Alemtuzumab Compared with Chlorambucil as First-Line Therapy for Chronic Lymphocytic Leukemia

Source: J. Clin. Onc. 2007 Dec 10;25(35): 5616-23
Authors: Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J.
Affiliation: Leeds Teaching Hospitals National Health Service Trust, Leeds General Infirmary, Leeds, United Kingdom

Background

• Chronic lymphocytic leukemia (CLL) is an indolent disease and can be observed. However, when treatment is required, there is no globally accepted first-line treatment
• Some patients have a worse prognosis based on cytogenetics, especially those with deletions in chromosomes 17p (where p53 resides) and 11q
• Along with chlorambucil and fludarabine, alemtuzumab (Campath) is approved by the FDA to treat patients with CLL
• Alemtuzumab is an antibody that targets CD52, which is found on most normal and malignant B and T lymphocytes, but not on hematopoietic stem cells
• Infection with the CMV (cytomegalovirus) is a significant morbidity associated with Campath therapy, especially in patients with advanced disease. The mechanism for this increased infection risk is tied to immune suppression from Campath treatment.

Methods

• Design: Multi-center, randomized, Phase III trial.
• Patients: 297 patients with CLL at 44 centers (9 in the U.S.), clinical Rai stages I through IV, with evidence of progression
• No previous chemotherapy allowed
• All patients had chromosomal analysis by FISH
• Randomized between:
  • Alemtuzumab 30 mg IV (up to 12 weeks)
  • Chlorambucil 40 mg/m 2 (up to 12 cycle
• Endpoints: Primary – progression free survival (PFS)
• Secondary – overall response rate (ORR), complete response (CR), time to alternate therapy, safety, and overall survival (OS).

Results

• The randomization appeared to be well-balanced for important pre-treatment factors, including age, Rai stage, bulk of disease, performance status, B symptoms, and karyotype by FISH
• Median treatment duration: alemtuzumab: 11.7 weeks; chlorambucil 7 cycles

• Response:
  • The primary endpoint, PFS was statistically better in patients treated with alemtuzumab (median 14.6 vs. 11.7 months, HR 0.58, p=0.0001)
  • ORR and CR was significantly better in alemtuzumab group
    • In the alemtuzumab group, 11/149 treated patients were negative for MRD (minimal residual disease) compared to 0/148 patients in the chlorambucil group
  • Median time to alternative therapy: 23.3 months alemtuzumab vs. 14.7 months chlorambucil
  • ORR in patients with 17p deletion:
    • 7/11 in alemtuzumab group (64%)
    • 2/10 in chlorambucil group (20%)
• No difference in OS between the 2 groups
• Safety:
  • Grade 3/4 neutropenia worse in alemtuzumab group (41% vs. 25%)
  • Similar rate of sepsis/bacteremia (3% vs. 1.4%)
  • 9.5% in alemtuzumab group required growth factors vs. 4.1% in chlorambucil group
  • Serious adverse events were more common in alemtuzumab group (26.5% vs 6.8%)
    • 6 patients in alemtuzumab group stopped drug due to serious CMV disease
  • CMV status did not affect ORR/PFS in the alemtuzumab group

Conclusion

• As first-line treatment in CLL, alemtuzumab had significantly better PFS, time to alternate treatment, ORR, CR, and MRD-negative remission compared to chlorambucil.
• The authors state that alemtuzumab may be the most active single agent for the treatment of patients with CLL, with a manageable safety profile.
• The authors point out that alemtuzumab in the first-line setting is probably safer than when given in more advanced disease.
• The authors state that alemtuzumab may have an important role in treating patients with poor-risk cytogenetics (such as 17p del) and in the eradication of minimal residual disease.

Discussion

• The authors should be commended on conducting a relatively large, multi-centered trial that was a "positive" study, in the sense that the primary endpoint (PFS) was highly significantly different between the arms.
• The biggest criticism of this study is the choice of control arm (single agent chlorambucil), as it is fairly "easy to beat" chlorambucil. Although chlorambucil and fludarabine are FDA-approved for the treatment of CLL, many treating physicians in the U.S. have moved toward rituximab-containing multi-agent chemotherapy regimens as standard treatment:
  • FCR (fludarabine, cytoxan, rituxan), FR (fludarabine, rituxan), PCR (pentostatin, cyclophosphamide, rituximab), CVP (cytoxan, vincristine, prednisone, rituximab)
• In single-arm trials, FCR has had a reported CR rate of 70%, compared with 24% for the alemtuzumab group in this study. Compared to the median PFS in the alemtuzumab group of 14.6 months as reported in this study, results with FCR have been much more impressive. In one study, FCR had a median PFS of 28 months, and in another 69% of patients treated with FCR were projected to be failure free at 4 years.
• Perhaps future studies will evaluate which is the most effective combination regimen, with special emphasis on risk stratification based on chromosomal abnormalities