Cerebrospinal fluid concentrations of posaconazole in paediatric leukaemia patients.

BACKGROUND: Little is known about the distribution of posaconazole in brain tissue and CSF. We therefore analysed trough concentrations of posaconazole in paediatric leukaemia patients in non-inflamed CSF. PATIENTS AND METHODS: The study included paediatric patients <18 years of age with acute leukaemia in remission who underwent repeat therapeutic lumbar punctures as part of their anti-leukaemia treatment. CSF and blood were obtained 20-24 h after dosing, and posaconazole was measured by LC-MS/MS. RESULTS: Six patients (median age: 10 years; range, 6-14) with acute lymphatic (three) or acute myeloid (three) leukaemia were included who received posaconazole gastroresistant tablets at weight-banded doses (five) or the oral solution (one). In contrast to 14 control samples, posaconazole was detectable in all 11 samples of treated patients. CSF concentrations ranged from 8.3 to 42 ng/mL with a median CSF concentration of 13.6 ng/mL. Concurrent serum concentrations were between 965 and 5177 ng/mL with a median of 1716 ng/mL. CONCLUSIONS: Trough concentrations of posaconazole in the CSF after systemic administration were low but detectable in all subjects. Concurrent serum concentrations were in the target range for prophylaxis and treatment in 100% and 90%, respectively.

New and emerging options for management of invasive fungal diseases in paediatric patients.

Invasive fungal diseases (IFDs) play an important role in the supportive care of paediatric patients with acute leukaemia and those undergoing allogeneic haematopoietic cell transplantation, and they are associated with significantly decreased overall survival rates in affected individuals. Relative to adults, children and adolescents are distinct in terms of host biology, predisposing conditions, presentation and epidemiology of fungal diseases, and in the pharmacology of antifungal agents. The paediatric development of antifungal agents has moved forward in a coordinated manner, and major advances have been made regarding concepts and recommendations for the prevention and treatment of IFDs. However, antifungal therapy is increasingly complex, and a solid knowledge of the available options is needed more than ever for successful management. This narrative review provides a summary of the paediatric development of agents that have been recently approved (anidulafungin, posaconazole) or are in advanced stages of development (isavuconazole). It also reviews the emerging evidence for the efficacy of echinocandins for prophylaxis of invasive aspergillosis, presents new data on alternative dosing regimens of echinocandins and voriconazole, and provides a brief overview of new antifungal agents in clinical development that are expected to be developed for paediatric patients.

Letermovir for Prophylaxis and Pre-emptive Therapy of Cytomegalovirus Infection in Paediatric Allogeneic Haematopoietic Cell Transplant Patients.

BACKGROUND: Cytomegalovirus (CMV) infection is a frequent event in patients undergoing allogeneic haematopoietic cell transplantation (HCT) and is associated with increased morbidity and mortality due to eventual progress to end-organ disease. Letermovir prophylaxis for CMV infections has become a standard of care in adult HCT recipients due to its efficacy and high tolerability. However, it is not yet approved for paediatric patients. OBJECTIVE: In a retrospective single-centre observational study we evaluated the use of letermovir for prophylaxis or pre-emptive treatment of cytomegalovirus (CMV) infection in seropositive paediatric HCT recipients receiving the compound outside of clinical trials. The primary endpoint was CMV reactivation requiring a change of medication. METHODS: A total of 17 patients (seven female/ten male; median age 12.2 [range 3.5-19] years, median body weight 39.5 [range 15-63] kg; median follow-up time 463.7 [range 41-1022] days) were identified who were started on oral (14) or intravenous (3) followed by oral (2) letermovir shortly after neutrophil engraftment at doses determined on the basis of age, weight, and concomitant cyclosporine use. RESULTS: Five patients had no evidence of viral replication (prophylactic use), while 12 patients had varying extents of viral replication (pre-emptive therapy). A change of therapy was required in one patient due to a sustained increase in CMV viral load, and in two patients, letermovir was stopped without later reactivation after initiation of palliative care for recurrent leukaemia. Of the 14 patients who completed treatment, 3 had evidence of transient viral replication after end of treatment that required no further antiviral treatment. No patients (of 17) discontinued letermovir due to an adverse event. CONCLUSION: Letermovir was effective in controlling CMV infection in seropositive paediatric allogeneic HCT recipients and was overall well tolerated. Pending completion of the still ongoing paediatric investigation plans, letermovir will be an important adjunct to our options for control of infectious complications in this special population.

Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma.

Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity (Transcription factor EB-TFEB, forkhead boxO-FOXO) and autophagic flux in neuroblastoma cells. In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.

Pharmacotherapeutic Management of Pediatric Lymphoma.

Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) comprise approximately 15% of all childhood malignancies. Cure rates for both lymphoma entities have evolved tremendously during the last couple of decades, raising the 5-year survival rates to almost 100% for HL and to 85% for NHL. The mainstay therapy for both malignancies is still chemotherapy-with different regimens recommended for different types of disease. In HL, combined modality treatment, i.e., chemotherapy followed by radiotherapy, has long been the standard regimen. In order to reduce long-term side effects, such as second malignancies, most major pediatric HL consortia have studied response-based radiotherapy reduction strategies over the last 3 decades. For recurrent disease, high-dose chemotherapy followed by an autologous or an allogeneic hematopoietic stem-cell transplant is an option. No targeted agents have yet gained regulatory approval for use in pediatric patients with lymphoma. For adult lymphoma patients, the CD20 antibody rituximab and the CD30 antibody-drug conjugate brentuximab vedotin are targeted agents used regularly in first- and second-line treatment regimens. More recently, immune checkpoint inhibitors, phosphatidyl-inositol-3-kinase inhibitors, and Bruton's tyrosine kinase inhibitors appear to be very promising new treatment options in adult lymphoma. Here, we discuss the current experience with these types of agents in pediatric lymphoma patients.