Novel approach to idursulfase and laronidase desensitization in type 2 and type 1 S mucopolysaccharidosis (MPS)

Abstract

Background: Idursulfase and laronidase are drugs used to treat Hunter syndrome (mucopolysaccharidosis type 2) and Scheie syndrome (mucopolysaccharidosis type 1 S), respectively. These are rare lysosomal storage disorders, leading to accumulation of glycosaminoglycans within lysosomes. Failure of early recognition of the disease and/or delay in starting the appropriate treatment result in severe clinical impairment and death. For almost 20 years, enzyme replacement therapy with recombinant proteins has represented the first line therapeutic option. However, administration of idursulfase and laronidase is associated with infusion-related hypersensitivity reactions, in approx. 20% of patients. In these patients, rapid desensitization by intravenous administration protocols has been used in order to avoid treatment discontinuation. This approach proved effective and safe. However, long-term tolerance could not be achieved. Thus, we decided to combine rapid desensitization with allergen immunotherapy-like desensitization. Results: Two patients with Hunter syndrome and one patient with Scheie syndrome developed severe allergy to idursulfase and laronidase, respectively, preventing them from continuing the otherwise indispensable therapy. In all three patients, the possible IgE-mediated nature of the reactions suffered was suggested by positive skin tests with the two enzymes, respectively. By devising 12-step, 3-dilution rapid desensitization protocols, we resumed the enzyme replacement therapy. However, the prolonged time required for administration (a not negligible pitfall, since therapy should be given weekly for life) and the persistent occurrence of reactions (mild but still requiring anti-allergic medication at full dosage) led us to combine rapid desensitization with a compact 11-step, 24-day allergen immunotherapy-like desensitization protocol. Thus, idursulfase and laronidase were injected subcutaneously, with a 500-fold increase from step 1 to step 11 for idursulfase and a 222-fold increase for laronidase. This strategy led to restoration of long-term tolerance, allowing weekly intravenous therapy administration under standard conditions, according to the manufacturer instructions, in the absence of side effects and with only precautionary low-dose premedication. Conclusion: Rapid desensitization is a suitable and safe option in the case of idursulfase and laronidase allergy. Combination with subcutaneous allergen immunotherapy-like desensitization afforded restoration of enzyme replacement therapy given by the normal administration schedule, by inducing sustained tolerance.

Desensitization of olipudase alfa-induced anaphylaxis in a child with chronic neurovisceral acid sphingomyelinase deficiency

“…[ 32 ] Therefore, subcutaneous allergen immunotherapy-like desensitization has been suggested in addition to rapid desensitization to obtain sustained tolerance. [ 33 ] Moreover, the application of the desensitization protocol proposed by Castells et al for chemotherapy drugs (2008) [ 34 ], including the administration of diphenhydramine, ranitidine, montelukast, acetaminophen and methylprednisolone during the infusion to block different allergy pathways, adapted for laronidase has been demonstrated to be safe and effective. [ 35 ]…”

Hypersensitivity reaction during enzyme replacement therapy in lysosomal storage disorders. A systematic review of desensitization strategies

“…19 When rapid desensitization is not effective (interruption for severe HR) or it is necessary to rapidly shorten the duration of infusion, the AIT-like desensitization protocol was implemented for idursulfase and laronidase (three patients in this review) with success, representing an effective and safe solution. 20 Furthermore, this approach is deemed to confer a long-lasting tolerance to the culprit recombinant enzyme allowing the ERT under standard infusion protocol. More information about the underlying HR mechanism is needed, but we can speculate that it could be similar to desensitization to Hymenoptera venom allergy, as already mentioned.…”