Waldenström macroglobulinemia: is newer really better?

In this issue of Leukemia and Lymphoma, Peinert and colleagues describe outcomes following fludarabine-based therapy in patients with Waldenström 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 reductase and DNA polymerase. It is active against dividing and resting cells, an important feature since Waldenström lymphoplasmacytes are non-proliferative 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 rituximab 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 Waldenström macroglobulinemia, but it is relevant to ask whether in an era of increasing focus on healthcare expenditures it is appropriate to consider newly introduced agents as first-line when inexpensive older alternatives exist. Bortezomib is clearly active in the treatment of patients with Waldenström 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 Waldenström macroglobulinemia 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 Waldenström 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].

Although not specifically tested in Waldenström macroglobulinemia, bendamustine has shown high activity in chronic lymphocytic leukemia and rituximab-refractory, low-grade non-Hodgkin lymphoma. In a phase III study comparing bendamustine with chlorambucil as a single agent, bendamustine's response rate was 68% compared with chlorambucil's 39%, with a median progression-free survival of 21.7 months. Although Waldenström macroglobulinemia is a phenotypically and genetically distinct lymphoproliferative disorder, agents that are active in the treatment of chronic lymphatic leukemia have consistently shown activity in Waldenström macroglobulinemia, and it is reasonable to suppose that bendamustine will be active as well. Treatment-associated infections have been reported, as have fatigue, nausea, xerostomia, and pyrexia. Bendamustine is a derivative of nitrogen mustard, and therefore is potentially a leukemogenic agent in a disease with a long median survival [8] and hence many at-risk years for late complications.

This does not mean that fludarabine itself is necessarily benign. In the study by Peinert et al. [1], three patients died from myelodysplasia and acute leukemia, which represents over 10% of the originally treated group. All patients had received prior alkylating agents, so the exact contribution of fludarabine is unclear. Fludarabine-based regimens have been reported to produce an increased incidence of transformation from low-grade to intermediate-grade lymphoma, as well as myelodysplasia and acute leukemia in Waldenström macroglobulinemia, at a median of 5 years, with an overall risk of 6.2% for either complication. Moreover, fludarabine has a profound effect on impairing the mobilization of stem cells [9]. Stem cell transplant has been shown to be a highly effective and likely underused regimen in the treatment of patients with Waldenström. In a heavily pretreated group of patients, progression-free and overall survival at 5 years were 39.7% and 68.5%, respectively, and this was achieved with a non-relapse mortality of only 3.8%. The use of fludarabine early in patients who could be potential stem cell transplant candidates would be ill-advised [10]. Fludarabine, because of its highly immunosuppressive nature and ability to produce protracted lymphopenia, was reported to produce fatal non-Pneumocystis pneumonia in two of 43 patients [3], as well as other opportunistic infections including Pneumocystis jiroveci and transfusion-associated graft-versus-host disease, necessitating life-long irradiated red cell support as required.

In conclusion, the outlook for patients with Waldenström macroglobulinemia has steadily improved over the past decade, due to the introduction of new agents as well as a better understanding and the safer utilization of older agents such as fludarabine in combination with monoclonal antibodies and alkylating agents. With these excellent outcomes, an increasing focus on quality of life and reducing late morbidity becomes important [11]. Older agents should not be discarded from the therapeutic armamentarium simply because newer agents have emerged.