Therapeutic ANC attainment during maintenance chemotherapy for pediatric acute lymphoblastic leukemia

Abstract Introduction: Acute Lymphoblastic Leukemia (ALL) is the most common pediatric malignancy. Pediatric ALL treatment requires a maintenance phase which includes daily oral mercaptopurine (6-MP) and weekly oral methotrexate (MTX). To balance safety and efficacy of oral maintenance chemotherapy, a target absolute neutrophil count (ANC) range of 500-1,500 cells/μL is recommended. After the start of maintenance cycle 2, dose titrations are indicated until target ANC is achieved. Although existing literature describes the association between low ANC and efficacy of treatment, there are limited data defining attainment of target ANC in standard clinical practice. We aimed to quantify the cumulative time that pediatric patients undergoing maintenance therapy for ALL spend within target ANC range and identify variables that affect this outcome. Methods: We conducted a single-center, retrospective cohort study of patients with B-ALL, diagnosed <19 years of age and completing at least 2 maintenance chemotherapy cycles between September 2012 and December 2021. Patients with Philadelphia + B-ALL or those receiving ruxolitinib were excluded. Data regarding demographics and clinical characteristics were extracted from the electronic health record. The primary outcome was the cumulative percentage of time spent within a target ANC range of 500-1,500 cells/μL after the start of maintenance cycle 2. Secondary outcomes included the incidence of hospitalizations, chemotherapy-related toxicities, and relapse rates. Descriptive statistics including mean, median, and range were used to summarize outcomes. Multivariable linear regression modeling was used to assess predictors of target ANC attainment by defining incident rate ratios (IRR). Results: Among the 81 patients meeting inclusion criteria, median age at diagnosis was 4.8 years (IQR: 3.2 – 9.5) and median duration of maintenance chemotherapy was 782 days (IQR: 465-828). The cohort was predominantly male (n=50, 62%), White (n=49, 74%), and used English for medical communication (n=67, 83%). A total of 37 patients (46%) were enrolled in a therapeutic clinical trial. Most were thiopurine methyltransferase normal metabolizers (n=68, 84%). On average, patients maintained a target ANC only 33.3% of the time after maintenance cycle 2 (range = 0-86.88%). Median duration of oral chemotherapy held was 25.8 days (range 0-93 days). ANC target attainment was higher among patients who used languages other than English (LOE) for medical communication (IRR 1.17, 95% CI 1.12-1.21, p < 0.001) and was lower among those who received standard of care treatment compared to those enrolled and treated on a therapeutic clinical trial (IRR 0.85, 95% CI 0.83 - 0.88, p < 0.001). Hepatotoxicity was the most prevalent toxicity, observed in 22 patients (27%). Hospitalizations were experienced by 42 patients (52%), most commonly for neutropenic fever. Fourteen patients (17%) experienced ALL relapses. ANC target attainment was lower among patients who relapsed (IRR 0.67, 95% CI 0.64 - 0.70, p < 0.001). Conclusions: Target ANC was maintained for only one-third (33.3%) of the maintenance period. Although low target ANC attainment may be related to patient factors such as oral chemotherapy adherence, the mean duration of oral 6-MP/MTX held as well as lower target ANC attainment in patients receiving treatment off a clinical trial suggests that medical team prescribing practices may have also contributed to this finding. Higher target ANC attainment among those enrolled on therapeutic clinical trials may be due to increased likelihood of protocol-directed dose adjustments and closer ANC monitoring. Of interest, patients using LOE for medical communication had higher ANC target attainment which may reflect family structure, closer surveillance by the medical team, and more intentional patient educational efforts via interpreter services to ensure understanding of prescribed medications. Limitations of this study include that it was retrospective and there was no measure of oral medication adherence. Despite these limitations, our findings highlight the challenges of achieving target ANC levels during ALL maintenance chemotherapy in clinical practice. Current ongoing analyses aim to establish how dose adjustments and prescribing practices of oral 6-MP and MTX during maintenance contributed to target ANC attainment. This work will inform quality improvement opportunities to enhance our oral chemotherapy prescribing practices.