Clinical presentation determines selection of patients for initial observation in mantle cell lymphoma.
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ABSTRACT:
SUBMITTER: Kumar A
PROVIDER: S-EPMC6442955 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
Clinical presentation determines selection of patients for initial observation in mantle cell lymphoma.
Kumar Anita A Ying Zhitao Z Alperovich Anna A Dogan Ahmet A Hamlin Paul P Moskowitz Craig C Pichardo Janine J Portlock Carol C Sha Fushen F Zelenetz Andrew D AD Zhang Zhigang Z Drill Esther E Woo Kaitlin K Younes Anas A
Haematologica 20190401 4
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Project description:BackgroundMantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy.MethodsWe conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life.ResultsA total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome ("tumor flare") (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be 85% (95% CI, 67 to 94), and the 2-year overall survival 97% (95% CI, 79 to 99). A response to treatment was associated with improvement in quality of life.ConclusionsCombination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle-cell lymphoma. (Funded by Celgene and Weill Cornell Medical College; ClinicalTrials.gov number, NCT01472562.).
| S-EPMC4710541 | biostudies-literature
Project description: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.
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Project description:Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic alterations for the malignant transformation. A short list of recurrently mutated genes including ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1, NOTCH2, and TRAF2 recently emerged as contributors to the pathogenesis of MCL. Notably, NOTCH1 and NOTCH2 were found to be mutated in multiple B cell lymphomas, including 5-10% of MCL, with most of these mutations occurring within the PEST domain of the protein. The NOTCH genes play a critical role in the early and late phases of normal B cell differentiation. In MCL, mutations in the PEST domain stabilize NOTCH proteins, rendering them resistant to degradation, which subsequently results in the upregulation of genes involved in angiogenesis, cell cycle progression, and cell migration and adhesion. At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions.
| S-EPMC10299455 | biostudies-literature
Project description:Although chemoimmunotherapy is the current standard of care for initial treatment of mantle cell lymphoma (MCL), newer data suggest that there may be a role for a chemotherapy-free approach. We report the 9-year follow-up results of a multicenter, phase 2 study of lenalidomide plus rituximab (LR) as the initial treatment of MCL. The LR doublet is used as induction and maintenance until progression, with optional discontinuation after 3 years. We previously reported an overall response rate of 92% in evaluable patients, with 64% achieving a complete response. At a median follow-up of 103 months, 17 of 36 evaluable patients (47%) remain in remission. The 9-year progression-free survival and overall survival were 51% and 66%, respectively. During maintenance, hematologic adverse events included asymptomatic grade 3 or 4 cytopenia (42% neutropenia, 5% thrombocytopenia, and 3% anemia) and mostly grade 1 to 2 infections managed in the outpatient setting (50% upper respiratory infections, 21% urinary tract infections, 16% sinusitis, 16% cellulitis, and 13% pneumonia, with 5% requiring hospitalization). More patients developed grade 1 and 2 neuropathy during maintenance therapy (29%) than during induction therapy (8%). Twenty-one percent of patients developed secondary malignancies, including 5% with invasive malignancies, whereas the remainder were noninvasive skin cancers treated with local skin-directed therapy. Two patients permanently discontinued therapy because of concerns of immunosuppression during the COVID-19 pandemic. With long-term follow-up, LR continues to demonstrate prolonged, durable responses with manageable safety as initial induction therapy. This trial was registered at www.clinicaltrials.gov as #NCT01472562.
| S-EPMC10641095 | biostudies-literature
Project description:We report 5-year follow-up of a multicenter phase 2 study of lenalidomide plus rituximab (LR) as initial treatment of mantle cell lymphoma (MCL). The regimen includes induction and maintenance with the LR doublet. Treatment was continuous until progression, with optional discontinuation after 3 years. The median age of the 38 participants was 65 years, with MCL international prognostic index scores balanced among low, intermediate, and high risk (34%, 34%, and 32%, respectively). Twenty-seven (75%) of the 36 evaluable patients completed ≥3 years of study treatment. At a median follow-up of 64 months (range, 21-78), the 3-year progression-free survival (PFS) and overall survival (OS) were 80% and 90%, respectively, with 5-year estimated PFS and OS of 64% and 77%, respectively. During maintenance, hematologic adverse events (AEs) included asymptomatic grade 3 or 4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia) and mostly grade 1 or 2 infections managed in the outpatient setting (45% upper respiratory infection, 21% urinary tract infection, 13% sinusitis, 11% cellulitis, 8% pneumonia). Nonhematologic AEs, such as constitutional and inflammatory symptoms, occurred at reduced frequency and intensity compared with induction. A peripheral blood minimal residual disease (MRD) assay (clonoSEQ) showed MRD-negative complete remission in 8 of 10 subjects who had completed ≥3 years of treatment and with available samples for analysis. With longer follow-up, LR continues to demonstrate durable responses and manageable safety as initial induction and maintenance therapy for MCL (ClinicalTrials.gov NCT01472562).
| S-EPMC6634960 | biostudies-literature
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| S-EPMC11655513 | biostudies-literature
Project description:While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6-182), 5-year progression-free survival (PFS) was 45% (95% CI: 35-54) and 5-year overall survival (OS) was 71% (95% CI: 62-79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.
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Project description:SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).
| S-EPMC8989861 | biostudies-literature
Project description:BackgroundWe conducted this trial to determine the maximum tolerated dose (MTD) of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma.Patients and methodsA standard phase I cohort of three study design was utilized. The fixed doses of rituximab and cladribine were 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. There were five planned temsirolimus i.v. dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1, 8 and 15; and 25 mg days 1, 8, 15, and 22.ResultsSeventeen patients were treated: three each at levels 1-4 and five at dose level 5. The median age was 75 years (52-86 years). Mantle Cell International Prognostic Index (MIPI) scores were low in 6% (1), intermediate in 59% (10), and high in 35% (6) of patients. Five patients were treated at level 5 without dose limiting toxicity. Hematologic toxicity was frequent: grade 3 anemia in 12%, grade 3 thrombocytopenia in 41%, grade 4 thrombocytopenia in 24%, grade 3 neutropenia in 6%, and grade 4 neutropenia in 18% of patients. The overall response rate (ORR) was 94% with 53% complete response and 41% partial response. The median progression-free survival was 18.7 months.ConclusionsTemsirolimus 25 mg i.v. weekly may be safely added to rituximab and cladribine at 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma.Clinicaltrialsgov identifierNCT00787969.
| S-EPMC5808677 | biostudies-literature