The MYD88 L265P gene mutation has shown to support growth and survival of WM cells in several studies. A knockdown model of MYD88 showed decreased survival of MYD88 L265P expressing WM cells, whereas survival was more enhanced by knock-in of mutant versus wild-type MYD88 [10]. MYD88 acts as an adaptor molecule in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling [11]. Following stimulation of TLR or IL-1R, MYD88 is recruited to the activated receptor complex as a homodimer which complexes with IL-1R-associated kinase 4 (IRAK4) and subsequently activates IRAK1 and IRAK2 [12]. IRAK1 activation then leads to NF-κB activation via IκBα phosphorylation [13]. Recently, a study has shown that MYD88 L265P also activates the Bruton’s Tyrosine Kinase (BTK) pathway [10]. In this preclinical study, the activation of BTK by MYD88 could be abrogated by the use of BTK kinase inhibitors. A diagram of the activation of BTK and NF-κB via MYD88 is shown in Fig. 1.

A recent study from our group first ever reported the occurrence of recurrent somatic CXCR4 gene mutations in approximately 30 % of WM patients [14]. The somatic mutations occur in the C-terminal domain and are similar to those observed in patients with WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. These mutations regulate signaling of CXCR4 by its ligand SDF-1a [15]. In WM patients, two classes of CXCR4 mutations occur: non-sense (CXCR4^WHIM/NS) and frameshift (CXCR4^WHIM/FS) mutations [14, 16]. Non-sense and frameshift mutations are almost equally divided among WM patients, and over 30 different types of CXCR4 mutations have been identified. Preclinical studies with the most common CXCR4 S338X mutation in WM have shown sustained signaling of AKT, ERK, and BTK following SDF-1a binding in comparison with wild-type CXCR4, as well increased cell growth and survival of WM cells [17]. Figure 2 shows (a) the protein sequence for the full-length transcript, (b) the crystal structure of CXCR4, and (c) the location of the WHIM-like mutations.

Given the indolent and incurable nature of WM, a large proportion of patients would not need immediate therapy upon diagnosis and will be placed on watchful waiting. Current guidelines do not recommend initiation of therapy based on IgM levels alone since they might not correlate with clinical manifestations of the disease [18]. Initiation of therapy is, however, reasonable in patients demonstrating rising IgM levels along with signs or symptoms associated with disease progression. Criteria for initiation of therapy are shown in Table 2. In patients in whom an immediate control of the disease is warranted, such as symptomatic hyperviscosity, coagulopathy, cryoglobulinemia, or cold agglutinin disease, a rapid reduction of the IgM paraprotein should be achieved with plasmapheresis. Treatment directed at WM should follow as soon as possible since plasmapheresis does not constitute definitive therapy and IgM levels will rise and return to baseline levels within 4 weeks.

There are several options for the frontline therapy of patients with WM. These options include alkylating agents (i.e., chlorambucil, cyclophosphamide, and bendamustine), nucleoside analogs (i.e., fludarabine and cladribine), the immunomodulator thalidomide, and the proteasome inhibitor bortezomib, with or without the anti-CD20 monoclonal antibody rituximab [19]. Individual patient considerations should be taken into account when making the choice of frontline treatment including the presence of cytopenias, need for rapid disease control, age, pre-therapy IgM levels, pre-existing neuropathy, and candidacy for autologous transplantation therapy. For candidates for autologous transplantation, exposure to alkylator therapy or nucleoside analogs should be limited because of the difficulties with stem cell collection. The use of nucleoside analogs should be approached cautiously given that increased risk of disease transformation, myelodysplasia, and acute myeloid leukemia have been reported.

For those patients with relapsed/refractory disease, any of the frontline therapies mentioned above are appropriate options. Therapies in the relapsed setting should also be personalized to the individual patient considering age, performance status, pre-existing neuropathy, IgM levels, and/or need for immediate control of the disease. One must also have in mind to avoid the use of stem cell toxic therapy in patients in whom high-dose chemotherapy with autologous stem cell rescue is being considered.

A retrospective study examined the outcome of 248 WM rituximab-naïve patients who were treated with rituximab-containing regimen and then either observed or received maintenance rituximab [45]. In this study, further improved responses after induction therapy were seen in 10 % (16 out of 162) of observed patients and in 42 % (36 out of 86) of patients who received maintenance rituximab. Both PFS (56 vs. 29 months) and OS (>120 vs. 116 months) were longer in patients who received maintenance rituximab. Improved PFS was evident despite previous treatment status or type of induction therapy. Among patients receiving maintenance rituximab, an increased number of infectious events, predominantly grades 1 and 2 sinusitis and bronchitis, were observed. A prospective study examining the role of maintenance rituximab in patients with WM has been initiated by the German STiL group [46]. After undergoing induction therapy with BR, 100 out 162 patients responded to BR (ORR 86 %). From these patients, 43 were then randomized to observation and 47 to maintenance rituximab. Enrollment for this study is complete, and final results are awaited.

The use of stem cell transplantation (SCT) therapy has been explored in patients with WM. Several small series have been reported for autologous and allogeneic transplantation, with variable outcomes. Kyriakou and colleagues reported the largest experience using European Bone Marrow Transplant (EBMT) data for WM patients receiving autologous SCT [47]. Among 158 relapsed/refractory WM patients receiving an autologous SCT, the 5-year PFS and OS rates were 49 and 69 %, respectively. Non-relapse mortality at 1 year was 4 %. Chemorefractory disease and number of prior lines of therapy at time of autologous SCT were the most important prognostic factors for PFS and OS. When used as consolidation at first response, autologous SCT provided a PFS rate of 44 % at 5 years. Long-term outcomes of WM patients undergoing allogeneic SCT from EBMT have been reported [48]. A total of 86 patients received allograft by either myeloablative or reduced-intensity conditioning (RIC). The median age was 49 years, and 47 patients had 3 or more previous lines of therapy. Eight patients failed prior autologous SCT. Fifty-nine patients (69 %) had chemotherapy-sensitive disease at the time of allogeneic SCT. Non-relapse mortality rate at 3 years was 33 % for patients receiving myeloablative transplant and 23 % for those who received RIC. The ORR was 76 %. The relapse rates at 3 years were 11 % for myeloablative and 25 % for RIC recipients. Five-year PFS and OS rates for WM patients who received a myeloablative allogeneic SCT were 56 and 62 %, respectively, and for patients who received RIC were 49 and 64 %, respectively. The occurrence of chronic graft-versus-host disease was associated with improved PFS and suggested the existence of relevant graft-versus-WM effect in this study.