Learn more about the current therapeutic options
for Waldenström’s macroglobulinemia.
Therapy of Waldenström’s macroglobulinemia
- Clinical practice guidelines are available from ESMO (2018, update planned) and NCCN.1,2
- Asymptomatic patients are usually not treated (watchful waiting).3
- Despite an indolent disease course, prompt treatment of Waldenström’s macroglobulinemia in symptomatic patients can be essential to address anemia, neuropathy, and other symptoms, and to avoid irreparable organ damage or fatal complications (such hyperviscosity syndrome).4
- According to the consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia (IWWM), the first-line therapy options for symptomatic patients with Waldenström macroglobulinemia are alkylating drugs (e.g., bendamustine, cyclophosphamide) and proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), as well as the Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib, alone or in combination with rituximab. Some combinations also include dexamethasone.5
- The approval of the oral Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib alone and in combination with rituximab has expanded the treatment options for WM patients, and BTK inhibition is an emerging standard of care.6
- For previously treated patients who had an initial durable response, reuse of a previous regimen or another primary therapy regimen is recommended.5
- Patients may join clinical trials based on discussion with their healthcare provider and study eligibility criteria.2
- Treatment strategy is dependent on patient and disease characteristics, genomic profile (MYD88/CXCR4 mutations), regional drug availability and guidelines, and the extent of symptoms and end-organ involvement.7
Factors which determine current treatment options in Waldenström’s macroglobulinemia
In this excerpt from the BeiGene satellite symposium at EHA 20207, Professor Véronique Leblond reviews the factors which determine current treatment options in Waldenström’s macroglobulinemia. She explains how the choice of treatment depends on patient characteristics, disease characteristics, genomic profile and drug availability.
Patient characteristics influencing treatment choice include performance status, comorbidities, and age. Younger patients may be candidates for high dose therapy. Nucleoside analogues should be avoided as they impair stem cell collection.5,4
Disease characteristics influencing treatment choice include levels of cytopenia, the need for rapid disease control, and the presence of neuropathy (with the latter, proteasome inhibitors should be avoided). Genetic profile impacts the choice of treatment, for example, the presence of MYD88 and CXCR4 mutations.5,4
A review of the importance of BTK inhibition in B‑cell malignancies such as Waldenström's macroglobulinemia
BTK plays an essential role in B‑cell development and function. Following activation by upstream effectors, BTK triggers signaling pathways that, in turn, promote the expression of genes involved in proliferation and survival. Constitutive activation of the B‑cell receptor and in turn, BTK, contributes to the pathogenesis of B‑cell lymphomas.8
BTK is therefore an important therapeutic target in the treatment of B‑cell malignancies.8
Malignant B cells overexpress BTK, and preclinical data suggest that even when pharmacologically inhibited, new synthesis of BTK can help resume the production of cancerous cells.9
This overexpression of BTK triggers signaling pathways that, in turn, promote the expression of genes involved in proliferation and survival of malignant B cells. Thus, full and sustained inhibition of BTK may be important in controlling B‑cell malignancies.
Without continuous full inhibition of BTK, lapses may allow newly synthesized BTK protein to continue proliferation signaling within malignant B cells. Further, BTK inhibitors must reach disease‑relevant tissues, including the lymph nodes, spleen, bone marrow, and peripheral blood, as well as the central nervous system, where primary lymphoma can occur.
The BTK inhibitor, ibrutinib, is currently the therapy of choice for patients who have relapsed within 12 months from chemoimmunotherapy, including rituximab-refractory patients and for patients ineligible for chemoimmunotherapy at first-line. For patients with late relapses after chemoimmunotherapy, ibrutinib is also considered an option.1 Long-term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström’s macroglobulinemia showed that after a median follow-up time of 59 months, the overall and major response rates were 90.5% and 79.4% respectively. Importantly, the median progression-free survival in previously treated patients with WM exceeded 5 years and was affected by both MYD88 and CXCR4 mutation status. Grade ≥ 3 adverse events in more than one patient deemed possibly related to ibrutinib therapy included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%).10
Treatment options in treatment-naïve Waldenström’s macroglobulinemia patients
Lecture: Professor Veronique LeBlond discusses treatment options in treatment-naïve Waldenström macroglobulinemia patients.
In this excerpt from the BeiGene satellite symposium at EHA 20207, Professor Véronique Leblond reviews current treatment options in treatment-naïve Waldenström’s macroglobulinemia patients. Professor Leblond explains that immunochemotherapy, generally consisting of a rituximab-based regimen with bendamustine or cyclophosphamide is used frequently in Europe. She identifies that rituximab-bendamustine is more active than rituximab-cyclophosphamide, but more toxic; with more hematological toxicity, long lasting cytopenia and rash.13,14,15,16
Professor Leblond outlines some treatment modifications depending on patient characteristics. For example, in frail patients, the number of cycles and doses can be reduced. In cases of hyperviscosity, plasmapheresis should be used concomitantly with systemic therapy. In case of high levels of IgM or high risk of IgM-related complications (e.g., cryoglobulinemia, acquired Von-Willebrand disease), plasmapheresis may be used preemptively. Professor Leblond goes on to outline other treatment options in treatment-naïve Waldenström’s macroglobulinemia patients, such as combining rituximab with a proteasome inhibitor. The most frequently used proteasome inhibitor is bortezomib, used with rituximab and with or without dexamethasone.17,18,19 The median progression free survival (PFS) with this combination is 43 to 66 months. Rituximab can be used as a single agent in anti-MAG neuropathy, cryoglobulinemia, or very frail patients.20,21,22 Overall response rate is quite low, with short progression-free survival (PFS) (>2 years). In Europe, ibrutinib as a single agent is indicated for the treatment of adult patients with Waldenström's macroglobulinemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy. Ibrutinib in combination with rituximab is indicated for the treatment of adult patients with WM. Overall response rates (ORR) are high, with 82% of patients progression-free at 30 months.23,24
Treatment options in relapsed/refractory Waldenström’s Macroglobulinemia patients
In this excerpt from the BeiGene satellite symposium at EHA 20207, Professor Véronique Leblond discusses treatment options in relapsed/refractory Waldenström’s macroglobulinemia patients. In this setting alternative rituximab-based regimens can be used at relapse, and alternated or repeated according to response duration. Ibrutinib is approved in this setting in Europe. For patients who have relapsed within 12 months from chemoimmunotherapy, including rituximab-refractory patients, single-agent ibrutinib is the treatment of choice.25,26
The risk of bleeding, hypertension (13%) and atrial arrhythmia (12%) are increased while on ibrutinib. Professor Leblond reviews stem-cell transplantation (SCT) options. Autologous SCT is not appropriate as part of first-line therapy in fit patients responding to induction therapy. Autologous SCT is appropriate following second or subsequent relapses in high-risk fit patients with chemotherapy-sensitive disease, and must be considered in Bruton’s tyrosine kinase inhibitor (BTKi)-naïve patients. Allogenic SCT is a curative treatment but limited outside clinical trials and should be considered only in highly selected young patients with aggressive disease, who have failed or are resistant to BTK inhibitors.