Overall survival (OS) of pediatric patients with acute myeloid leukemia (AML) increased in recent decades. However, it remained unknown whether advances in first-line treatment, supportive care, or second-line therapy mainly contributed to this improvement. Here, we retrospectively analyzed outcome and clinical data of 1940 pediatric AML patients (younger than 18 years of age), enrolled in the population-based AML-BFM trials between 1987 and 2012. While 5-year probability of OS (pOS) increased from 49 ± 3% (1987–1992) to 76 ± 4% (2010–2012; p < 0.0001), probability of event-free survival only improved from 41 ± 3% (1987–1992) to 50 ± 2% (1993–1998; p = 0.02) after introduction of high-dose cytarabine/mitoxantrone, but remained stable since then. Non-response and relapse rates stayed constant despite intensified first-line therapy (p = 0.08 and p = 0.17). Reduced fatal bleedings and leukostasis translated into fewer early deaths (8.1%vs. 2.2%; p = 0.001). Strikingly, pOS after non-response (13 ± 5% (1987–1992) vs. 43 ± 7% (2005–2010); p < 0.0001) or relapse (19 ± 4% vs. 45 ± 4%; p < 0.0001) improved. After 1999, more relapsed or refractory patients underwent hematopoietic stem cell transplantation (HSCT) with increased pOS after HSCT (29 ± 5% (1993–1998) vs. 50 ± 4% (2005–2010); p < 0.0001). Since efficacy of salvage therapy mainly contributed to better outcome in pediatric AML, our analysis indicates that a better allocation of patients, who cannot be cured with conventional chemotherapy, to an early “salvage-like” therapy is necessary.

/pdf/successes-and-challenges-in-the-treatment-of-pediatric-acute-welxl20ojh.pdf

Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012

Considerable progress has been made in the prevention, diagnosis, and management of pediatric patients with invasive fungal disease (IFD). The reported decreasing trend in the incidence of invasive candidiasis (IC) over the past 15 years in both neonates and children has been encouraging. Nevertheless, due to the growing number of immunocompromised children at risk for IFD, this disease continues to be associated with significant morbidity and death and with increased financial burden to the health care system. Therefore, it is important to understand the contemporary epidemiology of IFD. Incidence rates of IFD in children are affected by geographical, population, and time variability. There is an ongoing effort to constantly document and update the incidence of IFD and species distribution among different pediatric populations as a means to direct preventative, diagnostic, and therapeutic resources to the most appropriate subset of patients. Children with a hematologic malignancy or a primary or secondary immunodeficiency, those undergoing solid organ or hematopoietic stem cell transplantation, and premature neonates are the major subsets of pediatric patients at risk of developing IFD. In this review, we focus on fungal disease epidemiology with a specific emphasis on the 2 most common pediatric IFDs, IC and invasive aspergillosis (IA).

Epidemiology of Invasive Fungal Disease in Children.

Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review

8th European Conference on Infections in Leukaemia: 2020 guidelines for the use of antibiotics in paediatric patients with cancer or post-haematopoietic cell transplantation.

Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children’s Oncology Group AAML0431 trial

Invasive fungal infections (IFIs) cause high rates of morbidity and mortality in immunocompromised patients Pattern-recognition receptors present on the surfaces of innate immune cells recognize fungal pathogens and activate the first line of defense against fungal infection The second line of defense is the adaptive immune system which involves mainly CD4+ T cells, while CD8+ T cells also play a role CD8+ T cell-based vaccines designed to prevent IFIs are currently being investigated in clinical trials, their use could play an especially important role in acquired immune deficiency syndrome patients So far, none of the vaccines used to treat IFI have been approved by the FDA Here, we review current and future antifungal immunotherapy strategies involving CD8+ T cells We highlight recent advances in the use of T cells engineered using a Sleeping Beauty vector to treat IFIs Recent clinical trials using chimeric antigen receptor (CAR) T-cell therapy to treat patients with leukemia have shown very promising results We hypothesized that CAR T cells could also be used to control IFI Therefore, we designed a CAR that targets β-glucan, a sugar molecule found in most of the fungal cell walls, using the extracellular domain of Dectin-1, which binds to β-glucan Mice treated with D-CAR+ T cells displayed reductions in hyphal growth of Aspergillus compared to the untreated group Patients suffering from IFIs due to primary immunodeficiency, secondary immunodeficiency (eg, HIV), or hematopoietic transplant patients may benefit from bioengineered CAR T cell therapy

/pdf/methods-of-controlling-invasive-fungal-infections-using-cd8-423xppbc0w.pdf

Methods of Controlling Invasive Fungal Infections Using CD8 + T Cells

Background

Children with acute myeloid leukemia (AML) and Down syndrome have high survival rates with intensity-reduced chemotherapeutic regimens, although the optimal balance between dose intensity and treatment toxicity has not been determined. We, therefore, characterized infectious complications in children with AML and Down syndrome treated according to AML-BFM 2004 study (ClinicalTrials.gov NCT00111345; amended 2006 for Down syndrome with reduced intensity).



Procedure

Data on infectious complications were gathered from the medical records in the hospital where the patient was treated. Infectious complications were categorized as fever without identifiable source (FUO), or as microbiologically or clinically documented infections.



Results

A total of 157 infections occurred in 61 patients (60.5% FUO, 9.6% and 29.9% clinically and microbiologically documented infections, respectively). Almost 90% of the pathogens isolated from the bloodstream were Gram-positive bacteria, and approximately half of them were viridans group streptococci. All seven microbiologically documented episodes of pneumonia were caused by viruses. Infection-related mortality was 4.9%, and all three patients died due to viral infection.



Conclusions

Our data demonstrate that a reduced-intensity chemotherapeutic regimen in children with AML and Down syndrome is still associated with high morbidity. Although no patient died due to bacteria or fungi, viruses were responsible for all lethal events. Future studies, therefore, have to focus on the impact of viruses on morbidity and mortality of patients with AML and Down syndrome.

Infectious Complications in Children With Acute Myeloid Leukemia and Down Syndrome: Analysis of the Prospective Multicenter Trial AML-BFM 2004.

Infections are an important cause for morbidity and mortality in pediatric acute myeloid leukemia (AML). We therefore characterized infectious complications in children treated according to the trial AML-BFM 2004. Patients with Down syndrome were excluded from the analysis. Data were gathered from the medical records in the hospital where the patients were treated. A total of 405 patients (203 girls; median age 8.4 years) experienced 1326 infections. Fever without identifiable source occurred in 56.1% of the patients and clinically and microbiologically documented infections in 17.5% and 32.4% of the patients, respectively. In all, 240 Gram-positive (112 viridans group streptococci) and 90 Gram-negative isolates were recovered from the bloodstream. Invasive fungal infection was diagnosed in 3% of the patients. Three children each died of Gram-negative bacteremia and invasive aspergillosis, respectively. As compared with the results of AML-BFM 93 with lower dose intensity, infection-related morbidity was slightly higher in AML-BFM 2004 (3.3. versus 2.8 infections per patient), whereas infection-related mortality significantly decreased (1.5% versus 5.4%; P=0.003). Specific anti-infective recommendations included in the treatment protocol, regular training courses for pediatric hematologists and increasing experience may be the reason for reduced infection-related mortality in children with AML. Further studies are needed to decrease infection-related morbidity.

/pdf/infectious-complications-in-children-with-acute-myeloid-3jwpfrsx2u.pdf

Infectious complications in children with acute myeloid leukemia: decreased mortality in multicenter trial AML-BFM 2004.

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Infectious Complications in Children With Acute Myeloid Leukemia and Down Syndrome: Analysis of the Prospective Multicenter Trial AML-BFM 2004.

Infectious complications in children with acute myeloid leukemia: decreased mortality in multicenter trial AML-BFM 2004.