Waldenstrom macroglobulinemia (WM) is characterized by a concomitant lymphoplasmacytic lymphoma (LPL), most frequently in the bone marrow, spleen, and /or lymph nodes, and an IgM monoclonal component in the blood.
The most common presenting symptoms are anemia, sensorimotor peripheral neuropathy, and hyperviscosity syndrome. Hyperviscosity is usually not clinically appreciable until the serum viscosity reaches 4 centipoise.
For this illness, treatment is not always warranted at the time of initial diagnosis, and in many cases a period of watchful waiting is instituted.
When to Initiate Therapy
A panel at the Second International Workshop on WM, held in September 2002, signaled that the decision to initiate therapy for WM should not be based on the IgM level per se, since this value may not correlate with clinical manifestations. Rather, it should be based on the development of constitutional symptoms such as fever, night sweats, fatigue due to anemia, and weight loss.
Symptomatic lymphadenopathy or splenomegaly may warrant initiation of treatment as well, as may the presence of anemia with a hemoglobin value of <or= 10 g/dL; a platelet count of less than 100 x 10(9)/L due to marrow infiltration; or the presence of hyperviscosity syndrome, neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia.
New Insights, New Therapies
Several recent discoveries about the biology of WM have been crucial for developing new therapies. More than 90 percent of patients carry an activating mutation in MYD88, a gene that encodes a protein involved in Toll-like receptor (TLR) signaling, which plays a role in activating NF-kB.
The Bruton’s tyrosine kinase (BTK), which is a member of the B cell receptor pathway, appears to preferentially bind to the mutated MyD88. WM cells also express increased phosphorylated BTK, the active form of the protein. Collectively, these biologic insights provided scientific explanation and rationale for therapeutic targeting BTK in patients with WM.
The choice of first-line therapy for WM hinges on the patient’s symptoms and the rationale for initiation of treatment. Combinations typically used include rituximab with an alkylator, nucleoside analog, or proteasome inhibitor.
Steroids are also often part of the initial armamentarium. For patients with elevated IgM level and hyperviscosity, treatment with the proteasome inhibitor bortezomib is often the treatment of choice due to the rapid clearance of the paraprotein.
Less intense regimens such as RCP (rituximab, cyclophosphamide, and prednisone) are appropriate for patients with mild symptoms and less aggressive disease. R-Bendamustine has been shown to be very effective and well tolerated and remains an option for some patients. Fludarabine-based treatments are falling out of favor due to the increased risk for transformation and of secondary malignancy associated with this nucleoside analog.
Management of Relapsed or Refractory WM
Since 2004, significant strides have been made in the approach to relapsed or refractory WM. Agents such as bendamustine, everolimus, panobinostat, carfilzomib, and perifosine have all demonstrated efficacy, with ORRs (including minor responses) between 25 and 70 percent, with the first two being the most effective drugs.
Given what is now understood about the biology of WM, therapies directed at the inhibition of TLR and BCR signaling pathways are rapidly being developed.
In collaboration with Dana Farber Cancer Center and Stanford University, we have conducted a large study (n=63) of ibrutinib, an oral irreversible BTK inhibitor, for patients with relapsed or refractory WM. We observed an ORR of 81 percent (4 VGPR; 32 PR, 15 MR), with a major response rate (PR or better) of 57 percent and a median time to response of four weeks.
Responses were durable and most patients are still on therapy. Based on this data, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to ibrutinib monotherapy for the treatment of patients with WM, which is a first step for an accelerated approval by the FDA.
In fall 2014, a phase III randomized follow-up study will assess R-Ibrutininb versus R-placebo at Memorial Sloan Kettering.
In a different strategy, we will soon initiate a phase I clinical trial targeting TLR signaling pathway. This study will test the activity of IMO8400, a novel TLR antagonist oligonucleotide given subcutaneously every 21 days. Patients with relapsed refractory WM may also be eligible for an additional number of clinical trials currently open at MSK (listed below).
To refer a patient with WM, please call our lymphoma service referral line at 646-497-9137. To inquire about a clinical trial for a patient with WM, please contact Dr. M. Lia Palomba at 212-639-7186.