Successful Elosulfase Alfa Desensitization Protocol in a Patient With Morquio A Syndrome

Morquio A syndrome is a rare subtype of type IV mucopolysaccharide storage disease that is inherited in an autosomal recessive manner. In this type of lysosomal storage disease, there is a deficiency of N-acetylgalactosamine-6-sulfate sulfatase that leads to the accumulation of glycosaminoglycans, keratan sulfate, and chondroitin sulfate in the lysosomes of different tissues, mainly in cartilage, bone, and ligaments. Patients usually develop short stature, kyphoscoliosis, hypermobile joints, and other skeletal deformities. Deformities of the chest can restrict lung and heart function and patients may eventually die of respiratory failure. Hearing loss, weakness, and arthritis are also common. Patients typically have normal early development and intelligence.^1,2  Depending on the region of the world, prevalence is estimated to be ∼1 of 40 000 to 1 of 200 000 births worldwide.^1,2,3  There are several therapies for mucopolysaccharide storage disease that have been considered, including enzyme replacement therapy (ERT), gene therapy, substrate reduction therapy, and hematopoietic stem cell transplant. Unfortunately, therapeutic options are not able to reverse bone deformities.^1–4  Currently, the only Food and Drug Administration– approved treatment is ERT, of which there is only one product available on the market (elosulfase alfa or Vimizim), a recombinant human N-acetylgalactosamine-6-sulfate sulfatase.⁴ 

The development of adverse reactions including anaphylaxis poses a challenge in terms of treatment options, especially when there is only one drug available. In these cases, rapid drug desensitization is required. To our knowledge, there are only 2 published protocols on elosulfase alfa desensitization, but these protocols may not work on all patients.^5,6  Both protocols were attempted with our patient, albeit unsuccessfully. Given the positive impact on the quality of life that ERT provided her, we aimed to create a successful desensitization protocol for our patient, with the goal of providing the ERT according to the manufacturer’s recommendations.

We present a case of a now 22-year-old White, non-Hispanic female patient with Morquio A syndrome, allergic rhinitis, and moderate persistent asthma, who was started on weekly home elosulfase alfa infusions at 17 years of age. Written consent was obtained from the patient to publish her case. At 19 years of age, she presented to the emergency department with symptoms of lip edema, generalized hives, wheezing and dyspnea, 30 minutes into her home infusion. Symptoms were treated with intravenous diphenhydramine and intramuscular epinephrine. Her differential included infusion reaction versus possible anaphylaxis. Tryptase was not obtained at the time. Two subsequent infusions took place in the outpatient infusion center, and she was premedicated with diphenhydramine, hydrocortisone, and ranitidine with a slower infusion rate. Despite these interventions, she continued to develop hives, lip edema and respiratory symptoms 30 minutes into the infusion and was diagnosed with anaphylaxis. She was admitted in August 2018 for an elosulfase alfa desensitization by using the previously published protocol by Guvenir et al.⁵  However, she developed generalized hives at the cumulative dose of 0.881 mg (step 9).

A previously published 20-step desensitization protocol by Arroabarren et al⁶  was also attempted, which implemented omalizumab 300 mg subcutaneous. She only received omalizumab every 2 weeks from October 2018 to February 2019, but, despite this, she continued to have reactions with desensitization attempts. The patient was seen in the allergy clinic in July 2019, and skin testing was performed for elosulfase alfa, which demonstrated a poor histamine response and negative skin test result for elosulfase alfa, despite avoidance of all histamine suppressing medications. The previous administration of omalizumab may have potentially influenced the skin test results. The patient had been previously prescribed fluticasone propionate 176 μg per day and daily montelukast 10 mg for her asthma management. She did not report oral steroid bursts or emergency department visits due to asthma exacerbations in the previous 12 months. The patient did report symptoms of dyspnea and cough with minimal exertion and nocturnal cough 2 to 3 times per month. Spirometry performed July 2019 revealed the following results: pre–forced vital capacity (FVC): 106%; pre–forced expiratory volume in 1 second (FEV₁): 62%; pre–FEV₁ to FVC: 89%; pre–forced expiratory flow (FEF) 25%–75%: 38%; post-FVC: 112%; post-FEV₁: 68%; post–FEV₁ to FVC: 93%; post-FEF 25%–75%: 66%. On the basis of symptom history and spirometry findings, she was placed on fluticasone propionate 440 μg per day. Repeat spirometry testing demonstrated improvement in lung function after treatment modification (pre-FVC: 123%; pre-FEV₁: 75%; pre–FEV₁ to FVC: 94%; pre-FEF 25%–75%: 67%; post-FVC: 124%, post-FEV1: 74%; post-FEV1 to FVC: 92%; post-FEF 25%–75%: 83%). In August 2019, a new 18-step protocol (Supplemental Table 3) was attempted while taking daily cetirizine, ranitidine, and montelukast at home one week before admission. Of note, her asthma and allergic rhinitis were well controlled before desensitization. She developed generalized hives at the cumulative dose of 1.852 mg (step 12), despite premedications with cetirizine 10 mg, methylprednisolone 1 mg/kg, ranitidine 150 mg, montelukast 10 mg, and albuterol 4 puffs, 30–60 minutes before starting the desensitization. It was noted that in other patients who suffer from lysosomal storage diseases, longer infusion times would be required for successful rapid drug desensitization because the role of the lysosomes are compromised, and the mechanisms involved in rapid drug desensitization in these patients are not well understood.⁷ 

Given the patient's frequent reactions, despite premedications and use of the previously published protocols, we created a modified 18-step, 4-bag desensitization protocol (Table 1), which consisted of restarting omalizumab 300 mg subcutaneous every 2 week, followed by home premedications (cetirizine, famotidine, and montelukast) 1 week before the desensitization and premedications (cetirizine, famotidine, montelukast, methylprednisolone, and albuterol) 30–60 minutes before starting the protocol. Additionally, starting at step 15 of this protocol the infusion duration was increased from 15 minutes to 30 minutes, and steps 16 and 17 were increased to 60 minutes, and she was also given cetirizine 5 mg before starting bags 2, 3, and 4. Using this approach, the patient developed only skin pruritus around the intravenous site at the cumulative dose of 0.822 mg (step 14, bag 4). The symptom was treated with diphenhydramine and the 18-step, 4-bag protocol was successfully resumed and completed. To prevent future reactions using the 18-step, 4-bag protocol, we increased the infusion duration from 15 minutes to 30 minutes starting at step 13 (Bag 4) (Table 2). We continued her on this protocol weekly for 3 months, while she continued daily cetirizine, famotidine, and montelukast at home and bimonthly omalizumab. Thereafter, we removed one step of the protocol every week until we achieved a 1-bag, 7-step protocol that was in accordance with the manufacturer's infusion recommendations for weekly elosulfase alfa infusions.

ERT continues to be the only Food and Drug Administration–approved treatment option for patients with Morquio A syndrome, which means that desensitization is the only treatment option for patients experiencing hypersensitivity reactions to elosulfase alfa. To our knowledge, there have been only 2 previously published protocols for elosulfase alfa desensitization, which may not always work for all patients. We report a novel desensitization protocol for elosulfase alfa. Our case highlights the importance of tailoring treatment and providing alternative desensitization protocols when managing patients experiencing allergic reactions to a medication. Patients with a lysosomal storage disease may require longer infusion rates⁷  and additional premedications throughout the desensitization. The addition of omalizumab allows for successful desensitization in these patients. More importantly it calls attention to the need for more research and development of other treatment options for these patients to further support their quality of life.