SAN DIEGO, CA—Low-dose alemtuzumab in combination with fludarabine and cyclophosphamide (FCA) induced a higher rate and higher quality of complete remission (CR) than fludarabine and cyclophosphamide (FC) alone in a high-risk chronic lymphocytic leukemia (CLL) population, analysis of the HOVON68 trial presented at the 53rd Annual Meeting and Exposition of the American Society of Hematology concluded.

In this randomized, Phase 3 trial, Christian H. Geisler, MD, PhD, from the Haematology Department of Rigshospitalet, Copenhagen, Denmark, and colleagues sought to determine if the addition of alemtuzumab, a monoclonal antibody, to the currently best known chemotherapy, FC, improved outcomes in high-risk CLL. The investigators hypothesized that the addition of alemtuzumab to FC could increase the CR rate from the estimated 20% to 40% and median progression-free survival (PFS) from 32 to 40 months.

National Cancer Institute/International Workshop on Chronic Lymphocytic Leukemia (NCI/IWCLL) guidelines were used to define patient parameters and study endpoints. Treatment-naive, fit patients, ≤75 years of age with high-risk CLL were randomized to receive either oral FC (fludarabine 40mg/m2 Days 1–3 + cyclophosphamide 250mg/m2 Days 1–3) or AFC (oral FC + SQ alemtuzumab 30mg on Days -1 to +1 of Cycle 1 and 30mg on Day 1 of Cycles 2–6). A low-dose alemtuzumab approach was chosen because of the immunosuppressant activity of both treatment modalities. Excluded were those with a performance status >2, HIV or hepatitis B/C seropositivity, and active, uncontrolled infections.

Primary endpoint was PFS in the intent-to-treat population. Progression was defined as failure to respond after three cycles of induction treatment, disease relapse or progression, or death. Secondary endpoints included the rate of complete remission (CR) and the rate of MRD-negative CR (by PCR or flow cytometry), overall survival (OS), and toxicity.

A total of 281 patients were included from 2006–2010, with 272 evaluable. See Table for patient demographics. Study results demonstrated the overall response (OR) rate of FC to be 80% and FCA, 89% (P=0.048). CR rates were 47% and 57% (P=0.091), and the rates of MRD-negative CR were 17% and 29%, respectively (P=0.014). No responses were observed in 28 patients (20%) in the FC group and 15 (11%) in the FCA group. Overall response and CR rates to FISH for the FC and FCA groups were 44% and 71% for del17p, 80% and 89% for del11q, and 76% and 91% for trisomy 12, respectively.

Median PFS following FCA and FC was 37 and 31 months, respectively (P=0.08). By multivariate analysis, treatment with FCA resulted in a hazard ratio of 0.68 (95% CI: 0.49–0.95); when FISH data were added to the model, only del17p was significant.

Severe adverse events, mostly Grade 3, were associated more frequently with FCA than FC (147 vs 91, P<0.0001). These included flulike syndrome due to the antibody, opportunistic infections, and organ toxicity. The numbers of neutropenic and other infections did not differ between treatment groups. In the FCA group, 8 patients died, as did 7 in the FC arm. The FCA arm had a higher number of opportunistic infections, 26 vs 11, which was expected since the FCA combination is more immunosuppressant than chemotherapy alone.

Investigators noted that in this treatment-naive, high-risk CLL population, the addition of low-dose alemtuzumab to oral FC significantly increased the OR rate, rate of MRD-negative CR, and PFS; outcome is improved and is tolerable. However, it is too early to conclude on the outcome in subgroups. The FCA arm was clearly more immunosuppressive than FC alone, Dr. Geisler et al concluded; however, “with suitable vigilance towards opportunistic infections, the combination is tolerable.”