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Dose intensity in ALL treatment
intensity, the dosages of other medications were increased, and this could have compensated for the lower exposure to asparaginase. In fact, we found that patients with low asparaginase dose intensity had significantly higher dose intensity for methotrexate on T16 (Online Supplementary Figure S10), consistent with our protocol recommendations for substituting methotrexate in those who could not receive asparaginase due to allergy or pancreatitis. These findings represent what is unique about the current study, because we have data to indicate how dosages of each medication may have influenced each other. This is the sit- uation clinicians face: when pressing ahead with one med- ication is thwarted for some reason (drug shortages, adverse effects), other medications are often substituted. In these trials, it appears that the substitutions made were effective in maintaining efficacy, in that there were no asso- ciations between low exposure to any one drug and out- come.
In our studies, as in other ALL studies, the primary drugs for which dosage adjustments are routinely made are mer- captopurine and methotrexate, which are titrated to a desired ANC, and indeed the greatest variability in dosages was observed for these two drugs (Online Supplementary Table S3). There is controversy as to whether increasing the dose intensity of mercaptopurine and/or methotrexate increases,21 decreases22 or has no effect16 on the risk of relapse. Complicating the interpretation of the data is that most studies do not systematically assess adherence, and most protocols use both drugs orally; thus, patients with the highest prescribed dose intensity may be the patients who are actually taking the lowest percentage of their ther- apy, thereby complicating any interpretation of how dose intensity affects relapse. For example, those with lower measured mercaptopurine adherence had higher relapse risk, but there was no association with mercaptopurine dose intensity.23 It is possible that low adherence to mer- captopurine also translates into lower adherence with other drugs not measured (e.g., glucocorticoids, methotrex- ate, supportive care drugs), thus compounding the risk of relapse due to poor adherence. In the current analysis, dosages of all antileukemic drugs were captured, and the only drug whose prescribed dose intensity was associated with relapse in unadjusted analyses on both T15 and T16 was mercaptopurine (Online Supplementary Table S12, Online Supplementary Figure S7), albeit not in the same phases of therapy for both studies. It should be noted that the direction of association was that higher dose intensity was associated with higher relapse, indicating that it is likely that high dose intensity identified patients who were either noncompliant (and thus clinicians needed to push the dosage to achieve desired neutropenia) or had very fast drug clearance. However, it should be noted than no met- rics of dose intensity or of ANC were significantly associ- ated with relapse or outcome using P value thresholds adjusted for the large number of exploratory comparisons. Although our data comprehensively capture prescribed mercaptopurine dose, one limitation of these data is that we did not assess adherence to administration of pre- scribed drug in patients who were not under direct medical supervision, which applied to most of the oral doses of glu- cocorticoids and mercaptopurine. Any association between dose intensity and outcomes is likely to be affect- ed by the extent to which adherence is emphasized, the extent of thiopurine monitoring, and the rigor with which ANC targets are pursued. It should be noted that on T15,
there was a modest association between higher ANC and increased relapse, but this association was not statistically significant after correction for multiple testing, and was not reproducible, as no such association was observed on T16, and in subanalyses for different therapy phases, higher ANC tended to associate with both increased and decreased relapse.
In both our studies, thiopurine starting dose was adjusted based on TPMT status,24 which appropriately resulted in lower dosages of mercaptopurine in those with a genetic defect in TPMT; herein, we show for the first time that this allowed for uncompromised dosing of the other chemotherapeutic agents (Online Supplementary Table S7) and no difference in ANC based on TPMT status (Figure 6).
It is also worth noting that the dose intensity for mercap- topurine, especially in the first 6 months of therapy, was lower than reported by others;23 after reinduction, the medi- an dose intensity was as low as 49% for one phase on T16, suggesting that our planned dosages may have been too high (Online Supplementary Table S4). Interestingly, the median dose intensity for the comparable time period on T15, when native asparaginase rather than pegaspargase was used, was higher at 76%. Had we realized a priori the impact of asparaginase on patients’ tolerance of thiopurine therapy, we could have designed a more realistic dosage regimen, and this finding has implications for future proto- col design.
There are conflicting data on the importance of “inten- sive” non-antimetabolite therapy in ALL.3,5-7,25-29 Although the lack of association of outcomes with dose intensity for most drugs in our study is fairly consistent with studies touting deintensification strategies, St. Jude differs from many other centers in that patients receive all weekly methotrexate parenterally (and thus return to the clinic every week, in contrast to many centers that see patients only every 4-6 weeks during continuation), LR and SR patients received vincristine/dexamethasone pulses throughout continuation, and a high percentage of patients (~50%) received therapy on the SR and HR arms, which include more asparaginase and other non-antimetabolite agents (cytarabine, cyclophosphamide) than many other treatment protocols. Thus, the lack of association between dose intensity and relapse we observed may not be exten- sible to centers with less intensive monitoring and/or less chemotherapy-dense and diverse regimens. It also suggests that, for patients intolerant to specific components of ther- apy (e.g., asparaginase due to pancreatic or hepatic toxici- ty), substitution with alternative chemotherapy may miti- gate the adverse prognosis associated with early discontin- uation of the offending agent. Given that therapy-limiting toxicities may preclude delivery of prescribed chemothera- py in 12-25% of patients receiving treatment on modern tri- als,19 prospective evaluation of chemotherapy substitution to address therapy-limiting toxicity should be considered.
We conclude that intentional changes to the dose intensi- ty of one agent, e.g., asparaginase, can have dramatic con- sequences on the ability to administer other conventional agents. Comprehensive data on chemotherapy actually delivered in cancer clinical trials are needed to fully interpret results and further optimize therapy.
Disclosures
MVR and HI and St. Jude Children’s Research Hospital receive investigator-initiated research funding from Servier Pharmaceutical.
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