Alemtuzumab + Fludarabine

From OncoWiki
Jump to: navigation, search

Chronic Lymphocytic Leukemia

Alemtuzumab (Campath) SC +/- Fludarabine

  • Alemtuzumab 30 mg/d sc tiw (after dose escalation in first week) x 24 wks
  • Add fludarabine 40 mg/m2/d po for 3 days q4w for patients failing to response to alemtuzumab
  • Acyclovir and cotrimoxazole prophylaxis

References

Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab results in 33 to 50% responses in refractory CLL. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3x a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics reveal lower initial levels compared to IV. The UKCLL02 study assessed the safety and efficacy of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3x a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. Of 53 patients (median age 64, range 41 to 79) enrolled 2 patients died before receiving alemtuzumab and 1 withdrew consent. 50 patients have completed therapy and 49 are evaluable. Responses to alemtuzumab monotherapy (n=49) were 5 MRD negative CR, 2 MRD positive CR, 15 PR (including 1 MRD negative patient who remained cytopenic), 25 NR and 2 patients died on treatment. Alemtuzumab was given for a median of 18.8 weeks (range:1.6-24) with a median dose of 1370.5mg (range 106-2323mg). 17 patients (6 PRs and 11 NRs) received concurrent fludarabine and SC alemtuzumab (median 2 courses fludarabine [range 1-3]). 2 NR achieved a PR and 1 PR achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 24/49(49%) including 6 MRD negative patients (5CRs and 1 PR). IgVH gene was unmutated (>98% germ line homology ) in 23/31 patients. FISH revealed poor risk deletions (11q and/or 17p) in 28/46 patients (17p- in 15, 11q- in 7, both in 6). 25/38 patients had dysfunction p53 in a functional assay. 22/38 patients (58%) with poor risk deletions (11q- and/or 17p-) and/or p53 dysfunction responded to treatment, including 5 patients who achieved MRD-negative CRs, 3 MRD-positive CR, and 14 PR. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 26 patients (diameter 1 to 18cm), fever in 8 and rigors in 4. All reactions subsided in <48h. Serious infections during alemtuzumab monotherapy were: CMV reactivation (18); febrile neutropenia (10); invasive fungal infection (4); pneumonia (7) and septicaemia (2). On the combination, CMV reactivation (3 cases) and septicaemia in (1). All CMV reactivations resolved on antiviral therapy. Grade 3+ thrombocytopenia and neutropenia was seen in 26 and 41 patients on alemtuzumab monotherapy as well as in 1 and 5 patients on combined therapy, respectively. The median survival for responders was 25 months compared to 13 months for non-responders. In summary, we report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL and is well tolerated compared to IV therapy. A longer duration of SC alemtuzumab therapy (up to 24 weeks) was given. The addition of oral fludarabine improves the response rates with acceptable toxicity. Abstract #34 appears in Blood, Volume 108, issue 11, November 16, 2006