Outcomes of younger patients with mantle cell lymphoma experiencing late relapse (>24 months): the LATE-POD study.

ABSTRACT: Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are the established standard treatment at first relapse, but their effectiveness compared with chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes among patients at first, late POD beyond 24 months. The primary objective was progression-free survival from the time of second-line therapy (PFS-2) of BTKi vs CIT. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 years (range, 19-70), and 77% were male. Median follow-up from the time of second-line therapy was 53 months (range, 12-144). Overall, 114 patients had second-line BTKi, whereas 271 had CIT, consisting of rituximab-bendamustine (R-B; n = 101), R-B and cytarabine (R-BAC; n = 70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone]- or platinum-based; n = 100). The 2 groups were balanced in clinicopathological features and median time to first relapse. Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT (not reached [NR] vs 26 months, respectively; P = .0003) and overall survival (NR and 56 months, respectively; P = .03). Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio, 0.41 for R-B and 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in patients with BTKi-naïve MCL.

Pre-treatment health-related quality of life parameters have prognostic impact in patients >65 years with newly diagnosed mantle cell lymphoma: The Nordic Lymphoma Group MCL4 (LENA-BERIT) experience.

Mantle cell lymphoma (MCL) is a rare, often aggressive type of B-cell lymphoma with poor survival and no cure. Cancer and cancer treatment has a negative impact on health-related quality of life (HRQOL) both during active disease and in the long term, and improvement of HRQOL is a crucial objective of cancer therapy in older patients and no curative intent. Baseline HRQOL has in other lymphoma populations been shown to be predictive of outcome. Here, we explored HRQOL, and its association with survival, by the EORTC QLQ-C30 questionnaire, before, during and after chemotherapy in a patient cohort with MCL, treated within the NLG-MCL4 trial, designed to evaluate the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment. Fifty-one patients were enrolled, median age was 71 years (range 62-84), 37 were men (73%). Pre-treatment HRQOL was similar to scores from the reference population with healthy individuals. During treatment, HRQOL deteriorated, but reverted to the same level as the reference population after treatment. There was a correlation between physical function (p = 0.001) and role function (p = 0.006) at baseline and WHO performance status, but not with other clinical or genetic prognostic factors. None of the baseline factors were predictive for treatment related to HRQOL in this cohort. Pre-treatment physical (p = 0.011) and role function (p = 0.032) were independent factors associated with overall survival, and physical function (p = 0.002) was also associated with progression free survival. These findings may possibly be used to design support during treatment and improve rehabilitation. Further investigations are needed for assessment of long-term HRQOL.

Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma.

For elderly patients with mantle cell lymphoma (MCL), there is no defined standard therapy. In this multicenter, open-label phase 1/2 trial, we evaluated the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment for elderly patients with MCL. Patients >65 years with untreated MCL, stages II-IV were eligible for inclusion. Primary end points were maximally tolerable dose (MTD) of LEN and progression-free survival (PFS). Patients received 6 cycles every four weeks of L-B-R (L D1-14, B 90 mg/m2 IV, days 1-2 and R 375 mg/m2 IV, day 1) followed by single LEN (days 1-21, every four weeks, cycles 7-13). Fifty-one patients (median age 71 years) were enrolled from 2009 to 2013. In phase 1, the MTD of LEN was defined as 10 mg in cycles 2 through 6, and omitted in cycle 1. After 6 cycles, the complete remission rate (CRR) was 64%, and 36% were MRD negative. At a median follow-up time of 31 months, median PFS was 42 months and 3-year overall survival was 73%. Infection was the most common nonhematologic grade 3 to 5 event and occurred in 21 (42%) patients. Opportunistic infections occurred in 3 patients: 2 Pneumocystis carinii pneumonia and 1 cytomegalovirus retinitis. Second primary malignancies (SPM) were observed in 8 patients (16%). LEN could safely be combined with R-B when added from the second cycle in patients with MCL, and was associated with a high rate of CR and molecular remission. However, we observed a high degree of severe infections and an unexpected high number of SPMs, which may limit its use. This trial is registered at www.Clinicaltrials.gov as #NCT00963534.

Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study.

There is consensus that young patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens, but optimal treatment of elderly patients as well for as patients with limited or indolent disease is not defined. Our aim was to evaluate and compare outcome in relation to prognostic factors and first-line treatment in patients with MCL in a population-based data set. Data were collected from the Swedish and Danish Lymphoma Registries from the period of 2000 to 2011. A total of 1389 patients were diagnosed with MCL. During this period, age-standardized incidence MCL increased, most prominently among males. Furthermore, male gender was associated with inferior overall survival (OS) in multivariate analysis (hazard ratio [HR] = 1.36; P = .002). Forty-three (3.6%) patients with stage I-II disease received radiotherapy with curative intent, showing a 3-year OS of 93%. Twenty-nine (2.4%) patients followed a watch-and-wait approach and showed a 3-year OS of 79.8%. Among patients receiving systemic treatment, rituximab (n = 766; HR = 0.66; P = .001) and autologous stem cell transplant (n = 273; HR = 0.55; P = .004) were independently associated with improved OS in multivariate analysis. Hence, by a population-based approach, we were able to provide novel data on prognostic factors and primary treatment of MCL, applicable to routine clinical practice.

Infections in patients with mantle cell lymphoma.

Advancements in treatments have significantly improved the prognosis for mantle cell lymphoma (MCL), and there is a growing population of survivors with an increased susceptibility to infections. We assessed the incidence of infections by clinical characteristics and treatment both before and after MCL diagnosis in Sweden. Patients with a diagnosis of MCL ≥ 18 years between 2007 and 2019 were included, along with up to 10 matched comparators. Infectious disease diagnosis and anti-infective drug dispensation were identified by the National Patient and the Prescribed Drug Registers, respectively. Patients and comparators were followed from the diagnosis/matching date until death, emigration, or June 30, 2020. Overall, 1559 patients and 15,571 comparators were followed for a median duration of 2.9 and 5 years, respectively. The infection rate among patients was twofold higher, RRadj = 2.14 (2.01-2.27), contrasted to the comparator group. There was a notable rise in infection rates already 4 years before MCL diagnosis, which reached a fourfold increase in the first year after diagnosis and persisted significantly increased for an additional 8 years. Among patients, 69% (n = 1080) experienced at least one infection during the first year of follow-up. Influenza, pneumonia, other bacterial infections, urinary tract infections, and acute upper respiratory infections were the most frequent. Notably, MCL remained to be the primary leading cause of death among patients (57%, n = 467/817). Infections as the main cause of death were rare (2.6%, n = 21). Our study highlights the importance of thoroughly assessing infectious morbidity when appraising new treatments. Further investigations are warranted to explore strategies for reducing infectious disease burden.

Late effects in patients with mantle cell lymphoma treated with or without autologous stem cell transplantation.

Studies on late effects in patients with mantle cell lymphoma (MCL) are becoming increasingly important as survival is improving, and novel targeted drugs are being introduced. However, knowledge about late effects is limited. The aim of this population-based study was to describe the magnitude and panorama of late effects among patients treated with or without high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT). The study cohort included all patients with MCL, recorded in the Swedish Lymphoma Register, aged 18 to 69 years, diagnosed between 2000 and 2014 (N = 620; treated with HD-ASCT, n = 247) and 1:10 matched healthy comparators. Patients and comparators were followed up via the National Patient Register and Cause of Death Register, from 12 months after diagnosis or matching to December 2017. Incidence rate ratios of the numbers of outpatient visits, hospitalizations, and bed days were estimated using negative binomial regression models. In relation to the matched comparators, the rate of specialist and hospital visits was significantly higher among patients with MCL. Patients with MCL had especially high relative risks of infectious, respiratory, and blood disorders. Within this observation period, no difference in the rate of these complications, including secondary neoplasms, was observed between patients treated with and without HD-ASCT. Most of the patients died from their lymphoma and not from another cause or treatment complication. Taken together, our results imply that most of the posttreatment health care needs are related to the lymphoma disease itself, thus, indicating the need for more efficient treatment options.

Nationwide Assessment of Patient Trajectories in Mantle Cell Lymphoma: The Swedish MCLcomplete Project.

Mantle cell lymphoma (MCL) is a B-cell malignancy currently considered incurable. Although some patients obtain prolonged remission after first-line chemoimmunotherapy, many will need several treatment lines. Here, we present a nationwide assessment of treatment strategies, time to progression and survival in MCL. All patients diagnosed with MCL 2006-2018 were identified in the Swedish Lymphoma Register. Information on all lines of therapy was extracted from the medical records. Overall and progression-free survival (OS and PFS) were assessed through August 2021. In total, 1367 patients were included (median age, 71 years) and median follow-up was 6.8 years. Two hundred and one (15%) were managed initially with watch-and-wait, but 1235 (90%) eventually received treatment. The most frequently used first-line regimens were rituximab-bendamustine (BR) (n = 368; 30%) and Nordic MCL2 (n = 342; 28%). During follow-up, 630 patients (46%) experienced relapse/progression and 546 (40%) received second-line treatment. The most frequently used second-line regimen was BR (n = 185; 34%) but otherwise a wide variety of second-line treatments were used. Further, 382 and 228 patients experienced a second or third relapse/progression, respectively. Median PFS after first (PFS-1), second (PFS-2), third (PFS-3), and fourth (PFS-4) treatment lines was 29.4, 8.9, 4.3, and 2.7 months. Patients with early progression, defined as a PFS-1 <24 months, had an inferior median OS of 13 versus 37 months in patients with later relapse. For patients treated with frontline BR, however, time to relapse had no impact on later outcome. By use of nationwide population-based data, we provide important benchmarks for future studies of all treatment lines in MCL.

Secondary malignancies among mantle cell lymphoma patients.

PURPOSE: With modern treatments, mantle cell lymphoma (MCL) patients more frequently experience long-lasting remission resulting in a growing population of long-term survivors. Follow-up care includes identification and management of treatment-related late-effects, such as secondary malignancies (SM). We conducted a population-based study to describe the burden of SM in MCL patients. METHODS: All patients with a primary diagnosis of MCL, aged ≥ 18 years and diagnosed between 2000 and 2017 in Sweden were included along with up to 10 individually matched population comparators. Follow-up was from twelve months after diagnosis/matching until death, emigration, or December 2019, whichever occurred first. Rates of SM among patients and comparators were estimated using the Anderson-Gill method (accounting for repeated events) and presented as hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age at diagnosis, calendar year, sex, and the number of previous events. RESULTS: Overall, 1 452 patients and 13 992 comparators were followed for 6.6 years on average. Among patients, 230 (16%) developed at least one SM, and 264 SM were observed. Relative to comparators, patients had a higher rate of SM, HRadj= 1.6 (95%CI:1.4-1.8), and higher rates were observed across all primary treatment groups: the Nordic-MCL2 protocol, R-CHOP, R-bendamustine, ibrutinib, lenalidomide, and R-CHOP/Cytarabine. Compared to Nordic-MCL2, treatment with R-bendamustine was independently associated with an increased risk of SM, HRadj= 2.0 (95%CI:1.3-3.2). Risk groups among patients were those with a higher age at diagnosis (p < 0.001), males (p = 0.006), and having a family history of lymphoma (p = 0.009). Patients had preferably higher risk of melanoma, other neoplasms of the skin and other hematopoietic and lymphoid malignancies. CONCLUSIONS: MCL survivors have an increased risk of SM, particularly if treated with R-bendamustine. The intensive treatments needed for long-term remissions are a concern, and transition to treatment protocols with sustained efficacy but with a lower risk of SM is needed.

Unmarried or less-educated patients with mantle cell lymphoma are less likely to undergo a transplant, leading to lower survival.

It is unknown how many mantle cell lymphoma (MCL) patients undergo consolidation with autologous hematopoietic cell transplantation (AHCT), and the reasons governing the decision, are also unknown. The prognostic impact of omitting AHCT is also understudied. We identified all MCL patients diagnosed from 2000 to 2014, aged 18 to 65 years, in the Swedish Lymphoma Register. Odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models were used to compare the likelihood of AHCT within 18 months of diagnosis. All-cause mortality was compared between patients treated with/without AHCT using hazard ratios (HRs) and 95% CIs estimated from Cox regression models. Probabilities of being in each of the following states: alive without AHCT, alive with AHCT, dead before AHCT, and dead after AHCT, were estimated over time from an illness-death model. Among 369 patients, 148 (40%) were not treated with AHCT within 18 months. Compared with married patients, never married and divorced patients had lower likelihood of undergoing AHCT, as had patients with lower educational level, and comorbid patients. Receiving AHCT was associated with reduced all-cause mortality (HR = 0.58, 95% CI: 0.40-0.85). Transplantation-related mortality was low (2%). MCL patients not receiving an AHCT had an increased mortality rate, and furthermore, an undue concern about performing an AHCT in certain societal groups was seen. Improvements in supportive functions potentially increasing the likelihood of tolerating an AHCT and introduction of more tolerable treatments for these groups are needed.

Ibrutinib inhibits antibody dependent cellular cytotoxicity induced by rituximab or obinutuzumab in MCL cell lines, not overcome by addition of lenalidomide.

BACKGROUND: The Bruton's Tyrosine Kinase (BTK)-inhibitor ibrutinib is highly active in mantle cell lymphoma (MCL) but may inhibit response to anti-CD20 antibody as previously shown in CLL models. We investigated how antibody-dependent cellular cytotoxicity (ADCC) induced by type I/II anti-CD20 antibodies was affected by treatment with ibrutinib in MCL. Furthermore, we investigated if lenalidomide, a potential sensitizer to anti-CD20 treatment, could prevent an inhibitory effect of ibrutinib. METHODS: Anti-CD20 (rituximab/obinutuzumab) opsonized MCL cell lines were co-cultured with ibrutinib (± lenalidomide)-exposed effector cells, and analyzed for evaluation of cell death. RESULTS: Cell death induced by rituximab was reduced with 75% at 0.5 µM ibrutinib and with 52% at 0.1 µM ibrutinib when induced by obinutuzumab, even by addition of lenalidomide. Moreover, obinutuzumab was associated with higher rate of cell death compared to rituximab. CONCLUSION: Ibrutinib negatively affects anti-CD20 induced cell death in MCL, not reversed by lenalidomide. Explorations of sequential administration and selective BTK-inhibitors may reveal the optimal combination of novel agents in MCL.