Whole-body magnetic resonance imaging for staging Langerhans cell histiocytosis in children and young adults.

INTRODUCTION: Radiographic skeletal survey (R-SS) is the standard imaging technique for the initial staging of Langerhans cell histiocytosis (LCH). Whole-body magnetic resonance imaging (WB-MRI) has been proposed as an effective, radiation-free alternative. METHODS: We prospectively assessed patients with LCH followed at three tertiary centers in Italy and Austria. Two national study protocols were independently designed, and data were then pooled to increase the power of their findings. R-SS and WB-MRI were performed at diagnosis and repeated at the follow-up to confirm the nature of the identified lesions and to study their evolution. RESULTS: Data from 67 patients were analyzed (52 from Italy and 15 from Austria). Compared to R-SS, WB-MRI identified 29 additional skeletal lesions in 14 patients (including two false-positive lesions). Two skeletal lesions were detected at R-SS and missed at WB-MRI (false negative). Per-lesion sensitivity rates were 78.6% (95% CI: 71.0-85.9) for R-SS and 98.4% (95% CI: 94.4-99.8) for WB-MRI, respectively. Based on WB-MRI findings, six patients would have been upstaged to a higher risk class than staging with R-SS. CONCLUSIONS: WB-MRI had a significantly higher detection rate for skeletal lesions compared to R-SS. Clinical and radiology expertise is required to avoid upstaging and overtreatment.

Incidence and Risk Factors of Venous Thromboembolism in Childhood Acute Lymphoblastic Leukaemia - a Population-Based Analysis of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group.

Venous thromboembolism (VTE) is a well-known complication of the treatment of pediatric acute lymphoblastic leukemia (ALL). We analyzed 1026 ALL patients 1-18-years-old, who were enrolled into the AIEOP-BFM ALL 2000 or 2009 studies in Austria, with regard to the incidence and risk factors of VTE. The 2.5-year cumulative incidence (CI) of VTE ≥ grade 2 was 4%±1% (n = 36/1026). Twenty VTE (56%) were found in the central nervous system (19 cerebral venous sinus and 1 cortical vein thrombosis), and 16 (44%) at other sites (7 deep vein thromboses (DVT) of the lower extremity, 4 DVT of the upper extremity, 4 central venous line-thromboses, 1 pulmonary embolism). Most VTE occurred during induction and early consolidation therapy (81%) and were associated with L-asparaginase within 4 and corticosteroids withing 1 week(s) preceding the event (89 and 86%, respectively). In multivariable analysis, two independent risk factors were found. Patients 10-18-years-old had an increased (hazard-ratio: 2.156, p = 0.0389), whereas treatments in trial AIEOP-BFM ALL 2009 had a lower risk for VTE (hazard-ratio: 0.349, p = 0.0270). In conclusion, the 2.5-year CI of VTE among our pediatric patient cohort was <5% and adolescent age was the main patient-related risk factor. This older age group might benefit from primary prophylactic measures.

Langerhans Cell Histiocytosis of the Orbit: Spectrum of Clinical and Imaging Findings.

OBJECTIVE: To evaluate the clinical and imaging characteristics of orbital lesions of pediatric Langerhans cell histiocytosis (LCH). STUDY DESIGN: A retrospective analysis of clinical data and central review of magnetic resonance imaging scans in patients with LCH, enrolled into one of the consecutive international trials LCH I-III, or submitted for a second opinion between 1994 and 2015. RESULTS: Data from 31 children (34 involved orbits) were analyzed. Orbital LCH was the only disease manifestation in 15, part of a multifocal skeletal in 5, or a multisystem LCH in 11 patients. Orbital LCH was part of the initial disease presentation in 23 or developed at relapse in 8 cases. Orbital involvement was unilateral in 28 and bilateral in 3 patients (34 affected orbits). Proptosis was present in 9 patients. Frontal and zygomatic bone were most commonly affected. All orbital lesions were extraconal. Associated extraorbital imaging findings were dural tail sign in 19, neurodegeneration in 8, and hypothalamic-pituitary mass in 3 patients. Sixteen patients (52%) had at least 1 documented disease relapse. Permanent consequences were prominent proptosis in 1, diabetes insipidus in 8, growth hormone deficiency in 2, radiologic neurodegeneration in 8, and clinical neurodegeneration in 3 patients. CONCLUSIONS: Predominantly unilateral orbital LCH can be the only disease manifestation or part of a disseminated disease. Orbital lesions in LCH are exclusively extraconal, typically located at the roof and the lateral wall of the orbit. The optimal treatment approach of unifocal LCH of the orbit remains controversial and warrants a prospective evaluation.

Additive Prognostic Impact of Gastrointestinal Involvement in Severe Multisystem Langerhans Cell Histiocytosis.

OBJECTIVE: To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. STUDY DESIGN: This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. RESULTS: Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2 years at diagnosis (13% vs 6% in those aged >2 years; P < .001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P < .001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P = .789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P < .001). CONCLUSIONS: GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.

A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project.

BACKGROUND: Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort. METHODS: A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves. RESULTS: The nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of > 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1). CONCLUSIONS: In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.

Flow-cytometric minimal residual disease monitoring in blood predicts relapse risk in pediatric B-cell precursor acute lymphoblastic leukemia in trial AIEOP-BFM-ALL 2000.

BACKGROUND: Flow-cytometric monitoring of minimal residual disease (MRD) in bone marrow (BM) during induction of pediatric patients with acute lymphoblastic leukemia (ALL) is widely used for outcome prognostication and treatment stratification. Utilizing peripheral blood (PB) instead of BM might be favorable, but data on its usefulness are scarce. PROCEDURE: We investigated 1303 PB samples (days 0, 8, 15, 33, and 52) and 285 BMs (day 15) from 288 pediatric ALL patients treated in trial AIEOP-BFM ALL 2000. MRD was assessed by four-color flow cytometry and evaluated as relative, absolute, and kinetic result. RESULTS: In B-ALL only, PB measures from early time points correlated with relapse incidence (CIR). Best separation occurred at threshold <1 blast/µL at day 8 (5-year CIR 0.02 ± 0.02 vs 0.12 ± 0.03; P = 0.044). Patients with highest relapse risk were not distinguishable, but PB-MRD at days 33 and 52 correlated with prednisone response and postinduction BM-MRD by PCR (P < 0.001). Kinetic assessment did not convey any advantage. In multivariate analysis including day 15 BM-MRD, PB-MRD measures lost statistical power. CONCLUSIONS: In summary, PB-MRD in pediatric B-ALL correlates with outcome and risk parameters, but its prognostic significance is not strong enough to substitute for BM assessment in AIEOP-BFM trials. It might, however, be valuable in treatment environments not using multifaceted risk stratification with other MRD measures.

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial.

BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.

Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study.

BACKGROUND: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues. METHODS: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH. RESULTS: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse. CONCLUSIONS: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.

Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials.

BACKGROUND: Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations. RESULTS: The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0-6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response. CONCLUSIONS: Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

Assessing the effect of a partly unobserved, exogenous, binary time-dependent covariate on survival probabilities using generalised pseudo-values.

BACKGROUND: Investigating the impact of a time-dependent intervention on the probability of long-term survival is statistically challenging. A typical example is stem-cell transplantation performed after successful donor identification from registered donors. Here, a suggested simple analysis based on the exogenous donor availability status according to registered donors would allow the estimation and comparison of survival probabilities. As donor search is usually ceased after a patient's event, donor availability status is incompletely observed, so that this simple comparison is not possible and the waiting time to donor identification needs to be addressed in the analysis to avoid bias. It is methodologically unclear, how to directly address cumulative long-term treatment effects without relying on proportional hazards while avoiding waiting time bias. METHODS: The pseudo-value regression technique is able to handle the first two issues; a novel generalisation of this technique also avoids waiting time bias. Inverse-probability-of-censoring weighting is used to account for the partly unobserved exogenous covariate donor availability. RESULTS: Simulation studies demonstrate unbiasedness and satisfying coverage probabilities of the new method. A real data example demonstrates that study results based on generalised pseudo-values have a clear medical interpretation which supports the clinical decision making process. CONCLUSIONS: The proposed generalisation of the pseudo-value regression technique enables to compare survival probabilities between two independent groups where group membership becomes known over time and remains partly unknown. Hence, cumulative long-term treatment effects are directly addressed without relying on proportional hazards while avoiding waiting time bias.

Risk stratification of high-risk metastatic neuroblastoma: A report from the HR-NBL-1/SIOPEN study.

BACKGROUND: Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged ≥18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication. PROCEDURE: Data were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged ≥18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi-variable model and an additive scoring system developed based on estimated log-cumulative hazard ratios. RESULTS: The cohort included 1053 patients with median follow-up 5.5 years and EFS 27 ± 1%. In univariate analyses, age; serum LDH and ferritin; involvement of bone marrow, bone, liver or lung; and >1 metastatic system/compartment were associated with worse EFS. Tumour MNA was not associated with worse EFS. A multi-variable model and risk score incorporating age (>5 years, 2 points), serum LDH (>1250 U/L, 1 point) and number of metastatic systems (>1, 2 points) were developed. EFS was significantly correlated with risk score: EFS 52 ± 9% for score = 0 versus 6 ± 3% for score = 5 (P < 0.0001). CONCLUSIONS: A simple score can identify an "ultra-high risk" (UHR) cohort (score = 5) comprising 8% of patients with 5-year EFS <10%. These patients appear not to benefit from induction therapy and could potentially be directed earlier to alternative experimental therapies in future trials.

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial.

BACKGROUND: High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. METHODS: We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m2) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m2 per day for 4 days, and melphalan 70 mg/m2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. FINDINGS: Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3-9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. INTERPRETATION: Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. FUNDING: European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.

Antibiotic prophylaxis with teicoplanin on alternate days reduces rate of viridans sepsis and febrile neutropenia in pediatric patients with acute myeloid leukemia.

Intensive chemotherapy directed against acute myeloid leukemia of childhood is followed by profound neutropenia and high risk for bacterial and fungal infections, including viridans group streptococci as a common cause for gram-positive septicemia. Few retrospective studies have shown the efficacy of various antibiotic prophylactic regimens in children. We retrospectively studied 50 pediatric patients treated on the AML-BFM 2004 protocol between 2005 and 2015 at St. Anna Children's Hospital and assessed the effect of antibiotic prophylaxis on the frequency of febrile neutropenia and bacterial sepsis. Fifty pediatric patients underwent 199 evaluable chemotherapy cycles. Viridans sepsis occurred after none of 98 cycles with prophylactic administration of teicoplanin/vancomycin in comparison to 12 cases of viridans sepsis among 79 cycles without systemic antibacterial prophylaxis (0 vs. 15 %, p < 0.0001). In addition, there were significantly fewer episodes of febrile neutropenia in the teicoplanin/vancomycin group (44 % vs. no prophylaxis 82 %, p < 0.0001). Severity of infection seemed to be worse when no antibiotic prophylaxis had been administered with a higher rate of intensive care unit treatment (0/98, 0 %, vs. 4/79, 5 %, p = 0.038). So far, no increase of vancomycin-resistant enterococcus isolates in surveillance cultures was noticed. Antibiotic prophylaxis with teicoplanin (or vancomycin) appears safe and feasible and resulted in eradication of viridans sepsis and decreased incidence of febrile neutropenia in pediatric AML patients. The possibility to administer teicoplanin on alternate days on an outpatient basis or at home could contribute to patient's quality of life and decrease health care costs.

High hyperdiploid acute lymphoblastic leukemia (ALL)-A 25-year population-based survey of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

BACKGROUND: Approximately 30% of childhood acute lymphoblastic leukemia (ALL) cases are high hyperdiploid (HD). Despite their low relative recurrence risk, this group accounts for the overall largest relapse proportion. PROCEDURE: To evaluate potential risk factors in our population-based cohort of patients with HD ALL enrolled in four Austrian ALL-BFM (Berlin-Frankfurt-Münster) studies from 1986 to 2010 (n = 210), we reviewed the clinical, laboratory, and cytogenetic data of the respective cases in relation to their outcome. RESULTS: The 5-year event-free (EFS) and overall survival (OS) of the entire group was 83.1 ± 2.7% and 92.0 ± 1.9%, respectively. Univariate analysis revealed that trisomy 17 was significantly associated with a better EFS and OS, whereas trisomy 10 and a modal chromosome number (MCN) > 53 chromosomes were significantly associated with a better OS. Except for the latter, findings remained valid in multivariate analysis. CONCLUSIONS: In line with previous studies, our retrospective analysis shows that MCN and specific trisomies are relevant prognostic indicators in an ALL-BFM cohort of patients with HD ALL. However, considering the current dominant role of minimal residual disease monitoring for prognostic stratification in ALL, including this particular subgroup, it is unlikely that this information is compelling enough to be utilized for refined risk classification in future ALL-BFM treatment protocols.

Peripheral blood late mixed chimerism in leucocyte subpopulations following allogeneic stem cell transplantation for childhood malignancies: does it matter?

The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse.

Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia.

UNLABELLED: Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical. TRIALS: gov with the number NC01423747.

European Society for Blood and Marrow Transplantation Analysis of Treosulfan Conditioning Before Hematopoietic Stem Cell Transplantation in Children and Adolescents With Hematological Malignancies.

BACKGROUND: Standard myeloablative conditioning regimens for children with hematological malignancies undergoing allogeneic HSCT are based mainly on total body irradiation or busulfan. Their serious short- and long-term side effects warranted the exploration of less toxic alternatives. Treosulfan is increasingly used for adults and children before HSCT due to its potent immunosuppressive and cytotoxic effects combined with low organ toxicity. PROCEDURE: To further investigate the role of treosulfan conditioning in children, the EBMT Pediatric diseases working party performed a retrospective analysis of 193 children with hematological malignancies (ALL n = 71, AML n = 47, MDS/MPS n = 40, other leukemia/lymphoma n = 25) undergoing allogeneic HSCT following treosulfan between January 2005 and July 2010. RESULTS: Early regimen-related toxicity was low and mainly gastrointestinal. Veno-occlusive disease and neurological toxicity were rare. There was no association of toxicity with type of disease or treosulfan dose. High-grade early toxicity was not higher in infants or patients undergoing second or later transplantation. Treatment related mortality was low at 14%. Three-year event-free survival was 45 ± 4% and not significantly influenced by number of transplants, however it appeared to be significantly better for infants (P = 0.022). When compared to treosulfan plus fludarabine, the combination of treosulfan, fludarabine and an alkylator (either thiotepa or melphalan) resulted in significantly better overall survival (OS, P = 0.048) and a trend toward better EFS. CONCLUSIONS: Treosulfan based conditioning is a safe and effective approach for children with hematological malignancies, including and importantly for infants and those patients undergoing second or later transplantation.

Lack of bone lesions at diagnosis is associated with inferior outcome in multisystem langerhans cell histiocytosis of childhood.

Skeletal involvement is generally, but not universally, characteristic of Langerhans cell histiocytosis (LCH). We investigated whether the presence of bone lesions at diagnosis is a prognostic factor for survival in LCH. Nine hundred and thirty-eight children with multisystem (MS) LCH, both high (386 RO+) and low (RO-) risk, were evaluated for bone lesions at diagnosis. Risk organ (RO+) involvement was defined as: haematopoietic system (haemoglobin <100 g/l, and/or white blood cell count <4·0 × 10(9) /l and/or platelet count <100 × 10(9) /l), spleen (>2 cm below the costal margin), liver (>3 cm and/or hypoproteinaemia, hypoalbuminaemia, hyperbilirubinaemia, and/or increased aspartate transaminase/alanine transaminase). Given the general view that prognosis in LCH worsens with increasing extent of disease, the surprising finding was that in MS+RO+ LCH the probability of survival with bone involvement 74 ± 3% (n = 230, 56 events) was reduced to 62 ± 4% (n = 156, 55 events) if this was absent (P = 0·007). An even greater difference was seen in the subgroup of patients with both liver and either haematopoiesis or spleen involvement: 61 ± 5% survival (n = 105; 52 events) if patients had bony lesions, versus 47 ± 5% (n = 111; 39 events) if they did not (P = 0·014). This difference was retained in multivariate analysis (P = 0·048). Although as yet unexplained, we conclude that bone involvement at diagnosis is a previously unrecognized favourable prognostic factor in MS+RO+ LCH.

Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH)-III tested risk-adjusted, intensified, longer treatment of multisystem LCH (MS-LCH), for which optimal therapy has been elusive. Stratified by risk organ involvement (high [RO+] or low [RO-] risk groups), > 400 patients were randomized. RO+ patients received 1 to 2 six-week courses of vinblastine+prednisone (Arm A) or vinblastine + prednisone + methotrexate (Arm B). Response triggered milder continuation therapy with the same combinations, plus 6-mercaptopurine, for 12 months total treatment. 6/12-week response rates (mean, 71%) and 5-year survival (84%) and reactivation rates (27%) were similar in both arms. Notably, historical comparisons revealed survival superior to that of identically stratified RO+ patients treated for 6 months in predecessor trials LCH-I (62%) or LCH-II (69%, P < .001), and lower 5-year reactivation rates than in LCH-I (55%) or LCH-II (44%, P < .001). RO- patients received vinblastine+prednisone throughout. Response by 6 weeks triggered randomization to 6 or 12 months total treatment. Significantly lower 5-year reactivation rates characterized the 12-month Arm D (37%) compared with 6-month Arm C (54%, P = .03) or to 6-month schedules in LCH-I (52%) and LCH-II (48%, P < .001). Thus, prolonging treatment decreased RO- patient reactivations in LCH-III, and although methotrexate added no benefit, RO+ patient survival and reactivation rates have substantially improved in the 3 sequential trials. (Trial No. NCT00276757 www.ClinicalTrials.gov).

Treosulfan-based conditioning regimens for allogeneic HSCT in children with acute lymphoblastic leukaemia.

Standard myeloablative conditioning regimens for children with acute lymphoblastic leukaemia are based on total body irradiation (TBI). However, TBI causes profound short-term and long-term side effects, provoking the necessity for alternative regimens. Treosulfan combines a potent immunosuppressive and antileukaemic effect with myeloablative activity and low toxicity profile. We retrospectively studied toxicity and outcome of 71 paediatric patients with acute lymphoblastic leukaemia (ALL) undergoing haematopoietic stem cell transplantation (HSCT) following treosulfan-based conditioning aiming to identify risk factors for treatment failure and dose-depending outcome differences. Early regimen-related toxicity was low. No case of veno-occlusive disease was reported. There was no association of toxicity with age or number of HSCT. Event-free survival (EFS) of infants was significantly better compared to older children. Overall survival (OS) at 3 years was 51 % and not significantly influenced by number of HSCT (first HSCT 54 %, ≥second HSCT 44 %, p = 0.71). In multivariate analysis, OS and EFS were significantly worse for patients transplanted without complete remission (p = 0.04 and 0.004). Treatment-related mortality was low at 14 %. We conclude that treosulfan-based conditioning is a safe and efficacious approach for paediatric ALL.