Meinolf Suttorp

Carl Gustav Carus-Institut, Pforzheim, Baden-Württemberg, Germany

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Publications (156)505.81 Total impact

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    ABSTRACT: Background: The tyrosine kinase inhibitor (TKI) imatinib is applied as front-line treatment in adult and pediatric patients with chronic myeloid leukemia (CML) in order to selectively inhibit the causative oncogenic BCR-ABL1 tyrosine kinase. However, TKIs exhibit off-target effects on further kinases involved in the regulation of bone metabolism. As consequence, pediatric patients display longitudinal growth retardation while on imatinib treatment. As CML is a rare disease in children, growth experiences are limited so far (Millot F 2009 Blood; Shima H 2011 Pediatrics). Therefore, we examined longitudinal growth in a pediatric CML cohort and also established a juvenile rat model to investigate side effects of long-term TKI exposure on the growing skeleton. Methods: 102 CML patients (54♂/48♀) receiving upfront imatinib were enrolled in growth analysis using height standard deviation scores (SDS). The animal model comprises male Wistar rats which starting at the age of 4 weeks (w) were continuously or intermittently exposed to TKI at varying dosages over 10 w. After defined time intervals of exposure (after 2w, prepubertal stage; 4w, pubertal stage; 10w, postpubertal stage, respectively), rats were sacrificed and bone parameters and osseous metabolism were investigated. Results: A mean decrease in height of 0.48 SDS per year (y) during the first 2 years of imatinib treatment was observed, with prepubertal patients being more severely affected (-0.75 SDS/y) compared to pubertal teenagers (-0.02 SDS/y). The juvenile animal model demonstrated altered osseous parameters (bone length, trabecular BMD, bone strength) predominantly in long bones compared to vertebrae. Dose-dependently decreased Osteocalcin- and TRAP-serum levels were observed. Intermittent treatment minimized osseous and biochemical changes. Conclusion: Growth retardation is a significant adverse effect of TKI treatment in pediatric patients, which could be uniformly modeled in juvenile rats. In addition, high-dose, long-term TKI exposure in rats predicts an increased fracture risk. Skeletal side effects were reduced by intermittent treatment thus possibly reflecting a new therapeutic option. Ongoing investigations on next-generation TKI revealed identical osseous alterations with dasatinib, whereas bosutinib exhibited milder changes. Presently, TKI administration is considered a life-long treatment thus requiring regular monitoring of skeletal side effects under long-term exposure. Acknowledgement: Funded by DFG-grant SU122-3/1. Disclosure: The authors declared no competing interests.
    7th International Conference on Children's Bone Health, Salzburg, Austria; 06/2015
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    ABSTRACT: The tyrosine kinase (TK) inhibitor imatinib provides a highly effective therapy for chronic myeloid leukemia (CML) via inhibition of the oncogenic TK BCR-ABL1. However, off-target TKs like platelet-derived growth factor receptors (PDGF-R) and colony-stimulating factor-1 receptor (c-fms), involved in bone remodeling, are also inhibited. Thus, pediatric patients with CML on imatinib exhibit altered bone metabolism, leading to linear growth failure. As TKI treatment might be necessary for a lifetime, long-term effects exerted on bone in children are of major concern. Therefore, we studied the skeletal long-term effects of continuous and intermittent imatinib exposure in a juvenile rat model. Four-weeks-old male Wistar rats were chronically exposed to imatinib via drinking water over a period of 10 weeks. Animals were exposed to a standard and high imatinib dosage continuously and to the high imatinib dose intermittently. Bone mass and strength were assessed using pQCT, micro-computed tomography (μCT), and biomechanical testing at the prepubertal, pubertal, and postpubertal age. Bone length and vertebral height as well as biochemical markers of bone turnover were analyzed. Femoral and tibial bone length were dose-dependently reduced by up to 24% (p<0.0001), femoral and tibial trabecular bone mass density (BMD) were reduced by up to 25% (p<0.01), and femoral breaking strength was lowered by up to 20% (p<0.05). Intermittent exposure mitigated these skeletal effects. Long-term exposure resulted in reduced vertebral height by 15% and lower trabecular BMD by 5%. Skeletal changes were associated with suppressed serum osteocalcin (p<0.01) and non-significantly elevated serum CTX-I and PINP levels. In conclusion, imatinib mainly impaired longitudinal growth of long bones rather than the vertebrae of growing rats. Interestingly, intermittent imatinib exposure has less skeletal side effects, which may be beneficial in pediatric patients taking imatinib.
    PLoS ONE 06/2015; 10(6):e0131192. DOI:10.1371/journal.pone.0131192. · 3.53 Impact Factor
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    ABSTRACT: Objectives: The tyrosine kinase inhibitor (TKI) IMA has been licensed for treatment of CML in pediatric patients in the year 2003. IMA inhibits the oncogenic BCR-ABL tyrosine kinase causing CML, but is also well known for its inhibitory “off-target” effects on bone metabolism resulting in disturbed bone remodeling. This leads to longitudinal growth impairment in not outgrown individuals. In addition, IMA treatment exerts further “off-target” effects by disrupting the growth hormone:IGF-I axis which may aggravate bone growth impairment. The pediatric trial CML-PAED II starting in 2006 recruits approx. 15 pediatric patients with CML annually and as of today comprises the largest pediatric CML cohort on prospective TKI treatment. In this cohort we examined the alteration of bone growth depending on sex, age, and pubertal stage at start of IMA treatment. Methods: 102 CML patients (54 male / 48 female; median age 12 years, range: 1-18 years) receiving IMA as upfront treatment in participating centers in Germany and neighboring countries were enrolled retrospectively into this analysis. During IMA treatment body height and serum bone metabolic parameters were assessed in three month intervals. Height standard deviation scores (SDS) were derived from WHO-AnthroPlus software (version 1.04), a global tool providing normal range values of growth from birth till the age of 19 years. Results: In comparison to mean height SDS at diagnosis a mean decrease of 0.48 SDS per year was observed in the total cohort during the first two years on treatment. Growth impairment was more pronounced in prepubertal patients (27/102 patients; age: <10 years) with a mean reduction of 0.75 SDS per year compared to postpubertal teenagers (29/102 patients; age: >14 years) with a mean reduction in height of 0.02 SDS per year. Discussion: Longitudinal growth impairment is a significant adverse effect of IMA in pediatric patients with CML, affecting predominantly prepubertal children. Today, TKI administration is considered a decades-long treatment thus requiring regular monitoring of skeletal side effects under long-term exposure.
    7th Midsummer Meeting on Pediatric Hematology, Oncology and Stem Cell Transplantation, Liberec, Czech Republic; 06/2015
  • 7th Midsummer Meeting on Pediatric Hematology, Oncology and Stem Cell Transplantation, Liberec, Czech Republic; 06/2015
  • Vera Girke, Josephine Tabea Tauer, Meinolf Suttorp
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    ABSTRACT: Background: In pediatric patients suffering from chronic myeloid leukemia (CML) long-term tyrosine kinase inhibitor (TKI) treatment exposes several off-target side effects. TKIs inhibit c-kit and platelet derived growth factor receptor (PDGFR) which in testes are essentially required for spermatogenesis. The influence of TKI long-term treatment on spermatogenesis in pediatric patients with CML is not fully understood. Therefore, we studied testicular tissue in juvenile rats following TKI exposure in a time and dose dependent fashion. Methods: Juvenile, still growing Wistar rats (age: 4 weeks (w)) were exposed for 10 w to imatinib (IMA) or dasatinib (DASA) at different dosages (low dose [LD], high dose [HD], intermittently high dose [ID]). Prepubertal (age: 6 w), pubertal (8 w), and postpubertal (14 w) total testis weight as well as cellularity (spermatogonia, spermatocytes, spermatids, Ki-67 positive cells) in microscopic tubules cross section were evaluated after IMA treatment. Expression of genes involved in spermatogenesis comprising SCF, c-kit and PDGF-R α/β was studied under DASA exposure. Results: Overall, 64 and 40 testes specimen were analyzed for IMA and DASA, respectively. Testis weight was not influenced by any TKI exposure. Compared to non-exposed controls, spermatogenic cell counts were significantly decreased following IMA HD-exposure whereas LD- and ID-exposure attenuated this finding. However, cell proliferation investigated by Ki-67 expression was significantly lowered at all applied IMA doses. Long-term DASA treatment after 10 w at LD, HD and ID, respectively, resulted in significantly reduced gene expression of SCF, c-kit and PDGF-R α/β. Gene expression of PDGF-A was significantly decreased in HD and ID but not LD, whereas PDGF-B postpubertally showed no significant reduction. Conclusion: Long-term TKI exposure resulted in reduced progenitor cell proliferation of spermatogenesis dose-dependently. Thus, - at least in not yet outgrown rats - a long-term negative effect of chronic TKI exposure on spermatogenesis cannot be denied.
    7th Midsummer Meeting on Pediatric Hematology, Oncology and Stem Cell Transplantation.; 06/2015
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    ABSTRACT: Background: Application of DA in adults with CML may lead to adverse cardiac effects (pleural & pericardial effusion, abnormal heart rate, organ hypertrophy). Understanding underlying mechanisms is crucial for the application of DA in pediatrics. Methods: DA was administered chronically [either standard (SD) or high dose (HD)) or intermittently HD (3 days “on”, 4 days ”off”] via the drinking water to 4 week (w) old male rats for 10 w. Rats underwent regular ECG and cardiac ultrasound followed by necropsy to investigate heart weight. Results: Dose independently, heart weight increased in SD and HD after 2 w, 4 w, and 10 w exposure. Cardiac ejection fraction (EF) and fractional shortening (FS) was unaltered following short-term application but decreased after 10 w on HD. Concordant reduction of EF and FS following both SD and intermittent HD treatment points to a dose-dependent impairment of cardiac development. Conclusion: Cardiac parameters seem less affected by short term application of DA while long-term exposure results in development of cardiac insufficiency. However, intermittent application allows recovery of EF and FS during 10 w of treatment.
    Annual Meeting of the Kind-Philipp-Foundation for Leukemia Research, Wilsede, Lüneburger Heide, Germany; 06/2015
  • Vera Girke, Josephine Tabea Tauer, Meinolf Suttorp
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    ABSTRACT: Background: Long-term tyrosine kinase inhibitor (TKI) “targeted” treatment in pediatric patients with chronic myeloic leukemia reveals multiple off-target side effects. Specifically in testes, TKIs signaling cascades necessary for spermatogenesis are inhibited but the detailed action is not yet fully understood. Therefore, we investigated testicular tissue under TKI exposure in a juvenile rat model. Methods: Growing Wistar rats (age: 4 weeks (w)) were exposed over 10 w to imatinib (IM) or dasatinib (DASA) at different concentrations (low dose [LD], high dose [HD], intermittent high dose [ID]). At prepubertal (age: 6 w), pubertal (8 w), and postpubertal stage (14 w) total testis weight and cellularity (spermatogonia, spermatocytes, spermatids, Ki-67 positive cells) in microscopic tubulus cross section were analyzed under IM exposure. Expression of genes involved in spermatogenesis was analyzed under DASA exposure. Results: In total, 64 and 40 tissue specimen were analyzed for IM and DASA, respectively. Testis weight was not affected by TKI treatment. During IM treatment, compared to controls cell counts were significantly decreased in HD (p = 0.031) whereas LD and ID drug exposure minimized these adverse effects. However, proliferation as assessed by Ki-67 expression was significantly decreased at all IM doses applied. Long-term DASA HD exposure decreased gene expression of SCF, c-kit, PDGF-A/B, and PDGF-R α/β. Conclusion: Long-term TKI exposure seems to influence spermatogenesis dose-dependently, therefore a negative effect on fertility can not be excluded.
    Annual Meeting of the Kind-Philipp-Foundation for Leukemia Research, Wilsede, Lüneburger Heide, Germany; 06/2015
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    ABSTRACT: Objective: To investigate alteration of body height, BMI, and bone metabolism in a pediatric CML cohort on upfront IM treatment. Methods: During therapy standard deviation scores (SDS) of body height, body weight, urine and serum were collected in 3-month (mo) intervals. Results: 27 / 111 prepubertal pts (age: < 10 y; 14 ♂ / 13 ♀), 46 pts pubertal pts (age: 10 - 14 y; 25 ♂ / 21 ♀), and 38 postpubertal pts (age: > 15 y; 24 ♂ / 14 ♀) on IM (mean: 16 mo; median 12 mo; range: 0 – 103 mo) showed - compared to mean height SDS at diagnosis - a mean decrease of 0.45 SDS / y and increase in BMI of 0.34 SDS / y in the total cohort during the first 2 y. Height was more affected prepubertally while BMI was more altered pubertally. Urinary bone resorption markers Desoxy-/Pyridinoline continuously decreased during therapy whereas serum formation markers Osteocalcin and Alkaline Phosphatase increased within the first 3 mo followed by a decline until 12 mo and steady state level until 24 mo of therapy. All patients revealed hyperparathyroidism continuously. Conclusion: IM is considered a life-long therapy causing growth retardation as adverse effect in pediatric CML. Thus, regular monitoring of skeletal side effects is warranted.
    Annual Meeting of the Kind-Philipp-Foundation for Leukemia Research, Wilsede, Lüneburger Heide, Germany; 06/2015
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    ABSTRACT: Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 05/2015; DOI:10.1111/bjh.13462 · 4.96 Impact Factor
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    ABSTRACT: In contrast to adult medicine, specific scoring systems predicting the treatment response for an individual pediatric patient (pt) with chronic myeloid leukemia (CML) have not yet been defined. We evaluated to what extend prognostic scores as described for adults (e.g., Sokal, Hasford, EUTOS score) resulted in comparable risk group categorizations in a pediatric cohort. Parameters for score calculation were extracted from a data set of 90 patients enrolled into trial CML-PAED-II and treated by a standard dose of imatinib. At month 3 and at month 6, treatment response was analyzed based on the transcript ratio BCR-ABL1/ABL1. By the EUTOS, Hasford, and Sokal scores 81, 59, and 62 % of the patients were categorized as low risk, respectively; 19, 14, and 16 % of the patients as high risk, respectively; and by Hasford and Sokal scores 27 and 22 % of the patients, respectively, as intermediate risk. Twenty-seven out of 72 patients analyzable (38 %) exhibited a transcript ratio >10 % at month 3. We show that only the EUTOS score, but not the Sokal and Hasford score, correlates with this early outcome (p = 0.008). Analyzing the EUTOS score separately, we can demonstrate that lowering the cutoff from 87 to 48 points for categorization in low- and high-risk individuals increases the odds ratio from 2.4 (95 % CI 0.6 to 10.4) to 3.6 (95 % CI 1.3 to 10.9). Data are provided on the distribution of risk categories and resulting discrepancies when adult scores are applied on children and adolescents with CML at diagnosis. A larger number of patients and longer follow-up are still needed to develop a prognostic score specifically adapted to the pediatric and adolescent age cohorts.
    Annals of Hematology 04/2015; 94(8). DOI:10.1007/s00277-015-2367-2 · 2.40 Impact Factor
  • Blood 04/2015; 125(14):2311-3. DOI:10.1182/blood-2015-01-619734 · 10.43 Impact Factor
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    ABSTRACT: Here we report on a child with Li-Fraumeni syndrome with a de novo TP53 mutation c.818G>A, who developed three malignancies at the age of 4 months, 4 and 5 years, respectively. We show that (i) in the choroid plexus carcinoma, the germline mutation was detected in a homozygous state due to copy-neutral LOH/uniparental disomy, (ii) in the secondary AML, a complex karyotype led to loss of the wild-type TP53 allele, (iii) in the Wilms tumor, the somatic mutation c.814G>A led to compound heterozygosity. The findings show that the complete inactivation of TP53 by different mechanisms is an important step towards tumorigenesis. Pediatr Blood Cancer 2015; 9999:1-4. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2015; DOI:10.1002/pbc.25486 · 2.56 Impact Factor
  • Nobuko Hijiya, Frederic Millot, Meinolf Suttorp
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    ABSTRACT: Chronic myelogenous leukemia (CML) is a rare disease in children. There is little evidence of biological differences between CML in children and adults, although host factors are different. Children develop distinct morbidities related to the off-target effects of tyrosine kinase inhibitors. The goal of treatment in children should be cure rather than suppression of disease, which can be the treatment goal for many older adults. This article reviews data from the literature on the treatment of CML, discusses the issues that are unique to CML in children, and recommends management that takes these issues into consideration. Copyright © 2015 Elsevier Inc. All rights reserved.
    Pediatric Clinics of North America 02/2015; 62(1):107-119. DOI:10.1016/j.pcl.2014.09.008 · 2.20 Impact Factor
  • Frédéric Millot, Meinolf Suttorp
    British Journal of Haematology 01/2015; 169(5). DOI:10.1111/bjh.13249 · 4.96 Impact Factor
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    ABSTRACT: Background: Rothmund-Thomson syndrome (RTS) is associated with an increased risk of osteosarcoma, but information about affected patients is limited. Procedure: Seven patients with osteosarcoma, treated in the Cooperative Osteosarcoma Study Group-trials, had a diagnosis of RTS. Their patient-, tumor- and treatment-related variables and outcome were reviewed retrospectively. Results: Median age at diagnosis of osteosarcoma was 13 years (range 7-16), five were female, two male. Tumor involved proximal tibia (n = 4), distal tibia (n = 1), distal fibula (n = 1) and proximal ulna (n = 1). Three patients had metastatic disease at diagnosis. All patients received surgery and chemotherapy. Four of seven patients required dose modifications and three of them terminated treatment prematurely. Complete resection of the primary tumor was achieved in all individuals. Two of three affected patients failed to achieve surgical clearance of their primary metastases and died. The third patient relapsed with multiple metastases and died. Two of four patients with localized disease were alive in first complete remission, a third patient in second complete remission after recurrence and a fourth patient died of acute leukemia, while still in first complete remission of osteosarcoma. Conclusions: Patients with RTS and osteosarcoma may be cured of their cancer with appropriate multimodal therapy. They should be treated like other osteosarcoma patients but preexisting disorders, needs for special support and development of toxicities have to be considered.
    Pediatric Hematology and Oncology 12/2014; 32(1). DOI:10.3109/08880018.2014.987939 · 0.96 Impact Factor
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    ABSTRACT: Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of the BCR‑ABL1 fusion gene, a constitutively active, oncogenic tyrosine kinase that is responsible for the clinical features of CML. Tyrosine kinase inhibitors, such as imatinib, have markedly altered the treatment of CML. However, tyrosine kinase inhibitors are associated with side effects on bone metabolism, in adult and pediatric patients. Vitamin D3 is involved in the complex cycle of bone remodeling, therefore the present study aimed to investigate the influence of imatinib on vitamin D3 metabolism in the HaCaT human keratinocyte cell line, using commercially available enzyme assays. Imatinib was shown to significantly reduce the production of calcidiol and calcitriol. Based on interaction studies of imatinib with the cytochrome P450 (CYP450) inhibitors VID400 and ketoconazole, it is proposed that imatinib may interfere with the vitamin D3 cascade due to its metabolism by CYP27B1, which is involved in vitamin D3 metabolism.
    Molecular Medicine Reports 12/2014; 11(4). DOI:10.3892/mmr.2014.3074 · 1.48 Impact Factor
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    ABSTRACT: Objectives: A decade after being licensed for treatment of CML in minors, the TKI imatinib (IMA) is well known for it’s inhibitory “off-target” effects on activity and proliferative capacity of osteoclasts and osteoblasts resulting in impaired bone remodeling (Vandyke K et al 2010 Blood 115:766; Tauer JT et al Blood 2011:118). This causes longitudinal growth retardation in not outgrown individuals (Millot F et al 2009 Blood 114:863; Shima H et al 2011 Pediatrics 159:676; Bansal D et al 2012 Ped Blood Cancer 59:481) which can be aggravated by a disrupted growth hormone:IGF-I axis as a possible additional off-target effect exerted by TKI treatment (Ulmer A et al 2013 Klin Padiatr 225:120; Bansal D et al 2012 Ped Blood Cancer 59:481). Starting a pediatric trial in the year 2006 which recruits approx. 15 pediatric patients (pts) with CML annually, we investigated to what extend growth is impaired depending on sex, age, and pubertal stage at start of IMA treatment in a pediatric cohort. Methods: 102 pts (54 male / 48 female; median age 12 years, range: 1-18 years) at diagnosis of CML receiving IMA as upfront treatment were enrolled retrospectively in this analysis from centers in Germany and participating countries during 02/2006 to 06/2014. Height standard deviation scores (SDS) were derived from WHO-AnthroPlus, version 1.04 software, a global growth-monitoring tool providing normal range values for the age cohorts from birth till 19 years. 81 out of 102 pts fulfilled the criteria for continuous assessment of growth scheduled at three months intervals during IMA exposure. 21 pts were analyzed at intervals ≠ 3 month. Pts excluded comprised individuals shifted to a 2nd generation TKI, or cumulative interruptions of drug intake exceeding 4 weeks, or pts undergoing stem cell transplantation. Results: The mean and median duration of IMA exposure was 12 months and 9 months, respectively (range: 0–98 month). 27/102 pts (13 male, 14 female) were prepubertal (age: <10 years) at initiation of IMA treatment while 46/102 pts were pubertal (age: 10-14 years; 23 male, 23 female), and 29/102 pts were in postpubertal stage (age: >14 years; 18 male, 11 female). In comparison to mean SDS at diagnosis a mean decrease in height of 0.48 SDS per year was observed in the total cohort during the first three years of treatment, being more pronounced in prepubertal pts. In pts diagnosed shortly before or at puberty a mean reduction of 0.75 SDS per year during the first three years were observed. Older teenagers revealed no change in body height z-score during TKI treatment compared to height z-score at diagnosis. Discussion: Growth retardation is a significant adverse effect of IMA in children with CML affecting predominantly prepubertal children. Possible medical interventions still need to be investigated. Acknowledgement: Supported by grant DFG SU122-3/1 to MS.
    American Socienty of Hematology (ASH), San Francisco; 12/2014
  • Blood 12/2014; 124(21). · 10.43 Impact Factor
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    ABSTRACT: Approximately 40% of adults with chronic myeloid leukemia (CML) in prolonged complete molecular response (CMR) remain in CMR after imatinib discontinuation. Corresponding information in children is lacking. Two children with CML in CMR for 48 and 19 months after imatinib discontinuation showed low-level fluctuating disease at RNA transcript and genomic DNA levels. Both patients were low risk according to adult criteria. Since adults with molecular relapse responded to re-introduction of imatinib, we postulated that treatment discontinuation in low risk children might be justified within clinical trials with close monitoring. This may help to minimize exposure to imatinib and its potential side effects. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 11/2014; 61(11). DOI:10.1002/pbc.25090 · 2.56 Impact Factor
  • Pediatric Blood & Cancer 07/2014; 61(7). DOI:10.1002/pbc.24933 · 2.56 Impact Factor

Publication Stats

2k Citations
505.81 Total Impact Points

Institutions

  • 2005–2015
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 2003–2015
    • Technische Universität Dresden
      • Klinik und Poliklinik für Kinder- und Jugendmedizin
      Dresden, Saxony, Germany
  • 1990–2015
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 2009
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2008
    • Universitätsklinikum Dresden
      Dresden, Saxony, Germany
  • 2004
    • Universitätsklinikum Schleswig - Holstein
      • Klinik für Allgemeine Pädiatrie (Kiel)
      Kiel, Schleswig-Holstein, Germany
  • 1988–2001
    • Christian-Albrechts-Universität zu Kiel
      • • UKSH II. Medizinische Klinik und Poliklinik
      • • Abteilung für Allgemeine Pädagogik
      Kiel, Schleswig-Holstein, Germany