underlies the reduced response to conventional WM-directed therapies. Overall, this study reveals that MYD88 WT WM is epigenetically distinct from MYD88 MUT WM and regulators such as methylation may underlie the unique clinical and phenotypic properties observed.