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The importance of central pathology review in international trials: a comparison of local versus central bone marrow reticulin grading

Leukemia volume 29, pages 241–244 (2015)Cite this article

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Central pathology review for multicenter clinical trials was first introduced in the 1960s as an important quality control measure for lymphoma diagnoses.1 Although widely recognized as an essential measurement of quality assurance and in use for over half a century, only rare reports exist comparing the histopathological evaluation of hematopoietic neoplasms between the central review and the contributing local pathologists in clinical trials.2,3 The BCR-ABL1-negative myeloproliferative neoplasms (MPNs) primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocytopenia (ET) are characterized by variable degrees of bone marrow fibrosis (BMF) at presentation or upon disease progression.4, 5, 6 It is well known that development of BMF is an adverse event and has been associated with inferior prognosis in MPN.7, 8, 9 Better understanding of the molecular genetic features of MPN has led to development of novel therapeutic agents that specifically target BMF. These include JAK2 and JAK1 inhibitors such as ruxolitinib and fedratinib, which have been shown to stabilize or reduce and even completely resolve BMF.10, 11, 12 Thus, accurate and reproducible assessment of BMF is critical in evaluating patients with MPN, both at diagnosis and after treatment with disease-modifying therapies. Grading accuracy is particularly important in the context of clinical trials that evaluate the effectiveness of novel therapies.13 Recent studies have examined the reproducibility of the European Consensus System for grading BMF in the context of a review by expert hematopathologists in MPN patients undergoing treatment with fedratinib, with generally high concordance and an almost perfect rate of agreement (kappa values of up to 0.83) among the expert reviewers in both pre-treatment and post-treatment biopsies.14 However, to our knowledge, thus far there have been no studies examining the concordance of BMF grading between central review and local pathologists in the context of MPN patients on international clinical trials.

The aim of this study was to evaluate the agreement of BMF grading assigned by local pathologists with that assigned by a central review panel in three large studies of MPN patients treated with the JAK2 inhibitor fedratinib. Bone marrow biopsies were obtained from a total of 261 MPN patients (154 PMF, 67 post-PV myelofibrosis, 18 post-ET myelofibrosis in three fedratinib clinical trials: Phase 3 with 429 samples, Phase 1/2 with 131 samples and Phase 2 with 74 samples). Biopsies included 209 taken at baseline and 425 on therapy. As previously described, grading of BMF by both central review and the local pathologists was according to the 2008 WHO classification guidelines, with four possible grades (0, 1, 2 and 3).14 The central review panel consisted of three hematopathologists (OP, RPH, JT), who examined hematoxylin and eosin, silver impregnation-reticulin and trichrome stains. For the Phase 2 and 3 trials, the central review grading was made on stains performed at Covance Central Laboratory (Indianapolis, IN, USA) according to the manufacturer’s protocols, on unstained slides submitted by the participating institutions. For the Phase 1/2 study, grading was conducted on slides stained at the various US institutions where the biopsies had originated. The central review grade was based on a single grade independently assigned by at least two of the three panel hematopathologists; if all three pathologists disagreed or if disagreement with any panel hematopathologist was >1 grade, the central review grade was established by consensus following discussion among the panelists.14 Concordance of BMF grade between the central and local pathology review was measured by unweighted kappa statistic and Fisher’s exact test. Kappa values of 0.1–0.20 indicate slight agreement, 0.21–0.40 fair agreement, 0.41–0.60 moderate agreement, 0.61–0.80 substantial agreement and 0.81–1 almost perfect agreement.15

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Acknowledgements

We thank Thierry Bourlard, Pamela Butler and William Hatfield (Sanofi Oncology), and Aaron Goetz and Mark Slette (Covance) for their help and support.

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  1. K Wu

    Present address: 5Current address: Janssen Pharmaceutical, Raritan, NJ, USA.,

Authors and Affiliations

  1. Brigham and Women’s Hospital, Boston, MA, USA

    O Pozdnyakova & S Rodig

  2. Sanofi Oncology, Cambridge, MA, USA

    S Bhandarkar & K Wu

  3. University of Cologne, Cologne, Germany

    J Thiele

  4. Massachusetts General Hospital, Boston, MA, USA

    R Hasserjian

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  1. O Pozdnyakova
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Correspondence to R Hasserjian.

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Competing interests

Drs Pozdnyakova, Thiele, Rodig and Hasserjian received consulting income from Sanofi Oncology for reviewing biopsies within the context of the trials described. Drs Wu and Bhandarkar are employees of Sanofi Oncology. No authors received compensation for authoring the manuscript.

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Pozdnyakova, O., Rodig, S., Bhandarkar, S. et al. The importance of central pathology review in international trials: a comparison of local versus central bone marrow reticulin grading. Leukemia 29, 241–244 (2015). https://doi.org/10.1038/leu.2014.262

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