Chemoimmunotherapy with Chlorambucil and the Type II CD20-Antibody GA101 In Patients with Chronic Lymphocytic Leukemia and Comorbidity: Results of the Run-In Phase of the CLL11 (BO21004) Trial

Chemoimmunotherapy with purine analogues and the CD20-antibody rituximab is the standard of care in younger and physically fit patients with chronic lymphocytic leukemia (CLL). However, the majority of CLL patients are of advanced age and many of those are afflicted with comorbidity. To date, there is no established standard treatment for such patients and the alkylating drug chlorambucil remains a valuable treatment option. The addition of CD20-antibodies (including the novel type II antibody GA101) to chlorambucil (CLB) has been proposed to improve alkylator-based therapy in CLL. Whether these regimens are beneficial in CLL patients with comorbidity remains to be explored. The German CLL Study Group (GCLLSG) in collaboration with F. Hoffmann-La Roche Ltd has initiated the multicenter international 3-armed CLL11 trial comparing CLB alone with CLB plus rituximab (R-CLB) or GA101 (G-CLB) in comorbid CLL patients. Here, we present the results of six elderly and comorbid CLL patients having received G-CLB treatment within the CLL11 safety run-in phase.

Prior to the opening of the randomized phase of the CLL11 trial, six patients with previously untreated CLL in need of treatment and with a cumulative illness rating scale (CIRS) total score > 6 and/or a creatinine clearance (CrCl) < 70 ml/min were enrolled to receive 6 cycles of G-CLB. Chlorambucil was given orally at 0.5 mg/kgBW on d1 and d15 of each cycle (QW 28d). GA101 was administered intravenously on d1, d8 and d15 of cycle 1 and on d1 for cycles 2–6. Occurrence of (i) one treatment-related death or (ii) three episodes of febrile neutropenia/infections requiring antibiotic therapy during the first cycle were defined as stopping criteria for the trial.

All patients (2 females, 4 males) had CD20-positive CLL and active disease according to NCI/IWCLL criteria. The patients' age, CrCl and CIRS total score ranged between 71 and 79 years (median: 76 years), 38 and 83 ml/min (median: 51 ml/min), and from 5 to 9 (median: 8), respectively. So far, 4 patients completed therapy while 2 patients are still on treatment (both due to treatment delays). Therapy had to be delayed in 3 patients, mainly due to neutropenic episodes but also caused by a mechanical ileus unrelated to treatment and requiring surgical intervention and by a psychotic disorder. None of the patients have been withdrawn from treatment to date. Infusion-related reactions occurred in 5 patients, but were mild (grade 1–2) in all cases. NCI CTC grade 3 or 4 neutropenias were seen in 5 patients; 3 patients received G-CSF with immediate response. One patient had grade 3–4 thrombocytopenia while none of the patients developed grade 3–4 anemia. No grade 3–4 infections were observed and there were no febrile neutropenias or infections in the presence of neutropenia requiring antibiotic therapy. All 6 patients showed rapid clearing of lymphocytes from their peripheral blood within a few days of first dosing with G-CLB (response rates at the end-of-treatment will be reported).

Chemoimmunotherapy with CLB and GA101 appears to be feasible in CLL patients of advanced age and with high burden of comorbidity. However, neutropenia as well as complications associated with comorbidity need special consideration in this very fragile patient population. None of the stopping criteria defined for the CLL11 run-in phase were met. The CLL11 trial therefore was opened for randomization in April 2010.

Goede:Roche: Honoraria, Travel Grants. Fischer:Roche: Travel Grants. Fink:Roche: Travel Grants. Bieska:Roche: Employment. Humphrey:Roche: Employment. Bishop:Roche: Employment. Wenger:Roche: Employment. Hallek:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.