Article open access publication

Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale

Leukemia, Springer Nature, ISSN 1476-5551

Volume 30, 9, 2016

DOI:10.1038/leu.2016.90, Dimensions: pub.1037255467, PMC: PMC5240017, PMID: 27109508,



  1. (1) University of Southampton, grid.5491.9
  2. (2) Wessex Regional Genetics Laboratory, grid.433814.9
  3. (3) Jena University Hospital, grid.275559.9
  4. (4) Centre for Cancer Biology, grid.470344.0
  5. (5) Heidelberg University, grid.7700.0
  6. (6) University of Turin, grid.7605.4
  7. (7) University of Bordeaux, grid.412041.2
  8. (8) Novartis (United States), grid.418424.f
  9. (9) Birmingham Women’s and Children’s NHS Foundation Trust, grid.498025.2
  10. (10) University of Bari Aldo Moro, grid.7644.1
  11. (11) Hungarian National Blood Transfusion Service, grid.452091.b
  12. (12) Semmelweis University, grid.11804.3c
  13. (13) King's College Hospital, grid.46699.34
  14. (14) National Specialized Hospital for Active Treatment of Hematological Diseases, Sofia, Bulgaria
  15. (15) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, grid.411074.7
  16. (16) Fiona Stanley Hospital, grid.459958.c
  17. (17) Department of Oncology, KUL, Leuven, Belgium
  18. (18) Universitair Ziekenhuis Leuven, grid.410569.f
  19. (19) Portuguese Oncology Institute, grid.418711.a
  20. (20) Quest Diagnostics (United States), grid.418124.a
  21. (21) Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain
  22. (22) St Anna Children's Hospital, grid.416346.2
  23. (23) Laboratoire Hematologie, Centre Hospitalier Universitaire de Bordeaux, Universite Bordeaux, Bordeaux, France
  24. (24) Oslo University Hospital, grid.55325.34
  25. (25) Erasmus Hospital, grid.412157.4
  26. (26) Hammersmith Hospital, grid.413629.b
  27. (27) Poznan University of Medical Sciences, grid.22254.33
  28. (28) University of Naples Federico II, grid.4691.a
  29. (29) NeoGenomics (United States), grid.504533.4
  30. (30) VU University Medical Center, grid.16872.3a
  31. (31) Munich Leukemia Laboratory (Germany), grid.420057.4
  32. (32) University Hospital Brno, grid.412554.3
  33. (33) Catholic University of Korea, grid.411947.e
  34. (34) Institute of Haematology and Blood Transfusion, grid.419035.a
  35. (35) Department of Hematology, Hospital Universitario 12 de Octubre, Universidad Complutense, CNIO, Madrid, Spain
  36. (36) Peter MacCallum Cancer Centre, grid.1055.1
  37. (37) University Clinical Center Tuzla, grid.412410.2
  38. (38) Medical University of Vienna, grid.22937.3d
  39. (39) Institute Paoli-Calmettes, grid.418443.e
  40. (40) Ljubljana University Medical Centre, grid.29524.38
  41. (41) Zealand University Hospital, grid.476266.7, Zealand Region
  42. (42) First Department of Internal Medicine, Hematology Unit, Laiko Hospital, University of Athens, Athens, Greece
  43. (43) Oregon Health & Science University, grid.5288.7
  44. (44) Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China
  45. (45) Fred Hutchinson Cancer Research Center, grid.270240.3
  46. (46) Jagiellonian University, grid.5522.0
  47. (47) G. Papanikolaou General Hospital, grid.415248.e
  48. (48) Bristol Genetics Laboratory, Bristol, UK
  49. (49) HMDS, Leeds Teaching Hospitals, Leeds, UK
  50. (50) University of Zagreb, grid.4808.4
  51. (51) University of Adelaide, grid.1010.0
  52. (52) University of South Australia, grid.1026.5


Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.


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