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Dose intensity in ALL treatment
tion, and continuation was 135.5 weeks for both T15 and T16; interquartile range, 134.4-137.3 weeks). To assess the possible impact of delivered dose intensity on time to com- plete therapy, we analyzed the association between the dose intensity of asparaginase and mercaptopurine and time to complete therapy in patients completing treatment. We found an inverse association between dose intensity and time to complete therapy (P<0.0001 for both drugs), however, the correlation was relatively weak (r2 = 0.03 for both asparaginase and mercaptopurine). More importantly, there was no association between time to complete therapy and relapse risk (P=0.7 on T15, P=0.4 on T16). Of the 889 patients included on the study, 17 (1.9%) discontinued treatment early due to toxicity. With a median follow-up of 7.5 years from diagnosis for these patients, only one of 17 patients (5.9%) experienced a relapse (at 3.9 years after diagnosis).
Discussion
This study is the first to comprehensively evaluate dosages of all conventional drugs constituting modern ALL therapy. Our most striking observation was that mercap- topurine dose intensity was lower on T16 than on T15, despite no planned changes to mercaptopurine dosages on T16 versus T15. The most likely explanation for this decreased ability to administer full dosages of mercaptop- urine is higher planned and administered doses of asparag- inase on T16 than on T15. We suggest that asparaginase interfered with mercaptopurine delivery based on several findings: an inverse association between delivered asparag- inase and mercaptopurine dosages between protocols (Figure 2, Table 1, Online Supplementary Table S4), a higher delivered mercaptopurine dosage in those with antibodies to asparaginase than in those without antibodies (Figure 5), and a temporal decrease in dose intensity of mercaptop- urine that corresponds with the timing of asparaginase use (Online Supplementary Tables S8 and S9, Online Supplementary Figures S4 and S5). Moreover, we and others have shown that asparaginase can decrease the clearance of other drugs, such as dexamethasone, putatively through its hypoproteinemic effects on hepatic drug metabolizing enzymes and transporters. We found that this interaction is associated with an increased risk of at least one adverse effect of dexamethasone (osteonecrosis) and higher drug exposure both in the clinic13 and in preclinical models.14 Others have also hypothesized that asparaginase can influ- ence the dose intensity or toxicity of thiopurines and/or methotrexate.15,16
Asparaginase is an important part of ALL therapy, which is the reason that we chose to increase exposure to asparag- inase on T16 compared to that on T15. Early discontinua- tion of asparaginase was associated with lower event-free survival in the Dana-Farber 91-01 study1 and in ETV6/RUNX1 ALL,17 and patients treated with E. coli asparaginase had fewer relapses than those treated with Erwinase.18 Patients with allergy to pegaspargase treated on recent Children’s Oncology Group protocols who did not receive all asparaginase therapy had a lower disease-free survival, and drug shortages of Erwinase contributed to not being able to compensate fully for missed pegaspargase doses.19 However, prolonged asparaginase did not improve outcomes in two trials,2,20 and higher doses of pegaspargase did not improve outcome relative to standard doses.12 In the
Figure 5. Mercaptopurine cumulative dose intensity and absolute neutrophil count in patients negative or positive for anti-asparaginase antibodies. Mercaptopurine cumulative dose intensity (DI; left y axes) and absolute neu- trophil count (ANC) in cells/mm3 (right y axes) for continuation weeks 10-16 in patients who were negative or positive for anti-asparaginase antibodies against Elspar (T15) or Oncaspar (T16) measured at continuation week 7. Boxes and whiskers represent quartiles and non-outlier ranges. Nominal P values were *P<0.05; **P<0.01, ***P<0.001. There was a total of four comparisons, thus the Bonferroni significance threshold=0.01
current analysis, we did not find that asparaginase dose intensity was related to disease free-survival in either T15 (using primarily native E. coli asparaginase) or T16 (using primarily pegaspargase) (Online Supplementary Table S12, Online Supplementary Figure S8). There are several possible explanations for this finding. First, we used more asparagi- nase on our studies than others did, thus perhaps exceeding some threshold value for exposure, consistent with the lack of influence of pegaspargase dosage on relapse in T16.12 Second, in those with allergy to their front-line asparagi- nase preparation, substitution with another formulation was aggressive, such that asparaginase dose intensity was not lower for those with or without allergy on T15 or on T16 (Online Supplementary Figure S9) and interpatient vari- ability in dose intensity for asparaginase was low, i.e., <7% (Online Supplementary Table S3). Another possibility is that even in those patients with relatively low asparaginase dose
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