Extramedullary Waldenström macroglobulinemia

Disease assessment in Waldenstrom Macroglobulinemia (WM) is dependent on the percent involvement of B‐cell neoplasm in the bone marrow and IgM paraprotein in the serum. A subset of patients also demonstrates extramedullary involvement, which is infrequently examined. The role of extramedullary involvement in the diagnosis and prognosis of WM is poorly understood. The purpose of this study is to report the characteristics of WM patients with extramedullary disease (EMD). Nine hundred and eight‐five patients with WM were evaluated at one academic center and the presence of EMD was assessed in these patients. Forty‐three (4.4%) patients were identified to have EMD. Nine (21%) patients presented with involvement at WM diagnosis, while 34 (79%) developed EMD post‐therapy for WM. Most frequent EMD sites involved were pulmonary (30%), soft tissue (21%), cerebrospinal fluid (23%), renal (8%), and bone (9%). The median overall survival at 10 years was 79% (95% CI: 57–90%). This is the first study to describe the clinical characteristics, response and overall survival in patients with extramedullary WM. Further studies to define the molecular characteristics of this entity and mechanisms of its development are warranted. Am. J. Hematol. 90:100–104, 2015. © 2014 Wiley Periodicals, Inc.     

Update on therapeutic options in Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a B‐cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells (LPCs), along with demonstration of an IgM monoclonal gammopathy in the blood. WM remains incurable, with 5–6 yr median overall survival for patients with symptomatic WM. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either in monotherapy or in combination. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival are short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to develop new targeted therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors, of them bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Many agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.     

Waldenström macroglobulinemia terminating in acute leukemia: A report of three cases

Acute leukemia was observed to develop in three patients with Waldenst?m macroglobulinemia. Each patient had been treated with cytotoxic drug therapy. Pancytopenia preceded the onset of the terminal leukemia in two of the three cases. The acute leukemias were all of acute myelogenous type. All of the patients died soon after the development of the terminal leukemia. A number of recent reports have documented acute terminal leukemia in patients with macroglobulinemias and multiple myeloma, as well as other malignant and nonmalignant diseases. The role of the cytotoxic drugs, especially chlorambucil, cyclophosphamide, and melphalan, in leukemogenesis has been raised by these recent reports.     

MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is an immunoglobulin M‐associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88^L265P. Owing to low prevalence of the wild‐type (WT) MYD88 genotype in WM, clinically relevant data in this patient population are sparse, with one study showing nearly a 10‐fold increased risk of mortality in this subgroup compared to patients with MYD88^L265P mutation. We studied a large cohort of patients with MYD88^L265P and MYD88^WT WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016, to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88^L265P mutation status, as determined by allele‐specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88^L265P, 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88^WT genotype, 44 had active disease. The estimated median follow‐up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4‐16.5) for MYD88^L265P versus 13.9 years (95% CI: 6.4‐29.3) for the MYD88^WT (P = 0.86). The time‐to‐next therapy from frontline treatment and the presenting features were similar in the two patient populations. For patients with smoldering WM at diagnosis, the median time‐to‐progression to active disease was 2.8 years (95% CI: 2.2‐3.8) in the MYD88^L265P cohort and 1.9 years (95% CI: 0.7‐3.1) in the MYD88^WT cohort (P = 0.21). The frequency of transformation to high‐grade lymphoma, or the development of therapy‐elated myelodysplastic syndrome was higher in the MYD88^WT cohort (16% versus 4% in the MYD88^L265P, P = 0.009). In conclusion, MYD88^L265P mutation does not appear to be a determinant of outcome, and its presence may not be a disease‐defining feature in WM. Our findings warrant external validation, preferably through prospective studies.     

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies,outcomes, and IgM rebound

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4‐fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.     

Waldenström macroglobulinemia: 2015 update on diagnosis,risk stratification,and management

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. Risk Stratification : Age, hemoglobin level, platelet count, β₂ microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Risk‐Adapted Therapy : Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab‐based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analog (or both). The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Management of Refractory Disease : Bortezomib, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. Am. J. Hematol. 90:347–354, 2015. © 2015 Wiley Periodicals, Inc.     

Waldenström macroglobulinemia: 2017 update on diagnosis,risk stratification,and management

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. Risk Stratification: Age, hemoglobin level, platelet count, β₂ microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Risk‐Adapted Therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab‐based therapy is used in virtually all U.S. patients with WM and can be combined with bendamustine, an alkylating agent, or a proteosome inhibitor. Purine nucleoside analogues are widely used in Europe. The preferred Mayo Clinic nonstudy therapeutic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in induction therapy selection. Management of Refractory Disease: Bortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. Am. J. Hematol. 92:209–217, 2017. © 2016 Wiley Periodicals, Inc.     

Histological transformation to diffuse large B‐cell lymphoma in patients with Waldenström macroglobulinemia

Histological transformation to diffuse large B‐cell lymphoma (DLBCL) rarely occurs in patients with Waldenström Macroglobulinemia (WM). We identified 20 patients out of a cohort of 1,466 WM patients who experienced histologic transformation. The 5, 10, and 15‐year cumulative incidence rates were 1, 2.4, and 3.8%, respectively. Approximately half of the patients were naive to nucleoside analogues, and a quarter were previously untreated for WM at the time of transformation. More than 80% of patients presented with extranodal involvement, 65% with high IPI scores. DLBCL cells did not express CD10 but expressed BCL6 and BCL2. All patients were treated with chemoimmunotherapy. The median survival from histological transformation was 2.7 years. The median overall survival was shorter for transformed patients versus those who did not transform (estimated 9 vs. 16 years; P = 0.09). Histological transformation to DLBCL is rare, and is associated with inferior survival in WM. Am. J. Hematol. 91:1032–1035, 2016. © 2016 Wiley Periodicals, Inc.     

Spurious fibrinogen levels secondary to pyroglobulinemia in Waldenström's macroglobulinemia

We report two cases of pyroglobulinemia detected in the course of routine determination of fibrinogen levels measured by the heat-precipitation method and that led to the diagnosis of Waldenström's macroglobulinemia. The Incidence of pyroglobulinemia is briefly discussed, and the potential significance of this laboratory artifact is emphasized.     

Waldenström macroglobulinaemia: the key questions

In this review, the key issues that pertain to Waldenström disease are discussed in a concise question‐and‐answer format. Diagnosis, prognosis, and indications for state‐of‐the‐art therapy are updated. Current therapies presented at the 7th International Workshop for Waldenström Macroglobulinaemia are included.