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Prolonged neutropenia increases the risk for lethal invasive fungal infections (IFIs) such as those caused by Rhizopus species. Isavuconazonium sulfate is a new triazole that lacks pediatric dosing recommendations. Clinical courses of 4 pediatric patients with IFIs in the peri-allogeneic hematopoietic cell transplantation (alloHCT) period between 2015 and 2017 were reviewed. The reviews included previously unreported pharmacokinetic and safety data, and the IFIs included Rhizopus. Isavuconazonium sulfate was initiated with a loading dose followed by daily dosing, adjusted to a goal trough concentration of >3 mg/L based on adult literature. This target was achieved at a median of 7 days, demonstrating varying rates of metabolism. Renal insufficiency, electrolyte disturbances, and transaminitis were noted, although attribution was confounded by other alloHCT complications. One patient survived infection-free to hospital discharge and 1 of 3 deceased patients had evidence of an unresolved IFI (case 2). Case 2 was subtherapeutic for 39% of the duration of treatment, compared with others at an average of 29%, suggesting this target trough to be clinically relevant because case 2 demonstrated positive sinus and nasal cultures for Rhizopus on autopsy. We recommend initiation of isavuconazonium 10 mg/kg with a maximum dose of 372 mg. A loading dose of 10 mg/kg is used every 8 hours for 6 doses followed by 10 mg/kg dosing every 24 hours. Monitoring must continue beyond steady state. If early monitoring is not possible, we recommend a first drug level at week 3. If dose increases are required, a partial reload has been more successful instead of increasing daily doses. Further larger studies are needed to demonstrate optimum dosing in pediatric patients. ABBREVIATIONS alloHCT, allogeneic hematopoietic cell transplantation; CT, computed tomography; haploHCT, haploidentical hematopoietic stem cell transplant; HLA, human leukocyte antigen; IFI, invasive fungal infection; IV, intravenous; LAB, liposomal amphotericin B; MIC, minimum inhibitory concentration; MRI, magnetic resonance imaging; RIC, reduced intensity conditioning; UCBT, umbilical cord blood transplant. [ABSTRACT FROM AUTHOR]

Background Immune mediated cytopenias (IMC) – isolated or combined hemolytic anemia, thrombocytopenia, and neutropenia - are increasingly recognized as potentially serious complications following allogeneic hematopoietic cell transplantation (HCT) for non-malignant disorders (NMD). However, IMC incidence, severity, response to therapy, and risk factors are not well defined. Methods Pediatric patients undergoing HCT for NMD between 2010 and 2017 at a single institution were identified, excluding those experiencing graft failure or death prior to day +100. Demographics and HCT characteristics were obtained from a prospectively-maintained database. A retrospective chart review identified cases of IMC with positive direct Coombs test, anti-platelet antibody, and/or anti-granulocyte antibody; and documented treatment and response. IMC severity was defined by months to resolution: mild (0-3), moderate (3-6), or severe (>6). Results Of 271 NMD HCT recipients, 52 (19%) exhibited IMC at a median of 130 days post-HCT (range, 30-279); 23 (44% of cases) had multiple cell lines affected. IMC disease was mild, moderate, or severe in 44%, 25%, and 31%, respectively, with no deaths attributed to IMC. For those with moderate or severe IMC, all received steroid therapy, with a response rate of 34%. An average of 2.0 unique agents were used to achieve IMC resolution, at a median of 117 days (range 17 – 639). Univariate analysis revealed statistically significant associations between IMC and younger age at HCT (median 3.7 vs. 7.0 years, p<0.01), inherited metabolic disorder or hemoglobinopathy as indication for HCT (p<0.01), reduced toxicity conditioning (p<0.01), and use of serotherapy in conditioning (p=0.04). While presence of acute graft-versus-host disease (GvHD) was not associated, those with IMC were more likely to receive steroids for GvHD prophylaxis (p<0.01). Following HCT, a decline in peripheral blood donor CD3+ chimerism by at least 10% from day +60 to +100 was more common in those with IMC (p<0.01), with a trend toward lower peripheral blood CD3+ donor chimerism at day +100 (71% IMC vs 88.5% no IMC, p = 0.1). Lower absolute CD4 count at days +100 (median 100 vs. 163) and +180 (median 170 vs. 276) were observed (p<0.01) with no differences in CD8 or CD19. Conclusion Immune mediated cytopenias following HCT for NMD in a large pediatric cohort was common at 19%, with limited steroid responsiveness, use of multiple immunosuppressive agents and duration of therapy exceeding 3 months for the majority affected. Patient and transplant characteristics associated with IMC were consistent with previous reports, though we expand these findings with observation of declining donor T-lymphoid chimerism and CD4 counts by day +100, prior to median onset of IMC. While, the pathogenesis of IMC post-HCT for NMD remains elusive, further research may identify approaches to prevent this HCT complication. [ABSTRACT FROM AUTHOR]