Cell Lymphoma International Prognostic Index Research Articles

Matching-adjusted indirect comparison of Acalabrutinib versus Ibrutinib in relapsed/refractory mantle cell lymphoma

ABSTRACT Objective In the absence of head-to-head clinical trials, matching-adjusted indirect comparison (MAIC) was used to compare 2 Bruton tyrosine kinase inhibitors (BTKis) approved for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL). This analysis compares the efficacy and safety of acalabrutinib versus ibrutinib using a more mature dataset than a previously published MAIC. Methods Individual patient data from 122 patients treated with acalabrutinib in a phase 2 study were weighted to match aggregate baseline characteristics of patients pooled from 3 separate trials of ibrutinib. Patients were matched on Eastern Cooperative Oncology Group performance status, simplified Mantle Cell Lymphoma International Prognostic Index, lactate dehydrogenase, prior lines of therapy, tumor burden, and blastoid histology. Outcomes assessed included progression-free survival (PFS), overall survival (OS), and adverse events. Results After matching, differences in PFS between acalabrutinib (median 17.8 months) and ibrutinib (median 12.8 months) were not statistically significant (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.74–1.15; P = 0.48). Similarly, after matching, OS differences between acalabrutinib (median 36.5 months) and ibrutinib (median 27.9 months) did not reach statistical significance (HR, 0.87; 95% CI, 0.64–1.17; P = 0.35). Acalabrutinib was associated with an improved safety profile compared with ibrutinib, with statistically significantly lower rates of grade ≥3 atrial fibrillation and thrombocytopenia. Conclusions This comparison of 2 BTKis used in the treatment of R/R MCL showed that PFS and OS risk was not statistically different between the treatments; however, acalabrutinib had an improved safety profile compared with ibrutinib.

Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network

Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. Janssen and Leukemia & Lymphoma Society.

A retrospective analysis of ibrutinib outcomes in relapsed or refractory mantle cell lymphoma.

While treatment strategies for mantle cell lymphoma (MCL) have evolved, patients often experience disease progression and require additional treatment therapies. Ibrutinib presents a promising option for relapsed or refractory MCL (RR-MCL). This study investigated real-world treatment outcomes of ibrutinib in patients with RR-MCL. A single-center retrospective analysis investigated clinical characteristics and survival outcomes of patients with RR-MCL, treated with ibrutinib. Forty-two patients were included, with 16 received rituximab and bendamustine, and 26 receiving anthracycline-based regimens as front-line treatment. During a median follow-up of 46.0 months, the response rate to ibrutinib was 69%, with 12 CRs and 8 partial responses. Disease progression (54.8%) and adverse events (11.9%) were the primary reasons for discontinuation. Median progression-free survival (PFS) and overall survival (OS) were approximately 16.4 and 50.1 months, respectively. Patients older than 70 years (P=0.044 and P=0.006), those with splenomegaly (P=0.022 and P=0.006), and those with a high-risk simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) (P＜0.001 and P＜0.001) exhibited siginificantly inferior PFS and OS. Notably, patients with a high-risk sMIPI relapsed earlier. Post-ibrutinib treatment yilded an OS of 12.2 months, while clinical trial participants demonstrated superior survival compared to those receiving chemotherapy alone. This study underscores the importance of considering patient characteristics before administering ibrutinib as salvage therapy. Early relapse was associated with poor outcomes, highlighting the need for novel therapeutic strategies.

Indirect Comparison of Efficacy of Zanubrutinib Versus Orelabrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma (R/R MCL): An Updated Analysis with Long-Term Follow up

Introduction Zanubrutinib and orelabrutinib, both the next generation Bruton's tyrosine kinase inhibitors (BTKis), are used in China as treatment options for R/R MCL. A further evaluation to understand the differences between these two novel BTKis is helpful for future study. Our previously indirect comparison has suggested a favorable PFS trend in zanubrutinib over orelabrutinib in R/R MCL patients (Song Y, et al. Invest New Drugs 2023). Here, we conducted an updated analysis to indirectly compare the long-term efficacy between zanubrutinib (median follow up: 35.3 months) and orelabrutinib (median follow up: 23.8 months) in patients with R/R MCL. Methods Individual patient data from zanubrutinib study (BGB-3111-206, n=86; NCT03206970) were adjusted to match the patients population profile of the orelabrutinib study (ICP-CL-00102, n=106; NCT03494179). As both trials were single-arm and were not linked through a common control arm, an unanchored matching-adjusted indirect comparison (MAIC) was performed to adjust for effect modifiers and prognostic variables. The baseline characteristics included in population adjustment were identified from literature review and clinical experts' assessment, which were sex, bulky disease, bone marrow involvement, disease stage, simplified Mantle Cell Lymphoma International Prognostic Index, prior autologous stem cell transplantation, and the number of prior lines of treatment. The efficacy outcomes included investigator-assessed progression free survival (PFS), overall survival (OS), and overall response rate (ORR). After matching, a weighted Cox model or a weighted logistic model will be employed to analyze the PFS and OS through hazard ratio (HR) or to analyze the ORR through odds ratio (OR). Response evaluations were only CT-based assessment in orelabrutinib study, while PET- and CT-based assessment were both performed in zanubrutinib study. Thus, the PFS assessed by PET and CT of zanubrutinib study were used to compare with the PFS assessed by CT of orelabrutinib study, respectively. Results After matching, the baseline characteristics were balanced between zanubrutinib and orelabrutinib, with the (effective) sample size of 70 and 106 in zanubrutinib and orelabrutinib, respectively (Table). PFS assessed by CT was significantly longer in the zanubrutinib versus the orelabrutinib (median PFS: not estimable [NE] vs. 22.0 months; HR, 0.54 [95% CI: 0.34-0.86]; P = 0.009) (Figure). Additionally, PFS assessed by PET of zanubrutinib was also significantly longer than the PFS assessed by CT of orelabrutinib (median PFS: NE vs. 22.0 months; HR, 0.63 [95% CI: 0.40-0.99]; P = 0.044). There are clinically meaningful differences observed for both the PFS (assessed by CT or PET) of zanubrutinib versus the PFS assessed by CT of orelabrutinib and the 24-month PFS rate (assessed by CT or PET) in the zanubrutinib versus that assessed by CT in the orelabrutinib (67.3% vs. 46.5% and 62.2% vs. 46.5%, respectively). Due to very limited number of OS events, the analysis of OS was not powered enough to detect a statistical meaningful difference between two groups (median OS: NE vs. NE; HR, 0.68 [95% CI: 0.36-1.27]; P = 0.223). However, the 24-month OS rate was numerically higher in the zanubrutinib than the orelabrutinib (83.7% vs. 74.3%). ORR was comparable between zanubrutinib and orelabrutinib (85.5% vs. 82.1%; OR, 1.28 [95% CI: 0.56-2.94]; P = 0.556). Conclusions MAIC results demonstrated that zanubrutinib had significantly longer PFS compared with orelabrutinib in the treatment of R/R MCL patients.

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.

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%.

Clinical features and prognostic factors of elderly patients with mantle cell lymphoma

Objective: To examine the clinical characteristics and prognostic factors of elderly patients with mantle cell lymphoma (MCL) and the impact of nutrition and underlying diseases on the prognosis of elderly patients with MCL. Methods: retrospectively analyzed 255 elderly patients with MCL from 11 medical centers, including Peking University Third Hospital between January 2000 and February 2021. We analyzed clinical data, such as age, gender, Mantle Cell Lymphoma International Prognostic Index score, and treatment options, and performed univariate and multivariate prognostic analysis. We performed a comprehensive geriatric assessment on elderly MCL patients with medical records that included retraceable underlying disease and albumin levels, and we investigated the impact of basic nutrition and underlying disorders on MCL prognosis in the elderly. Results: There were 255 senior individuals among the 795 MCL patients. Elderly MCL was more common in males (78.4%), with a median age of 69 yr (ages 65-88), and the majority (88.6%) were identified at a late stage. The 3-yr overall survival (OS) rate was 42.0%, with a 21.2% progression-free survival (PFS) rate. The overall response rate (ORR) was 77.3%, with a 33.3% total remission rate. Elderly patients were more likely than younger patients to have persistent underlying illnesses, such as hypertension. Multivariate analysis revealed that variables related with poor PFS included age of ≥80 (P=0.021), Ann Arbor stage Ⅲ-Ⅳ (P=0.003), high LDH level (P=0.003), involvement of bone marrow (P=0.014). Age of ≥80 (P=0.001) and a high LDH level (P=0.003) were risk factors for OS. The complete geriatric assessment revealed that renal deficiency was associated with poorer OS (P=0.047) . Conclusions: Elderly MCL patients had greater comorbidities. Age, LDH, renal function, bone marrow involvement, and Ann Arbor stage are all independent risk factors for MCL in the elderly.

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.

Polatuzumab-bendamustine-rituximab as bridge to CD19-directed CAR T cells in mantle cell lymphoma refractory to ibrutinib and venetoclax.

Polatuzumab-bendamustine-rituximab as bridge to CD19-directed CAR T cells in mantle cell lymphoma refractory to ibrutinib and venetoclax.

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

Assessment of Durable Responses after Brexucabtagene Autoleucel (KTE-X19) in the ZUMA-2 Study in Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL)

Introduction: Brexucabtagene autoleucel (brexu-cel, formerly known as KTE-X19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the United States for the treatment of adults with R/R MCL and in the European Union for adults with R/R MCL after ≥2 prior therapies, including a Bruton tyrosine kinase inhibitor (BTKi). At a median 35.6-months (mo) follow-up in the Phase 2, multicenter ZUMA-2 study of brexu-cel in R/R MCL, the objective response rate was 91% (68% complete response [CR] rate), with a median duration of response (DOR) of 28.2 mo, and overall survival (OS) of 46.6 mo among all 68 treated patients (pts) and not reached in pts with a CR (Wang et al. J Clin Oncol. 2022). To identify factors associated with long-term response to KTE-X19, we evaluated patient and product characteristics by response status at 24 mo post infusion in ZUMA-2. Methods: Adults (≥18 years) with R/R MCL who had received ≤5 prior regimens including a BTKi underwent leukapheresis and conditioning chemotherapy followed by a single infusion of brexu-cel (2×106 anti-CD19 CAR T cells/kg). Post hoc assessments of patient, disease, pharmacokinetic, and product characteristics are reported by response status at 24 mo (ongoing vs relapsed). Results: At a median follow-up of 35.6 mo (range, 25.9-56.3), 62 pts had achieved a CR or partial response; 3 did not reach the 24-mo assessment visit and were excluded from this analysis. Of the 59 evaluable pts with response, 29 (49%) had ongoing responses at 24 mo (ongoing responders), and 30 (51%) had relapsed prior to 24 mo (relapsed responders). At baseline, the median age was 65 years and median number of prior therapies was 3 in both subgroups. Among ongoing vs relapsed responders, 66% vs 43% had ibrutinib as last prior therapy and 14% vs 13% had acalabrutinib as last prior therapy, with a median (range) time from last prior therapy of 63 (26-748) vs 64.5 mo (22-443), respectively. A smaller proportion of ongoing responders compared with relapsed responders received bridging therapy (21% vs 53%) and prior platinum therapy (10% vs 40%), respectively; while similar proportions received prior bendamustine therapy (45% vs 53%), prior proteosome inhibitor therapy (41% and 37%), and prior autologous stem cell transplant (48% vs 37%), respectively. At baseline, a greater proportion of ongoing responders had an ECOG score of 0 compared to relapsed responders (79% vs 57%, respectively), and the median (range) tumor burden (SPD) was 935.1 (260-6133) in ongoing responders and 4233.6 (386-14390) in relapsed responders. The incidence of high-risk features was similar between ongoing responders and relapsed responders, with 66% and 60% having a baseline Ki-67 proliferation index score of ≥30%, 10% of both subgroups having TP53 mutations, 45% and 37% having elevated lactose dehydrogenase levels (ULN to ≥1.5 ULN), and 10% and 13% having high-risk Simplified Mantle Cell Lymphoma International Prognostic Index scores (>6), respectively. The median (range) DOR in ongoing responders with CR (n=28) was not reached (46.7-not estimable) and was 8.3 mo (5-13.6) in relapsed responders with CR (n=15). Of the relapsed responders, 67% had received subsequent anticancer therapy by data cutoff, the most common of which were radiotherapy (23%), dexamethasone (23%), rituximab (23%), venetoclax (20%), and lenalidomide (20%; patients could have received multiple subsequent therapies and multiple lines of subsequent therapy). Median [range] peak (102.4 [0.3-2241.6] vs 59.9 [1.6-2589.5]) and area under the curve (1487 [3.8-16,700] vs 688.2 [19-27,200]) CAR T-cell levels were ~2x higher in ongoing responders than in relapsed responders, respectively. A modest increase in the median [range] total number of infused CCR7+ cells was observed in ongoing vs relapsed responders (119.8 [37-249.9] vs 89.1 [6.1-353.4]), suggesting a potential role of continuous memory T-cell differentiation in achieving durable responses. Conclusions: After ~3-years median follow-up, brexu-cel continues to demonstrate durable responses with 49% of patients in ongoing response at 24 mo post infusion. In summary, ongoing responders had lower ECOG scores and tumor burden, as well as less frequent use of bridging therapy and less intense regimens for previous relapses, suggesting the potential for greater benefit with brexu-cel if given in earlier course of disease.

Ibrutinib Plus Bendamustine Plus Rituximab and Rituximab Maintenance (I+BR) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone Regimen (R-CHOP) and Rituximab, Cyclophosphamide, Doxorubicin, Bortezomib, Prednisone Regimen (VR-CAP) in First-Line Mantle Cell Lymphoma Patients: An Adjusted Treatment Comparison Using Inverse Probability Weighting

The two first/last authors contributed equally Background The phase 3 SHINE trial (NCT01776840 ) showed that I+BR significantly prolonged progression free survival (PFS) versus BR with R maintenance (BR) in older patients with previously untreated mantle cell lymphoma (1L MCL) (Wang ML et al. NEJM 2022). Other commonly used 1L MCL regimens in older patients in Europe also include rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP) or a modified version of this regimen where bortezomib is substituted for vincristine (VR-CAP). In the phase 3 LYM-3002 trial (NCT00722137), VR-CAP showed improved PFS, and overall survival (OS) compared to R-CHOP (Robak T et al. Lancet 2018). In the absence of a randomized comparison of I+BR versus these treatments, we performed an adjusted comparative analysis of PFS and OS with the I+BR arm from the SHINE study and the R-CHOP and VR-CAP arms from the LYM-3002 trial. Methods In SHINE trial, patients were treated with ibrutinib once daily until disease progression or unacceptable toxicity, plus 6 cycles of BR, and patients with a partial or complete response received rituximab maintenance every 8 weeks for up to 12 additional doses. In LYM-3002 trial, patients were treated with 6-8 cycles of R-CHOP or VR-CAP and did not receive maintenance therapy. PFS was the primary endpoint for both trials. To address potential confounding bias due to lack of randomization, individual patient level data of the 2 trials were used to estimate propensity scores and apply inverse probability weighting where the R-CHOP and VR-CAP arms are reweighted to match the I+BR arm to estimate the average treatment effect of the treated (ATT) (Phillippo D et al. NICE 2019, Schneeweiss S et al. Clin Pharmacol Ther 2007). Standardized mean differences (SMD) for each baseline characteristic were calculated and considered balanced between treatment cohorts if SMD ≤ 0.25 (Li F et al. JASA 2019). Relative treatment effects are presented as hazard ratios (HR) and 95% confidence intervals (CI). Results Overall, 261 patients treated with I+BR, 134 patients with R-CHOP and 130 patients with VR-CAP were included in the analyses. Baseline characteristics (Age, Morphology, Eastern Cooperative Oncology Group (ECOG), Bone Marrow, Stage, Sex, Mantle Cell Lymphoma International Prognostic Index (MIPI)) for ATT-weighted R-CHOP and VR-CAP cohorts were well balanced versus the I+BR patient cohort. When compared to R-CHOP, the ATT adjusted PFS and OS were both statistically significantly improved with I+BR. Median PFS with I+BR vs R-CHOP is 80.8 [62.0, Not reached (NR)] vs 18.4 [13.9, 20.1] months, respectively; the PFS HR is 0.24 [0.16-0.36], p<0.001. Median OS with I+BR vs R-CHOP is NR [81.2, NR] vs 64.6 [44.6, 79.0] months, respectively; the OS HR is 0.62 [0.43-0.90], p=0.012. (Figure 1) When compared to VR-CAP, the ATT adjusted PFS was statistically significantly improved with I+BR. Median PFS with I+BR vs VR-CAP is 80.8 [62.0, NR] vs 30.7 [19.6, NR] months, respectively; the PFS HR is 0.50 [0.33-0.76], p=0.001. OS was numerically improved with I+BR. Median OS with I+BR vs VR-CAP is NR [81.2, NR] vs 64.4 [51.5, NR] months, respectively; the OS HR is 0.73 [0.51-1.05], p=0.093 (Figure 1) With one additional year of follow-up of SHINE results (median follow-up of 94.5 months), there were 110 deaths in the I+BR group and 119 deaths in the BR group, and the OS HR between I+BR vs. BR is 1.00 [95% CI 0.77-1.30]. We plan to present updated adjusted indirect comparison of OS versus VR-CAP and R-CHOP at the meeting. Conclusion In this adjusted cross-trial comparative analysis, I+BR with R maintenance demonstrated improved PFS versus two commonly used 1L MCL regimens in Europe (R-CHOP and VR-CAP). This finding is consistent with the phase 3 SHINE results where the upfront ibrutinib combination is a highly effective treatment option compared to standard chemo immunotherapies for older patients with previously untreated MCL. In addition, it also potentially supports that R maintenance should be considered routinely in patients with MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

18F]FDG-PET/CT volumetric parameters can predict outcome in untreated mantle cell lymphoma

Several studies have shown a strong predictive value for pretreatment [18F]FDG-PET/CT metabolic parameters in different lymphoma subtypes. However, few publications exist concerning the role of metabolic parameters in mantle cell lymphoma (MCL). We retrospectively investigated the prognostic value of baseline metabolic tumor volume (MTV) and lesion dissemination in untreated MCL. We compared it to currently used prognostic factors such as stage, mantle cell lymphoma international prognostic index (MIPI) and KI-67. We report that a higher baseline MTV is a risk factor for worse overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) in univariate analysis. In multivariate analysis, MTV was significantly associated with DSS, but not with OS and PFS. We found no correlation between lesion dissemination and outcome. The MIPI score remains the strongest predictor of outcome. These results show that MTV is an important prognostic tool and can improve patient risk stratification at staging of untreated MCL.

Analysis of Clinical Characteristics and Prognostic Factors of Patients with Limited-Stage Mantle Cell Lymphoma

To investigate the clinical characteristics, prognostic factors, and treatment outcomes of patients with limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL). Examining consecutive the clinical characteristics, treatment outcomes and prognostic factors of 47 patients with stage I or II MCL diagnosed in Affiliated Tumor Hospital of Guangxi Medical University from January 2005 to June 2020 were analyzed retrospectively. The median age of patients was 62(37-78) years old. 36 patients were male, accounting for 76.6% of the whole. Among these, 74.5% (n=35) of the diagnoses were estimated at II stage. According to Mantle cell lymphoma International Prognostic Index (MIPI), 28 patients (59.6%) were classified as low risk. Patients who received first-line treatment and could be evaluated received rituximab combined chemotherapy, chemotherapy alone, cytarabine containing chemotherapy or chemotherapy combined with local radiotherapy, the different first-line therapies did not affect the complete response (CR) rate of patients (P＞0.05). The median follow-up time was 81.5 months, the 5-year progression-free survival (PFS) was 37.4% and the 5-year overall survival (OS) rate was 80.6%. Multivariate analysis showed that Ki-67＞30% (P＜0.05) the independent adverse prognostic factor for PFS and OS. Limited-stage MCL is rare. Patients with limited-stage MCL had a better outcome than those with III-IV stage MCL. Patients with limited-stage MCL whose Ki-67≤30% had better PFS and OS.

Treatment of Mantle Cell Lymphoma in the Frontline Setting: Are We Ready for a Risk-Adapted Approach?

Mantle cell lymphoma (MCL), a type of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13q32) translocation, is a clinically heterogenous disease which can range from indolent to highly aggressive. Numerous prognostic factors have been identified, including blastoid histology, the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, high proliferation index, p53 deletions and/or mutations, complex karyotype, minimal residual disease, and several others. However, using these prognostic factors to guide treatment selection has largely remained elusive. Given the heterogeneous behavior of this disease and varying patient characteristics, we suggest that the time has come for a more risk-adapted approach to this disease. In this article, we review the numerous prognostic factors that have been described for MCL, both at the time of diagnosis and following first-line treatment. We then propose a risk-adapted approach to first-line therapy for MCL, which would reserve intensive therapy for the highest risk patients and spare others excessive toxicity.

New Directions for Mantle Cell Lymphoma in 2022.

Mantle cell lymphoma is a rare B-cell non-Hodgkin lymphoma that is clinically and biologically heterogeneous. Risk stratification at the time of diagnosis is critical. One of the most powerful prognostic indices is the Mantle Cell Lymphoma International Prognostic Index-Combined, which integrates an estimate of proliferation (Ki67 index) with the standard Mantle Cell Lymphoma International Prognostic Index clinical factors. In addition, the presence of TP53 mutation is associated with suboptimal response to intensive chemoimmunotherapy and particularly dismal survival outcomes. Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics-such as covalent Bruton tyrosine kinase inhibitors, lenalidomide, and venetoclax-are being incorporated into "chemotherapy-free" regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve mantle cell lymphoma. In addition, risk-adapted treatment programs are increasingly being studied. These programs tailor treatment according to baseline prognostic factors (e.g., presence of TP53 mutation) and may incorporate biomarkers of response such as minimal residual disease assessment. Although still investigational, these studies present an opportunity to move beyond the biology-agnostic, historical fitness-based treatment selection paradigm and toward a more personalized, tailored treatment approach in mantle cell lymphoma. After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib. These new therapies show promising efficacy, even among high-risk patients, and will likely translate to improvements in survival outcomes for patients with progressive mantle cell lymphoma following treatment with a Bruton tyrosine kinase inhibitor.

Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase 3 trial in mantle cell lymphoma

AbstractMinimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase 3 MCL0208 prospective clinical trial assessing lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood [PB] and bone marrow [BM]), taken at well-defined time points. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 time points. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time polymerase chain reaction [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month time to progression [TTP] hazard ratio [HR], 3.83; P < .001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance, we developed a time-varying kinetic model based on regularly updated MRD results and the MIPI (Mantle Cell Lymphoma International Prognostic Index), showing an area under the ROC (Receiver Operating Characteristic) curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81; with kinetic analysis, it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and is suitable for models with a continuous adaptation of patient risk. The study can be found in EudraCT N. 2009-012807-25 (https://eudract.ema.europa.eu/).

A novel clinical immune-related prognostic model predicts the overall survival of mantle cell lymphoma.

The mantle cell lymphoma (MCL) International Prognostic Index (MIPI) and combined MIPI (MIPI-c) are commonly used for risk classification of MCL patients. However, these indexes lack immune-related parameters. The purpose of this study was to develop a novel prognostic model that integrated clinical and immune parameters. A total of 189 patients with newly diagnosed MCL from January 2010 to June 2020 were enrolled in our study. A nomogram and immune-related prognostic index (IRPI) were established to predict the overall survival (OS) of patients according to univariate and multivariate analyses. Discrimination and calibration were used to compare the prognostic performance of the IRPI, MIPI, and MIPI-c. External validation was performed based on validation dataset (n=150) from two other centers. The results for the training dataset indicated that B symptoms, platelet count, B2M level, CD4+ T-cell count<26.7% and CD8+ T-cell count>44.2% were predictors for OS. All the prognostic factors were integrated into the nomogram. For the overlap of confidence intervals of each variable, we assigned one point for each factor. The IRPI categorized patients into three risk categories: a score of zero indicated low risk, a score of one or two indicated intermediate risk, and a score of ≥3 indicated high risk. The IRPI showed better discrimination and calibration power than the MIPI and MIPI-c in the training dataset and validation dataset. The novel IRPI is a refined risk stratification index and reflects the strong complementary prognostic effects between clinical and immune parameters in MCL.

Diagnosis and Follow Up of Non Hodgkin Lymphoma in Dakar, Senegal

Introduction: The management of Non-Hodgkin Lymphoma (NHL) in Senegal is challenging due to the lack of exploration tools and the inaccessibility of anticancer drugs. This study aimed to identify the prognostic factors at diagnosis and to assess their outcome under treatment. Methodology: We conducted a descriptive and analytical prospective study range from 1st January 2018 to 3rd July 2020 covering NHL cases. Initial prognostic factors were assessed according to the International Prognostic Index for diffuse large cell B lymphoma and T-cell lymphoma, the Mantle Cell Lymphoma International Prognostic Index and the Follicular Lymphoma International Index for mantle cell lymphoma and small cell lymphoma respectively. B-cell lymphomas were treated with polychemotherapy with or without rituximab, T-cell lymphomas were treated with polychemotherapy alone. Progression was assessed on the basis of response to treatment, toxicity and survival. Results: We included 40 patients, 30 males and 10 females with a sex ratio of 3. The mean age was 43.38 years +15.87. The mean time from symptom onset to diagnostic confirmation was 7.4 months. The total follow-up time of the cohort was 30.5 patient-years. B-cell lymphomas accounted for 57.5% of cases, T-cell lymphomas for 27.5% of cases. Twenty-five patients (67.6% of cases) were at an advanced stage at diagnosis. The initial prognosis was unfavourable in 29.7% of cases, all histological types combined. The overall survival at 30 months was 70%. Conclusion: Our patients were diagnosed with advanced disease stage. The overall survival at 30 months was short. Early diagnosis and better access to immunochemotherapy could improve these results.

Initial Treatment Patterns and Survival Outcomes of Mantle Cell Lymphoma Patients Managed at Chinese Academic Centers in the Rituximab Era: A Real-World Study.

PurposeThe aim of the study was to delineate the disease characteristics, the initial treatment patterns, and survival in patients with mantle cell lymphoma (MCL) managed in the real world.MethodsData of 518 MCL patients from 5 major Chinese Hematology Centers in the period from 2007 to 2017 were retrospectively analyzed.ResultsThe median age was 58 years. Of the patients, 88.6% had Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1 and 80.7% had advanced-stage disease. Ki67 expression was <30% in 39.6% of the patients, and 43.2% of patients were categorized into a low-risk group based on the Mantle Cell Lymphoma International Prognostic Index (MIPI) scoring system. Overall, 73.4% of the patients received rituximab as their first-line therapy. The most commonly used chemotherapy was the CHOP-like (cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone) regimen (45.2%), followed by high-dose cytarabine-containing chemotherapy (31.3%) and bendamustine (3.3%). Of the patients, 13.7% (n = 71) underwent consolidative autologous stem cell transplantation (ASCT), and 19.3% (n = 100) received novel agents containing first-line regimens. With a median follow-up time of 52 months, the 3- and 5-year overall survival (OS) rates were 73.7% and 61.4%, respectively. Age ≤60 years, ECOG PS 0–1, stages I–II, normal lactate dehydrogenase (LDH), absence of bone marrow involvement, Ki67 <30%, and lower-risk IPI/MIPI scores were significantly associated with improved OS (p < 0.05). The inclusion of rituximab improved the 5-year OS, with borderline significance (62.5% vs. 55.2%, p = 0.076). High-dose cytarabine-containing chemotherapy showed significant clinical benefit in 5-year OS (72.1% vs. 55.9%, p = 0.010). Patients with ASCT had better 5-year OS in the younger (≤60 years) age group (87.2% vs. 64.8%, p = 0.002).ConclusionThis large retrospective dataset unequivocally confirmed the survival advantage afforded by cytarabine-containing regimen and ASCT in a first-line setting under real-world management in the rituximab era.