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It is becoming increasingly clear that interhemispheric transfer is an important factor in visual word recognition. One of the two computational models of visual word recognition that includes this aspect, the SERIOL model, is tested on the basis of recently obtained behavioural word naming data. Optimal viewing position (OVP) data were collected from participants with left hemisphere language dominance, right hemisphere language dominance, and bilateral language representation (as determined by fMRI). We employ a mathematical model, which is based on some of the underlying assumptions of SERIOL, to investigate the model's ability to predict our results. We show that this mathematical model, which makes use of the original parameters, is able to perfectly predict the differences in the OVP curves observed in the three groups of participants. [ABSTRACT FROM AUTHOR]

Background: Polymorphisms in FcγRIIa and FcγRIIIa receptors are associated with responses to the CD20-directed immunoglobulin G1 (IgG1) monoclonal antibody rituximab among patients with indolent lymphoma. At odds with the aforementioned clinical observations has been the finding that IgG1 binding is impacted by polymorphisms in FcγRIIIa but not FcγRIIa. One possibility for this discrepancy might involve linkage of polymorphisms between FcγRIIa and FcγRIIIa. Materials and Methods: As such, we performed allelespecific polymerase chain reaction and directed sequencing of the genomic DNA coding region of FcγRIIA and FcγRIIIA for 52 healthy individuals. Results: Two common polymorphisms were observed for FcγRIIA (at positions 27 and 131) and FcγRIIIA (at positions 48 and 158). Importantly, we observed linkage among polymorphisms within and between FcγRIIa and FcγRIIIa, including the expression of histidine at FcγRIIa-131 and valine at FcγRIIIa, both of which are associated with enhanced responses to rituximab. The results of these studies demonstrate that there is wide linkage within and between polymorphisms in FcγRIIa and FcγRIIIa and might provide an explanation for why polymorphisms at FcγRIIa are associated with rituximab responses despite a lack of impact on IgG1 binding. Conclusion: Knowledge of such linkages could facilitate the development of diagnostic tests aimed at identifying patients who might be more suitable for treatment with rituximab and possibly other therapeutic antibodies. [ABSTRACT FROM AUTHOR]

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., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) with immunoglobulin M (IgM) monoclonal gammopathy and morphologic evidence of bone marrow infiltration by LPL. Immunophenotyping and genotyping provide a firm pathological basis for diagnosis and are particularly valuable in differential diagnosis between WM and related diseases. Emerging technologies in mutational analysis present new opportunities, but challenges remain around standardization of methodologies and reporting of mutational data across centers., Areas Covered: The review provides an overview of the diagnosis of WM, with a particular focus on the role of immunophenotyping and genotyping., Expert Opinion: Demonstration of LPL with a bone marrow biopsy is essential to reach a definitive diagnosis of WM. However, MYD88 L265P and a typical WM immunophenotypic profile are valuable for the differential diagnosis of WM and related diseases, such as marginal zone lymphoma, multiple myeloma, and chronic lymphocytic leukemia. These methodologies must be utilized across centers and with appropriate standards followed in the evaluation and reporting of sensitivities and specificities. The diagnostic and/or prognostic value of mutations in genes such as CXCR4 and TP53 that are currently not routinely evaluated in the diagnosis of WM should be explored.

Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by malignant lymphoplasmacytic cells in the bone marrow (BM). To dissect the pathophysiology of WM, we evaluated clonal cells by mapping of B cell lymphomagenesis with adaptive and innate immune tumor microenvironment (TME) in the BM of WM patients using mass cytometry (CyTOF). In-depth immunophenotypic profiling of WM cells exhibited profound expansion of clonal cells in both unswitched and switched memory B cells and also plasma cells with aberrant expression variations. WM B lymphomagenesis was associated with reduction of most B cell precursors assessed with the same clonally restricted light chain and phenotypic changes. The immune TME was infiltrated by mature monocytes, neutrophils and adaptive T cells, preferentially subsets of effector T helper, effector CTL and effector memory CTL cells that were associated with superior overall survival (OS), in contrast to progenitors of T cells and myeloid/monocytic lineage subsets that were suppressed in WM cohort. Moreover, decrease in immature B and NKT cells was related to worse OS in WM patients. Innate and adaptive immune subsets of WM TME were modulated by immune checkpoints, including PD-1/PD-L1&PD-L2, TIGIT/PVR, CD137/CD137-L, CTLA-4, BTLA and KIR expression. The response of ibrutinib treatment to the reduction of clonal memory B cell was associated with high levels of immature B cells and effector memory CTL cells. Our study demonstrates that CyTOF technology is a powerful approach for characterizing the pathophysiology of WM at various stages, predicting patient risk and monitoring the effectiveness of treatment strategies., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The SRC family kinase (SFK) HCK is transcriptionally upregulated and activated by mutated MYD88 (MYD88Mut), a key adaptor for Toll-receptor signaling. HCK activates BTK, AKT, and ERK in MYD88Mut lymphomas. SYK, a B-cell receptor (BCR) component, is activated in MYD88Mut lymphoma cells. Although the SFK LYN serves as a trigger for SYK activation in MYD88Mut ABC DLBCL cells, LYN activity is muted in MYD88Mut Waldenstrom macroglobulinemia (WM) cells. We therefore investigated a role for HCK in mediating SYK activation. Overexpression of wild-type (WT) (HCKWT) or gatekeeper mutated (HCKThr333Met) HCK in MYD88Mut lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88Mut lymphoma cells. Coimmunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88Mut BCWM.1 and TMD8 cells, but not in MYD88 WT Ramos cells. Rescue experiments in MYD88Mut lymphoma cells expressing HCKThr333Met led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88Mut WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88Mut B-cell lymphomas cells, broaden the prosurvival signaling generated by aberrant HCK expression in response to MYD88Mut, and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07- 18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate., (© 2021. The Author(s).)

Purpose: BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified., Patients and Methods: We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years., Results: Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P -mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred., Conclusion: Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response., Competing Interests: Jorge J. CastilloConsulting or Advisory Role: Janssen, Roche/Genentech, Beigene, AbbVie/PharmacyclicsResearch Funding: Pharmacyclics (Inst), AbbVie (Inst), Janssen (Inst), BeiGene (Inst), TG Therapeutics (Inst) John N. AllanHonoraria: AstraZeneca, AbbVie, Pharmacyclics/Janssen, BeiGeneConsulting or Advisory Role: AbbVie/Genentech, Pharmacyclics, Ascentage Pharma, BeiGene, Janssen Oncology, Epizyme, AstraZeneca, TG Therapeutics, ADC TherapeuticsResearch Funding: Genentech, Janssen, Celgene, TG Therapeutics Tanya SiddiqiConsulting or Advisory Role: Juno Therapeutics, AstraZeneca, BeiGene, Celgene, Pharmacyclics, Bristol Myers Squibb/CelgeneSpeakers' Bureau: Pharmacyclics/Janssen, AstraZeneca, BeiGene, Bristol Myers Squibb/CelgeneResearch Funding: Juno Therapeutics (Inst), Kite, a Gilead company (Inst), Acerta Pharma (Inst), TG Therapeutics (Inst), BeiGene (Inst), Pharmacyclics (Inst), Celgene (Inst), Oncternal Therapeutics (Inst), Bristol-Myers Squibb/Sanofi (Inst) Ranjana H. AdvaniConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Takeda, Portola Pharmaceuticals, Celgene, Sanofi, Kura Oncology, Merck, Karyopharm Therapeutics, ADC Therapeutics, Daiichi Sankyo, Bristol Myers Squibb/Celgene, Epizyme, IncyteResearch Funding: Millennium (Inst), Seattle Genetics (Inst), Genentech/Roche (Inst), Pharmacyclics (Inst), Janssen (Inst), Merck (Inst), Kura Oncology (Inst), Forty Seven (Inst), Cyteir (Inst) Catherine A. FlynnConsulting or Advisory Role: Pharmacyclics, Karyopharm Therapeutics Shayna SarosiekResearch Funding: Acrotech Biopharma (Inst) Andrew R. BranaganConsulting or Advisory Role: Pharmacyclics/Janssen, Genzyme, Adaptive Biotechnologies, BeiGene, Karyopharm Therapeutics, CSL Behring Xia LiuEmployment: Merck (I) Guang YangEmployment: AbbVie (I), Blueprint MedicinesStock and Other Ownership Interests: Blueprint MedicinesHonoraria: Janssen Matthew S. DavidsHonoraria: Research to PracticeConsulting or Advisory Role: Genentech, Janssen, Pharmacyclics, TG Therapeutics, AbbVie, AstraZeneca, Celgene, MEI Pharma, Adaptive Biotechnologies, Verastem, Ascentage Pharma, BeiGene, Lilly, Novartis, Takeda, Bristol Myers SquibbResearch Funding: Genentech (Inst), TG Therapeutics (Inst), Pharmacyclics (Inst), Surface Oncology (Inst), MEI Pharma (Inst), Verastem (Inst), Ascentage Pharma (Inst), AstraZeneca (Inst), Novartis (Inst)Travel, Accommodations, Expenses: TG Therapeutics, Janssen, AbbVie, BeiGene, Genentech Richard R. FurmanHonoraria: Janssen, AstraZeneca, Pharmacyclics, Janssen Biotech, Genentech/Roche, Loxo, TG Therapeutics, Verastem, Acerta Pharma, AstraZeneca, Beigene, Incyte, OncoTracker, AbbVie, MorphoSys, SanofiResearch Funding: Acerta Pharma, TG TherapeuticsExpert Testimony: AbbVie, Janssen OncologyTravel, Accommodations, Expenses: TG Therapeutics, Janssen OncologyOther Relationship: Incyte, Janssen Biotech Steven P. TreonHonoraria: Abbvie/Pharmacyclics, Janssen Oncology, BeiGeneConsulting or Advisory Role: Janssen, Pharmacyclics, Beigene, X4 Pharmaceuticals, Bristol Myers SquibbResearch Funding: Pharmacyclics, Bristol Myers Squibb (Inst), X4 Pharmaceuticals (Inst), Lilly (Inst), Beigene (Inst), AbbVie (Inst)Patents, Royalties, Other Intellectual Property: My institution holds patents related to use of MYD88 and CXCR4 testing for which a predetermined financial distribution to the laboratory and individuals is provided. I have not received any income to this date related to these patents (Inst)Travel, Accommodations, Expenses: Janssen OncologyOther Relationship: Janssen, Pharmacyclics, BeigeneNo other potential conflicts of interest were reported.

Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)- or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL&#95;2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK., (© 2021 by The American Society of Hematology.)

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716., (© 2021 by The American Society of Hematology.)

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland)., (© 2021. The Author(s).)

CXCR4 mutations impact disease presentation and treatment outcomes in Waldenström macroglobulinaemia (WM). Non-uniform testing for CXCR4 mutations may account for discordant findings in WM clinical trials. We compared two approaches used in these trials for detection of the most common CXCR4 (S338X) variant: targeted next-generation sequencing (NGS) using unselected bone marrow (BM) samples, and combined allele-specific polymerase chain reaction (AS-PCR) and Sanger sequencing with unselected and CD19-selected BM samples. Our findings showed that targeted NGS frequently yielded false-negative results. Both CD19 selection and AS-PCR markedly improved detection of CXCR4 S338X mutations. Sensitivity was adversely impacted by low BM involvement and CXCR4 mutation clonality., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM)., Patients and Methods: Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity., Results: The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL ( P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88 Mut , wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88 Mut CXCR4 Mut . Conversely, four patients who had MYD88 WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88 Mut CXCR4 WT and MYD88 Mut CXCR4 Mut WM, respectively ( P = .02). In patients with MYD88 WT , the median PFS was 0.4 years ( P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management., Conclusion: Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.

It is one of the major aims in cancer research to improve our understanding of the underlying mechanisms which initiate and maintain tumor growth and to translate these findings into novel clinical diagnostic and therapeutic concepts with the ultimate goal to improve patient care. One of the greater success stories in this respect has been Waldenström's Macroglobulinemia (WM), which is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow. Recent years have succeeded to describe the molecular landscape of WM in detail, highlighting two recurrently mutated genes, the MYD88 and the CXCR4 genes: MYD88 with an almost constant and recurrent point mutation present in over 90% of patients and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.

Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Cases of non-IgM lymphoplasmacytic lymphoma (LPL) are rare. We performed a case-control study comparing features and outcomes of 31 non-IgM LPL cases and 93 Waldenström macroglobulinemia (WM) controls matched by age, sex, and year of diagnosis. Odds of MYD88 mutations were lower (odds ratio (OR) 0.22, p  = .05), and median time to treatment was shorter in cases than in controls (4 vs. 32 months; p  < .001). Odds of extramedullary disease were higher (OR 4.20, p  = .01), while odds of neuropathy (OR 0.22, p  = .25), and hyperviscosity (OR 0.26, p  = .26) were lower in cases than in controls. Odds of using chemoimmunotherapy were higher (OR 2.62, p  = .11) while odds of using proteasome inhibitors (OR 0.35, p  = .15) and BTK inhibitors (OR 0.17, p  = .21) were lower in cases than in controls. There were no differences in response and overall survival (OS) between cases and controls. Despite clinicopathological differences, response, and survival outcomes are similar between non-IgM LPL cases and WM controls.

Ibrutinib is highly active in Waldenström macroglobulinaemia (WM) patients, but disease progression can occur due to acquired mutations in BTK, the target of ibrutinib, or PLCG2, the protein downstream of BTK. However, not all resistant patients harbour these alterations. We have performed a whole-exome sequencing study to identify alternative molecular mechanisms that can drive ibrutinib resistance. Our findings include deletions on chromosomes 6q, including homozygous deletions, and 8p, which encompass key regulators of BTK, MYD88/NF-κB, and apoptotic signalling. Moreover, we have identified recurring mutations in ubiquitin ligases, innate immune signalling, and TLR/MYD88 pathway regulators in ibrutinib-resistant WM patients., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The approval was based on a single, multicenter, phase II trial in previously treated WM patients. We sought to evaluate whether there were differences in clinical characteristics, response, and survival outcomes to ibrutinib monotherapy between WM patients treated on and off clinical trials. Treatment naïve and previously treated patients who received ibrutinib monotherapy at our institution and participated in two prospective studies (ON trial; n = 72) or a prospective database (OFF trial; n = 157) were included. The median times from WM diagnosis to ibrutinib initiation were 3.1 and 3.5 years for ON and OFF trial patients, respectively (p = 0.38). Similar rates of categorical response at 6, 12, and 24 months and at best response were also observed between ON trial and OFF trial patients. The 4-year PFS and OS rates for ON trial and OFF trial patients were 72% and 63%, respectively (log-rank p = 0.14) and 83% and 81%, respectively (log-rank p = 0.14). CXCR4 mutations impacted response and survival outcomes to ibrutinib monotherapy. The 4-year rates of ibrutinib discontinuation in ON and OFF trial patients were 36% and 44%, respectively (p = 0.11). Ibrutinib is effective in the routine clinical care of both treatment-naïve and previously treated WM patients. The findings of our study validate the efficacy of ibrutinib monotherapy reported in multiple phase II clinical trials., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%). Deletions involving chromosome 6q are common in patients with mutated MYD88 and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type MYD88 WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of MYD88 and CXCR4 mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.

Rituximab-containing regimens are commonly used for frontline therapy in patients with symptomatic Waldenström macroglobulinemia (WM). We had observed that a portion of WM patients experienced deepening of response months to years after therapy completion. We carried a retrospective study aimed at describing this phenomenon. We gathered baseline data, and responses at end of induction, end of maintenance and best response. Deepening of response was defined as ≥25% decrease in serum IgM achieved at a later time from therapy completion. Of 178 patients included, 116 (65%) received maintenance therapy and 62 (35%) were observed. In patients who received maintenance, 44 (38%) had ≥25% decrease in serum IgM level after the end of maintenance with a median time from end of maintenance to lowest IgM level of 1.6 years (range 0.1-7.9 years). In patients who were observed, 19 (31%) had ≥25% decrease in serum IgM level after the end of induction with a median time from end of induction to lowest IgM level of 1.6 years (range 0.2-5.1 years). Baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations and serum IgM ≥4000 mg/dL were associated with lower odds of deepening of response after therapy completion. Deepening of response was associated with better progression-free survival (PFS; HR 0.46, 95% CI 0.26-0.80; P = .006) and better survival after frontline treatment initiation (SAFTI; HR 0.21, 95% CI 0.06-0.73; P = .01). In conclusion, deepening of response occurs in one third of WM patients after completing rituximab-containing regimens and was associated with better PFS and SAFTI., (© 2019 Wiley Periodicals, Inc.)

Activating MYD88 mutations promote pro-survival signaling through BTK and HCK, both targets of ibrutinib. Despite high response rates, complete responses to ibrutinib are lacking, and other MYD88 triggered pro-survival pathways may contribute to primary drug resistance. B-cell receptor (BCR) signaling has been observed in lymphomas driven by mutated MYD88, even without activating the BCR pathway mutations. We identified activated SYK (p-SYK), a component of BCR in complex with MYD88 in MYD88-mutated WM and ABC DLBCL lymphoma cells. Confocal microscopy confirmed co-localization of MYD88 with SYK in MYD88-mutated cells. Knockdown of MYD88 or use of a MYD88 signaling inhibitor abrogated SYK activation, while expression of mutated but not wild-type MYD88 amplified p-SYK in MYD88-mutated and wild-type lymphoma cells. Knockdown of SYK or use of inhibitors targeting SYK blocked p-STAT3 and p-AKT signaling in MYD88-mutated cells. Cell viability analysis showed that combining ibrutinib and SYK inhibitors triggered synthetic killing of MYD88-mutated lymphoma cells. Our findings extend the spectrum of mutated MYD88 pro-survival signaling to include SYK directed BCR cross talk in MYD88-mutated lymphomas. Targeting SYK in combination with ibrutinib produces synthetic lethality, providing a framework for the clinical investigation of ibrutinib with SYK inhibitors in MYD88-mutated lymphomas.

Hematopoietic cell kinase (HCK) is an SRC family member that is aberrantly upregulated in B-cell neoplasms dependent on MYD88-activating mutations and supports their growth and survival. We showed herein that activation of Toll-like receptor (TLR) signaling in MYD88 wild-type B cells also triggered HCK expression, denoting on path regulatory function for HCK by MYD88. To clarify the signaling cascades responsible for aberrant HCK expression in MYD88-mutated B-cell lymphomas, we performed promoter-binding transcription factor (TF) profiling, PROMO weighted TF consensus binding motif analysis, and chromatin immunoprecipitation studies. We identified PAX5, and the mutated MYD88 downstream signaling mediators STAT3, NF-κB, and AP-1, as important drivers of HCK transcription. Knockdown of PAX5, a crucial regulatory factor required for B-cell commitment and identity, abrogated HCK transcription in MYD88-mutated lymphoma cells. Among AP-1 complex components, JunB showed greatest relevance to TLR/MYD88 signaling and HCK transcription regulation. In MYD88-mutated Waldenström macroglobulinemia and activated B-cell-diffuse large B-cell lymphoma cells, knockdown of MYD88 reduced phosphorylation of JunB but not c-Jun, and knockdown of JunB reduced HCK protein levels. Deletion of STAT3, NF-κB, and AP-1 binding sites reduced corresponding TFs binding and HCK promoter activity. Moreover, inhibitors to STAT3, NF-κB, and AP-1 reduced HCK promoter activity and messenger RNA levels, particularly in combination, in MYD88-mutated lymphoma cells. The findings provide new insights into the transcriptional regulation of HCK prosurvival signaling by mutated MYD88, and the importance of JunB as a downstream mediator of the MYD88-directed signaling apparatus., (© 2020 by The American Society of Hematology.)

MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma., (© 2019 by The American Society of Hematology.)

Ibrutinib is associated with response rate of 90% and median progression-free survival (PFS) in excess of 5 years in Waldenström macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30-40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift (CXCR4 FS ) and nonsense (CXCR4 NS ) CXCR4 mutations have been described. The impact of these mutations on outcomes to ibrutinib have not been evaluated in WM patients. We studied consecutive patients with a diagnosis of WM, on ibrutinib therapy, for the presence of CXCR4 FS and CXCR4 NS mutations and evaluated the differences in response and PFS between groups. Of 180 patients, 68 patients (38%) had CXCR4 mutations; 49 (27%) had CXCR4 NS and 19 (11%) had CXCR4 FS mutations. In multivariate models, patients with CXCR4 NS had lower odds of major response (Odds ratio 0·25, 95% confidence interval [CI] 0·12-0·53; P < 0·001) and worse PFS (Hazard ratio 4·02, 95% CI 1·95-8·26; P < 0·001) than patients without CXCR4 mutations. CXCR4 FS was not associated with worse major response or PFS rates than patients without CXCR4 mutations. Our results suggest different response and PFS rates to ibrutinib for WM patients with CXCR4 NS and CXCR4 FS , and advocate in favour of CXCR4 mutational testing as well as CXCR4-directed therapy., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Introduction : The genomic landscape of Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 ( MYD88 L265P ) and CXCR4 mutations ( CXCR4 MUT ), detected in 90% and 30% of cases, respectively. The role of CXCR4 MUT in clinical features and outcomes to therapy in WM patients is evolving. Areas covered : We performed a systematic review aimed at evaluating the prevalence of CXCR4 MUT in WM patients, and at assessing differences in clinical features and outcomes to therapy between WM patients with and without CXCR4 MUT . Seventeen studies were included in our analysis. The pooled prevalence of CXCR4 MUT in WM patients was 31%; 34% in MYD88 L265P and 5% in MYD88 WT patients. CXCR4 MUT were associated with higher serum IgM levels and higher risk of hyperviscosity than CXCR4 WT patients. Very good partial response (VGPR) and progression-free survival (PFS) rates to ibrutinib, with and without rituximab, appeared lower in CXCR4 MUT than in CXCR4 WT patients. Response and PFS rates were not affected by CXCR4 MUT status on patients treated with proteasome inhibitors. Expert opinion : Our systematic review shows that WM patients with CXCR4 MUT have specific clinical features and have lower response and PFS rates to BTK inhibitors. Our findings support standardization of CXCR4 testing and development of CXCR4-directed therapy.

Competing Interests: The authors report no conflicts of interest.

Little is known about TP53 mutations in Waldenström Macroglobulinaemia (WM). We evaluated 265 WM patients for TP53 mutations by next-generation sequencing, and validated the findings by Sanger sequencing. TP53 mutations were identified and validated in 6 (2·6%) patients that impacted the DNA-binding domain. All six were MYD88- and CXCR4-mutated. Ibrutinib showed activity in patients carrying all three mutations. With a median follow-up of 18 months, 2 (33%) with biallelic TP53 inactivation died of progressive disease. TP53 mutations are rare in WM, and associate with MYD88 and CXCR4 mutations. WM patients with TP53 mutations show response to ibrutinib., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Activating MYD88 mutations are present in 95% of Waldenström macroglobulinemia (WM) patients, and trigger NF-κB through BTK and IRAK. The BTK inhibitor ibrutinib is active in MYD88- mutated (MYD88 MUT ) WM patients, but shows lower activity in MYD88 wild-type ( MYD88 WT ) disease. MYD88 WT patients also show shorter overall survival, and increased risk of disease transformation in some series. The genomic basis for these findings remains to be clarified. We performed whole exome and transcriptome sequencing of sorted tumor samples from 18 MYD88 WT patients and compared findings with WM patients with MYD88 MUT disease. We identified somatic mutations predicted to activate NF-κB ( TBL1XR1 , PTPN13, MALT1 , BCL10 , NFKB2 , NFKBIB , NFKBIZ, and UDRL1F ), impart epigenomic dysregulation ( KMT2D , KMT2C, and KDM6A) , or impair DNA damage repair ( TP53 , ATM , and TRRAP ). Predicted NF-κB activating mutations were downstream of BTK and IRAK, and many overlapped with somatic mutations found in diffuse large B-cell lymphoma. A distinctive transcriptional profile in MYD88 WT WM was identified, although most differentially expressed genes overlapped with MYD88 MUT WM consistent with the many clinical and morphological characteristics that are shared by these WM subgroups. Overall survival was adversely affected by mutations in DNA damage response in MYD88 WT WM patients. The findings depict genomic and transcriptional events associated with MYD88 WT WM and provide mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population., (© 2018 by The American Society of Hematology.)

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Common mutations include MYD88 (95%-97%), as well as CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%), which are typically found in MYD88-mutated patients. The genomic findings provide important insights into the pathogenesis, prognostication, and treatment outcome in WM. We discuss the genomic landscape of WM, and the impact of underlying genomics on disease presentation, transcriptional changes, treatment outcome, and overall survival impact., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose Ibrutinib is active in previously treated Waldenström macroglobulinemia (WM). MYD88 mutations ( MYD88 MUT ) and CXCR4 mutations ( CXCR4 MUT ) affect ibrutinib response. We report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4 MUT status on outcome. Patients and Methods Symptomatic, treatment-naïve patients with WM were eligible. Ibrutinib (420 mg) was administered daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88 MUT and CXCR4 MUT . Results A total of 30 patients with WM received ibrutinib. All carried MYD88 MUT , and 14 (47%) carried a CXCR4 MUT . After ibrutinib treatment, median serum IgM levels declined from 4,370 to 1,513 mg/dL, bone marrow involvement declined from 65% to 20%, and hemoglobin level rose from 10.3 to 13.9 g/dL ( P < .001 for all comparisons). Overall (minor or more than minor) and major (partial or greater than partial) responses for all patients were 100% and 83%, respectively. Rates of major (94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with CXCR4 MUT , respectively. With a median follow-up of 14.6 months, disease in two patients (both with CXCR4 MUT ) progressed. The 18-month, estimated progression-free survival is 92% (95% CI, 73% to 98%). All patients are alive. Grade 2/3 treatment-related toxicities in > 5% of patients included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%), urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or unexpected toxicities. Conclusion Ibrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with symptomatic WM. CXCR4 MUT status affects responses to ibrutinib.