The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolutionized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy. Although mutation- or pathway-directed targeted therapy (e.g., using tyrosine kinase inhibitors to treat Philadelphia chromosome [Ph]-positive and Phlike B-cell-ALL) is currently available for only a minority of children with ALL, many of the newly identified molecular alterations have led to the exploration of approaches targeting deregulated cell pathways. The efficacy of cellular or humoral immunotherapy has been demonstrated with the success of chimeric antigen receptor T-cell therapy and the bispecific engager blinatumomab in treating advanced disease. This review describes key advances in our understanding of the biology of ALL and optimal approaches to risk-stratification and therapy, and it suggests key areas for basic and clinical research.

/pdf/pediatric-acute-lymphoblastic-leukemia-5d53erk0go.pdf

Pediatric acute lymphoblastic leukemia.

How I treat relapsed acute lymphoblastic leukemia in the pediatric population

Additional co-authors: Helen Dignum, Edward Belsham, Jeff Neilson, Beth Harrison, Anand Lokare, Gavin Campbell, Michael Hamblin, Peter Hawkey, Eric Low, Janet A Dunn, for the TEAMM Trial Management Group and Trial Investigators

/pdf/levofloxacin-prophylaxis-in-patients-with-newly-diagnosed-46dzityz79.pdf

Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial

Purpose of reviewDespite advances in therapy over the past decades, overall survival for children with acute myeloid leukemia (AML) has not exceeded 70%. In this review, we highlight recent insights into risk stratification for patients with pediatric AML and discuss data driving current and develop

Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy.

INTRODUCTION

Bacteremia and other invasive bacterial infections are common among children with cancer receiving intensive chemotherapy and in pediatric recipients of hematopoietic stem cell transplantation (HSCT). Systemic antibacterial prophylaxis is one approach that can be used to reduce the risk of these infections. Our purpose was to develop a clinical practice guideline (CPG) for systemic antibacterial prophylaxis administration in pediatric cancer and HSCT patients.

METHODS

An international and multi-disciplinary panel was convened with representation from pediatric hematology/oncology and HSCT, pediatric infectious diseases (including antibiotic stewardship), nursing, pharmacy, a patient advocate and a CPG methodologist. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to generate recommendations based on the results of a systematic review of the literature.

RESULTS

The systematic review identified 114 eligible randomized trials of antibiotic prophylaxis. The panel made a weak recommendation for systemic antibacterial prophylaxis for children receiving intensive chemotherapy for acute myeloid leukemia and relapsed acute lymphoblastic leukemia (ALL). Weak recommendations against the routine use of systemic antibacterial prophylaxis were made for children undergoing induction chemotherapy for ALL, autologous HSCT and allogeneic HSCT. A strong recommendation against its routine use was made for children whose therapy is not expected to result in prolonged severe neutropenia. If used, prophylaxis with levofloxacin was recommended during severe neutropenia.

CONCLUSIONS

We present a CPG for systemic antibacterial prophylaxis administration in pediatric cancer and HSCT patients. Future research should evaluate the long-term effectiveness and adverse effects of prophylaxis.

/pdf/guideline-for-antibacterial-prophylaxis-administration-in-gdg1p1vyir.pdf

Guideline for Antibacterial Prophylaxis Administration in Pediatric Cancer and Hematopoietic Stem Cell Transplantation.

Importance Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT) There are limited data on the effect of antibiotic prophylaxis in children Objective To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT Design, setting, and participants In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups-acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients-at 76 centers in the United States and Canada, with follow-up completed September 2017 Interventions Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n = 100) or no prophylaxis (n = 100) Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n = 210) or no prophylaxis (n = 214) Main outcomes and measures The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT) Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile-associated diarrhea, and musculoskeletal toxic effects Results A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6-15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3-14]; 38% female), were enrolled Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (219% vs 434%; risk difference, 216%; 95% CI, 88%-344%, P = 001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (110% vs 173%; risk difference, 63%; 95% CI, 03%-130%; P = 06) Fever and neutropenia were less common in the levofloxacin group (712% vs 821%; risk difference, 108%; 95% CI, 42%-175%; P = 002) There were no significant differences in severe infection (36% vs 59%; risk difference, 23%; 95% CI, -11% to 56%; P = 20), invasive fungal disease (29% vs 20%; risk difference, -10%; 95% CI, -34% to 15%, P = 41), C difficile-associated diarrhea (23% vs 52%; risk difference, 29%; 95% CI, -01% to 59%; P = 07), or musculoskeletal toxic effects at 2 months (114% vs 163%; risk difference, 48%; 95% CI, -16% to 112%; P = 15) or at 12 months (101% vs 144%; risk difference, 43%; 95% CI, -34% to 120%; P = 28) between the levofloxacin and control groups Conclusions and relevance Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT

/pdf/effect-of-levofloxacin-prophylaxis-on-bacteremia-in-children-3cab4j8eyj.pdf

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.

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Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.