Waldenström macroglobulinemia: is newer really better?

In this issue of Leukemia and Lymphoma, Peinert and colleagues describe outcomes follow- ing fludarabine-based therapy in patients with Waldenstrom macroglobulinemia (1). Responses were seen in 90%, and were 100% in previously untreated patients. Responses were durable, with a median progression-free survival of 43.1 months, but only two out of 12 pretreated and none of eight previously untreated patients had a high-risk international prognostic stage, which may have contributed to the excellent outcomes. Fludarabine phosphate is a purine nucleoside analog. The nitrogen base represents adenine with a fluoride atom in the 2-position, bound to the ribose sugar stereoisomer arabinose and to a phosphate representing a nucleoside analog that inhibits DNA synthesis by interfering with ribonucleotide reduc- tase and DNA polymerase. It is active against dividing and resting cells, an important feature since Waldenstrom lymphoplasmacytes are non-prolifera- tive over long periods of time. This work builds on previous publications that demonstrate the activity of fludarabine as a single agent. In new untreated patients, only 21% required therapy at a median follow-up of 100 months, and the 8-year survival in patients with a low international prognostic score was 55% (2). Fludarabine was approved for use by the US Food and Drug Administration (FDA) in 1991, and its efficacy when combined with rituxi- mab has been validated by others (3), with overall and major response rates of 95.3% and 86%, respectively, and a median time to progression of 51.2 months. A whole host of new agents have been developed and are shown to be active in Waldenstrom macroglobulinemia, but it is relevant to ask whether in an era of increasing focus on healthcare expendi- tures it is appropriate to consider newly introduced agents as first-line when inexpensive older alterna- tives exist. Bortezomib is clearly active in the treat- ment of patients with Waldenstrom when combined with rituximab (4). At least a minor response was observed in 88%, with partial responses in 58%. Peripheral neuropathy is well recognized to be a major morbidity in patients treated with bortezomib, and the underlying predisposition to peripheral neuropathy in patients with Waldenstrom macro- globulinemia may yet predispose them to higher levels of neurotoxicity following bortezomib (5). It is fair to ask whether even grade 1 or 2 neuropathy is an acceptable toxicity, when patients are destined to live a median of 10 years and quality of life issues are as relevant as relapse-free survival. Moreover, cardiotoxicity has been reported with the use of bortezomib (6), and given the age of patients with Waldenstrom macroglobulinemia, the possibility of occult underlying coronary artery disease must be taken into consideration. Recently everolimus, an orally available inhibitor of mTOR (mammalian target of rapamycin), as a single agent showed a 70% response rate in heavily pretreated patients and an estimated 12-month progression-free survival of 62%. However, grade 3 or higher toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias and significant pulmonary toxicity in 10%. Despite the high single-agent activity with this drug, its role as a new therapeutic agent when fludarabine combinations produce a response rate of 90% is unclear (7).