Clinical management

• Patients with asymptomatic lymphocytosis simply require monitoring.

• Note: some patients have very indolent disease (e.g. 'Smouldering CLL': Binet stage A, non-diffuse bone marrow involvement; lymphocytes <30 x 109/L, Hb >12g/dL, lymphocyte doubling time >12 months; Binet stage A with somatic mutation of IgVH gene have median survival 25 years).

- Chemotherapy reserved for patients with symptomatic or progressive disease: anaemia (Hb <10g/dL) or thrombocytopenia (<100 x 109/L), constitutional symptoms due to CLL (>10% weight loss in 6 months, fatigue, fever, night sweats), progressive lymphocytosis >300 x 109/L; doubling time <12 months, symptomatic lym-phadenopathy/hepatosplenomegaly, autoimmune disease refractory to steroids, repeated infections ± hypogammaglobulinaemia.

- Advise patients to report infection promptly since immunocompro-mised ± added effects of hypogammaglobulinaemia.

- Monthly IVIg reduces recurrent infections but no effect on survival.

- Manage symptomatic autoimmune complications with corticos-teroids.

• First line therapy generally the alkylating agent chlorambucil at a dose of 6-10mg/d (0.1-0.2mg/kg/d) PO for 7-14 days in 28 day cycles until disease stabilised (usually 6-12 cycles). Produces improved FBC and shrinks lymph nodes and spleen in most patients. CR 3%. No effect on survival. Further responses in most patients if repeated on progression. Side effect myelosuppression. Long-term exposure increases risk of myelodysplasia or 2° leukaemia. Cyclophosphamide is alternative but offers no advantage.

• Higher doses of chlorambucil (15mg/d to maximum response or toxicity) followed by twice weekly maintenance for 3 years improves response rate and survival.

- Avoid steroids except for autoimmune complications or for 1-2 weeks as preliminary treatment in very cytopenic patients with extensive BM infiltration.

- Radiotherapy helpful for persistent or bulky lymphadenopathy;

172 splenic irradiation is sometimes helpful in frail patients unfit for splenectomy.

- Splenectomy is useful therapy for massive splenomegaly or hyper-splenism.

• Purine analogue therapy induces apoptosis in CLL. Higher response rate, CR rate (27%) and progression-free survival but not curative. Fludarabine (25mg/m2/d IV or 40mg/m2/d PO x 5 days q28) is currently second line treatment in UK. Cladribine is an alternative. Side effects include infection, myelosuppression and autoimmune anaemia or thrombocytopenia.

• Note: purine analogues cause profound lymphodepletion with risk of opportunistic infection due to P carinii, M tuberculosis, H zoster and other organisms. Patients should receive cotrimoxazole prophylaxis (480mg bd tiw) throughout therapy and for 6 months post therapy and all blood products should be irradiated for 2 years post therapy.

• Addition of cyclophosphamide (250mg/m2 IV or 400mg/m2 PO x 5 days) concurrently to fludarabine improves response rates in refractory patients Ifflp616.

• Autologous SCT has been carried out after high dose chemotherapy ± TBI for younger (<55 years) patients who achieve CR with fludarabine. Remains an investigative treatment.

• Allogeneic SCT has been successful in small numbers of younger, symptomatic patients with high risk CLL and HLA-matched siblings.

• Campath-IH is a humanised anti-CD52 monoclonal antibody (administered IV or SC) which preferentially eliminates CLL cells from blood, marrow and spleen. It has been approved in the USA for fludarabine-refractory CLL but its role may be in the treatment of minimal residual disease after fludarabine. Side effects: immunosuppression and virus reactivation (HZV and CMV).

• Rituximab is an anti-CD20 chimeric monoclonal antibody; less effective monotherapy than campath-IH; addition to fludarabine-improves the de novo patient CR rate to 47% and addition to fludarabine-cyclophos-phamide improves the CR rate to 66% with no evidence of MRD by RT-PCR.

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