Annette Sander

Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98.

PURPOSE Because cytogenetic data are essential for risk stratification of childhood acute myeloid leukemia (AML), the impact of chromosomal aberrations is crucial. PATIENTS AND METHODS Data of a large group of patients younger than 18 years treated according to study AML-Berlin-Frankfurt-Münster (BFM) 98 (n = 454), including their cytogenetics, were analyzed. RESULTS The favorable outcome in the subgroups of patients with t(8;21), inv(16), and t(15;17), with an overall survival of 91% (SE, 4%), 92% (SE, 6%), and 87% (SE, 5%), respectively, was confirmed. Within this group, the 5-year probability of event-free survival (pEFS) of all 17 children with t(8;21) and additional aberrations apart from del(9q) or -X/-Y was 100%. As expected, the cytogenetic finding of a complex karyotype (n = 35; pEFS, 33%; SE, 8%) or a monosomy 7 (n = 12; pEFS, 17%; SE, 11%) was associated with a poor outcome. Compared with remaining patients with cytogenetic data (pEFS, 48%; SE, 2%), prognosis in patients with an MLL rearrangement (n = 91) was inferior (pEFS, 34%; SE, 5%; P = .0005). Particularly, children with t(9;11) and additional aberrations (n = 13; pEFS, 31%; SE, 14%) and MLL rearrangements other than t(9;11) and t(11;19) (n = 41; pEFS, 24%; SE, 7%) had an unfavorable outcome. Nine patients with aberrations in 12p showed an adverse prognosis (pEFS, 11%; SE, 10%). The outcome of patients with aberrations of chromosome 5 (n = 13) was better than expected (pEFS, 50%; SE, 13%). CONCLUSION Because the prognostic value of rare recurrent chromosomal aberrations still has to be elucidated, these data will contribute to future risk stratification for the treatment of pediatric AML.

Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004

Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensification of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m(2) per day for 3 days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% ± 3% [L-DNR] vs 75% ± 3% [idarubicin], Plogrank = .65; event-free survival [EFS] 59% ± 3% vs 53% ± 3%, Plogrank = .25; cumulative incidence of relapse 29% ± 3% vs 31% ± 3%, P(Gray) = .75), as were EFS results for standard (72% ± 5% vs 68% ± 5%, Plogrank = .47) and high-risk (51% ± 4% vs 46% ± 4%, Plogrank = .45) patients. L-DNR resulted in significantly better probability of EFS in patients with t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P = .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345.

Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials

Relapse remains the major cause of treatment failure in pediatric acute myeloid leukemia (AML). We analyzed the clinical characteristics, treatment response to relapse treatment and overall survival (OS) of 379 children with AML relapse treated according to three consecutive frontline protocols of the AML-Berlin/Frankfurt/Muenster study group (AML-BFM-87/-93/-98). Of 313 treated patients with data on remission status, 198 children (63%) achieved a second complete remission (CR2). There were no significant differences in remission rates and OS for the intensive reinduction treatment schedules used. The 5-year OS rate was 23% for the total group and 29% for patients treated with curative intent. OS rates increased with study periods from 18 to 34% (Plog rank=0.012), whereas the proportion of patients receiving only palliative treatment decreased from 23 to 11% (PCMH=0.005). Late relapse, no allogeneic stem cell transplantation (SCT) in CR1, age <10 years and favorable cytogenetics were independent favorable prognostic factors for survival. Achievement of CR2 was the most important prognostic factor (OS 44 vs 3%; Plog rank<0.0001). Overall, one-third of children with relapsed AML can be cured today. SCT in CR2 is recommended for most patients, although its impact on CR2 is discussed.

Monitoring of Adenovirus Infection in Pediatric Transplant Recipients by Quantitative PCR: Report of Six Cases and Review of the Literature

Adenoviral (AdV) infections after transplantation remain a challenge in pediatric patients. Qualitative and quantitative PCR offer new approaches to early diagnosis and monitoring. However, their role in the management of AdV infections in pediatric transplant recipients remains to be determined.

Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16)

Patients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) and inv(16)/t (16;16) subtypes requires intensification remained to be determined. In the 2 successive studies (AML-BFM-1998 and AML-BFM-2004), 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study AML-BFM-1998 but not in AML-BFM-2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n = 78) compared with without HAM (n = 53): OS 92% ± 3% versus 80% ± 6%, p(logrank)0.047, EFS 84% ± 4% versus 59% ± 7%, p(logrank)0.001, and CIR 14% ± 4% versus 34% ± 7%, p((gray))0.006. These differences were not seen for inv(16) (n = 43 and 46, respectively): OS 93% ± 4% versus 94% ± 4%, EFS 75% ± 7% versus 71% ± 9% and CIR 15% ± 6% versus 23% ± 8% (not significant). The subtype t(8;21), but not inv(16), was an independent predictor of worse outcome without HAM reinduction. Based on our data, a 5-year OS of > 90% can be expected for CBF-AML, when stratifying t(8;21), but not inv(16), patients to high-risk chemotherapy, including HAM reinduction.

CNS Irradiation in Pediatric Acute Myleoid Leukemia: Equal Results by 12 or 18 Gy in Studies AML-BFM98 and 2004

The impact of preventive central nervous system irradiation (CNS‐RT) in childhood acute myeloid leukemia (AML) is still discussed. As results of study AML‐BFM87 revealed an increased risk for relapse when CNS‐RT was not performed, studies AML‐BFM98 and ‐2004 randomized CNS‐RT of 18 or 12 Gy in order to evaluate the efficacy of the lower dose and to reduce late effects.

Paediatric palliative home care in areas of Germany with low population density and long distances: a questionnaire survey with general paediatricians

BackgroundIn 2007, the patient’s right to specialised palliative home care became law in Germany. However, childhood palliative care in territorial states with low patient numbers and long distances requires adapted models to ensure an area-wide maintenance. Actually, general paediatricians are the basic care providers for children and adolescents. They also provide home care. The aim of this study was to improve the knowledge about general paediatrician’s involvement in and contribution to palliative care in children.FindingsTo evaluate the current status of palliative home care provided by general paediatricians and their cooperation with other paediatric palliative care providers, a questionnaire survey was disseminated to general paediatricians in Lower Saxony, a German federal state with nearly eight million inhabitants and a predominantly rural infrastructure. Data analysis was descriptive.One hundred forty one of 157 included general paediatricians completed the questionnaire (response rate: 89.8%). A total of 792 children and adolescents suffering from life-limiting conditions were cared for by these general paediatricians in 2008. Severe cerebral palsy was the most prevalent diagnosis. Eighty-nine per cent of the general paediatricians stated that they had professional experience with paediatric palliative care.Collaboration of general paediatricians and other palliative care providers was stated as not well developed. The support by a specialised team including 24-hour on-call duty and the intensification of educational programs were emphasised.ConclusionsThe current regional infrastructure of palliative home care in Lower Saxony can benefit from the establishment of a coordinated network of palliative home care providers.

Genetic prognostic factors in childhood acute myeloid leukemia

The survival rate of children and adolescents suffering acute myeloid leukemia (AML) has been significantly improved within the last decades. This has been achieved by a continuously intensified therapy and progress in supportive care to prevent and treat complications. In Germany, the AML-BFM trials 98 (n=413) and 2004 (n=499) enrolled 912 children and adolescents as protocol patients (1998-2010). The 5-year-overall survival was 71±2%. In the previous studies prognosis and subsequent treatment stratification based on morphology, cytochemistry and white blood cell count. Today, the identification of new genetic aberrations in AML enables a genetically determined estimation of prognosis, although treatment response must be considered for treatment stratification. The group with a favorable prognosis summarized AML with t(8;21), inv(16), t(15;17), t(1;11), and AML with normal karyotype and NPM1-mutation (n=253; EFS 74±3%, OS 88±2%). A poor prognosis (HR-group) must be expected in AML with t(4;11), t(5;11), t(6;11), t(6;9), t(7;12), t(9;22), Monosomy 7, combined FLT3/WT1-mutation, and AML with der(12p)-aberration (n=101; EFS 30±5%; OS 56±5%). The intermediate group summarizes all other subgroups especially AML with normal karyotyp, AML with FLT3-ITD or t(9;11) (n=558; EFS 43±2%; OS 64±2%). The validation of the internationally identified, genetically determined prognostic factors within the AML-BFM (Germany) study population will support treatment recommendations.

Quantitative microstructural cerebral changes in neurofibromatosis type 1

OBJECTIVES To evaluate microstructural cerebral changes in children with neurofibromatosis type 1 (NF1) based on T2 relaxation time measurements at 3Tesla. METHODS From our dataset of pediatric MRI examinations at 3T 19 pediatric NF1 patients (1.9-14.3 years of age, 9 girls, 10 boys) were retrospectively selected and compared with the previously published group of 44 healthy children (0-16 years of age). MRI examination included a triple echo TSE sequence as basis for T2 maps. T2 relaxation times were measured in 37 brain regions. RESULTS Compared with healthy controls, T2 relaxation times had the tendency to be increased by 1.01% (GM) to 11.85% (dentate nucleus) for NF1 patients. Only in posterior limb of the internal capsule and parietooccipital white matter values were reduced. No differences were observed between both hemispheres. Overall, no strong evidence supporting a difference between NF1 patients with and without optic glioma or with normal and impaired neuropsychological development was observed. CONCLUSIONS Using T2 relaxation times it was possible to describe measurable microstructural differences in multiple brain regions between NF1 patients and healthy children regardless of whether signal abnormalities were visible on conventional images.

Prognostische Relevanz genetischer Aberrationen der akuten myeloischen Leukämie bei Kindern und Jugendlichen

The survival rate of children and adolescents suffering acute myeloid leukemia (AML) has been significantly improved within the last decades. This has been achieved by a continuously intensified therapy and progress in supportive care to prevent and treat complications. In Germany, the AML-BFM trials 98 (n = 413) and 2004 (n = 499) enrolled 912 children and adolescents as protocol patients (1998 - 2010). The 5-year-overall survival was 71 ± 2 %. In the previous studies prognosis and subsequent treatment stratification based on morphology, cytochemistry and white blood cell count. Today, the identification of new genetic aberrations in AML enables a genetically determined estimation of prognosis, although treatment response must be considered for treatment stratification. The group with a favorable prognosis summarized AML with t(8;21), inv(16), t(15;17), t(1;11), and AML with normal karyotype and NPM1-mutation (n = 253; EFS 74 ± 3 %, OS 88 ± 2 %). A poor prognosis (HR-group) must be expected in AML with t(4;11), t(5;11), t(6;11), t(6;9), t(7;12), t(9;22), Monosomy 7, combined FLT3 / WT1-mutation, and AML with der(12 p)-aberration (n = 101; EFS 30 ± 5 %; OS 56 ± 5 %). The intermediate group summarizes all other subgroups especially AML with normal karyotyp, AML with FLT3-ITD or t(9;11) (n = 558; EFS 43 ± 2 %; OS 64 ± 2 %). The validation of the internationally identified, genetically determined prognostic factors within the AML-BFM (Germany) study population will support treatment recommendations.