Table 1.

Clinical and biological factors associated with TFR

Type of factor		Variable	Evidence	Association	References
Clinical	Patient-related	Age	Lacking	• Some studies suggest higher TFR in older population	[92]
		Sokal score	Suggested	• Low Sokal score associated with better outcomes	[35, 93, 94]
		Gender	Lacking	• Some studies suggest association of female gender with higher TFR	[95]
	Treatment-related	Total TKI duration	Strong	• Favorable impact of a longer duration of therapy	[5, 28, 36, 96, 97]
		Duration of DMR	Strong	• Favorable impact of a longer duration of response	[5, 28, 36, 71, 98]
		TKI resistance	Lacking	• Decreased TFR rate but few studies have investigated this	[65, 66]
Biological	Immune-related	CTLs	Suggested	• Deficit in the expression of HLA class II and CT function in CML • Proliferation after TKI treatment • Low levels of CD8+ TCRγβ + T cells seem to be associated with relapse after TKI stop	[12•, 13, 21, 26]
		Tregs	Suggested	• Decrease in number with TKI treatment • Lower counts related with TFR	[12•, 14, 25]
		pDC	Suggested	• Lower CD86 + pDC cell ratio was found to be predictive of TFR	[12•, 22, 23]
		MDSCs	Suggested	• Decrease in number with TKI treatment • Lower counts related with TFR	[12•, 25]
		NK cells	Strong	• Proliferation with TKI treatment • Increased activating NK cells associated with maintained TFR	[12•, 19–21, 25]
		LSC	Evidence lacking	• LSC intrinsic factors and medullary microenvironment implicated in residual disease and a possible target for future therapeutic pathways	[6, 18]
	Transcript and molecular-related	Type of transcript	Conflicting	• Superior patient outcomes for e14a2 vs. e13a2 • Possible technical bias as amplification efficiency with qPCR higher for e13a2	[41–45, 46••, 47–51]
		BCR::ABL1 DNA/RNA positivity	Suggested	• Positivity for both DNA and RNA indicative of a higher rate of relapse when TKI was discontinued • DNA negativity in granulocytes indicator of TFR	[59•, 60, 61••, 63••, 71]
		Rate of transcript reduction	Suggested	• Faster decline of BCR::ABL1 transcripts in the first 3 months of TKI therapy associated with a higher probability of TFR	[52–56]
		Somatic mutations	Suggested	• Various polymorphisms and somatic mutations associated with TFR	[21, 65, 66, 69, 70, 72, 73]
		RNA expression	Suggested	• Different expression profiles for patients who maintain TFR vs. those who relapse	[82•, 83–87]
		Telomere length	Suggested	• Correlates with response to treatment and disease progression • Shorter length related with higher TFR	[76–79]