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Bone marrow fibrosis in childhood acute lymphoblastic leukemia correlates to biological factors, treatment response and outcome
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2008 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 3, 504-510 p.Article in journal (Refereed) Published
Abstract [en]

We retrospectively evaluated reticulin fiber density (RFD) in 166 diagnostic bone marrow (BM) biopsies and 62 biopsies obtained at treatment day 29 from children with acute lymphoblastic leukemia (ALL). Patients with B-cell precursor (BCP)-ALL showed higher RFD as compared to patients with T-cell ALL (P<0.001). RFD correlated negatively with white blood cell count (P=0.008) in BCP-ALL patients. Patients with high-hyperdiploid ALL (51–61 chromosomes), no high-risk criteria and low RFD showed a favorable outcome when compared to similar patients with high RFD (P=0.002). In BCP-ALL patients, RFD at diagnosis correlated to the levels of minimal residual disease (MRD) analyzed by flow cytometry on treatment day 29 (P=0.001). Accordingly, patients with MRD10-4 presented higher RFD at diagnosis compared to patients with MRD<10-4 (P=0.003). BCP-ALL patients with low RFD at diagnosis and a rapid reduction of RFD on day 29 had a favorable outcome compared to patients with the same baseline RFD level at diagnosis but a slow RFD reduction (P=0.041). To our knowledge, these findings are novel and may indicate BM fibrosis as a new valuable prognostic marker in childhood ALL. Expanded use of BM biopsy both at diagnosis and during follow-up is suggested.

Place, publisher, year, edition, pages
Baltimore: Williams & Wilkins , 2008. Vol. 22, no 3, 504-510 p.
Keyword [en]
acute lymphoblastic leukemia, high-hyperdiploid, childhood, bone marrow fibrosis, MRD, prognosis
URN: urn:nbn:se:umu:diva-7570DOI: 10.1038/sj.leu.2405072PubMedID: 18094715OAI: diva2:147241
Available from: 2008-02-27 Created: 2008-02-27 Last updated: 2011-09-02Bibliographically approved
In thesis
1. Vascular density and bone marrow fibrosis in childhood acute lymphoblastic leukemia
Open this publication in new window or tab >>Vascular density and bone marrow fibrosis in childhood acute lymphoblastic leukemia
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: In childhood acute lymphoblastic leukemia (ALL), the cure rate has now reached 80% in the western world. Even so, 15¬–20% will die from the disease or treatment-related causes, among them children who did not present any known unfavorable features at diagnosis. Treatment of childhood ALL is risk-adapted, meaning that certain factors that are related to the child or the leukemic blasts stratifies to more or less intensive treatment. In this thesis, characteristics of the bone marrow (BM) stroma, reflecting the interaction between the leukemic cells and their microenvironment, were evaluated. The aims were to investigate these factors in relation to other known data in order to further understand the biology of leukemia, and to suggest additional risk factors that would further improve decision making for the treatment of individual children diagnosed with ALL.

Methods: We retrospectively investigated microvessel density (MVD), blast-congested vessel fraction (BCVF), and degree of fibrosis – reticulin fiber density (RFD) – in sections from diagnostic BM biopsies from children diagnosed in Umeå, Uppsala, and Stockholm. RFD was also studied in BM sections from treatment day 29.

Results: RFD had prognostic impact in patients with high-hyperdiploid (HeH) leukemia. Moreover, rapid reduction of RFD during induction treatment was associated with a favorable prognosis compared to slow reduction, in B-cell precursor (BCP) ALL patients. There was also a correlation between RFD at diagnosis and minimal residual disease (MRD) measured by flow cytometry on treatment day 29 in BCP patients.

BCP patients with high RFD and high MVD had an unfavorable outcome compared to all other BCP patients. In addition, MVD and RFD were both associated with immunophenotype, and MVD with cytogenetic aberrations. There was a correlation between MVD and WBC count in BCP high-risk patients. There was also a strong correlation between BCVF and WBC count in all BCP patients, but not between BCVF and MVD or RFD.

There was a negative correlation between MVD and in vitro cellular resistance to several drugs in BCP patients. A drug-resistance score combining the drugs most strongly correlated to MVD – cytarabine, doxorubicin, and dexametasone (ADD score) – identified the prognostic potential of ADD score in HeH patients with no unfavorable features.

Conclusions: Taken together, these studies indicate that stroma factors in leukemia are related to both phenotypic and genotypic features of acute leukemia. Stroma factors also seem to influence the response to induction treatment, in vitro drug resistance, and outcome in certain subgroups of childhood ALL patients. The results emphasize the importance of BM stroma in leukemia and the need for greater use of BM biopsy at diagnosis.

Place, publisher, year, edition, pages
Umeå: Pediatrik, 2008. 51 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1183
Childhood acute lymphoblastic leukemia, microvessel density, bone marrow fibrosis, in vitro drug resistance, minimal residual disease, outcome
National Category
Cancer and Oncology
urn:nbn:se:umu:diva-1642 (URN)978-91-7264-572-1 (ISBN)
Public defence
2008-05-30, Sal Betula, 6M, Norrlands Universitetssjukhus, 901 85 UMEÅ, 13:00 (English)
Available from: 2008-05-09 Created: 2008-05-09 Last updated: 2010-01-18Bibliographically approved

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