Princess Margaret Hospital/Ontario Cancer Institute, Toronto, Ontario, Canada
Received 16 September 2003; accepted 30 September 2003
ABSTRACT
Waldenstroms macroglobulinemia is a rare form of indolent lymphoma characterized by the production of a monoclonal immunoglobulin M protein, and complications such as hyperviscosity, cytopenias and peripheral neuropathy. Conventional treatment approaches are based on alkylators or nucleoside analogs, but in the absence of a clearly superior regimen, a broad array of alternative therapies exists. Choices range from biological agents to combination chemotherapy to stem-cell transplantation. A rational approach therefore must be based on careful patient assessment and individualization of therapy.
Key words: Waldenstroms macroglobulinemia, lymphoplasmacytic lymphoma, therapy, alkylating agents, nucleoside analogs, IgM monoclonal protein
Introduction
Waldenstroms macroglobulinemia (WM) is a rare B-cell disorder characterized by the production of a monoclonal immunoglobulin M (IgM) protein that can lead to complications of hyperviscosity, bleeding and peripheral neuropathy. As WM is categorized as an indolent lymphoma, treatment options have traditionally been guided by indolent lymphoma chemotherapy regimens. Difficulties may arise, however, in differentiating WM from entities, in particular the marginal zone lymphomas (mucosa-associated lymphoid tissue and splenic marginal zone lymphomas). Although these indolent disorders overlap clinically, immunophenotypically and histologically with WM, unique management approaches in the former (e.g. splenectomy as primary treatment) warrant a distinction. Recent strides in new drug development and novel approaches for malignancies have provided a wide array of therapies for patients with lymphomas, including WM. This article will review current treatment options available for WM from the conservative to the investigational.
When to initiate therapy
As with other indolent lymphomas, treatment for WM is generally reserved until onset of symptoms or complications. With this approach, median survival for patients ranges from 5 to 10 years [1]. Since a subset of patients may enjoy survival well beyond 10 years without treatment, careful selection of patients for therapy is needed. Indications for initiating therapy include presence of systemic symptoms (fevers, weight loss, sweating), hyperviscosity, cytopenias (hemoglobin <100110 g/l or platelets <100 x 109/l), symptomatic lymphadenopathy or hepatosplenomegaly. Other complications such as neuropathy, cryoglobulinemia and hemolysis are accepted indications to treat. The clinical status of the patient, not the level of the paraprotein, determines the need to treat.
Response criteria for WM
Standardization of response criteria in WM is needed to enable direct comparison between studies. In most studies, partial responses (PRs) are identified as an IgM decrease of 50% sustained for
2 months and
50% reduction in size of involved organs [24]. A notable exception is the Southwest Oncology Group (SWOG) use of a
75% drop in IgM with a
50% reduction in tumor mass lesions and a decrease in marrow lymphocytosis to <25% [5]. Many centers have adopted the Cheson criteria for lymphoma (dominant nodes or nodal masses decreased by
50% in the sum of the products of their diameters) [6] plus a decrease in the serum M-protein to <50% baseline value, maintained for
6 weeks after PR. Response criteria specific to WM formulated by the consensus panel at the Second International Workshop on WM are similar to those described here [7].
First-line therapy
Currently, there is no specific agent/regimen that reigns superior in WM. Choice of therapy therefore must consider toxicity, mode of administration and cost to the individual patient. In WM, as with other indolent diseases, single-agent alkylators or nucleoside analogs are standard choices for first-line therapy.
Single-agent alkylators
Chlorambucil is the most common alkylating agent used for indolent lymphoproliferative disorders. In WM, it is well-tolerated orally when given either continuously (0.1 mg/kg/day) or intermittently (0.3 mg/kg for 7 days or 8 mg/m2 for 10 days every 6 weeks) [8, 9]. In a randomized trial comparing the two different dosing schedules in WM, no significant differences were noted in responses or survival [8]. Although numbers were too small to make conclusions regarding leukemogenic differences in this study, four patients, all in the intermittent dosing group, developed acute nonmyelocytic leukemia or refractory anemia (8.3% of total).
Chlorambucil leads to responses in up to 75% of symptomatic WM patients, but complete responses (CR) are rare [8, 9]. The addition of prednisone likely contributes little unless used for autoimmune complications. With a median as long as 1821 months to response [8], treatment durations tend to be prolonged (months to years), with slow resolution of symptoms. It cannot therefore be recommended for urgent therapy; however, it remains a reasonable gentle first-line option for elderly or debilitated patients.
Alkylating agents in combination
Combination chemotherapy with more than one alkylator has been used in WM, but there is no evidence of enhanced efficacy over single-agent alkylators. Case et al. treated 33 WM patients (seven previously received chlorambucil) with the M2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, prednisone) administered every 5 weeks for 2 years [10]. The overall response rate was 82% (six patients in CR, 21 in PR), with a median time to response of 6 months (range 312 months). These results are comparable to single-agent chlorambucil historically, but the M2 regimen is clearly more complex and expensive to administer. Petrucci et al. treated 31 previously untreated, symptomatic WM patients with a simpler oral combination of melphalan, cyclophosphamide and prednisone every 46 weeks for 12 cycles [11]. An overall response rate of 74% (26% CR) was attained. Median time to relapse or progression had not yet been reached by a median follow-up of 66 months. These results again do not appear significantly better than those of chlorambucil alone. Anthracycline-containing combination chemotherapy regimens (e.g. CHOP), usually administered for treatment of aggressive lymphomas, also do not appear more effective than chlorambucil as first-line therapy in WM [12]. However, selected patients requiring more rapid control of disease, but not felt to be candidates for newer agents such as nucleoside analogs, might be considered for combination chemotherapy.
Nucleoside analogs
Fludarabine and cladribine (2-chlorodeoxyadenosine) are nucleoside analogs with activity in indolent lymphomas and chronic lymphocytic leukemia (CLL). Published experience with first-line use in WM is limited but there is growing support for this approach. In the absence of direct comparison studies, the two structurally similar agents are considered to have comparable efficacy.
Small studies using fludarabine or cladribine as first-line therapy for WM report responses of 5585% (CR 310%) (Table 1) [1317]. In the largest published study using a nucleoside analog as upfront WM therapy, 118 symptomatic patients were treated with four of more cycles of fludarabine (30 mg/m2/day for 5 days) [5]. In sharp contrast to other studies, this US Intergroup study reported an unimpressive response rate of 38% (CR 3%), with 5-year progression-free survival (PFS) of 49%. The reason for such a discrepancy remains unclear, but may be related to patient selection. When used first line, fludarabine and cladribine lead to prompt responses, usually within the first two to three cycles. However, with CR rates no greater than 10%, they are clearly not curative.
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Both fludarabine and cladribine are administered similarly in WM as in other lymphoproliferative disorders. Intravenous (i.v.) fludarabine is given at doses of 2530 mg/kg/day for 5 days per cycle. Although oral fludarabine is in common usage in Europe, there are no studies evaluating this formulation in WM. The target number of treatment cycles is debatable, but convention and experience dictate a minimum of four to six cycles. Cladribine dosing ranges from 0.6 to 0.7 mg/kg/cycle, but mode of administration and schedule vary. Initially, cladribine was used in a continuous i.v. infusion, but the more convenient 2-h daily bolus has been shown to have comparable kinetics [17, 20]. When used as a daily subcutaneous (s.c.) infusion over 5 days (median three cycles) in one study, a reasonable 40% PR rate was reported [19]. Three times daily s.c. administration has also been used [12]. Although it is convenient for outpatient use, s.c. use requires further exploration. Cladribine can be repeated every 46 weeks to maximal response; however, myelosuppression is common and can preclude repeated dosing. Hence, a course of two to three cycles is common practice.
Considering the toxicity, cost and inconvenience of nucleoside analogs, it is debatable whether their upfront use should be recommended over alkylating agents. Nucleoside analogs are attractive for younger patients, in particular those who require rapid control of their disease and have adequate reserve to tolerate toxicities. Alkylating agents continue to be a reasonable choice in older patients with co-morbidities.
Second-line therapy
WM patients who have failed alkylator-based therapy can be salvaged with a nucleoside analog (Table 2), although ultimately most patients, even if responsive, require further therapy. Conversely, failure of front-line fludarabine or cladribine is unlikely to be salvaged by alkylator-based treatment. Alternative regimens and agents are therefore needed.
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Cladribine
Table 3 lists the published experience to date using cladribine in previously treated WM patients. Response rates appear to range from 38 to 64% (majority PR). Responses are generally rapid in onset, often within 12 months, and times to treatment failure vary widely (0.5 to over 33 months) [15, 1720].
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Combination chemotherapy
Anthracycline-based chemotherapy regimens used for aggressive histology lymphoma (CHOP, CAP) have been used to salvage patients with indolent lymphomas failing single-agent alkylators. Although used with some frequency in WM, there is little evidence to support this approach [21, 27]. Leblond et al. treated 45 WM patients with CAP (cyclophosphamide, adriamycin, prednisone) as salvage therapy after single-agent alkylators [21]. Patients were either in first relapse or resistant to alkylators. A dismal 11% (five of 45 patients) receiving CAP responded (no CR), with a median survival of 45 months.
Alternative treatment options
This section will review novel, alternative regimens used in WM, in both untreated and previously treated patients. Most of these treatments have been evaluated in small studies, and larger prospective studies will be needed to validate routine use. Nevertheless, for clinicians treating patients with aggressive WM (especially in those failing alkylators and nucleoside analogs), it is useful to have a variety of active agents from which to choose and combine.
Nucleoside analog combinations
Combining nucleoside analogs with alkylators and other agents in indolent lymphomas shows promise. Cladribine or fludarabine in combination with cyclophosphamide appears more effective than either nucleoside analog alone, although there is limited experience specifically in WM. Anagnostopoulos et al. reported a 92% response rate (median remission duration 37 months) in 37 previously untreated WM patients receiving combination s.c. cladribine and oral cyclophosphamide [28]. In the same series, 12 patients received a combination of cladribine, cyclophosphamide and rituximab (4-weekly doses), with all patients responding. Further evaluation of nucleoside analog combinations is needed.
Rituximab
Rituximab is an anti-CD20 monoclonal antibody that has emerged as a useful biological agent in lymphoma. CD20 is expressed consistently in WM, thereby providing rationale for its use [29]. A small number of case series support the activity of this agent in WM. Treon et al. performed a retrospective study of 30 patients treated with up to 11 weekly doses (median four) of rituximab at 375 mg/m2/week [30]. Fourteen patients (47%) had received prior nucleoside analogs. Objective PRs were attained in eight of 30 patients (27%). An additional 19 patients (63%), however, either responded with <PR (25% drop in M-protein) or stable disease. Interestingly, despite a modest objective response rate, hematological improvements were seen in the majority: 12 of 14 (86%) anemic patients and nine of 12 (75%) thrombocytopenic patients sustained significant improvements in their blood counts. Supporting the notion that stabilization of disease may indeed be a worthy end point for WM therapy, Dimopoulos et al. reported similar findings in a prospective study of 27 patients with WM (22% previously treated with nucleoside analogs) [31]. These patients received 4-weekly infusions of rituximab followed by a repeat 4-week course at 3 months if a PR had not yet been reached. Overall responses were seen in 44%, with an additional 37% attaining stable disease.
In general, rituximab appears well tolerated and safe for use in WM. Toxicity appears similar to that reported in other diseases. As a single agent, however, response durations in WM are short (median 8 months in the Treon study, 16 months in the Dimopoulos study) and CRs elusive. Repeated dosing at regular intervals (perhaps every 36 months) may be beneficial.
Rituximabs unique toxicity profile and lack of myelosuppression makes it attractive for use in WM patients (either upfront or as salvage) with severe cytopenias or poor performance status. Rituximab in combination with chemotherapy (e.g. CHOP) appears more effective than CHOP alone in aggressive histology lymphomas, and therefore warrants investigation in WM. An NCI-sponsored Eastern Cooperative Oncology Group (ECOG) study combining rituximab with fludarabine in WM is underway, and evaluations of the combination of rituximab, cyclophosphamide and a nucleoside analog are planned.
Thalidomide
Thalidomide is an immunomodulatory agent with significant activity in myeloma. It is currently under investigation in various malignancies including WM. In a recent report, Dimopoulos et al. treated 20 symptomatic WM patients (10 previously untreated) with thalidomide [32]. A maximum dose of 600 mg/day was targeted, but reached by only five patients. Although toxicities were common, they were not unexpected, and reversed with drug withdrawal. Five patients (25%) achieved a PR and five stable disease. Hence, thalidomide as a single agent appears to have moderate activity in WM. As in myeloma, combining thalidomide with steroids or chemotherapy may enhance activity. Coleman et al. recently reported the promising use of clarithromycin (500 mg orally twice daily), low-dose thalidomide (50 mg escalated to 200 mg daily) and dexamethasone (40 mg orally once weekly) in 12 patients with previously treated WM [33]. Of the 12 patients, 10 (83%) had at least a PR (three CR). The most concerning toxicity was neurological, likely reflecting a predisposing subclinical neuropathy from the IgM paraprotein. The immunomodulatory derivatives of thalidomide (IMiDs), now under phase III investigation in myeloma, have less neurotoxicity than thalidomide and may prove to be useful in WM. The IMiDs and other thalidomide combinations warrant further exploration.
Interferon
Alpha-interferon (-IFN) is effective therapy for hairy cell leukemia and other lymphoproliferative disorders. Case reports suggest activity in WM. Rotoli et al. treated 36 WM patients with
-IFN-2b (3 x 106 U s.c. daily for 1 month followed three times weekly for 5 months) [34]. Twelve patients (33%) achieved
50% reduction in their IgM paraprotein, most within 46 months. Three patients dropped out due to toxicity. Legouffe et al. treated 14 patients with
-IFN-2a (13 x 106 U s.c. three times weekly) with no significant reductions in paraprotein levels, although hematological improvements were seen [35]. Flu-like symptoms, immunohemolytical anemia and thrombocytopenia are limiting toxicities associated with IFN. In elderly patients, a 1520% drop-out rate can be anticipated [34]. As a result, combining IFN with other agents to enhance its modest activity may not be feasible. With its toxicity, inconvenience and modest activity, IFN does not have a clear role in WM therapy.
PS-341
PS-341 is a reversible proteasome inhibitor that has shown remarkable efficacy in myeloma and appears to have activity in other hematological malignancies including lymphoma and WM. PS-341 is administered i.v. twice weekly for a varying number of weeks followed by 1 week of rest. With this scheduling, it is generally well tolerated and appears to have minimal myelosuppression. A Canadian NCIC study using this agent in a phase II study for symptomatic WM is in progress.
Other investigational agents
Studies using novel agents such as UCN-01 (a protein kinase C inhibitor), Campath-1H (monoclonal antibody to CD52) and dolastatin (a microtubule inhibitor) are under investigation for patients with WM. Their unique mechanisms of action and toxicity profiles hold promise for the development of rational targeted therapy in WM.
Transplantation
Autologous stem-cell transplantation
High-dose therapy followed by autologous stem-cell transplantation (ASCT) has been reported thus far in a small number of WM patients (Table 4). Transplanted patients have had aggressive relapsed or refractory disease, most moving on to transplant within 1 year of diagnosis. High response rates are promising but follow-up is generally short and survival data difficult to interpret with so few patients. Nevertheless, the low treatment-related mortality and absence of unexpected toxicity in these early reports suggest that ASCT is feasible in this disease. With the median age of transplanted patients 50 years, however, these results may be generalizable only to a small subset of WM patients.
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Allogeneic stem-cell transplantation
To date, allogeneic transplantation has been reported in only six patients (Table 5). All patients were heavily pretreated, and all except one had refractory disease at time of transplant. Both myeloablative (with or without total body irradication) and non-myeloablative preparatory regimens have been used. Allotransplantation, though attractive for potential graft versus disease effects, continues to be experimental in this population.
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Splenectomy
In lymphoma, splenectomy is usually used as a palliative maneuver to improve cytopenias by removing the site of sequestration. Interestingly, prolonged disease-free intervals have been reported following this procedure, suggesting an alternative mechanism of action. Hypothesized mechanisms for this systemic effect include removal of IgM-secreting cells (preferentially found in the spleen) [37], removal of T cells necessary for B lymphocyte differentiation into IgM-producing cells [38], or decreased production of splenic factors in the serum blocking tumor growth [39]. Experience in WM patients is largely anecdotal. Humphrey and Conley described two patients with refractory WM who, upon splenectomy, promptly entered CRs lasting 12 and 13 years [37]. The authors performed a literature review of 15 WM patients who underwent splenectomy, nine of whom sustained dramatic and often durable systemic responses. Notable but shorter responses with splenic irradiation have also been reported [40].
Plasmapheresis
Plasmapheresis can be used acutely in patients with high levels of IgM paraprotein causing hyperviscosity symptoms (headache, visual blurring, bleeding and central nervous system impairment). Patients typically manifest symptoms with serum viscosity levels 4 cp (normal 1.62.4 cp). Although there is no linear relationship between serum viscosity and M-protein level, hyperviscosity symptoms are usually seen with IgM levels
40 g/l. IgM is a large molecule of which 7080% remains intravascular; hence, 50% of circulating IgM can be cleared with one exchange [41]. Daily or every other day exchanges can be performed until symptoms resolve, but often dramatic responses occur with just one exchange. Since plasmapheresis does not alter production of IgM, concurrent systemic therapy is required for long-term management. In those patients who are refractory to systemic therapy, long-term plasmapheresis at regular intervals may be considered [42].
Approximately 10% of patients with WM will develop a neuropathy during the course of their disease. Of these, up to 40% will have myelin-associated glycoprotein (MAG) reactivity of their IgM paraprotein causing demyelination [43]. Plasmapheresis may be useful in removing the MAG-reactive paraprotein and slowing progression of the neuropathy [44]. Neurological improvement has also been reported in an anecdotal fashion with conventional chemotherapy, interferon, fludarabine and rituximab [4548].
Prognostic factors in WM
With the growing armamentarium of therapies available for WM, determining when and which regimen to use can be difficult. Since no approach is clearly superior, and choices range from do nothing to aggressive experimental therapy, stratifying patients by prognosis is a rational approach to treatment. Table 6 lists adverse predictors for survival identified from large cohorts of WM patients (both untreated and treated). Interestingly, a high IgM paraprotein level does not consistently portend a poor prognosis, thereby supporting the caveat to treat the patient, not the numbers.
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Conclusion
Waldenstroms macroglobulinemia is a rare disorder that is often considered a hybrid of myeloma and indolent lymphoma. Treatment options for WM therefore tend to be generalized from studies in these associated disorders. As our understanding of the pathogenesis and biology of WM deepens, the development of novel treatments and approaches specific to WM can be anticipated. Until then, current treatment must be guided by both a critical view of the limited published data and practical experience.
FOOTNOTES
* Correspondence to: Dr C. I. Chen, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Suite 5-220, Toronto, Ontario, Canada M5M 2M9. E-mail: Christine.chen{at}uhn.on.ca
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