Pharmacokinetic Analysis of Subcutaneous Alemtuzumab as Consolidation Therapy To Achieve MRD-Negative Responses.

Abstract

Persistence of minimal residual disease (MRD) after therapy has been shown to be a powerful prognostic factor for relapse among patients with chronic lymphocytic leukemia (CLL). Treatment with the anti-CD52 monoclonal antibody alemtuzumab (Campath®), either as a single agent or in combination with fludarabine, has been shown to induce MRD-negative responses, even among patients who are not responsive to traditional therapeutic interventions. Dramatically improved responses and MRD negativity have also been achieved using alemtuzumab as consolidation therapy, to purge MRD after initial therapy with a fludarabine-based regimen. The pharmacokinetics (PK) of alemtuzumab administered subcutaneously to achieve MRD negativity after induction therapy with fludarabine are reported here. Of 41 patients (median age, 54 years) who received consolidation therapy with alemtuzumab, all 16 patients participating in the PK analysis were MRD-positive after receiving induction therapy as measured by PCR consensus primer. At least 8 weeks following the completion of induction therapy, dose escalated alemtuzumab 10 mg was administered for 6 weeks, 3 times a week. Plasma samples were collected from 16 patients on Days 1, 3, 5, 15, 17, 22 and 31, and ELISA was used to assess the PK of alemtuzumab. On Day 15, blood samples were drawn at 1, 2, 3, 4, 6, 8 and 12 hours after alemtuzumab administration. Alemtuzumab plasma concentrations gradually increased during the first 2 weeks, and reached concentrations 25.5-fold higher on Week 3. The median pre-dose concentrations (Cpre-dose) were: 0.01 μg/mL (range, 0–0.07 μg/mL) on Day 3, 0.58 μg/mL (range, 0–1.2 μg/mL) on Day 15, 0.51 μg/mL (range, 0–2.61 μg/mL) on Day 17, and 1.09 μg/mL (range, 0.19–3.08 μg/mL) on Day 31. The median Cmax plasma concentration was 1.05 μg/mL (range, 0.097–1.75 μg/mL) and the median Cpre-dose was 0.58 μg/mL (range, 0–1.2 μg/mL). An analysis was performed to correlate quantitative response as represented by polyclonal complete remission and AUC0–12 values. Preliminary data indicate that the systemic exposure associated with effective therapy corresponds with an AUC0–12 value higher than 5 μg•h/mL on Day 15 of the administration schedule. Therefore, complete response (CR) rates, expressed as percentage of patients with AUC0–12 values correlating with effective treatment, increased with higher levels of systemic exposure to alemtuzumab.