Professor Meletios A. Dimopoulosfrom the National and Kapodistrian University of Athens, Greece, presented an educational session on Waldenström Macroglobulinemia (WM) during the ESMO congress in October 2016 in Copenhagen, Denmark.
The session began with explaining the background and clinical origins of the classification of WM, before moving on to discuss the diagnostic criteria used currently. These criteria were: any concentration of monoclonal IgM, lymphoplasmacytic cells found within bone marrow, immunophenotypes of surface IgM+, FMC7+ CD103-, CD138-, CD5+, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, and CD27+. The last two of these criteria are considered supportive but not necessary for diagnosis.
The genetics of WM were the next topic of discussion and data presented stated that 91% of patients with WM have the MYD88 somatic mutation L265P ( Treon, et al. 2012). MY88 protein is involved in the phosphorylation of IRAK4, interacts with IL1R, its downstream of TLR4, and upstream of NEMO, p50 and p65. Additionally, a somatic C-tail WHIM-like mutation in CXCR4 is present in 27–31% of WM patients.
Data presented from Treon et al. at ICML 2011 showed that of over 1,000 patients diagnosed with WM, 26.1% had a first or second degree relative with a form of B-cell lymphoproliferative disorder.
The next topic covered was the clinicopathologic manifestations of WM, shown below, along with the recommendations for the initiation of therapy for WM, noting that IgM levels by itself is not sufficient for the initiation of therapy.
Morel et al. in 2009presented an international prognostic scoring system for WM in which they found five factors affecting prognosis and these were: age >65 years, monoclonal IgM > 7.0 g/dL, platelet count ≤ 100 x 10 9/L, β2-microglobulin > 3 mg/L, and hemoglobin ≤11.5 g/d. Low-risk patients presented with no or one of these factors, intermediate risk with two factors or only age >65 years, and high-risk patients were classified as having more than two of these factors. The survival rates are shown in the graph below.
A summary slide of the challenges facing the management of WM was presented. Outlined were the facts that WM is a rare disease, mostly in the elderly, and that eradication of the disease is not currently realistic. Furthermore, there are ‘hardly any’ drugs approved for treating WM, large trials are difficult and that for most patients, an intense treatment is not feasible.
The recommended frontline therapy options, from the 8 thInternational Workshop for WM, were then summarized on the two slides pictured below:
Finally, Professor Dimopoulos summarized the talk with the following points:
- Diagnostic role of MYD88 L265P: is there MYD88 WT WM?
- Individualized therapy based on clinical demands: is it feasible?
- Short duration (~4 months) of rituximab-based regimens for most patients with untreated WM (DRC, BR, BDR in selected patients) --> high ORR, PFS >3 years
- BTK inhibitor oral therapy for prolonged periods (how long?)
- Can we choose therapy based on mutational status of MYD88 and CXCR4?
- Ibrutinib may be a primary choice for selected patients (i.e. high IgM, cytopenias, neuropathy) - may not be a good choice if bleeding diathesis
- For patients with rituximab-refractory disease, ibrutinib is probably the best option
- Limited data exists for patients who fail ibrutinib, but proteasome inhibitors (bortezomib) may be active
- Ibrutinib therapy is long lasting and expensive - IgM increases may occur if discontinued
Data for the efficacy of the different treatment options discussed for WM in this talk are presented in the following publications: Dimopoulos, et al. Blood. 2014 , Kastritis, et al. Blood. 2015 , Rummel, et al. Lancet. 2013 , Dimopoulos, et al. Blood. 2013 , Treon, et al. Blood. 2014 , and Treon, et al. NEJM. 2015.