Publications by authors named "Josefine Palle"

29 Publications

  • Page 1 of 1

Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets.

Blood Adv 2021 Feb;5(3):900-912

Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.
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http://dx.doi.org/10.1182/bloodadvances.2020003709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876890PMC
February 2021

Extracorporeal Membrane Oxygenation Support in Children With Hematologic Malignancies in Sweden.

J Pediatr Hematol Oncol 2021 03;43(2):e272-e275

Department of Women's and Children's Health, Uppsala University.

Background: Extracorporeal membrane oxygenation (ECMO) is used in severe respiratory and/or circulatory failure when conventional critical care fails. Studies on patients with hematologic malignancies on ECMO have shown contradictory results; immunosuppression and coagulopathy are relative contraindications to ECMO.

Observations: This nationwide Swedish retrospective chart review identified 958 children with hematologic malignancies of whom 12 (1.3%) required ECMO support. Eight patients survived ECMO, 7 the total intensive care period, and 6 survived the underlying malignancy.

Conclusions: ECMO may be considered in children with hematologic malignancy. Short-term and long-term survival, in this limited group, was similar to that of children on ECMO at large.
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http://dx.doi.org/10.1097/MPH.0000000000001808DOI Listing
March 2021

Associations between pretherapeutic body mass index, outcome, and cytogenetic abnormalities in pediatric acute myeloid leukemia.

Cancer Med 2019 11 18;8(15):6634-6643. Epub 2019 Sep 18.

Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus N, Denmark.

Background: Associations between body mass index (BMI), outcome, and leukemia-related factors in children with acute myeloid leukemia (AML) remain unclear. We investigated associations between pretherapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML.

Methods: We included patients, age 2-17 years, diagnosed with de novo AML from the five Nordic countries (2004-2016), Hong Kong (2007-2016), the Netherlands and Belgium (2010-2016), and Canada and USA (1995-2012). BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Kaplan-Meier estimator, Cox regression, and logistic regression were used to investigate associations.

Results: In total, 867 patients were included. The median age was 10 years (range 2-17 years). At diagnosis, 32 (4%) were underweight, 632 (73%) were healthy weight, 127 (15%) were overweight, and 76 (9%) were obese. There was no difference in relapse risk, treatment-related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age, and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1-3.4) and 2.8 (95% CI 1.3-5.8), respectively, compared to healthy weight patients.

Conclusions: This study did not confirm previous reports of associations between overweight and increased treatment-related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status.
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http://dx.doi.org/10.1002/cam4.2554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825997PMC
November 2019

Use of granulocyte colony-stimulating factor and risk of relapse in pediatric patients treated for acute myeloid leukemia according to NOPHO-AML 2004 and DB AML-01.

Pediatr Blood Cancer 2019 06 7;66(6):e27701. Epub 2019 Mar 7.

Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Supportive-care use of granulocyte colony-stimulating factor (G-CSF) in pediatric acute myeloid leukemia (AML) remains controversial due to a theoretical increased risk of relapse and limited impact on neutropenic complications. We describe the use of G-CSF in patients treated according to NOPHO-AML 2004 and DB AML-01 and investigated associations with relapse.

Procedure: Patients diagnosed with de novo AML completing the first week of therapy and not treated with hematopoietic stem cell transplantation in the first complete remission were included (n = 367). Information on G-CSF treatment after each course (yes/no) was registered prospectively in the study database and detailed information was gathered retrospectively from each center. Descriptive statistics were used to describe G-CSF use and Cox regression to assess the association between G-CSF and risk of relapse.

Results: G-CSF as supportive care was given to 128 (35%) patients after 268 (39%) courses, with a large variation between centers (0-93%). The use decreased with time-the country-adjusted odds ratio was 0.8/diagnostic year (95% confidence interval [CI] 0.7-0.9). The median daily dose was 5 μg/kg (range 3-12 μg/kg) and the median cumulative dose was 75 μg/kg (range 7-1460 μg/kg). Filgrastim was used in 82% of G-CSF administrations and infection was the indication in 44% of G-CSF administrations. G-CSF was associated with increased risk of relapse-the adjusted hazard ratio was 1.5 (95% CI 1.1-2.2).

Conclusions: G-CSF as supportive care was used in a third of patients, and use decreased with time. Our results indicate that the use of G-CSF may be associated with an increased risk of relapse.
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http://dx.doi.org/10.1002/pbc.27701DOI Listing
June 2019

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study.

Br J Haematol 2018 11 8;183(4):618-628. Epub 2018 Nov 8.

Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.
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http://dx.doi.org/10.1111/bjh.15587DOI Listing
November 2018

Associations between neutrophil recovery time, infections and relapse in pediatric acute myeloid leukemia.

Pediatr Blood Cancer 2018 09 21;65(9):e27231. Epub 2018 May 21.

Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.

Background: Children with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first induction course, infection and relapse in children treated according to NOPHO-AML 2004 and DB AML-01.

Procedure: Newly diagnosed patients with AML with bone marrow blast <5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n = 279). Neutrophil recovery time was defined as the time from the start of the course to the last day with absolute neutrophil count <0.5 × 10 /l. Linear and Cox regressions were used to investigate associations.

Results: Neutrophil recovery time after the first induction course was positively associated with neutrophil recovery time after the remaining courses, and longer neutrophil recovery time (≥25 days) was associated with increased risk of grade 3-4 infections (hazard ratio 1.4, 95% confidence interval [CI], 1.1-1.8). Longer neutrophil recovery time after the first induction (>30 days) was associated with the increased risk of relapse (5-year cumulative incidence: 48% vs. 42%, hazard ratio 1.7, 95% CI, 1.1-2.6) for cases not treated with hematopoietic stem cell transplantation in first complete remission.

Conclusion: Longer neutrophil recovery time after the first induction course was associated with grade 3-4 infections and relapse. If confirmed, this knowledge could be incorporated into risk stratification strategies in pediatric AML.
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http://dx.doi.org/10.1002/pbc.27231DOI Listing
September 2018

Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature.

Genes Chromosomes Cancer 2018 Jul 30;57(7):359-365. Epub 2018 Apr 30.

Department of Pediatrics, Aarhus University Hospital Skejby, Denmark.

The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
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http://dx.doi.org/10.1002/gcc.22538DOI Listing
July 2018

DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia.

Clin Epigenetics 2018 5;10:31. Epub 2018 Mar 5.

1Department of Medical Biosciences, Umeå University, Blg 6M, 2nd floor, SE-90185 Umeå, Sweden.

Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

Results: Among the 137 patients that later relapsed, patients with a CIMP- profile ( = 42) at initial diagnosis had an inferior overall survival (pOS 33%) compared to CIMP+ patients ( = 95, pOS 65%) ( = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.
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http://dx.doi.org/10.1186/s13148-018-0466-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836434PMC
February 2019

Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 × 10 /l. The NOPHO experience 1984-2014.

Br J Haematol 2017 08 25;178(3):448-456. Epub 2017 May 25.

Department of Paediatrics, Institution for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC >200 × 10/l). Eighty-six patients (10%) had WBC 100-199 × 10 /l and 57 (6%) had WBC ≥200 × 10 /l. Patients with WBC ≥200 × 10 /l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 × 10 /l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.
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http://dx.doi.org/10.1111/bjh.14692DOI Listing
August 2017

Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia.

Br J Haematol 2017 08 25;178(4):592-602. Epub 2017 Apr 25.

Institution for Clinical Sciences, Department of Paediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS ) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML.
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http://dx.doi.org/10.1111/bjh.14720DOI Listing
August 2017

Extramedullary leukemia in children with acute myeloid leukemia: A population-based cohort study from the Nordic Society of Pediatric Hematology and Oncology (NOPHO).

Pediatr Blood Cancer 2017 Dec 23;64(12). Epub 2017 Mar 23.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Background: The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified.

Procedure: This population-based study included 315 children from the NOPHO-AML 2004 trial.

Results: At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 × 10 /l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%). No patient received involved field radiotherapy. Five-year event-free survival did not differ significantly between the EML and the non-EML patients (54% vs. 45%, P = 0.57), whereas 5-year overall survival (OS) was significantly lower in the EML group (64% vs. 73%, P = 0.04). The risk of induction death was significantly higher for EML patients (8% vs. 1%, P = 0.002). There was a trend toward a lower risk of relapse for EML patients (5-year cumulative incidence of relapse 33% vs. 49%, P = 0.16). Traumatic lumbar puncture did not adversely affect survival in this cohort.

Conclusions: EML was associated with increased risk of induction death impacting the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy.
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http://dx.doi.org/10.1002/pbc.26520DOI Listing
December 2017

Effect of age and body weight on toxicity and survival in pediatric acute myeloid leukemia: results from NOPHO-AML 2004.

Haematologica 2016 11 28;101(11):1359-1367. Epub 2016 Jul 28.

Department of Pediatrics, Aarhus University Hospital Skejby, Denmark.

Treatment for pediatric acute myeloid leukemia is very toxic and the association between outcome and age and Body Mass Index is unclear. We investigated effect of age and Body Mass Index on toxicity and survival in pediatric acute myeloid leukemia. We studied all patients who completed first induction course of NOPHO-AML 2004 (n=318). Toxicity following induction and consolidation courses (n=6) was analyzed. The probabilities of toxicity and death were determined using time-to-event analyses with Cox multivariate proportional hazard regression for comparative analyses. Age 10-17 years was associated with sepsis with hypotension [hazard ratio 2.3 (95% confidence interval 1.1-4.6)]. Being overweight (>1 standard deviation) was associated with requiring supplemental oxygen [1.9 (1.0-3.5)]. The 5-year event-free and overall survival were 47% and 71%. Children aged 10-17 years showed a trend for inferior 5-year overall survival compared to children aged 2-9 (64% vs. 76%; P=0.07). Infants showed a trend for superior 5-year event-free survival (66% vs. 43%; P=0.06). Overweight children aged 10-17 years showed a trend for superior survival [5-year event-free survival 59% vs. 40% (P=0.09) and 5-year overall survival 78% vs. 56% (P=0.06)] compared to healthy weight children aged 10-17 years. In conclusion, children aged 10-17 years and overweight children had a higher risk of grade 3-4 toxicity. Children aged 10-17 years showed inferior survival, but, unexpectedly, in this age group overweight children tended to have increased survival. This suggests different pharmacokinetics of chemotherapeutic drugs in adolescents and warrants further studies.
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http://dx.doi.org/10.3324/haematol.2016.146175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394883PMC
November 2016

Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes.

Oncotarget 2016 Sep;7(39):64071-64088

Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.
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http://dx.doi.org/10.18632/oncotarget.11773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325426PMC
September 2016

Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO-AML study.

Genes Chromosomes Cancer 2016 09 23;55(9):719-26. Epub 2016 Jun 23.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22373DOI Listing
September 2016

Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study.

Br J Haematol 2016 Aug 13;174(4):600-9. Epub 2016 Apr 13.

Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.

Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0·1% RD cut-off level. RD-negative and -positive patients after first induction showed a 5-year EFS of 65 ± 7% and 22 ± 7%, respectively (P < 0·001) and an OS of 77 ± 6% (P = 0·025) and 51 ± 8%. RD-negative and -positive patients at start of consolidation therapy had a 5-year EFS of 57 ± 7% and 11 ± 7%, respectively (P < 0·001) and an OS of 78 ± 6% and 28 ± 11%) (P < 0·001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR):5·0; 95% confidence interval (CI):1·9-13·3] and OS (HR:7·0; 95%CI:2·0-24·5). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials.
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http://dx.doi.org/10.1111/bjh.14093DOI Listing
August 2016

Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy.

Ophthalmology 2016 06 4;123(6):1401-4. Epub 2016 Feb 4.

Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

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http://dx.doi.org/10.1016/j.ophtha.2015.12.031DOI Listing
June 2016

Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries.

Pediatr Blood Cancer 2016 Jan 18;63(1):83-92. Epub 2015 Aug 18.

Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.

Background: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited.

Procedure: We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries.

Results: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor.

Conclusions: No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.
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http://dx.doi.org/10.1002/pbc.25713DOI Listing
January 2016

The applicability of the WHO classification in paediatric AML. A NOPHO-AML study.

Br J Haematol 2015 Jun 29;169(6):859-67. Epub 2015 Mar 29.

Department of Paediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.

The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18 years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n = 14) had significantly poorer outcome than del(7q) (n = 11); 5-year event-free survival 26% vs. 67%, (P = 0·02), and 5-year overall survival 51% vs. 90%, (P = 0·04). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n = 280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML.
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http://dx.doi.org/10.1111/bjh.13366DOI Listing
June 2015

DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia.

Clin Epigenetics 2015 17;7:11. Epub 2015 Feb 17.

Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Box 1432, BMC, SE-751 44 Uppsala, Sweden.

Background: We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL.

Results: We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5.

Conclusions: Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.
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http://dx.doi.org/10.1186/s13148-014-0039-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343276PMC
March 2015

The mutational landscape in pediatric acute lymphoblastic leukemia deciphered by whole genome sequencing.

Hum Mutat 2015 Jan;36(1):118-28

Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.
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http://dx.doi.org/10.1002/humu.22719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309499PMC
January 2015

Ploidy and clinical characteristics of childhood acute myeloid leukemia: A NOPHO-AML study.

Genes Chromosomes Cancer 2014 Aug 18;53(8):667-75. Epub 2014 Apr 18.

Department of Pediatrics, Aarhus University Hospital, Skejby, Aarhus, Denmark.

We report the first large series (n = 596) of pediatric acute myeloid leukemia (AML) focusing on modal numbers (MN) from the population-based NOPHO-AML trials. Abnormal karyotypes were present in 452 cases (76%) and numerical aberrations were present in 40% (n = 237) of all pediatric AML. Among patients with an abnormal karyotype, the MN 46 was most common (n = 251; 56%) of which 36 (8%) were pseudodiploid with numerical aberrations, followed by MN 47 (n = 80; 18%) and MN 43-45 (n = 48; 8%). No cases had MN less than 43. Hyperdiploid AML with MN 48-65 comprised 11% of all cases and was associated with early onset (median age 2 years), female sex (57%), and a dominance of acute megakaryoblastic leukemia (AMKL) (29%). Hypodiploidy constituted 8% of all AML and was associated with older age (median age 9 years), male predominance (60%), FAB M2 (56%), and t(8;21)(q22;q22) (56%) with loss of sex chromosomes. Inferior outcome was observed for hypodiploid cases (5-year event-free survival 40% and 5-year overall survival 40%) but did not reach statistical significance. Chromosomes were gained in a nonrandom pattern, where chromosomes 8, 21, 19, and 6 were the most commonly gained. In conclusion, based on MNs, two cytogenetic subgroups with characteristic clinical features are described; hypodiploidy found in 8% and associated with high median age, male sex, t(8;21)(q22;q22), and FAB M2 and possibly associated with inferior outcome (P = 0.13), and hyperdiploidy with MN 48-65 in 11% associated with early onset, female sex, and AMKL.
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http://dx.doi.org/10.1002/gcc.22177DOI Listing
August 2014

Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia.

Genome Biol 2013 Sep 24;14(9):r105. Epub 2013 Sep 24.

Background: Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.

Results: We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.

Conclusions: Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.
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http://dx.doi.org/10.1186/gb-2013-14-9-r105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014804PMC
September 2013

Outcome of poor response paediatric AML using early SCT.

Eur J Haematol 2013 Mar 20;90(3):187-94. Epub 2013 Jan 20.

Department of Paediatrics, The University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: Children with poor response acute myeloid leukaemia (AML) generally have a very poor outcome. Allogeneic stem cell transplantation (SCT) is often recommended for these children but the benefit is unclear. The aim of this study was to investigate survival for poor response AML patients treated with SCT.

Material And Methods: Treatment was given according to the NOPHO-AML 2004 protocol. All patients received AIET (Cytarabine, Idarubicin, Etoposide, Thioguanine) and AM (Cytarabine, Mitoxantrone) as induction. We included poor response defined as > 15% blasts on day 15 after AIET (n = 17) or > 5% blasts after AM (n = 14, refractory disease). Poor response patients received intensively timed induction and proceeded to SCT when a donor was available.

Results: Thirty-one of 267 evaluable patients (12%) had a poor response. SCT was performed in 25; using matched unrelated donors in 13, matched sibling donors in 6, cord blood donor in 4, and haploidentical donor in two. The median follow-up for the 31 poor responding patients was 2.6 years (range 0.4 - 8.1 years) and 3-year probability of survival 70% (95% CI 59-77%).

Conclusions: The poor responders in the NOPHO-AML 2004 protocol had a favourable prognosis treated with time-intensive induction followed by SCT.
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http://dx.doi.org/10.1111/ejh.12051DOI Listing
March 2013

Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004.

Blood 2012 Aug 22;120(5):978-84. Epub 2012 Jun 22.

Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark.

There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of veno-occlusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541).
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http://dx.doi.org/10.1182/blood-2012-03-416701DOI Listing
August 2012

Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia.

Blood 2011 Nov 3;118(22):5905-13. Epub 2011 Oct 3.

Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden.

Mutation status of FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in patients with pediatric AML enrolled in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients, respectively. Presence of FLT3-internal tandem duplication (ITD) was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of patients with pediatric AML and that determination of the BAALC gene expression level can add valuable information.
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http://dx.doi.org/10.1182/blood-2011-05-353185DOI Listing
November 2011

Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate.

J Clin Oncol 2011 Jan 13;29(3):310-5. Epub 2010 Dec 13.

Institution of Clinical Sciences, Department of Pediatrics, Sahlgrenska University Hospital, 41685 Gothenburg, Sweden.

Purpose: To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course.

Patients And Methods: All Nordic children with AML younger than 15 years (n = 151) were treated on the Nordic Society for Pediatric Hematology and Oncology (NOPHO) AML 2004 protocol. After the first course of idarubicin, cytarabine, etoposide, and 6-thioguanin, patients with good response were allowed hematologic recovery before the second course, whereas patients with a poor (≥ 15% blasts) or intermediate (5% to 14.9% blasts) were recommended to proceed immediately with therapy. Patients not in remission after the second course received fludarabine, cytarabine, and granulocyte colony-stimulating factor. Poor responders received allogeneic stem-cell transplantation (SCT) as consolidation.

Results: Seventy-four percent of patients had good response, 17% had intermediate response, and 7% had poor response after the first course. The overall remission frequency was 97.4%, with 92% in remission after the second course. The rate of induction death was 1.3%. Patients with an intermediate response had a lower event-free survival of 35% compared with good (61%) and poor responders (82%).

Conclusion: The NOPHO-AML 2004 induction strategy gives an excellent remission rate with low toxic mortality in an unselected population. Outcome is worse in patients with intermediate response but may be improved by intensifying consolidation in this group using SCT.
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http://dx.doi.org/10.1200/JCO.2010.30.6829DOI Listing
January 2011

Thioguanine pharmacokinetics in induction therapy of children with acute myeloid leukemia.

Anticancer Drugs 2009 Jan;20(1):7-14

Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden.

We studied the pharmacokinetics of 6-thioguanine (6TG) in 50 children treated for newly diagnosed acute myeloid leukemia, four of them with Down syndrome (DS). They received oral 6TG 100 mg/m2 body surface area twice daily for 4 days. Etoposide, 100 mg/m2/24 h, and cytarabine, 200 mg/m2/24 h, were administered concomitantly by intravenous infusion. On day 5, doxorubicin 75 mg/m2 was given as an 8-h infusion. The concentration of thioguanine nucleotides (TGN) in erythrocytes, the active metabolites of 6TG, was determined by high-performance liquid chromatography. The mean TGN concentration from 72, 95, and 106-h samples was used as a measure of drug exposure for each individual. The median TGN concentration in non-DS children above 2 years of age was 2.30 micromol/mmol Hb (range 0.57-25.3). The TGN concentrations varied widely (30-fold) also after dose normalization. We found no correlation with demographic, clinical, or biochemical parameters, and differences in bioavailability might be the most important explanation to interpatient variability. Children with high TGN concentration tended to have longer treatment interval to the next course, but we found no correlation with our predefined parameters for clinical response, that is, remission and relapse rate. Therefore, 6TG does not seem to be a candidate for therapeutic drug monitoring by TGN measurement, at least not in the setting of short multidrug treatment courses. Children with DS had significantly higher TGN concentrations, indicating that dose reduction might be considered to reach the same drug exposure as in non-DS children.
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http://dx.doi.org/10.1097/CAD.0b013e32831bc086DOI Listing
January 2009

Etoposide pharmacokinetics in children treated for acute myeloid leukemia.

Anticancer Drugs 2006 Oct;17(9):1087-94

Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden.

We studied the pharmacokinetics of etoposide in 45 children treated for newly diagnosed acute myeloid leukemia. Etoposide, 100 mg/m body surface area/24 h, was administered by 96-h continuous intravenous infusion. Concomitantly, the children received cytarabine 200 mg/m/24 h by intravenous infusion and 6-thioguanine 100 mg/m twice daily orally. Median total body clearance in children 0.5-1.8 (n=4) and 2.3-17.7 years old (n=36) without Down's syndrome was 17.1 and 17.6 ml/min/m, respectively (P=0.96). Five children with Down's syndrome had a median clearance of 13.6 ml/min/m (P=0.067 compared with non-Down's syndrome children). Eighteen of the children received a second identical treatment course 3-4 weeks later; there was a significant correlation between individual clearance values (rho=0.56; P=0.017). We found no significant correlation between etoposide pharmacokinetics and the remission rate or the relapse rate. In conclusion, our findings indicate that special dose-calculation guidelines for infants above 3 months old are not substantiated by age-dependent pharmacokinetics of etoposide. Down's syndrome children might be candidates for dose reduction if our data are confirmed in larger numbers of patients. Low course-to-course variability indicates that pharmacokinetically guided dosing of etoposide might be clinically relevant, if larger studies can demonstrate that this approach decreases toxicity or increases response rates.
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http://dx.doi.org/10.1097/01.cad.0000231470.54288.49DOI Listing
October 2006

Doxorubicin pharmacokinetics is correlated to the effect of induction therapy in children with acute myeloid leukemia.

Anticancer Drugs 2006 Apr;17(4):385-92

Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden.

We studied the pharmacokinetics of doxorubicin in 41 children treated for newly diagnosed acute myeloid leukemia. Doxorubicin, 75 mg/m2 body surface area, was administered by constant i.v. infusion over 8 h. Four children with Down's syndrome (DS), 1.2-2.3 years old, had a median total body clearance of 523 ml/min/m2. The median clearance in non-DS children, 0.6-1.8 years old (n = 4) and 2.5-17.7 years old (n = 33), was 446 and 538 ml/min/m2, respectively. Patients who went into complete remission (CR) after induction therapy had a significantly higher median plasma concentration of doxorubicin than those who did not, 249 compared with 180 ng/ml, respectively (P = 0.036; analysis restricted to non-DS patients). Doxorubicin plasma concentration was an independent factor for CR, both in univariate (P = 0.031) and multivariate analysis including sex, age and white blood cell count at diagnosis (P = 0.021). Patients who reached CR had a significantly lower doxorubicin clearance than those who did not, 513 and 657 ml/min/m2, respectively (P = 0.017). In conclusion, doxorubicin plasma concentration and total body clearance during up-front treatment were correlated to the effect of induction therapy. Prospective studies should be performed to confirm the concentration-effect relationship and explore the possibility of therapeutic monitoring.
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http://dx.doi.org/10.1097/01.cad.0000198911.98442.16DOI Listing
April 2006