A Phase II Trial of Alemtizimab and Rituximab in Patients with Previously Untreated CLL.

Without a HSCT, CLL remains an incurable disease. A dramatic response to intensive chemo-immunotherapy may be accompanied by the irreversible long term consequences to the bone marrow, limiting further therapeutic options. For this reason we have initiated a clinical trial combining Rituximab (RIT) and Alemtuzumab (ALEM), two monoclonal antibodies with established activity and side effects profiles, as an initial therapy for patients with CLL requiring intervention.

Methods This trial will enroll 21 previously untreated CLL patients and be considered promising if ≥ 85% of them respond. Therapy duration is 18 weeks. Subcutaneous (SQ) ALEM dose escalation: 3 mg – 10 mg – 30 mg on days 1, 3, 5, is followed by the 30 mg 3 times/week for 17 weeks. RIT, 375 mg/m²/dose IV is administered every other week staring on the 3^d week for 8 cycles. All patients received PCP, herpes virus, and fungal prophylaxis as well as CMV viral DNA monitoring. Responses were based on NCI-WG 1996 criteria, however, lymphadenopathy and organomegaly was also assessed by serial CT scans. MRD was measured in peripheral blood and bone marrow aspirate using flow cytometry for CD19+/CD5+/CD23 lymphocytes.

Results Since September 2005, 13 patients have been enrolled and the interim analyses are available for the 11 patients who have completed the therapy. All patients met ECOG criteria for treatment requirement. Median age was 54 years (29 – 75) with 6 males and 7 females. The median time from the diagnosis to treatment was 13 months (1–56 months). Clinical stage (Rai) was I in 4, II in 4, and IV in 5 patients. Median β₂ microglobulin was 2.54 (0.34–4.29). Median WBC was 42 ×10⁹/L (16 – 119), Hgb 13.3 g/dL (10.7 – 15.6), and platelet count 144 × 10⁹/L (67 – 302). Cytogenetic analysis, by FISH panel, was 13q in 6 patients, trisomy 12 in 5 patients, and 13q/11p in 2 patients. 3 patients were Zap70+ and 1 patient was Zap70+ and CD38+. All of the patients responded with 2 CR, 8 PR, and 1 SD. By NCI-WG 1996 criteria, without CT scans, 8 patients (72%) achieved CR and 3 patients (27%) achieved PR. At the completion of the study 9 patients (81%) had no evidence of MRD by flowcytometry, 1 had too few cells to access clonality, and 1 was MRD positive. Median duration of the response has not been reached with a median follow-up of 15 months (9–23+). 3 patients had increased lymphadenopathy by CT scan (by 5, 6, and 8 month after completion of therapy), none reached the definition of disease progression. 4 patients had CMV reactivation by PCR, 2 of whom had symptom of malaise, none suffered organ involvement, and all of them cleared the infection with gancyclovir administration. No other serious infectious complications were documented. All patients developed grade 1–2 skin rash at the site of ALEM injection after the 1^st dose of 3mg only; none required intervention. All patients developed grade 3–4 lymphopenia; neutropenia: grade 2 in 2, grade 3 in 4, and grade 4 in 1 patients; anemia: grade 1 in 9, grade 2 in 2 patients. 5 patients have not achieved full T cell recovery by 22, 21, 18, 15, and 9 months. The other 6 evaluable patients achieved T cell recovery by 1 (n=2), 4 (n=2), 7, and 10 months. Patients who suffered CMV reactivation achieved faster T cell recovery. None of the patients developed an autoimmune phenomena or Richter’s transformation Summary Combination of ALEM and RIT is well tolerated and active regimen for patients with CLL and may represent a viable alternative to the combination chemotherapy.