RESUMO
ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.
Assuntos
Adenina , Linfoma de Célula do Manto , Piperidinas , Adulto , Idoso , Feminino , Humanos , Masculino , Adenina/análogos & derivados , Estudos de Coortes , Inglaterra , Linfoma de Célula do Manto/tratamento farmacológico , Rituximab/uso terapêuticoRESUMO
Time to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton's tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto , Adulto , Humanos , Linfoma de Célula do Manto/patologia , Antígeno Ki-67 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , PrognósticoRESUMO
In a large multicentre retrospective real-world analysis, Hess and colleagues describe outcomes in post-Bruton tyrosine kinase inhibitor (BTKi) mantle cell lymphoma patients managed in clinical practice prior to availability of brexucabtagene autoleucel (Tecartus). Outcome data not only provide a useful benchmark for future studies but also highlight the great challenges that still lie ahead in managing this challenging patient cohort. Commentary on: Hess et al. Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR-2 retrospective chart review study. Br J Haematol 2023;202:749-759.
Assuntos
Linfoma de Célula do Manto , Receptores de Antígenos Quiméricos , Adulto , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Estudos Retrospectivos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Primary central nervous system lymphoma is rare, comprising 4% of intracranial neoplasms. Although haematologists or oncologists subsequently manage the condition, it is often neurologists who first make, or at least suspect, the diagnosis. This article reviews the disease, its clinical and radiological features and details the work-up needed to achieve a diagnosis (namely histological or cytological confirmation) and to prepare the patient for treatment. We note the importance of brain biopsy, the role of corticosteroids and the varied treatment options.
Assuntos
Neoplasias Encefálicas , Linfoma , Humanos , Neurologistas , Neoplasias Encefálicas/diagnóstico , Corticosteroides , Linfoma/diagnóstico , Linfoma/terapia , Linfoma/patologia , Sistema Nervoso CentralRESUMO
Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.
Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Progressão da Doença , Feminino , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Recidiva , Estudos Retrospectivos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Medicina Estatal/organização & administração , Reino Unido , Suspensão de TratamentoRESUMO
Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n = 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n = 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/mortalidade , Recidiva Local de Neoplasia/mortalidade , Terapia de Salvação , Adulto , Idoso , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Agências Internacionais , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Terapia Combinada , Feminino , Seguimentos , Genes p53 , Doenças Hematológicas/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Estimativa de Kaplan-Meier , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
In this review, we explore insights into the pathophysiology of Bruton tyrosine kinase inhibitor (BTKi) resistance in mantle cell lymphoma, and consider potential therapeutic targets. We review the possible clinical benefits of giving BTKis alongside other novel therapies, and evaluate clinical data for treatment strategies post BTKi progression that may help guide current practice. We conclude by considering future approaches, including the potential role of chimeric antigen receptor T-cell therapy.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Resistencia a Medicamentos Antineoplásicos , Imunoterapia Adotiva , Linfoma de Célula do Manto , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/metabolismo , Humanos , Linfoma de Célula do Manto/enzimologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapiaRESUMO
Data on older patients with primary central nervous system lymphoma (PCNSL) are scarce. Comorbidities and performance status frequently compromise outcomes in this group. Medical records for consecutive patients ≥65 years (n = 244) with PCNSL diagnosed 2012-2017 from 14 UK centres were retrospectively reviewed. Of these 192 patients received methotrexate (MTX)-based treatment. Patients were categorised based on clinician's treatment choice into 'palliative' (n = 52), 'less intensive: MTX ± rituximab ± alkylators' (n = 74) and 'intensive: MTX/cytarabine combinations' (n = 118) groups. Complete remission (CR) rate, two-year progression-free survival (PFS) and overall survival (OS) rates were 49%, 11% and 24% for the less intensive and 69%, 40% and 50% for the intensive groups. Treatment-related mortality (TRM) was 6·8% for MTX-treated patients. Median MTX cumulative dose was 8·8 g/m2 (range 1·5-21) over a median of three cycles. Higher relative dose intensity of MTX (MTX-RDI) was associated with improved PFS and OS in both groups adjusting for age, Eastern cooperative oncology group (ECOG) score and baseline parameters. Two-year PFS and OS for patients receiving four or more induction cycles followed by consolidation (n = 36) were 65% and 70% respectively. Older patients completing MTX-based induction and consolidation had clinical outcomes similar to those in younger cohorts. These retrospective data suggest that maximising MTX-RDI and delivering consolidation in a subgroup of older patients may improve clinical outcomes.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/administração & dosagem , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/mortalidade , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/mortalidade , Masculino , Metotrexato/uso terapêutico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Indução de Remissão , Estudos Retrospectivos , Rituximab/administração & dosagem , Reino Unido/epidemiologiaRESUMO
Patients with mantle cell lymphoma progressing on Bruton's tyrosine kinase inhibitor (BTKi) have very poor prognosis and there is currently no standard of care. In this retrospective cohort study, patients progressing on BTKi received R-BAC (rituximab, bendamustine, cytarabine). Overall response rate was 83% (complete response 60%) and 31% were bridged to allogeneic stem cell transplant (alloSCT). Median progression-free survival was 10.1 months (95% confidence interval (CI) 6·9-13·3) and median overall survival was 12·5 months (95% CI 11·0-14·0). In those consolidated with alloSCT only one patient relapsed. R-BAC demonstrates a high response rate in the post-BTKi setting and in transplant eligible patients is an effective bridge to alloSCT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Citarabina/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cloridrato de Bendamustina/farmacologia , Citarabina/farmacologia , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Rituximab/farmacologiaRESUMO
The last 20 years has seen considerable advances made in the management of younger patients with mantle cell lymphoma. The use of high dose cytarabine and rituximab in induction therapy, usually followed by autologous stem cell transplant consolidation, has become established practice and the median overall survival now exceeds 10 years. However, this high intensity upfront approach is not necessarily appropriate for all newly diagnosed patients. A minority exhibit disease that behaves in an indolent fashion with no proven benefit from early intervention, and at the opposite end of the spectrum a high-risk group exists who do poorly with conventional treatment. This review considers the role of watch and wait strategies in indolent presentations, examines the evidence behind current induction approaches and considers ways to modify these for those young patients presenting with adverse features. It concludes with an assessment of the emerging role of novel agents and the search for robust risk-adapted treatment strategies.