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Patients with Waldenström's macroglobulinemia without mutations in MYD88 tend to have a shorter median survival and a lower probability of response to ibrutinib than do those with MYD88 mutations. To the Editor: Whole-genome sequencing identified the MYD88 L265P variant as the most prevalent mutation in patients with Waldenström's macroglobulinemia (WM), a type of non-Hodgkin's lymphoma. 1 In 93 to 97% of patients with this disorder, allele-specific polymerase-chain-reaction (AS-PCR) assays identified MYD88 L265P, which results from a T→C transversion at position 38182641 on chromosome 3p22.2. Signaling studies showed that the mutant protein that is encoded by MYD88 L265P triggers tumor growth through the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) by Bruton's tyrosine kinase. This kinase is targeted by ibrutinib, a drug that is widely used . . .

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.

A randomized trial comparing ibrutinib plus rituximab with rituximab alone in patients with Waldenström’s macroglobulinemia showed significantly higher rates of progression-free survival and overall response with the addition of ibrutinib.

In a study conducted at three institutions, ibrutinib was associated with major responses in 73% of patients with Waldenström's macroglobulinemia who had received at least one previous treatment. Toxic effects of grade 2 or higher included neutropenia in 22% of the patients. Waldenström’s macroglobulinemia is a malignant B-cell lymphoma that is associated with an accumulation of clonal lymphoplasmacytic cells and monoclonal IgM secretion. 1 Despite advances in treatment, the disease eventually progresses in most patients, and new treatment options are needed. Whole-genome sequencing has revealed a single activating somatic mutation in MYD88 (resulting in a predicted protein change from leucine to proline at amino acid position 265) and multiple activating mutations in the C-terminal domain of CXCR4 in patients with Waldenström’s macroglobulinemia. 2 , 3 In tumor cells, MYD88L265P triggers activation of nuclear factor κB (NF-κB) through two divergent pathways involving Bruton’s tyrosine kinase (BTK) . . .

Waldenström's macroglobulinemia is a lymphoplasmacytic lymphoma. Genetic analysis has revealed a common mutation (L265P) in MYD88 in more than 90% of patients with this disease. The mutation appears to activate NF-κB. Waldenström's macroglobulinemia is an IgM-secreting lymphoplasmacytic lymphoma (LPL). 1 , 2 Clinical manifestations of Waldenström's macroglobulinemia include cytopenia resulting from bone marrow infiltration by lymphoplasmacytic cells, paraprotein-related cryoglobulinemia, the cold agglutinin syndrome, demyelinating neuropathy, and symptomatic hyperviscosity. 3 The oncogenic basis of Waldenström's macroglobulinemia has not been defined. Familial clustering of Waldenström's macroglobulinemia and other B-cell disorders suggests that genetic factors play a role in the pathogenesis of Waldenström's macroglobulinemia in certain patients. 4 – 6 IgM monoclonal gammopathy of unknown significance (MGUS) is characterized by the presence of a monoclonal IgM protein and the absence of bone marrow disease involvement on histologic examination. 1 IgM . . .

Waldenstrom macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma. The diagnosis of WM is established by the presence of lymphoplasmacytic lymphoma in the bone marrow or other organs, a monoclonal IgM paraproteinemia and the recurrent MYD88 L265P somatic mutation. Some patients with WM can be asymptomatic, in which case treatment is not indicated. However, most patients with WM will become symptomatic during the course of the disease, due to anemia, hyperviscosity, neuropathy, or other processes, necessitating therapy. Current treatment options for symptomatic WM patients include alkylating agents, proteasome inhibitors and anti-CD20 monoclonal antibodies. The approval of the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone and in combination with rituximab has expanded the treatment options for WM patients. The present Perspective would focus on exciting treatment strategies under development for WM patients, such as proteasome inhibitors (e.g., ixazomib), BTK inhibitors (e.g., acalabrutinib, zanubrutinib, vecabrutinib), BCL2 inhibitors (e.g., venetoclax), and anti-CXCR4 antibodies (e.g., ulocuplumab), among others. It is certainly an exciting time for WM therapy development with novel and promising treatment options in the horizon.

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.

Waldenstrom’s Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks. Patient T and NK cells show systemic hypo-responsiveness to interferon, which improves with interferon administration and may represent a therapeutic vulnerability. MYD88 -mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a DUSP22 / CD9 -positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice. The impact of tumor intrinsic and immune alterations on disease progression in patients with Waldenstrom’s Macroglobulinemia (WM) remains to be characterized. Here, the authors perform single-cell RNA-sequencing and identify distinct tumor subtypes, tumour microenvironment features and potential therapeutic vulnerabilities in patients with WM.

Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs' specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease.

Cyclophilin A, secreted by bone marrow endothelial cells, acts as a chemotactic factor for myeloma cells, which helps explain their homing to the bone marrow and suggests a potential new therapeutic strategy. B cell malignancies frequently colonize the bone marrow. The mechanisms responsible for this preferential homing are incompletely understood. Here we studied multiple myeloma (MM) as a model of a terminally differentiated B cell malignancy that selectively colonizes the bone marrow. We found that extracellular CyPA (eCyPA), secreted by bone marrow endothelial cells (BMECs), promoted the colonization and proliferation of MM cells in an in vivo scaffold system via binding to its receptor, CD147, on MM cells. The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt–β-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147. These findings suggest that eCyPA-CD147 signaling promotes the bone marrow homing of B cell malignancies and offer a compelling rationale for exploring this axis as a therapeutic target for these malignancies.