Stopping antibacterial prophylaxis in pediatric allogeneic hematopoietic cell transplantation: An internal audit.

BACKGROUND: Antibacterial prophylaxis in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) is controversial and not recommended by international guidelines. We analyzed relevant posttransplant outcomes following discontinuation of antibacterial prophylaxis at a major European pediatric transplant center. METHODS: The single-center retrospective audit included all pediatric allogeneic HCT patients (pts) transplanted between 2011 and 2020 before (≤2014) and after (≥2015) stopping routine antibacterial prophylaxis with penicillin, metronidazole, and ciprofloxacin upon start of the conditioning regimen. The primary endpoint was overall survival until the first hospital discharge. Secondary endpoints included the occurrence of fever; bacterial infections; and cumulative days with antibacterial agents until discharge. RESULTS: A total of 257 HCT procedures were performed in 249 pts (median age: 10 years, range, 0.2-22.5) for leukemia/lymphoma (n = 150) and nonmalignant disorders (n = 107). Of these, 104 procedures were performed before (cohort 1) and 153 after (cohort 2) stopping prophylaxis. Overall survival until discharge was 90.4% in cohort 1 and 96.1% in cohort 2 (p = .06). No differences were observed in the occurrence of fever (92.3 vs. 94.1%; p = .57) and bacterial infections (34.6 vs. 25.5%; p = .11). The median number of days on antibacterial agents was significantly lower in cohort 2 (39 vs. 34; p = .002). Detection rates of resistant organisms were overall low. CONCLUSION: In this single-center audit, the stop of routine antibacterial prophylaxis had no effect on the occurrence of fever, bacterial infections, resistant organisms, and GVHD. Overall antibiotic use was significantly reduced, and survival was noninferior to the historical control cohort.

Characteristics and Outcome of Elderly Patients (>55 Years) with Acute Lymphoblastic Leukemia.

Prognosis of elderly ALL patients remains dismal. Here, we retrospectively analyzed the course of 93 patients > 55 years with B-precursor (n = 88) or T-ALL (n = 5), who received age-adapted, pediatric-inspired chemotherapy regimens at our center between May 2003 and October 2020. The median age at diagnosis was 65.7 years, and surviving patients had a median follow-up of 3.7 years. CR after induction therapy was documented in 76.5%, while the rate of treatment-related death within 100 days was 6.4%. The OS of the entire cohort at 1 and 3 year(s) was 75.2% (95% CI: 66.4-84.0%) and 47.3% (95% CI: 36.8-57.7%), respectively, while the EFS at 1 and 3 years(s) was 59.0% (95% CI: 48.9-69.0%) and 32.9% (95% CI: 23.0-42.8%), respectively. At 3 years, the cumulative incidence (CI) of relapse was 48.3% (95% CI: 38.9-59.9%), and the CI rate of death in CR was 17.3% (95% CI: 10.9-27.5%). Older age and an ECOG > 2 represented risk factors for inferior OS, while BCR::ABL1 status, immunophenotype, and intensity of chemotherapy did not significantly affect OS. We conclude that intensive treatment is feasible in selected elderly ALL patients, but high rates of relapse and death in CR underline the need for novel therapeutic strategies.

Cytomegalovirus retinitis in children and adolescents with acute leukemia following allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus retinitis (CMVR) may occur after allogeneic hematopoietic stem cell transplantation (HSCT). However, little is known about its incidence, strategies for ophthalmic surveillance, and timely implementation of adequate antiviral treatment in pediatric allogeneic HSCT recipients. We provide a retrospective analysis of the epidemiology and clinical features of CMVR in pediatric allogeneic HSCT patients transplanted at our center over a 16-year period. Two patients of this cohort with leukemia are presented. Our analysis is supplemented by a systematic review on pediatric patients with leukemia and CMVR in the setting of allogeneic HSCT. The overall incidence of CMVR in our cohort was 1% (4/338) and 14.2% (3/21) in leukemic patients. In published cases, CMVR occurred at a median of 143 days after transplantation, and, in the majority of patients, was preceded by CMV detection in blood by a median of 93 days. Continued immune suppression following engraftment likely triggers CMVR. Preemptive treatment with ganciclovir as standard is usually successful. Foscarnet is used in case of resistance to ganciclovir or drug-induced granulocytopenia. Overall, CMVR after HSCT in pediatric leukemic patients is rare, but a potentially higher vulnerability of this population for involvement of the eye warrants a standardized ophthalmological examination plan.

Azole-based chemoprophylaxis of invasive fungal infections in paediatric patients with acute leukaemia: an internal audit.

OBJECTIVES: Children and adolescents with acute myeloid leukaemia (AML) and recurrent acute leukaemias (RALs) are at high risk of life-threatening invasive fungal infections (IFIs). We analysed implementation, safety and efficacy of a standard operating procedure for oral, azole-based, mould-active antifungal prophylaxis. METHODS: Patients with AML and RALs aged ≥13 years received 200 mg of posaconazole three times daily and patients aged 2-12 years received 200 mg of voriconazole two times daily from the completion of chemotherapy until haematopoietic recovery. Algorithms for fever or focal findings in all patients with haematological malignancies included blood cultures, high-resolution CT and other appropriate imaging, serial serum galactomannan, invasive diagnostics and pre-emptive therapy with change in class if on antifungal medication. RESULTS: From 2006 to 2010, 40 patients (0.8-17 years; 21 males) with newly diagnosed AML (n = 31) or RAL (n = 9) were admitted, of whom 36 received a total of 149 courses of chemotherapy (reasons for exclusion: contraindications and early death ≤3 days). Azole prophylaxis was given in 87.2% (n = 130/149) of episodes. Pre-emptive antifungal therapy for pulmonary infiltrates was initiated in 5/36 (13.9%) patients or 6/130 (4.6%) episodes for a duration of 3-22 days. No proven or probable IFIs occurred. Adverse events (AEs) were common but mostly low grade and reversible. Three courses (2.3%) were discontinued due to AEs. In simultaneously admitted new patients with acute lymphatic leukaemia (ALL; n = 101) and paediatric lymphomas (n = 29) not receiving standard antifungal prophylaxis, proven/probable IFIs occurred in 4 patients with ALL (4.0%) and 7/130 patients (5.4%) received pre-emptive therapy. CONCLUSIONS: Azole-based, mould-active antifungal prophylaxis in high-risk paediatric patients with AML and RALs was satisfactorily implemented, well tolerated and effective. The low rate of IFIs in patients with ALL/lymphoma supports the lack of a general indication for prophylaxis in this population in the presence of a diagnostic and therapeutic algorithm.

Monitoring of voriconazole plasma concentrations in immunocompromised paediatric patients.

OBJECTIVES: Voriconazole is approved for management of invasive fungal diseases (IFDs) in paediatric patients. We analysed plasma trough concentrations and explored their association with endpoints of antifungal therapy. PATIENTS AND METHODS: The cohort included 74 immunocompromised patients (0.2-18 years of age) who received 101 courses of voriconazole for possible (7) and probable/proven (13) IFDs, as prophylaxis (79) or empirical therapy (2). Voriconazole was given intravenously (4), intravenously and orally (15) and orally (82) at recommended dosages until intolerance or maximum efficacy. IFDs and outcomes were assessed by EORTC/MSG consensus criteria. RESULTS: Voriconazole was administered at a median maintenance dosage of 4.8 mg/kg twice daily (range 2.2-17.4) for a median of 40 days (range 6-1002). Trough plasma concentrations at steady state (251 samples; 3.4 ±â€Š4.3/patient) ranged from <0.2 to 14.9 mg/L with high intra- and inter-individual variability and no apparent relationship to dose (P = 0.074, ANOVA). Of the samples 22%, 42% and 58% had voriconazole concentrations <0.2, ≤0.5 and ≤1.0 mg/L, respectively. Adverse events (AEs) occurred in 77/101 (76.2%) courses and were mostly grade I or II. Ten courses (9.9%) were discontinued due to AEs. Treatment success was observed in 8/20 patients (40%) with IFDs, and in 67/81 courses (82.7%) of empirical therapy/prophylaxis. There were no consistent correlations between dose, trough concentrations and laboratory/clinical AEs or treatment response, and proposed threshold values were not discriminative. CONCLUSIONS: Voriconazole had acceptable safety and useful efficacy in the management of paediatric IFDs. Pharmacokinetic variability was high and no predictable dose-concentration-effect relationships were observed.

Population pharmacokinetics of liposomal amphotericin B and caspofungin in allogeneic hematopoietic stem cell recipients.

Liposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoietic stem cell transplant (aHSCT) recipients. Little is known, however, about the pharmacokinetics (PK) of both agents and their combination in this population. The PK of LAMB and CAS and the potential for PK interactions between both agents were investigated within a risk-stratified, randomized phase II clinical trial in 53 adult aHSCT recipients with granulocytopenia and refractory fever. Patients received either LAMB (n = 17; 3 mg/kg once a day [QD]), CAS (n = 19; 50 mg QD; day 1, 70 mg), or the combination of both (CAS-LAMB; n = 17) for a median duration of 10 to 13 days (range, 4 to 28 days) until defervescence and granulocyte recovery. PK sampling was performed on days 1 and 4. Drug concentrations in plasma (LAMB, 405 samples; CAS, 458 samples) were quantified by high-pressure liquid chromatography and were analyzed using population pharmacokinetic modeling. CAS concentration data best fitted a two-compartment model with a proportional error model and interindividual variability (IIV) for clearance (CL) and central volume of distribution (V(1)) (CL, 0.462 liter/h ± 25%; V(1), 8.33 liters ± 29%; intercompartmental clearance [Q], 1.25 liters/h; peripheral volume of distribution [V(2)], 3.59 liters). Concentration data for LAMB best fitted a two-compartment model with a proportional error model and IIV for all parameters (CL, 1.22 liters/h ± 64%; V(1), 19.2 liters ± 38%; Q, 2.18 liters/h ± 47%; V(2), 52.8 liters ± 84%). Internal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB or CAS comedication, gender, body weight, age, body surface area, serum bilirubin, and creatinine clearance) further improved the models. In summary, the disposition of LAMB and CAS was best described by two-compartment models. Drug exposures in aHSCT patients were comparable to those in other populations, and no PK interactions were observed between the two compounds.

Randomized comparison of safety and pharmacokinetics of caspofungin, liposomal amphotericin B, and the combination of both in allogeneic hematopoietic stem cell recipients.

The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.

Safety, tolerance and outcome of treatment with liposomal amphotericin B in paediatric patients with cancer or undergoing haematopoietic stem cell transplantation.

OBJECTIVES: To assess safety, tolerance and efficacy of liposomal amphotericin B (LAMB) in a large unselected series of paediatric cancer/haematopoietic stem cell transplantation (HSCT) patients requiring LAMB therapy. PATIENTS AND METHODS: The study included 84 children and adolescents (median age: 11 years) who received 141 consecutive courses of LAMB for prophylaxis (32), empirical therapy (83), possible (19) or probable/proven (7) invasive infections. LAMB was administered until intolerance or maximum efficacy at dosages individually determined by the responsible physician. RESULTS: Fifty-nine courses were post-HSCT (42%, 49 allogeneic), and 92 courses were started during granulocytopenia (65%). The median duration of LAMB therapy was 13 days (range 1-79), and the median maximum dosage was 2.8 mg/kg (range 0.93-5.10). Mild-to-moderate adverse events were noted during 109 courses (77%; hepatic, 58.8%; electrolyte wasting, 52.5%; renal, 31.9%; infusion-related reactions, 8.5%); adverse events necessitating discontinuation of LAMB occurred in 6 courses (4.3%; renal, 3; anaphylaxis, 2; hepatic, 1). While median hepatic transaminase, alkaline phosphatase and blood urea nitrogen values were slightly (P < 0.01) higher at end of treatment (EOT), bilirubin and creatinine values were not different from baseline. Complete or partial responses were observed in 16/19 and 2/7 courses for possible and probable/proven invasive infections. Thirty-two of 33 courses of prophylaxis and 74 of 83 courses of empirical therapy were completed with success. Overall survival was 90.8% at 3 months post-EOT. CONCLUSIONS: LAMB had acceptable safety and tolerance and was useful in prevention and treatment in unselected, mostly granulocytopenic paediatric patients undergoing treatment for cancer or HSCT.

Secondary antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell recipients.

OBJECTIVES: Presumed or proven invasive pulmonary aspergillosis (IPA) is an important cause of infectious morbidity in patients with acute leukaemia. Although prior IPA is not a contraindication for subsequent allogeneic haematopoietic stem cell transplantation (HSCT), its management during granulocytopenia and immunosuppression remains challenging. PATIENTS AND METHODS: In the absence of an evidence-based approach, 11 adolescents (11-18 years) with acute leukaemia and a history of antecedent possible (4) or probable (7) IPA received liposomal amphotericin B (LAMB; 1 mg/kg once a day) from the start of the conditioning regimen until engraftment and ability to take oral medication, followed by oral voriconazole (200 mg twice a day) until the end of the at-risk period. Nine patients had a good partial response (>50% reduction in pulmonary infiltrates) and two had a complete response prior to HSCT. RESULTS: The median duration of intravenous treatment with LAMB was 30 days (range, 19-36), followed by a median of 152 days (range, 19-210) of oral voriconazole. LAMB was discontinued early in one patient and voriconazole was transiently or permanently discontinued due to adverse events/new contraindications in two and two patients, respectively. At +180 days post-transplant, eight patients were alive, six with complete, and one each with near complete and ongoing resolution of pulmonary infiltrates; all but one were in continuing haematological remission. Three patients had succumbed either to recurrent leukaemia (two) or refractory graft failure (one); whereas one of these patients had maintained a complete response, two died with secondary possible (one) or probable (one) IPA. Both patients had discontinued voriconazole early and developed IPA in lung areas involved during the primary episode. CONCLUSIONS: This prospective paediatric series supports the notion that secondary antifungal prophylaxis for possible or probable IPA can be safely achieved in allogeneic HSCT. In the absence of chronic graft-versus-host disease, breakthrough infection appeared to be associated with recurrent leukaemia/graft failure and shorter duration of post-engraftment prophylaxis.

Pharmacokinetic interaction between voriconazole and ciclosporin A following allogeneic bone marrow transplantation.

Voriconazole is a novel antifungal triazole that undergoes extensive oxidative metabolization involving several CYP450 isoenzymes. We report the case of a 14-year-old patient who received voriconazole concomitant with ciclosporin A as secondary antifungal prophylaxis after bone marrow transplantation. Temporary discontinuation of voriconazole due to worsening liver function tests (LFTs) resulted in a sudden drop of ciclosporin A trough levels in blood. Ciclosporin A trough levels returned to baseline following normalization of LFTs and re-institution of voriconazole. This report emphasizes the need for careful monitoring and dose adjustments of ciclosporin A in patients receiving concomitant voriconazole, and in whom voriconazole is discontinued in order to prevent subtherapeutic ciclosporin A levels with the potential consequence of graft-versus-host disease.