CML without the classic BCR–ABL1 fusion site. Monitoring to a very high sensitivity using techniques such as RT-qPCR is crucial during TFR in order to assess the depth of molecular remission and to identify early re-emergence of BCR–ABL1 transcripts. Most BCR–ABL1 translocations occur between exon 1 of ABL1 and exon 13 or 14 of BCR, and primers for RT-qPCR are designed for such transcripts. Occasionally, however, the BCR–ABL1 fusion may occur at a different point, meaning that transcripts may not be detectable using conventional primers. While patients with these transcripts may respond to TKIs and achieve remission, they are less suitable for TFR because early molecular relapse cannot be detected using standard techniques, so the patient is at risk of full haematological relapse.
Atypical CML is not driven by the BCR–ABL1 translocation and is associated with a variety of chromosomal aberrations and mutations. Issues with monitoring preclude these patients from TFR, as described above.
History of TKI resistance. While clinical trials have shown that patients who have a molecular relapse during TFR are sensitive to the TKI that they achieved remission with, this has not been confirmed in patients with TKI resistance mutations. These patients may develop further mutations (compound heterozygotes) that would render them resistant to any TKI. Thus, there is reluctance to attempt TFR in patients with known TKI resistance.
Children. CML is quite rare in childhood. While the same theoretical principles should apply, whereby a deep remission correlates with a successful TFR, there have been no clinical trials to demonstrate this. In addition, factors such as growth and fertility need to be considered, which may not be adequately explored in adult trials. TKIs are known to affect other growth receptor molecules; whether alternating between treatment and no treatment would have any deleterious effect on growth or fertility is unknown.
