What's new in Waldenström macroglobulinemia

In this issue of Leukemia and Lymphoma, Rourke and colleagues comprehensively review available data on the treatment of Waldenström macroglobulinemia [1]. This is a rapidly evolving field, and a number of new developments form the subject of this Commentary. Due to the development of new chemotherapeutic agents and their use in combination, survival in Waldenström macroglobulinemia is steadily improving. A number of investigators now report both overall survival and disease-specific survival. Waldenström macroglobulinemia is a disorder with a median age of 67 years. In an elderly population there are competing causes of death, and patients may succumb, not to their Waldenström, but to common illnesses seen in the elderly. At Mayo Clinic, median disease-specific survival is 11.2 years [2]. With these excellent outcomes, quality of life, often affected by the selected treatment, becomes as important a consideration as response rate and progression-free survival. Waldenström is a unique lymphoma. A distinguishing cytogenetic abnormality, 6q-, is seen in 54%. Waldenström is not a variant of follicular lymphoma, chronic lymphatic leukemia, or multiple myeloma. Studies in those disorders are not necessarily applicable to this unique population [3]. Patients with 6q- have higher levels of β₂-microglobulin and M-protein, and a greater tendency to display anemia and hypoalbuminemia. The incidence of 6q- rises with international stage. Patients with smoldering Waldenström with a 6q- tended to require treatment sooner [4].

A new international prognostic scoring system has been developed for Waldenström macroglobulinemia that is completely different from the standard International Prognostic Index (IPI) or Follicular Lymphoma International Prognostic Index (FLIPI) used in large cell and follicular lymphomas [5]. The five factors associated with shortened survival have been identified as: (1) hemoglobin ≤11.5 g/dL, (2) platelet count ≤100 000/µL, (3) β₂-microglobulin ≤3 mg/L, (4) serum monoclonal protein concentration >7 g/dL, and (5) age >65 years. (Note: the immunoglobulin M [IgM] level does not attain prognostic significance until it is >7 g/dL.) Low-risk patients with no or one adverse characteristic and advanced age, intermediate-risk patients with two adverse characteristics or only advanced age, and high-risk patients with more than two adverse characteristics have 5-year survival rates of 87%, 68%, and 36%, respectively [5].

What is the ultimate goal of therapy? For the first time, complete responses are being seen with combinations of chemotherapeutic agents in Waldenström. Despite the ability to achieve a complete response, it may not be the only endpoint of value. There appears to be no survival difference between a 25–50% reduction in the IgM level and a >50% reduction in the IgM level for patients treated with single-agent rituximab [6]. As a consequence, patients who have only a modest reduction in the IgM level achieve clinically meaningful results. More aggressive or intensive therapy for these minor responders is not required. Treatment with single agents can be effective in the management of Waldenström. However, single-agent rituximab produces only a 55% response rate [6] and is not necessarily superior to single-agent chlorambucil, at a greater cost. Single-agent fludarabine is associated with 8-year survivals of 55% in patients with low stage [7]. Treatment recommendations from the Fourth International Workshop on Waldenström Macroglobulinemia include combination therapy such as rituximab with nucleoside analogs, with or without alkylating agents, or with cyclophosphamide-based therapy, or for patients with cytopenia, the combination of rituximab with thalidomide. The approach with multiple agents is likely to yield responses at least as good as, if not better than, those with monotherapy [8]. Recently, the role of autologous stem cell transplant and its ability to produce durable responses has been reported. Non-relapse mortality in a registry study was 3.8% at 1 year with a progression-free and overall survival at 5 years of 39.7% and 68.5%, respectively. These are respectable results for previously treated patients, with nearly one-third of patients having failed three prior lines of therapy [9]. Stem cell transplant may be underutilized in Waldenström macroglobulinemia. Recently, bortezomib has shown activity in this disease [10]. However, the neurotoxicity of this agent in a disorder that responds to a wide variety of alternative agents will be a concern particularly for those patients destined to live more than a decade. The mTOR (mammalian target of rapamycin) inhibitor, everolimus, is an oral agent shown to be active in the treatment of Waldenström. It is oral, taken once a day, and can produce durable responses [11]. With the large number of available options, how does a clinician decide? The Mayo Clinic has wrestled with this problem and has developed consensus guidelines for the treatment of newly diagnosed and relapsed Waldenström macroglobulinemia. These can be found at http://msmart.org/.