Abstract
Abstract 60
The length of remission in patients with chronic lymphocytic leukemia (CLL) is dependent on the level of minimal residual disease (MRD) at the end of therapy, regardless of the therapy received. The conversion of remissions from MRD positive to negative should prolong remissions and survival. Several small studies have used alemtuzumab as consolidation therapy following conventional chemotherapy but with concerns over toxicity; primarily due to immune suppression and infections. The dose and timing (i.e. interval between prior chemotherapy and alemtuzumab) seem to be critical.
The Phase II NCRN CLL207 Trial assessed alemtuzumab consolidation post-chemotherapy. Between 6 and 24 months from completing treatment (1 to 3 prior therapies) blood was screened for MRD using multi-parameter flow cytometry with a sensitivity of less than a single CLL cell in 10,000 leucocytes (0.01%). The marrow of MRD positive patients was assessed to quantify the CLL before treatment with alemtuzumab at a dose of 30mg given subcutaneously 3 times a week for 6 weeks, at which time the marrow was repeated. MRD negative patients and non-responders stopped therapy; MRD positive patients with at least one log reduction in MRD continued therapy for a further 6 weeks. All patients received prophylaxis with co-trimoxazole and aciclovir as well as weekly cytomegalovirus (CMV) monitoring by PCR. It was pre-determined that at least 14 of up to 54 (26%) patients would need to be converted from MRD positivity to negativity to justify further studies of this treatment strategy.
47 patients received alemtuzumab in NCRN CLL207 with median age of 58 yrs (40-77) and 35 (74.5%) males. There was a median of 2 prior therapies (range 1 to 4) with 46 pts receiving fludarabine combinations as the latest therapy and 9 receiving rituximab-containing combinations. There were a total of 21 SAE's in 17 (36.2%) pts with 2 (4.3%) treatment related deaths (EBV-LPD and a parainfluenza infection). Alemtuzumab was stopped in 6 patients before week 6 mainly due to toxicity, 32 patients received 6–8 weeks of treatment and 9 patients received a 12-week course. G-CSF was given when the neutrophil count fell below 1 × 10^9/l and 14 (30%) patients required G-CSF during alemtuzumab with an additional 13 (28%) receiving G-CSF after completion of alemtuzumab. Positive CMV PCRs were detected in 21 (45%) patients, all of whom were successfully treated with pre-emptive antiviral therapy. Prior to alemtuzumab 24 patients were in complete remission (CR) and 23 were in partial remission (PR). Three months after alemtuzumab 13/23 (56%) PR converted to CR. 39/47 (83%) patients had MRD negative marrows at the end of alemtuzumab, 7 (15%) remained MRD positive and 1 (2%) was not evaluable. Blood MRD assessment 6 months after completing alemtuzumab showed that 15/31 (48%) MRD negative patients became MRD positive, although all except 2 had low CLL levels (below 0.1×10^9/l) at this time-point. Therefore overall 16/39 (41%) patients were MRD negative 6 months after completing alemtuzumab and of these 8/9 (89%) remained MRD negative in the blood at 12 months. Therefore MRD negativity in the blood at 6 months seems to better predict for persistent MRD negativity than the marrow at the end of therapy and appears to be the most appropriate assessment for the outcome of consolidation. Patients who are MRD negative at this time-point usually have durable remissions. 6 of the 9 patients receiving 12 weeks of alemtuzumab were MRD negative at the end of treatment but only 1 (11%) remained MRD negative in the blood at 6 months. In contrast 33/38 patients receiving up to 8 weeks of alemtuzumab were MRD negative at the end of treatment and 15 (39%) remained MRD negative at 6 months suggesting that the patients who benefit most from alemtuzumab consolidation are those who are MRD negative at 6 weeks.
Alemtuzumab consolidation results in the eradication of detectable MRD in 83% of patients and 41% remain MRD negative 6 months later. Consolidation with alemtuzumab is associated with mainly infective toxicities, which are largely manageable with prophylaxis and close monitoring. These results justify the continued investigation of this approach in CLL within a clinical trial setting and with appropriate monitoring of patients. To this end we are now commencing a randomized Phase III trial of consolidation with alemtuzumab compared to observation (the CLARET study).
Pocock:F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hillmen:Genzyme: Honoraria, Research Funding, Speakers Bureau; Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Research Funding.
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