Treatment for Waldenstrom’s macroglobulinemia

Annals of Oncology 15: 550–558, 2004 DOI: 10.1093/annonc/mdh128

Review Treatment for Waldenstrom’s macroglobulinemia C. I. Chen* Princess Margaret Hospital/Ontario Cancer Institute, Toronto, Ontario, Canada Received 16 September 2003; accepted 30 September 2003

Introduction Waldenstrom’s 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 <100–110 g/l or platelets <100 × 109/l), symptomatic lymphadenopathy or hepatosplenomegaly. Other complications such as neuropathy, cryoglobulinemia and hemolysis

*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: [email protected] © 2004 European Society for Medical Oncology

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 [2–4]. 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

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Waldenstrom’s 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: Waldenstrom’s macroglobulinemia, lymphoplasmacytic lymphoma, therapy, alkylating agents, nucleoside analogs, IgM monoclonal protein

551 Table 1. Fludarabine or cladribine as first-line therapy in Waldenstrom’s macroglobulinemia No. of patients

Agent

Response rate (%)

Overall survival (OS)

Duration of response

Treatmentrelated deaths

Dhodapkar et al. [5]

118

Fludarabine

38

Estimated 5-y OS 62%

5-y PFS 49%

3% due to infections

Lewandowski et al. [15]

11

Cladribine

64

NA

17 months (mean)a

2 deaths due to thrombocytopenic bleedinga

Foran et al. [13]

19

Fludarabine

79

>1.9 y (not yet reached)

40 months

None

7

Cladribine

57

NA

NA

2 died of infections and progressive diseasea

Cladribine (interferon maintenance)

90

9 of 10 alive at 14 months follow-up

3 of 10 patients progressed at median follow-up 14 months

None

5

Cladribine

40

NA

NA

1 death due to infectiona

26

Cladribine

85

5 of 26 (19%) dead at median follow-up 13 months

5 of 26 (19%) relapsed at median follow-up 13 months

1 death due to disseminated herpes

Liu et al. [17]

Fridrik et al. [14]

Delannoy et al. [51] Dimopoulos et al. [16]

10

a Study includes both untreated and previously treated patients. Numbers reflect those for the entire cohort. NA, not available; PFS, progression-free survival.

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 18–21 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 3–12 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 4–6 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 signifi-

cantly better than those of chlorambucil alone. Anthracyclinecontaining 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 firstline 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 55–85% (CR 3–10%) (Table 1) [13– 17]. 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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Reference

552 Table 2. Fludarabine as second-line therapy in Waldenstrom’s macroglobulinemia No. of patients

Disease status

Dose

Median no. of cycles

Response rate (%)

Duration of response

Leblond et al. [21]

45

Primary refractory or 1st relapse (on or off therapy)

25 mg/m2 for 5 days

6

30

Median 19 months

Dhodapkar et al. [5]

64

Primary refractory or relapsed (on or off therapy)

30 mg/m2 for 5 days

Minimum 4

33

Estimated 5-y PFS 30%

Leblond et al. [2]

71

Primary refractory or refractory relapse only

25 mg/m2 for 5 days

6 (range 1–9)

30

Median 32 months

Zinzani et al. [23]

12

Primary refractory or refractory relapse only

25 mg/m2 for 5 days

6

41

6–15+ months

Dimopoulos et al. [22]

28

Primary refractory or refractory relapse only

30 mg/m2 for 3–5 days

5

30

NA

Kantarjian et al. [24]

10

Refractory or relapsed (on or off therapy)

30 mg/m2 for 5 days

Range 2–9

40

9–19+ months

NA, not available; PFS, progression-free survival.

Toxicities associated with nucleoside analogs (e.g. myelosuppression) can be limiting. Even in chemonaïve patients, National Cancer Institute (NCI) grade 3–4 neutropenia can occur in half of patients receiving fludarabine [5]. Cladribine appears even more myelosuppressive than fludarabine on a per cycle basis. With either agent, thrombocytopenia tends to be moderate but can be prolonged [18]. Lewandowski et al. reported two deaths (total 25 patients) attributable to cladribine-associated thrombocytopenia [15]. Immunosuppression from profound and prolonged T-cell depression predisposes to opportunistic infections such as aspergillus, listeria and herpesviruses [17–19]. Routine antibiotic prophylaxis can be justified, but the use of more expensive, toxic antifungals or antivirals for routine prophylaxis has yet to be established. Toxicities reported with fludarabine in other chronic disorders (hemolysis, neuropathy) have rarely been reported in WM. Secondary myelodysplasia can follow cladribine/fludarabine therapy and is not only restricted to those with heavy alkylator exposure. Delannoy et al. reported three cases of myelodysplasia, two of whom had no or minimal alkylator exposure, amongst a cohort of 27 patients treated with cladribine [3]. Treatment-related deaths, usually due to infections, are not rare (3% of previously untreated patients in the Intergroup study) [5]. In contrast, death due to toxicity from single-agent alkylators is extremely rare. Both fludarabine and cladribine are administered similarly in WM as in other lymphoproliferative disorders. Intravenous (i.v.) fludarabine is given at doses of 25–30 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 4–6 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.

Fludarabine In previously treated WM patients (refractory or relapsed postalkylators), fludarabine leads to responses in one-third of patients (Table 2). Despite variation in dose and number of cycles, response rates are remarkably consistent in the literature. In the US Intergroup study, 64 of the total 182 WM patients on study were treated previously (alkylating agents in all but four patients), however, prior response status (relapsed or refractory) was not available [5]. After a minimum of four cycles of fludarabine (30 mg/m2/day for 5 days), 23 patients (33%) achieved a PR. As discussed earlier, PR in this study (≥75% paraprotein decrease) was defined more stringently than in other studies. There were no CRs achieved in this group. The 5-year OS and PFS were 36% and 30%, respectively. Similarly, Leblond et al. [21] reported 30% PR (no CR) in 46 patients with previously treated WM. In this pro-

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Reference

553 Table 3. Cladribine as second-line therapy in Waldenstrom’s macroglobulinemia No. of patients

Disease status

Dose/cycle, mg/kg

Median number of cycles (range)

Response rate (%)

Duration of response

Lewandowski et al. [15]a

14

Unspecified

0.7 mg/cycle 4 bolus

3 (1–5)

64

Mean 17 months for previously untreated/treated

Hellmann et al. [20]a

13

Primary refractory

0.7 mg/cycle 4 bolus

4 (1–11)

38

Mean 12 months for previously untreated/treated

Delannoy et al. [3]a

16

Relapsed or refractory

0.7 mg/cycle 4 bolus or CI

2 (1–6)

50

NA

Liu et al. [17]a

13

Relapsed or refractory

0.6 mg/cycle 4 bolus

3 (2–7)

54

Median not yet reached at 28 months

Betticher et al. [19]

24

Relapsed or refractory

0.5 mg/cycle SC

3 (1–6)

40

8 months (range 5–29 months)

Dimopoulos et al. [18]

46

Relapsed or refractory

0.7 mg/cycle 4 CI

2 cycles only

43

Median PFS 12 months

a

Studies with mixed patient population (untreated/previously treated). CI, continuous infusion; NA, not available; PFS, progression-free survival; SC, subcutaneous.

spective study, patients received six cycles of fludarabine with a median time-to-treatment failure of 19 months. The same group had previously reported, retrospectively, overall responses of 30% in 71 pretreated patients [2]. In the latter study, patients were restricted to those resistant to prior therapy (patients relapsing off therapy were not included), a particularly difficult patient population to treat. A number of smaller studies cite similar PR rates with response durations hovering at 12 months [22–24]. Overall, fludarabine does have significant activity in previously treated WM patients, but it should be emphasized that few CRs are achieved. Those patients with primary resistance or relapsing off chemotherapy appear to respond better than those in refractory relapse [4, 22]. Responses to fludarabine can be prompt (within 1 month), but delays of over 1 year are reported [5].

Combination chemotherapy

Cladribine

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.

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 1–2 months, and times to treatment failure vary widely (0.5 to over 33 months) [15, 17–20].

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

Fludarabine/cladribine crossover Similarities in structure and mechanism of action between the two agents suggests that failure of one is unlikely to be salvaged by the other. Dimopoulos et al. reported only 1 of 10 fludarabine-resistant patients responsive to cladribine [25]. Three of four patients relapsing but still responsive to fludarabine responded to cladribine. Conversely, Lewandowski treated six cladribine-resistant patients with fludarabine, achieving PR in two patients and stabilization of disease in another four patients. These limited data and experience in other lymphoproliferative disorders suggest cross-resistance between the two agents [26]. Therefore, it is not recommended that fludarabine be used for patients failing cladribine and vice versa.

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.

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554

Rituximab

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)

Interferon Alpha-interferon (α-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 α-IFN2b (3 × 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 4–6 months. Three patients dropped out due to toxicity. Legouffe et al. treated 14 patients with α-IFN-2a (1–3 × 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 15–20% dropout 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

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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
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.

555 Table 4. Autotransplants in Waldenstrom’s macroglobulinemia Reference

No. of patients

Median age, years (range)

Disease status

Prior nucleoside analogue (n)

High-dose therapy

Response

Early deaths

Anagnostopoulos et al. [28]

4

48 (28–55)

Previously treated and resistant

4

TBC in 2

3 PR

1 death from CVA day 30, 1 secondary AML day 37

5 PR

0

CY + TBI in 1 VP-16, CY, TBI in 1 Dreger et al. [52]

7

49 (39–61)

4 untreated, 3 previously treated

None

3–4 cycles dexaBEAM followed by CY + TBI

2 CR Desikan et al. [53]

6

51.5 (45–69)

Previously treated

4

5

NA

Previously treated and sensitive

None

Yang et al. [55]

1

50

Refractory

No

Mazza et al. [56]

1

71

Refractory

No

5 PR

0

MEL140 + TBI in 1

1 CR

VAMP/CVAMP to max response followed by MEL200

1 PR

No TBI

4 CR

MEL200

CR

0

CR

0

0

No TBI Busulfan + MEL

AML, acute myelogenous leukemia; CR, complete response; CVA, cerebrovascular accident; CY, cyclophosphamide; MEL, melphalan; NA, not available; PR, partial response; TBC, thiotepa, busulfan, cyclophosphamide; TBI, total body irradiation.

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. Heavy prior treatment can impair the collection of adequate numbers of stem cells needed for ASCT. Most autotransplant candidates with WM will likely have received prior nucleoside analog therapy. Fludarabine has been shown to reduce stem-cell numbers, particularly when administered within 2 months of stem-cell collection [36]. Anticipatory collection of stem cells prior to use of nucleoside analogs may be a consideration, particularly in young patients.

estingly, 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].

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 nonmyeloablative preparatory regimens have been used. Allotransplantation, though attractive for potential graft versus disease effects, continues to be experimental in this population.

Adjuncts to systemic therapy Splenectomy In lymphoma, splenectomy is usually used as a palliative maneuver to improve cytopenias by removing the site of sequestration. Inter-

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 1.6–2.4 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 70–80% 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.

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Mustafa et al. [54]

MEL200 in 5

556 Table 5. Allogeneic transplants in Waldenstrom’s macroglobulinemia Reference

No. of patients

Age, years

Disease status

Prior nucleoside analog (n)

High-dose therapy

Response

Early deaths

Anagnostopoulos et al. [28]

3

30

Refractory relapse

2

TBC

1 PR

1 due to GVHD day 39

51 60 Ueda et al. [57]

1

55

Refractory relapse

0

Fludarabine + MEL140

PR

0

Martino et al. [58]

2

34

Relapse: 1 refractory, 1 sensitive

1

CY + TBI

2 CR

0

39

Chlor, CY, TBI

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 [45–48].

Table 6. Adverse prognostic factors Demographics Advanced age [49, 50, 59–61] Male sex [50, 60] Clinical features General symptoms (e.g. weight loss) [49, 60] Lymphadenopathy [61] Hepatomegaly [50] ECOG PS 3–4 [59] Previous therapy [5]

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’. Three prognostic scoring systems specific to WM have been developed. Gobbi et al. identified four independent prognostic indicators (hemoglobin, age, weight loss and cryoglobulinemia) from a study of 144 previously untreated WM patients [49]. Survival in patients with two or more factors was significantly worse than that in patients with less than two factors. Morel et al. identified three risk categories of patients using a combination of age, albumin level and number of cytopenias [50]. Five-year survival rates separated at 87% (low risk group), 62% (intermediate risk group) and 25% (high risk group) (P <0.0001). This scoring system is attractive for its use of simple and easily available items. Dhodapkar et al. identified β2 microglobulin as the key predictor for need for therapy and survival [5]. A scoring system using β2 microglobulin, IgM levels and hemoglobin was subsequently proposed. All three scoring systems require further prospective

Disease duration >1 year [5] Laboratory factors Low hemoglobin [5, 49, 50, 60] Low white blood cell count [50, 60] Low absolute neutrophil count [60] Higher number of cytopenias [50, 59] Low platelets [49, 50, 59, 60] High β2 microglobulin [5] Low serum IgM [5] Low albumin [50] Presence of cryoglobulinemia [49] High ESR [49] Presence of abnormal RBCs in urine [49] High percentage of bone marrow infiltration [61] Diffuse bone marrow pattern [59] Others High score in the International Prognostic Index [61] ECOG PS, Eastern Coperative Oncology Group Performance Status; ESR, erythrocyte sedimentation rate; IgM, immunoglobulin M; RBC, red blood cells.

validation. To date, there have been no consistent cytogenetic or molecular abnormalities identified in WM. With the advent of more sophisticated and sensitive techniques such as SKY, FISH

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Chlor, chlorambucil; CR, complete response; CY, cyclophosphamide; GVHD, graft versus host disease; PR, partial response; TBC, thiotepa, busulfan, cyclophosphamide.

557 and microarray, one can foresee the identification of genetic markers useful in guiding future therapy.

Conclusion Waldenstrom’s 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.

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