TABLE 1.

Study Characteristics

First Author	Year	Trial Sponsor	Multicenter	Method of Mutational Analysis	Timing of Mutation Analysis	Study Definition of Failure	Medication	Dosing
Radich, J17	2012	Canadian Cancer Society Research Institute, NIH, Public Health Service Cooperative Agreement	Yes	Direct nucleotide sequencing	Tx failure or discontinuation	Failure to achieve CHR by 3 months, loss of CHR, loss of PCyR or CCyR, or progression to AP or BP CML	Imatinib	400 mg D
					Tx failure or discontinuation		Dasatinib	100 mg D
Soverini, S38	2005	European Leukemia Net and others	Yes	D-HPLC or direct sequencing	Baseline/scheduled/tx failure/discontinuation	Cytogenetic resistance: failure to obtain at least a MCyR at 12 months	Imatinib	400 mg D
Branford, S39	2007	Novartis Australia	Yes	Direct sequencing	Scheduled/tx failure/discontinuation	Death from any cause, development of AP or blast crisis, loss of CHR, and loss of a MCyR	Imatinib	400 mg D
Branford, S30	2003	Novartis Australia	Yes	Direct sequencing	Scheduled/tx failure/discontinuation	CP: disease progression, loss of a sustained CHR, MCyR, or CCyR with a corresponding increase in BCR-ABL levels of at least 1 log (refer to the reference for the definitions of acquired and primary resistance in CP or AP)	Imatinib	400 mg D
de Lavallade, H40	2008	NR	No	RQ-PCR and pyrosequencing	Scheduled/tx failure/discontinuation	Loss of CHR or progression to advanced phase, loss of MCyR or CCyR, an increase by a factor of 2 in the transcript level, and failure to achieve CHR by 12 weeks	Imatinib	400 mg D
He, H20	2012	NR	No	Semi-nested transcriptase PCR followed by direct sequencing	Baseline/scheduled/tx failure/discontinuation	Loss of CCyR or MCyR, MCyR not achieved within 12 months, and progression to advanced phase	Imatinib	400 mg D
Kantarjian, H16	2012	Bristol-Myers Squibb	Yes	Direct sequencing	Tx failure/discontinuation	No hematologic response by 3 months, no CHR or cytogenetic response by 6 months, no partial cytogenetic response by 12 months, or no CCyR by 18 months	Imatinib	400 mg D
					Tx failure/discontinuation		Dasatinib	100 mg D
Roche-Lestienne, C13	2002	NR	No	Sequencing	Scheduled/tx failure/discontinuation	No cytogenetic response after 3 months	Imatinib	400-800 mg D
Elnahass, Y33	2013	NR	No	Sequencing	Scheduled/tx failure/discontinuation	Greater than 2-fold rising BCR-ABL level	Imatinib	400 mg D
Wei, Y41	2006	Swedish Research Council and others	No	Sequencing	Baseline/scheduled/tx failure/discontinuation	Failure to achieve CHR after 3 months of imatinib therapy, failure to achieve at least a minimal cytogenetic response (65%-95% Ph+ metaphases) after 6 months of imatinib therapy, failure to achieve a MCyR <35% Ph+ metaphases at 12 months of imatinib therapy (1-3=primary resistance), and loss of an earlier obtained CHR or CyR (acquired resistance)	Imatinib	400-600 mg D
Cortes, J19	2010	National Cancer Institute	No	Sequencing	Baseline/scheduled/tx failure/discontinuation	Patients who had not achieved CCyR by 6 months after treatment or who developed resistance	Nilotinib	400 mg BID
						Patients who do not achieve MCyR or patients who discontinue therapy because of toxicity are also considered as experiencing treatment failure
Cortes, J18	2010	National Cancer Institute	No	Sequencing	Baseline/scheduled/tx failure/discontinuation	Patients who had not achieved CCyR by 6 months after treatment or who developed resistance	Dasatinib	50 mg BID or 100 mg D

AP = accelerated phase; BID = twice daily; BP = blast phase; CCyR = complete cytogenetic response; CHR = complete hematologic response; CML = chronic myeloid leukemia; CP = chronic phase; CyR = cytogenetic response; D = daily; D-HPLC = denaturing high pressure liquid chromatography; MCyR = major cytogenetic response; mg = milligram; NR = not reported; PCR = polymerase chain reaction; PCyR = partial cytogenetic response; Ph = Philadelphia; RQ-PCR = real-time quantitative polymerase chain reaction; tx = treatment.