Alemtuzumab and Rituximab Combination Therapy for Patients with Untreated CLL – a Phase II Trial.

Despite the availability of multiple therapeutic regimens, without a stem cell transplant, chronic lymphocytic leukemia (CLL) remains an incurable disease. A dramatic response rate with intensive chemo-immunotherapy in patients with CLL is frequently associated with 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: Data is available on 20 out of 21 enrolled patients. Therapy duration is 18 weeks. Subcutaneous (SQ) ALEM dose escalation: 3 mg - 10 mg - 30 mg on days 1, 3, 5, followed by the 30 mg Monday, Wednesday and Friday for 17 weeks. RIT at a dose of 375 mg/m²/dose IV is administered every other week staring on the 3^d week for 8 doses. 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 were also assessed by serial CT scans. Minimal residual disease (MRD) was measured in peripheral blood and bone marrow aspirate using flow cytometry for CD19+/CD5+/CD23 lymphocytes.

Patients’ characteristics: Since September 2005, 21 patients have been enrolled and 20 completed the therapy. All patients met ECOG criteria for requiring treatment. Median age was 54 years (28 – 74) with 12 males and 8 females; 19 Caucasian and 1 African American. The median time from the diagnosis to treatment was 21.5 months (2–144 months). Clinical stage (Rai) was I in 2 patients, II in 8 patients, III in 4, and IV in 6 patients. Median β² microglobulin was 3.23 (0.34–15.3). Median WBC was 56 x10⁹/L (17.4 – 157.6), Hgb 12.6 g/dL (10 – 14.7), and platelet count 172 x 10⁹/L (66 – 307). Cytogenetic analysis, by FISH panel, was 13q- in 7, trisomy 12 in 6, and 13q-/11q- in 3, 11q- in 1, 11q-/p53/13q- in 1, and 13q-/11q-/6q- in 1 patient. Half of the patients were Zap70+ and 3 patients were CD38+. Mutational analysis is pending.

Results: Based on the NCI-WG 1996 criteria, 15 patients (75%) achieved CR, 3 patients (15%) achieved PR, and 2 patients (10%) had stable disease. With utilization of CT scans responses were: 8 CR (40%), 9 PR (45%), and 3 SD (15%). At the completion of the study 14 patients (70%) had no evidence of MRD by flow cytometry. Median duration of the response has not been reached with a median follow-up of 20 months (1–31+). All 5 patients with 11q- achieved CR based on the NCI-WG 96 criteria. Three patients (15%) required alternative therapy for the disease progression at 4, 24, and 27 months after the completion of study.

Six patients (30%), all of whom were baseline CMV IgG+, had CMV reactivation by PCR. Two of them developed symptom of malaise and required hospitalization, none suffered organ involvement, and all of them cleared the infection with valgancyclovir administration. One patient suffered neutropenic fever requiring empiric antibiotic therapy followed by Clostridium difficile and adenovirus infections. 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 3, grade 3 in 5, and grade 4 in 3 patients; anemia: grade 1 in 9, grade 2 in 2 patients; thrombocytopenia: grade 1 in 8, grade 2 in 4, and grade 3 in 3 patients.

Seven patients have not achieved full T cell recovery (CD4 >200) by 1, 4, 5, 7, 12, and 18 months. The other 13 patients achieved T cell recovery by 1 (n=2), 4 (n=2), 6 (n=1), 7 (n=2), 9 (n=1), 10 (n=1), 15 (n=1), 16 (n=2), and 22 months. All of the patients who suffered CMV reactivation achieved faster T cell recovery than those who did not (median time 5 vs. 22 months). Two patients developed clinically significant autoimmune hemolytic anemia and none suffered Richter’s transformation. No death occurred.

Discussion: 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.