Treatment recommendations for Waldenström macroglobulinemia have been updated based on the advice of a task force convened at the Eighth International Workshop on Waldenström Macroglobulinemia; the guidelines have been published in Blood.
The task force was impaneled to review recently published and ongoing clinical trial data as well as the impact of the newly recognized mutations MYD88 and CXCR4 on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives.
Michail Charakidis, David Joseph Russell/Wikimedia Commons/CC BY 2.0
Waldenström macroglobulinemia
The panel reiterated that the criteria for initiating therapy include immunoglobulin M (IgM)-related complications and/or symptoms that are related to direct involvement of the bone marrow by tumor cells, constitutional symptoms, and bulky extramedullary disease. Patients presenting with symptoms that include symptomatic hyperviscosity, moderate to severe hemolytic anemia, and symptomatic cryoglobulinemia need immediate treatment.
Close observation is recommended for the subgroup of patients who do not really fulfill the criteria for a diagnosis of Waldenström macroglobulinemia (WM), and whose laboratory findings may be the only indicator of the presence of a progressive disease.
Treatment recommendations
For symptomatic patients in the first-line setting, “anti-CD20 monoclonal antibody therapy alone or in combination with chemotherapy is an important standard of care for most patients with WM,” the authors, led by Veronique Leblond, MD, of Pitié-Salpêtrière Hôpital, Paris, wrote.
Rituximab is frequently used in WM, either as monotherapy or in combination with chemotherapeutic agents. The panel cautions that rituximab as monotherapy should be avoided in patients with high IgM levels, because of a lower chance of response and the risk of an IgM flare.
In patients with high IgM levels (typically around 4,000 mg/dL), plasmapheresis can be initiated before rituximab therapy, and plasmapheresis should always and immediately be used when symptomatic hyperviscosity is present. However, plasmapheresis alone is not an effective treatment for WM and must be followed by a rapidly acting cytoreductive regimen.
Several rituximab combinations are recommended by the panel. These include:
• Dexamethasone-rituximab-cyclophosphamide, which is an active and safe option, has a manageable toxicity, and can be considered for frail patients who need combination therapy.
• Bendamustine-rituximab is effective for front-line treatment and is well tolerated even in elderly patients who experience limited episodes of myelosuppression and infections.
Other therapeutic regimens include bortezomib-based therapy, which is recommended for patients with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia or cold agglutinemia, amyloidosis, and renal impairment or in young patients who prefer to avoid alkylator or nucleoside analogue therapy.
Another option is carfilzomib-based therapy, which is an emerging “neuropathy-sparing” regimen for proteasome-inhibitor–based therapy, although it may not be the best choice for elderly patients with preexisting cardiac conditions due to potential cardiac toxicity.
Ibrutinib has been approved as a primary therapy for patients who are not candidates for chemoimmunotherapy, but the authors point out that the optimal use of this agent is still being investigated.
“The aim of the first-line treatments is to reach a high response rate with a prolonged progression-free survival,” write the authors. “The panel agrees that there is need to perform clinical trials with chemotherapy-free combinations with new compounds alone or in combination with anti-CD20 antibodies.”
For symptomatic previously treated patients
The panel also offered recommendations for previously treated symptomatic patients who have relapsed or are refractory to treatment.
Any of the interventions recommended for symptomatic, untreated patients can be considered for those who have already gone through first line therapy. Retreatment can be considered with a specific intervention if a response was achieved for 2 or more years with that therapy, although they caution that patients who have progressed on first-line ibrutinib should not use it again.
Ofatumumab is a potential option for patients who are unable to tolerate rituximab, and nucleoside analogues can be considered in fit patients who have not responded to less-toxic treatments.
Another option in this setting is everolimus, although since it is associated with considerable toxicities, the best candidates for this drug are those who have not responded to or have progressed after multiple lines of other better-tolerated regimens.
Immunomodulatory agents can also be considered, but in the context of a clinical trial only, because of their potential adverse events.
Finally, the panel also agreed that stem cell transplantation should be discussed with select patients, and while it is a feasible and effective treatment option for high-risk WM patients, it should be ideally offered at early relapse.