Reduced intensity and reduced toxicity conditioning regimens offer low rates of toxicities and superior survival for patients with inborn errors of immunity undergoing allogeneic HCT. However, these approaches can be associated with increased rates of mixed chimerism and secondary graft loss. Day 0 alemtuzumab levels of 0.15-0.9 μg/mL minimize the risks of acute GVHD, clinically significant mixed chimerism, and secondary graft failure. We hypothesized that model-informed precision dosing of alemtuzumab with therapeutic concentration intervention (precision alemtuzumab dosing) could achieve target Day 0 alemtuzumab levels of 0.15-0.9 ug/mL in >80% of patients.
Prospectively enrolled patients were given model-informed initial alemtuzumab dosing of 10 mg/m2 divided over Days -14 to -12. Alemtuzumab levels were measured through Day -5 or -4. Individual PK profiles were estimated using MW/Pharm software (version 2.4) based on our previously reported population PK model. Patients who were projected to clear alemtuzumab by Day 0 to <0.15 ug/mL were given additional model-informed individualized “top-up” alemtuzumab dosing on Day -3 or -2 (Figure 1).
Twenty patients of median age 1.5 years (range 3 months-23 years) were treated. The underlying diagnoses included HLH (n = 10), sJIA (n = 5), WAS (n = 2), XMEN (n = 1), CGD (n = 1), and SCID (n = 1). Sixteen patients received fludarabine, melphalan, and thiotepa, and 4 patients received busulfan and fludarabine in addition to alemtuzumab. Sixteen patients (80%) achieved Day 0 alemtuzumab levels within the optimal therapeutic range of 0.15-0.9 μg/mL. Fifteen patients were evaluable for Day +100 outcomes. One patient developed acute grade I GVHD. Six patients (40%) experienced mixed chimerism, predominantly in the T cell lineage as is typical of alemtuzumab-containing RTC preparative regimens. Five of these patients maintained myeloid chimerism >97% and one patient who had reactivated HLH during conditioning experienced clinically significant mixed chimerism in all lineages and subsequent secondary graft failure.
Precision alemtuzumab dosing is feasible and results in target range achievement in 80% of patients compared with only approximately 25% of patients treated with standard-of-care alemtuzumab dosing regimens. Use as part of reduced toxicity conditioning approaches appears to result in low rates of acute GVHD, clinically significant mixed chimerism, and secondary graft failure at Day +100.
