ALPS like: Trekking Sirolimus and its Fallouts

Abstract

A three-year-old male presented to our multispecialty clinic with recurrent fever without periodicity, neutropenia, diffuse lymphadenopathy, and splenomegaly. Family history was notable for two maternal cousins with hypogammaglobulinemia and neutropenia. Pertinent labs include elevated CD3 positive, double negative cells (7.7%, 156 cells/mcl), elevated IL-10 (85.6 pg/mL); and elevated IL-18 (3145 pg/mL). Rheumatologic studies returned unremarkable (ANA was weakly positive, with extracted nuclear antigen antibody panel within normal limits). Abdominal ultrasound revealed splenomegaly (14 cm). Whole genome sequencing for the patient and parents was negative, including no diagnostic abnormalities in the FAS, FASLG or CASP10 genes.The patient was diagnosed with probable ALPS, per the 2009 revised ALPS criteria (Oliveira et al, Blood, 2010). He was started on colchicine for fevers but was transitioned to sirolimus several weeks later due to lack of clinical improvement. Mirroring a prior study that evaluated sirolimus for children with ALPS, sirolimus was initiated at a dose of 2.3 mg/m2, targeting goal trough levels 5–15 ng/mL (Bride et al. Blood, 2016). Sirolimus trough levels are depicted in Table 1 and Figure 1. [Display omitted] At follow up 3 months later, the patient’s CD3 positive, double negative T cells normalized (0.2%, 3 cells/mcl), splenomegaly improved (10.7 cm), lymphadenopathy was no longer palpable, and cytokine levels normalized. Despite consecutive subtherapeutic sirolimus trough levels preceding the 3-month evaluation, probable ALPS markers improved.Sirolimus has caused toxicity. Baseline lipid panel prior to sirolimus therapy demonstrated elevated triglycerides and low HDL, likely related to ALPS (Sriram et al, Case Reports Immunol, 2016). While HDL improved, total cholesterol and LDL increased and triglycerides remain elevated. He has developed hypertension while on sirolimus.These findings demonstrate that sirolimus trough alone may not predict clinical response. Given the excellent correlation between trough levels and area under the concentration-time curve (AUC) for sirolimus (Stenton et al. Clin Pharmacokinetics 2005), it is unlikely that AUC sirolimus measurements would either be of clinical benefit or better explain the patient’s clinical response. This patient’s excellent clinical response despite multiple subtherapeutic sirolimus trough levels suggests that further research to determine the optimal sirolimus trough range may be indicated.