Effectiveness of premedication and rapid desensitization in hypersensitivity to L-asparaginase

Da Hye Yoon; Sung Hee Kang; Hwan Soo Kim; Jae Wook Lee; Jong-Seo Yoon; Nack Gyun Chung; Bin Cho

doi:10.4168/aard.2015.3.4.288

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Yoon, Kang, Kim, Lee, Yoon, Chung, and Cho: Effectiveness of premedication and rapid desensitization in hypersensitivity to L-asparaginase

Original Article

Allergy, Asthma & Respiratory Disease 2015; 3(4): 288-293.

Published online: 28 July 2015

DOI: https://doi.org/10.4168/aard.2015.3.4.288

Effectiveness of premedication and rapid desensitization in hypersensitivity to L-asparaginase

Da Hye Yoon, Sung Hee Kang, Hwan Soo Kim

, Jae Wook Lee, Jong-Seo Yoon, Nack Gyun Chung, Bin Cho

Department of Pediatrics, The Catholic University of Korea College of Medicine, Seoul, Korea.

Correspondence to: Hwan Soo Kim. Department of Pediatrics, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Korea. Tel: +82-2-961-4530, Fax: +82-2-537-4544, tibia78@nate.com

Received 23 December 2014 Revised 17 June 2015 Accepted 18 June 2015

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).

Abstract

Purpose

L-asparaginase is a crucial chemotherapeutic agent for the treatment of acute lymphoblastic leukemia. However, hypersensitivity to L-asparaginase is common which limits its clinical use.

Methods

We performed 44 cases of premedication and 3 cases of desensitization in 16 patients with hypersensitivity to L-asparaginase.

Results

With premedication, 33 cases completed L-asparaginase injection with no hypersensitivity reactions. Eleven cases showed mild hypersensitivity reactions, such as urticaria. Desensitization was performed in 3 cases: in 2 cases, desensitization was successful, and in 1 case the medication was switched to Erwinia asparaginase.

Conclusion

Premedication and desensitization appear to be useful in helping patients receive desired doses of L-asparaginase in pediatric patients with acute lymphoblastic leukemia.

Keywords: Asparaginase, Drug hypersensitivity, Premedication, Immunologic desensitization, Acute lymphoblastic leukemia

Figures and Tables

Fig. 1

Protocol for management of L-asparaginase hypersensitivity. IM, intramuscular.

Fig. 2

Flow chart of study population.

Table 1

Definition of adverse event according to common terminology criteria for adverse event

	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Allergic reaction	Transient flushing or rash, drug fever < 38℃; intervention not indicated	Intervention or infusion interruption indicated; responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic medications indicated for < 24 hours	Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates)	Life-threatening consequences; urgent intervention indicated	Death
Anaphylaxis	-	-	Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy-related edema/angioedema; hypotension	Life-threatening consequences; urgent intervention indicated	Death

NSAID, nonsteroidal anti-inflammatory drug.

Table 2A

Example of desensitization protocol for asparaginase (7,000 IU)

Total dose	Solution component (asparaginase/vol)	Solution concentration (IU/mL)	Total dose in each solution (IU)
Solution A	15 IU/15 mL	1.0	15
Solution B	240 IU/24 mL	10.0	240
Solution C	6,745 IU/84.31 mL	80.0	6,745

Table 2B

Stepwise doubling of doses for asparaginase (7,000 IU)

Step No.	Solution No.	Rate (mL/hr)	Time (min)	Volume infused per step (mL)	Administered dose (IU)	Cumulative dose (IU)
1	A	6	10	1	1	1
2	A	12	10	2	2	3
3	A	24	10	4	4	7
4	A	48	10	8	8	15
5	B	9.6	10	1.6	16	31
6	B	19.2	10	3.2	32	63
7	B	38.4	10	6.4	64	127
8	B	76.8	10	12.8	128	255
9	C	19.2	10	3.2	256	511
10	C	38.4	10	6.4	512	1,023
11	C	76.8	10	12.8	1,024	2,047
12	C	153.6	10	25.6	2,048	4,095
13	C	217.9	10	36.3	2,905	7,000

Total dose in solution C is calculated by subtracting the cumulative dose administered in steps 1-8 from the total desired dose. Solutions were prepared by the Pharmacy Department Cytotoxic Unit and then spiked at bedside by the specialized nursing staff with an individual infusion line.

Table 3

Characteristics of study population (n=16)

Characteristic	Value
Male sex	11 (68.8)
Age (yr)	8.1±4.5
Immunophenotype
B lineage	14 (87.5)
T lineage	2 (12.5)
Mixed lineage	0 (0)
Risk status of leukemia
Low	2 (12.5)
Standard	2 (12.5)
High	9 (56.3)
Very high	3 (18.8)
Blood eosinophil (%)	1.7±2.8 (0.7-10.0)

Values are presented as number (%) or mean±standard error of the mean (range).

Table 4

Clinical and laboratory characteristics of the patients with L-asparaginase hypersensitivity

Case	Sex	Age (yr)	Blood eosinophil (%)	Dose (IU/m²)	Previous doses of asparginase (time)	Asparaginase injection related symptoms after premedication	Hypersensitivity reaction (grade)	Desensitization	Asparaginase injection related symptoms after desensitization	Completion
1	F	14	0.17	10,000	6	None	0	No
2	M	9	1.48	6,000	9	None	0	No
3	M	4	1.00	4,000	3	None	0	No
4	F	4	2.33	4,400	3	Urticaria (mild)	1	Yea	Urticaria (moderate)	Yes
5	F	12	0	8,500	2	None	0	No
6	M	11	4.20	8,000	5	None	0	No
7	M	5	10.00	4,500	1	Tenderness on injection site, urticaria (mild)	1	No
8	M	10	0.67	7,000	3	Urticaria (mild)	1	Yea	Urticaria (mild)	Yes
9	F	4	2.33	4,200	3	None	0	No
10	F	3	0.70	3,800	1	None	0	No
11	M	15	1.00	10,000	1	None	0	No
12	M	11	2.20	8,000	6	None	0	No
13	M	3	0.10	4,000	2	Urticaria (mild)	1	Yea	Chilling	Switch to Erwinase
14	M	16	0.35	10,000	2	None	0	No
15	M	3	5.50	4,000	3	Urticaria (mild)	1	No
16	M	1	0.87	3,000	3	Flushing on face	1	No

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ORCID iDs: Hwan Soo Kim
https://orcid.org/http://orcid.org/0000-0002-5952-7849
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