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
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)
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.
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
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
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.
1. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 2016;374:2419-29.
2. Arai S, Fanale M, Devos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leukemia & Lymphoma 2013;54:2531-3.
3. Fermé C, Mounier N, Diviné M, et al. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the Groupe d’Etudes des Lymphomes de l’Adulte H89 Trial. Journal of Clinical Oncology 2002;20:467-75.
4. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 Activity and EBV Infection Induce PD-L1 in Hodgkin Lymphomas and Posttransplant Lymphoproliferative Disorders: Implications for Targeted Therapy. Clinical Cancer Research 2012;18:1611-8.
5. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015;372:311-9.
6. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. Journal of Clinical Oncology 2016;34:3733.
7. Timmerman JM, Engert A, Younes A, et al. Checkmate 205 Update with Minimum 12-Month Follow up: A Phase 2 Study of Nivolumab in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma. Blood 2016;128:1110-.
8. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 2016;17:1283-94.
9. Zinzani PL, Engert A, Younes A, et al. Checkmate 205 Cohort C: Nivolumab in patients with classical Hodgkin lymphoma after prior brentuximab vedotin and autologous hematopoetic stem cell transplantation. Haematologica 2016;101:43-4.
10. Armand P, Engert A, Younes A, et al. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol 2018;36:1428-39.
11. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. Journal of Clinical Oncology 2017;35:2125.
12. Chen R, Zinzani PL, Lee HJ, et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood 2019;134:1144-53.
13. von Tresckow B, Fanale M, Ardeshna KM, et al. Patient-reported outcomes in KEYNOTE-087, a phase 2 study of pembrolizumab in patients with classical Hodgkin lymphoma. Leukemia & lymphoma 2019.
14. Zinzani PL, Ramchandren R, Santoro A, et al. Effect of Pembrolizumab Monotherapy Versus Brentuximab Vedotin (BV) on Symptoms Associated with Health-Related Quality of Life (HRQoL) in Relapsed/Refractory (R/R) Classical Hodgkin Lymphoma (cHL) in the Randomized, Phase 3, Keynote-204 Study. Blood 2020;136:19-20.
15. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. N Engl J Med 2018;378:331-44.
16. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015;385:1853-62.
17. Advani RH, Moskowitz AJ, Bartlett NL, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood 2021;138:427-38.
18. Mei MG, Lee HJ, Palmer J, et al. Response-adapted anti-PD1 based salvage therapy for Hodgkin lymphoma with nivolumab +/- ICE (NICE). Blood 2022.
19. Kuruvilla J, Keating A, Crump M. How I treat relapsed and refractory Hodgkin lymphoma. Blood 2011;117:4208-17.
20. Baetz T, Belch A, Couban S, et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin’s disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 2003;14:1762-7.
21. Moskowitz AJ, Shah G, Schöder H, et al. Phase II Trial of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma. Journal of Clinical Oncology 2021:JCO. 21.01056.
22. Brockelmann PJ, Goergen H, Keller U, et al. Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma: The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial. JAMA Oncol 2020.
23. Ramchandren R, Domingo-Domenech E, Rueda A, et al. Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. J Clin Oncol 2019;37:1997-2007.
24. Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced stage classical Hodgkin lymphoma. Blood 2020.
25. Cheson BD, Bartlett NL, LaPlant B, et al. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol 2020;7:e808-e15.