5.47 Tyrosine Kinase Inhibitor, Gefitinib, is Cytotoxic Against Zeta-Chain-Associated Protein Kinase 70-Positive but not Zeta-Chain-Associated Protein Kinase 70-Negative CLL Cells

Abstract

liferative disorder and parainfluenza infection). Alemtuzumab was stopped in 6 patients before week 6 due to toxicity, but was continued in 32 patients for 6-8 weeks and in 9 patients for 12 weeks. Twenty-one (45%) developed CMV PCR-positivity and all were successfully treated with pre-emptive valganciclovir. Three monthspost-alemtuzumab, 13/23 (56%) patients with partial response patients had converted to complete response. At the end of alemtuzumab treatment 39/47 (83%) patients had MRD-negative marrows, and 6 months after treatment 19/47 (40.4%) remained MRD negative in their peripheral blood, 27/47 (57.4%) were MRD positive and in 1 patient the response was missing. Of the 19 MRDnegative patients only 5 (26.3%) relapsed at MRD level after a median follow up of 20 months. This progression at MRD level was comparable to those patients who were followed up in the monitoring arm of the study as they were MRD negative at least 6 months after their conventional treatment. Therefore MRD negativity in the blood 6 months post-alemtuzumab better predicts persistent MRD negativity than the post treatment marrow. After a median follow up of23months15patientseitherprogressedclinically(n11)ordied (n 4). Of the 19 patients who were MRD negative at 6 months, only 2 (10.5%) progressed, at 15 and 37 months after treatment. Progression occurred in 12/27 (44.4%) patients with detectable MRD 6 months after their treatment. Serum alemtuzumab concentration was analysed in 5 patients at different time intervals using indirect immunofluorescence described by Rebello and Hale 1,2 . Lympholytic level was reached within 3 weeks (when the 1st post dose sample was tested) in all 5 patients, unlike refractory patients treated with alemtuzumab in whom it took an average of 6 weeks to reach a concentration of 1 g/mL 2 . The highest concentration in individual patient ranges from 2.70 g/mL to 11.97 g/mL, mean 8.24 g/mL which is similar to the refractory patient group. The drugwasdetectedinplasmaupto11weeksafterfinishingtreatment. Earlier troughing of the level was seen in patients with persistent disease even though they had maximum duration and cumulative dose of treatment. Level of drug in the blood did not seem to correlate with the duration of MRD negativity. In summary, alemtuzumab consolidation is associated with significant but usually manageable toxicity. Detectable MRD is eradicated in the bone marrow of 83% of patients at the end of alemtuzumab consolidation, with 40%remainingMRDnegativeintheblood6monthslater,and74% of these patients remaining MRD negative after a median follow up of 20 months. Clinical progression of patients who remain MRD negative 6 months after treatment is significantly slower (p 0.018) than for patients who are MRD positive at that time. This is comparable with the disease progression of those patients who remain MRD negative for at least 6 months after their conventional treatment, providing further evidence that consolidation to MRD eradication alters the outcome for patients rather than merely predicting prognosis. Drug levels peak much earlier than for refractory patients, possibly due to low levels of disease to bind the drug in this group. On the basis of these very promising results a randomised Phase III trial of alemtuzumab consolidation for poor prognosis patients with CLL is due to start shortly.