Arend von Stackelberg

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

Are you Arend von Stackelberg?

Claim your profile

Publications (80)543.05 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: For most children who relapse with acute lymphoblastic leukaemia, the prognosis is poor and there is a need for novel therapies to improve outcome. We screened samples from children with B lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (ClinicalTrials.gov identifier: NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3 and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high risk features including early relapse, CNS involvement and specifically for NRAS/KRAS mutations, chemoresistance. KRAS mutations were associated with a reduced overall survival. Mutation screening of the matched diagnostic samples found many to be wildtype but using more sensitive allelic specific assays, low level mutated subpopulations were found in many cases, suggesting that they survived up front therapy and subsequently emerged at relapse. Preclinical evaluation of the MEK1/2 inhibitor, selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway mutated ALL compared to wild type cells both in vitro and in a orthotopic xenograft model engrafted with primary ALL and in the latter, reduced RAS mutated CNS leukaemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway mutated relapsed ALL.
    Blood 09/2014; · 9.78 Impact Factor
  • Haematologica 08/2014; · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Brief Summary Precursor T-cell acute lymphoblastic leukemia represents one of the major challenges of pediatric oncology, because relapses are frequently fatal and the molecular understanding of leukemogenesis and maintenance is limited in this entity. Here, we aimed at identifying novel leukemogenic driver mutations and first analyzed trios of bone marrow DNA of 5 patients with T-cell acute lymphoblastic leukemia obtained at initial diagnosis, remission and relapse by whole exome sequencing. We identified a recurrent, leukemia-specific mutation resulting in a N642H amino acid substitution in the SH2-domain of STAT5B. We subsequently validated these results by sequencing the entire STAT5B gene in two independent large cohorts of patients and identified this mutation in 17 of 301 patients (6.3%) with primary T-cell acute lymphoblastic leukemia recruited from the ALL-BFM 2000 trial and in 7 of 78 relapsed T-cell acute lymphoblastic leukemia patients (9.0%) from the BFM-ALL-REZ trials. The analysis of clinical data revealed that the presence of this mutation was associated with a significantly increased risk of relapse (RR 2.47, p=0.038). Cell based assays in transduced BaF3 cells and in xenografted leukemic cells showed this mutation to confer constitutive STAT5 phosphorylation, cytokine independent growth characteristics. We conclude that the STAT5B N642H mutation is common in pediatric T-cell acute lymphoblastic leukemia and results in an activation of oncogenic pathways, conferring an increased risk of relapse.
    Haematologica 06/2014; · 5.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The clinical heterogeneity among first relapses of childhood ETV6/RUNX1-positive acute lymphoblastic leukemia indicates that further genetic altera-tions in leukemic cells might affect the course of salvage therapy and be of prognostic relevance. To assess the incidence and prognostic relevance of additional copy number alterations at relapse of the disease, we performed whole genome array comparative genomic hybridization of leukemic cell DNA from 51 patients with first ETV6/RUNX1-positive relapse enrolled in and treated according to the relapse trials ALL-REZ of the Berlin-Frankfurt-Munster Study Group. Within this largest cohort of relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia analyzed for genome wide DNA copy number alterations to date, alterations were present in every ETV6/RUNX1-positive relapse and a high proportion of them occurred in recurrent overlap-ping chromosomal regions. Recurrent losses affected chromosomal regions 12p13, 6q21, 15q15.1, 9p21, 3p21, 5q and 3p14.2, whereas gains the re-gions 21q22 and 12p. Loss of 12p13 including CDKN1B was associated with a shorter remission duration (P=0.009) and a lower probability of event-free survival (P=0.001). Distribution of X-chromosomal copy number alterations was gender-specific: whole X-chromosome loss occurred exclusively in fe-males, gain of Xq only in males. Loss of the glucocorticoid receptor gene NR3C1 (5q31.3) conveyed a poor response to induction treatment (P=0.003) possibly accounting for the adverse prognosis of some of the ETV6/RUNX1-positive relapses.
    Haematologica 11/2013; · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute lymphoblastic leukemia (ALL) accounts for approximately 25% of pediatric malignancies. Of interest, the incidence of ALL is observed approximately 20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in approximately 30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P <0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P=0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared to girls.
    Human Molecular Genetics 09/2013; · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSEIn children with intermediate risk of relapse of acute lymphoblastic leukemia (ALL), it is essential to identify patients in need of treatment intensification. We hypothesized that the prognosis of patients with unsatisfactory reduction of minimal residual disease (MRD) can be improved by allogeneic hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS In the Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 2002, patients with an MRD level of ≥ 10(-3) (n = 99) at the end of induction therapy were allocated to HSCT, whereas those with an MRD level less than 10(-3) (n = 109) continued to receive chemotherapy. MRD was quantified by real-time polymerase chain reaction for clone-specific T-cell receptor/immunoglobulin gene rearrangements.ResultsThe probability of event-free survival for patients with MRD ≥ 10(-3) was 64% ± 5% in ALL-REZ BFM 2002 compared with 18% ± 7% in the predecessor study ALL-REZ BFM P95/96 (P < .001). This was mainly achieved by reducing the cumulative incidence of subsequent relapse (CIR) at 8 years from 59% ± 9% to 27% ± 5% (P < .001). The favorable prognosis of patients with MRD less than 10(-3) could be confirmed in those with a late combined or isolated bone marrow B-cell precursor (BCP) -ALL relapse (CIR, 20% ± 5%), whereas patients with an early combined BCP-ALL relapse had an unfavorable outcome (CIR, 63% ± 13%; P < .001). CONCLUSION Allogeneic HSCT markedly improved the prognosis of patients with intermediate risk of relapse of ALL and unsatisfactory MRD response. As a result, outcomes in this group approximated those of patients with favorable MRD response. Patients with early combined relapse require treatment intensification even in case of favorable MRD response, demonstrating the prognostic impact of time to relapse.
    Journal of Clinical Oncology 06/2013; · 18.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pharmacokinetics, pharmacodynamics, efficacy and safety of a new recombinant E.coli-asparaginase preparation was evaluated in infants (< 1 year of age) with de novo acute lymphoblastic leukemia. Twelve patients were treated according to the INTERFANT-06 protocol and received up to 10,000 U/m2; recombinant asparaginase as intravenous infusion on days 15, 18, 22, 25, 29 and 33 of remission induction treatment. The asparaginase dose was individually adjusted by protocol to 67% of the calculated dose for infants < 6 months, and to 75% of the calculated dose for infants aged 6-12 months. The trough serum asparaginase activities observed were above 20, 50, or 100 U/L in 86%, 71%, and 51% of measured samples, respectively. Looking only at the data assessed 3 days after asparaginase infusion these percentages were 91%, 84%, and 74% respectively. Asparagine was completely depleted in serum in all but one patient who was the youngest in the study. No anti-asparaginase-antibodies were detected during this treatment phase. Observed adverse reactions are known as possible and labeled side effects of asparaginase treatment and chemotherapy. We conclude that the asparaginase dose regimen used in infants is safe and provides complete asparagine depletion for the desired time period in nearly all patients. Measured asparaginase trough serum levels justify the higher doses used in infants compared to older children and show that the 3 days intervals are preferred over 4 days intervals. (This trial was registered at www.clinicaltrialsregister.eu as EudraCT number 2008-006300-27).
    Haematologica 06/2013; · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals. Pediatr Blood Cancer 2013;9999:1-8. © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 06/2013; · 2.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Outcome of adult and pediatric patients with AML improved significantly by intensification of induction treatment. To further intensify anthracycline-dosage without increasing cardiotoxicity, we compared the potentially less cardiotoxic liposomal daunorubicin (L-DNR) at a higher than equivalent dose (80mg/m(2)/day/x3) to idarubicin (12mg/m(2)/day/x3) during induction. In study AML-BFM 2004, 521/611 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 [pEFS]: 59%±3% vs. 53%±3%, plogrank=.25; cumulative incidence of relapse: 29%±3% vs. 31%±3%, p(Gray)=0.75), as were EFS results for standard (72%±5% vs. 68%±5%, plogrank=.47) and high-risk patients (51%±4% vs. 46%±4%, plogrank=.45). L-DNR resulted in significantly better pEFS in t(8;21) patients. Overall, treatment-related mortality (TRM), was lower in the L-DNR- than in the idarubicin-group (2/257 vs. 10/264 patients, p=.04). Grade III/IV cardiotoxicity was rare after induction (4 L-DNR- vs. 5 idarubicin-patients). Only one L-DNR- and 3 idarubicin-patients presented with subclinical or mild cardiomyopathy during follow-up. We conclude that L-DNR has - at the given dose - an overall anti-leukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less TRM. These results with high survival rates support its use in the forthcoming AML-BFM trial. ClinicalTrials.gov Identifier: NCT00111345.
    Blood 05/2013; · 9.78 Impact Factor
  • G Henze, A V Stackelberg, C Eckert
    [Show abstract] [Hide abstract]
    ABSTRACT: The BFM studies for relapsed childhood acute lymphoblastic leukemia (ALL) were started in 1983, at a time when cure rates for ALL were still lower and the number of children with ALL relapse equaled about the number of children with newly diagnosed neuroblastoma. Today, relapses have become relatively rare events in ALL although, because of the frequency of ALL, they are still a significant cause of death in children and adolescents. With currently used treatment modalities, cure rates of about 50% after relapse can be achieved, and, together with the improved results of front-line therapy, the survival rate of childhood ALL is now about 90%. Most children with extramedullary and late bone marrow (BM) relapses achieve a second CR; remission rates in patients with high-risk features, however, remain still unsatisfactory. With improved techniques allogeneic hematopoietic stem cell transplant (HSCT) has become a relatively safe treatment but is not necessary for all patients as postremission therapy. HSCT is not required in children with isolated extramedullary and late BM relapses with rapid response to induction therapy measured by molecular techniques (minimal residual disease, MRD) but absolutely indicated in patients with early BM relapses and systemic relapses of T-cell ALL. For patients with insufficient response innovative therapies such as small molecules or targeted immunological or pharmacological approaches are urgently required. Efforts have to be made, therefore, in order to detect potential biological or molecular targets, which can be used for individualized, more effective and hopefully less toxic therapies in the future.
    Klinische Pädiatrie 05/2013; 225(S 01):S73-S78. · 1.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Children with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of survival and causes of treatment failure were determined for 49 children with DS and a matched cohort of 98 children without DS among 2160 children treated for relapsed ALL in clinical trials conducted by the Berlin-Frankfurt-Münster ALL Relapse Study Group between 1983 and 2012. Despite more favourable ALL relapse characteristics, children with DS experienced lower event-free (EFS) and overall survival (OS) than the control group without DS (EFS 17 ± 08% vs. non-DS 41 ± 06%, P = 0·006; OS 17 ± 09% vs. non-DS 51 ± 06%, P < 0·001). Children with DS developed more frequently fatal complications of treatment (34 ± 07% vs. non-DS 10 ± 04%, P < 0·001). During the last decade, EFS and OS were no longer significantly different in children with and without DS (EFS 31 ± 09% vs. 36 ± 09%, P = 0·399; OS 31 ± 12% vs. 53 ± 09%, P = 0·151). DS proved an independent prognostic factor of outcome after ALL relapse. Induction deaths and treatment-related mortality but not subsequent relapse were the main barrier to successful outcomes of relapse therapy in children with DS.
    British Journal of Haematology 04/2013; · 4.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACis) with a toxicity profile differing from that of conventional cytotoxic agents are needed for these extensively pre-treated patients. EXPERIMENTAL DESIGN: Anti-proliferative and pro-apoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP-ALL monocultures, cocultures with primary mesenchymal stroma cells from ALL-patients and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation. RESULTS: We identified the proteasome inhibitor bortezomib (BTZ) as a promising combination partner for HDACis due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK-, PI3K/AKT-, p53-, ubiquitin-proteasome and NF-κB pathways. We observed an activation of NF-κB after BTZ treatment and the induction of apoptosis-related NF-κB target genes such as TNFαRs after concomitant treatment, indicating a possible involvement of NF-κB as pro-apoptotic mediator. In this context, significantly lower NF-κB subunits gene expression was detected in leukemia cells from patients, who developed a relapse during frontline chemotherapy, compared to those who relapsed after cessation of frontline therapy. CONCLUSION: These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols.
    Clinical Cancer Research 01/2013; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT). METHODS: Included were 80 children and adolescents with first intermediate risk BM relapse of ALL recruited in trial ALL-REZ BFM P95/96. We assessed the prognostic value of minimal residual disease (MRD) after induction therapy quantified by PCR using leukaemia clone-specific T-cell receptor/immunoglobulin gene rearrangements. RESULTS: Molecular good responders (MRD<10(-3), n=46) had a probability of event-free survival (pEFS) at 10years of 76% standard error (SE)±6% and a cumulative incidence of second relapse (CIR) at 10years of 21% SE±6%; pEFS of molecular poor responders (MRD⩾10(-3), n=34) at 10years was 18% SE±7% and CIR 61% SE±9% (p<0.001). Cox regression analysis revealed MRD after induction to be the strongest independent prognostic parameter with a 6.6-fold increased risk (95% confidence interval 3.3-13.5, p<0.001) for molecular poor responders to suffer a subsequent adverse event compared to good responders. CONCLUSION: In patients with intermediate risk BM relapse of ALL, low MRD after induction is associated with an excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with insufficient response have an extremely poor prognosis. Therefore, in the subsequent trial ALL-REZ BFM 2002, MRD is used to allocate molecular good responders to conventional post-induction therapy and molecular poor responders to allogeneic HSCT.
    European journal of cancer (Oxford, England: 1990) 12/2012; · 4.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.Leukemia advance online publication, 3 July 2012; doi:10.1038/leu.2012.155.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2012; · 10.16 Impact Factor
  • Gesche Tallen, Guenter Henze, Arend von Stackelberg
    Pharmazie in unserer Zeit 05/2012; 41(3-3):214-221.
  • Gesche Tallen, Günter Henze, Arend von Stackelberg
    Pharmazie in unserer Zeit 05/2012; 41(3):214-21.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations of the hematopoietic transcription factor GATA1 (GATA1s) are pathognomonic in newborn with transient leukemia and children with Down syndrome and myeloid leukemia (ML-DS). Both TL and ML-DS can also occur in children with trisomy 21 mosaic.Between 2002 and 2011, 15 newborns and infants were diagnosed with DS mosaic. 9 of them presented with TL and 8 children suffered from ML-DS; 2 of them with a history of TL. In children without stigmata the special morphology and immunophenotype of blasts triggered the screening for GATA1 mutation and trisomy 21 mosaic.All newborns with TL achieved complete remission (CR). Due to clinical symptoms caused by the leukemic blasts, in 3 children low-dose cytarabine was applied. 1 patient died due to cardiac defect. In all patients GATA 1 s was confirmed. 6 children with ML-DS were initially treated according the AML-BFM protocol. After ML-DS was confirmed, therapy was continued with the intensity reduced schedule according to the ML-DS 2006 protocol. All children are still in CR (follow-up 1.8-7 years, median 2.7 yrs). 2 children with unknown trisomy 21 mosaic were diagnosed as acute megakaryoblastic leukemia (AMKL) and treated according the high risk arm of the AML-BFM 2004 including allogeneic stem cell transplantation in one child). GATA1 mutation was identified retrospectively. Both children are alive in CR.GATA1s associated leukemia has to be excluded in all young children with AMKL (<5 years old) to prevent overtreatment. Treatment with reduced intensity seems sufficient in children trisomy 21 mosaic and ML-DS.
    Klinische Pädiatrie 04/2012; 224(3):153-5. · 1.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia (AML) were treated in studies AML-BFM-98 (n = 59) and -2004 (n = 66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66 ± 4%, and improved from 61 ± 6% in study-98 to 75 ± 6% in study-2004 (P(logrank) 0.14) and event-free survival rates were 44 ± 6% and 51 ± 6% (P(logrank) 0.66), respectively. Results in HR infants were similar to those of older HR children (1-<2- or 2-<10-year olds, P(logrank) 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2011; 26(4):654-61. · 10.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Platelet counts below normal values define thrombocytopenia. However, platelet counts alone do not reveal the underlying pathomechanism. New blood cell counters provide additional information on platelet size and volume, and enable the distinction of sub-populations. In this preliminary study, we evaluate whether one of these markers can be used for diagnosis of isolated thrombocytopenia in children. We provide normal values for mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR), platelet mean-frequent volume (P-MFV), relative immature platelet fraction (IPF%), and absolute IPF (IPF#) for 100 healthy children and analyzed 87 children with thrombocytopenia. In children with platelet production defects, IPF% was low, while in acute immune thrombocytopenia (ITP), IPF% was markedly increased (median 25.2%, P < 0.01), representing accelerated platelet turnover. Interestingly, children diagnosed with acute lymphocytic leukemia (ALL) also had elevated IPF% (median 10%, P < 0.01), suggesting that thrombopoiesis is stimulated despite virtual absence of bone marrow progenitors. Low IPF# was only found in patients with acute ITP. IPF% is a marker for thrombocytopenia due to defective platelet production while IPF#, representing the immature platelet count, might become a practical parameter to distinguish acute ITP from thrombocytopenia in children with newly diagnosed ALL (P < 0.01).
    Pediatric Blood & Cancer 10/2011; 57(4):641-7. · 2.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the clinical management of children with relapsed acute lymphoblastic leukemia (ALL), treatment resistance remains a major challenge. Alterations of the TP53 gene are frequently associated with resistance to chemotherapy, but their significance in relapsed childhood ALL has remained controversial because of small studies. Therefore, we systematically studied 265 first-relapse patients enrolled in the German Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Mü nster 2002 (ALL-REZ BFM 2002) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation-dependent probe amplification. We observed copy number and sequence alterations of TP53 in 12.4% (27 of 218) of patients with B-cell precursor ALL and 6.4% (three of 47) of patients with T-cell ALL relapse. Backtracking to initial ALL in 23 matched samples revealed that 54% of all TP53 alterations were gained at relapse. Within B-cell precursor ALL, TP53 alterations were consistently associated with nonresponse to chemotherapy (P < .001) and poor event-free survival (P < .001) and overall survival rates (P = .002). TP53 alterations also had a significant impact on survival within intermediate-risk (S2) and high-risk (S3/S4) relapse patients (P = .007 and P = .019, respectively). This prognostic significance of TP53 alterations was confirmed in multivariate analysis. Besides their clinical impact, TP53 alterations were associated with a higher fraction of leukemic cells in S/G(2)-M phase of the cell cycle at relapse diagnosis. Alterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.
    Journal of Clinical Oncology 08/2011; 29(23):3185-93. · 18.04 Impact Factor

Publication Stats

1k Citations
543.05 Total Impact Points

Institutions

  • 2005–2014
    • Charité Universitätsmedizin Berlin
      • Department of Pediatrics, Division of Oncology and Hematology
      Berlín, Berlin, Germany
  • 2011
    • Gesellschaft für Pädiatrische Onkologie und Hämatologie
      Berlín, Berlin, Germany
  • 2010
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
    • University College London
      • Department of Haematology
      London, ENG, United Kingdom
  • 2009
    • Goethe-Universität Frankfurt am Main
      Frankfurt, Hesse, Germany
    • University Children's Hospital Basel
      Bâle, Basel-City, Switzerland
  • 1998–2009
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2008
    • Federal Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology
      Moskva, Moscow, Russia