Current concerns of undertreatment and overtreatment in chronic myeloid leukemia based on European LeukemiaNet 2013 recommendations

Figures & data

Table 1. The comparative target end points of the ELN 2009 [2] and ELN 2013 [1] recommendations for CML.

	ELN CML 2009 [2]			ELN CML 2013 [1]
	Optimal response	Primary failure	Secondary failure	Optimal response	Primary failure	Secondary failure
3 months	CHR and at least minor CyR (Ph+ ≤ 65%)	No CHR		CHR and BCR-ABL < 10% and/or at least PCyR (Ph+ < 35%)	No CHR and/or No CyR (Ph+ > 95%)
6 months	At least PCyR (Ph+ < 35%)	No CyR (Ph+ > 95%)		BCR ABL < 1% and/or CCyR (Ph+ = 0%)	BCR-ABL > 10% and/or less than PCyR (Ph+ > 35%)
12 months	CCyR (Ph+ = 0%)	Less than PCyR (Ph+ > 35%)		MMR (BCR-ABL ≤ 0.1%)	BCR-ABL > 1% and/or less than CCyR (Ph+ ≥ 1%)
THEN (at any time)	MMR (MR 3) or better		Loss of CHR; loss of CCyR mutations CCA/ Ph+	MMR (MR 3) or better		Loss of CHR; loss of CCyR mutations CCA/Ph+ confirmed loss of MMR

Table 2. Major critical conclusions of the major clinical trials in the field of CML.

Clinical study	Major critical conclusion	CCyR 12 months with imatinib	MMR 12 months with imatinib
IRIS [3]	Imatinib is superior to IFN + Ara-C treatment with regard to hematological, cytogenetic and molecular responses (imatinib is the ‘standard of care' in CML)	68%	38%
TOPS [16]	High-dose imatinib may obtain faster but not more responses	66% (w/400 mg) 70% (w/800 mg)	40% (w/400 mg) 46% (w/800 mg)
ELN/GIMEMA STUDY (only high-Sokal CML) [4]	High-dose imatinib could not increase responses in high-risk CML	58% (w/400 mg) 64% (w/800 mg)	36% (w/400 mg) 43% (w/800 mg)
GERMAN CML STUDY IV [5,8]	Imatinib dose optimization may obtain earlier and more molecular responses (addition of non-PEG IFN is not useful)	49% (w/400 mg) 63% (w/800 mg)	34% (w/400 mg) 46% (w/800 mg)
FRENCH SPIRIT [17]	PEG-IFN and imatinib combination may obtain earlier, deeper and more molecular responses (increasing the dose of imatinib is not useful)	58%	38%
ENESTnd [13]	Nilotinib is superior to imatinib with regard to cytogenetic and molecular responses	65%	22%
DASISION [12]	Dasatinib is superior to imatinib with regard to cytogenetic and molecular responses	72%	28%
BELA [18]	Bosutinib may obtain more molecular (but not cytogenetic) responses than imatinib	68%	27%
TIDEL [9]	CML treatment optimization with imatinib dosage, plasma level monitorization and convenient shift to nilotinib is possible with better responses	88%	47%

Those clinical studies have used the imatinib treatment as the research arm or the control arm for another TKI. Thus, the end points of CCyR and MMR at 12 months were depicted as an idea of comparison among the trials.

BELA: Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia; CCyR: Complete cytogenetic response; CML: Chronic myeloid leukemia; DASISION: Dasatinib versus Imatinib Study in Treatment-naive CML patients; ELN: European LeukemiaNet; ENESTnd: Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients; IFN + Ara-C: Interferon plus cytosine arabinoside combination; IRIS: The International Randomized Study of Interferon and STI571; MMR: Major molecular response; PEG-IFN: Polyethylene glycol-added interferon; TIDEL: Therapeutic Intensification in De-novo Leukemia; TOPS: Tyrosine Kinase Inhibitor Optimization and Selectivity.

Figure 1. Illustration of clinical decision making for any TKI drug in CML. Number one [1] clinical decision should be reached based on the optimization of the best available evidence, individual patient/disease characteristics and the clinical experience.

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