Clinical Utility of Pegaspargase in Children, Adolescents and Young Adult Patients with Acute Lymphoblastic Leukemia: A Review

Figures & data

Table 1 Pediatric Acute Lymphoblastic Leukemia Trials with Pegaspargase Associated Objectives

Cooperative Group/Study	Enrollment Period (N)	Asparaginase Objective(s)	Asparaginase Associated Findings
Upfront studies
DFCI 91–01^Citation3	1991–1995 (377)	ASP intensification	Intensification improves outcomes
		PEG (IM) vs. L-asp (IM)	No significant difference in EFS with ASP preparation
CCG 1962^Citation24	1997–1998 (187)	PEG (IM) vs. L-asp (IM)	PEG: increased clearance of blasts, decreased antibodies
AIEOP ALL 2000^Citation50	2002 (20)	PEG (IV) as first line therapy	Adequate SAA and ASN depletion
DFCI 05–001^Citation33	2005–2010 (463)	PEG (IV) vs. L-asp (IM)	PEG: increased ASP course completion success and increased SAA No significant difference in DFS with ASP preparation
COG AALL07P4^Citation34,Citation38	2008–2010 (166)	PEG (IV) vs. CALASP (IV)	CALASP: prolonged SAA
DFCI 11–001^Citation39	2012–2015 (230)	PEG (IV) vs. CALASP (IV)	CALASP: prolonged SAA
Relapsed studies
CCG 1941^Citation18	1995–1998 (93)	PEG (IM) in relapse	Decreased ASN led to increased second remission
CHMC 1001^Citation51	1997–2001 (28)	PEG (IM) in relapse	Adequate SAA and ASN depletion

Abbreviations: DFCI, Dana-Farber Cancer Institute; CCG, Children’s Cancer Group; AIEOP, Associazione Italiana di Ematologia e Oncologia Pediatrica; COG, Children’s Oncology Group; CHMC, Children’s Hospital and Regional Medical Center; PEG, pegaspargase; L-asp, L-asparaginase; CALASP, calaspargase; ASP, asparaginase; IM, intramuscular; IV, intravenous; EFS, event-free survival; DFS, disease-free survival; SAA, serum asparaginase activity level; ASN, asparagine.

Table 2 Standard Risk B-ALL Regimen (Adapted from Children’s Oncology Group AALL0932)

Phase	Chemotherapy Agents	Schedule
Induction (35 days)	Dexamethasone PO	Days 1–28
	Vincristine IV	Days 1, 8, 15, 22
	Pegaspargase IV	Day 4
	Cytarabine IT	Day 1 (CNS2 require more)
	Methotrexate IT	Days 8, 29
Consolidation (28 days)	Mercaptopurine PO	Days 1–28
	Vincristine IV	Day 1
	Methotrexate IT	Days 1, 8, 15
Interim Maintenance (IM 1) (56 days)	Vincristine IV	Days 1, 11, 21, 31, 41
	Methotrexate IV (escalating dose)	Days 1, 11, 21, 31, 41
	Methotrexate IT	Day 31
Delayed Intensification (56 days)	Dexamethasone PO	Days 1–7 and 15–21
	Thioguanine PO	Days 29–42
	Vincristine IV	Days 1, 8, 15
	Doxorubicin IV	Days 1, 8, 15
	Pegaspargase IV	Day 4
	Cyclophosphamide IV	Day 29
	Cytarabine IV	Days 29–32 and 36–39
	Methotrexate IT	Days 1, 29
Interim Maintenance (IM 2) (56 days)	Vincristine IV	Days 1, 11, 21, 31, 41
	Methotrexate IV (escalating dose)	Days 1, 11, 21, 31, 41
	Methotrexate IT	Days 1, 31
Maintenance (12-week cycles for 2 years from IM 1)	Dexamethasone PO	Days 1–5, 29–33, and 57–61
	Mercaptopurine PO	Days 1–84
	Methotrexate PO	Weekly starting Day 8
	Vincristine IV	Days 1, 29, 57
	Methotrexate IT	Day 1

Abbreviations: PO, oral; IV, intravenous; IT, intrathecal; CNS, central nervous system.

Table 3 High-Risk B and T-ALL Regimens (Adapted from Children’s Oncology Group AALL1131, AALL0431)

Phase	Chemotherapy Agents	Schedule
Induction (35 days)	Dexamethasone PO (< 10 years of age)^a	Days 1–14
	Prednisone PO (≥ 10 years of age)^a	Days 1–28
	Vincristine IV	Days 1, 8, 15, 22
	Daunorubicin IV	Days 1, 8, 15, 22
	Pegaspargase IM/IV	Day 4
	Cytarabine IT	Day 1 (B-ALL CNS2 require more)
	Methotrexate IT	Days 8, 29 (also Days 15, 22 for CNS3)
Consolidation^b (56 days for B-ALL; 77 days for T-ALL)	Mercaptopurine PO	B-ALL: Days 1–14 and 29–42
		T-ALL: Days 8–21 and 50–63
	Cyclophosphamide IV	B-ALL: Days 1, 29
		T-ALL: Days 8, 50
	Cytarabine IV	B-ALL: Days 1–4, 8–11, 29–32, 36–39
		T-ALL: Days 8–11, 15–18, 50–53, 57–60
	Vincristine IV	B-ALL: Days 15, 22, 43, 50
		T-ALL: Days 22, 29, 64, 71
	Pegaspargase IM/IV	B-ALL: Days 15, 43
		T-ALL: Days 22, 64
	Methotrexate IT	B-ALL: Days 1, 8, 15, 22
		T-ALL: Days 15, 22, 57, 64 (CNS3 omit d22)
Interim Maintenance (IM)^c (63 days for B-ALL; 56 days for T-ALL)	Mercaptopurine PO	B-ALL only: Days 1–56
	Vincristine IV	B-ALL: Days 1, 15, 29, 43
		T-ALL: Days 1, 11, 21, 31, 41
	High Dose Methotrexate IV	B-ALL only: Days 1, 15, 29, 43
	Escalating Dose Methotrexate IV	T-ALL only: Days 1, 11, 21, 31, 41
	Methotrexate IT	B-ALL: Days 1, 29
		T-ALL: Days 1, 31
	Pegaspargase IV/IM	T-ALL only: Days 2, 22
Delayed Intensification (56 days for B-ALL; 63 days for T-ALL)	Dexamethasone PO	Days 1–7 and 15–21
	Thioguanine PO	B-ALL: Days 29–42
		T-ALL: Days 36–49
	Vincristine IV	Days 1, 8, 15, 43, 50 (T-ALL omit d43)
	Doxorubicin IV	Days 1, 8, 15
	Pegaspargase IM/IV	B-ALL: Days 4, 43
		T-ALL: Days 4, 50
	Cyclophosphamide IV	Day 29
	Cytarabine IV	Days 29–32 and 36–39
	Methotrexate IT	Days 1, 29, 36 (T-ALL d29 given on d43)
Maintenance^d (12-week cycles for 2 years from IM)	Prednisone PO	Days 1–5, 29–33, and 57–61
	Mercaptopurine PO	Days 1–84
	Methotrexate PO	Weekly starting Day 8
	Vincristine IV	Days 1, 29, 57
	Methotrexate IT	B-ALL: Days 1, 29 (first 4 cycles only) T-ALL: Day 1 only

Notes: ^aT-ALL patients receive prednisone only Days 1–28. ^bT-ALL patients receive nelarabine Days 1–5 and 43–47. ^cT-ALL patients receive nelarabine on Days 29–33. ^dT-ALL patients receive an additional 3 cycles of nelarabine-based therapy prior to the start of maintenance (each cycle 84 days).

Abbreviations: PO, oral; IM, intramuscular; IV, intravenous; IT, intrathecal; CNS, central nervous system.

Table 4 Relapse ALL Regimen (Adapted from UKALLR3)

Phase	Chemotherapy Agents	Schedule
Induction (28 days)	Dexamethasone PO	Days 1–5, 15–19
	Vincristine IV	Days 3, 10, 17, 24
	Mitoxantrone IV	Days 1, 2
	Pegaspargase IM/IV	Days 3, 18
	Methotrexate IT	Days 1, 8 (also Days 15, 22 for CNS3)
Consolidation (28 days)	Dexamethasone PO	Days 1–5
	Vincristine IV	Day 3
	Methotrexate IV	Day 8
	Pegaspargase IM/IV	Day 9
	Cyclophosphamide IV	Days 15–19
	Etoposide IV	Days 15–19
	Methotrexate IT	Day 8
Intensification (28 days)	Dexamethasone PO	Days 1–5
	Vincristine IV	Day 3
	Cytarabine IV, every 12 hours	Days 1, 2, 8, 9
	Erwinia ASP IM	Days 2, 4, 9, 11, 23
	Methotrexate IV	Day 22
	Methotrexate IT	Days 1, 22
Before SCT	Fludarabine IV	Days 1–5
	Cytarabine IV	Days 1–5
	Liposomal Daunorubicin IV	Day 1
Before Maintenance^a (weeks 14–29)	Dexamethasone PO	Days 1–5, 57–61
	Vincristine IV	Days 3, 59
	6-mercaptopurine PO	Days 1–42, 57–98
	Methotrexate PO	Days 10, 17, 31, 38, 67, 74, 88, 95
	Etoposide IV	Days 42, 49, 99, 106
	Cyclophosphamide IV	Days 42, 49, 99, 106
	Cytarabine IV	Days 43–46, 50–53, 100–103, 107–110
	Methotrexate IT	Days 1, 43, 57, 99
Maintenance^a (4-week cycles from weeks 30–104)	Dexamethasone PO	Days 1–5
	Mercaptopurine PO	Days 1–28
	Methotrexate PO	Weekly
	Vincristine IV	Day 1
	Methotrexate IT	Day 1

Note: ^aPhase given to patients who did not go to SCT.

Abbreviations: PO, oral; IV, intravenous; IM, intramuscular; IT, intrathecal; CNS, central nervous system; SCT, stem cell transplant; ASP, asparaginase.

Table 5 Relapse ALL Regimen* (Adapted from VXLD Re-Induction)

Phase	Chemotherapy Agents	Schedule
Induction (28 days)	Dexamethasone PO	Days 1–14
	Vincristine IV	Days 1, 8, 15, 22
	Doxorubicin IV	Day 1
	Pegaspargase IM/IV	Days 2, 16
	Methotrexate IT	Day 1
	Cytarabine IT	Day 1
Consolidation^a (28 days)	Dexamethasone PO	Days 1–5
	Vincristine IV	Day 3
	Methotrexate IV	Day 8
	Pegaspargase IM/IV	Day 9
	Cyclophosphamide IV	Days 15–19
	Etoposide IV	Days 15–19
	Methotrexate IT	Day 8
Consolidation^b (56 days)	Mercaptopurine PO	Days 1–14 and 29–42
	Cyclophosphamide IV	Days 1, 29
	Cytarabine IV	Days 1–4, 8–11, 29–32, and 36–39
	Vincristine IV	Days 15, 22, 43, 50
	Pegaspargase IM/IV	Days 15, 43
	Methotrexate IT	Days 1, 8, 15, 22

Notes: *Regimen used as backbone for relapsed ALL after window with novel agents eg, Bortezomib, Carfilzomib, Pevonedistat, Daratumumab, Blinatumomab, and Nivolumab. ^{a, b} Depending on study protocol. ^bConsolidation based on modified BFM.

Abbreviations: VXLD, vincristine, dexamethasone, pegaspargase, doxorubicin; PO, oral; IV, intravenous; IM, intramuscular; IT, intrathecal.

Figure 1 Pegaspargase toxicity. *Due to lack of reported percentages for specific toxicities, hyperglycemia is not included.

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