●Novel fixed-duration combination of ibrutinib + venetoclax in treatment-naive WM
●Aims to achieve deep responses with time-limited therapy
●Represents shift toward combination approaches

Details DOI ↗

Grade ARCTn=201

Zanubrutinib vs Ibrutinib in Symptomatic WM: Final Analysis From the ASPEN Study

Tam CS, et al. · J Clin Oncol · 2023

●At 44.4-month follow-up, VGPR+CR: 36.3% zanubrutinib vs 25.3% ibrutinib
●Ibrutinib had higher rates of atrial fibrillation (23.5% vs 7.9%), hypertension, diarrhea
●Zanubrutinib confirmed as having improved long-term safety profile

Details DOI ↗

Grade Bcohortn=250

Bendamustine plus rituximab for treatment of WM: patient outcomes and impact of dosing

Castillo JJ, et al. · Am J Hematol · 2023

●250 WM patients treated with BR in frontline and relapsed settings
●Frontline response rate (PR or better) 91.4% vs 73.9% in relapsed
●Major multicenter study establishing BR efficacy in WM

Details DOI ↗

Grade ARCTn=150

Ibrutinib Plus Rituximab vs Placebo Plus Rituximab for WM: Final iNNOVATE Analysis

Dimopoulos MA, et al. · J Clin Oncol · 2022

●At 50-month median follow-up, median PFS not reached with ibrutinib-rituximab vs 20.3 months for placebo-rituximab
●Sustained superiority regardless of MYD88 or CXCR4 mutation status
●Confirmed long-term benefit of ibrutinib-rituximab combination

Details DOI ↗

Grade ARCTn=201

A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic WM: the ASPEN study

Tam CS, et al. · Blood · 2020

●VGPR rate 28% zanubrutinib vs 19% ibrutinib (non-significant trend, P=0.09)
●Zanubrutinib associated with less cardiovascular toxicity, particularly atrial fibrillation
●Both agents highly effective; zanubrutinib better tolerated

Details DOI ↗

Grade Acohort

Ibrutinib Monotherapy in Symptomatic, Treatment-Naive Patients With WM

Treon SP, et al. · J Clin Oncol · 2018

●Ibrutinib highly active as primary therapy in treatment-naive WM
●CXCR4 mutation status impacts response to ibrutinib
●Durable responses with acceptable safety profile

Details DOI ↗

Grade ARCTn=150

Phase 3 Trial of Ibrutinib plus Rituximab in WM (iNNOVATE)

Dimopoulos MA, et al. · N Engl J Med · 2018

●Ibrutinib-rituximab: 82% 30-month PFS vs 28% for placebo-rituximab (HR 0.20, P<0.001)
●Benefits seen regardless of prior treatment status
●Established ibrutinib-rituximab as standard of care

Details DOI ↗

Grade Acohortn=63

Ibrutinib in Previously Treated Waldenström's Macroglobulinemia

Treon SP, et al. · N Engl J Med · 2015

●Overall response rate 90.5%, major response rate 73% in previously treated WM
●MYD88 and CXCR4 status affected response: MYD88mut/CXCR4wt had 100% ORR
●Led to FDA approval of ibrutinib for WM

Details DOI ↗

Grade Bexpert opinion

How I treat Waldenström macroglobulinemia

Treon SP · Blood · 2015

●Comprehensive treatment algorithm for WM
●Indications for therapy: hyperviscosity, amyloidosis, cryoglobulinemia, cold agglutinemia, Bing-Neel, neuropathy
●Patient selection based on clinical and molecular features

Details DOI ↗

clinical

2 sources

Grade Bnarrative review

Pathophysiology and treatments of complications of WM

Patel N, et al. · Clin Hematol Int · 2024

●Pentameric IgM structure drives hyperviscosity, cryoglobulinemia, and neuropathy
●CNS infiltration (Bing-Neel syndrome) is a rare but serious complication
●Comprehensive review of IgM-related complications and their management

Details DOI ↗

Grade Bnarrative review

WM: hyperviscosity syndrome and cryoglobulinemia

Stone MJ · Clin Lymphoma Myeloma · 2009

●Hyperviscosity detectable by funduscopic 'sausaging' of retinal veins
●Reversed by plasmapheresis
●IgM levels <3000 mg/dL rarely cause symptomatic hyperviscosity

Details DOI ↗

diagnostics

4 sources

Grade Bexpert opinion

Diagnostics in WM: consensus statement of the European Consortium for WM

Dogliotti I, et al. · Leukemia · 2023

●Updated ECWM diagnostic consensus with molecular testing guidance
●Standardized procedures for flow cytometry, FISH, and molecular tests
●MYD88 mutation testing recommended for all suspected WM cases

Details DOI ↗

Grade Bexpert opinion

Diagnosis and management of WM: BSH guideline

D'Sa S, et al. · Br J Haematol · 2022

●British Society for Haematology guidelines for WM diagnosis and management
●Recommended MYD88 and CXCR4 testing for all patients
●Treatment algorithm based on mutation status

Details DOI ↗

Grade Bexpert opinion

Developing diagnostic criteria in Waldenstrom's macroglobulinemia

Owen RG, et al. · Semin Oncol · 2003

●Proposed first consensus diagnostic criteria for WM from Second International Workshop
●Defined WM as IgM monoclonal gammopathy with bone marrow infiltration by lymphoplasmacytic cells
●Established immunophenotype: sIg+, CD19+, CD20+, CD5-, CD10-, CD23-

Details DOI ↗

Grade Bcohortn=111

WM: development of diagnostic criteria and identification of prognostic factors

Owen RG, et al. · Am J Clin Pathol · 2001

●Clinicopathological assessment of 111 WM patients
●Identified key histopathological patterns of bone marrow involvement
●Proposed diagnostic criteria framework

Details DOI ↗

genetics

10 sources

Grade Bnarrative review

CXCR4 in Waldenström's Macroglobulinemia: chances and challenges

Buske C, et al. · Leukemia · 2021

●CXCR4 mutations affect up to 40% of WM patients with >40 different mutations described
●Mutations similar to germline WHIM syndrome mutations
●CXCR4 mutations lead to more aggressive clinical course and inferior BTK inhibitor response

Details DOI ↗

Grade Asystematic review

CXCR4 mutations affect presentation and outcomes in patients with WM: a systematic review

Castillo JJ, et al. · Expert Rev Hematol · 2019

●Pooled CXCR4 mutation prevalence 31%; 34% in MYD88-mutated, 5% in MYD88-WT
●Associated with higher IgM levels and hyperviscosity risk
●Did not impact overall survival despite worse treatment response

Details DOI ↗

Grade Bcohort

CXCR4 mutation subtypes impact response and survival outcomes in ibrutinib-treated WM

Castillo JJ, et al. · Br J Haematol · 2019

●CXCR4 nonsense mutations associated with more aggressive presentation
●Lower major response rates (67% vs 86%) in CXCR4-mutated patients on ibrutinib
●CXCR4 mutations and low platelets predict worse PFS

Details DOI ↗

Grade Acohort

Insights into the genomic landscape of MYD88 wild-type WM

Treon SP, et al. · Blood · 2018

●MYD88 wild-type WM has distinct genomic landscape
●NF-kB-activating mutations (TBL1XR1, PTPN13, MALT1, BCL10) found in wild-type cases
●Wild-type MYD88 associated with shorter overall survival

Details DOI ↗

Grade Acohort

The genomic landscape of Waldenström macroglobulinemia

Hunter ZR, et al. · Blood · 2014

●Comprehensive genomic characterisation of WM
●Identified CXCR4 WHIM-like mutations in ~30% of patients
●Mapped additional recurrent somatic mutations in ARID1A, TP53, CD79B

Details DOI ↗

Grade Acohortn=58

Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in WM and related lymphoid neoplasms

Varettoni M, et al. · Blood · 2013

●MYD88 L265P detected in 100% of WM patients using AS-PCR
●Present in 47% of IgM-MGUS, 6% of SMZL, 4% of B-CLPD
●Represents a molecular hallmark of WM

Details DOI ↗

Grade Acohort

MYD88 L265P mutation in Waldenstrom macroglobulinemia

Poulain S, et al. · Blood · 2013

●MYD88 L265P acquired in 79% of WM patients by Sanger sequencing
●MYD88 locus altered in 91% including copy number gains at 3p22
●MYD88 mutations activate NF-kB signaling

Details DOI ↗

Grade Acohortn=54

MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia

Treon SP, et al. · N Engl J Med · 2012

●Identified MYD88 L265P in 91% of WM patients by whole-genome sequencing
●Mutation absent in paired normal tissue and healthy donor B cells
●Absent or rarely expressed in myeloma, marginal-zone lymphoma, and IgM-MGUS

Details DOI ↗

Grade Bnarrative review

What causes WM: genetic or immune-related factors, or a combination?

Kristinsson SY, et al. · Clin Lymphoma Myeloma Leuk · 2011

●First-degree relatives of WM patients have significantly increased risk of WM and other NHL
●Similar excess risk in parents, siblings, and offspring suggests dominant gene effects
●Both genetic and environmental components contribute to WM susceptibility

Details DOI ↗

Grade Bcohort

Differential characteristics of WM according to patterns of familial aggregation

Royer RH, et al. · Blood · 2010

●~20% of WM patients have a first-degree relative with a B-cell disorder
●Familial WM more likely to report autoimmune disease and infections
●Farming, pesticides, wood dust, organic solvents associated with higher risk

Details DOI ↗

epidemiology

4 sources

Grade Bcohort

Incidence, prevalence, mortality, and causes of death in WM: nationwide population-based cohort study

Jeong SH, et al. · Blood Adv · 2020

●Nationwide Korean epidemiological study of WM
●Confirmed low incidence in Asian populations compared to Western cohorts
●Incidence increased from 0.03 to 0.10 per 100,000 between 2003-2016

Details DOI ↗

Grade Acohort

A revised international prognostic score system for WM

Kastritis E, et al. · Leukemia · 2019

●Revised IPSSWM with age, B2M >=4, albumin <3.5, LDH >=250
●Five prognostic groups with 10-year survival: 84% to 9%
●Improved risk stratification over original IPSSWM

Details DOI ↗

Grade Bcohort

Overall survival and competing risks of death in patients with WM

Castillo JJ, et al. · Cancer · 2015

●SEER-based analysis: 5-year relative survival 78% (2001-2010) vs 67% (1980-2000)
●10-year relative survival 66% vs 49% respectively
●Survival improvement over recent decades

Details DOI ↗

Grade Acohortn=587

International prognostic scoring system for Waldenström macroglobulinemia

Morel P, et al. · Blood · 2009

●Developed IPSSWM with 5 adverse covariates: age >65, Hb <=11.5, platelets <=100K, B2M >3, IgM >7g/dL
●5-year survival: low risk 87%, intermediate 68%, high 36%
●Applicable across treatment regimens

Details DOI ↗

pathogenesis

1 sources

Grade Bnarrative review

Schnitzler's syndrome - a novel hypothesis of a shared pathophysiologic mechanism with WM

Van Leersum FS, et al. · Orphanet J Rare Dis · 2019

●MYD88 hypothesised as shared pathogenic factor between Schnitzler syndrome and WM
●MYD88 L265P links NF-kB, NLRP3, and inflammasome pathways
●15-20% of Schnitzler patients eventually develop WM

Details DOI ↗