Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

Figures & data

Figure 1. Simulation of serum asparaginase activity following repeated administration of intravenous (IV) and intramuscular (IM) asparaginase Erwinia chrysanthemi in two example patients.[17] Reproduced with permission from Albertsen et al. [17].

Table 1. Common symptoms of hypersensitivity and infusion reactions by body system.[27]

Body system	Common clinical manifestation
	Hypersensitivity reaction	Infusion reaction
Cardiovascular	Chest pain, palpitations, hypotension, tachycardia, bradycardia, arrhythmia, edema, ischemia or infarction, cardiac arrest	Hypertension, hypotension, tachycardia,
Central nervous system	Dizziness, loss of consciousness	Headache (throbbing in nature), confusion,loss of consciousness
Dermatologic	Pruritus, urticaria, local or diffuse erythema, conjunctival erythema, and tearing, angioedema	Flushing, rash, local, or diffuse erythema
Endocrine	Diaphoresis, fever, generalized feeling of warmth	Rigors, fever
Gastrointestinal	Nausea, vomiting, metallic taste, diarrhea, abdominal cramping, and bloating	Nausea, vomiting
Genitourinary	Renal impairment	Incontinence, uterine cramping, or pelvic pain
Musculoskeletal	Arthralgias, myalgias, tumor pain, hypotonia	Fatigue, hypotonia
Psychiatric	Anxiety, sense of impending doom	Anxiety, sense of impending doom
Respiratory	Cough, dyspnea, nasal congestion, rhinitis, sneezing, hoarseness, tachypnea, wheezing, chest tightness,hypoxemia, bronchospasm, reduced pulmonary expiratory flow, oropharyngeal or laryngeal edema, stridor,pulmonary infiltrates, cyanosis, acute respiratory distress syndrome	Dyspnea, tachypnea

Adapted with permission from Vogel [27].

Table 2. Prevalence of hypersensitivity reactions (any grade) across trials by the method of administration and type of asparaginase.

Study	Total patients, n	E. coli	PEG	Erwinia
IM administration
Salzer et al., 2015 [60]^a	2771	−	13.7	−
Maloney et al., 2015 [34]^a	NR	−	0.5%	−
Henriksen et al., 2015 [47]	615	−	12.8%	6%
Fernandez et al., 2014 [48]	1870	39%	11.4%	−
Vora et al., 2014 [58]	533	−	3.75%	−
Plourde et al., 2014 [49]	940	−	−	11.7%
Salzer et al., 2013 [24]	55	−	−	10.9%
Liu et al., 2012 [38]	410	41.2%	25.5%	12.5%
Vrooman et al., 2010 [50]	215	20%	−	33%
Silverman et al., 2011 [59]	231	9%	–	–
Chen et al., 2010 [51]	498	41%	−	−
Moghrabi et al., 2007 [52]	286	14.3%	−	5.8%
Wacker et al., 2007 [53]	540	75.6%	–	−
Zalewska-Szewczyk et al., 2007 [54]	47	36.2%	−	−
Albertsen et al., 2002 [55]	39	−	−	0%
Avramis et al., 2002 [23]	118	0%	3.7%	−
Abshire et al., 2000 [56]	144	−	4.2%	−
Woo et al., 2000 [14]	154	32.5%	−	19.4%
IV administration
Vrooman et al., 2016 [25]	30	−	−	37%
Aldoss et al., 2016 [46]	152	−	7.2%	−
Maloney et al., 2015 [34]^a	NR	−	1.8%	−
Salzer et al., 2015 [60]^a	1797	−	6.9%	−
Tong et al., 2014 [42]	89	−	22.5%	3.4%
Silverman et al., 2011 [59]	232	–	11%	–
Müller et al., 2001 [57]	76	23.7%	−	−

^aGrade 3–4 allergic reaction anaphylaxis only.

E coli: Escherichia coli asparaginase; PEG: pegylated E coli asparaginase; Erwinia: asparaginase Erwinia chrysanthemi; IM: intramuscular; NR: not reported; IV: intravenous.

Table 3. Summary of retrospective comparisons of the prevalence of hypersensitivity reactions with IV and IM PEG-asparaginase.

Asparaginase	Evaluable patients, n	Reaction (any grade), n (%)	Significance, p value	Study
PEG-ASNase	IM = 2771	IM = 379 (14)^a	IND = 0.10	Salzer et al., 2015 [60]
	IV = 1797	IV = 125 (7)^a	CON = 0.18
			DI = 0.07
PEG-ASNase	IM = NR	IM = NR (0.5)^a	.0007	Maloney et al., 2015 [34]
	IV = NR	IV = NR (1.8)^a
PEG-ASNase	IM = 69	IM = 8 (12)	.011	Abbott et al., 2015 [61]
	IV = 40	IV = 14 (35)
PEG-ASNase	IM = 159	IM = 17 (11)	.028	Petersen et al., 2014 [62]
	IV = 159	IV = 31 (20)
PEG-ASNase	IM = 77	IM = 2 (3)	.029	MacDonald et al., 2014 [64]
	IV = 51	IV = 7 (14)
PEG-ASNase	IM = 186	IM = 17 (9)	.019	Pidapardi and Bostrom, 2012 [63]
	IV = 11	IV = 4 (36)
PEG-ASNase	IM = 27	IM = 3 (11)	Non-significant (p value NR)	August et al., 2013 [8]
	IV = 16	IV = 2 (13)

^aGrade 3–4 allergic reaction anaphylaxis only.

ASNase: asparaginase; CON: consolidation; DI: delayed intensification; IM: intramuscular; IND: induction; IV: intravenous; NR: not reported; PEG: pegylated.

Figure 2. Suggested clinical pathway to classification and management of adverse reactions to asparaginase. E coli: Escherichia coli; LLQ: lower limit of quantification; M/W/F: Monday/Wednesday/Friday; PEG: pegylated.

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