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Diego Villa, MD, MPH, FRCPC

Diego Villa, MD, MPH, FRCPC

Diego Villa is Clinical Associate Professor at the University of British Columbia and a medical oncologist at the BC Cancer – Vancouver Cancer Center. He is involved in the care of patients with lymphoid malignancies and breast cancer. His research interests include the management of transformed indolent lymphomas, management of mantle cell lymphoma, primary and secondary CNS lymphomas, and the role of PET/CT in aggressive lymphoma. Dr. Villa has ongoing research collaborations with Canadian, American, European, and Australian lymphoma groups. He is also the local principal investigator for various international lymphoma and breast cancer clinical trials open in Vancouver. He actively participates in the teaching of medical students, residents, and fellows at BC Cancer and VGH, and is the faculty coordinator for the medical oncology rotation at BC Cancer for the UBC Internal Medicine Residency Program. Dr. Villa is a member of the UBC Medical Oncology Residency Training Program committee and its Competence by Design subcommittee.

Tailoring therapy in Waldenström Macroglobulinemia



Waldenström Macroglobulinemia (WM) is a mature B-cell neoplasm categorized as a lymphoplasmacytic lymphoma (LPL) with monoclonal immunoglobulin M (IgM) production.1  WM comprises a spectrum of clinical manifestations related to (a) excessive infiltration of the bone marrow and/or other organs (lymph nodes, spleen, extranodal organs) by the LPL infiltrate, and (b) the impact of excess IgM on the circulatory and immune systems, and end organs. The latter includes serum hyperviscosity, infection related to suppression of other immunoglobulins, autoimmune cytopenias, cryoglobulinemia, production of anti-myelin-associated glycoprotein antibodies leading to peripheral neuropathy, and occasionally AL amyloidosis with end-organ deposition.

Assessment of WM

The assessment of a patient with WM requires 6 steps. (Table 1). The first step is to confirm the diagnosis, especially in patients with newly diagnosed disease. The diagnosis requires confirmation of a LPL with its characteristic morphology and immunoprofile, together with a monoclonal serum IgM. The MYD88 L265P mutation, typically identified using the polymerase chain reaction or other forms of sequencing in a bone marrow sample, is present in > 90% of patients with WM.2   The presence of this mutation may help differentiate WM from other lymphoid neoplasms, and is both prognostic and predictive of response to treatment.3, 4  The impact of several additional recurrent mutations in WM (including CXCR4) on the diagnosis, prognosis, and treatment selection for routine clinical practice has not yet been established.3, 5 

Table 1. Steps in the assessment of a patient with WM in the treatment-naïve and/or relapsed/refractory settings; courtesy of Diego Villa, MD

The second step in the assessment of a patient with WM is a thorough evaluation of the various compartments that may be involved directly or indirectly. Such assessment requires a full history and physical examination, comprehensive blood testing including measurements of total/monoclonal IgM and serum viscosity, bone marrow biopsy, and imaging investigations. Patients with neurologic signs or symptoms require brain imaging and cerebrospinal fluid analysis because WM can occasionally involve the central nervous system in the form of Bing-Neel syndrome in which malignant lymphoplasmacytic cells invade the central nervous system.6, 7   Patients with high serum viscosity or IgM levels require referral to ophthalmology because hyperviscosity can damage retinal blood vessels and impair vision.

Principles of management of WM

The third step in the assessment of a patient with WM is to determine whether there is a treatment indication. The goals of treatment of WM include palliating symptoms, reducing and/or preventing end-organ damage, and improving both quality and quantity of life. Observation is a valid management option in select patients without symptoms or clinically significant findings on initial investigations. This principle holds true in both the treatment-naïve and relapsed/refractory settings. However, most patients with WM require treatment for symptomatic disease or laboratory findings suggesting impending complications (i.e. cytopenias) even when asymptomatic. The International Workshop on WM (IWWM) has established clear treatment initiation criteria.8 

The fourth step in the initial assessment of a patient with WM is to determine whether plasmapheresis is necessary prior to systemic therapy. Excessive circulating IgM can lead to hyperviscosity syndrome (HVS) which classically presents with mucosal bleeding, retinopathy, and neurologic symptoms. HVS, particularly when associated with ocular or neurologic complications, is considered a medical emergency requiring urgent plasmapheresis. In patients with high IgM or serum viscosity, rituximab administration can cause a hyperviscosity flare.9   Plasmapheresis and/or omission of rituximab with the first cycle of chemotherapy may reduce the risk of this complication and should generally be considered in patients with serum IgM >50 g/L or viscosity >3.5 centipoise, although there is no definitive threshold. Plasmapheresis is a temporizing intervention and should always be followed by systemic therapy.10 

The fifth step in the assessment of a patient with WM is to determine the most appropriate treatment option. The interplay between the genomic profile of WM and available therapeutics is progressively informing treatment selection.3, 4   Specifically, consensus recommendations from the most recent IWWM suggest testing for MYD88 mutations before starting treatment because patients without MYD88 mutations are less likely to respond to ibrutinib monotherapy. The same guidelines do not currently recommend the use of CXCR4 testing to inform treatment decision-making outside of a research setting.5  The subsequent sections of this review describe therapeutic options for WM.

The sixth step in the assessment of a patient with WM is to determine the clinical response to a particular line of therapy. Response assessment to treatment for WM does not follow traditional criteria for other lymphomas such as the Lugano classification for the initial evaluation, staging, and response assessment of lymphomas11  because of the specific biology of WM and its response kinetics to therapy. The IWWM criteria for response assessment incorporate additional categories that quantify the degree of response in IgM and qualify response in nodal and extranodal organs, as well as other clinical parameters including symptoms.12  (Table 2)


Table 2. Current response assessment criteria in WM. Table modified from the Sixth International Workshop on WM publication. 12;
courtesy of Diego Villa, MD
BM: bone marrow, CR: complete response, MR: minor response, MRR: major response rate, ORR: overall response rate, PD: progressive disease, PR: partial response, SD: stable disease.


Rituximab-containing therapy

Over the past 1-2 decades, frontline therapy for WM has included rituximab alone or in combination with cytotoxic chemotherapy. Combinations with alkylators such as bendamustine (BR) are associated with high response rates, a generally acceptable toxicity profile, and prolonged remission in many patients (Table 3). An additional advantage of these regimens is their fixed duration, which improves quality of life in responders and provides the option of retreatment in those who relapse after long treatment-free periods.13-16  The use of maintenance rituximab after chemoimmunotherapy, particularly after BR, is not indicated because it prolongs immune suppression and does not improve progression-free survival (PFS).15

Proteasome inhibitors are also active against WM, with phase 2 trials showing high response rates when combined with rituximab (Table 3). It is difficult to assess whether the long-term outcomes achieved with proteasome inhibitors are comparable to those achieved with BR given the relatively limited sample size of these trials and the lack of head-to-head comparisons.17-20  The risks and benefits of using proteasome inhibitors should be weighed carefully in patients with peripheral neuropathy which is common in WM. Also, access to these agents, especially in the frontline setting, has historically been limited in Canada.

Table 3. Prospective studies of rituximab-containing therapies in the front-line setting; courtesy of Diego Villa, MD
*Difference was not statistically significant (HR 0.80 [95% CI 0.51-1.25], p=0.32)
^Difference was statistically significant (HR 0.33 [95% CI 0.11-0.64], p=0.003)
B: bendamustine, C: cyclophosphamide, CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone, D: dexamethasone, I: ixazomib,
K: carfilzomib, M: maintenance rituximab, MRR: major response rate, NA: not available, NR: not reached, ORR: overall response rage,
R: rituximab, V: bortezomib, VGPR: very good partial response

Bruton Tyrosine Kinase inhibitors

Covalent Bruton Tyrosine Kinase inhibitors (BTKi) have been studied in the frontline and relapsed/refractory settings.21-25  (Table 4) The two largest randomized clinical trials in WM performed to date have evaluated the role of BTKi. The iNNOVATE trial showed the combination of ibrutinib and rituximab both in treatment-naïve and relapsed/refractory WM was associated with a significant improvement in PFS compared to rituximab alone, and led to regulatory approval of ibrutinib in WM.21   In the ASPEN trial, zanubrutinib was associated with a higher very good partial response rate compared to ibrutinib (28% vs. 19%), although this difference was not statistically significant, and in the end PFS rates were similar with both agents at the 18 month timepoint. Zanubrutinib was associated with a lower incidence of known BTKi toxicities including atrial fibrillation, hypertension, diarrhea, and bleeding.23   BTKi are known to cross the blood-brain barrier and are the treatment of choice for patients with Bing-Neel syndrome.26


Table 5. Studies of other therapies in relapsed/refractory WM; courtesy of Diego Villa, MD
*Also included a proportion of treatment-naïve patients.
CR: complete response, GVHD: acute graft vs. host disease, mEFS: median event-free survival
mTTP: median time to progression (calculated only in responding patients), mPFS: median progression-free survival, NRM: 1-year non-relapse mortality, pPFS: pooled progression-free survival (estimated at 3-5 years given reporting differences between studies), mOS: median overall survival, ORR: overall response rate, pOS: pooled overall survival (estimated at 3-5 given reporting differences between studies), VGPR: very good partial response.


Potentially available therapies in Canada with activity against WM

Several classic and novel agents currently used in other malignancies demonstrate activity against WM in phase 2 trials (Table 5). Certain agents are associated with significant toxicity limiting their future use in WM including fludarabine (prolonged cytopenias and infection),27, 28  lenalidomide (severe rapid-onset anemia),29  and idelalisib (cytopenias, diarrhea, liver toxicity).30   Other agents with single-agent activity and expected toxicity profiles such as everolimus, venetoclax, daratumumab may be more appropriate for off-label use, although access in Canada remains limited.31-33   Autologous and allogeneic stem cell transplantation may benefit selected patients with treatment-responsive R/R WM at the expense of significant toxicity, including a high non-relapse mortality rate with allogeneic stem cell transplantation.34

Table 5. Studies of other therapies in relapsed/refractory WM; courtesy of Diego Villa, MD
*Also included a proportion of treatment-naïve patients.
CR: complete response, GVHD: acute graft vs. host disease, mEFS: median event-free survival
mTTP: median time to progression (calculated only in responding patients), mPFS: median progression-free survival, NRM: 1-year non-relapse mortality, pPFS: pooled progression-free survival (estimated at 3-5 years given reporting differences between studies), mOS: median overall survival, ORR: overall response rate, pOS: pooled overall survival (estimated at 3-5 given reporting differences between studies), VGPR: very good partial response.

Conclusions and future directions

WM is a lymphoid malignancy with a unique biology, natural history, and management considerations. The treatment of WM is becoming increasingly complex as more treatment options become available, and genomic profiling is playing an increasingly important prognostic and predictive role. Despite these advances, WM remains incurable, and patients with disease refractory to chemoimmunotherapy and BTKi face limited options and a poor prognosis. Non-covalent BTKi 35 , novel combinations, and immune therapies are currently under investigation and may provide additional opportunities to improve outcomes in WM.


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