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Forestier, Erik
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Publications (10 of 98) Show all publications
Borssén, M., Nordlund, J., Haider, Z., Landfors, M., Larsson, P., Kanerva, J., . . . Degerman, S. (2018). DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. Clinical Epigenetics, 10, Article ID 31.
Open this publication in new window or tab >>DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia
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2018 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed) Published
Abstract [en]

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 (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 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.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
DNA methylation, BCP-ALL, prognosis, CIMP, relapse, risk stratification
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-146216 (URN)10.1186/s13148-018-0466-3 (DOI)000427080200001 ()29515676 (PubMedID)
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-02-20Bibliographically approved
Karlsson, L., Nyvold, C. G., Palmqvist, L., Tierens, A., Hasle, H., Lausen, B., . . . Fogelstrand, L. (2018). Quantification of Fusion Transcripts Reveals Slower Treatment Kinetics As Compared with Multiparameter Flow Cytometry during Induction Treatment of Acute Myeloid Leukemia in Children. Paper presented at 60th Annual Meeting of the American-Society-of-Hematology (ASH), DEC 01-04, 2018, San Diego, CA. Blood, 132
Open this publication in new window or tab >>Quantification of Fusion Transcripts Reveals Slower Treatment Kinetics As Compared with Multiparameter Flow Cytometry during Induction Treatment of Acute Myeloid Leukemia in Children
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2018 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Society of Hematology, 2018
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-156902 (URN)10.1182/blood-2018-99-116618 (DOI)000454842800015 ()
Conference
60th Annual Meeting of the American-Society-of-Hematology (ASH), DEC 01-04, 2018, San Diego, CA
Note

Supplement 1

Meeting abstract 2814

Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-04-15Bibliographically approved
Oskarsson, T., Söderhäll, S., Arvidson, J., Forestier, E., Frandsen, T. L., Hellebostad, M., . . . Heyman, M. (2018). Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia. Pediatric Blood & Cancer, 65(4), Article ID e26909.
Open this publication in new window or tab >>Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia
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2018 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 65, no 4, article id e26909Article in journal (Refereed) Published
Abstract [en]

Background: Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment-related toxicity impacts survival.

Procedure: In this retrospective population-based study, we described the causes of death and estimated the risk for treatment-related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL-92 and ALL-2000 trials.

Results: Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment-related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment-related mortality were as follows: high-risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3-3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3-9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17-9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment-related causes.

Conclusions: Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.

Keywords
acute lymphoblastic leukemia, hematopoietic stem cell transplantation, infection, pediatric, relapse, treatment-related mortality
National Category
Hematology Pediatrics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-146193 (URN)10.1002/pbc.26909 (DOI)000425642100015 ()
Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2019-05-09Bibliographically approved
Nielsen, S. N., Eriksson, F., Rosthoej, S., Andersen, M. K., Forestier, E., Hasle, H., . . . Schmiegelow, K. (2017). Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers. Pediatric Blood & Cancer, 64(10), Article ID e26518.
Open this publication in new window or tab >>Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers
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2017 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 64, no 10, article id e26518Article in journal (Refereed) Published
Abstract [en]

Background: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. Procedure: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. Results: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). Conclusions: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2017
Keywords
childhood acute lymphoblastic leukemia, 6-mercaptopurine, methotrexate, second cancer
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-139123 (URN)10.1002/pbc.26518 (DOI)000408045800011 ()
Available from: 2017-10-06 Created: 2017-10-06 Last updated: 2018-06-09Bibliographically approved
Zeller, B., Glosli, H., Forestier, E., Ha, S.-Y., Jahnukainen, K., Jonsson, O. G., . . . Abrahamsson, J. (2017). Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 x 10(9)/l. The NOPHO experience 1984-2014. British Journal of Haematology, 178(3), 448-456
Open this publication in new window or tab >>Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 x 10(9)/l. The NOPHO experience 1984-2014
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2017 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 3, p. 448-456Article in journal (Refereed) Published
Abstract [en]

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 x 10/l). Eighty-six patients (10%) had WBC 100-199 x 10(9)/l and 57 (6%) had WBC >= 200 x 10(9)/l. Patients with WBC >= 200 x 10(9)/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 x 10(9)/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.

Place, publisher, year, edition, pages
WILEY, 2017
Keywords
hyperleucocytosis, acute myeloid leukaemia, children, early death, leukapheresis
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-138416 (URN)10.1111/bjh.14692 (DOI)000406058400013 ()
Available from: 2017-08-23 Created: 2017-08-23 Last updated: 2018-06-09Bibliographically approved
Karlsson, L., Forestier, E., Hasle, H., Jahnukainen, K., Jonsson, O. G., Lausen, B., . . . Abrahamsson, J. (2017). Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia. British Journal of Haematology, 178(4), 592-602
Open this publication in new window or tab >>Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia
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2017 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 4, p. 592-602Article in journal (Refereed) Published
Abstract [en]

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 (OS5y) 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, OS5y 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.

Place, publisher, year, edition, pages
WILEY, 2017
Keywords
acute myeloid leukaemia, relapsed, childhood, allogenic stem cell transplant, survival
National Category
Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-138591 (URN)10.1111/bjh.14720 (DOI)000406911500013 ()28439893 (PubMedID)
Available from: 2017-09-21 Created: 2017-09-21 Last updated: 2018-06-09Bibliographically approved
Marincevic-Zuniga, Y., Dahlberg, J., Nilsson, S., Raine, A., Nystedt, S., Lindqvist, C. M., . . . Syvanen, A.-C. (2017). Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles. Journal of Hematology & Oncology, 10, Article ID 148.
Open this publication in new window or tab >>Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles
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2017 (English)In: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 10, article id 148Article in journal (Refereed) Published
Abstract [en]

Background: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts.

Methods: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes.

Results: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations.

Conclusion: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keywords
Pediatric acute lymphoblastic leukemia, RNA sequencing, Fusion genes, BCP-ALL, T-ALL, Translocation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-139626 (URN)10.1186/s13045-017-0515-y (DOI)000408001300001 ()
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2019-05-09Bibliographically approved
Wennström, L., Edslev, P. W., Abrahamsson, J., Nørgaard, J. M., Fløisand, Y., Forestier, E., . . . Hasle, H. (2016). Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries. Pediatric Blood & Cancer, 63(1), 83-92
Open this publication in new window or tab >>Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries
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2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 1, p. 83-92Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016
Keywords
acute myeloid leukemia, adolescents, age, outcome, young adults
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-114613 (URN)10.1002/pbc.25713 (DOI)000367097800013 ()
Available from: 2016-02-08 Created: 2016-01-25 Last updated: 2019-05-10Bibliographically approved
Lindqvist, C. M., Lundmark, A., Nordlund, J., Freyhult, E., Ekman, D., Almlof, J. C., . . . Syvanen, A.-C. (2016). Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes. OncoTarget, 7(39), 64071-64088
Open this publication in new window or tab >>Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, p. 64071-64088Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
acute lymphoblastic leukemia, targeted next generation sequencing, somatic mutation, relapse, clonal evolution
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-128476 (URN)10.18632/oncotarget.11773 (DOI)000387167800099 ()
Available from: 2016-12-15 Created: 2016-12-05 Last updated: 2019-05-10Bibliographically approved
Borssén, M., Haider, Z., Landfors, M., Norén-Nyström, U., Schmiegelow, K., Åsberg, A. E., . . . Degerman, S. (2016). DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia. Pediatric Blood & Cancer, 63(7), 1185-1192
Open this publication in new window or tab >>DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
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2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article in journal (Refereed) Published
Abstract [en]

Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

Keywords
childhood leukemia, DNA methylation, MRD, prognosis, T-ALL, WBC
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-124837 (URN)10.1002/pbc.25958 (DOI)000380105400008 ()26928953 (PubMedID)
Available from: 2016-10-03 Created: 2016-08-26 Last updated: 2019-05-10Bibliographically approved
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