Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management

Abstract

Disease Overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Diagnosis: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients. Risk Stratification: Age, hemoglobin level, platelet count, β 2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Risk-Adapted Therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Management of Refractory Disease: Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection. PATIENT A 55-year-old male was found to have an IgM monoclonal gammopathy in January 2001. He was observed until November 2006 when his IgM level climbed to 9135 mg/dL. He was treated with rituximab, bortezomib and dexamethasone for 4 months. Treatment was interrupted due to neuropathy, but the IgM level fell to 1150 mg/dL. He was observed until April 2011. At the time of progression his IgM was 11 500 mg/dL and he was treated with single agent rituximab. At that time he was found to have acquired von Willebrand disease. Rituximab failed to produce a minor response so he was placed on a trial of bendamustine, lenalidomide and rituximab. His response lasted less than 1 year. In 2014 he was placed on an experimental trial of oprozomib. This resulted in a response of 5 years duration. At relapse in August of 2019 he was placed on a trial of ixazomib and ibrutinib. Ixazomib was poorly tolerated due to diarrhea and he continued on ibrutinib alone. He has now been on ibrutinib 15 months and has achieved a very good partial response.

MYD88L265P Detection in IgM Monoclonal Gammopathies: Methodological Considerations for Routine Implementation

“…IgM-MGUS is defined by the absence of bone marrow (BM) infiltration by lymphoma cells, the presence of a serum monoclonal Immunoglobulin M (IgM) paraprotein lower than 3 g/dL and the absence of end-organ damage [ 4 ]. WM is characterized by the heterogeneous infiltration of monoclonal lymphocytes, lymphoplasmacytic cells, and plasma cells in BM, which are responsible for the production of IgM paraprotein in the serum [ 5 , 6 ].…”

“…Based on current criteria, the diagnosis of WM requires histological confirmation of monoclonal lymphoplasmacytic cells infiltration by BM aspirate and trephine biopsy: both flow cytometry (MFC) and immunohistochemistry (IC) are advisable in achieving a correct diagnosis [ 5 , 6 , 7 , 8 ].…”

Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

“…bortezomib, are advised ( 19 ). These treatments generally induce durable responses, are typically well-tolerated and remain essential in the management of the disease ( 7 , 20 ). However, LPL/WM almost invariably relapses, and the goal of therapy is the control of symptoms and the achievement of the deepest and longest response.…”

Transformation of IgM-MGUS into Waldenström´s macroglobulinemia in two of six patients treated for Schnitzler´s syndrome

“…Uvádí se i možnost transformace do mnohočetného myelomu typu IgM, ale tyto případy jsou podstatně vzácnější a odlišit tyto dvě jednotky není zcela jednoduché, jak popisuje Elba (18). Při průkazu M-IgM připadají v úvahu diagnózy uvedené v tabulce 5 (19).…”

“…. Klinické jednotky spojené s monoklonálním imunoglobulinem typu IgM dle doporučení pro diagnostiku a léčbu z roku 2021, Morie Gerz a kol(19). Toto doporučení je z Mayo Clinic, kde stále definují Waldenströmovu makroglulinemii s pomocí 10% hranice, zatímco poslední mezinárodní kritéria 8. a 10. International Workshop on Waldenström´s macroglobulinemia potvrzují původní Owenova kritéria(17) a neobsahují žádnou procentovou hranici pro lymfoplazmocytární infiltraci nutnou pro stanovení diagnózy a proto pro stanovení diagnózy je pouze zásadní konstatování patologa lymfoplazmocytární infiltrace je nebo není přítomna(48,49)…”