Adverse effects of antibiotics in children with cancer: are short-course antibiotics for febrile neutropenia part of the solution?

INTRODUCTION: Febrile neutropenia is a common complication experienced by children with cancer or those undergoing hematopoietic stem cell transplantation. Repeated episodes of febrile neutropenia result in cumulative exposure to broad-spectrum antibiotics with potential for a range of serious adverse effects. Short-course antibiotics, even in patients with high-risk febrile neutropenia, may offer a solution. AREAS COVERED: This review addresses the known broad effects of antibiotics, highlights developments in understanding the relationship between cancer, antibiotics, and the gut microbiome, and discusses emerging evidence regarding long-term adverse antibiotic effects. The authors consider available evidence to guide the duration of empiric antibiotics in pediatric febrile neutropenia and directions for future research. EXPERT OPINION: Broad-spectrum antibiotics are associated with antimicrobial resistance, Clostridioides difficile infection, invasive candidiasis, significant disturbance of the gut microbiome and may seriously impact outcomes in children with cancer or undergoing allogenic hematopoietic stem cell transplant. Short-course empiric antibiotics are likely safe in most children with febrile neutropenia and present a valuable opportunity to reduce the risks of antibiotic exposure.

Cotargeting BCL-2 and MCL-1 in high-risk B-ALL.

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.

Dysregulation of BCL-2 family proteins by leukemia fusion genes.

The genomic lesions that characterize acute lymphoblastic leukemia in childhood include recurrent translocations that result in the expression of fusion proteins that typically involve genes encoding tyrosine kinases, cytokine receptors, and transcription factors. These genetic rearrangements confer phenotypic hallmarks of malignant transformation, including unrestricted proliferation and a relative resistance to apoptosis. In this Minireview, we discuss the molecular mechanisms that link these fusions to the control of cell death. We examine how these fusion genes dysregulate the BCL-2 family of proteins, preventing activation of the apoptotic effectors, BAX and BAK, and promoting cell survival.