Further treatment of indolent lymphomas

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When indolent lymphoma progresses after a partial or complete response to initial therapy, it is important to rule out transformation to DLBCL (esp. if LDH 4, LN rapidly enlarging, constitutional symptoms, extranodal disease). In recurrent indolent NHL, further responses can be achieved with the prior therapy in most patients who have achieved a durable response (>12 months). However, chemoresistance to alkylating agents ultimately develops.

Interferon-a maintenance: several large randomised trials demonstrate a beneficial effect on survival for patients treated with >9 million units/week administered with and after intensive chemotherapy for >18 months or until progression; side effects reduce quality of life and the attraction of this therapy.

Purine analogues: fludarabine has a response rate of 70% (38% CRs) in untreated patients and ~50% (15% CRs) in previously treated patients. Responses to cladribine are similar for previously treated patients but less in de novo treatment and responses are less durable. Neither convincingly improve disease free or overall survival. Fludarabine achieves responses in most patients with FL or SLL refractory to chlorambucil. Combinations of fludarabine with cyclophosphamide or with mitoxantrone (mitozantrone) and dexamethasone (FMD) increase response rates and are widely used. Prophylaxis of P carinii by cotrimoxazole in all patients and HZV by acyclovir in some is required during and for 6 months after therapy. Cellular blood products must be irradiated for 2 years after therapy.

Monoclonal antibody therapy:

• Rituximab (MabThera, Rituxan) is a humanised anti-CD20 monoclonal antibody. As a single agent 375mg/m2 infusion weekly x 4 weeks achieves a response rate ~50% (6% CRs) in previously treated patients; median duration 13 months1. On relapse 40% will respond again. In newly diagnosed patients 4 further doses given over 9 months as maintenance therapy enhances EFS (22 vs. 13 months). Toxicity is mild though there is a risk of anaphylaxis with the first course. Combination with chemotherapy enhances the response rate. In newly diagnosed patients: CHOP-R 100% responses, 66% CRs, >50% progression-free survival (PFS) with median follow up of 6 years. It has been used for 'in vivo purging' prior to stem cell harvest to improve the prospect of a PCR-negative harvest. In the UK, NICE recommends its use in chemoresistant disease.

• Tositumomab, (Bexaar) a 131I-radiolabelled murine anti-CD20 monoclonal antibody; beta and gamma emission; due to the targeted radiation a single infusion achieves higher response rates (97% OR and 76% CR in untreated patients; 74% OR & 30% CRs in treated patients) and a higher response rate and more prolonged responses in advanced disease than the prior chemotherapy had achieved; transient mild to moderate myelosuppression; antimurine antibodies develop especially in untreated patients.

• Ipritumomab (Zevalin) a 90Yt-labelled murine anti-CD20 monoclonal antibody; beta emission only; also achieves superior response rates (80%) to rituximab in relapsed FL.

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