Management

• Therapeutic principles as for CLL and FL; no indication for therapy in asymptomatic WM; regular review (3-6 monthly) of clinical and laboratory features required: consistently monitor paraprotein by densitometry (more reliable than IgM nephelometry).

• Initiation of therapy should not be based simply on IgM level alone as this does not correlate directly with clinical manifestations of WM but for:

- Constitutional symptoms: recurrent fever, night sweats, fatigue due to anaemia, weight loss.

- Progressive symptomatic lymphadenopathy or splenomegaly.

- Hb <10g/dL and/or platelets <100 x 109/L due to BM infiltration.

- Hyperviscosity syndrome, symptomatic peripheral neuropathy, systemic amyloidosis, symptomatic cryoglobulinaemia, renal failure.

- Note: avoid red cell transfusion simply to correct low Hb (plasma volume 4 causing spuriously low Hb; low Hb protects against clinical effects of hyperviscosity).

• Plasmapheresis may be necessary as urgent initial therapy for patients with symptoms of hyperviscosity; 3L exchange efficiently reduces plasma viscosity (80% of large IgM molecule is intravascular); may rarely be required regularly in treatment of neuropathic or chemo-intolerant patients; in an emergency venesection and exchange transfusion will 5 plasma viscosity.

• Chlorambucil at a dose of 6-10mg/d for 7-14 days ± prednisolone in a 28d cycle is widely used initial therapy; continue to maximum response; up to 75% achieve >50% reduction in paraprotein; duration of response 2-4 years; <10% achieve CR; reinstitute treatment when paraprotein approaches previously symptomatic levels; often effective on several occasions; resistance ultimately develops; side effects; myelosuppression; cyclophosphamide may achieve comparable results.

• Purine analogues: fludarabine (40mg/m2 PO x 5d or 25mg/m2 IV x 5d repeated monthly for 4-6 cycles) has a response rate of 40-80% in untreated patients and achieves ~33% response rate even after chlorambucil resistance; response duration 30-40 months; similar results with cladribine (0.1mg/kg continuous infusion x 7d); both agents achieve more rapid responses than chlorambucil; side effects: myelo-suppression; profound immunosuppression (see p558); need P carinii prophylaxis and irradiated blood products; addition of cyclophos-phamide to a purine analogue increases response rates.

• Rituximab: monoclonal anti-CD20 antibody administered on 4 occasions achieves 60% responses >25% 5 in WM and useful in patients with marked cytopenia; abrupt elevation in serum paraprotein and PV may occur after rituximab therapy and patients should be closely monitored; may be of benefit for symptomatic neuropathy; administration of 4 further doses over 12 months extends the response from ~9 months to up to 3 years; under examination in clinical trials in combination with purine analogue therapy.

• High dose therapy and autologous or allogeneic SCT: has been undertaken in a small number of younger patients; high response rates (~80%; up to 40% CR) are achieved but relapse rate is high after autograft and treatment related mortality of ~40% occurs after allograft; the latter does offer survivors the prospect of long-term disease control; HDT should be performed in a trial context where possible and patients in whom this treatment is planned should have limited prior exposure to alkylator and purine analogue therapy.

• Treatment of relapse: if a response of >1year has been achieved most patients will respond to the same therapy; refractory patients or those relapsing shortly after prior therapy may respond to an alternative listed above; ~33% of patients with refractory WM respond to thalidomide (50-200mg) in combination with dexamethasone (20-40mg once weekly) and/or clarithromycin (250-500mg bd).

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