Marit Hellebostad

Oslo University Hospital, Kristiania (historical), Oslo County, Norway

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Publications (20)62.55 Total impact

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    ABSTRACT: Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the upfront therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following ALL relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications; and identify additional prognostic factors for overall survival. In total 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included. There were no statistically significant differences in outcome between the upfront protocols or between the relapse-protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing 2002-2011 was 57.5 +/- 3.4% but 44.7 +/- 3.2% (p<0.001) if relapse occurred 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ≥10 years, unfavorable cytogenetics and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0 +/- 10.6%) which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, development of novel approaches is urgent to increase survival in relapsed childhood acute lymphoblastic leukemia.
    Full-text · Article · Oct 2015 · Haematologica
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    ABSTRACT: Juvenile myelomonocytic leukemia is a rare hematopoietic stem cell disease in children with features of both myelodysplasia and myeloproliferation. Extramedullary involvement has been reported and pulmonary involvement secondary to leukemic infiltration is an initial manifestation, which may result in acute respiratory failure. We present 3 children with juvenile myelomonocytic leukemia and suspected pulmonary leukemic cell infiltration who all also suffered from respiratory insufficiency. The differential diagnosis included asthma and infections. In each case the patients improved rapidly after initiation of antileukemic treatment including 6-mercaptopurine or cytarabine.
    No preview · Article · May 2011 · Journal of Pediatric Hematology/Oncology
  • Bernward Zeller · Marit Hellebostad
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    ABSTRACT:   To describe the impact of H1N1 infections in children with haematological and oncological diseases during the 2009 H1N1 pandemics.   A short questionnaire was e-mailed to all paediatric departments taking care of patients with oncological and chronic haematological diseases, asking for known cases of H1N1 infections in this patient group.   Nine children treated for cancer and seven children with haematological diseases were registered. No death occurred, but two patients treated for cancer (acute lymphoblastic leukaemia at diagnosis, acute myeloid leukaemia in chemotherapy-induced bone marrow aplasia) experienced life-threatening respiratory complications.   In all patients with haematological disease and most cases of oncological diseases, the infections ran a mild course. However, life-threatening complications occurred in severely immunosuppressed and neutropenic patients. Delay of anticancer treatment is a concern even in mild cases.
    No preview · Article · Mar 2011 · Acta Paediatrica
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    ABSTRACT: A 15 month-old girl was admitted after a couple of months' history of illness with remittent fever, increasing pallor and a swollen abdomen. On admission she was highly febrile, with palpably enlarged liver and spleen. Blood tests revealed pancytopenia, a high CRP level and a high serum ferritin level. We describe the diagnostic evaluation, interpretation and treatment.
    No preview · Article · Jan 2011 · Tidsskrift for den Norske laegeforening
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    ABSTRACT: Prognostic impact of peripheral blood white blood cell count (WBC) at the diagnosis of childhood acute lymphoblastic leukaemia (ALL) was evaluated in a population-based consecutive series of 2666 children aged 1-15 treated for ALL between 1992 and 2008 in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). Ten-year event-free (pEFS(10 y)) survival and overall (pOS(10 y)) survival were 0.75 ± 0.01 and 0.85 ± 0.01, respectively. Although treatment intensity was determined by WBC, non-remission and relapsed patients still had significantly higher WBC than those in remission for B-cell precursor (BCP) (median WBC: 24.8 vs. 14.0 vs. 8.3 × 10(9) /L, P < 0.001), but not for T-lineage (T-ALL) (median WBC: 127.8 vs. 113.0 vs. 86.8 × 10(9) /L, P = 0.22). pEFS was inversely related to WBC for BCP (P < 0.001), but not for T-ALL. WBC was not associated with risk of event for BCP or T-ALL for patients with minimal residual disease at the end of induction (MRD(d29) ) <10(-3). In contrast, for MRD(d29) ≥ 10(-3) and <5% leukaemic blasts in bone marrow at day 29, the pEFS(5 y) for WBC < 100.0 (N = 152) vs. ≥ 100.0 (N = 19) was 0.76 vs. 0.50 (P = 0.001). That was the case both for BCP (pEFS(5 y) 0.76 vs. 0.58) and for T-ALL (pEFS(5 y) 0.71 vs. 0.38). Whether the inferior EFS for the subset of patients with high WBC and slow initial response to treatment reflects rare or overlooked cytogenetic aberrations as well as the factors that determine WBC levels at diagnosis awaits exploration.
    No preview · Article · Sep 2010 · European Journal Of Haematology
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    ABSTRACT: Analysis of 2668 children with acute lymphoblastic leukemia (ALL) treated in two successive Nordic clinical trials (Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000) showed that 75% of all patients are cured by first-line therapy, and 83% are long-term survivors. Improvements in systemic and intrathecal chemotherapy have reduced the use of central nervous system (CNS) irradiation to <10% of the patients and provided a 5-year risk of isolated CNS relapse of 2.6%. Improved risk stratification and chemotherapy have eliminated the previous independent prognostic significance of gender, CNS leukemia and translocation t(1;19)(q23;p13), whereas the post-induction level of minimal residual disease (MRD) has emerged as a new risk grouping feature. Infant leukemia, high leukocyte count, T-lineage immunophenotype, translocation t(4;11)(q21;q23) and hypodiploidy persist to be associated with lower cure rates. To reduce the overall toxicity of the treatment, including the risk of therapy-related second malignant neoplasms, the current NOPHO ALL-2008 protocol does not include CNS irradiation in first remission, the dose of 6-mercaptopurine is reduced for patients with low thiopurine methyltransferase activity, and the protocol restricts the use of hematopoietic stem cell transplantation in first remission to patients without morphological remission after induction therapy or with high levels of MRD after 3 months of therapy.
    Preview · Article · Mar 2010 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: The number of circulating B-cells in peripheral blood plateaus between 2 and 24 months of age, and thereafter declines gradually. How this reflects the kinetics of the precursor B-cell pool in the bone marrow is of clinical interest, but has not been studied thoroughly in humans. The authors analyzed bone marrow (n = 37) from healthy children and adults (flow cytometry) searching for age-related changes in the total precursor B-cell compartment. In an age-matched cohort (n = 25) they examined age-related global gene expression changes (Affymetrix) in unsorted bone marrow with special reference to the recombination activating gene 1, RAG1. Subsequently, they searched the entire gene set for transcripts correlating to the RAG1 profile to discover other known and possibly new precursor B-cell related transcripts. Both methods disclosed a marked, transient increase of total precursor B-cells at 6-20 months, followed by a rapid decrease confined to the first 2 years. The decline thereafter was considerably slower, but continued until adulthood. The relative composition of total precursor B-cells, however, did not change significantly with age. The authors identified 54 genes that were highly correlated to the RAG1 profile (r >or= .9, p < 1 x 10(-8)). Of these 54 genes, 15 were characteristically B-lineage associated like CD19, CD79, VPREB, EBF1, and PAX5; the remaining 39 previously not described as distinctively B-lineage related. The marked, transient increase in precursor B-cells and RAG1 transcriptional activity is not reflected by a similar peak in B-cells in peripheral blood, whereas the sustained plateau concurs in time.
    No preview · Article · Feb 2010 · Pediatric Hematology and Oncology

  • No preview · Article · Jan 2010
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    ABSTRACT: 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.
    No preview · Article · Feb 2009 · Anti-cancer drugs
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    ABSTRACT: Familial haemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin (PRF1), syntaxin-11 (STX11), and Munc13-4 (UNC13D). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well defined patient cohort. Sequencing of UNC13D was performed in 38 FHL patients from 34 FHL families in which PRF1 and STX11 mutations had been excluded. We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11-negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in the age at diagnosis, ranging from time of birth to 14 years (median 69 days). Three of nine patients (33%) developed central nervous system (CNS) symptoms. Natural killer (NK) cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in the patient with onset during infancy than in the patient with adolescent onset. Biallelic UNC13D mutations were found in 18% of the PRF1/STX11-negative FHL families. Impairment of NK cell degranulation was less pronounced in a patient with adolescent onset. FHL should be considered not only in infants but also in adolescents, and possibly young adults, presenting with fever, splenomegaly, cytopenia, hyperferritinaemia, and/or CNS symptoms.
    Full-text · Article · Apr 2008 · Journal of Medical Genetics
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    ABSTRACT: Acute lymphoblastic leukemia is the most common malignancy in childhood. The survival rate has increased steadily over the last 40 years. All children aged 0-15 years and diagnosed in Norway in the period 1992-2000, were included in the study (n = 301). The patients were followed up until 1.1. 2005. The diagnosis was made in 301 children, 33 new cases per year (range 24 to 40) on average. The peak incidence was between 2 and 5 years. Four of 6 infants with acute lymphoblastic leukemia and all 4 with mature B-cell leukemia are alive. Two of the remaining 291 children died before treatment was started. 289 were all treated according to the common Nordic NOPHO-ALL 1992 protocol. All children achieved remission (99.7%), except for one who died before remission was achieved. 55 children (19%) relapsed. Radiation to the brain as part of central nervous system prophylaxis was given to just 10% of the children. The 10-year event-free survival (p-EFS) was 76%, and 244 of 289 (84%) were alive 4-13 years after the diagnosis was made. The data are comparable with the best international results.
    No preview · Article · Jun 2007 · Tidsskrift for den Norske laegeforening
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    ABSTRACT: 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.
    No preview · Article · Nov 2006 · Anti-Cancer Drugs
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    ABSTRACT: 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.
    No preview · Article · May 2006 · Anti-Cancer Drugs
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    ABSTRACT: Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.
    Full-text · Article · Apr 2005 · British Journal of Haematology
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    Full-text · Article · Feb 2005 · Leukemia
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    ABSTRACT: The t(12;21) (p13;q22) translocation resulting in ETV6/RUNX1 (previously named TEL/AML1) gene fusion is present in about 25% of children with precursor B-lineage acute lymphoblastic leukemia (B-ALL). We successfully tested 275 precursor B-ALL samples from children aged 1 to 17 years to determine the relation between t(12;21) and in vitro cellular drug resistance, measured by the fluorometric microculture cytotoxicity assay (FMCA). Samples from 83 patients (30%) were positive for t(12;21). The ETV6/RUNX1(+) samples were significantly more sensitive than ETV6/RUNX1(-) samples to doxorubicin, etoposide, amsacrine, and dexamethasone, whereas the opposite was true for cytarabine. After matching for unevenly distributed patient characteristics, that is, excluding patients with high hyperdiploidy (> 51 chromosomes), t(9; 22), t(1;19), or 11q23 rearrangement, the ETV6/RUNX1(+) samples remained significantly more sensitive to doxorubicin (P = .001) and etoposide (P = .001). For the other drugs tested (amsacrine, cytarabine, dexamethasone, prednisolone, vincristine, 6-thioguanine, and 4-hydroperoxy-cyclophosphamide), no significant difference in cellular drug sensitivity was found. In conclusion, we found that the presence of the t(12;21) translocation in childhood precursor B-ALL is associated with a high tumor cell sensitivity to doxorubicin and etoposide. High throughput techniques should now be used to elucidate the cellular mechanisms by which ETV6/RUNX1 gene fusion is linked to increased sensitivity to these drugs.
    Full-text · Article · Oct 2004 · Blood
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    ABSTRACT: This study included all 690 children in Norway diagnosed as having acute lymphocytic leukemia (ALL) from July 1975 till the end of 1997. Relapses and deaths were monitored until the end of 2000. Neuroleukemia prophylaxis was intravenous methotrexate (MTX) infusions as intermediate-dose methotrexate (IDM) or high-dose methotrexate (HDM) combined with intrathecal MTX. From 1992, systemic therapy was considerably intensified, and, in addition, patients in a subgroup of the high-risk and very high-risk groups were given prophylactic cranial irradiation. The overall findings showed that MTX significantly reduced central nervous system (CNS)-related relapses, and, in general, reinforced systemic therapy reduced significantly non-CNS relapses and deaths. The overall crude survival was 75%. During the study period, the crude survival improved for patients on standard protocols from initially 65 to 90%. Forty patients (6%) developed isolated CNS relapse, 27 (4%) had combined CNS relapse, whereas 180 (26%) had non-CNS relapse. When IDM and HDM were compared, the cumulative risk for isolated CNS relapse was significantly lower with HDM, 12 and 5%, respectively. For any relapses that involved the CNS, the risk remained significantly lower for HDM, 8 versus 18%. Of the 40 patients with isolated CNS relapse, 23 survived (58%).
    No preview · Article · Apr 2003 · Pediatric Hematology and Oncology
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    ABSTRACT: A prospective, population-based registration of children with immune thrombocytopenic purpura (ITP) was performed in Norway in 1996 and 1997. Ninety-two cases were identified, indicating an incidence of 5.3 per 100,000 children under 15 years. The sex ratio (female/male) was 1.2/1. Fifty-six percent presented with cutaneous signs only. The lowest platelet count was < 20 x 10(9)/L in 91%. In spite of mild bleeding symptoms, medical treatment was given in 68%, in most cases (57/63) with intravenous immunoglobulin. A total of 41/44 patients with platelet counts of < or = 5 x 10(9)/L were treated, regardless of whether they had mucous bleedings or not. Eighteen percent had platelet counts < 150 x 10(9)/L at 6 months, and 9% at 12 months following diagnosis. One patient with therapy-resistant chronic ITP died 16 months after diagnosis from an anesthesia complication related to profound epistaxis. This study shows a relatively high incidence. As in other studies, there was a tendency to treat platelet counts rather than bleeding symptoms.
    No preview · Article · Oct 2000 · Pediatric Hematology and Oncology
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    ABSTRACT: From 1975 to 1980, 153 Norwegian children were diagnosed with acute lymphocytic leukaemia. In 1995, all 98 survivors were studied and compared to matched family controls. 132 children were treated with the national protocol. Of these, 93 (70.5%) were survivors at the time of the study. The remaining five survivors were treated with different treatment schemes. The national protocol included methotrexate infusions combined with intrathecal methotrexate as prophylactics against neuroleukaemia, instead of the irradiation. Neither doxorubicin nor cyclophosphamide were included. In this study, a questionnaire was used that covered demographic data, quality of life, and medical information the response rates were 96% (94 persons) for survivors and 92% (90 persons) for family controls. Information was also obtained for the remaining four survivors. No significant differences were found between survivors and controls with regard to quality of life and demographics, with one exception, Somatisation on the GHQ-28. Hospital records of all patients were checked for possible late effects. One case of serious sequela (hemiparesis during therapy) was found, probably related to methotrexate therapy. Seven other serious, possible sequelae were recorded, but probably not related to methotrexate. There were no cases of secondary malignant neoplasm.
    No preview · Article · Mar 1999 · Tidsskrift for Den norske legeforening
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    ABSTRACT: In a follow-up matched control study the 93 (70.5%) survivors of 132 children treated with a national protocol for acute lymphoblastic leukemia (ALL) and 5 survivors of the other 21 cases of ALL in childhood diagnosed in the same period were evaluated. Thus it was also a population-based study. The national treatment protocol was used in the period 1975-1980. Methotrexate (MTX) infusions combined with intrathecal MTX were used as prophylaxis against neuroleukemia instead of irradiation. Neither doxorubicin (Adriamycin) nor cyclophosphamide was used in the protocol. A questionnaire covering demographic data, number of offspring, learning problems, level of athletic performance, education, and work status as well as medical information was used. Forms were received from 94 (96%) of the 98 adult surviving cases and corresponding controls in the family. Interviews were performed in the remaining four cases (4%). There were no statistical differences between the two groups with respect to physical and mental health and quality of life. Hospital records of all patients were also checked for possible late effects. There was no definite case of secondary malignant neoplasm; however, there was one case of prolactinoma and only one case of serious sequelae (hemiparesis during therapy), probably due to intrathecal and intravenous MTX.
    No preview · Article · Nov 1997 · Pediatric Hematology and Oncology