Mantle Cell Lymphoma Cohort Research Articles

Estimating the health care costs associated with receipt of lisocabtagene maraleucel: Insights from adults with mantle cell lymphoma (TRANSCEND NHL 001).

7028 Background: Anti-CD19 CAR T cell therapy is a major advancement for treating R/R B-cell malignancies such as mantle cell lymphoma (MCL). While effective disease management with CAR T cell therapy is expected to reduce patients’ health care resource utilization (HCRU) over the long-term, few studies have examined the short-term impacts of this treatment on HCRU and associated health care costs. Here, we used data from the TRANSCEND NHL 001 (NCT02631044) clinical trial to estimate the HCRU-related costs incurred by patients with R/R MCL over the first 12 months after receipt of lisocabtagene maraleucel (liso-cel). Methods: A retrospective analysis of clinical trial data was conducted to calculate the frequency of HCRU (medications [excluding liso-cel], diagnostics, procedures, ICU and non-ICU hospitalizations) observed over the 12 months immediately after administration of liso-cel. Costs for each HCRU event were derived from public databases and literature, adjusted to 2023 United States (US) dollars, and used to estimate patient-level health care costs. Results: Of the patients treated (N = 88), 76.1% were male, 87.5% were White, and mean ± standard deviation (SD) age was 67.5 ± 9 years. All patients were treated in the US and completed a median (range) of 3 (1–11) prior lines of therapy before receiving liso-cel. Most patients (93.2%) received the recommended dose of 100 × 106 CAR+ T cells. The total mean ± SD per-patient cost (excluding liso-cel) was estimated at $138,413 ± $58,555 over 12 months. Facility use accounted for 77.7% of all costs, primarily owing to non-ICU hospitalizations (98.9%), which had a mean ± SD length of stay of 19.5 ± 16.7 days per eligible patient. Half of all health care costs were incurred within the first month of infusion (53.2%), with each subsequent month contributing a fraction (1.5%–6.3%) of total costs. A total of 13 out of 88 patients received their initial infusion in an outpatient setting and incurred 23% fewer costs compared with those who received their infusion in an inpatient setting ($110,050 vs $143,418), primarily as a function of reduced first-month facility use. Total costs for patients receiving liso-cel in outpatient settings were further reduced to $72,771 upon exclusion of 3 outliers. Conclusions: Non-ICU hospitalizations were the largest driver of liso-cel–related costs in this R/R MCL cohort of clinical trial participants. Most of the cost burden was incurred within 1 month of treatment, with dramatic reductions in HCRU and health care costs observed thereafter. Results suggest that treatment in the outpatient setting, even in part (eg, at initial infusion only), may confer substantial cost savings to the health care system.

Front-line and second-line treatment for mantle cell lymphoma in clinical practice: A multicenter retrospective analysis.

There are few reports of clinical practice treatment patterns and efficacy in mantle cell lymphoma (MCL). We retrospectively studied a large, multicenter, cohort of patients with MCL diagnosed between 2000 and 2020 in eight institutions. 536 patients were registered (73% male, median of 70 years). Front-line treatment was based on high-dose cytarabine, bendamustine, and anthracyclines in 42%, 12%, and 15%, respectively. The median PFS for all patients was 45 months; 68, 34, and 30 months for those who received high-dose cytarabine-based, bendamustine-based and anthracycline-based therapy. 204 patients received second-line. Bendamustine-based treatment was the most common second-line regimen (36% of patients). The median second-line PFS (sPFS) for the entire cohort was 14 months; 19, 24, and 31 for bendamustine-, platinum-, and high-dose cytarabine-based regimens, with broad confidence intervals for these latter estimates. Patients treated with cytarabine-based therapies in the front-line and those with front-line PFS longer than 24 months had a substantially superior sPFS. Front-line treatment in this cohort of MCL was as expected and with a median PFS of over 3.5 years. Second-line treatment strategies were heterogeneous and the median second-line PFS was little over 1 year.

Integrative analysis of clinicopathological features defines novel prognostic models for mantle cell lymphoma in the immunochemotherapy era: a report from The North American Mantle Cell Lymphoma Consortium

BackgroundPatients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes.MethodsThe North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases.ResultsIn front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort.ConclusionsThe outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.

Up-Front ASCT Overcomes the Survival Benefit Provided By HDAC-Based Induction Regimens in Mantle Cell Lymphoma: Data from a Real-Life and Long-Term Cohort

Introduction: Mantle cell lymphoma (MCL) is a rare malignancy with heterogeneous behavior. Despite the therapeutic advances recently achieved, MCL remains incurable. Currently, the standard of care for young and fit patients involves induction immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). However, the role of more intensive induction regimens, such as those based on high-doses of cytarabine (HDAC) remains controversial in the management of ASCT-eligible patients. Based on this premise, the current study aims to describe clinical and laboratory characteristics, assess outcomes, determine survival predictors, and compare responses between different primary therapeutic strategies, with focus on assessing the impact of HDAC-based regimens on outcomes in ASCT-eligible patients. Methods: This retrospective, observational, and single-center study involved 165 MCL patients, diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2010 to December 2022. Endpoints included overall survival (OS), event-free survival (EFS), and progression of disease within 24 months (POD-24) from up-front treatment. Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The results were presented in hazard ratio (HR) and 95% confidence interval (95% CI), and a p-value ≤ 0.05 was considered statistically significant. Results: The median age at diagnosis was 65 years (38-89) and 73.9% (122/165) were male. More than 90% of cases (150/165) had a classic nodal variant (cnMCL), 76.4% (120/157) had bone marrow infiltration, and 56.4% (93/165) presented splenomegaly. Bulky ≥ 7 cm, B-symptoms, ECOG ≥ 2, and advanced-stage III/IV were observed in 32.7% (54/165), 64.8% (107/165), 32.1% (53/165), and 95.8% (158/165), respectively [ Table 1]. Sixty-four percent of patients (106/165) were categorized as high-risk according to MIPI score. Table 2 summarizes the main therapeutic modalities applied to the whole cohort. With a median follow-up of 71.1 months (95% CI: 61.8-80.4) the estimated 2-year OS and EFS were 64.1% (95% CI: 56.2-71.9%) and 31.8% (95% CI: 23.0-40.6%), respectively. The ORR for the whole cohort was 64.7% (95% CI: 57.1-71.7%), with CR achieved in 41.5% (95% CI: 34.1-49.1%). POD-24 was observed in 46.7% (95% CI: 39.1-54.3%), and the overall mortality rate (OMR) during all follow-up was 58.2% (95% CI: 50.6-65.5%), with disease progression being the main cause of death. Patients treated with R-HDAC-based regimens (43.4%-66/152) had higher ORR (85.9% vs 65.7%, p=0.007) compared to those receiving R-CHOP (46.0%-70/152), as well as lower POD-24 rates (61.9% vs 80.4%, p=0.043) and lower mortality (43.9% vs 68.6%, p=0.004). However, intensified induction regimens using R-HDAC were not associated with a real OS benefit in MCL patients undergoing up-front consolidation with ASCT (N=41) (2-year OS: 88.7% for R-HDAC plus ASCT vs 78.8% for R-CHOP plus ASCT, p=0.289), as summarized in Figure 1. Furthermore, up-front ASCT was independently associated with increased OS (p&amp;lt;0.001), EFS (p=0.005), and lower POD-24 rates (p&amp;lt;0.001) in MCL. Additionally, CNS involvement (HR: 3.12, 95% CI: 1.45-6.73, p=0.004), tumor lysis syndrome (HR: 2.79, 95% CI: 1.13-6.86, p=0.026), albumin &amp;lt; 3.5 g/dL (HR: 2.69, 95% CI: 1.61-4.50, p&amp;lt;0.001), and failure to achieve remission after induction therapy (HR: 3.71, 95% CI: 2.07-6.67, p&amp;lt; 0.001) were predictors of poor OS. Conclusion: In the largest Latin American cohort of MCL reported to date, we confirmed the OS benefit promoted by up-front consolidation with ASCT in young anf fit patients, regardless of the intensity of the immunochemotherapy regimen used in the pre-ASCT induction. Although HDAC-based regimens were not associated with an unequivocal increase in OS, it was associated with higher ORR and lower rates of early-relapses.

A Window Study of Acalabrutinib & Rituximab, Followed By Chemotherapy & Autograft (ASCT) in Fit Patients with Treatment Naïve Mantle Cell Lymphoma (MCL): First Report of the Investigator-Initiated Australasian Leukaemia & Lymphoma Group NHL33 ‘Wamm’ Trial

Introduction Bruton's tyrosine kinase inhibitors (BTKi) have improved 1 st line therapy efficacy in elderly (Wang NEJM 2022) and young, fit, MCL-the latter with intermittent dosing during RCHOP in an alternating RCHOP/cytarabine-based regimen (Dreyling Blood 2022). However direct combination of BTKi &amp; intensive chemo is toxic in DLBCL studies. (Kuruvilla Haematol Oncol 2017). The highly selective BTKi, acalabrutinib (A), has proven efficacy and tolerability in relapsed MCL (Wang Lancet 2018). RDHAOx chemotherapy (rituximab, dexamethasone, cytarabine, oxaliplatin) prior to ASCT provides a complete response (CR) rate of 77% and favourable toxicity compared to many induction regimens (Le Gouill Blood 2017). Furthermore, Obinutuzumab-DHAP yields undetectable minimum residual disease (MRD) in 85% of young MCL patients. (Le Gouill Haematol Oncol 2019). Here we report the primary endpoint from the Australasian Leukaemia &amp; Lymphoma Group phase 2 ‘WAMM’ trial exploring a ‘sandwich’ model of an acalabrutinib-rituximab (AR) ‘window’ before RDHAOx +/- ASCT, followed by fixed-duration AR-maintenance to improve therapy response and minimise additional toxicity. Methods NHL33'WAMM' (ACTRN12619000990123) is a multicentre single-arm phase 2 trial. Key eligibility included: age 18-70 years, untreated histologically-proven stage II-IV MCL, ECOG&amp;lt;2; no contraindications to ASCT or BTKi. Pts received 2 cycles of AR (AR window); ‘A’ dose; 100mg BD PO, ‘R’ dose; 375mg/m 2 IV (day 1) every 4 weeks, followed by RDHAOx x4 cycles. Those with an objective response (CR or partial response-PR) underwent BEAM ASCT (carmustine, etoposide, cytarabine, melphalan) then AR maintenance (A; 1yr continuous &amp; R; 3-monthly x 8 cycles). Those who did not undergo BEAM ASCT were able to remain on study and proceed to maintenance AR in the event of ongoing response. Co-primary endpoints (EP) were safety; defined by lack of prohibitive toxicity causing treatment cessation AND PET-determined complete response (CR) rate after AR+RDHAOx. Secondary EP include overall response rates (ORR), toxicity, overall survival (OS) &amp; progression-free survival (PFS), MRD negativity rates and quality of life. Only Grade 3+ toxicity related to acalabrutinib was collected during the ASCT period. Baseline whole exome sequencing was performed to identify mutations, MRD analysis was done by LymphoTrack® Dx and MRD Assay platform (Invivoscribe, Inc) using Illumina® MiSeq. This study was the first Australian blood cancer trial to use telehealth and a ‘hub-and-spoke’ transplant model. Results 44 pts were enrolled from Sept 2020 to Apr 2022 (43 evaluable for the primary endpoint). Baseline characteristics were typical of a young MCL cohort: median age 59 years (Interquartile range 54-64), 77% were male, ECOG was 0-1 in 98%, 84% had stage IV, lactate dehydrogenase was elevated in 35%, Ki-67 &amp;gt;30% in 66% and blastoid/pleomorphic histology 9%. TP53 by NGS will be reported at presentation. CR rate post AR+RDHAOx induction was 88%; (95%CI 72-95) with ORR 95% and no prohibitive toxicity. AR window ORR was 93% (CR 57%). MRD negativity was achieved in 18% (7/38) post AR window, and 94% (34/36) post RDHAOx. 43 patients remained evaluable for response after R-DHAOX and pre-maintenance with 35 (80%) who underwent ASCT and 38 (86%) who commenced AR maintenance; 7 remain on maintenance. Response in specific subgroups will be reported at the meeting. At data lock, 35 pts (81%) experienced ≥1 G3+ adverse events during induction or maintenance phases, most common were neutropenia (58% of pts), febrile neutropenia (27%), thrombocytopenia (25%), diarrhea (14%). No G5 treatment-related events have occurred to date. There have been 22 SAEs, most common were COVID (3), febrile neutropenia (2) and fever (2). 5 deaths have been reported: 4 in pts with progressive disease and 1 COVID pneumonitis during AR maintenance. After a median follow up of 22 months (range 17-28m), the 2-year OS was 89%. Analysis of survival, quality of life and biomarkers will be reported with more mature follow up. Conclusion AR delivered in a sandwich approach is active and safe. An AR window yields a high ORR and compared to historical studies, improves post-chemo induction CR rates and MRD negativity. A telehealth model allowed rapid recruitment in a rare cancer.

Trial-in-Progress: A Phase 1/2 Multi-Center Study of Onct-808, a ROR1-Specific CAR T, in Adult Patients with Relapsed/Refractory Aggressive B Cell Lymphoma

BACKGROUND: The therapeutic landscape for B-cell lymphomas (BCL) leverages several modalities, including chemotherapy, targeted agents, adoptive cell therapy, and immunotherapy. While these approaches have shown clinical benefit, challenges remain, such as variable response rates, treatment resistance, and toxicities. ROR1-specific CAR T-cell therapy represents a promising potential advancement in the treatment of aggressive BCL in patients (pts) who have failed previous CD19 CAR T therapy. ROR1-targeted CAR T therapy offers several advantages that could address these challenges. By directing CAR T cells to specifically recognize and eliminate ROR1-expressing tumor cells, it offers a highly targeted approach with the potential for enhanced efficacy. Moreover, ROR1 is often highly expressed on aggressive BCL, making it a suitable therapeutic target. This focused approach may help overcome the limitations associated with current treatments and improve response rates. After birth ROR1 is predominantly expressed on malignant cells; therefore, this selective expression pattern may reduce the risk of toxicities, including off-tumor target elimination and non-specific activation of immune cells. The development of ROR1-specific CAR T holds promise in enhancing the treatment outcomes for patients with aggressive BCL. With targeted action and potential to reduce toxicity, ROR1-specific CAR T cell therapy offers an innovative and novel strategy for improving patient outcomes in BCL. The ROR1 binding moiety for ONCT-808 is derived from zilovertamab. Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022). METHODS: This is a Phase 1/2, single-arm, open-label, multi-center trial to evaluate the safety and efficacy of ONCT-808 in pts with aggressive BCL, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL) with no approved therapy available. The study comprises two distinct phases: Phase 1 for dose escalation followed by Phase 2 for dose expansion. In Phase 1, a standard 3+3 dose escalation design will be used with 3 provisional dose levels and expected sample size of up to 18 patients. Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion. The dose of ONCT-808 will be sequentially escalated to determine the recommended Phase 2 dose (RP2D) for LBCL and MCL cohorts. Bridging therapy is permitted if clinically indicated. Phase 2 will enroll LBCL and MCL patients into separate dose expansion cohorts at the RP2D determined in Phase 1. ONCT-808 will be administered as a single IV infusion of autologous CAR T cells. The primary outcomes include assessing the incidence, severity, and relationship of Dose Limiting Toxicities (DLT), Treatment Emergent Adverse Events (TEAE), and RP2D selection of ONCT-808. Secondary outcomes include evaluating the Overall Response Rate (ORR), Complete Response (CR) rate, Duration of Response (DOR), pharmacokinetics of ONCT-808, expansion, persistence of ROR1 CAR-positive T cells, overall safety and tolerability. Key inclusion criteria include histologically confirmed aggressive B-cell NHL, measurable lesions per Lugano criteria (Cheson, 2014), and relapsed/refractory (R/R) disease without available therapy (must be previously treated with systemic therapy, progressed after or ineligible for autologous HSCT, and received prior approved anti-CD19 CAR-T at least 6 months prior to enrollment unless refused/ineligible). Key exclusion criteria include previous ROR1-targeted therapy, ongoing immunosuppression, and CNS involvement. The trial is currently active and patients have been treated in the phase 1 dose escalation. Clinical Trial Identifier: NCT05588440

Pirtobrutinib in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Patients with Prior cBTKi: Safety and Efficacy Including High-Risk Subgroup Analyses from the Phase 1/2 BRUIN Study

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

Phase I Safety and Preliminary Efficacy of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), even when treated with novel targeted agents, generally have only limited benefit (Rule et al., Leukemia 2018). The triple combination of the first-generation Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, the BCL-2 inhibitor, venetoclax, and anti-CD20 monoclonal antibody, obinutuzumab has demonstrated preliminary safety and efficacy in R/R and treatment naïve (TN) MCL (Le Gouill et al., Blood 2021). We therefore hypothesized that given the favorable toxicity profile of the second-generation BTKi, acalabrutinib, when given in combination with venetoclax and obinutuzumab (AVO), would be effective and well tolerated in both R/R and TN MCL. Here, we report the results of the phase I dose-finding cohort of AVO in patients with R/R MCL. Methods: This is an investigator-initiated, multicenter, multi-cohort phase I/II trial (NCT04855695). The primary endpoints of the phase I portion are the recommended phase II dose (RP2D) and the safety and tolerability of AVO in R/R MCL. The study was designed to evaluate up to 2 dose levels of acalabrutinib, starting with the FDA-approved dose (100 mg po bid, dose level 0 [DL0]) followed by a lower dose (100 mg po daily, DL-1) if dose limiting toxicities (DLTs) occurred in &amp;gt; 1/6 patients in DL0 during the first 4 cycles. Patients were treated in 28-day cycles with acalabrutinib starting with cycle 1, followed by obinutuzumab in cycle 2 (100 mg IV on day 1, 900 mg IV on day 2, 1000 mg IV on days 8 and 15, and on day 1 of cycles 3-7), and venetoclax (weekly dose ramp-up starting in cycle 3 to a target dose of 400 mg daily). Acalabrutinib and venetoclax were continued indefinitely and obinutuzumab maintenance was given every 2 cycles starting with cycle 9 for 12 doses. Patients with progressive disease (PD) or who were unable to receive &amp;gt; 80% of the doses of acalabrutinib and venetoclax during the first 4 cycles were replaced. Key eligibility criteria included R/R MCL after at least one anti-CD20 mAb-based therapy, ECOG PS ≤ 2, and adequate hematologic and organ function. Key exclusion criteria were progression or relapse following prior BTKi or BCL-2 inhibitor and CNS involvement. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy, respectively. Results: As of July 26, 2023, 9 patients in DL0 were evaluable for response as 3 patients were replaced prior to reaching the DLT window. The median age was 67 (range 63-79). 78% were male. Median number of prior treatments was 1 (range 1-2). 33% relapsed after autologous stem cell transplant and 22% had primary refractory disease. All patients had advanced stage MCL, with stage IV disease in 89%. MIPI score was 22% high, 56% intermediate, and 22% low risk. Ki67 index ≥ 30% in 44% and ≥ 50% in 33%. 33% patients had complex karyotype, 22% TP53 mutation, 33% p53 IHC expression &amp;gt; 50%, and 33% blastoid variant. No DLTs were observed and DL0 was determined to be the RP2D. All 9 patients were evaluable for toxicity (Figure 1A). Hematologic toxicity included neutropenia (67%; 33% Gr 3), thrombocytopenia (56%; 22% Gr 3/4), and anemia (22%; all Gr 3). The most common toxicities were headache (77%; all Gr 1/2), bruising (67%; all Gr 1), diarrhea (44%; all Gr 1/2), and upper respiratory infection (22%; 11% Gr 3). There were no serious adverse events. There was no occurrence of febrile neutropenia, atrial fibrillation, bleeding, or laboratory or clinical tumor lysis syndrome. Median follow-up was 6 months (range 1-21). ORR was 78% (7/9) and CR rate was 67% (6/9) after 3 cycles of AVO. Both patients with TP53 mutation and 2/3 patients with blastoid variant achieved CR. Of the 3 patients replaced prior to the DLT window, 2 patients had PD and 1 patient was unable to receive &amp;gt; 80% of the acalabrutinib and venetoclax doses due to grade 4 thrombocytopenia, although achieved CR. 5 patients (56%) remain on treatment and in CR. 1 patient achieved PR after cycle 3 but progressed after cycle 7. Median overall and progression-free survival were not reached. Conclusions: AVO is safe and feasible in patients with R/R MCL with no DLTs observed. RP2D was determined at the full FDA approved dosage of all three drugs. Preliminary efficacy is encouraging in this high-risk R/R MCL population. The phase II TN transplant ineligible or TP53 mutated MCL cohort is now enrolling with minimal residual disease (MRD)-guided time-limited therapy (Figure 1B). The phase I R/R expansion cohort will also open to enrollment.

Treatment (tx) patterns and real-world outcomes among patients (pt) with mantle cell lymphoma (MCL) in the Flatiron database.

152 Background: Despite the increasing number of tx options for MCL, data on novel agents and associated OS are scarce. We assessed the tx patterns and estimated OS by line of therapy (LOT) among pts with MCL in the United States (US). Methods: This retrospective observational study using the Flatiron Health database included pts aged ≥ 18 y at initial MCL diagnosis who received first-line (1L) systemic tx for MCL during the index period (01/01/2011–03/31/2022) on the date of 1L tx initiation. Pts who had &lt; 1 mo of data after the index date, received clinical study drug during the study period, or had other primary cancer diagnoses or active primary malignancies were excluded. Time to next tx (TTNT) was calculated from LOT start date to next LOT start date. OS was estimated using Kaplan-Meier methodology. Results: Of 4846 pts diagnosed with MCL, 2072 met all eligibility criteria and were included in the final cohort. The median age was 69 y; pts were mostly male (71%), from the Southern US (43%), had commercial health plan insurance (47%), and had stage IV disease at diagnosis (64%). The median length of follow-up from index was 27.4 mo. The most common 1L tx was bendamustine + rituximab (29%) and ibrutinib was the most common second-line (2L) and third-line or later (3L+) tx (25.5% and 10.5%, respectively); only 17% received a stem cell transplant. Median TTNT and OS were similar across subgroups (Table). Median time to start of LOT, TTNT, and OS for subgroups of pts who (1) received ≥ 2 LOTs, including an alkylating agent, Bruton tyrosine kinase inhibitor, and CD20-targeting agent (TRANSCEND NHL 001, MCL cohort eligibility criteria; n = 508); (2) received second-line or later (2L+) tx (n = 859); and (3) received 3L+ tx (n = 363) are shown in the Table. Conclusions: Bendamustine + rituximab and ibrutinib were the most common tx in 1L and 2L/3L+, respectively, among pts receiving approved tx. For all pts/subgroups,median TTNT was longest for the 1L LOT; median OS was longest from 1L start date. Diminishing TTNT and OS in subsequent LOTs after 1L tx provide benchmarks for future tx.[Table: see text]

The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma-a pooled trials analysis.

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting.We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50-0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61-0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53-0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54-0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment.

IMMUNE‐DEPLETED TUMOR MICROENVIRONMENT IS ASSOCIATED WITH POOR OUTCOMES AND BTK INHIBITOR RESISTANCE IN MANTLE CELL LYMPHOMA

Introduction: An understanding of the tumor microenvironment (TME) and its cellular and analyte composition plays a critical role in promoting mantle cell lymphoma (MCL) cell growth, proliferation. To further understand the relevance of the tumor-immune landscape in tissue microenvironments, we performed multiomic profiling to characterize the TME in tissues from MCL patients and examined the relationship between TME subtypes and their impact on clinical outcome and the response to BTKi. Methods: This cohort study was conducted under an IRB approved protocol for MCL patients at our Center. Tissue biopsies (28 lymph nodes and 13 other tissues) were collected from 41 patients with MCL. We conducted whole exome sequencing (WES; n = 41) and RNA-seq (n = 41) from MCL tissue biopsies from patients treated with BTKi (ibrutinib, acalabrutinib or zanubrutinib) in combination with the analysis of a published MCL cohort (n = 122). Joint WES and RNA-seq mutation calling and TME molecular signatures were categorized based on response to BTKi. All WES and bulk RNA sequencing was performed with Illumina HiSeq4000 using a 76 bp paired end configuration. Results: Unsupervised clustering identified four MCL TME subtypes reflecting distinct tumor-immune cell gene signatures. Four distinct groups—normal lymph node (n = 27), immune cell-enriched (n = 46), mesenchymal (n = 44) and immune cell-depleted “D” (n = 51). “D” subtype was predominant in patients with primary BTKi resistance. A high tumor proliferation gene signature was observed exclusively in the “D” group. We further observed that Ki-67% from tissue biopsies had a linear correlation with proliferation rate signature genes and significantly overexpressed in the D group (p = 0.002). Somatic mutations such as TP53, NSD2, NOTCH1, KMT2D, SMARCA4, which were previously reported in ibrutinib-resistant MCL and/or in refractory high-risk MCL patients, were predominant in the Dsubtype. Finally, the evaluable patients (n = 39) were divided according to response to BTKi- sensitive, primary resistant and acquired resistant and MFP clusters. Patients with primary and acquired resistance had significant proportion of patients with D subtype (p = 0.004), compared to N and IE subtypes. Primary and BTKi resistant patients had a trend of inferior survival compared to sensitive patients (p = 0.07). Furthermore, we demonstrated that the D TME group had worse overall survival compared to other TME categories (p = 0.001). Keyword: microenvironment The research was funded by: Boston Gene Corp

Central nervous system involvement by mantle cell lymphoma

Involvement of the central nervous system (CNS) is a rare complication of mantle cell lymphoma (MCL) with limited treatment options. We report the outcomes of 36 patients with CNS involvement compared to 72 matched control MCL patients without CNS involvement. Four patients (11%) with CNS MCL were diagnosed with CNS involvement at time of MCL diagnosis. Median OS from MCL diagnosis was 50.3 months (95% CI: 22.8–79.6) for the CNS MCL group compared to 97.1 months (95% CI: 82.8–NR; p= <0.001) for the control group. Median OS from CNS involvement was 4.7 months (95% CI: 2.3–6.7). CNS involvement by MCL has dismal outcomes as evident by a short median OS and PFS after CNS involvement. Advanced stage, blastoid variant, elevated LDH, and elevated Ki67 at MCL diagnosis were features more commonly seen in the CNS MCL cohort.

A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 As Monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with Non-Hodgkin Lymphoma (NHL) or Waldenström Macroglobulinemia (WM): Preliminary Data

Background/introduction: The Bcl-2 inhibitor venetoclax has exhibited activity in pts with NHL in monotherapy (Clin Cancer Res 2021;27:4690-5) and in combination regimens (Blood 2019;133;1964-7). BGB-11417 is a highly selective Bcl-2 inhibitor with potency >10 times that of venetoclax in biochemical assays. BGB-11417 has favorable pharmacokinetics and a broad therapeutic index that may result in an improved safety profile. BGB-11417 monotherapy is tolerable, with no maximum tolerated dose (MTD) reached after dose escalation through all planned doses to 640 mg once daily (QD) in pts with NHL (EHA 2022. Abstract P687). The combination of Bcl-2 and Bruton tyrosine kinase (BTK) inhibitors is tolerable with synergistic activity in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL) (J Clin Oncol 2019;37:2722-9; N Engl J Med 2019; 380:2095-103; ASH 2020 Abstract S158; N Engl J Med 2018;378:1211-23). ZANU is a next-generation BTK inhibitor with favorable activity and safety profiles in pts with CLL/SLL (EHA 2021 Abstract LB1900) and WM (Blood. 2020;136(18):2038-2050) with FDA approval for treatment in MCL, marginal zone lymphoma (MZL), and WM. BGB-11417-101 is an ongoing first-in-human phase 1/1b dose-escalation/expansion study (NCT04277637). Data from separate cohorts of MCL, WM and combined NHL (Follicular lymphoma [FL], diffuse large B cell lymphoma [DLBCL], MZL, transformed FL) are presented here. Methods: In the monotherapy cohorts, pts received BGB-11417 (40, 80, 160, 320, or 640 mg QD) with a ramp-up to the intended dose. In combination cohorts, pts received ZANU (320 mg QD or 160 mg twice daily) 8-12 weeks before BGB-11417. Dose-limiting toxicity for each dose cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at the intended dose. Responses were assessed per Lugano criteria. Adverse events (AEs) were reported per Common Terminology Criteria for AEs v5.0, and tumor lysis syndrome (TLS) was assessed per Howard (2011) criteria. Results: As of May 15 2022, 45 pts with NHL, WM, or MCL received BGB-11417 (34 monotherapy; 11 combination). Monotherapy pts (n=28 NHL [n=18 DLBCL, n=6 FL, n=4 MZL]; n=6 WM) received BGB-11417 doses ≤640 mg. Combination pts (n=11 MCL) received ZANU, and 9 (82%) had also received BGB-11417 doses ≤160 mg (data include 2 pts who are still in the pretreatment phase with ZANU). Dose escalation to 640 mg was completed for NHL monotherapy; all planned doses were tested, with no MTD reached. Dose escalation is ongoing for monotherapy in WM and combination therapy in MCL cohorts. Median follow-up was 6.5 months (range 0.4-25.3) for monotherapy and 4.8 months (range 0.4-8.9) for combination therapy. Treatment-emergent AEs (TEAEs) across all dose levels are listed in the Table. For monotherapy, the most common TEAEs (≥20%) were nausea (38%), fatigue (24%), constipation, diarrhea and dizziness (21% each); the most common grade ≥3 TEAE was neutropenia (12%). For combination therapy, the most common TEAEs were contusion and neutropenia; grade ≥3 AEs were infrequent. Twenty-five monotherapy pts (22 disease progression [PD]; 1 AE; 2 other reasons) and 2 combination therapy pts (PD) discontinued treatment. No TEAEs leading to death and no TLS were reported to date. Amongst combined NHL cohorts, 23 pts reached the first response assessment time point, but most were treated below the recommended phase 2 dose (RP2D). Of these pts, 3 responded (n=2 DLBCL, n=1 MZL) including 1 complete response (DLBCL), and notable reductions in the sum of the product of perpendicular diameters (SPD) were seen (Figure). In the MCL combination cohort, 6 of 11 (55%) pts responded. In the monotherapy WM cohort, 1 of 4 evaluable pts exhibited minor response at the first dose level tested (80 mg); hemoglobin count increases of more than 20 g/L were seen in 3 of 6 treated pts and all remain on treatment. Conclusion: These initial data show an encouraging safety profile and preliminary evidence of efficacy for BGB-11417 in NHL, MCL, and WM cohorts. No MTD was reached even at the highest dose level of 640 mg QD. All low-grade TEAEs and grade ≥3 neutropenia were manageable. The response data includes NHL patients mostly treated at doses below the RP2D; longer follow-up of BGB-11417 monotherapy and combination therapy at the RP2D is needed. Monotherapy MCL data are forthcoming. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pharmacokinetics, Safety, and Efficacy of Acalabrutinib in Chinese Patients with Relapsed/Refractory Mantle Cell Lymphoma and Other B-Cell Malignancies: An Open-Label, Multicenter Phase 1/2 Trial

Background: Acalabrutinib (Acala), a highly selective covalent inhibitor of Bruton tyrosine kinase with minimal off-target activity, is approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The pivotal studies that supported Acala's approval were conducted predominantly in Europe and North America, with limited representation from Asian populations. This phase 1/2 study (NCT03932331) assessed the pharmacokinetics (PK), safety, and efficacy of Acala in Chinese patients (pts) with R/R MCL and other advanced B-cell malignancies. Methods: In phase 1, adult pts with R/R B-cell malignancies received a single dose of Acala 100 mg orally (day 1/cycle 0) followed by a 2-day washout period and subsequent treatment with Acala 100 mg orally twice daily in 28-day cycles, until progressive disease (PD) or treatment discontinuation (TD) for any other reason. Blood samples were collected to assess PK characteristics of Acala and its major metabolite, ACP-5862. In phase 2, adult pts with R/R MCL and ECOG status ≤2 received Acala 100 mg orally twice daily in 28-day cycles until PD or TD. Primary efficacy endpoint was overall response rate (ORR) per Lugano classification for non-Hodgkin lymphoma (Cheson 2014) assessed by blinded independent central review (BICR). Secondary endpoints were investigator (INV)-assessed ORR; BICR- and INV-assessed time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Patients were enrolled at 14 sites in China from April 29, 2020, to March 2, 2021. In phase 1, 14 pts were screened and 12 received treatment (CLL, n=4; follicular lymphoma, n=4; MCL, n=1; diffuse large B-cell lymphoma, n=1; SLL, n=2). At data cutoff (May 6, 2022), 7 pts were receiving Acala and 5 had TD (PD, n=4; AE, n=1). Acala exhibited time-independent PK and moderate to high variability (parent drug and metabolite), rapid drug absorption, approximately 2-fold higher exposure of metabolite than parent drug, rapid elimination of Acala and ACP-5862, and no significant accumulation of either parent drug or metabolite after multiple dosing (Table 1). In phase 2 (MCL cohort), 45 pts were screened; 34 were enrolled (phase 1, n=1; phase 2, n=33), all received ≥1 dose of Acala, and were included in the safety and efficacy analyses. The MCL cohort was predominantly male (88.2%), median age was 63 y, 73.5% had ECOG status 0, 64.7% had extranodal disease, 35.3% had bone marrow involvement, 5.9% had high simplified MCL International Prognostic Index score, and median number of prior anticancer therapy regimens was 3 (range 1-5). Median duration of treatment was 14.0 mo (range 1.2-23.6). ORR by BICR was 82.4% (95% CI 65.5-93.2); CR rate was 35.3%, median TTR was 1.8 mo (range 1.6-3.7), and estimated 12-mo DOR rate was 62.7% (95% CI 41.5-78.0); median DOR was not reached. INV assessments were generally concordant with BICR assessments for ORR (73.5% [95% CI 55.6-87.1]), CR rate (38.2%), median TTR (1.9 mo; range 1.6-3.7), and estimated 12-mo DOR rate (65.5% [95% CI 42.1-81.3]). Estimated 12-mo PFS rate was 51.5% (95% CI 33.3-67.0) by BICR and 58.3% (95% CI 39.9-72.9) by INV. Estimated 12-mo OS was 84.5% (95% CI 66.6-93.3).Twenty-nine pts (85.3%) reported AEs of any grade; 15 pts (44.1%) had grade ≥3 AEs, most commonly anemia (8.8%, n=3) and decreased neutrophil count (8.8%, n=3) (Table 2). AEs led to treatment discontinuation in 3 pts (8.8%) due to aplastic anemia (n=1), thrombocytopenia (n=1), and gastrointestinal infection (n=1). Six pts (17.6%) had serious AEs. Fatal AEs were reported in 2 pts (aplastic anemia [n=1], multiple organ dysfunction syndrome [n=1]). There were no cases of atrial fibrillation, major hemorrhage, hypertension, second primary malignancies, or tumor lysis syndrome. Conclusions: This is the first study to evaluate Acala PK, safety, and efficacy in a Chinese population with R/R B-cell malignancies. Acala was rapidly absorbed and showed no signs of accumulation after multiple doses. Treatment with Acala provided high response rates in the R/R MCL cohort, with efficacy results similar to those of the pivotal, global ACE-LY-004 study in a predominantly Caucasian population with R/R MCL (Wang M et al. Lancet 2018;391:659-67). Acala had a tolerable safety profile in Chinese pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety, Efficiency and Long-Term Follow-up of AUTO1, a Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia and Other B-Cell Malignancies

INTRODUCTION: AUTO1 is a fast off-rate CD19 binding domain CAR, designed to reduce immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL (Ghorashian S et al., Nat Med 2019; Roddie C et al., JCO 2021) and now in adult B-NHL and CLL/SLL (NCT02935257). Here we present data from adult B-NHL and CLL cohorts treated with AUTO1, and report on long-term follow-up of adult B-ALL patients post-AUTO1. METHODS:Manufacturing: AUTO1 products were generated using a closed process from non-mobilised patient leukapheresis. Study design: Subjects ≥ 16y received fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) conditioning. DLBCL patients additionally received pembrolizumab (200mg) on day -1. In B-ALL, patients received split dose AUTO1 (day 0: ≥20% Bone Marrow (BM) blasts, AUTO1 dose=10 x106; <20% BM blasts, AUTO1 dose=100 x106. At day+9: if no grade 3-5 CRS/ICANS, dose 2 is administered to a total AUTO1 dose of 410 x106. Split dosing is employed in the CLL cohort (day 0 AUTO1 dose= 30 x106; day 9 AUTO1 dose= 200 x106). B-NHL patients receive a single AUTO1 dose of 200 x106. Study endpoints include manufacture feasibility, grade 3-5 toxicity and remission rates at 1 and 3 months. RESULTS:NHL/CLL cohort: as of 27th July 2022, 28 patients were enrolled: 9 with Follicular Lymphoma (FL), 4 with Mantle Cell Lymphoma (MCL), 8 with DLBCL and 7 with CLL. Apheresis/ manufacture was successful in 26 (1x pending; 1x not harvested due to intracerebral haemorrhage). Median age was 61 years (range 39-79), and patients received a median of 3 prior treatment lines (range 2-8). To date, 23 patients have been infused: 7 FL, 3 MCL, 8 DLBCL and 5 CLL. 2 patients died pre-infusion (1x MCL, COVID-19; 1x CLL, intracerebral haemorrhage). Grade 1 CRS was reported in 7/23 and Grade 2 CRS in 7/23 patients. No ICANS was observed. AUTO1 engraftment was demonstrated in 18/18 patients evaluated by qPCR with ongoing persistence in 17/18 patients at last follow-up. The ORR at month 1 in the FL, MCL and DLBCL cohorts was 7/7 (100%), 3/3 (100%) and 7/8 (88%) respectively, and ongoing responses at last follow-up (FU) were observed in 5/7 FL (FU range, 5-21 months), 2/3 MCL (range, 12-18 months), and 7/8 DLBCL (range, 1-12 months). 2 patients died in remission from COVID-19. In the CLL cohort, 4/5 patients achieved flow negative remission in the bone marrow with ongoing response in all 4 at last FU. B-ALL cohort: of the 20 B-ALL patients treated previously, 8/20 (40%) are in ongoing CR at a median FU of 35 months (IQR 24-36) post-AUTO1, with ongoing B-cell aplasia in 7/8 (89%). CONCLUSIONS: AUTO1 has a tolerable safety profile in patients with r/r B-cell cancers despite high disease burden. In the B-ALL cohort, long-term follow-up indicates that 40% of patients continue in remission post-AUTO1. In both indolent and aggressive NHL and in CLL, AUTO1 shows excellent ORR and CAR engraftment/persistence. Additional patients, updated data and longer follow up will be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genotyping and Minimal Residual Disease (MRD) Assessment in cfDNA By the Euroclonality-NGS DNA Capture (EC-NDC) Panel in Mantle Cell Lymphoma (MCL)

Background Modern concepts for the treatment of mantle cell lymphomas (MCL) increasingly integrate clinical and biological variables for risk-adapted treatment strategies. Novel next-generation sequencing (NGS) technologies are highly suited for tumor genotyping as well as disease monitoring by minimal residual disease (MRD) assessment, identifying patients (pts) with a high risk of relapse. Here, we investigated whether the EuroClonality (EC)-NGS DNA Capture (EC-NDC) assay is a) applicable for genotyping of MCL in peripheral blood (PB) and plasma cell-free (cf)DNA and b) suitable for MRD assessment in plasma as compared to the amplicon-based EuroClonality Immunoglobulin-based (IG-)NGS assay. Patients and methods A total of 109 PB samples (55 baseline and 54 interim staging) from a cohort of MCL treated within the TRIANGLE trial by the European MCL network (NCT02858258) were selected according to a PB infiltration ≥10% at diagnosis. From prospectively collected PB samples in national reference labs, DNA from the cellular blood compartment (PBC) and plasma cfDNA was extracted. For targeted capture, the EC-NDC assay (Univ8® Genomics, UK) was used to simultaneously detect immunoglobulin and T cell receptor (IG/TR) rearrangements, structural variants (SV) and single nucleotide variants (SNVs) in 72 genes (Stewart, Blood Adv, 2021). For diagnostic PBC and cfDNA samples, IG clonotypes were called with ≥6 unique reads and ≥5% of annotated IG reads, SV were called with ≥4 unique reads and SNV were called with ≥6 unique reads at ≥4% variant allele frequency (VAF). For amplicon-based MRD analysis the EuroClonality IG-NGS (IG-NGS) assay was used with IG clonotypes called with ≥5% of annotated IG reads and at ≥1 log higher abundance to the polyclonal background. MRD was analyzed by IG-NGS in PBC using 8 µg PBC DNA to reach a sensitivity of 10-6. For MRD analysis in cfDNA, we aimed to use ≥5000 genome equivalents (GE) for both IG-NGS and EC-NDC. Data were analyzed by ARResT/Interrogate (Bystry, Bioinformatics, 2017) with an adapted pipeline for targeted capture in cfDNA. MRD status was defined as positive by detecting a lymphoma-specific IG clonotype and/or SV at ≥1 read, or alternatively by retrieval of ≥1 disease-specific mutation at ≥3 reads. Results Total cfDNA amounts at baseline were high (mean 92.6 ng/mL plasma) and even increasing at interim staging (mean 123.8 ng/mL) while decreasing by 10-fold in 38 samples at end of treatment (EoT)(mean 11.45 ng/mL). At baseline, a tumor-specific IGH-VJ clonotype was detected by IG-NGS in all 55 PBC and cfDNA samples. Genotyping by EC-NDC showed fully concordant results in 55 PBC and cfDNA samples with respect to IG clonotypes, SV and SNV, except for 3 PBC samples with low usable reads covering IGH-VJ regions. The presence of a t(11;14)(q13;q32) translocation was confirmed in 54/55 pts in PBC and cfDNA, while one patient with unknown t(11;14) translocation status by FISH was negative by EC-NDC. EC-NDC identified 106 putative somatic SNVs (VAF 2.7-75%, median 30%) in PBC and cfDNA, and among those were genes described as drivers in MCL (ATM (25/55), TP53 (11/55), KMT2D (9/55), SAMHD1 (5/55), CCND1 (5/55) and 18 other genes (Fig. 1). Six pts with detectable t(11;14) and IG rearrangement did not show additional SNVs. On average, 6 MRD markers/pt were identified (range: 3-10). At interim staging, MRD was analyzed in 54 PBC and 44 cfDNA samples. Twenty-five (47%) pts were MRD+ in PBC by IG-NGS. Twenty (46%) pts were MRD+ in cfDNA by EC-NDC (8 cases with ≥2 markers, 4 with 2 markers, and 8 with 1 marker). From 10/44 (23%) cfDNA samples MRD+ by IG-NGS, 9 were also MRD+ by ED-NDC. From 44 pts with parallel analysis of PBC and cfDNA, 14 (32%) were MRD+ and 18 (41%) were MRD-, while 12 (27%) showed discordant results. Conclusion To the best of our knowledge, this is the first analysis comparing targeted capture and amplicon assays for application in PBC and cfDNA in MCL. The capture-based EC-NDC assay allows a comprehensive liquid biopsy-based genotyping of MCL. In addition, both IG-NGS and EC-NDC assays are suitable for MRD assessment in cfDNA with evidence of more sensitive MRD detection EC-NDC due to multiple MRD targets detected and traced by this assay. Clinical data are still needed to explore the potential prognostic impact of MRD assessment in plasma vs PBC. Updated MRD analysis at EoT and correlation with clinical data will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Integrative Analysis of Genetic and Tumor Microenvironment Topology to Delineate Prognostic Subtypes in Mantle Cell Lymphoma

BACKGROUND Mantle Cell Lymphoma (MCL) is a B-cell lymphoma characterized by t(11;14) leading to CyclinD1 overexpression with highly variable clinical response. Although the tumor intrinsic mechanisms have been well studied and the role of the tumor microenvironment (TME) in survival and therapeutic responses are marginally examined, understanding how distinct tumors regulate their respective immune landscapes has been constrained, by a lack of appropriate experimental techniques that recapitulate the heterogeneity of the TME in MCL. Herein, we integrated high-throughput genomics and characterized TME using a highly multiplexed, spatially resolved, single-cell digital pathology approach termed imaging mass cytometry (IMC) to delineate the tumor-immune landscape. Thus, comprehensive whole exome sequencing and TME imaging analysis demonstrated prognostic subtypes elucidating the interplay between tumor intrinsic and extrinsic factors in MCL. METHODS MCL cohort with complete clinicopathological information and treatment protocol (n=580) was utilized from the North America Mantle Cell Lymphoma Consortium. These cases have been reviewed by at least two hematopathologists to confirm the MCL diagnosis. Whole exome sequencing (WES) was performed on 179 formalin-fixed tissue embedded (FFPE) samples. 44 samples have matched microarray data. Genetic driver lesions were identified using VarScan 2.4, MutSigCV 1.3.01, and GISTIC 2.0. Formalin-fixed paraffin-embedded (FFPE) tissue tumor microarrays (TMA) consisting of 55 MCL cases with duplicate or triplicate cores were generated. To perform the TME analysis, we designed a 42 marker IMC panel which includes canonical markers for immune cell subsets and markers for two additional highly mutated/aberrated genes in MCL (ATM and TP53). TMA was stained with antibodies tagged with heavy metal isotopes, laser ablated to generate spatial digital maps of the tissue and unsupervised clustering was performed to identify immune cell types using the Phenograph algorithm. Survival analysis was performed using the Kaplan-Meier method (logrank test). RESULTS Initial genomic analysis (n=179) suggested at least two prognostic subtypes, dependent on ATM or TP53 mutation status, and the latter associated with inferior-clinical outcome. Transcriptional profiling in a subset identified enrichment of gene signatures associated with B-cell receptor (BCR), MYC Targets, apoptosis, and CCND1 upregulation in the TP53-mutant subgroup. TME analysis showed that the TP53 positive tumor cell populations exhibited a receded T cell population (CD4+ and CD8+). Interestingly, the TP53-positive tumor cells expressed high protein levels of p-STAT-3, p-NFKB, and HLA expression compared to ATM-positive tumor cells. Additionally, unsupervised analysis using NMF consensus clustering showed four patient subgroups wherein the worst survival subgroup (OS: 45 months vs 62 months, p < 0.05) was independent of TP53 mutations and highly enriched in ATM mutations, 17p11.1-13.3 deletions, and depleted in CD8 naïve T cell and Macrophages M1. Whereas the good survival group (OS: 75 months) was highly enriched in ATM and TP53 mutations but deficient in 17p deletions. CONCLUSION While most MCL studies looked at the MCL heterogeneity at the genomic level, this study shows the integration of genomic and TME factors to elucidate prognostic MCL subtypes from paraffin samples at a single cell resolution. The current analysis suggests that the TP53 mutated MCL subgroup has reduced T-cell enrichment in the TME and high protein expression of oncogenes. A patient subgroup highly enriched in ATM mutations, independent of the TP53 mutations and depleted immune inflitration showed the worst prognosis. Thus, this study suggests a new angle of ATM mutations in MCL pathogenesis which could improve risk stratification. Overall, this study may unravel distinct mechanisms of tumorigenesis with relevant clinical and biological implications.

The Age, Comorbidities and Albumin (ACA) Index Is Independently Associated with Overall Survival in Patients with Mantle Cell Lymphoma (MCL)

Background: Mantle cell lymphoma (MCL) is a biologically and clinically heterogenous disease with variable outcomes. Numerous prognostic factors have been identified, including blastoid histology, the MCL International Prognostic Index (MIPI) score, high proliferation index, TP53 deletions and/or mutations, complex karyotype, minimal residual disease positivity, and several others. Most prognostic scores do not take patient characteristics into account and require additional testing which may not be routinely available. In particular, older adults have heterogenous outcomes due to the presence of comorbidities, impaired functional and/or nutritional status which is not factored into the MIPI score. The age, comorbidities and albumin (ACA) index is a simple score that can be gleaned from the electronic health record either in real-time or retrospectively and has been validated in patients with diffuse large B cell lymphoma. We evaluated the impact of the ACA index on outcomes in patients with MCL. Methods: The Roswell Park MCL database includes all patients with MCL evaluated at Roswell Park Comprehensive Cancer Center from 2007 to 2019. A serum albumin (SA) level of <3.7 g/dL was defined as "low". The age, comorbidities and albumin (ACA) index included a low SA level, age ≥ 75 years, and a Charlson comorbidity index (CCI) score of ≥3 (representing moderate to severe comorbidity burden), with each variable when present contributing to a score of 1. A score of 0 was defined as "excellent", 1 as "good", 2 as "moderate" and 3 as "poor". The log-rank test was used to compare overall survival (OS), and the Cox-proportional hazard model was used for univariate (UVA) and multivariate (MVA) survival analyses. Results: A total of 245 patients with a median age of 64 years [interquartile range (IQR), 56-73 years] were included in the study, with a median follow-up of 90.2 months (95% CI, 75.1 - 107 months). Overall, 111 (45%) patients were age ≥65 years, 81 (33.1%) were age ≥70 years, and 44 (18.0%) were age ≥75 years; 73% of patients were male, and 11 patients had an ECOG PS ≥2. Older adults (age ≥75 years) had a greater burden of comorbidities (CCI≥3, p<0.001), and poor PS (ECOG ≥2, p=0.006) compared with younger patients. The median SA in the entire cohort was 4.30 g/dL (IQR 3.90, 4.50), with lower median levels in patients age ≥75 versus age <75 years (4.00 vs 4.35, p<0.001); however, there was no difference in frequency of patients with low SA levels (<3.7 g/dL) (19% vs 14%, p=0.4). A low SA level, CCI≥3, high or intermediate MIPIb risk, ki-67>30%, and increased age (≥75 years) were significantly associated with inferior OS. Patients who received an autologous or allogeneic stem cell transplant (SCT) in any line of therapy had improved OS (HR 0.5517, p=0.001). The ACA score could be calculated in 69.8% of patients- 58% of patients had an excellent ACA score (0), 30% of patients had a good score (1) and 9.9% of patients had a moderate score (2). Only 2 (1.2%) patients had a poor score (3). Patients with higher ACA scores had significantly inferior OS (HR 2.117, p<0.0001). In a MVA that adjusted for MIPIb risk and treatment with SCT in any line, this risk remained significant (HR 1.67, p=.007). Conclusion: A simple, patient-factor based scoring system incorporating hypoalbuminemia and the presence of comorbidities is strongly predictive of survival in patients with MCL, irrespective of disease stage, MIPIb risk score, and known molecular risk factors. Further steps include validation of the ACA index in an independent MCL cohort and incorporation of elements from the ACA index into known prognostic models to develop a new score that takes both disease biology and patient physiology into account. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Central Nervous System Involvement By Mantle Cell Lymphoma

Central Nervous System Involvement By Mantle Cell Lymphoma

Real-World Disease Burden, Costs and Resource Utilization of Hospital-Based Care Among Mantle Cell Lymphoma, Waldenström Macroglobulinemia, Marginal Zone Lymphoma and Chronic Lymphocytic Leukemia: Disparities and Risk Factors

Introduction: Mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL) and chronic lymphocytic leukemia (CLL) are subtypes of non-Hodgkin's lymphoma. Collectively, these subtypes constitute a large proportion of all B-cell malignancies; however, they are typically associated with survival spanning several years with multiple interspersed treatment periods due to frequent relapses. This can predispose patients to repeated hospitalization resulting in significant economic impact. The objectives of this study were to examine real-world treatment patterns, costs and healthcare resource utilization for patients with these lymphomas, as well as identify disparities and risk factors associated with costs incurred in US hospitals.Methods: A retrospective study was conducted using the Premier Healthcare Database, a geographically diverse all-payer, hospital administrative database containing more than one billion inpatient and hospital-based outpatient encounters. Patients aged ≥18 years with at least 1 inpatient or 2 hospital-based outpatient visits with a MCL, WM, CLL, or MZL diagnosis, and who received treatment for these conditions from 1/1/2014 to 10/31/2019 were included in the study. Descriptive analysis was conducted to examine patient sociodemographic and hospital characteristics, all-cause and lymphoma-related healthcare resource utilization and costs. Costs were obtained from patients' discharge files and hospital billing records. Multivariable analysis was performed using generalized linear models to examine risk factors associated with costs and LOS for each lymphoma type. Treatment evaluated including any use of supportive care (blood transfusion, granulocyte colony stimulating factors [GCSF]), and by regimen (steroids alone, chemotherapy alone, chemo-immunotherapy, rituximab alone, targeted therapy alone, targeted therapy in combination with chemotherapy, other). Statistical significance was determined as a p-value of <0.05.Results: The study population included 23,952 CLL, 3,387 MCL, 2,655 MZL, and 1,811 WM patients in the US hospital database. Patients with WM were statistically significantly older (77 ± 58.5 years) compared to patients with CLL (74.2 ± 30.2 years), MCL (70.7 ± 37.3 years) or MZL (69.3 ± 33.8 years). More male (71.7%) and white (87.8%) patients were identified in the MCL cohort compared to the general lymphoma cohorts (Males: 58.7%; whites: 86.3). The most common comorbidities included chronic pulmonary disease (27.1%), gastroesophageal reflux disease (17.6%), moderate-severe renal disease (16.6%), congestive heart failure (15.7%) and diabetes without chronic complications (15.2%). Overall, more than two-thirds of patients in each lymphoma group received treatment with steroids alone during hospitalizations. While the use of steroids alone was higher among whites compared to non-white patients (69.5% vs. 60.4%), the use of chemo-immunotherapy was lower in whites compared to non-whites (11.9% vs. 16.2%). The average LOS of inpatient hospitalization ranged from 6.3 days for CLL to 7.4 days for MCL, with the mean costs per hospitalization from $19,566 (CLL) to $24,439 (MCL). Non-white patients have significantly longer mean LOS days compared with white patients (CLL: 18.3 vs. 14.8; MCL: 21.7 vs. 18.3; MZL: 21.6 vs. 18.5; WM 19.0 vs. 14.5). Across the 4 lymphoma types, multivariable regression confirmed the descriptive results and demonstrated that higher hospitals costs were associated with patients who were non-white, Hispanic/Latino, treated in hospitals located in the Northeast or West, or had Medicaid; statistically significant increased cost of care was also noted for patients who received targeted therapy or supportive care, such as blood transfusion or GCSF (Table 1).Conclusions: Real-world data demonstrated the significantly high total hospital costs once patients with MCL, WM, MZL, and CLL patients were hospitalized, with significantly higher impact to minority populations. Given the increased availability of effective oral therapeutics, optimal and timely disease control in the outpatients setting can potentially prevent or decrease hospitalizations and reduce economic burden on healthcare. Future studies are needed to explore the reason for admission, clinical outcomes, and potential preventive interventions. [Display omitted] DisclosuresChanan-Khan: Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; Cellectar: Current equity holder in publicly-traded company; Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Cao: Premier, Inc.: Current Employment; BeiGene, Ltd.: Consultancy. Baumer: BeiGene, Ltd.: Consultancy; Premier, Inc.: Current Employment. Krishnaswami: BeiGene, Ltd.: Consultancy; Premier, Inc.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.