Alemtuzumab clearance, lymphocyte count, and T‐cell chimerism after hematopoietic stem cell transplant in sickle cell disease

Abstract

Study Objective: Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes.Design: PK and PD analysis of patient data from a single-center clinical trial.Setting: Clinical research center.Patients: Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI). Measurements and Main Results:Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the halflife was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R 2 = 0.40 and p = 0.004 at 2 months, R 2 = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism. Conclusion:Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, | 15 FURSTENAU ET Al.

Therapeutic Apheresis, Immunosuppression and Human Monoclonal Anti-bodies in Hematologic diseases most with im-munologic origin

“…In patients with acute, severe sickle cell-related complications beside RBC TPE can be indicated and successfully (31 -33). In milder forms of the diseases, monoclonal antibodies such as rituximab or alemtuzumab could be used (34).…”

Population pharmacokinetics of subcutaneous alemtuzumab in kidney transplantation

“…Unfortunately, translation of these pharmacometric studies to the kidney transplant setting is complicated by divergent dosing algorithms, concomitant immunosuppressive therapy, patient characteristics and CD52 expression. These HSCT patients received sequential body size-adjusted cumulative dosages of 0.2-1.5 mg/kg 10,12,13 or 45 mg/m 2 11 administered over 4-5 consecutive days 7-15 days before graft infusion. [10][11][12][13] By contrast, MS patients received fixed dosages of 12-24 mg/day on five consecutive days, followed by 12-24 mg/day on three consecutive days 12 months thereafter.…”

“…These HSCT patients received sequential body size-adjusted cumulative dosages of 0.2-1.5 mg/kg 10,12,13 or 45 mg/m 2 11 administered over 4-5 consecutive days 7-15 days before graft infusion. [10][11][12][13] By contrast, MS patients received fixed dosages of 12-24 mg/day on five consecutive days, followed by 12-24 mg/day on three consecutive days 12 months thereafter. 9 For CLL, patients received dosages of 0.3-50 mg thrice-weekly over a course of 6-12 weeks, administered as multiple fixed dosages or by dose escalation.…”

“…Similarly, HSCT recipients in these studies received concomitant immunomodulating therapy with sirolimus, cyclosporine or mycophenolate, combined with melphalan, fludarabine, cyclophosphamide or methotrexate. [10][11][12][13] The additional immunomodulating effects of these agents may impact CD52 expression and thereby affect the degree of CD52 expressiondependent target-mediated drug disposition (TMDD) of alemtuzumab. 14 By contrast, these MS and CLL patients received no concomitant immunomodulating therapy 9,14 and will thus likely display different extents of TMDD than seen in HSCT or kidney transplantation.…”

“…In these populations, considerable PK variability is apparent, with between-subject variabilities in alemtuzumab clearance, distribution and absorption of 36-104%, [9][10][11][12][13] 26-84% [9][10][11][12]14 and 73-101%, 11,12 respectively. Furthermore, only limited evidence on exposure-response relationships of alemtuzumab is available.…”