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S.E. Karol et al.
existing ALL regimens,10 predicting the tolerability of new combination protocols has proven challenging without accurate information on how current conventional ALL therapy is actually administered.
Our aim was to tabulate the actual dosages and dose intensities of conventional chemotherapy in two consecu- tive multiagent front-line pediatric St. Jude ALL trials that used highly similar backbones but different formulations of asparaginase: E. coli L-asparaginase in Total 15 (T15) and pegaspargase in Total 16 (T16).
Methods
Patients
Patients were enrolled on St. Jude Children’s Research Hospital protocols T15 (ClinicalTrials.gov ID: NCT00137111)11 and T16 (ClinicalTrials.gov ID: NCT00549848)12 for newly diag- nosed ALL (Online Supplementary Figure S1). T15 and T16 thera- py included remission induction therapy followed by consolida- tion therapy and 120 weeks of continuation therapy (146 weeks for boys on T15) which included two phases of reinduction (Online Supplementary Table S1). After remission induction, patients were classified for risk-adapted therapy as low-risk (LR, about 40% of patients), standard-risk (SR, about 50% of patients) or high-risk (HR, about 10% of patients).11,12 Patients with Down syndrome received altered methotrexate and leu- covorin regimens, and HR patients received intensification phas- es, and thus both groups were excluded from this analysis. This
report focuses on the ~90% of patients who were treated on either the LR or SR arms. Ninety patients on T15 who received most of their therapy at a collaborating institution11 were also excluded, because their drug administration data were difficult to verify (Online Supplementary Figure S2). The studies were approved by the Institutional Review Board. Informed consent was obtained from either the parents or the patients, consistent with the Declaration of Helsinki.
Treatment
Drug administration data were recorded prospectively on pro- tocol-specific forms, generally on a daily basis for induction and reinduction and on a weekly basis for other phases, by clinical staff and research nurses, and entered into centralized St. Jude databases by protocol-specific research data managers. Reasons for dose modifications were protocol-specified (Online Supplement).
Treatment regimens have been described previously11,12 and are summarized in Online Supplementary Figure S1 and Online Supplementary Table S1. The two protocols differed primarily by first-line asparaginase formulation, although there were a few other differences (Online Supplementary Figure S1, Online Supplementary Tables S1 and S2).11 Patients received E. coli asparaginase (Elspar) in T15, and pegaspargase (Oncaspar) in T16. In the case of allergic reaction to either E. coli asparaginase or pegaspargase, an asparaginase formulation change was per- mitted by the protocol (Online Supplement). To compare planned dosages roughly between protocols, Elspar doses were convert- ed to comparable doses of pegaspargase based on protocol-spec-
Figure 1. Planned cumulative doses of drugs used in the low- and standard-risk arms of T15 and T16. The only drugs with at least a 10% difference in planned cumulative dosages between T16 and T15 (within risk arms) were asparaginase (34% higher in the standard risk arm), dexamethasone (17.4% lower in the stan- dard-risk arm), and doxorubicin (50% less in the low-risk arm). Thus, only asparaginase was planned for higher dosages on T16 than on T15. There were no differ- ences between T15 and T16 in planned cumulative dosages of prednisone, vincristine, daunorubicin, cytarabine, cyclophosphamide, mercaptopurine; there was a planned decrease of only 6.0% in low-dose methotrexate dosages in the standard-risk arm on T16 versus T15. See Online Supplementary Table S2 for details on planned dosages.
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haematologica | 2022; 107(2)