Journal article
Antimetabolite Dose Intensity and Adverse Outcomes in Children with Acute Lymphoblastic Leukemia: A COG-AALL03N1 Report
Blood, Vol.144(22), pp.2327-2335
11/28/2024
DOI: 10.1182/blood.2024024455
PMCID: PMC11619787
PMID: 39190431
Abstract
The association between antimetabolite dose intensity (DI) and adverse events among children receiving maintenance therapy for acute lymphoblastic leukemia (ALL) remains unclear, especially in context of antimetabolite adherence. Using COG-AALL03N1 data, we examined the association between high DI during the first four study months and (i) treatment-related toxicities during the subsequent two study months; and (ii) relapse risk. Patients were classified into a high DI phenotype (either 6-mercaptopurine [6-MP] or methotrexate [MTX] DI ≥110% during the first four study months, or 6-MPDI or MTXDI 100%-110% at study enrollment and ≥25% increase over the four study months) and normal DI phenotype (all others). Only patients with wildtype TPMT and NUDT15 were included. 6-MP adherence data were available for 63.7% of study participants and used to stratify as adherent (median adherence ≥85%) and non-adherent (median adherence <85%) participants. Multivariable analyses were adjusted for sociodemographic and clinical prognosticators. Of the 644 patients, 29.3% were exposed to high DI. High DI was associated with a 2.1-fold greater odds of hematologic toxicity (95%CI=1.4-3.1; reference: normal DI) in the entire cohort and 2.9-fold higher among adherers (95%CI=1.6-5.1); odds were comparable among non-adherers (2.1-fold, 95%CI=0.4-10.1).. While high DI was not associated with relapse in the entire cohort (adjusted hazard ratio [aHR]=1.4, 95%CI=0.8-2.4), it was associated with a greater hazard of relapse among adherent participants (aHR=2.4, 95%CI=1.0-5.5) but not among non-adherent participants (aHR=0.9, 95%CI=0.2-3.8). Dose escalation above protocol doses during maintenance therapy for ALL should be done cautiously after assessing adherence to prescribed therapy.The association between antimetabolite dose intensity (DI) and adverse events among children receiving maintenance therapy for acute lymphoblastic leukemia (ALL) remains unclear, especially in context of antimetabolite adherence. Using COG-AALL03N1 data, we examined the association between high DI during the first four study months and (i) treatment-related toxicities during the subsequent two study months; and (ii) relapse risk. Patients were classified into a high DI phenotype (either 6-mercaptopurine [6-MP] or methotrexate [MTX] DI ≥110% during the first four study months, or 6-MPDI or MTXDI 100%-110% at study enrollment and ≥25% increase over the four study months) and normal DI phenotype (all others). Only patients with wildtype TPMT and NUDT15 were included. 6-MP adherence data were available for 63.7% of study participants and used to stratify as adherent (median adherence ≥85%) and non-adherent (median adherence <85%) participants. Multivariable analyses were adjusted for sociodemographic and clinical prognosticators. Of the 644 patients, 29.3% were exposed to high DI. High DI was associated with a 2.1-fold greater odds of hematologic toxicity (95%CI=1.4-3.1; reference: normal DI) in the entire cohort and 2.9-fold higher among adherers (95%CI=1.6-5.1); odds were comparable among non-adherers (2.1-fold, 95%CI=0.4-10.1).. While high DI was not associated with relapse in the entire cohort (adjusted hazard ratio [aHR]=1.4, 95%CI=0.8-2.4), it was associated with a greater hazard of relapse among adherent participants (aHR=2.4, 95%CI=1.0-5.5) but not among non-adherent participants (aHR=0.9, 95%CI=0.2-3.8). Dose escalation above protocol doses during maintenance therapy for ALL should be done cautiously after assessing adherence to prescribed therapy.
Details
- Title: Subtitle
- Antimetabolite Dose Intensity and Adverse Outcomes in Children with Acute Lymphoblastic Leukemia: A COG-AALL03N1 Report
- Creators
- Aman Wadhwa - University of Alabama at BirminghamYanjun Chen - University of Alabama at BirminghamLindsey Hageman - University of Alabama at BirminghamAnne AngiolilloDavid Dickens - University of IowaJoseph P Neglia - University of MinnesotaYaddanapudi Ravindranath - Wayne State UniversityAmanda Termuhlen - Grosse Pointe Public LibraryF Lennie Wong - City Of Hope National Medical CenterWendy Landier - University of Alabama at BirminghamSmita Bhatia - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.144(22), pp.2327-2335
- DOI
- 10.1182/blood.2024024455
- PMID
- 39190431
- PMCID
- PMC11619787
- NLM abbreviation
- Blood
- ISSN
- 1528-0020
- eISSN
- 1528-0020
- Publisher
- ELSEVIER
- Grant note
- National Clinical Trials Network (NCTN) Operations Center grant: U10CA180886 NCTN Statistics Data Center: U10CA180899 St. Baldrick's FoundationNCI Community Oncology Research Program: UG1CA189955 National Cancer Institute: R01 CA096670
The authors acknowledge support from National Clinical Trials Network (NCTN) Operations Center grant (U10CA180886), NCTN Statistics & Data Center grant (U10CA180899), St. Baldrick's Foundation, and NCI Community Oncology Research Program grant (UG1CA189955) to the Children's Oncology Group, as well as a National Cancer Institute grant (R01 CA096670) to S.B.
- Language
- English
- Electronic publication date
- 08/27/2024
- Date published
- 11/28/2024
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984699052602771
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