[Show abstract][Hide abstract] ABSTRACT: Autologous stem cell transplantation (ASCT) is applied to consolidate first remission in patients with acute myeloid leukaemia (AML). However, outcome after ASCT widely varies among AML patients. We analyzed the prognostic significance of haematological recovery for neutrophils [absolute neutrophil count (ANC) >1·0 × 109/l] and platelets (platelet count >20·0 × 109/l), stratifying at day 20 after ASCT in 88 consecutive and homogeneously treated AML patients in first remission. We observed that patients with delayed recovery had better overall survival (OS; ANC: P < 0·0001 and platelets: P = 0·0062) and time to progression (TTP; ANC: P = 0·0003 and platelets: P = 0·0125). Delayed recovery was an independent marker for better OS and TTP in a multivariate analysis including age, gender, number of transfused CD34+ cells, cytogenetics, FLT3-internal tandem duplication and NPM1 mutation. Our results suggest that delayed neutrophil and platelet recovery is associated with longer OS and TTP in AML patients consolidated with ASCT in first remission.
British Journal of Haematology 09/2014; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In children and adolescents with fever in neutropenia (FN) during chemotherapy for cancer, hemoglobin ≥90 g/L at presentation with FN had been associated with adverse events (AE). This analysis explored three hypothetical pathophysiological mechanisms potentially explaining this counterintuitive finding, and further analyzed the statistical association between hemoglobin and AE.
PLoS ONE 07/2014; 9(7):e101696. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Current practice in Switzerland for the mobilization of autologous stem cells in myeloma patients is combining vinorelbine chemotherapy and G-CSF cytokine stimulation. We prospectively investigated adding intravenous plerixafor to the vinorelbine/G-CSF combination (VGP), and compared it to vinorelbine/plerixafor (VP) and G-CSF/plerixafor (GP) combinations. In a final cohort (VP-late), plerixafor was given on the first day of CD34+ cells rising >15'000/ml peripheral blood. Four consecutive cohorts of ten myeloma patients were studied. We observed that intravenously administered plerixafor can be safely combined with vinorelbine/G-CSF. VGP was superior in mobilizing peripheral stem and progenitor cells compared to the three double combinations (VP, GP and VP-late), and GP mobilized better than VP. Our data indicate that the triple combination of vinorelbine, G-CSF and plerixafor is an efficient strategy to collect autologous CD34+ cells, with G-CSF contributing predominantly in this concept. Plerixafor can be safely added to G-CSF and/or to vinorelbine chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: Gamma irradiation is currently the standard care to avoid transfusion-associated graft-versus-host disease. Guidelines on gamma irradiation of blood components state that platelets (PLTs) can be irradiated at any stage in their 5-day storage and can thereafter be stored up to their normal shelf life of 5 days after collection. In this study, we explored whether the timing of irradiation has an effect on transfusion efficacy of apheresis PLT concentrates (APCs).
[Show abstract][Hide abstract] ABSTRACT: Fever and neutropenia (FN) often complicate anticancer treatment and can be caused by potentially fatal infections. Knowledge of pathogen distribution is paramount for optimal patient management.
Microbiologically defined infections (MDI) in pediatric cancer patients presenting with FN by nonmyeloablative chemotherapy enrolled in a prospective multi-center study were analyzed. Effectiveness of empiric antibiotic therapy in FN episodes with bacteremia was assessed taking into consideration recently published treatment guidelines for pediatric patients with FN.
MDI were identified in a minority (22%) of pediatric cancer patients with FN. In patients with, compared to without MDI, fever (median, 5 [IQR 3-8] vs. 2 [IQR1-3] days, p < 0.001) and hospitalization (10 [6-14] vs. 5 [3-8] days, p < 0.001) lasted longer, transfer to the intensive care unit was more likely (13 of 95 [14%] vs. 7 of 346 [2.0%], p < 0.001), and antibiotics were given longer (10 [7-14] vs. 5 [4-7], p < 0.001). Empiric antibiotic therapy in FN episodes with bacteremia was highly effective if not only intrinsic and reported antimicrobial susceptibilities were considered but the purposeful omission of coverage for coagulase negative staphylococci and enterococci was also taken into account (81% [95%CI 68 - 90] vs. 96.6% [95%CI 87 - 99.4], p = 0.004) CONCLUSIONS: MDI were identified in a minority of FN episodes but they significantly affected management and the clinical course of pediatric cancer patients. Compliance with published guidelines was associated with effectiveness of empiric antibiotic therapy in FN episodes with bacteremia.
The Pediatric Infectious Disease Journal 03/2014; · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.
British Journal of Haematology 02/2013; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Voriconazole is used in antifungal prophylaxis. We performed a retrospective review of immunocompromised children receiving prophylaxis with voriconazole during major hospital renovation, who developed phototoxic skin reactions. The overall incidence of phototoxic skin reactions was 33%. A voriconazole dose of ≥6 mg/kg of body weight per dose twice daily was associated with a significantly greater risk to develop phototoxic skin reactions compared with lower doses.
[Show abstract][Hide abstract] ABSTRACT: The standard treatment of fever in chemotherapy-induced neutropenia (FN) includes emergency hospitalization and empirical intravenous antimicrobial therapy. This study determined if first-day step-down to oral outpatient treatment is not inferior to continued standard regarding safety and efficacy in children with low-risk FN.
In a randomized controlled non-blinded multicenter study, pediatric patients with FN after non-myeloablative chemotherapy were reassessed after 8-22 hours of inpatient intravenous antimicrobial therapy. Low-risk patients were randomized to first-day step-down to experimental (outpatient, oral amoxicillin plus ciprofloxacin) versus continued standard treatment. Exact non-inferiority tests were used for safety (no serious medical complication; non-inferiority margin of difference, 3.5%) and efficacy (resolution of infection without recurrence, no modification of antimicrobial therapy, no adverse event; 10%).
In 93 (26%) of 355 potentially eligible FN episodes low-risk criteria were fulfilled, and 62 were randomized, 28 to experimental (1 lost to follow-up) and 34 to standard treatment. In intention-to-treat analyses, non-inferiority was not proven for safety [27 of 27 (100%) vs. 33 of 34 (97%; 1 death) episodes; 95% upper confidence border, 6.7%; P = 0.11], but non-inferiority was proven for efficacy [23 of 27 (85%) vs. 26 of 34 (76%) episodes; 95% upper confidence border, 9.4%; P = 0.045]. Per-protocol analyses confirmed these results.
In children with low-risk FN, the efficacy of first-day step-down to oral antimicrobial therapy with amoxicillin and ciprofloxacin in an outpatient setting was non-inferior to continued hospitalization and intravenous antimicrobial therapy. The safety of this procedure, however, was not assessable with sufficient power.
Pediatric Blood & Cancer 01/2012; 59(3):423-30. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fever and chemotherapy-induced neutropenia (FN) is the most frequent potentially lethal complication of therapy in children with cancer. This study aimed to describe serious medical complications (SMC) in children with FN regarding incidence, clinical spectrum, and associated characteristics.
Pediatric patients presenting with FN induced by non-myeloablative chemotherapy were observed in a prospective multicenter study. SMC was defined as potentially life-threatening complication (PLTC), transfer to the pediatric intensive care unit (PICU), or death.
A total of 443 FN episodes were reported from 8 centers. Of these, 411 episodes were reported from 4 centers recruiting consecutively and without bias regarding the risk of complications. They were used for calculation of proportions. An SMC was reported in 23 episodes [5.6%; 95% confidence interval (CI): 3.7-8.1], usually defined by more than one criterion. These were PLTC in 13 episodes, PICU in 22, and death in 3 (mortality, 0.7%; 95% CI: 0.2-2.1). Both a delayed onset of SMC (14 of 23 episodes, 61%) and a biphasic clinical course (11 of 23, 48%) were frequently observed. In a multivariate logistic regression analysis, 4 characteristics were significantly and independently associated with the risk of SMC: diagnosis of acute myeloid leukemia, interval since chemotherapy ≤7 days, severely reduced general condition, and hemoglobin ≥9.0 g/dl at presentation.
In children with FN, SMC were rare, and mortality was very low. Those with SMC often had a delayed onset and biphasic clinical course with secondary deterioration.
Pediatric Blood & Cancer 08/2011; 59(1):90-5. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kinetic investigations in pediatric acute lymphoblastic leukemia (ALL) are based on all blast cells and, therefore, reflect the proliferative characteristics of the predominant immunophenotype of leukemic cells. Nothing is known about proliferation of immunologically defined rare subpopulations of leukemic cells. In this study, mononuclear cells from the bone marrow of 15 children with untreated CD19 B-cell precursor ALL were examined for proliferative features according to the immunophenotype. After exclusion of highly proliferating residual normal hematopoietic cells, ∼ 3% of blast cells were CD19 and showed a low percentage of cells in S-phase assessed by the bromodeoxyuridine labeling index (BrdU-LI): median BrdU-LI, 0.19% [interquartile range (IQR), 0.15-0.40%]. In contrast, a median BrdU-LI of 7.2% (IQR, 5.7-8.8%) was found for the major CD19 blast cell compartment. Staining smears of sorted CD19 cells for CD10 or CD34 revealed a small fraction of CD19CD10 or CD19CD34 blast cells. These cells were almost nonproliferating with a median BrdU-LI of <0.1% (IQR, 0-0.2%). This proliferative behavior is suggestive of a stem/progenitor cell function and, in addition, the low proliferative activity might render them more resistant to an antiproliferation-based chemotherapy. However, xenotransplantation experiments will be necessary to demonstrate a possible stem cell function.
Pediatric Research 03/2011; 69(3):194-9. · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To develop a score predicting the risk of bacteremia in cancer patients with fever and neutropenia (FN), and to evaluate its performance.
Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of bacteremia was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules.
Bacteremia was reported in 67 (16%) of 423 FN episodes. In 34 episodes (8%), bacteremia became known only after reassessment after 8 to 24 hours of inpatient management. Predicting bacteremia at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The reassessment score predicting future bacteremia in 390 episodes without known bacteremia used the following 4 variables: hemoglobin ≥ 90 g/L at presentation (weight 3), platelet count <50 G/L (3), shaking chills (5), and other need for inpatient treatment or observation according to the treating physician (3). Applying a threshold ≥ 3, the score--simplified into a low-risk checklist--predicted bacteremia with 100% sensitivity, with 54 episodes (13%) classified as low-risk, and a specificity of 15%.
This reassessment score, simplified into a low-risk checklist of 4 routinely accessible characteristics, identifies pediatric patients with FN at risk for bacteremia. It has the potential to contribute to the reduction of use of antimicrobials in, and to shorten the length of hospital stays of pediatric patients with cancer and FN.
[Show abstract][Hide abstract] ABSTRACT: We present 2 patients, who were admitted owing to rapidly progressing purpuric lesions due to postvaricella purpura fulminans, a coagulopathy leading to life- or limb-threatening thrombosis caused by a severe transient autoimmune protein S deficiency. Laboratory results were being consistent with disseminated intravascular coagulation secondary to protein S deficiency; treatment with fresh frozen plasma, intravenous immunoglobulins, and prednisone was started. In our experience, a prompt therapy may limit the course and the extent of the disease. We present a review of the topic with supporting literature for the therapeutic options. Therefore, we should be reminded that purpura fulminans is a rare but severe complication of chickenpox, which demands quick action.
Pediatric emergency care 12/2010; 26(12):932-4. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: M-ficolin (ficolin-1) is a complement-activating pattern-recognition molecule structurally related to mannan-binding lectin. It is produced by monocytes and neutrophils, and is found in serum. Its biological role is largely unknown. We assessed M-ficolin concentration in serum from pediatric cancer patients. The aim of this study was to explore association of M-ficolin with clinical and hematological parameters, and to investigate whether the risk of chemotherapy-related infections was related to M-ficolin concentrations in serum.
M-ficolin was measured by time-resolved immunofluorometric assay in serum taken at cancer diagnosis and was correlated with peripheral blood counts and bone marrow examinations performed at the same time.
Median M-ficolin concentration in 94 children with cancer was 1.6 μg/mL (interquartile range, 0.57-2.7; range, 0.055-25.8), and was not different from age-matched controls (median, 1.7 μg/mL; p=0.92). M-ficolin was strongly associated with absolute counts of neutrophils (Spearman's rho, 0.45; 95%-CI, 0.26-0.65; p<0.001), monocytes (0.34; 0.12-0.55; p<0.001), and thus phagocytes (0.42; 0.20-0.63; p<0.001) in peripheral blood. Similarly, M-ficolin correlated strongly with neutrophils (0.36; 0.14-0.59; p=0.002) and phagocytes (0.31; 0.08-0.54; p=0.009) in bone marrow. Low serum M-ficolin (≤0.5 μg/mL) was not associated with an increased incidence of fever in neutropenia during chemotherapy (multivariate Poisson rate ratio, 1.04; 95%-CI, 0.68-1.60; p=0.85).
The concentration of M-ficolin in serum from children with cancer was strongly associated with neutrophil and monocyte counts in blood and bone marrow. These results suggest that M-ficolin concentrations in serum reflect the pool of phagocytes.
[Show abstract][Hide abstract] ABSTRACT: ABO major compatibility is essential in transfusions of red blood cells but is not requisite in PLT transfusions. In adults there is some evidence that transfusion efficacy of ABO blood group-identical platelets (PLTs) is superior to major-mismatched PLTs. However, in children this question has not been investigated for more than 30 years.
In a prospective study, the efficacy (based on the 1-hour percentage of PLT recovery [PPR(1hr)]) of 400 eligible ABO blood group-identical or out-of-group apheresis PLT concentrates (APCs), transfused mainly prophylactically to 50 children with hematologic malignancies, solid tumors, or aplastic anemia was investigated. The primary objective was to compare PPR(1hr) between ABO-identical and major-mismatched transfusions.
After ABO major-mismatched transfusions, PPR(1hr) was significantly lower than after ABO blood group-identical transfusions (median 21% vs. 32%; p = 0.034). Multivariate analysis showed major-mismatched transfusions to be significantly more often unsuccessful than identical transfusions (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.52-10.39; p = 0.005). Using flow cytometry and fluorescent microscopy, it could be demonstrated that PLTs of subgroup A(1), significantly expressing A antigen on their surface, were rapidly cleared from the circulation of group O or B recipients. In contrast, major-mismatched transfusions of A(2) PLTs, expressing no detectable A antigen, were as successful as identical transfusions (OR, 1.13; 95% CI, 0.16-7.88; p = 0.90).
These data clearly indicate that in children ABO major-mismatched PLT transfusions result in inferior transfusion efficacy, with the only exception of group A(2) PLTs. ABO minor-mismatched PLTs showed comparable efficacy to identical transfusions.
[Show abstract][Hide abstract] ABSTRACT: Fever in severe chemotherapy-induced neutropenia (FN) is the most frequent manifestation of a potentially lethal complication of current intensive chemotherapy regimens. This study aimed at establishing models predicting the risk of FN, and of FN with bacteremia, in pediatric cancer patients.
In a single-centre cohort study, characteristics potentially associated with FN and episodes of FN were retrospectively extracted from charts. Poisson regression accounting for chemotherapy exposure time was used for analysis. Prediction models were constructed based on a derivation set of two thirds of observations, and validated based on the remaining third of observations.
In 360 pediatric cancer patients diagnosed and treated for a cumulative chemotherapy exposure time of 424 years, 629 FN were recorded (1.48 FN per patient per year, 95% confidence interval (CI), 1.37-1.61), 145 of them with bacteremia (23% of FN; 0.34; 0.29-0.40). More intensive chemotherapy, shorter time since diagnosis, bone marrow involvement, central venous access device (CVAD), and prior FN were significantly and independently associated with a higher risk to develop both FN and FN with bacteremia. The prediction models explained more than 30% of the respective risks.
The two models predicting FN and FN with bacteremia were based on five easily accessible clinical variables. Before clinical application, they need to be validated by prospective studies.
Pediatric Blood & Cancer 09/2008; 51(6):778-83. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The steadily increasing demands for single-donor apheresis platelet (PLT) concentrates (APCs) are a challenge to the PLT supply system. Therefore, efforts to improve plateletpheresis yield, allowing apheresis products to be split into 2 or more units, are valuable strategies. No data to demonstrate in vivo transfusion efficacy of these high-yield split-APCs are currently available, however.
The transfusion efficacy of APCs produced by two apheresis methods involving different harvest and storing procedures and varying PLT yields was investigated. Efficacy measures were the 1-hour percent PLT recovery (PPR(1h)) and the 1-hour corrected count increment (CCI(1h)). In total, 400 APCs, produced with either an Amicus device (Baxter) and stored in PLT additive solution (T-Sol; Amicus method [AM], n = 107) or a Trima device (Gambro) and stored in plasma (Trima method [TM], n = 293), were transfused to 55 children (31 girls; median age, 9.5 years; range, 0.2-18.5 years) with thrombocytopenia due to chemotherapy or aplastic anemia (median, 4 APCs per child; range, 1-68).
Transfusion efficacy was significantly lower for AM-APCs than for TM-APCs (median PPR(1h), 17 and 33%; median CCI(1h), 7.9 and 15.6, respectively; p < 0.001). Reduced transfusion efficacy correlated in a yield-dependent manner with high apheresis PLT yields (> or =6 x 10(11)) for AM-APCs (p < 0.001).
Although in vitro validation of AM- and TM-APCs has been performed, only by evaluating transfusion efficacy in vivo did the AM turn out to be not suitable for high-yield thrombocytapheresis. This study recommends the implementation of in vivo transfusion efficacy studies for high-yield APC apheresis donations.