Third-line treatment with second-generation tyrosine kinase inhibitors (dasatinib or nilotinib) in patients with chronic myeloid leukemia after two prior TKIs: real-life data on a single center experience along with the review of the literature

Figures & data

Figure 1. The consort diagram showing the study cohort and treatment outcomes (2G, second generation; BC, blast crisis; CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia in chronic phase; DAS, dasatinib; IM, imatinib; MMR, major molecular response; NIL, nilotinib; TKI, tyrosine kinase inhibitor). *One patient in each group died due to non-CML related causes while they were in MMR, the others deceased due to disease progression.

Table 1. Baseline characteristics and treatment outcomes of patients who received third-line 2GTKIs.

Patient #	Age, years/gender	Sokal Risk Score	Treatment prior to IM	Duration of IM, months	Reason for stopping IM	Best response under IM	Mutation status prior to second-line TKI	The choice of second-lineTKI	Duration of second-line TKI, months	Reason for stopping second-line TKI	Best response under second-line TKI	Mutation status prior to third-line TKI	The choice of third-line TKI	Duration of third-line TKI, months	Reason for stopping third-line TKI	Best response under third-line TKI	Follow-up duration, months	Outcome
1	20/M	Low	None	22	Failure	PCyR	E255K^b	NIL	2	Failure	NA	E255K^b	DAS	26	Continued	MMR	48	Alive
2	57/M	Low	IFN-α+ARA-C	83	Failure	CCyR	WT	DAS	25	PE	CCyR	WT	NIL	12	QTc ↑ and myalgia	PCyR	177	Dead
3	32/M	Low	HU	12	Failure	PCyR	WT	NIL	31	Failure	PCyR	WT	DAS	6	Continued	CHR	50	Alive
4	33/M	Low	HU	26	Failure	PCyR	WT	DAS	28	Failure	PCyR	WT	NIL	3	Bone pain and myalgia	CHR	145	Alive
5	55/M	High	None	23	Failure	PCyR	WT	DAS	52	COPD, PE	MMR	WT	NIL	4	Continued	CHR	79	Alive
6	57/M	Intermediate	HU/ IFN-α+ARA-C	48	Failure	PCyR	WT	DAS	39	PE and thrombocytopenia	MMR	WT	NIL	34	Continued	MMR	131	Alive
7	47/F	Low	HU+IFN-α	89	Failure	MMR	WT	DAS	36	PE	MMR	WT	NIL	13	Continued	MMR	208	Alive
8	29/F	-^a	HU	31	Failure	PCyR	WT	DAS	32	Failure	PCyR	WT	NIL	4	Neutropenia	CHR	112	Deadφ
9	51/M	Intermediate	HU	60	Failure	MMR	M244V	DAS	19	PE	MMR	ND	NIL	33	Continued	MMR	161	Alive
10	39/F	Intermediate	HU	49	Failure	MMR	WT	DAS	56	Failure	PCyR	WT	NIL	23	Continued	MMR	172	Alive
11	48/F	Low	HU+IFN-α	80	Failure	MMR	WT	DAS	24	PE + Failure	PCyR	WT	NIL	12	Progression	NR	144	Dead
12	46/F	Low	IFN-α+ARA-C	42	Failure	PCyR	WT	DAS	11	Failure	PCyR	WT	NIL	2	QTc ↑	CHR	144	Alive
13	65/F	Intermediate	None	2	Myalgia	CHR	ND	DAS	24	PE	MMR	ND	NIL	22	Continued	MMR	48	Alive
14	59/M	Intermediate	HU	18	Failure	PCyR	WT	NIL	1	Thrombocytopenia	NA	WT	DAS	14	PE + Failure	CHR	80	Alive
15	67/F	High	None	23	Failure	MMR	G250E	DAS	12	PE	MMR	WT	NIL	42	Continued	MMR	77	Alive
16	66/F	Low	None	2	Skin rash	PCyR	ND	DAS	42	PE	MMR	WT	NIL	1	Skin rash	MMR	45	Alive
17	25/M	Low	None	52	Failure	MMR	M244V, A287V	NIL	5	QTc ↑	MMR	WT	DAS	10	Continued	MMR	67	Alive
18	52/M	Low	HU+IFN-α	40	Failure	CCyR	WT	DAS	24	Failure	PCyR	F317L, K357R	NIL	1	Progression	NA	100	Dead
19	36/M	Low	None	20	Failure	PCyR	Y253H	NIL	19	Failure	PCyR	WT	DAS	7	Continued	CCyR	46	Alive
20	50/M	Low	None	63	Failure	CCyR	WT	DAS	12	Failure	MMR	WT	NIL	22	Continued	MMR	97	Alive
21	53/M	High	HU	123	Failure	MMR	WT	NIL	5	PAOD	CHR	WT	DAS	1	Continued	CHR	129	Alive

Notes: Ara-C: cytarabine; CHR: complete hematologic response; CCyR: complete cytogenetic response; COPD: chronic obstructive pulmonary disease; DAS: dasatinib; F: female; HU: hydroxyurea; IFN-α: interferon-alpha; IM: imatinib; M: male; MMR: major molecular response; NA: not available; NIL: nilotinib; NR: no response; PCyR: partial cytogenetic response; PAOD: peripheral arterial occlusive disease; PE: pleural effusion; QTc ↑: the prolongation of QTc interval.

^aPatient had splenectomy prior to the diagnosis of CML so Sokal score could not be calculated.

^bAfter imatinib failure, this patient was first switched to nilotinib but when mutation analysis was found to be positive for E255K, the TKI treatment was changed to dasatinib afterwards.

φPatient died after allo-HSCT.

Figure 2. The distribution of best responses achieved under third-line TKI therapy.

Figure 3. The event-free (A) and overall (B) survivals of patients when cases were divided into two according to the reason of switching to third-line TKI therapy as patients with failure (PF; n = 9) and intolerance (PI; n = 11) [OS was calculated from the date of diagnosis until the time of death or last follow-up. EFS was calculated from the onset of third-line TKI therapy until the date of any event defined].

Table 2. The summary of studies displaying third-line 2GTKI treatment with dasatinib or nilotinib in the literature.

First author, year, [reference #]	Number of patients, n		Median age, years	Disease stage at diagnosis, CP/AP/BC	First-line therapy	Median duration of first-line therapy, months	Reason for second-line therapy, failure/intolerance	Disease stage prior to second-line therapy, CP/AP/BC	second-line therapy	Median duration of second-line therapy, months	Reason for third-line therapy, failure/intolerance/both or undefined	Disease stage prior to third-line therapy, CP/AP/BC	Third-line therapy	Median duration of third-line therapy, months	Best responses under third-line therapy	Median follow-up duration, months	Outcome, alive/dead
Quintas-Cardama, 2007, [11]	23		58	N/A	IM	21	NA	NA	NIL	8	23/0/0	4/10/9	DAS	4	CHR (22%) CCyR (9%) PCyR (17%) mCyR (9%) NR (43%)	69	16/7
Garg, 2009, [12]	48	Third-line DAS (n = 34)	53	29/5/0	IM	30	34/0	17/10/7	NIL	7.7	30/4/0	16/8/10	DAS	13	CHR (21%)^a PCyR (10%) mCyR (10%) CCyR (13%) MMR (15%) NR (27%) RCP (4%)	NA	30/4
		Third-line NIL (n = 14)	49	10/3/1	IM	43	13/1	8/3/3	DAS	10.3	9/5/0	9/2/3	NIL				13/1
İbrahim, 2010, [13]	26	Third-line NIL (n = 20)	64	20/0/0	IM	NA	NA	NA	DAS	NA	NA	NA	NIL	21.5	MCyR (50%) CCyR (35%) MMR (19%)	NA	17/9
		Third-line DAS (n = 6)		6/0/0		NA	NA	NA	NIL	NA	NA	NA	DAS
Giels, 2010, [14]	60		62 (CP) 58 (AP)	N/A	IM	NA	51/9	NA	DAS	NA	24/33/3	39/21/0	NIL	11 (CP) 3.4 (AP)	CP^b CHR (38%) CCyR (24%) PCyR (19%) mCyR (3%) miCyR (16%) AP HR (29%) PCyR (12%) mCyR (24%) miCyR (6%)	100 (CP) 86.4 (AP)	58/2
Russo Rossi, 2013, [15]	82	Third-line DAS (n = 34)	60	34/0/0	IM	47	32/2	30/2/2	NIL	30	17/14/3	30/1/3	DAS	NA	CHR (31.7%) mCYR (7.3%) PCyR (15%) CCyR (17.1%) MMR (15.9%) NR (14.6%)	NA	70/12
		Third-line NIL (n = 48)		48/0/0		NA	42/6	42/5/1	DAS	13	24/24/0	38/8/2	NIL
Riberia, 2015, [16]	25		56	NA	IM	30	NA	NA	NIL	NA	NA	18/3/4	DAS (n = 9)	NA	CP CHR (45%) CCyR (11%) MMR (33%) NR (11%) AP CHR (67%) MMR (33%) BC NR (100%)	52	21/4
								DAS				NIL (n = 16)
Present study, 2017	21		50	21/0/0	IM	40	19/2	21/0/0	NIL	24.5	9/11/1	21/0/0	DAS (n = 6)	12	CHR (33%) PCyR (5%) CCyR (5%) MMR (47%) NR (5%) NA (5%)	100	17/4
								DAS				NIL (n = 15)

Notes: ^aThese response rates vary according to the disease phase at the start of third-line treatment-please refer to original paper for details.

^bThese percentages were given separately according to disease phase-please refer to original papers for details.

AP: accelerated phase; BC: blast crisis; CP: chronic phase; HR: hematologic response; mCyR: minor cytogenetic response; miCyR: minimal cytogenetic response; RCP: return to chronic phase.

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