Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia (ALL) trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities (DIs) for all medications on the low-risk (LR) or standard-risk (SR) arms, analyzing 504,039 dosing records. The median DI for each drug ranged from 61-100%; DIs for several drugs were over 10% higher on T15 than on T16: cyclophosphamide (p < 0.0001 for SR), cytarabine (p < 0.0001 for SR), and mercaptopurine (p < 0.0001 for LR and < 0.0001 for SR). We attributed the lower dosages on T16 to the higher asparaginase dosages on T16 than T15 (p<0.0001 for both LR and SR arms), with higher DI for mercaptopurine in those with anti-asparaginase antibodies than in those without (p=5.62x10-3 for T15 SR and p=1.43x10-4 for T16 SR). Neutrophil count did not differ between protocols for LR (p=0.18) and was actually lower for SR patients on T16 than T15 (p<0.0001) despite lower dosages of most drugs on T16. Patients with low asparaginase DI had higher methotrexate DI with no impact on prognosis. The only DI measure predicting a higher risk of relapse on both studies was higher mercaptopurine DI, but did not reach significance (p=0.03 T15; p=0.07 T16). In these intensive multiagent trials, higher dosages of asparaginase compromised the dosing for other ALL drugs, particularly mercaptopurine, but lower chemotherapy dose intensity was not associated with relapse.
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