Choice of therapy for patients with Waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by the presence of lymphoplasmacytic cells in the bone marrow (BM), along with demonstration of an immunoglobulin (Ig) M monoclonal protein in the serum. In 1944, Jan Gosta Waldenstrom first reported this syndrome by describing two patients with lymphadenopathy, oronasal bleeding, anemia, thrombocytopenia, and infiltration of the BM by lymphoid cells. Since then, many advances have occurred in the biology and therapy of this unique entity. Most recently, whole genome sequencing of lymphoplasmacytic cells was performed from 30 patients with WM, showing a recurring sequence variant in chromosome 3p22.2 that results in a single nucleotide change in the myeloid differentiation primary response (MYD88) gene with a predicted nonsynonymous change at amino acid position 265 from leucine to proline (L265P). This MYD88 L265P mutation occurred in 90% of the WM samples and was not observed in normal germline cells or in most cases of multiple myeloma. Despite these advances, there are no US Food and Drug Administration–approved therapeutic agents for the specific treatment of WM, and no standard therapy exists for the upfront management of patients with newly diagnosed disease. The recommendations for upfront therapy include alkylating agents, nucleoside analogs, proteasome inhibitors, and the monoclonal antibody rituximab. Many novel therapeutic agents are being tested in clinical trials for this rare disease, including second-generation proteasome inhibitors, immunomodulators, mammalian target of rapamycin inhibitors, histone deacetylase inhibitors, and bruton tyrosine kinase inhibitors. However, most of these studies are conducted in small numbers of patients, and many include heterogeneous patient populations, such as untreated or relapsed and refractory patients. Given the paucity of large clinical trials in WM, especially phase III clinical trials, the establishment of a standard treatment regimen that can be used as a benchmark for assessing novel, experimental agents is of critical importance. To date, few randomized clinical trials have been performed in WM. The first of these studies, to our knowledge, randomly assigned 46 patients to continuous or intermittent chlorambucil therapy and demonstrated an overall response rate of 75% in patients who received continuous chlorambucil. Leblond et al randomly assigned 92 patients with relapsed WM to fludarabine versus CAP (cyclophosphamide, doxorubicin, and prednisone) chemotherapy. Partial responses were obtained in 30% treated with fludarabine compared with only 11% in those treated with CAP. Patients treated with fludarabine had a more durable response and longer event-free survival. Two phase III trials of low-grade lymphoma that included patients with lymphoplasmacytic lymphoma or WM have been reported. In 2009, Buske et al reported that the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, prednisone, and vincristine) chemotherapy improves treatment outcome in lymphoplasmacytic leukemia (LPL) and the subgroup of patients with LPL fulfilling the criteria of WM. A total of 69 patients with previously untreated LPL were enrolled onto the trial; 48 patients fulfilled the criteria of WM. CHOP plus rituximab (R-CHOP) resulted in a significantly higher overall response rate (94% v 67%) in the patients with LPL. R-CHOP also demonstrated a significantly longer time to treatment failure. Another trial by Rummel et al, which has been presented in abstract form, showed that 22 patients with WM enrolled onto a low-grade lymphoma trial of bendamustine and rituximab (B-R) showed a better progression-free survival (PFS) compared with the 19 patients treated with R-CHOP. The median PFS for the patients with WM randomly assigned to R-CHOP was 35 months, whereas median PFS was not reached for those treated with B-R. In contrast to these smaller trials, a large randomized phase III trial in WM would not only set the standard of care for WM but also more rigorously reveal the overall survival (OS) associated with therapy in this disease. In the article accompanying this editorial, Leblond et al present the results of a large phase III trial of patients with WM or marginal zone lymphoma and lymphoplasmacytic lymphoma randomly assigned to receive either chlorambucil or fludarabine. Of the 414 eligible patients, 339 were diagnosed with WM and 38 with lymphoplasmacytic lymphoma. The study showed no difference in the overall response rate between the two arms. However, with a median follow-up of 36 months, the median PFS and duration of response were significantly higher in the fludarabine arm compared with the chlorambucil arm (PFS, 36.3 v 27.1 months; P .012). Similarly, the median OS was significantly better in patients treated with fludarabine compared with in those treated with chorlumabucil; the median OS was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (P .014). This study showed the superiority of single-agent fludarabine compared with chlorambucil in the treatment of WM. The results were not surprising, given that many prior small studies have shown the efficacy of fludarabine in this patient population. However, this study represents one of the largest efforts to establish a standard of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 3 JANUARY 2