Alemtuzumab Precision Dosing in Allogeneic Hematopoietic Cell Transplantation

Abstract

<h3>Background</h3> Alemtuzumab is frequently used as part of reduced-intensity and reduced-toxicity conditioning regimens. High alemtuzumab levels at day 0 are associated with decreased rates of acute graft-versus-host disease (aGVHD) but increased rates of mixed chimerism, viral reactivation and delayed immune reconstitution. Prior studies performed at our center identified an ideal therapeutic range of 0.15-0.6 mcg/mL at day 0. We aimed to determine if precision dosing of alemtuzumab is feasible in the pediatric HCT setting. <h3>Methods</h3> Twelve patients with non-malignant diseases were enrolled. Alemtuzumab was dosed, and levels were checked per the schema in Figure 1. Pharmacokinetic modeling was performed on Day -5 to predict Day 0 levels. If patients were predicted to fall below 0.15 mcg/mL, simulations were performed, and a top-up dose of alemtuzumab was given on Day -3. Conditioning also included fludarabine 150 mg/m² or 5 mg/kg if <10 kg and melphalan 140 mg/m² or 4.7 mg/kg if <10 kg. GVHD prophylaxis was cyclosporine or tacrolimus plus methylprednisolone. <h3>Results</h3> Observed alemtuzumab level was within predicted range for 6 (50%) patients, and 6 (50%) patients were within the ideal therapeutic range (Figure 2). This is double the percent of patients within the ideal therapeutic range with traditional dosing (Figure 3). Four patients received a top-up dose of alemtuzumab on day -3. One patient developed acute cholecystitis, and conditioning was halted after alemtuzumab. The patient was included in alemtuzumab level analysis but excluded from clinical outcomes. Ten (91%) patients engrafted on median day +12 (range 10-15). One (9%) patient had primary graft failure with autologous neutrophil recovery and was successfully re-transplanted 8 months later. There was one (9%) case of Grade II aGVHD. Six (55%) patients had full (>95%) donor chimerism at day +100. Four (36%) patients with day 0 alemtuzumab levels ranging from 0.35-1.12 mcg/mL developed mixed chimerism (lowest chimerism 29.6-78.7% prior to Day +100). Three of these received CD34+ cell boosts, and one went on to second transplant. All 11 patients are alive and well at a median of 16 months (range 10-24) follow-up. <h3>Conclusions</h3> Our results confirm the feasibility of successful alemtuzumab precision dosing in HCT. Further dose de-escalation is needed to target the majority of patients to the goal range, and additional myelosuppression may decrease the incidence of mixed chimerism.