Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia

Abstract

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenströ m macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m 2 per day for 5 days) of fludarabine and 8 infusions (375 mg/m 2 per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n ‫؍‬ 2), very good partial response (n ‫؍‬ 14), partial response (n ‫؍‬ 21), and minor response (n ‫؍‬ 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P ‫؍‬ .017) and those achieving at least a very good partial response (P ‫؍‬ .049). Grade 3 or higher toxicities included neutropenia (n ‫؍‬ 27), thrombocytopenia (n ‫؍‬ 7), and pneumonia (n ‫؍‬ 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/ acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short-and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800. IntroductionWaldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an immunoglobulin M (IgM) monoclonal gammopathy. [1][2][3] Among treatment options for patients with WM, nucleoside analogs, as well as the CD20-directed monoclonal antibody rituximab, have been commonly used. Response rates of 30% to 70% and durations of response of 20 to 24 months have been reported with the use of nucleoside analogs in WM patients. [4][5][6][7][8][9][10][11][12][13] Importantly, similar response rates were reported in these studies whether nucleoside analogs were used as first line or salvage therapy. The use of rituximab has also been extensively evaluated in patients with WM. Using standard dose (ie, 4 weekly infusions at 375 mg/m 2 ), overall response rates of 25% to 30% have been observed. More recently, an extended dose regimen giving rituximab at 375 mg/m 2 per week for 4 weeks, then repeated again at week 12, has resulted in higher (40%-50%) overall response rates. 4,[14][15][16][17][18][19] In preclinical studies, the potential for rituximab and fludarabine to enhance each other's activity has been demonstrated and may involve a spectrum of intracellular as well as extracellular mechanisms. [20][21][22] Moreover, in other indolent B-cell malignancies, the combination of rituximab and fludarabine has led to higher response rates than those observed with either agent alone. [23][24][25][26][27] The potential for enhanced clinical benefit by giving rituximab with fludarabine concurrently vs sequentially has also bee...

Unresolved issues in the comparison of therapies and determination of responses in Waldenström macroglobulinemia

“…This is particularly important as, with nucleoside analogs like fludarabine, responses seem to be particularly durable even in previously treated patients [11,12], whereas with other alternatives such as alkylator-based combinations or new agents like bortezomib there appears to be a discrepancy between relatively high RR, and rather short RD/ PFS. This may be due to the differential reduction of paraprotein level to an apparently greater degree than the reduction of organ infiltration [13,14].…”

“…Differing from other lymphomas and also from MM, responses in WM can be delayed by many months, as it has been shown particularly after fludarabine-based treatment [11]. Therefore, we recommend that in WM responses are assessed at 3, 6, and 12 months post-treatment in order not to miss the best response achieved.…”

“…However, given the already known differences in correlations of responses of paraprotein, tissue infiltration, and response durations after different treatments, such a beneficial effect of a minor response cannot be assumed on a general basis, but still needs to be shown for other treatment regimens. We think that the comparison of PFS or RD amongst different treatment options has much more relevance for patients, and the evidence suggests that in WM the RRs correlate with PFS or OS to varying extents, depending on treatment agents and schedules [11][12][13][14][15][16][17][18][19][20][21].…”

Waldenström macroglobulinemia: is newer really better?

“…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.…”

“…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.…”