Fluoroquinolone prophylaxis does not increase risk of neuropathy in children with acute lymphoblastic leukemia.

BACKGROUND: Fluoroquinolone antibiotics are frequently utilized in pediatric oncology patients as prophylaxis or step-down therapy following broad spectrum beta-lactam therapy for febrile neutropenia. Concerns regarding neurotoxicity limit the use of these agents. No studies have evaluated the association between fluoroquinolone use and neurotoxicity in pediatric oncology patients receiving other neurotoxic agents such as vincristine. METHODS: An observational cohort study comprising patients aged 0-18 at diagnosis enrolled on a prospective study for treatment of acute lymphoblastic leukemia (ALL) at a pediatric comprehensive cancer center between October 2007 and November 2018. Data for neuropathic pain and sensory or motor neuropathy were collected prospectively, and a Cox proportional hazards regression model was used to evaluate associations between administration of fluoroquinolone antibiotics during induction therapy and subsequent development of vincristine-induced peripheral neurotoxicity (VIPN). RESULTS: A total of 598 participants were enrolled, including 338 (57%) who received fluoroquinolones during induction therapy; of these 470 (79%) were diagnosed with VIPN and 139 (23%) were diagnosed with high-grade (Grade 3+) VIPN. On unadjusted analyses, and analyses adjusted for age and race, there was no evidence of an association between fluoroquinolone exposure and subsequent VIPN (hazard ratio [HR] 0.8, 95% CI 0.5-1.04, P = .08) or high-grade VIPN (HR 1.1, 95% CI 0.4-2.2, P = .87). CONCLUSIONS: The results of this observational study do not show an association between exposure to fluoroquinolone antibiotics during induction therapy for ALL and subsequent development of vincristine-induced peripheral neuropathies, and suggest that a large increase in VIPN is unlikely.

Asparaginase combined with discontinuous dexamethasone improves antileukemic efficacy without increasing osteonecrosis in preclinical models.

INTRODUCTION: Combination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule. METHODS: Using the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts. RESULTS: The addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied. CONCLUSIONS: When discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase.

Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia.

PURPOSE: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. PATIENTS AND METHODS: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. RESULTS: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. CONCLUSION: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments.

PURPOSE: It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments. METHODS: In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual's previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 µM (approximately 2.5 or 5 g/m(2)/day) for low- and standard-/high-risk patients, respectively. RESULTS: Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3-4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003). CONCLUSIONS: Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.

Genome-wide study of methotrexate clearance replicates SLCO1B1.

Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P = 7 x 10(-7)), girls (P = 2.7 x 10(-4)), and those who received a delayed-intensification phase (P = .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P = 2.1 x 10(-11)). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 x 10(-19) for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. Validation of this variant with 5 different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. This study is registered at http://www.clinicaltrials.gov as NCT00005585 and NCT00005596.

Moving towards individualized medicine with pharmacogenomics.

Individuals respond differently to drugs and sometimes the effects are unpredictable. Differences in DNA that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals. Many of the genes examined in early studies were linked to highly penetrant, single-gene traits, but future advances hinge on the more difficult challenge of elucidating multi-gene determinants of drug response. This intersection of genomics and medicine has the potential to yield a new set of molecular diagnostic tools that can be used to individualize and optimize drug therapy.