<div>OMALIZUMAB MAY FACILITATE DRUG DESENSITIZATION IN PATIENTS FAILING
STANDARD PROTOCOLS</div><div>To the Editor,</div><div>Nephrotic syndrome (NS) is a common glomerular disorder in children, for
which steroids are the first-line treatment. While most children with NS
respond to steroid therapy, 20% of children are resistant to steroids.
Some children with steroid-responsive NS develop a frequently relapsing
or steroid-dependent course and experience significant side effects of
steroid therapy. Alternative medications such as calcineurin inhibitors,
mycophenolate mofetil, cyclophosphamide, and rituximab, an anti-CD20
monoclonal antibody, are being considered for such patients with
difficult-to-treat NS (1,2).</div><div>Hypersensitivity reactions to monoclonal antibodies are quite limited in
clinical practice, such as the release of cytokines that occur during
intravenous infusion. However, IgE-mediated reactions may also occur.
Life-threatening IgE-mediated reactions such as anaphylaxis lead to
discontinuation of treatment or conversion to a less beneficial
treatment. Rapid drug desensitization (RDD) is a therapeutic option that
allows continuation of treatment with the causative drug (3). Omalizumab
is a recombinant humanized anti-IgE monoclonal antibody. Treatment
indications include severe asthma and idiopathic chronic urticaria.
However, the efficacy of omalizumab has also been described in food
allergy, as a bridge to oral immunotherapies, atopic dermatitis,
idiopathic anaphylaxis, and mastocytosis (4). Previous studies have
reported the use of omalizumab for rapid desensitization to
chemotherapeutic agents (5). Here, we describe a patient with
steroid-resistant NS who developed anaphylaxis on the first infusion of
rituximab and subsequent type 1 hypersensitivity reactions during
desensitization trials with rituximab using 12-, 16-, and 20-step
protocols.</div><div>A 4-year-old boy diagnosed with steroid-resistant NS and unresponsive to
calcineurin inhibitors, either cyclosporine A or tacrolimus, and in
their combination with mycophenolate mofetil, received rituximab. After
premedication with methylprednisolone at a dose of 2 mg/kg, rituximab
375 mg/m<sup>2</sup> was administered intravenously. During the
infusion, he developed anaphylaxis (vomiting and dyspnea). The infusion
was stopped and intramuscular epinephrine was administered, and a
12-step rapid desensitization protocol was planned for further infusions
(Table 1). He was premedicated with H1 blockers and systemic steroids.
However, the patient developed breakthrough reactions (urticaria) that
required additional antihistamines at the 4th step. Infusion was resumed
at a slower rate. Ten minutes after re-administration, generalized
urticaria and angioedema developed. Montelukast was administered
according to ENDA/EAACI recommendations for rapid desensitization in
drug allergy (6). After 7 days, the protocol was modified to administer
375 mg/m<sup>2</sup> rituximab in 16 steps with premedication
(Table 2). The patient developed generalized urticaria and angioedema
again at the 4th step. The next week, the desensitization protocol was
designed with 375 mg/m<sup>2</sup> rituximab in 20 steps (Table
3). Again, generalized urticaria and angioedema occurred in the 2nd
step. A skin prick test was performed 3 weeks after the initial
reaction. During the skin prick test, the patient developed generalized
urticaria.</div><div>In the absence of alternative treatment options for NS, desensitization
with omalizumab treatment was suggested to prevent hypersensitivity
reactions to rituksimab. Omalizumab (patient weight: 17.5 kg; total
IgE:71 UI /ml; dose: 150 mg/ every 2 weeks) was added to treatment. The
last omalizumab dose was administered 1 day before the following
desensitization. After premedication, 375 mg/m<sup>2</sup>rituximab was administered in 20 steps. In the 5th step, the patient
developed local urticaria requiring an antihistamine. The infusion was
resumed and successfully completed. Under omalizumab treatment, the
patient was administered 375 mg/m<sup>2</sup> rituximab for the
second time in a 20-step protocol. After the 6th dose, the interval of
omalizumab treatment was changed to every 4 weeks. The rituximab dose
was then increased to 750 mg/m<sup>2</sup> at the third infusion.
After premedication, the 20-step desensitization protocols were
successfully applied in the following days.</div><div>Rituximab is a chimeric monoclonal antibody that targets the CD20
antigen on the surface of B cells and causes elimination of B
lymphocytes by complement- and antibody-dependent cellular cytotoxicity
for 6-12 months (2). Efficacy has also been demonstrated in the
treatment of steroid-resistant NS (7). Rituximab is one of the most
common biologic agents with infusion-related reactions.
Rituximab-associated hypersensitivity reactions can be classified as
infusion-related reactions, cytokine release,
IgE-mediated/non-IgE-mediated hypersensitivity reactions, mixed
reactions, type 3 and type 4 hypersensitivity reactions (8).</div><div>Omalizumab is a recombinant humanized IgG1 monoclonal antibody and
prevents degranulation in effector cells by specifically binding to the
FceRI receptor site of free IgE, causing a decrease in the level of free
IgE in serum, and causing downregulation of FceRI receptors (9).
Omalizumab has previously been used as a co-adjuvant in RDD along with
insulin, the enzyme elosulfase alpha, chemotherapeutic agents, and
aspirin (9). In a randomized, double-blind, placebo-controlled trial by
Lang et al, desensitization was achieved after 16 weeks treatment with
omalizumab. In other case reports, omalizumab treatment was generally
started 7-14 days before RDD; only in one case report was the first
omalizumab dose given 4 days before RDD (9). In previous studies,
omalizumab dosing in allergic asthma was based on patient weight and
total IgE. In our case, we administered 6 doses of omalizumab (150
mg/dose) every two weeks before desensitization and continued treatment
once a month until completion of rituximab therapy. In patients with
successful RDD on omalizumab, RDD steps can be reduced on subsequent
infusions. Arroaberran et al. (10) presented a patient who tolerated
elosulfase alpha enzyme without desensitization after omalizumab
treatment.</div><div>In conclusion, omalizumab may facilitate desensitization protocols and
allow continuation of the preferred treatment.</div><div><sup>1</sup>Hatice Betul Gemici Karaaslan,</div>