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Pediatric acute lymphoblastic leukemia
ly efficacious, no more toxic, and associated with decreased patient anxiety at administration (Table 1).5 Although pegaspargase is typically used at 1000 IU/m2 to 2500 IU/m2, a therapeutic drug monitoring study showed trough levels of asparaginase activity of >100 IU/L even with administration at 450 IU/m2 every two weeks.103 Interestingly, the incidence of asparaginase-related toxici- ties (e.g., pancreatitis, central neurotoxicity, and throm- bosis) was not associated with asparaginase activity lev- els except in the case of liver toxicities. In a randomized study to assign non-high-risk patients to either ten con- tinuous doses (2-week intervals) or three intermittent doses (6-week intervals) of intramuscular pegaspargase (1000 IU/m2), after receiving five doses every two weeks, asparaginase-related toxicities (hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism) were significantly reduced in the latter group without compro- mising disease-free survival (DFS), suggesting that pro- longed continuous administration of pegaspargase might not be necessary in the context of multiagent chemother- apy.104 Most allergic reactions to pegaspargase occur after two or three doses, and are mediated by the PEG moiety and not by the L-asparaginase, possibly because of the patients’ exposure to other PEG-containing products, such as laxatives and tablet coatings, before the diagnosis of ALL.105 Although adding rituximab to ALL therapy decreased the allergic reaction to native E. coli L-asparagi- nase and improved the outcome in adults with CD20- positive Ph-negative ALL,106 the efficacy of rituximab on PEG-related allergy is unknown. Discontinuation of planned asparaginase doses is associated with worse prognosis in high-risk patients.107 In cases of allergy to pegaspargase or native E. coli asparaginase, Erwinia asparaginase (Erwinase) is considered an acceptable alter- native. However, Erwinase is more expensive, is intermit- tently unavailable, and requires frequent administration because of its short half-life.108 Universal premedication with diphenhydramine and an H2-blocker can decrease the incidence of allergic reactions,109 and drug desensitiza- tion in patients with previous and persistent anti-PEG antibodies is feasible.110
Consolidation (intensification) therapy
Induction with the 3- or 4-drug regimen (the IA phase) is followed by consolidation (the IB phase) with cyclophosphamide, cytarabine, and mercaptopurine. In patients with B-ALL, 5-year EFS was 92.3% for those with negative MRD at the end of both the IA phase (day 33) and the IB phase (day 78), which was better than the 5-year EFS for those with positive MRD at one or both time points but at a level of <10−3 on day 78 (77.6%) and for those with positive MRD at a level of ≥10−3 on day 78 (50.1%).111 Interestingly, the MRD level on day 33 in patients with T-ALL was not relevant if MRD was nega- tive on day 78, suggesting the importance of the IB phase in T-ALL.112 Similarly, in ETP ALL, which is often associ- ated with poor early response to 4-drug induction, IB- phase consolidation is effective at reducing MRD,113 and outcomes were comparable among patients with ETP, near-ETP, and non-ETP ALL in the Children’s Oncology Group AALL0434 study.114
Methotrexate is crucial for controlling systemic leukemia and also CNS and testicular disease. Methotrexate is administered as a high dose (2-5 g/m2) plus leucovorin rescue, together with 6-mercaptopurine,
or as escalating intermediate doses of methotrexate (100- 300 mg/m2) without leucovorin rescue followed by asparaginase (the Capizzi regimen). In randomized stud- ies, high-dose methotrexate was superior to the Capizzi methotrexate regimen in patients with high-risk B-ALL (Table 1).2 Interestingly, in patients with T-ALL, Capizzi methotrexate was associated with better outcomes than high-dose methotrexate (Table 1).4 However, approxi- mately 90% of the patients received cranial irradiation, and those in the high-dose methotrexate arm underwent irradiation five months later than those in the Capizzi regimen arm. As cranial irradiation can control both CNS and systemic relapses, this difference in timing of irradia- tion might have contributed to the different outcomes.
In a randomized trial of nelarabine in patients with intermediate- or high-risk T-ALL, the 5-year DFS and CNS relapse (isolated and combined) rates were signifi- cantly better in patients who received nelarabine than in those who did not (88.2% vs. 82.1% and 1.3% vs. 6.9%, respectively).115
Consolidation therapy is followed by reinduction (delayed intensification) therapy, which consists of med- ication similar to that used during the IA and IB phases and is a critical component of ALL therapy in both stan- dard-risk and high-risk patients. Reducing the duration and chemotherapy doses of delayed intensification led to an increased incidence of relapse in standard-risk patients, especially those who did not have ETV6- RUNX1-positive ALL or were aged ≥7 years at diagno- sis.116
There is interpatient variability in mercaptopurine toler- ance. Inherited heterozygous or homozygous deficiency of thiopurine methyltransferase (TPMT) leads to higher levels of active thiopurine metabolites and excess hemato- logic toxicities, which are more common in patients of European descent.88 For patients with East Asian or Native American ancestry, germline variants of NUDT15, which encodes a nucleoside diphosphatase, reduce degradation of active thiopurine nucleotide metabolites and were strongly associated with mercaptopurine intolerance.88 Therefore, thiopurine dosing adjustments based on TPMT and NUDT15 genotypes are recommended.118
Adherence of <95% to planned daily mercaptopurine doses is associated with a 2.7-fold increase in incidence of relapse compared with that seen when adherence is ≥95%.119 Confirming adherence by directly asking patients or by measuring their erythrocyte thioguanine nucleotide levels is important, especially for patients with persistently high WBC counts or absolute neutrophil counts, although self-reporting can overestimate the true intake in non-compliant patients. Patients were previous- ly instructed to take mercaptopurine in the evening and without food/dairy products, but these restrictions did not affect outcomes or erythrocyte thioguanine
Maintenance therapy
Maintenance therapy typically lasts ≥1 year and consists of daily mercaptopurine and weekly methotrexate with or without vincristine and steroid pulses. One study found that completing maintenance therapy at one year after diagnosis resulted in a high relapse rate (38.8±2.8% at 12 years after diagnosis), although this approach cured more than half of the children with ALL, and some genetic sub- groups, such as TCF3-PBX1 and ETV6-RUNX1, were associated with excellent DFS.117
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