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  • Letter to the Editor
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Transmission of CML or of t(9; 22) and BCR/ABL? They are not the same

Bone Marrow Transplantation volume 50, page 1582 (2015)Cite this article

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In a recent Letter to the Editor de Brito et al.1 describe a transplant donor retrospectively found to have t(9;22) and BCR/ABL along with other cytogenetic abnormalities often associated with acute phase or blastic transformation of CML. There are several interesting points including: (1) the donor had normal blood parameters and no evolution to chronic or acute phase CML for >6 months (but possibly several years) when t(9;22) and BCR/ABL were detected in a substantial proportion of her myeloid cells; (2) although the donor was chimeric for cells with and without t(9;22) and BCR/ABL, initial engraftment was with the normal donor cells; and (3) the recipient did not develop chronic or acute phase CML after >6 months follow-up.

Several points warrant consideration. First, it was reported many years ago that persons with chronic phase CML at diagnosis may have CML cells with cytogenetic abnormalities consistent with acute phase.2 This is conceptually consistent with recent data from ultra-deep sequencing of the BCR/ABL tyrosine kinase domain in persons with chronic phase CML, where many mutations are identified before drug exposure.3 These data suggest a long latency from acquisition of BCR/ABL to diagnosis of chronic phase CML. Second, having BCR/ABL is not equivalent to having CML. Data from several centres report normal persons with BCR/ABL.4 The point is that to have CML the BCR/ABL mutation must be in a cell biologically capable of causing the disease. Whether this was so in this donor (and/or recipient) is unknown. Consequently, starting CML therapy may have been premature and/or unnecessary, especially absent data-treating chronic phase CML earlier is of benefit. Third, latency from BCR/ABL to developing CML is unknown and likely highly variable. The common notion derived from the A-bomb survivors of 10–15 years latency is probably wrong. Some children with typical CML, t(9;22) and BCR/ABL, were diagnosed before age 1 year and have a somatic (acquired) mutation implying CML latency can be<2 years. Also, our and other reviews of the A-bomb data suggest an early peak of CML may have occurred<5 years and even<2 years after exposure.5 Organised surveillance of CML risk did not begin until about 10 years after the A-bomb exposures. More importantly, an increased CML-risk persisted in exposed persons for up to 40 years.6 Based on these data and the ages of donor and recipient, they may never have developed CML in their lifetimes. We do not fault de Brito et al. for treating these persons but it may have been unnecessary. Certainly it would have been interesting to follow these persons to determine if they developed CML. A final point is CML cells do not always have a substantial growth advantage over normal myeloid cells, which is often used to explain why the chronic phase CML clone eventually displaces (or replaces) normal haematopoietic cells. In this case initial engraftment was with normal donor cells followed by appearance of cells from the CML clone but no clinical features of CML for >6 months.

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References

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  1. Division of Experimental Medicine, Department of Medicine, Haematology Research Centre, Imperial College London, London, UK

    R P Gale & J F Apperley

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  1. R P Gale
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Gale, R., Apperley, J. Transmission of CML or of t(9; 22) and BCR/ABL? They are not the same. Bone Marrow Transplant 50, 1582 (2015). https://doi.org/10.1038/bmt.2015.199

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