An intact gut microbiome protects genetically predisposed mice against leukemia.

The majority of childhood leukemias are precursor B-cell acute lymphoblastic leukemias (pB-ALLs) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1% to 5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. Although infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, by using murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice, even in the absence of infectious stimuli and independent of T cells. By using V4 and full-length 16S ribosomal RNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3983 amplicon sequence variants as proxies for bacterial species. Transplantation of either wild-type (WT) or Pax5+/- hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor genotype-specific manner. Gas chromatography-mass spectrometry (GC-MS) analyses of sera from WT and Pax5+/- mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.

Tratamiento exitoso de una fusariosis diseminada en un paciente neutropénico febril con terapia antifúngica combinada de voriconazol más anfotericina B deoxicolato / Successful treatment of disseminated fusariosis in a febrile neutropenic patient with combined antifungal therapy of voriconazol plus amphotericin B deoxycholate

Resumen Presentamos el caso clínico de un paciente con una leucemia linfoblástica aguda (LLA) que desarrolló una fusariosis diseminada por Fusarium verticillioides durante un episodio prolongado de neutropenia febril post quimioterapia. Fue exitosamente tratado cuando se usó terapia combinada de voriconazol más anfotericina B deoxicolato.

We report a case of a patient with acute lymphoblastic leukemia (ALL), who developed a disseminated infection by Fusarium verticillioides during chemotherapy-induced neutropenia. He was successfully treated only after combination therapy with voriconazole plus amphotericin B deoxycolate was used, but not when these compounds were used in an isolated form.

Multimodal Treatment of Rhinocerebral Mucormycosis in a Pediatric Patient With Relapsed Pre-B Acute Lymphoblastic Leukemia.

A 17-year-old girl developed invasive rhinocerebral mucormycosis during intensive re-induction chemotherapy for relapsed pre-B acute lymphoblastic leukemia. Due to the high case fatality rate for invasive mucormycosis in profoundly immunosuppressed patients, an aggressive treatment regimen was pursued. In addition to the standard of care treatments with intravenous amphotericin and aggressive surgical debridements, she received intraventricular amphotericin to the brain via an Ommaya reservoir, hyperbaric oxygen treatments, filgrastim, intravenous immunoglobulin and antifungal in vitro synergy testing to allow for more targeted antifungal therapy with the addition of micafungin. After a 3-month treatment course, it was determined that her mucormycosis was under appropriate control, allowing her to continue treatment for her leukemia with hematopoietic stem cell transplant with a plan for continued intravenous antifungal therapy through engraftment.

Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases.

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365-77. ©2017 AACR.

Safety and tolerability of high-dose weekly liposomal amphotericin B antifungal prophylaxis.

Children with hematologic malignancies are at an increased risk of invasive fungal infections and a greater risk has been seen with exposure to building construction. Prophylaxis with high-dose (IV) liposomal amphotericin B (L-AmB) 10 mg/kg once weekly was initiated in our high risk children based on previous pharmacokinetic studies. This treatment regimen was associated with a 26% incidence of adverse infusion reactions.

Bacteremia due to imipenem-resistant Roseomonas mucosa in a child with acute lymphoblastic leukemia.

Roseomonas are described as opportunistic pathogens rarely involved in human infections. Their identification requires molecular methods and their antimicrobial susceptibility pattern varies according to the species. We report the first case of bacteremia due to Roseomonas mucosa in a child with leukemia and reviewed pediatric cases of Roseomonas infection, for which undoubted strain identification was available. Favorable outcome was observed despite resistance to numerous ß-lactams that may account for delayed effective treatment, suggesting the low virulence of Roseomonas in children. Here, the strain also displayed unusual resistance to imipenem, highlighting the possible acquisition of additional resistance by this pathogen.

Trimethoprim-sulfamethoxazole salvage for refractory listeriosis during maintenance chemotherapy for acute lymphoblastic leukemia.

A 5-year-old boy with acute lymphoblastic leukemia (ALL) and intolerance to oral trimethoprim-sulfamethoxazole (TMP/SMX) had Listeria monocytogenes bacteremia and meningitis develop during maintenance chemotherapy. Despite prompt administration of IV amoxicillin/gentamicin and microbiologic clearance of the bloodstream, the patient had no response to therapy after a course of 7 days. Intravenous TMP/SMX (10 mg/kg per day of TMP) was added to the antibiotic regimen after desensitization. Fever and meningeal signs rapidly resolved, and the patient was ultimately cured. Amoxicillin and gentamicin, although highly active and synergistic in vitro against L. monocytogenes, have limited intracellular penetration and activity. In contrast, TMP/SMX has bactericidal extracellular and intracellular activity against Listeria and excellent central nervous system penetration, and thus may be effective for the treatment of refractory listeriosis.