5.46 NCRN CLL207 Study of Alemtuzumab Consolidation in Chronic Lymphocytic Leukaemia: Response Assessment Follow-up and Pharmacokinetic studies (on Behalf of the NCRI CLL Trials Sub-Group)

Clinical Lymphoma, Myeloma & Leukemia(2011)

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Abstract
The length of remission in patients with chronic lymphocytic leukaemia (CLL) is dependent on the level of minimal residual disease (MRD) after treatment, regardless of the type of therapy received. Several small studies of alemtuzumab consolidation following conventional chemotherapy suggest activity, but with concerns over toxicity, mainly due to immunosuppression. The dose and interval between prior chemotherapy and consolidation seem to be important here. This phase II NCRN CLL207 trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with low levels of disease. Blood was screened for MRD using multi-parameter flow cytometry with a sensitivity of detecting less than a single CLL cell in 10,000 leukocytes, 6 to 24 months post-chemotherapy. MRD-positive patients received consolidation with alemtuzumab 30 mg subcutaneously 3 × weekly for 6 weeks when a marrow was repeated, at which time MRD-negative patients and non-responders stopped therapy; and MRD-positive patients with 1+ log reduction had 6 more weeks of alemtuzumab. All patients received prophylaxis with co-trimoxazole and aciclovir and weekly cytomegalovirus polymerase chain reaction (CMV PCR). Forty-seven patients received alemtuzumab (median age 59 yrs), and 23 serious adverse events were reported in 18 (38.3%) patients, with 2 (4.3%) treatment-related deaths (Epstein-Barr virus-associated lymphoproliferative 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 MRD-negative 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 of 23 months 15 patients either progressed clinically (n = 11) or died (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 Rebello P. et al. Pharmacokinetics of CAMPATH-1H assay development and validation. Journal of Immunological Methods. 2002; : 285-302 Crossref PubMed Scopus (74) Google Scholar , 2 Hale G. et al. Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration. Blood. 2004; : 948-995 Crossref PubMed Scopus (155) Google Scholar . 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 μg/mL. 2 Hale G. et al. Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration. Blood. 2004; : 948-995 Crossref PubMed Scopus (155) Google Scholar The highest concentration in individual patient ranges from 2.70 μg/mL to 11.97 μg/mL, mean 8.24 μg/mL which is similar to the refractory patient group. The drug was detected in plasma up to 11 weeks after finishing treatment. 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% remaining MRD negative in the blood 6 months later, and 74% 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.
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Key words
alemtuzumab consolidation,chronic lymphocytic leukaemia,pharmacokinetic studies,ncrn cll207 study,sub-group
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