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WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA (Page 7)

Nucleoside analogue therapy

Both cladribine and fludarabine have been extensively evaluated in untreated as well as previously treated WM patients. Cladribine administered as a single agent by continuous intravenous infusion, by 2-hour daily infusion, or by subcutaneous bolus injections for 5–7 days has resulted in major responses in 40–90% of patients who received primary therapy, whilst in the salvage setting responses have ranged from 38% to 54%. 113-120 Median time to achievement of response in responding patients following cladribine ranged from 1.2 to 5 months. The overall response rate with daily infusional fludarabine therapy administered mainly on 5-day schedules in previously untreated and treated WM patients has ranged from 38 to 100% and 30–40%, respectively,121-126 which are on par with the response data for cladribine. Median time to achievement of response for fludarabine was also on par with cladribine at 3–6 months. In general, response rates and durations of responses have been greater for patients receiving nucleoside analogues as first-line agents, although in several of the above studies wherein both untreated and previously treated patients were enrolled, no substantial difference in the overall response rate was reported. Myelosuppression commonly occurred following prolonged exposure to either of the nucleoside analogues, as did lymphopenia with sustained depletion of both CD4+ and CD8+ T-lymphocytes observed in WM patients 1 year following initiation of therapy.113,115 Treatment-related mortality due to myelosuppression and/or opportunistic infections attributable to immunosuppression occurred in up to 5% of all treated patients in some series with either nucleoside analogue. Factors predicting for response to nucleoside analogues in WM included age at start of treatment (<70 years), pre-treatment hemoglobin >95 g/L, platelets >75,000/mm3, disease relapsing off therapy, patients with resistant disease within the first year of diagnosis, and a long interval between first-line therapy and initiation of a nucleoside analogue in relapsing patients.113,119,125 There are limited data on the use of an alternate nucleoside analogue to salvage patients whose disease relapsed or demonstrated resistance off cladribine or fludarabine therapy127,128. Three of four (75%) patients responded to cladribine to salvage patients who progressed following an unmaintained remission to fludarabine, whereas only one of ten (10%) with disease resistant to fludarabine responded to cladribine.127 However, Lewandowski et al.128 reported a response in two of six patients (33%) and disease stabilization in the remaining patients to fludarabine, in spite of an inadequate response or progressive disease following cladribine therapy.

The safety of nucleoside analogues has been the subject of investigation in several recent studies. Thomas et al recently reported their experiences in harvesting stem cells in 21 patients with symptomatic WM in whom autologous peripheral blood stem cell collection was attempted. ASCC succeeded on 1st attempt in 14/15 patients who received non-nucleoside analogue based therapy vs. 2/6 patients who received a nucleoside analogue.129 The long term safety of nucleoside analogues in WM was recently examined by Leleu et al105 in a large series of WM patients. A 7-fold increase in transformation to an aggressive lymphoma, and a 3-fold increase in the development of acute myelogenous leukemia/myelodysplasia were observed amongst patients who received a nucleoside analogue versus other therapies for their WM. A recent metanalysis by Leleu et al130 of several trials utilizing nucleoside analogues in WM patients, which included patients who had previously received an alkylator agent showed a crude incidence of 6.6-10% for development of disease transformation, and 1.4-8.9% for development of myelodysplasia or acute myelogenous leukemia. None of the studied risk factors, i.e. gender, age, family history of WM or B-cell malignancies, typical markers of tumor burden and prognosis, type of nucleoside analogue therapy (cladribine versus fludarabine), time from diagnosis to nucleoside analogue use, nucleoside analogue treatment as primary or salvage therapy, as well as treatment with an oral alkylator (i.e. chlorambucil) predicted for the occurrence of transformation or development of myelodysplasia/acute myelogenous leukemia for WM patients treated with a nucleoside analogue130.

CD20-directed antibody therapy

Rituximab is a chimeric monoclonal antibody which targets CD20, a widely expressed antigen on lymphoplasmacytic cells in WM131. Several retrospective and prospective studies have indicated that rituximab, when used at standard dosimetry (i.e. 4 weekly infusions at 375 mg/m2) induced major responses in approximately 27-35% of previously treated and untreated patients.132-138 Furthermore, it was shown in some of these studies, that patients who achieved minor responses or even stable disease benefited from rituximab as evidenced by improved hemoglobin and platelet counts, and reduction of lymphadenopathy and/or splenomegaly. The median time to treatment failure in these studies was found to range from 8 to 27+ months. Studies evaluating an extended rituximab schedule consisting of 4 weekly courses at 375 mg/m2/week, repeated 3 months later by another 4 week course have demonstrated major response rates of 44-48%, with time to progression estimates of 16+ to 29+ months.138,139

In many WM patients, a transient increase of serum IgM may be noted immediately following initiation of treatment.138,140-142  Such an increase does not herald treatment failure, and while most patients will return to their baseline serum IgM level by 12 weeks some continue to show prolonged spiking despite demonstrating a reduction in their bone marrow tumor load. However, patients with baseline serum IgM levels of >50g/dL or serum viscosity of >3.5cp may be particularly at risk for a hyperviscosity related event and in such patients plasmapheresis should be considered in advance of rituximab therapy.141 Because of the decreased likelihood of response in patients with higher IgM levels, as well as the possibility that serum IgM and viscosity levels may abruptly rise, rituximab monotherapy should not be used as sole therapy for the treatment of patients at risk for hyperviscosity symptoms. 

Time to response after rituximab is slow and exceeds 3 months on the average. The time to best response in one study was 18 months.139 Patients with baseline serum IgM levels of <60g/dL are more likely to respond, irrespective of the underlying bone marrow involvement by tumor cells.138,139 A recent analysis of 52 patients who were treated with single agent rituximab has indicated that the objective response rate was significantly lower in patients who had either low serum albumin (<35g/L) or elevated serum monoclonal protein (>40g/L M-spike). Furthermore, the presence of both adverse prognostic factors was related with a short time to progression (3.6 months). Moreover patients who had normal serum albumin and relatively low serum monoclonal protein levels derived a substantial benefit from rituximab with a time to progression exceeding 40 months.143

The genetic background of patients may also be important for determining response to rituximab. In particular, a correlation between polymorphisms at position 158 in the Fc gamma RIIIa receptor (CD16), an activating Fc receptor on important effector cells that mediate antibody-dependent cell-mediated cytotoxicity (ADCC), and rituximab response was observed in WM patients. Individuals may encode either the amino acid valine or phenylalanine at position 158 in the FcgRIIIa receptor. WM patients who carried the valine amino acid (either in a homozygous or heterozygous pattern) had a fourfold higher major response rate (i.e. 50% decline in serum IgM levels) to rituximab versus those patients who expressed phenylalanine in a homozygous pattern.144

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