Pharmacokinetics and Response to

Treatment Using a Combination of

Fludarabine and Alemtuzumab (FluCam) in
Patients with Relapsed/Refractory CLL.
T. Elter, J. Kilp, T. Piironen, P. Borchmann, H. Schulz, J. Bohlius, Michael J. Hallek and
Andreas Engert
Blood 2006 108:4991;

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Abstract
Combination chemoimmunotherapy regimens have shown substantial efficacy in the
treatment of lymphoproliferative disorders, particularly in comparison to the efficacy of
single-agent therapies. Fludarabine has become an established treatment regimen in CLL, and
although overall response rates (ORR) in previously untreated patients range between 60% to
80%, patients who are refractory to fludarabine have poor outcomes. Alemtuzumab, the antiCD52 monoclonal antibody, is the most effective single-agent therapy in CLL, and is capable
of inducing minimal residual disease (MRD)-negative responses even among patients with
fludarabine-refractory disease. Our previous clinical experience with the combination of
alemtuzumab and fludarabine (FluCam) resulted in 83% ORR in 36 patients with
relapsed/refractory CLL, with 30% achieving a complete response (CR; Elter et al J Clin
Oncol 2005;23:70247031). In addition, among 12 patients with fludarabine-refractory
disease, 8 achieved responses (4 CRs), and median time-to-progression (TTP) for all patients
was 13 months. In order to optimize the dose and schedule of the FluCam combination, we
performed pharmacokinetic (PK) analysis of the previously reported 6-cycle regimen. PK data
were collected for a 14-patient cohort that participated in the phase 2 FluCam trial. Median
patient age was 60 years (range, 4973), 9 patients had Binet C disease (5 were Binet B), and
patients received a mean 2.5 prior therapies. Alemtuzumab 30 mg (after initial dose
escalation) and fludarabine 30 mg/m2 were administered on days 13 of a 28-day cycle for up
to 6 cycles. PK parameters were measured from samples collected before each subsequent
cycle, and at days 1, 4, 7, 14, 21, 28, and 42, for a total of 158 patient samples, of which 120
were tested. Plasma concentration of alemtuzumab increased steadily from day 1 to day 4 of
therapy to a median Cmax 1.55 mg/mL, but decreased to a median 0.145 mg/mL by 7 days after
initiation of treatment. By day 21 of therapy, alemtuzumab plasma concentration decreased to
undetectable levels. Because efficacy of alemtuzumab has been shown to correlate with serum
levels of this antibody, significant improvement in progression free survival (PFS) may
require a elevated plasma levels of alemtuzumab for the duration of the treatment cycle.
Therefore, the significant responses seen in this trial can be attributed to documented

synergistic activity between alemtuzumab and fludarabine, which has been demonstrated both
in vitro and in vivo. Despite low CD4 counts through the duration of therapy, favorable safety
results seen in the trial could be attributed to opportunity for hematologic recovery between
treatment cycles. Detailed PK analysis is currently being completed and will be presented at
the conference.
Conclusions: Treatment with the FluCam immunotherapy combination yielded positive results
among patients with fludarabine resistant/refractory CLL, a difficult-to-treat population. As
shown previously, response rates correlate with higher alemtuzumab plasma concentrations.
Therefore, longer PFS durations may require longer, more sustained alemtuzumab plasma
levels, which may be achieved with either consolidation or maintenance.

2006, The American Society of Hematology

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