How I treat Waldenström macroglobulinemia

Dimopoulos, Meletios Α.; Kastritis, Efstathios

doi:10.1182/blood.2019000725

Cited by 69 publications

(68 citation statements)

References 96 publications

(108 reference statements)

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“…We included in the analysis only patients diagnosed since 2000, when rituximab became widely available in Italy, to provide information on the outcome of patients treated with modern approaches. Although a comparison with older WM patients was beyond the scope of this study, the clinical presenting features as well as the rate of MYD88 (L265P) mutation in young WM patients included in this study are mostly consistent with those described in older patients 11 . Of note, a higher number of cases was diagnosed in the second decade as compared with the first one.…”

Section: Discussionsupporting

confidence: 73%

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies

et al. 2020

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We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous

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Section: Discussionsupporting

confidence: 73%

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies

et al. 2020

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“…In addition, hematologic and non-hematologic toxicities, including peripheral neuropathy, infections, and secondary malignancies, remain major concerns for these treatments. 9 Therefore, the development of new treatment strategies is necessary.…”

Section: Introductionmentioning

confidence: 99%

A multicenter, open‐label, phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

et al. 2020

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Tirabrutinib is a second‐generation Bruton’s tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment‐naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström’s macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression‐free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow‐up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug‐related atrial fibrillation or hypertension. Although the follow‐up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI‐173646).

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“…Waldenström's macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma, characterized by bone marrow (BM) infiltration of small, IgM-positive lymphocytes with varying degrees of plasmacytoid or plasma cell differentiation and the presence of monoclonal immunoglobulin M (IgM) paraproteins (M-spikes) in the serum (1)(2)(3)(4)(5). The great majority of malignant WM cells are monoclonal and carry somatically mutated antibody V region rearrangements, suggesting that transformation occurs at a mature, antigen-experienced B cell stage (6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

B-Cell-Specific Myd88 L252P Expression Causes a Premalignant Gammopathy Resembling IgM MGUS

et al. 2020

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A highly recurrent somatic L265P mutation in the TIR domain of the signaling adapter MYD88 constitutively activates NF-κB. It occurs in nearly all human patients with Waldenström’s macroglobulinemia (WM), a B cell malignancy caused by IgM-expressing cells. Here, we introduced an inducible leucine to proline point mutation into the mouse Myd88 locus, at the orthologous position L252P. When the mutation was introduced early during B cell development, B cells developed normally. However, IgM-expressing plasma cells accumulated with age in spleen and bone, leading to more than 20-fold elevated serum IgM titers. When introduced into germinal center B cells in the context of an immunization, the Myd88L252P mutation caused prolonged persistence of antigen-specific serum IgM and elevated numbers of antigen-specific IgM plasma cells. Myd88L252P-expressing B cells switched normally, but plasma cells expressing other immunoglobulin isotypes did not increase in numbers, implying that IgM expression may be required for the observed cellular expansion. In order to test whether the Myd88L252P mutation can cause clonal expansions, we introduced it into a small fraction of CD19-positive B cells. In this scenario, five out of five mice developed monoclonal IgM serum paraproteins accompanied by an expansion of clonally related plasma cells that expressed mostly hypermutated VDJ regions. Taken together, our data suggest that the Myd88L252P mutation is sufficient to promote aberrant survival and expansion of IgM-expressing plasma cells which in turn can cause IgM monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition that precedes WM.

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How I treat Waldenström macroglobulinemia

Abstract: In this How I Treat article on Waldenström macroglobulinemia, the authors present different case-based clinical scenarios and discuss available treatment options.

Cited by 69 publications

References 96 publications

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies

A multicenter, open‐label, phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

B-Cell-Specific Myd88 L252P Expression Causes a Premalignant Gammopathy Resembling IgM MGUS

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