Asparaginase in the Treatment of Acute Lymphoblastic Leukemia in Adults: Current Evidence and Place in Therapy

Figures & data

Figure 1 Depiction of the pharmacologic effects of asparaginase. Asparaginase catalyzes (top panel) the degradation of L-asparagine to L-aspartic acid and ammonia (NH₃). Unlike normal cells, which express asparagine synthetase, leukemic cells are unable to generate L-asparagine, so its serum depletion results in apoptosis (left panel). Toxicities due to asparaginase (right panel) occur through a variety of mechanisms including decreased protein synthesis, direct effects on metabolites, or more complex mechanisms. Therapeutic drug monitoring (TDM) may allow for individualized asparaginase dosing and maximization of treatment efficacy with reduction of toxicity, but this is not yet widely practiced. Created with BioRender.com.

Table 1 Pharmacokinetic Properties of L-Asparaginase Products

	E. coli Asparaginase (Native)	Pegaspargase	Calaspargase Pegol	Erwinia Asparaginase (Native)	Erwinia Asparaginase (Recombinant)
Common dose range	6000–25,000 IU/m^2	2000–2500 IU/m^2	2500 IU/m^2	25,000 IU/m^2	25 mg/m^2
Administration frequency	1–3x/week	Every 2 weeks	Every 3 weeks	3x/week	Every 48 hr
Bioavailability	IM: ~50% IV: 100%	IM: 82–98% IV: 100%	IV: 100%	IM: 37% IV: 100%	IM: 37%
Volume of distribution (L)	–	1.86–2	2.96	–	1.48
Half-life	IM: 34–49 hr IV: 8–30 hr	IM: 5.8 days IV: 5.3 days	IV: 16.1 days	IM: 16 hr IV: 7.5 hr	IM: 18.2 hr

Note: References: 22, 24, 25, 29, 32, 34.

Table 2 Selected Pediatric Studies Incorporating Asparaginase in ALL Treatment Regimens

Study (Design)	Enrollment Period	Age Range	Number (Evaluable)	Disease (Status)	Asparaginase Formulation	Treatment Phase and Dosing	Selected Outcomes	Selected Events Including Asparaginase-Related Toxicities
CCG 101/143 (Non-randomized prospective)	1971 – NR	< 16	823 (815)	ALL or AUL (untreated)	Native E. coli	Induction 6000 IU/m^2 IM 3/week (9 doses)	CR 93% versus 86% in CCG 903	Death during induction – 26 (3.2%) L-asparaginase discontinued due to associated toxicities – 2 (0.25%) L-asparaginase-related not requiring cessation – 35 (4.3%)  Hyperglycemia – 20 (2.5%)  Allergic reactions – 6 (0.74%)  Hypofibrinogenemia – 4 (0.49%)  Pancreatitis – 4 (0.49%)  Hepatotoxicity – 1 (0.12%)
DFCI 77–01 (Randomized prospective)	1977–1979	< 20	74 (72)	Non-T-cell ALL or AUL (untreated)	Native E. coli	Early consolidation (all patients) Age < 6: 50,000 IU/m^2 IV QOD Age ≥ 6: 25,000 IU/m^2 IV QOD (5 doses) Intensification (if randomized) Age < 6: 50,000 IU/m^2 IV weekly Age ≥ 6: 25,000 IU/m^2 IV weekly (until cumulative doxorubicin dose reached)	DFS 72% (asp) versus 42% (no asp) p = 0.04 DFS 86% (SR) DFS 64% (HR)	Pancreatitis – 3 (4.2%) Hepatitis – 2 (2.8%) Hypersensitivity – 1 (1.4%)
DCFI 88–01 (Non-randomized prospective)	1981–1985	≤ 18	289 (289)	ALL (untreated)	Native E. coli	Intensification SR: 25,000 IU/m^2 IM weekly (20 doses) HR: 25,000 IU/m^2 IM weekly (until cumulative doxorubicin dose reached)	Overall: 4Y EFS 77% SR: 4Y EFS 86% HR: 4Y EFS 71% p = 0.003	Allergy to E. coli – 54 (19%) Allergy to Erwinia – 9 (17%) Hyperamylasemia – 16 (6%) Pancreatitis – 11 (4%) Stroke – 8 (3%) Hyperlipidemia – 3 (1%) Thrombophlebitis – 3 (1%) Hepatitis – 1 (<1%) PE – 1 (<1%) Encephalopathy – 2 (<1%)
POG 8704 (Randomized prospective)	1987–1992	1–21	552 (484)	Untreated T-cell ALL and advanced LBL	Native E. coli	Induction 10,000 U/m^2 IM D27, 29, 31 Consolidation (if randomized) 25,000 IU/m^2 IM weekly x 20 doses	Overall: 4Y CCR 71.3% (asp) vs 57.8% (no-asp), p < 0.001 T-ALL: 4Y CCR 68% (asp) vs 55% (no-asp), p = 0.002 LBL: 4Y CCR 78% (asp) vs 64% (no-asp), p = 0.048	Asp cohort vs no-asp cohort: Allergic reactions – 24% vs 10% Pancreatitis – 0.82% vs 0.10%, p < 0.001 Elevated transaminases – 2.6% vs 0.9%,  p < 0.001 Bilirubin elevation – 1.2% vs 0.05%,  p < 0.001 Thrombocytopenia – 6.2% vs 2.6%,  p < 0.001
IDH-ALL-91 (Randomized prospective)	1991–1997	1–15	494 (490)	SR non-T-cell ALL (untreated)	Native E. coli Erwinia	Induction/Reinduction 10,000 U/m^2 D8, 15, 22, 29 Continuation (if randomized) 25,000 U/m^2 weekly (20 doses)	Asp vs no-asp cohorts: 10Y DFS 87.5% vs 78.7% p = 0.03 Hazard ratio 0.60 (90% CI 0.38–0.93) 10Y survival estimate 93.7% vs 88.6%, p = 0.05	Allergic reactions ~10% (~3% required discontinuation)
POG 9310 (Randomized prospective)	NR	< 22	148 (147)	B-cell ALL (first relapse)	Pegaspargase	Induction (randomized) 2500 U/m^2 IM Weekly (4 doses) or biweekly (2 doses)	CR: 90% (overall) 97% (weekly) vs 82% (biweekly), p = 0.003	Hypofibrinogenemia – 32 (25%) hypoalbuminemia – 29 (20%) elevated bilirubin – 22 (15%) elevated ALT – 13 (9%) hypersensitivity – 6 (4%) hyperglycemia – 5 (3%) thrombotic events – 3 (2%) CNS events – 3 (2%) clinical pancreatitis – 2 (1%) (No significant difference between groups)
DFCI 91–01 (Randomized prospective)	1991–1995	0–18	386 (377)	ALL (untreated)	Native E. coli Pegaspargase	Intensification (randomized) 25,000 IU/m^2 IM weekly E. coli (30 doses) 2500 IU/m^2 IM biweekly pegaspargase (15 doses)	Overall 5Y EFS: 83% ± 2% 5Y EFS (weeks of asp): 90% ± 2% (≤ 25) vs 73% ± 7% (≥ 26), p < 0.01 5Y EFS (asp formulation): 84% ± 4% (E. coli) vs 78% ± 4% (pegaspargase), p = 0.29	Any asparaginase related toxicity – 29%  allergic reactions – 15%  pancreatitis – 7%  coagulopathy – 4.5%  CNS thrombosis – 1% Asparaginase-related toxicity by age: 48% (9–18) vs 24% (<9), p < 0.01
COG AALL0232 (Randomized prospective 2 x 2 factorial)	2004–2011	1–30	3154 (2554)	B-cell ALL (untreated)	Pegaspargase	Induction/Extended induction 2500 IU/m^2 D4, 5, or 6 Consolidation 2500 IU/m^2 D15, 43 Interim Maintenance (if randomized) 2500 IU/m^2 D2, 22	HD-MTX vs C-MTX 5Y EFS 82% vs 75.4%, p = 0.006	NR
COG AALL0434 (Randomized prospective 2 x 2 pseudofactorial)	2007–2014	1–31	1895 (1189)	T-cell ALL (untreated)	Pegaspargase	Induction 2500 IU/m^2 D4, 5, or 6 Consolidation 2500 IU/m^2 D15, 43 Interim Maintenance (C-MTX, if randomized) 2500 IU/m^2 D2, 22	C-MTX vs HD-MTX 5Y DFS: 91.5% (95% CI 88.1–94.8) vs 85.3% (95% CI 81.0–89.5%), p = 0.005 5Y OS 93.7% (95% CI 90.8–96.6%) vs 89.4% (95% CI 85.7–93.2%), p = 0.04	NR

Note: References: 40–48.

Abbreviations: ALL, acute lymphoblastic leukemia; ALT, alanine aminotransferase; AUL, acute undifferentiated leukemia; asp, asparaginase; CCG, Children’s Cancer Study Group; COG, Children’s Oncology Group; CI, confidence interval; CR, complete remission; D, day; DFCI, Dana-Farber Cancer Institute; CCR, continuous complete remission; DFS, disease-free survival; EFS, event-free survival; HD-MT, high-dose methotrexate; C-MTX, Capizzi methotrexate; HR, high-risk; IDH, Italian, Dutch, Hungarian; IM, intramuscular; IV, intravenous; LBL, lymphoblastic lymphoma; NR, not reported; POG, Pediatric Oncology Group; QOD, every other day; SR, standard-risk; Y, year.

Table 3 Selected AYA and Adult Studies Utilizing Asparaginase-Containing Pediatric or Pediatric-Inspired Regimens

Study (Design)	Enrollment Period	Age Range	Number (Evaluable)	Disease (Status)	Asparaginase Formulation	Treatment Phase and Dosing	Selected Outcomes	Selected Events Including Asparagine-Related Toxicities
PETHEMA ALL-96 (Non-randomized prospective)	1996–2005	15–30	87 (81)	SR ALL (untreated)	Native E. coli	Induction 10,000 IU/m^2 IV D10–12, 17–19, 24–26 Consolidation/Reinduction 10,000 IU/m^2 IM/IV D1–3, 15–17 Maintenance/Reinduction 20,000 IU/m^2 IV D1 monthly x 12 (cumulative 320,000 U/m^2)	Full cohort: CR: 98% 6Y EFS: 61% (95% CI 51–72%) 6Y OS: 69% (95% CI 59–81%) Young adult versus adolescent: 6Y EFS: 63% (95% CI 48–78) vs 60% (95% CI 43–77), p = 0.97 6Y OS: 63% (95% CI 46–80) vs 77% (95% CI 63–90), p = 0.44	Hypersensitivity – 7 (8%) Dose modifications (vincristine or asp):  19% of cycles (total)  15% of cycles (adolescents)  33% of cycles (young adults)  p = 0.03
HOVON-70 (Non-randomized prospective)	2005–2007	17–40	54 (54)	ALL (untreated)	Native E. coli	Induction 6000 IU/m^2 IV D8, 10, 12, 20, 22, 24, 26, 28 Intensification 6000 IU/m^2 IV D4, 6, 8, 10, 12, 15	CR 91% 24 mo EFS 66% (95% CI 52–77%) 24 mo OS 72% (95% CI 55–82%)	Hypersensitivity – 10 Grade ≥ 3 liver dysfunction – 45 Grade ≥ 3 thrombosis – 9
GRAALL 2003 (Non-randomized prospective)	2003–2005	15–60	225 (225)	Ph-negative ALL (untreated)	Native E. coli	Induction 6000 IU/m^2 IV D8, 10, 12, 15, 17, 19, 22, 24, 26 Consolidation 10,000 IU/m^2 IV D3 Intensification 6000 IU/m^2 IV D8, 10, 12, 20, 22	CR 93.5% 42 mo EFS 55% (95% CI 48–52%) 42 mo OS 60% (95% CI 53–66%) 42 month OS: 66% (age ≤45) vs  41% (age >45)  Hazard ratio 2.2 (95% CI 1.4–3.4),  p < 0.001	Age 15–45 vs 46–60  Median asp doses (U/m^2) received:   Induction: 48,000 vs 36,000 (p=0.006)   Postresmission: 81,000 vs 29,000   (p=0.003)  Allergy or pancreatitis   Induction: 2 vs 2 (p = 0.24)   Post-remission: 5 vs 4 (p = 0.21)  Liver toxicity   Induction: 31 vs 15 (p = 0.12)   Postremission: 27 vs 9 (p = 0.64) Cumulative incidence of treatment-related deaths: 23% (age >45) vs 5% (age ≤ 45),  p < 0.001
GRAAL 2005 (Randomized prospective)	2006–2014	18–59	813 (787)	Ph-negative ALL (untreated)	Native E. coli	Induction and Late Intensification 6000 IU/m^2 IV D8, 10, 12, 20, 22, 24, 26, 28 Consolidation 10,000 IU/m^2 IV D3, D16 Interphase 10,000 IU/m^2 IV D2	CR 91.9% 5Y OS 52.5% (95% CI 48.5–55.7%) 5Y EFS 52.2% (95% CI 48.5–55.7%) 5Y EFS 25.8% (age ≥ 55) vs 55.7% (age < 55), hazard ratio 2.16, p<0.001	Cumulative asp (IU/m^2) actually received: Induction:  48,000 (age 18–54) vs 36,000 (age ≥55)  p < 0.001 Late intensification:  48,000 (age 18–54) vs 36,000 (age ≥55)  p < 0.150
GMALL 05/93 07/03 (Non-randomized prospective)	NR	15–35	3060 - total (642–05/93) (887–07/03)	ALL (untreated)	Native E. coli (05/93) Pegaspargase (07/03)	Induction 5000 IU/m^2 IV D15–28  QOD (05/93) 2000 U/m^2 IV D20 (07/03) Consolidation 10,000 IU/m^2 IV D2, 16  (05/93) 2000 U/m^2 IV D20 (07/03)	CR 91% vs 88% (07/93 vs 05/93), p = 0.001 OS 65% vs 46% (07/93 vs 05/93), p < 0.0001	NR
CALGB 9511 (Non-randomized prospective)	1995–1997	17–71	104 (102)	ALL or AUL (untreated)	Pegaspargase	Induction 2000 IU/m^2 (3750 IU cap) D5, 22 Intensification Day 15, 43 *First 21 patients received only one dose during each phase	CR 77% (overall) Asparagine depleted versus non-depleted: CR: 87% vs 73%, p = 0.113 DFS (25 mo vs 12 mo), p = 0.010 HR 1.8 (95% CI 0.9–3.6, p = 0.084) Median OS: 31 mo vs 13 mo,  p = 0.001 HR 1.8 (95% CI 1.0–3.2, p = 0.056)	Elevated bilirubin – 54% Hyperglycemia – 40% Hypofibrinogenemia – 30%
DCFI 01–175 (Non-randomized prospective)	2002–2008	18–50	100 (92)	ALL (untreated)	Native E. coli	Induction 25,000 IU/m^2 IM D5 Intensification 12,500 IU/m^2 IM weekly for 30 weeks with pharmacokinetic dose adjustment	CR 85% 4Y DFS 69% (95% CI 56–78%) 4Y OS 67% (95% CI 56–76%)	Hepatic toxicity – 33 (53%)  Hyperbilirubinemia – 10 (11%)  Elevated transaminases – 20 (22%)  Liver dysfunction or failure – 3 (3%) Thrombosis – 16 (17%) Pancreatitis – 10 (11%) Osteonecrosis – 5 (5%) Allergic reactions – 5 (5%)
NOPHO ALL2008 (Randomized prospective)	2008–2014	1–45	1591 (1509)	Ph-negative ALL (untreated)	Pegaspargase	SR, IR: Consolidation 1000 IU/m^2 IM D30, 43, 57, 71, 85 Intensification and Maintenance 1000 IU/m^2 IM D99, 113, 127, 141, every 2 weeks from week 23–33 HR: Consolidation 1000 IU/m^2 IM D6 Intensification 1000 IU/m^2 IM D7, then D1, 15 during week 99–104	EFS 89%, 80%, 74% (age 1–9, 10–17, and 18–45)	Anaphylaxis 14.5%, 9.5%, 5.2% (age 1–9, 10–17, and 18–45) Pancreatitis 5.9%, 11.1%, 11.3% (age 1–9, 10–17, and 18–45) Hyperlipidemia 7.1%, 9.9%, 7.1% (age 1–9, 10–17, and 18–45) Thrombosis 3.6%, 15.3%, 17.5% (age 1–9, 10–17, and 18–45) Osteonecrosis 2.3%, 13.4%, 8.5% (age 1–9, 10–17, and 18–45)
CALGB 10403 (Non-randomized prospective)	2007–2018	17–39	318 (295)	Ph-negative ALL (untreated)	Pegaspargase	Induction 2500 IU/m^2 IM/IV D4 Remission Consolidation 2500 IU/m^2 IM/IV D15, 43 Interim Maintenance 2500 IU/m^2 IM/IV D2, 22 Delayed Intensification 2500 IU/m^2 IM/IV D4, 5, or 6 and 43	Median OS: NR Estimated 3Y OS: 73%  (95% CI 68–78%) 3Y EFS: 59%  (95% CI 54–65%) median EFS: 78.1 mo  (95% CI 41.8 – NR)	hypofibrinogenemia – 42% hyperglycemia – 30% elevated transaminases – 28% bilirubinemia – 18% hypertriglyceridemia – 11% thrombotic events – 5% pancreatitis – 5% osteonecrosis – 4%
UKALL14 (Non-randomized prospective)	2014–2017	18–60	43 (39)	Ph-negative ALL or LBL (untreated)	Pegaspargase	Induction Phase I and II 2000 IU/m^2 IV D15 Intensification I and II 2000 IU/m^2 IV D16, 17 Reinduction I and II 2000 IU/m^2 IV D15	CR: 97% MRD negativity rate: 33% (post-induction I) 83% (post-induction II) 3Y EFS: 67.8% 3Y OS: 76.4%	Hypofibrinogenemia – 59% Hypertriglyceridemia – 59% Elevated ALT – 41% Hyperglycemia – 31% Elevated AST – 26% Hyperbilirubinemia – 26% Elevated alkaline phosphatase – 10% Hypoalbuminemia – 10% Pancreatitis – 3% Thrombosis – 3%
MDACC ABFM vs HyperCVAD (Non-randomized prospective)	2006–2012	12–40	85 (85)	Ph-negative ALL (untreated)	Pegaspargase	Induction 2500 IU/m^2 D4 Consolidation 1 2500 IU/m^2 week 3 and 4 Consolidation 2 2500 IU/m^2 Week 1 and 4 Consolidation 3A 2500 IU/m^2 Week 1 Consolidation 3B 2500 IU/m^2 Week 3	CR 94% ABFM vs hyperCVAD 3Y CRD: 70% vs 66% 3Y OS 74% vs 71%	Hepatotoxicity – 35–39% Thrombosis – 22% Pancreatitis – 11% Osteonecrosis – 11%

Note: References: 6, 50, 51, 53, 55, 56, 57, 58, 59, 61, 62.

Abbreviations: ABFM, Augmented Berlin-Frankfurt-Münster; CALGB, Cancer and Leukemia Group B; CR, complete remission; CRD, complete remission duration; D, treatment day; DFS, disease-free survival; DFCI, Dana-Farber Cancer Institute; EFS, event-free survival; GRAALL, Group of Research on ALL; GMALL, German Multicenter Study Group for Adult; HOVON, Dutch-Belgian Hemato-Oncology Cooperative Study Group; HR, high-risk; HyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine; IM, intramuscular; IR, intermediate-risk; IV, intravenous; MDACC, MD, Anderson Cancer Center; MRD, minimal residual disease; mo, month; NOPHO, Nordic Society of Pediatric Hematology and Oncology; NR, not reported; PETHEMA, Programa Español de Tratamiento en Hematología; Ph, Philadelphia chromosome; SR, standard-risk; UKALL, United Kingdom ALL.

Table 4 Selected Asparaginase Associated Toxicities and Their Management

Toxicity	Incidence – n (%) – Grade ≥ 3 Unless Specified	Management Recommendations
Hypersensitivity	CALGB 10403–29 (9.8) NOPHO2008 – 11 (5.2) UKALL14 – 3 (4) DFCI – 5 (5)	NCCN: Grade ≤ 2 allergy: continue same asparaginase formulation with addition of premedication, reduction of infusion rate, or concurrent saline administration. Grade ≥ 3 allergy or anaphylaxis: permanently discontinue offending formulation. Erwinia asparaginase should be used in the second-line. Additional/alternative recommendations based on expert opinion: For grade 1 reactions, SAA should be measured within 3–7 days of asparaginase administration with a therapeutic trough ≥ 0.1 IU/mL to ensure adequate anti-leukemic activity. Transition to Erwinia asparaginase for subtherapeutic level or recheck at day 14 and transition at that point. Some experts recommend switching asparaginase preparations with grade ≥ 2 allergy.
Elevated transaminases	CALGB 10403 ALT – 158 (53.6) AST – 98 (33.2) NOPHO2008 – NR UKALL14 ALT – 10 (14) AST – 4 (5) ALP – 15 (20) DFCI – 20 (22) (AST or ALT)	NCCN: Grade 3: Hold asparaginase until grade 1, then resume; Grade 4: Hold asparaginase until grade 1, then resume. Consider discontinuation or resumption with close monitoring if > 1 week to resolution. Additional expert recommendations: Discontinuation of asparaginase is not recommended due to reversibility of hepatotoxicity and impaired outcomes with undertreatment.
Hyperbilirubinemia	CALGB 10403–77 (26.1) NOPHO2008 – 5 (2.4) (bilirubin > 5 x ULN or encephalopathy) UKALL14 – 17 (23) DFCI – 10 (11)	NCCN: Continue asparaginase for direct bilirubin ≤ 3.0 mg/dL. Hold for 3.1–5.0 mg/dL until < 2.0 mg/dL. For > 5.0 mg/dL, discontinue asparaginase or hold and resume when < 2.0 mg/dL with close monitoring and consideration of dose reduction
Hyperlipidemia / hypertriglyceridemia	CALGB 10403–33 (11.2) NOPHO2008 – 15 (7.1) (> 5 ULN) UKALL14 – 1 (1) DFCI – NR	NCCN: Grade 4: hold asparaginase and resume when normalized. Treat as indicated. Additional expert recommendations: Several experts recommend treatment with gemfibrozil or other fibrates, particularly for high-grade triglyceridemia (>1000 mg/dL), though the benefits are unclear. Most experts recommend continuing asparaginase without interruption or dose adjustment regardless of grade.
Pancreatitis	CALGB 10403–14 (4.7) NOPHO2008 – 24 (11.3) (Grade ≥ 2) UKALL14 – 2 (3) DFCI – 10 (11)	NCCN: Grade 2: hold asparaginase until enzyme levels or radiologic findings resolve. Grade ≥ 3: permanently discontinue asparaginase
Hyperglycemia	CALGB 10403–35 (11.9) NOPHO2008 - NR UKALL14 – 0 (0) DFCI – 41 (45)	NCCN: Continue asparaginase for grade ≤ 2 toxicity and hold asparaginase and glucocorticoids for grade ≥ 3 toxicity. Insulin therapy should be initiated to achieve glycemic control.
Thrombosis	CALGB 10403–33 (11.2) NOPHO2008 – 37 (17.5) UKALL14 – 4 (5) DFCI – 16 (17)	NCCN: For grade ≥ 2 non-CNS thromboembolism, systemic anticoagulation should be initiated with antithrombotic agent (heparin or low molecular weight heparin). Asparaginase should be held until symptomatic resolution and completion of anticoagulation or stability. AT levels should be tested if heparin is administered. For CNS thrombosis, stroke, or ischemic event, asparaginase should be discontinued and antithrombotic therapy initiated if appropriate. Grade ≤ 3, resumption of asparaginase, with possible dose reduction or greater intervals between doses should be considered. Grade 4: asparaginase should be discontinued permanently. Additional expert recommendations: The use of DOACs is generally not recommended due to limited data. Continue therapeutic anticoagulation for at least 6 months and minimum of 4–6 weeks following asparaginase therapy, with longer duration (through achievement of CR) considered for patients with life threatening VTE. Anti-Xa and AT level monitoring (target 80–120%) is recommended. For life-threatening VTE, consider short-term administration of AT concentrate pending stability. There is limited data for prophylactic anticoagulation with some experts recommending prophylaxis during induction for all patients throughout asparaginase therapy for patients with risk factors (prior VTE, obesity). Cryoprecipitate should not be administered for hypofibrinogenemia in the absence of bleeding due to increased risk of thrombosis.
Hemorrhage	CALGB 10403 (CNS) – 4 (1.4) NOPHO2008 – 11 (5.2) - (CNS or other catastrophic) UKALL14 (CNS) – 1 (1) DFCI (CNS) – 1 (1)	NCCN: For non-CNS Grade ≥ 2: hold asparaginase until Grade 1. Consider coagulation factor replacement. Treatment should not be held for asymptomatic abnormal laboratory findings. For CNS asparaginase should be discontinued and coagulation factor replacement considered. Resumption can be considered for grade ≤ 3 pending resolution with dose reduction or greater intervals between doses but should not be resumed for grade 4. It is recommended that magnetic resonance angiography/venography be performed to assess for associated CST

Notes: References: 65, 66, 67, 68, 84, 87. “Grade” Refers to Common Terminology Criteria for Adverse Events (CTACE) Grade.

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AT, anti-thrombin, CALGB, Cancer and Leukemia Group B; CNS, central nervous system; CST, cavernous sinus thrombosis; DFCI, Dana-Farber Cancer Institute; DOAC, direct-acting oral anticoagulant; NCCN, National Comprehensive Cancer Network; NOPHO, Nordic Society of Pediatric Hematology and Oncology; NR, not reported; SAA, serum asparaginase activity; UKALL, United Kingdom Acute Lymphoblastic Leukaemia; ULN, upper limit of normal; VTE, venous thromboembolism.