Team approach: Management of osteonecrosis in children with acute lymphoblastic leukemia.

With current treatments for acute lymphoblastic leukemia (ALL), the overall prognosis for survival is favorable. Increasing emphasis is placed on recognizing and managing the long-term consequences of ALL and its treatment, particularly involving osteonecrosis. Early osteonecrosis diagnosis and management may improve outcomes and is best accomplished through coordinated teams that may include hematologic oncologists, radiologists, orthopedic surgeons, physical therapists, and the patient and their family. Magnetic resonance imaging is the "gold standard" for diagnosis of early-stage and/or multifocal osteonecrosis. Treatments for osteonecrosis in ALL patients are risk stratified and may include observation, corticosteroid or chemotherapy adjustment, and pharmaceutical or surgical approaches.

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.