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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-6, 2006

Interim results of CAM 307 presented here showed that alemtuzumab compared favourably with standard chlorambucil as first-line therapy of progressive B-cell chronic lymphocytic leukemia (B-CLL). Patients who received the monoclonal antibody (MAb) exhibited significantly higher overall and complete response rates compared with chlorambucil and the toxicity was manageable, commented lead investigator Dr. Peter Hillmen, Leeds General Infirmary, UK.

He told delegates, “This is the first study to compare alemtuzumab as a first-line therapy with standard chemotherapy, and we are encouraged by the results.” In addition to the promising overall safety and efficacy findings at this interim analysis, Dr. Hillmen added that alemtuzumab achieved impressive responses in patients with poor-risk cytogenetic abnormalities. “These poor-risk patients have very low response rates and short survival when treated with conventional chemotherapy. The good results suggest that alemtuzumab can provide a new and more effective therapeutic option for patients with poor-risk CLL. We await the final results of CAM 307 for responses and survival in this difficult-to-treat population, he explained.”

Interim Findings

The study enrolled 297 previously untreated patients with B-CLL at 44 medical centres in the US and Europe. Patients were randomized to alemtuzumab or chlorambucil. Dr. Hillmen reported results of a preplanned interim analysis, which demonstrated an overall response rate (ORR) of 83% for alemtuzumab vs. 56% for chlorambucil; complete response rates (CRR) were significantly increased by almost 30% for patients in the alemtuzumab group (P<0.0001). The CRR was seen in 24% of MAb patients vs. 2% in the chlorambucil arm (P<0.0001).

Chlorambucil has a tolerable safety profile for previously untreated patients, and in this analysis, alemtuzumab was equally well tolerated. Serious treatment-related adverse events occurred in 25% of alemtuzumab-treated patients and 6% of those given chlorambucil. The rates of grade 3-4 thrombocytopenia, anemia, and serious infections were similar between the two arms. The MAb was associated with higher rates of cytomegalovirus (CMV), neutropenia and leukopenia compared with chlorambucil; no significant difference in febrile neutropenia was found between the two arms. As expected, the most common treatment-related adverse events in the study were pyrexia, rigors, nausea, hypotension, and vomiting. Nausea and vomiting were more frequent in the chlorambucil arm.

Patients with cytogenetic abnormalities characteristic of B-CLL (i.e., 13q, 11q and 17p deletions) had high response rates to alemtuzumab compared with chlorambucil. As Dr. Hillmen explained 13q deletion is common in B-CLL, and 11q and 17p deletions are associated with poor prognosis. Patients with 13q and 11q deletions had significantly higher overall response rates. Twenty-two patients with 17p deletions had an ORR of 64% on alemtuzumab compared with 20% on chlorambucil. Although ORRs were three times higher in the MAb group, the number of patients with 17p deletions was too small to achieve statistical significance.

Encouraging Results

“Based on the response rates in this trial, this is a wonderful, positive direction in front-line treatment of CLL,” commented Dr. Kanti Rai, Chief of Hematology/Oncology, Long Island Jewish Medical Center, New Hyde Park, New York and Professor, Albert Einstein College of Medicine, The Bronx.

Formal discussant of this trial Dr. Michael Keating, Department of Hematology, Professor of Medicine, M.D. Anderson Cancer Center, Houston,Texas, explained, “Alemtuzumab is probably equivalent to fludarabine as the most active single drugs in CLL. We’ve learned a lot about alemtuzumab. It is the most active single drug in patients with 17p deletions and it is not as good in patients with very large lymph nodes. Now we know how to handle prophylaxis for infections. Alemtuzumab will play a major role in our practice with CLL patients.”

Reduced Intensity Regimen

According to the principal investigator, Dr. Raimundo Bezares, Hospital General de Agudos “Dr. Teodoro Alvarez”, Buenos Aires, Argentina, an interim analysis of a phase II trial showed that a reduced-intensity regimen of subcutaneous alemtuzumab was feasible, achieved very high response rates, and was well tolerated in patients with relapsed/refractory B-CLL.

As he presented to the audience, the study enrolled 36 patients with a mean age of 67 (range, 43 to 86); 78% were male. Twenty-nine patients (81%) were relapsed and seven patients (19%) were refractory.

The treatment was escalated from 10 to 20 mg during the first week, 30 mg twice weekly during weeks 2 and 3; then 30 mg once weekly during weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34 and 40. Median duration of treatment was seven weeks (range, two to 24 weeks). Median cumulative dose of 412 mg (range, 150 to 1080 mg). Antiviral prophylaxis with trimethoprim/sulfamethoxazole was given three times a week, and acyclovir 200 mg was given three times daily.

Response and Flow Cytometry Results

In the single-arm, phase II trial with a reduced-intensity regimen of alemtuzumab, thirty-two of 36 patients were evaluable for response. The ORR was 93%; confirmed CR was seen in 34% and unconfirmed CR in 6%. Partial response was found in 53% of patients.

Of the seven refractory patients (21%), five had partial response (15%), one had no response (3%), and one was not evaluable (3%). Overall survival for all patients was 83% at 11 months, with a median overall survival of 10 months. Overall survival was 100% in relapsed patients and 78% in refractory patients.

CR with eradication of minimal residual disease is the goal of treatment. In five patients (15%) with CR, flow cytometry revealed the presence of <0.5% CLL cells in three patients, <5% CLL cells in one participant, and <10% CLL cells in one patient.

The regimen was well tolerated, with grade 3 or 4 infections in five patients (15%), grade 3 granulocytopenia/thrombocytopenia in two patients, CMV reactivation in one patient, and Epstein-Barr virus with fever in one patient.

Summary

Studies presented at ASCO suggest that the MAb alemtuzumab may be an effective first-line therapy for B-CLL, since an interim analysis of the first phase III trial to compare alemtuzumab with standard chlorambucil directly showed improved response rates for alemtuzumab with comparable safety. A second study suggests that subcutaneous alemtuzumab given in a less intensive regimen may be a good therapeutic option for patients who relapse or fail to respond to previous therapies.

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