Mantle Cell Lymphoma International Prognostic Index Research Articles

Impact of rituximab maintenance on survival of patients with mantle cell lymphoma: A north Indian tertiary care center experience.

e19047 Background: Mantle cell lymphoma (MCL) is an aggressive variant of non-Hodgkin lymphoma. Indian data is scarce owing to its rarity in south-east Asia. Till now, studies have not shown overall survival benefit with rituximab maintenance (RM). Our study aims to assess if RM improves overall survival of MCL patients. Methods: We retrospectively analysed clinicopathological data of 90 transplant-ineligible MCL patients treated between January’2013-December’2023 at Institute Rotary Cancer Hospital - All India Institute of Medical Sciences, New Delhi, India. Rituximab-based induction chemotherapy was used in all patients as per institutional protocol. RM was used in twenty-eight (31.0%) patients due to financial constraints. Primary outcome was overall survival (OS). Secondary outcomes were event free survival (EFS) and factors affecting OS, EFS. OS was defined as time from treatment initiation to demise from any cause or last follow-up. EFS was defined as time from treatment initiation to disease progression or relapse or demise from any cause. Response was assessed by modified Cheson’s lymphoma response evaluation criteria. STATA 13.0 was used to assess survival by Kaplan-Meier analysis and log rank test. Factors affecting survival were assessed by multivariate analysis (Cox proportional hazards model) and expressed as adjusted hazard ratio (aHR). p value < 0.05 defined statistical significance. Results: Median age was sixty years; male-female ratio 3:1. Thirty-five (39.0%) had one or more co-morbidities, 79(88.0%) generalised lymphadenopathy, 72(80.0%) extra-nodal involvement, 49(54.0%) B symptoms, 84(93.0%) advanced stage (III/IV), 49(54.0%) high risk MCL international prognostic index (MIPI). Clinical and tumor characteristics, response rates after initial induction were similar in both maintenance and non-maintenance groups. Overall, 52(58.0%) patients were alive with median follow-up of 63.0 months (inter-quartile range 37.0-90.0 months). Median OS was 37.5 months in non-maintenance group and did not reach in maintenance group. Estimated 1.0-, 2.0, 3.0-year OS were 100.0%, 91.0%, 81.0% vs 75.0%, 63.0%, 55.0% respectively in maintenance vs non-maintenance group. RM was significantly associated with better OS [aHR (95% confidence interval): 0.31 (0.13-0.75), p=0.01]. Advanced stage, Eastern Co-operative Oncology Group performance status (ECOG PS) ≥2 at presentation were also significant factors for poor OS. Median EFS was significantly lower in non-maintenance group [14.0 vs 42.5 months; aHR (95% confidence interval): 0.34 (0.18-0.64), p=0.001]. Advanced stage, anemia, high risk MIPI at presentation were also significant factors for poor EFS. Conclusions: This was the first study from south-east Asia demonstrating impact of rituximab maintenance in MCL. Rituximab maintenance significantly improved OS and EFS of MCL patients.

B-cell receptor signaling activity identifies patients with mantle cell lymphoma at higher risk of progression

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy characterized by a high clinical variability. Therefore, there is a critical need to define parameters that identify high-risk patients for aggressive disease and therapy resistance. B-cell receptor (BCR) signaling is crucial for MCL initiation and progression and is a target for therapeutic intervention. We interrogated BCR signaling proteins (SYK, LCK, BTK, PLCγ2, p38, AKT, NF-κB p65, and STAT5) in 30 primary MCL samples using phospho-specific flow cytometry. Anti-IgM modulation induced heterogeneous BCR signaling responses among samples allowing the identification of two clusters with differential responses. The cluster with higher response was associated with shorter progression free survival (PFS) and overall survival (OS). Moreover, higher constitutive AKT activity was predictive of inferior response to the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib. Time-to-event analyses showed that MCL international prognostic index (MIPI) high-risk category and higher STAT5 response were predictors of shorter PFS and OS whilst MIPI high-risk category and high SYK response predicted shorter OS. In conclusion, we identified BCR signaling properties associated with poor clinical outcome and resistance to ibrutinib, thus highlighting the prognostic and predictive significance of BCR activity and advancing our understanding of signaling heterogeneity underlying clinical behavior of MCL.

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine KinaseInhibitor.

Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor Tcell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95%CI 2.81-38.46]) and complete response (OR 10.11 [95%CI 4.26-24.00]), and improved progression-free survival (HR0.44 [95%CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Beyond MIPI: Harnessing Machine Learning and Histological Subtype for Enhanced MCL Prognostication of Survival

Introduction Mantle cell lymphoma (MCL) presents challenges due to its aggressive nature and dismal treatment outcomes. The Mantle Cell Lymphoma International Prognostic Index (MIPI) score is valuable for risk stratification, but it may not fully capture the complexity of MCL biology. To address this, we explored innovative data-driven methods based on machine learning to augment the MIPI score. By integrating clinical and histological data with advanced algorithms, this study aimed to enhance risk assessment in MCL. Improved prognostication of survival could facilitate the design of risk-tailored therapeutic approaches, directing more aggressive treatments to high-risk patients, ultimately leading to personalized and precise management. Methods The following patient-level variables were retrieved: age, gender, Ann-Arbor stage (I-II vs III-IV), Bulky disease, extranodal disease, histopathological variant (classic vs pleomorphic/blastoid lymphoma), and Ki67+ cells. The MIPI score was used to categorize patients into low, intermediate, and high-risk groups. Employing random survival forests, we developed a novel risk score by integrating clinical and histological data. Missing variables were imputed using a random forests algorithm. Harrel's concordance indexes (c-indexes) were used to evaluate model's accuracy. Results We assembled a real-world database of 231 MCL patients from 6 Spanish tertiary hospitals (Jan 2000-Dec 2021), and another cohort for validation from another Spanish tertiary hospital (N=44). Median age at diagnosis was 64 years in both cohorts. Median follow-up was 6.28 y and 8.67 y in the training and test sets, and median overall survival (OS) was 11.48 y and 5.61 y. According to the MIPI score, 44% and 38% of patients were of high risk in the training and validation sets; 26% and 39% were of intermediate risk, and 30% & 23% were of low risk. The c-index of the MIPI groups for the prediction of OS was 0.716 and 0.684 in the training and validation sets, respectively. Then, a random survival forest algorithm was used to derive a new risk score in the training set. The first model contained all the available variables mentioned previously. This 8-variable model achieved a cross-validated c-index of 0.764 in the training set. A variable reduction technique was implemented to remove those variables that provided less independent prognostic value. A simplified model was developed, which contained the following variables by order of importance: histological subtype, MIPI-derived groups, age at diagnosis and Ann-Arbor stage. This model outperformed the conventional MIPI grouping strategy, achieving c-indexes of 0.764 and 0.775 in the training and validation sets, respectively ( Figure 1). Conclusion This study showcases the potential of a novel machine learning model in MCL prognostication beyond the traditional MIPI score, utilizing easily accessible clinical information. The inclusion of histological subtype, MIPI score, age at diagnosis, and Ann-Arbor stage as robust independent prognostic factors improves risk prediction accuracy. Future research may further refine the model and explore additional variables to continue optimizing prognostication and treatment strategies for MCL patients.

Safety and Efficacy Results from the Phase I Study of a Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton's Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Background: Relapsed/Refractory (R/R) mantle cell Lymphoma (MCL) has poor long-term survival compared with other B-cell malignancies. As a result, there is an urgent need for safe and effective treatments, particularly for patients who have progressed on covalent (c) Bruton tyrosine kinase inhibitors (BTKis) therapy. LP-168 is a highly selective, next-generation BTKi with a unique dual binding mode: covalent binding to wild-type BTK and reversible binding to mutated BTK. Pre-clinical data has demonstrated that LP-168 is highly potent in inhibiting C481 mutated BTK. Here, we report the safety and efficacy of LP-168 monotherapy in the R/R MCL patients as part of an ongoing phase 1 study (NCT04993690) in B-cell malignancies. Methods: This is a Phase 1 first-in-human multicenter open-label study of LP-168 enrolling Chinese patients with B cell Non-Hodgkin Lymphoma (NHL) who have progressed after at least 1 or 2 prior treatments. The study has two parts: Phase 1a: “3+3” dose escalation and Phase 1b: dose expansion in disease-specific cohorts (e.g. R/R MCL, R/R MZL, etc.). Results: Between 10 August 2021 and 31 May 2023, 33 R/R MCL patients who received at least one dose were enrolled and received LP-168 100mg (n=8), 150mg (n=24), and 200mg (n=1) QD, respectively. Baseline characteristics are summarized in Table 1. The median age was 58 (range, 32-79) years old; 27 (81.8%) were male. 15 (45.5%) subjects had intermediate to high risk disease per MCL International Prognostic Index (MIPI). Median lines of prior therapies were 2 (range, 1-11) with 24.2% refractory to the last prior treatment. All patients have received rituximab or a rituximab-containing regimen. 19 (57.6%) subjects have received at least a cBTKi or cBTKi-containing regimen. The most common treatment emergent adverse events (TEAEs) (occurring in ≥20% subjects) were platelet count decreased (30.3%), neutropenia and anemia (27.3% each) and COVID-19 (24.2%), most of which were Grade 1. Grade 3 or more TEAEs were seen in 9 (27.3%) subjects. Serious AE (SAE) (lung infection, oral cavity infection and lymphocytosis, all Grade 3) occurred in 3 (9.1%) subjects. Dose interruptions due to AE occurred in 7 patients (21.2%)，but no AE has led to dose adjustment, drug discontinuation or death. Of 31 efficacy evaluable subjects with median follow up of 5.5 months (range: 2.0-22.5), 24 (77.4%) achieved response including 12 (38.7%) complete metabolic response or complete response (CMR/CR). In addition, 5 (71.4%) out of 7 subjects with blastoid/ pleomorphic variant MCL achieved response (2 CMR/CR, 3 PMR/PR). More importantly, of 17 subjects who had prior cBTKi exposure, 12 (70.6%) responded to LP-168 and 6 (35.3%) achieved CMR. LP-168 also showed efficacy in 2 subjects who have received ≥ 2 cBTKi treatments. Another 2 subjects responded to LP-168 even after disease progression on a cBTKi and a BTK degrader. 5 subjects have achieved progression-free survival (PFS) more than 1 year and are still on treatment (Figure 1). Conclusion: In this Phase 1 trial, the novel BTK inhibitor LP-168 demonstrated a high CR rate and durable response in heavily pre-treated R/R MCL including blastoid/pleomorphic variant with favorable safety. Moreover, LP-168 could effectively overcome the acquired resistance to prior cBTKi. Based on the safety, PK and preliminary efficacy data from the Phase 1 study so far, we have determined the recommended phase 2 dose (RP2D) for MCL as 150 mg QD. A phase 2 trial of LP-168 in R/R MCL is currently ongoing (NCT05716087).

Induction and Maintenance Therapy in Elderly Patients with Mantle Cell Lymphoma: Double-Randomized MCL R2 Elderly Clinical Trial By the European Mantle Cell Lymphoma Network

Background: Mantle cell lymphoma (MCL) formally remains an incurable disease. Recent trials in younger patients have demonstrated the benefit of a cytarabin-containing induction (Hermine, JCO 2022) and a rituximab (Le Gouill, NEJM 2017) as well as a lenalidomide maintenance (Ladetto, Lancet Haematol 2021). The MCL-R2 elderly trial investigated whether an induction with intermediate dose of cytarabine improves long term outcome over R-CHOP alone in elderly patients (>60 yrs). In addition, responders to induction therapy were randomized between a 2 year maintenance with rituximab-lenalidomide (R2) compared to rituximab alone. Here, we present the results of the 2 randomizations. Methods: Patients >60 yrs not eligible for high dose therapy with stage II-IV MCL were included. Initially, patients were randomized between 8 cycles of 3-weekly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or 6 cycles of alternating 3-weekly R-CHOP and 4-weekly R-HAD (rituximab, cytarabine, Dexamethasone). Subsequently, patients in complete or partial remission (CR, CRunconfirmed or PR) underwent a second randomization between rituximab maintenance every 2 months or R2 (lenalidomide 15 mg d2-22 every 4 weeks plus rituximab). Second randomization was stratified for induction regimen, study group, age, MCL international prognostic index (MIPI) and response (CR/CRu vs PR). Both maintenance regimens were continued for 24 months. The primary endpoint was EFS for the maintenance and overall survival for Induction therapy. Results: Out of 624 patients from 7 countries, 620 were randomized for induction, 492 responded (78 % ORR, CR/CRu 41%) and 495 were randomized for maintenance. Median age was 71 yrs, 69% male, 85% stage IV, 47% intermediate and 46% high risk MIPI. Response rate at the end of induction was similar in the 2 groups (OR 88% and 86% in the R-CHOP and R-CHOP/RHAD arm, respectively; CR 33% in both arms). No major safety difference were observed between the 2 induction arms. So far, PFS and OS were not different between the two induction regimen (70.6% vs. 66.8%; p=0.28 and 83% vs. 83% ; p=0.92 respectively: Figure 1A). After a median follow-up of 4.2 years from maintenance randomization, patients in the R2 maintenance arm had a significantly improved PFS in comparison to R alone. The 4-year PFS was 60.9% in the R2 arm vs. 42.9 % in the R arm (p= 0.0002, figure 1B). Adverse events (AEs) were more pronounced in the R2 maintenance arm. Recurrent (> 5%) AEs grade >3 were: neutropenia (50.8% vs 19.2%), respiratory tract infection (6.3% vs. 0.8%), and skin cancer (5.9% vs 3.2%). In 46% of patients in the R2 arm, the dose of lenalidomide had to be reduced at least once. Overall survival (OS) was not different between the two maintenance arms, (R2: 87.6% and R: 85.1% at 2 years). The majority of relapsed/refractory patients were treated with a BTK inhibitor alone or in combination (67.5%; 63% after R-CHOP and 71% after RHOP/RHAD). Conclusions: While no efficacy or toxicity differences were observed between the two induction regimens (8x R-CHOP vs 6x R-CHOP/HAD), the combined R2 maintenance significantly prolonged PFS compared to rituximab alone. However, no difference in OS was observed, and toxicity was increased in the R2 arm. Figure 1: OS(A) stratified by the CHOP and R-CHOP/RHAD arms and PFS (B) stratified by maintenance with rituximab (R) or rituximab-lenalidomide (R2) stratified by the four groups according to induction and maintenance arms.

Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study

Background: Ibrutinib (Ibr) is a once-daily Bruton tyrosine kinase (BTK) inhibitor approved in multiple regions for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Venetoclax (Ven) is a BCL-2 inhibitor approved in the US for pts with chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. Ibr and Ven have distinct and complementary modes of action, and the combination has shown promising clinical activity in early phase studies in MCL (Tam, N Engl J Med 2018; Wang, J Hematol Oncol 2021). Here, we report the primary analysis results from the multinational, randomized, double-blind, phase 3 SYMPATICO (NCT03112174) study comparing Ibr+Ven vs Ibr + placebo (Pbo) in pts with relapsed/refractory (R/R) MCL. Methods: Pts aged ≥18 y with R/R MCL after 1-5 prior therapies were randomly assigned 1:1 to receive oral Ibr 560 mg once daily concurrently with oral Ven (standard 5-wk ramp-up to a target dose of 400 mg once daily) or Pbo for 2 y, followed by single-agent Ibr until progressive disease (PD) or unacceptable toxicity. Randomization was stratified based on ECOG PS, prior lines of therapy, and tumor lysis syndrome (TLS) risk based on tumor burden and CrCl. The primary endpoint was progression-free survival (PFS) by investigator (INV) assessment using Lugano criteria; pts without PD or death were censored at the last non-PD assessment (per global censoring rules). Additional sensitivity analyses included PFS assessment by independent review committee (IRC) and censoring per US FDA rules (Table). Key secondary endpoints were tested hierarchically in the following order: complete response (CR) rate by INV assessment, time to next treatment (TTNT), overall survival (OS, interim analysis), and overall response rate (ORR) by INV assessment. Results: A total of 267 pts were enrolled and randomly assigned to receive Ibr+Ven (n=134) or Ibr+Pbo (n=133). Median age was 68 y; 96% of pts had an ECOG PS of 0-1, 17% had ≥3 prior lines of therapy, and 22% were at increased risk for TLS. At baseline, pts in the Ibr+Ven vs Ibr+Pbo arms had median ages 69 vs 67 y, high-risk simplified MCL International Prognostic Index score 38% vs 31%, bulky disease ≥5 cm 46% vs 40%, bone marrow involvement 46% vs 41%, splenomegaly 31% vs 25%, and TP53 mutated 30% vs 28%; other baseline characteristics were generally similar between arms. With a median time on study of 51.2 mo, median PFS by INV assessment was significantly longer with Ibr+Ven vs Ibr+Pbo (31.9 vs 22.1 mo), with a hazard ratio (HR) of 0.65 (95% CI, 0.47-0.88; stratified log-rank P=0.0052) (Figure). PFS rates at 24 mo were 57% and 45% with Ibr+Ven and Ibr+Pbo, respectively. PFS benefit with Ibr+Ven vs Ibr+Pbo was generally consistent across prespecified subgroups, including those with blastoid variant or TP53-mutated MCL. Sensitivity analyses of PFS were consistent with the primary analysis (Table). Ibr+Ven significantly improved CR rates (54% vs 32%) and TTNT (median not reached [NR] vs 35.4 mo); at the current 51.2 mo median follow-up, median OS was 44.9 mo with Ibr+Ven vs 38.6 mo with Ibr+Pbo (HR 0.85 [95% CI, 0.62-1.19]) (Table). Median duration of treatment was 22.2 mo for the Ibr+Ven arm and 17.7 mo for the Ibr+Pbo arm; at the time of analysis, 30% of pts in the Ibr+Ven arm and 20% of pts in the Ibr+Pbo arm remained on single-agent Ibr. Grade ≥3 adverse events (AEs) occurred in 84% of pts with Ibr+Ven vs 76% with Ibr+Pbo; the most frequent (occurring in ≥5% of pts) were neutropenia (31% vs 11%), pneumonia (13% vs 11%), thrombocytopenia (13% vs 8%), anemia (10% vs 3%), diarrhea (8% vs 2%), leukopenia (7% vs 0%), MCL (7% vs 12%), atrial fibrillation (5% vs 5%), COVID-19 (5% vs 1%), and hypertension (4% vs 9%). Serious AEs occurred in 60% of pts in each arm. No clinical TLS occurred; laboratory TLS occurred in 5% and 2% of pts in the Ibr+Ven and Ibr+Pbo arms, respectively. COVID-19 deaths occurred in 10 pts in each arm and had no meaningful impact on PFS or OS HRs. Conclusion: The Ibr+Ven combination demonstrated a statistically significant improvement in PFS compared with Ibr+Pbo in pts with R/R MCL; CR rates and TTNT were also significantly improved with Ibr+Ven. OS was numerically but not significantly improved at this interim analysis. The safety profile of Ibr+Ven was consistent with known AEs for each agent, with no new safety signals observed. Overall, these results demonstrate a favorable benefit-risk profile for Ibr+Ven in pts with R/R MCL.

Matching-Adjusted Indirect Comparison (MAIC) of Brexucabtagene Autoleucel (Brexu-cel) and Pirtobrutinib in Patients with Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor (cBTKi)

Introduction: Patients with MCL often require multiple lines of therapy and exhibit a generally unfavorable prognosis, particularly following failure of cBTKi therapy. Therapies such as chimeric antigen receptor (CAR) T-cell therapies and non-covalent BTKi therapies have shown promise in improving outcomes. Brexu-cel (formerly known as KTE-X19) is the only CAR T-cell therapy approved in the US for R/R MCL based on results from a phase 2 multicenter, single-arm trial (ZUMA-2; NCT02601313) in patients with R/R MCL who had 1-5 prior therapies, including a BTKi. Pirtobrutinib, a highly selective, non-covalent BTKi, was recently approved in the US for treatment of R/R MCL after at least two lines of systemic therapy including a BTKi, based on ongoing results from a multicenter phase 1/2 study (BRUIN; NCT03740529). In the absence of a direct head-to-head trial comparing brexu-cel and pirtobrutinib, we performed an unanchored MAIC to estimate the relative treatment effects of these therapies in the post-BTKi setting for R/R MCL. Methods: Individual patient-level data were available for ZUMA-2 (N=68; 35.8 months median follow-up as of July 24, 2021 data cut-off) whereas study-level data were available for BRUIN (N=90 in the BTKi pre-treated cohort; 23.5 months median follow-up as of July 29, 2022 data cut-off). Longer-term overall survival (OS) data for ZUMA-2 from the July 23, 2022 data cut-off (46.1 months median follow-up) were available and used. Logistic propensity score models were used to weight the brexu-cel infused population from ZUMA-2 to match the aggregate baseline characteristics of the BTKi pre-treated cohort in BRUIN. These baseline characteristics represented clinically relevant prognostic factors which were pre-specified based on input from clinical experts and data availability. The base-case model incorporated the top five most pertinent factors, which were reported in at least 50% of patients in both trials: blastoid morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplantation. A sensitivity analysis additionally incorporated TP53 mutation (missing in >50% of patients in ZUMA-2 and BRUIN) and Ki-67 proliferation index (missing in >50% of patients in BRUIN). Several prognostic factors (response to prior BTKi therapy, response to last therapy, and duration on prior BTKi therapy) could not be considered due to not being reported for BRUIN. The effective sample size was calculated as a measure of the degree of precision after weighting, reflecting the extent of overlap in the distribution of covariates between the trial populations. Relative treatment effects were expressed as odds ratios or hazard ratios with 95% confidence intervals. Outcomes included objective response (ORR), complete response (CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: In the base-case MAIC, a significant difference in the odds of ORR and CR in favor of brexu-cel versus pirtobrutinib was observed (Table 1). Similarly, brexu-cel demonstrated a significant improvement in PFS (Table 2). OS and DOR point estimates were in favor of brexu-cel when compared to pirtobrutinib, although not statistically significant. These findings were consistent with unadjusted naïve analyses as well as the sensitivity analyses including adjustment for TP53 mutation and Ki-67 proliferation index. Conclusions: While acknowledging the inherent limitations of an unanchored indirect comparison, our findings suggest that brexu-cel offers clinically and statistically significant efficacy benefits in terms of ORR, CR, and PFS compared to pirtobrutinib in patients with R/R MCL after prior cBTKi therapy. Both treatments were not statistically different in terms of OS and DOR although the estimated hazard ratios indicated a favorable trend for brexu-cel; however, given the relatively shorter follow-up and the high degree of censoring in BRUIN, an updated analysis incorporating longer follow-up data with more events from BRUIN could provide more reliable results. Although efforts were made to ensure a robust approach to the selection of prognostic factors for inclusion in the model, the possibility of some residual confounding variables cannot be completely ruled out. Nevertheless, these results provide valuable insights that may help inform treatment decisions for this population.

Overall Survival in Advanced Stage Mantle Cell Lymphoma after Early Autologous Stem Cell Transplantation with Cisplatin, Etoposide, Cytarabine and Melphalan (PEAM) As a Conditioning Regimen

Introduction. Autologous hematopoietic stem cell transplantation (ASCT) currently is the standard of treatment for patients in first remission diagnosed with Mantle cell Lymphoma (MCL). Overall survival (OS) was reported at five-years of 57.2% in a single center retrospective study published in 2011. OS has been improved by using conventional and high intensity induction chemo immunotherapy continuing with maintenance therapy as the GELA study reports a 5 year OS of 75%. LyMa Trial has proved an improvement in the global survival and progression free survival. In this study we aimed to describe the OS patients diagnosed with MCL with PEAM as a conditioning regimen. Methods A retrospective study was conducted on patients diagnosed with MCL and ASCT as consolidation therapy at the Instituto Nacional de Cancerología in Mexico City between 2011 and 2022. Our institutional conditioning regimen PEAM: Cisplatin 100 mg/m2 (-4), etoposide 750 mg/m2 (-4,-3), cytarabine 800 mg/m2 (-4,-3,-2) and melphalan 140 mg/m2( 4).OS results were obtained using the Kaplan-Meier method. Results We analyzed 19 patients with MCL after ASCT as consolidation therapy, a median follow-up of 10 years, the median age at transplantation was 56 years (range 39- 68 y), with male predominance (68.4%). Eleven patients with at least one comorbidity, the most predominant being diabetes mellitus type II (45.5%). Most patients with ECOG score of 1 (58%), 12 patients (63%) with high risk according to Mantle Cell lymphoma International Prognostic Index (MIPI), all patients with clinical stage III-IV, 26% of them with bone marrow infiltration. Eighteen patients (95%) received one line of chemoimmunotherapy, most were treated with R-CHOP plus + R-DHAP( 58%), 3 receive Hiper-CVAD (16%), 4 R-CHOP (21%) and only one R-DHAP . Eighteen patients (79%) with complete response, three (16%) with partial response and one patient (5%) with stable disease before ASCT. Sixteen patients (84%) received PEAM plus rituximab as myeloablative conditioning regimen, Three (16%) PEAM without rituximab. Neutrophil recovery median was 10 days, eleven patients (58%) developed complications being febrile neutropenia the most common (82%). Fifteen patients (79%) received maintenance with rituximab. Fourteen (74%) had complete response at last follow up after ASCT, three (20%) with relapsed disease, two stable disease (10%) Conclusion Conventional chemoimmunotherapy is effective followed by ASCT as consolidation therapy in mantle cell lymphoma with advanced stage disease. We describe higher OS 5-years (81%) as compared with other series (57% and 75%) with similar chemo immunotherapy and conventional conditioning regimen. Three patients relapsed, all died. The OS at 5-years was 81%.

Traverse: A Phase 2, Open-Label, Randomized Study of Acalabrutinib in Combination with Venetoclax and Rituximab in Patients with Treatment-Naive Mantle Cell Lymphoma

Background and Significance: Despite advances in treatment for mantle cell lymphoma (MCL), no curative option exists. Currently, the majority of patients with treatment-naive (TN) MCL receive chemoimmunotherapy, which can result in prolonged remissions, but is associated with significant toxicity. Almost all patients inevitably relapse, and therefore, frontline chemotherapy-free options are being increasingly explored. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of adult patients with relapsed/refractory (R/R) MCL. In a phase 1b study in patients with TN MCL, acalabrutinib in combination with venetoclax and rituximab (AVR) demonstrated high rates of clinical and molecular response with an acceptable toxicity profile, supporting its continued development as a chemotherapy-free treatment option (Wang et al. Blood. 2021; Wang et al. Blood. 2022). Furthermore, the occurrence of complete responses (CRs) with clearance of minimal residual disease (MRD) in MCL clinical trials suggests that treatment may be stopped in these patients, as observed in patients with chronic lymphocytic leukemia who received combination therapy with venetoclax and rituximab. Study Design and Methods: TrAVeRse (NCT#05951959) is a phase 2, open-label, randomized, multicenter, international study of AVR in patients with TN MCL. Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0-2 (3 if due to lymphoma), and Ann Arbor stage II, III, or IV disease are eligible. Key exclusion criteria are active central nervous system involvement by lymphoma or leptomeningeal disease, severe/life-threatening illness or medical condition, clinically significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of enrollment, and any active uncontrolled infection. Approximately 125 patients will be screened to achieve a study population of 100 patients. During the induction phase, patients will receive oral acalabrutinib 100 mg twice daily (BID) in 28-day cycles for 13 cycles, starting at cycle 1; oral venetoclax once daily, starting at cycle 2 at a dose of 20 mg daily, with ramp-up to a maximum of 400 mg daily over 5 weeks for a total of 12 cycles; and intravenous rituximab 375 mg/m 2 on day 1 of every cycle for 12 cycles, starting at cycle 1. Patients who complete 13 cycles of AVR induction will be centrally tested for MRD status and continue to receive acalabrutinib 100 mg BID for 1 additional cycle (cycle 14) while awaiting disease response assessment and MRD results. Patients who achieve an MRD-negative CR (in peripheral blood at a threshold of 10 -5) at the end of induction will be randomly assigned in a 1:1 ratio to either continue to receive acalabrutinib 100 mg BID or to observation from cycle 15. Randomization will be stratified according to the simplified MCL International Prognostic Index [sMIPI] score (low [score, 0-3] and intermediate risk [4-5] vs high risk [6-11]), histologic features (blastoid or pleomorphic vs classical histology), and TP53 status (mutated vs unmutated). Those with an MRD-positive CR, partial response (PR), or stable disease (SD) at end of induction will continue to receive acalabrutinib 100 mg BID until disease progression, death, or unacceptable toxicity. Patients who progress during observation may be retreated with acalabrutinib 100 mg BID at relapse. The primary endpoint of this study is the MRD-negative CR rate at the end of AVR induction (ie, end of cycle 13). Secondary endpoints include MRD-negative CR rate at any point during the study, objective response rate and CR rate, duration of response, time to next treatment, progression-free survival, event-free survival, overall survival, safety, and tolerability. The study will also assess the feasibility of response-adapted treatment cessation for those who achieve MRD-negative CR after AVR induction and the efficacy of acalabrutinib retreatment in the subgroup of patients randomized to observation who subsequently relapse. Patients will be followed for 36 months post last patient randomized. Enrollment is planned to begin Q3 of 2023 including sites in North America, Australia, and Europe. Summary: This study will evaluate the efficacy of AVR, a chemotherapy-free triplet combination therapy, in patients with TN MCL.

Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma

AbstractMantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Evaluation of clinical parameters and biomarkers in older, untreated mantle cell lymphoma patients receiving bendamustine-rituximab.

Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.

Clinical outcome of Mantle Cell Lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression)

Currently, treatment allocation of patients with Mantle Cell Lymphoma (MCL) is mainly based on age and medical fitness. The combined MCL International Prognostic Index (MIPI-c) allows to predict prognosis using clinical factors (MIPI) and the Ki-67 index. However, high p53 expression as surrogate for TP53 alterations has demonstrated to be an independent predictor for poor outcome. We aimed to define a clear high-risk group based on the combination of MIPI, Ki-67 and p53 expression/TP53 alteration. A total of 684 patients from the prospective European MCL-Younger and MCL-Elderly trials were evaluable. The classification of high-risk disease (HRD) as high-risk MIPI-c or p53 expression >50% versus low-risk disease (LRD) as low, low-intermediate or high-intermediate MIPI-c and p53 expression ≤50% allowed to characterize two distinct groups with highly divergent outcome. Patients with HRD had significantly shorter median failure-free survival (FFS) (1.1 vs. 5.6 years, p < 0.0001) and overall survival (OS) (2.2 vs. 13.2 years, p < 0.0001) compared to those with LRD. These major differences were confirmed in two validation cohorts from the Italian MCL0208 and the Nordic-MCL4 trials. The results suggest that this subset of HRD patients is not sufficiently managed with the current standard treatment and is asking for novel treatment strategies.

Time to progression of disease and outcomes with second-line BTK inhibitors in relapsed/refractory mantle cell lymphoma

AbstractTime to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton’s tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.

PAX5 aberrant expression incorporated in MIPI-SP risk scoring system exhibits additive value in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma with highly heterogeneous clinical courses. Paired-box 5 (PAX5), the regulator of B cell differentiation and growth, is abnormally expressed in several types of cancers. Herein, we explored the prognostic value of PAX5 in MCL by comprehensively analyzing the clinical features and laboratory data of 82 MCL cases. PAX5 positivity was associated with shorter overall survival (OS; p = 0.011) and was identified as an independent prognostic factor in MCL patients. The elevated β2-MG (p = 0.027) and advanced Mantle Cell Lymphoma International Prognostic Index (MIPI) score (p = 0.014) were related to positive PAX5 expression. The MIPI-SP risk scoring system was established and exhibited a superior prognostic value for OS depending on an area under the curve (AUC) of 0.770 (95% CI, 0.658-0.881) than MIPI score. Bioinformatic analysis of PAX5-related genes supported the mechanistic roles of PAX5 in MCL. This study provides insight into the potential role of PAX5 in MCL, and the novel risk scoring system MIPI-SP optimizes the risk stratification and facilitates prognosis evaluation in MCL patients. KEY MESSAGES: • Paired-box 5 positivity indicated adverse prognosis in mantle cell lymphoma patients. • Positive PAX5 expression was related to MIPI score and β2-MG in MCL patients. • MIPI-SP risk scoring system has superior prognostic value than MIPI score in MCL.

Abstract 5377: An integrative prognostic machine learning model in mantle cell lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is an uncommon B-cell lymphoma. The clinical course is highly variable: some patients have aggressive disease and relapse after treatment, while others have indolent disease or respond exceptionally to frontline therapy. Prognostication of MCL patients is dynamic and continues to evolve as novel therapies develop. Current prognostic indicators, such as the MCL international prognostic index (MIPI), were primarily designed with patients treated with chemo-immunotherapies. Using machine learning (ML) and molecular data, we provide a novel predictive method to improve upon conventional clinical markers. Methods: We studied 785 MCL patients diagnosed at MD Anderson since 2014 and retrospectively classified them as “aggressive MCL” (n=311): relapsed or refractory to frontline treatment, and “mild MCL” (n=474): those who did not relapse after the first treatment (exceptional response) or had indolent disease never requiring treatment. After data extraction and feature engineering, 195 baseline features comprised of clinical, genomic, pathology, and cytogenetic data were integrated into an extreme gradient-boosted ensemble ML model (XGBoost). The dataset containing all patients was split (75/25) into a training and test set. Hyperparameters for the model were tuned using a grid-based, space-filling (Latin hypercube) technique and resampled 10-fold cross-validation from the training set. Training, validation, and testing sets were split using stratification of the classification variable to avoid class imbalance. Results: Our integrative model achieved area under the curve (AUC) = .82 and accuracy = .76 on the test set and outperformed an XGBoost model using only clinical features (AUC = .78, accuracy = .68). Additionally, the fully integrated model improved on metrics from a similar multivariate logistic model including all patients (AUC = .72, accuracy =.72). Univariate logistic models were fit on the classification variable using the MIPI and other prognostic indices. The integrated ML model significantly outperformed the MIPI (AUC = .62, accuracy = .60) and other indices in predicting patient class. Clinical, pathological, cytogenetic, and genomic data were all represented as impactful features in a variable importance plot (VIP) and Shapley (SHAP) additive values of the fully integrated ML model. This model was used to launch a rest application programming interface (API) in which important features could be entered and a prediction returned. Conclusion: Our study demonstrates that the current paradigm of using limited features in disease prognostics should be replaced with more advanced ML models that utilize genomic and other molecular data. Future work will include expanding the features included in the model and using the rest API to construct a graphical user interface accessible to clinicians and other researchers to make treatment decisions in precision oncology. Citation Format: Holly A. Hill, Preetesh Jain, Michael L. Wang, Ken Chen. An integrative prognostic machine learning model in mantle cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5377.

Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium.

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

Overexpression of the key metabolic protein CPT1A defines mantle cell lymphoma patients with poor response to standard high-dose chemotherapy independent of MIPI and complement established highrisk factors.

The variable outcome to standard immunochemotherapy for mantle cell lymphoma (MCL) patients is a clinical challenge. Established risk factors, including high MCL International Prognostic Index (MIPI), high proliferation (Ki-67), non-classic (blastoid/pleomorphic) morphology, and mutated TP53, only partly identify patients in need of alternative treatment. Deepened understanding of biological factors that influence time to progression and relapse would allow for an improved stratification, and identification of novel targets for high-risk patients. We performed gene expression analyses to identify pathways and genes associated with outcome in a cohort of homogeneously treated patients. In addition to deregulated proliferation, we show that thermogenesis, fatty acid degradation and oxidative phosphorylation are altered in patients with poor survival, and that high expression of carnitine palmitoyltransferase 1A (CPT1A), an enzyme involved in fatty acid degradation, can specifically identify high-risk patients independent of the established high-risk factors. We suggest that complementary investigations of metabolism may increase the accuracy of patient stratification and that immunohistochemistry- based assessment of CPT1A can contribute to defining high-risk MCL.

Exploring New Prognostic Biomarkers in Mantle Cell Lymphoma: The Best RNA Based Risk Score

INTRODUCTION Mantle Cell Lymphoma (MCL) is characterized by heterogenous disease courses ranging from indolent cases, that do not require therapy for years, to highly aggressive disease with a poor prognosis despite intensive treatment regimens. This emphasizes the need for accurate prognostic biomarkers to guide risk-adapted treatment strategies. The established risk factors used in the clinic today including high Mantle Cell Lymphoma International Prognostic Index (MIPI), high Ki67 proliferation index, high MIPI-c, TP53 mutations, and blastoid morphology, only partly identify patients in need of alternative treatment. Therefore, the search for clinically fit and biologically relevant biomarkers has been intensified. This has led to the proposal of two new NanoString-based, proliferation-associated prognostic biomarkers: the mRNA-based MCL35 score (Scott et al. 2017) and the circular RNA based circSCORE (Dahl et al. 2021). Both biomarkers have shown promising prognostic potential, but a comparison has never been done before. In this study we aimed at comparing MCL35 and circSCORE in 149 patients from the uniformly treated MCL2 and MCL3 cohorts. MATERIALS AND METHODS We included 149 patients from the Nordic patient cohorts MCL2 (70 patients) and MCL3 (79 patients) with sample data on both circSCORE and MCL35 along with long-term follow up data including progression free survival (PFS) and overall survival (OS). Gene expression analysis was obtained with the NanoString nCounter technology after RNA-isolation, using samples originating from both diagnostic lymph-nodes and non-nodal tissue. We also performed individual analyses on the MCL3 cohort only to eliminate the potential risk of overfitting, since the circSCORE is trained upon the MCL2 cohort. RESULTS We report that both circSCORE (PFS log-RANK p-value 0.0048 and OS log-RANK p-value 0.0426) and MCL35 (PFS log-RANK p-value 0.0422 and OS log-RANK p-value 0.0444) in the MCL3 only survival analyses displayed equal significant, prognostic potential in stratifying high and low risk groups. These analyses also revealed inability to significantly stratify the MCL35 standard risk group from the high- and low MCL35 risk groups (figure 1). Neither continuous circSCORE nor continuous MCL35 held prognostic significance when adjusting for known high-risk factors in multivariable cox regression, where only MIPI and TP53 mutation maintained significant results in all settings, except for PFS in MCL3 only (data not shown). The categorial data were analyzed with log-likelihood (LL) using the MIPI and TP53wt (wild type) cox models as baseline models (table 1). The results showed that both circSCORE and Ki67 added significant improvement to the MIPI baseline model in the pooled, MCL2+MCL3 setting, but most interestingly, only circSCORE added significant improvement in MCL3 only for PFS (LL -97.655 vs -100.197, p-value 0.011). Neither circSCORE, MCL35 nor Ki67 added significant improvement to the TP53wt baseline model (table 1). CONCLUSION Both circSCORE and MCL35 demonstrated equal prognostic potential in separating high-and low risk groups in this study. Neither circSCORE, MCL35 nor Ki67 added significant improved value to the TP53wt baseline cox model, but circSCORE added significant improved value to the MIPI baseline cox model, even outperforming Ki67. This implies a new combined prognostic biomarker "MIPI-circSCORE", which could reflect the complexity of MCL through both clinical and biological, proliferation-associated features. However, the overall performance of the MCL35 risk score might be affected due to the inability of separating the standard risk group from the other MCL35 risk groups, the limited number of patients, and the tissue specific criteria of the MCL35 score not being met in this study. Therefore, the findings of this study should be further explored in larger MCL-cohorts to ensure stronger statistical power. Also, testing the biomarkers in MCL-relapse would be of great value to examine the prognostic potential in other settings of the heterogenic course of MCL. This is warranted to clarify the clinical future relevance of these biomarkers in supporting risk-adapted treatment regimens in patients with MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Outcomes in Patients with Mantle Cell Lymphoma Who Received Autologous Stem Cell Transplant in the Second Line Setting

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with a variable clinical outcome. The standard of care for transplant-eligible patients has been to employ autologous stem cell transplant (ASCT) in first remission and this strategy is currently being tested in the NCTN trial EA4151. The utilization and outcomes of ASCT in second line (2L) treatment is unclear and this knowledge is important for those in the non-transplant control arm in EA4151. In this report, we studied the outcomes of patients who received ASCT in 2L for relapsed/refractory (R/R) MCL. Methods: Patients with newly diagnosed MCL between August 2002 and April 2015 were enrolled in the Mayo Clinic/University of Iowa Lymphoma SPORE Molecular Epidemiology Resource (MER) prospective cohort study. Patients who received ASCT at 2L, or at 1L as a reference group, were included in this study. Clinical characteristics and treatment details were abstracted from MER and by additional chart review. Event-free Survival (EFS) was defined as time from ASCT to progression, retreatment, or death due to any cause, and overall Survival (OS) was defined as time from ASCT to death due to any cause. Survival rates were generated using the Kaplan-Meier method in Rv4.1.2. Results: Among a total of 343 patients with MCL enrolled in the MER, 177 had disease progression or relapse following 1L therapy and had complete 2L treatment information available. Eighteen patients were considered for ASCT as part of 2L therapy. Two (11%) patients did not have an adequate response to 2L induction therapy, and 1 (6%) patient did not meet criteria due to failure of the stem cell mobilization and harvest. Therefore, 15 (83%) patients went on to receive ASCT at the 2L. For the 15 patients who received ASCT at 2L, 1L therapies were R-CHOP (N=9, 60%), rituximab and bendamustine (R-bendamustine, N=2, 13%), rituximab and cladribine (N=3, 20%); 1 (7%) received surgical intervention. All 15 patients were considered for ASCT at 1L. Eight (53%) did not proceed due to inadequate response or progression of disease in the 1L setting; 2 (13%) were treated on clinical trials at 1L that precluded ASCT (one with R-CHOP with 90Yibritumomab tiuxetan and the other with R-Bendamustine); 2 (13%) were considered low risk for relapse and deferred ASCT, and 1 (7%) decided not to proceed (patient decision); the reason was unclear in 2 (13%) other patients. The median time from diagnosis to 1L disease progression/relapse was 6.4 months (range 1.1-35.8). Of the 15 patients who received ASCT as 2L therapy, the median age at time of ASCT was 58 years old, 14 (93%) were male, 13 (87%) had stage III/IV disease, and MCL international prognostic index (MIPI) score was low in 5 (63%) and intermediate in 3 (38%) (MIPI missing in 7 patients). Induction therapy at 2L prior to ASCT included R-CHOP alternating with R-DHAP (N=1, 7%), Hyper-CVAD (N=2, 13%), R-CHOP (N=3, 20%), R-DHAP (N=2, 13%), R-EPOCH (N=1, 7%), ROAD (N=1, 7%), R-ICE (N=1, 7%), R-bendamustine (N=3, 20%), and ibrutinib (N=1, 7%). At a median follow-up of 6.3 years from transplant for patients receiving ASCT at 2L, 9 patients had disease progression or relapse, and 8 patients died (3 without known progression or relapse). The median EFS was 3.8 years and the 2-year EFS rate was 59% (CI 38-91%) and 5-year EFS rate was 37% (CI 18-73%). The 2-year OS rate was 73% (CI 54-99%) and 5-year OS rate was 60% (CI 41-91%). As a reference, 113 patients in the MER received ASCT in the 1L setting. The median EFS from date of ASCT was 5.2 years and the 2-year EFS rate was 77% (CI 70-85%) and the 5-year rate was EFS 54% (CI 45-64%). The 2-year OS rate was 86% (CI 80-93%) and 5-year OS rate was 79% (CI 72-87%). Conclusion: ASCT consolidation after salvage therapy in the 2L setting appeared feasible in select patients with R/R MCL. The PFS and OS outcomes following 2L appeared reasonable. In the evolving landscape of R/R MCL treatment, it is unclear whether ASCT will still have a role. It is possible that select patients with R/R MCL would still benefit from ASCT. Larger studies, although likely limited to retrospective setting, are needed to further evaluate the feasibility, outcomes, and prognostic factors of ASCT at 2L and beyond. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal