RESUMO
Aim ASPEN is a randomized, open-label, Phase III study comparing zanubrutinib and ibrutinib in patients with Waldenström macroglobulinemia (WM).Materials & methods: Patient-reported outcomes were exploratory end points assessed using the EORTC QLQ-C30 and EQ-5D-5L VAS scores.Results: Overall, 201 patients (102 zanubrutinib; 99 ibrutinib) were enrolled. Clinically meaningful differences were observed in diarrhea and nausea/vomiting in both the intent-to-treat population and in patients attaining very good partial response (VGPR) in earlier cycles of treatment, as well as in long-term physical functioning and fatigue in patients achieving VGPR.Conclusion: Treatment with zanubrutinib was associated with greater improvements in health-related quality of life compared with ibrutinib in patients with WM and MYD88 mutations.Clinical Trial Registration: NCT03053440 (ClinicalTrials.gov).
Patient quality of life is importantWhat is this article about? This article talks about a study called the ASPEN trial, which compares two medicines used for treating a rare blood cancer that doctors call Waldenström macroglobulinemia. The medicines are called zanubrutinib (ZAN) and ibrutinib (IBR). They work in the same way, by blocking a protein called Bruton tyrosine kinase. When patients take medicines for an illness, it is important to learn about their physical, social, emotional and mental well-being (quality of life). In this study, we asked patients to fill out questionnaires about their well-being before starting the study treatment for their blood cancer, and again a few times while taking the medication, to see if there were any changes.What were the results of the study? There were two groups of patients. One group took ZAN and the other took IBR. The patients could not choose which medicine they were going to take. Results from both groups of patients were compared. Patients taking ZAN did not feel worse or better about their diarrhea and sickness, but those taking IBR said these symptoms had become worse. Both medicines improved how patients were feeling. However, improvement in tiredness and physical ability was larger in patients taking ZAN than those on IBR, especially for the patients whose cancer was getting better.What do the results mean? For patients with a rare blood cancer in this study, those taking ZAN had a better quality of life than those taking IBR.
Assuntos
Adenina , Piperidinas , Pirazóis , Pirimidinas , Qualidade de Vida , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Masculino , Feminino , Piperidinas/uso terapêutico , Idoso , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Fator 88 de Diferenciação Mieloide/genética , Medidas de Resultados Relatados pelo Paciente , Idoso de 80 Anos ou mais , Resultado do Tratamento , Mutação , AdultoRESUMO
PURPOSE: Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS: We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS: In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively (P < .0001). CONCLUSION: Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.
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Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/mortalidade , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Medição de Risco , Prognóstico , L-Lactato Desidrogenase/sangue , Estudos Retrospectivos , Idoso de 80 Anos ou maisRESUMO
ABSTRACT: Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.
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Antígenos CD19 , Imunoterapia Adotiva , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/terapia , Macroglobulinemia de Waldenstrom/imunologia , Macroglobulinemia de Waldenstrom/patologia , Masculino , Idoso , Imunoterapia Adotiva/métodos , Feminino , Antígenos CD19/imunologia , Pessoa de Meia-Idade , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Resultado do TratamentoRESUMO
Although Bruton's tyrosine kinase (BTK) inhibitors (BTKi) have significantly improved patient prognosis, mantle cell lymphoma (MCL) is still considered incurable due to primary and acquired resistance. We have recently shown that aberrant expression of the Src-family tyrosine kinase hematopoietic cell kinase (HCK) in MCL correlates with poor prognosis, and that genetic HCK perturbation impairs growth and integrin-mediated adhesion of MCL cells. Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). In BTKi-resistant cells this is mediated by inhibition of HCK, which results in repression of AKT-S6 signaling. In addition, KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner. Finally, we show that MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194. Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients.
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Tirosina Quinase da Agamaglobulinemia , Adesão Celular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Integrinas , Linfoma de Célula do Manto , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-hck , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/genética , Humanos , Adesão Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-hck/metabolismo , Proteínas Proto-Oncogênicas c-hck/genética , Proteínas Proto-Oncogênicas c-hck/antagonistas & inibidores , Integrinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.
Assuntos
Adenina/análogos & derivados , Piperidinas , Pirazóis , Pirimidinas , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Fator 88 de Diferenciação Mieloide/genética , BiomarcadoresRESUMO
ABSTRACT: Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.
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Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases , Macroglobulinemia de Waldenstrom , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Genômica/métodos , Mutação , Fator 88 de Diferenciação Mieloide/genética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirimidinas/uso terapêutico , Receptores CXCR4/genética , Receptores CXCR4/antagonistas & inibidores , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genéticaAssuntos
Adenina , Mutação , Fator 88 de Diferenciação Mieloide , Piperidinas , Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Humanos , Fator 88 de Diferenciação Mieloide/genética , Piperidinas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Masculino , Resultado do Tratamento , Feminino , Prognóstico , MultiômicaRESUMO
ABSTRACT: Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.
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Adenina/análogos & derivados , Compostos Bicíclicos Heterocíclicos com Pontes , Sulfonamidas , Macroglobulinemia de Waldenstrom , Humanos , Idoso , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Piperidinas , Arritmias CardíacasRESUMO
The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.
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Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Piperidinas/uso terapêutico , Pirimidinas/efeitos adversosRESUMO
Consensus Panel 4 (CP4) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current criteria for diagnosis and response assessment. Since the initial consensus reports of the 2nd International Workshop, there have been updates in the understanding of the mutational landscape of IgM related diseases, including the discovery and prevalence of MYD88 and CXCR4 mutations; an improved recognition of disease related morbidities attributed to monoclonal IgM and tumor infiltration; and a better understanding of response assessment based on multiple, prospective trials that have evaluated diverse agents in Waldenstrom's macroglobulinemia. The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report.
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Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Fator 88 de Diferenciação Mieloide/genética , Consenso , Estudos Prospectivos , Imunoglobulina M/metabolismoRESUMO
Consensus Panel 1 (CP1) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with updating guidelines for the management of symptomatic, treatment-naïve patients with WM. The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function. For first-line treatment, chemoimmunotherapy (CIT) regimens such as dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine, rituximab (Benda-R) continue to play a central role in managing WM, as they are effective, of fixed duration, generally well-tolerated, and affordable. Covalent BTK inhibitors (cBTKi) offer a continuous, generally well-tolerated alternative for the primary treatment of WM patients, particularly those unsuitable for CIT. In a Phase III randomized trial updated at IWWM-11, the second-generation cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper remissions, thus categorizing zanubrutinib as a suitable treatment option in WM. While the overall findings of a prospective, randomized trial updated at IWWM-11 did not show superiority of fixed duration rituximab maintenance over observation following attainment of a major response to Benda-R induction, a subset analysis showed benefit in patients >65 years and those with a high IPPSWM score. Whenever possible, the mutational status of MYD88 and CXCR4 should be determined before treatment initiation, as alterations in these 2 genes predict sensitivity towards cBTKi activity. Treatment approaches for WM-associated cryoglobulins, cold agglutinins, AL amyloidosis, Bing-Neel syndrome (BNS), peripheral neuropathy, and hyperviscosity syndrome follow the common principle of reducing tumor and abnormal protein burden rapidly and deeply to improve symptoms. In BNS, ibrutinib can be highly active and produce durable responses. In contrast, cBTKi are not recommended for treating AL amyloidosis. The panel emphasized that continuous improvement of treatment options for symptomatic, treatment-naïve WM patients critically depends on the participation of patients in clinical trials, whenever possible.
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Amiloidose de Cadeia Leve de Imunoglobulina , Macroglobulinemia de Waldenstrom , Humanos , Rituximab/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/diagnóstico , Consenso , Estudos Prospectivos , Cloridrato de Bendamustina/uso terapêuticoRESUMO
Consensus Panel 6 (CP6) of the 11th International Workshop on Waldenström's Macroglobulinemia (IWWM-11) was tasked with reviewing the state of the art for diagnosis, prognosis, and therapy of AL amyloidosis associated with Waldenström macroglobulinemia (WM). Since significant advances have been made in the management of AL amyloidosis an update for this rare disease associated with WM was necessary. The key recommendations from IWWM-11 CP6 included: (1) The need to improve the diagnostic process by recognizing red flags and using biomarkers and imaging; (2) The essential tests for appropriate workup; (3) The diagnostic flowchart, including mandatory amyloid typing, that improves the differential diagnosis with transthyretin amyloidosis; (4) Criteria for therapy response assessment; (5) State of the art of the treatment including therapy of wild type transthyretin amyloidosis associated with WM.
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Neuropatias Amiloides Familiares , Amiloidose de Cadeia Leve de Imunoglobulina , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/terapia , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Consenso , Neuropatias Amiloides Familiares/complicaçõesRESUMO
WHAT IS THIS SUMMARY ABOUT?: This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo ("sugar pill") plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months). WHAT WERE THE RESULTS?: During the 5 years of monitoring, more people who took ibrutinib plus rituximab experienced an improvement in their disease and lived longer without their disease getting worse compared to those who took placebo plus rituximab. Side effects from ibrutinib and rituximab were manageable and generally decreased over time. Participants in both study groups reported improvements in quality of life, but those who took ibrutinib plus rituximab reported significantly greater improvement in their quality of life (as measured by FACT-An score) compared to those who took placebo plus rituximab. WHAT DO THE RESULTS MEAN?: These results show that ibrutinib plus rituximab is better than rituximab alone in people with WM and that ibrutinib plus rituximab is safe and effective in the long term. This information confirms the role of ibrutinib plus rituximab as a standard of care for WM. Clinical Trial Registration: NCT02165397 (ClinicalTrials.gov).