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

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

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma-a randomized, open-label phase III trial of the European mantle cell lymphoma network.

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47-1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29-0.79) and without previous ASCT (aHR 0.52, 0.28-0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344.

Phase 1/2 multicenter trial of acalabrutinib in Chinese patients with relapsed/refractory mantle cell lymphoma.

Acalabrutinib studies have limited Asian participation. This phase 1/2 study (NCT03932331) assessed acalabrutinib in Chinese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). Overall, 34 patients were enrolled. Most patients were men (88%); median age was 63 years and 59% had ≥3 prior treatments. Median treatment duration was 14 months (range, 1-24). Any-grade adverse events (AEs) and grade ≥3 AEs occurred in 85.3% and 44.1% of patients, respectively. AEs causing treatment discontinuation were aplastic anemia, thrombocytopenia, and gastrointestinal infection (n = 1 each). Fatal AEs occurred in 2 patients (aplastic anemia and multiple organ dysfunction syndrome [n = 1 each]). BICR-assessed ORR was 82.4% (95% confidence interval [CI]: 65.5, 93.2); 12 (35.3%) patients achieved complete response. Estimated 12-month OS was 84.5% (95% CI: 66.6, 93.3). Acalabrutinib yielded tolerable safety and high response rates in Chinese patients with R/R MCL.

Obinutuzumab vs rituximab for transplant-eligible patients with mantle cell lymphoma.

ABSTRACT: Obinutuzumab (O) and rituximab (R) are 2 CD antibodies that have never been compared in a prospective randomized trial of mantle cell lymphoma (MCL). Herein, we report the long-term outcome of the LyMa-101 trial, in which newly diagnosed patients with MCL were treated with chemotherapy plus O before transplantation, followed by O maintenance (O group). We then compared these patients with those treated with the same treatment design with R instead of O (R group). A propensity score matching (PSM) was used to compare the 2 populations (O vs R groups) in terms of measurable residual disease (MRD) at the end of induction (EOI), progression-free survival (PFS), and overall survival (OS). In LyMa-101, the estimated 5-year PFS and OS after inclusion (n = 85) were 83.4% (95% confidence interval [CI], 73.5-89.8) and 86.9% (95% CI, 77.6-92.5), respectively. At EOI, patients treated in the O group had more frequent bone marrow MRD negativity than those treated in the R group (83.1% vs 63.4%; χ2, P = .007). PSM resulted in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, the O group had a longer estimated 5-year PFS (P = .029; 82.8% vs 66.6%; hazard ratio [HR], 1.99; 95% confidence interval (CI), 1.05-3.76) and OS (P = .039; 86.4% vs 71.4%; HR, 2.08; 95% CI, 1.01-4.16) compared with the R group. Causes of death were comparable in the 2 groups, the most common cause being lymphoma. O before transplantation and in maintenance provides better disease control and enhances PFS and OS compared with R in transplant-eligible patients with MCL. These trials were registered at www.clinicaltrials.gov as #NCT00921414 and NCT02896582.

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group.

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

TP53 mutation is frequent in mantle cell lymphoma with EZH2 expression and have dismal outcome when both are present.

Enhancer of zeste homolog 2 (EZH2) expression is found in about 40% of mantle cell lymphoma (MCL) patients, which is associated with aggressive histology, high Ki-67 proliferation rate, p53 mutant pattern and inferior overall survival (OS). We conducted 11-gene (ATM, BIRC3, CCND1, KMT2C, KMT2D, NOTCH1, NOTCH2, RB1, TP53, TRAF2 and UBR5) next generation sequencing panel to shed more light on MCL with EZH2 expression (EZH2+ MCL). EZH2+ MCL more frequently harbor TP53 mutation compared to EZH2(-) MCL (41.2% vs. 19.1%, respectively, p = 0.045). TP53 mutation and EZH2 expression demonstrated overlapping features including aggressive histology, high Ki-67 proliferation rate and p53 mutant pattern by immunohistochemistry. Comparative analysis disclosed that EZH2 expression correlates with high Ki-67 proliferation rate irrespective of TP53 mutation. Aggressive histology is associated with EZH2 expression or TP53 mutation, possibly via independent mechanisms. p53 mutant pattern is due to TP53 mutation. MCL patients with EZH2 expression or TP53 mutation show inferior outcome and when both are present, patients have dismal outcome.

Modified R-BAC plus BTK inhibitor regimen in newly diagnosed young patients with mantle cell lymphoma: a real-world retrospective study.

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65 years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42-65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17 months (2-86 months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3-4 lymphopenia and grade 3-4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable.

Genetic and prognostic analysis of blastoid and pleomorphic mantle cell lymphoma: a multicenter analysis in China.

Blastoid or pleomorphic mantle cell lymphoma (B/P-MCL) is characterized by high invasiveness and unfavorable outcomes, which is still a challenge for treating MCL. This retrospective study was performed to comprehensively analyze the clinical, genomic characteristics and treatment options of patients with B/PMCL from multicenter in China. Data were obtained from 693 patients with B/PMCL from three centers in China between April 1999 and December 2019. Seventy-four patients with BMCL (n = 43) or PMCL (n = 31) were included in the analysis. The median age of the cohort was 60.0 years with a male-to-female ratio of 2.89:1. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 44.1% and 46.0%, respectively. Mutations of TP53, ATM, NOTCH1, NOTCH2, NSD2, SMARCA4, CREBBP, KMT2D, FAT1, and TRAF2 genes were the most common genetic changes in B/P-MCL. Progression of disease within 12 months (POD12) could independently predict the poor prognosis of patients with blastoid and pleomorphic variants. Patients with POD12 carried a distinct mutation profile (TP53, SMARCA4, NSD2, NOTCH2, KMT2D, PTPRD, CREBBP, and CDKN2A mutations) compared to patients with non-POD12. First-line high-dose cytosine arabinoside exposure obtained survival benefits in these populations, and BTKi combination therapy as the front-line treatment had somewhat improvement in survival with no significant difference in the statistic. In conclusion, B/P-MCL had inferior outcomes and a distinct genomic profile. Patients with POD12 displayed a distinct mutation profile and a poor prognosis. New therapeutic drugs and clinical trials for B/P-MCL need to be further explored.

First Report of FARSA in the Regulation of Cell Cycle and Survival in Mantle Cell Lymphoma Cells via PI3K-AKT and FOXO1-RAG1 Axes.

Cancer-associated factors have been largely identified in the understanding of tumorigenesis and progression. However, aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) have so far been neglected in cancer research due to their canonical activities in protein translation and synthesis. FARSA, the alpha subunit of the phenylalanyl-tRNA synthetase is elevated across many cancer types, but its function in mantle cell lymphoma (MCL) remains undetermined. Herein, we found the lowest levels of FARSA in patients with MCL compared with other subtypes of lymphomas, and the same lower levels of FARSA were observed in chemoresistant MCL cell lines. Unexpectedly, despite the essential catalytic roles of FARSA, knockdown of FARSA in MCL cells did not lead to cell death but resulted in accelerated cell proliferation and cell cycle, whereas overexpression of FARSA induced remarkable cell-cycle arrest and overwhelming apoptosis. Further RNA sequencing (RNA-seq) analysis and validation experiments confirmed a strong connection between FARSA and cell cycle in MCL cells. Importantly, FARSA leads to the alteration of cell cycle and survival via both PI3K-AKT and FOXO1-RAG1 axes, highlighting a FARSA-mediated regulatory network in MCL cells. Our findings, for the first time, reveal the noncanonical roles of FARSA in MCL cells, and provide novel insights into understanding the pathogenesis and progression of B-cell malignancies.

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma.

PURPOSE: Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years). METHODS: We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed. RESULTS: The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response. CONCLUSION: IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1-C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

EZH2 expression is associated with inferior overall survival in mantle cell lymphoma.

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.

Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma. METHODS: We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 106 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenously on day 1, and prednisone 100 mg/m2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR [aHR]). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation. FINDINGS: Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 [53%] in the autologous HSCT group and 81 [47%] in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39%) of 174 patients. The median progression-free survival was 3·3 years (95% CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p<0·0001; aHR 0·50 [95% CI 0·36-0·69]). The median overall survival was 7·5 years (95% CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 [95% CI 0·46-0·95]). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab. INTERPRETATION: Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma. FUNDING: Deutsche Krebshilfe, the European Community, and the Bundesministerium für Bildung und Forschung, Kompetenznetz Maligne Lymphome.

Association of minimal residual disease levels with clinical outcomes in patients with mantle cell lymphoma: A meta-analysis.

Some studies have elucidated that Minimal residual disease (MRD) in patient with Mantle Cell Lymphoma (MCL) was a significant prognostic factor, with potential value in assessing overall survival (OS) and progression-free survival (PFS). However, most studies were widely varied in included population, sample sources and MRD detection time points. Some studies even have conflicting results. In view of this, a meta-analysis was performed to evaluate association of MRD levels with clinical outcomes in patients with MCL. We identified 7 included articles, which were published in recent 20 years. Then, we extracted or calculated hazard ratios (HRs) and their 95 % confidence intervals (CIs). Our results reveal that patients with MRD negativity have improved OS (HR = 0.63; 95 % CI: 0.50-0.79) and PFS (HR = 0.40, 95 % CI: 0.21-0.76), comparing with patients with MRD positivity. There are also consistent results in subgroups based on sample sources and MRD detection time points. Our study also demonstrates that MRD level is a strong prognostic factor of clinical outcomes. Thus, MRD is expected to be an effective clinical indicator for assessing prognosis and guide treatment decisions in MCL patients.

The value of complete remission according to positron emission tomography prior to autologous stem cell transplantation in lymphoma: a population-based study showing improved outcome.

BACKGROUND: Chimeric antigen-receptor T-cell and bispecific antibody therapies will likely necessitate a reconsideration of the role of autologous stem-cell transplantation (ASCT) in lymphoma. Patients who are likely to profit from ASCT need to be better identified. METHODS: Here, we investigated the value of positron emission tomography/computerized tomography (PET/CT) before ASCT. All 521 patients transplanted for lymphoma 1994-2019 at Karolinska (497 conditioned with BEAM) were included. RESULTS: Outcome improved over three calendar periods 1994-2004, 2005-2014, 2015-2019 (2-year overall survival [OS]: 66, 73, 83%; P = 0.018). Non-relapse mortality (NRM) at 100 days over the three periods were 9.8, 3.9, 2.9%, respectively. The OS improvement between 1994 and 2004 and 2005-2014 was due to lower NRM (P = 0.027), but the large OS advance from 2015 was not accompanied by a significant reduction in NRM (P = 0.6). The fraction of PET/CT as pre-ASCT assessment also increased over time: 1994-2004, 2%; 2005-2014, 24%; 2015-2019, 60% (P < 0.00005). Complete responses (PET/CT-CR) were observed in 77% and metabolically active partial responses (PET/CT-PR) in 23%. PET/CT-CR was a predictor for survival in the entire population (P = 0.0003), also in the subpopulations of aggressive B-cell (P = 0.004) and peripheral T-cell (P = 0.024) lymphomas. Two-year OS and progression-free survival (OS/PFS) for patients in PET/CT-CR were in relapsed/refractory aggressive B-cell lymphoma 87%/75% and peripheral T-cell lymphoma 91%/78%. The corresponding figures in PET/CT-PR were 43%/44 and 33%/33%. Patients with solitary PET/CT-positive lesions showed acceptable outcome with ASCT followed by local irradiation (2-year OS/PFS 80%/60%). CT was less discriminative: 2-year OS/PFS: CT-CR, 76%/66%; CT-PR, 62%/51%. Outcome was inferior after BEAC compared with BEAM conditioning. CONCLUSIONS: We conclude that the improved outcome reflects better, PET/CT-informed, identification of patients who should proceed to ASCT. The excellent survival of patients in PET/CT-CR indicates that ASCT should remain part of standard therapy for lymphoma.

Intensive induction regimens after deferring initial therapy for mantle cell lymphoma are not associated with improved survival.

INTRODUCTION: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. METHODS: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131). RESULTS: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model. CONCLUSIONS: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.

Treatment patterns and outcomes of older patients with mantle cell lymphoma in an Asian population.

BACKGROUND: Significant progress has been made in the treatment outcomes of mantle cell lymphoma (MCL) since the introduction of cytarabine and rituximab in modern regimens. However, older patients may not readily tolerate these agents nor derive benefit. We investigated the impact of age on treatment patterns and clinical outcomes of MCL patients in an Asian population. METHODS: A retrospective study was conducted on patients (n = 66) diagnosed with MCL at the National Cancer Centre Singapore between 1998 and 2018. The median follow-up duration was 40 months. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. RESULTS: The median age of the cohort was 59 years (range, 26-84), with a male predominance (73%). The majority (86%) had advanced stage 3-4 disease at diagnosis. Compared with younger patients, older patients aged ≥60 years (n = 32; 48.5%) presented more frequently with B-symptoms (75% vs 38%, p = 0.0028), anaemia (75% vs 35%, p = 0.0013), and carried higher prognostic risk scores (sMIPI high risk 84% vs 56%, p = 0.016). Non-cytarabine-based induction chemotherapy was more commonly administered in older patients (76% vs 32%, p = 0.0012). The 5-year overall survival (OS) and progression-free survival (PFS) was 68 and 25% respectively. In a multivariable model, older age (HR 3.42, 95%CI 1.48-7.92, p = 0.004) and anemia (HR 2.56, 95%CI 1.10-5.96, p = 0.029) were independently associated with poorer OS while older age (HR 2.24, 95%CI 1.21-4.14, p = 0.010) and hypoalbuminemia (HR 2.20, 95%CI 1.17-4.13, p = 0.014) were independently associated with poorer PFS. In an exploratory analysis, maintenance rituximab following induction chemotherapy improved PFS in younger patients, with median PFS of 131 months and 45 months with or without maintenance therapy respectively (HR 0.39, 95%CI 0.16-0.93, p = 0.035). In contrast, no survival benefit was observed in older patients. CONCLUSIONS: We demonstrated in our analysis that older patients with MCL may harbor adverse clinical features and may not derive benefit from maintenance rituximab, highlighting the need for further research in this area of need.

Transcriptome integration analysis and specific diagnosis model construction for Hodgkin's lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma.

Transcriptome differences between Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL), which are all derived from B cell, remained unclear. This study aimed to construct lymphoma-specific diagnostic models by screening lymphoma marker genes. Transcriptome data of HL, DLBCL, and MCL were obtained from public databases. Lymphoma marker genes were screened by comparing cases and controls as well as the intergroup differences among lymphomas. A total of 9 HL marker genes, 7 DLBCL marker genes, and 4 MCL marker genes were screened in this study. Most HL marker genes were upregulated, whereas DLBCL and MCL marker genes were downregulated compared to controls. The optimal HL-specific diagnostic model contains one marker gene (MYH2) with an AUC of 0.901. The optimal DLBCL-specific diagnostic model contains 7 marker genes (LIPF, CCDC144B, PRO2964, PHF1, SFTPA2, NTS, and HP) with an AUC of 0.951. The optimal MCL-specific diagnostic model contains 3 marker genes (IGLV3-19, IGKV4-1, and PRB3) with an AUC of 0.843. The present study reveals the transcriptome data-based differences between HL, DLBCL, and MCL, when combined with other clinical markers, may help the clinical diagnosis and prognosis.

Infiltration of CD163-, PD-L1- and FoxP3-positive cells adversely affects outcome in patients with mantle cell lymphoma independent of established risk factors.

We characterised patients with mantle cell lymphoma (MCL) with poor prognosis based on differences in immune infiltration. Different expressions of the tumour cell markers Cyclin D1 and sex-determining region Y-box transcription factor 11 (SOX11), and the immune markers cluster of differentiation 3 (CD3), CD4, CD8, CD25, forkhead box protein P3 (FoxP3), T-box transcription factor TBX21 (T-bet), programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1) and CD163 were investigated for all-cause mortality in 282 patients with MCL and time-to-progression (TTP) in 106 clinical trial patients. With increasing age, a significantly lower infiltration of CD3+ T lymphocytes was seen. T-cell infiltration was independent of cellular tumour antigen p53 (p53) expression, Ki-67, morphology and frequency of tumour cells. The all-cause mortality was higher in patients with PD-L1-expression above cut-off [hazard ratio (HR) 1·97, 95% confidence interval (CI) 1·18-3·25, adjusted for sex and MCL International Prognostic Index (MIPI)] and a higher frequency of CD163+ cells (continuously, HR 1·51, 95% CI 1·03-2·23, adjusting for age, sex, morphology, Ki-67 and p53). In patients treated within the Nordic Lymphoma Group MCL2/3 trials, TTP was shorter in patients with a higher frequency of FoxP3+ cells (HR 3·22, 95% CI 1·40-7·43) and CD163+ cells (HR 6·09, 95% CI 1·84-20·21), independent of sex and MIPI. When combined a higher frequency of CD163+ macrophages and PD-L1+ cells or high CD163+ macrophages and FoxP3+ regulatory T cells indicated worse outcome independent of established risk factors. The T-cell infiltrate was in turn independent of molecular characteristics of the malignant cells and decreased with age.