Safety and Efficacy of Bosutinib in Fourth Line Therapy of Chronic Myeloid Leukemia Patients

BACKGROUND: Despite the excellent prognostic of chronic myeloid leukemia (CML) patients since the introduction of tyrosine kinase inhibitors (TKIs), approximately 50% of patients that are treated with TKIs will discontinue first line treatment due to lack of efficacy or intolerance. Once patients need a second line treatment, a considerable proportion of patients will need third or even fourth line therapy during further evolution. At this moment, there is a lack of data about real benefit of this group of patients. We have recently published our experience of 30 CML patients treated with bosutinib in 4th line. We present an update of the study where we have increased the number of patients, and the follow-up. The aim of this study is to present safety and efficacy data CML chronic phase patients treated with bosutinib in 4^thline.

METHODS: We have collected data from 59 CML patients treated with bosutinib in 4^thline after resistance or intolerance to IM, NI and DA. 51 patients have been treated under the Spanish compassionate use program (36 centers) and 10 patients were treated in a single institution from United Kingdom. Median age of patients at diagnosis was 53 years. The percentage of low, intermediate and high risk Sokal groups were 47%, 37% and 16%. Median time TKIs exposure before bosutinib was 9 years. The most common indication (30/59) was intolerant to DA and NI. Patients’ dispositions and main line characteristics are shown in table 1.

RESULTS: Median follow-up was 14.3 months. All patients started bosutinib at 500mg/d, median dose of was 450mg/d. Overall probabilities to either achieve or maintain previous response were 96% (57/59), 62% (37/59), 40% (24/59) and 17% (10/59) for complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5 respectively. However, probabilities to obtain responses (in patients without response evaluated at baseline) were 27% (7/26), 26% (12/45) and 12% (7/55) for CCyR, MMR and MR4.5. As expected, probabilities to obtain CCyR were lower for patients resistant to DA and NI patients than for patients intolerant to DA and NI (8% VS 44%). Event free survival (EFS) and progression free survival (PFS) probabilities were 50% and 83% by 27 month. Treatment was discontinued in 20/58 (34%), most frequent reasons being adverse events 9/59(15%), lack of efficacy 5/59 (8.5%), disease progression 2/59 (3.4%) and death 1/59 (1.7%). Two patients discontinued due to stem cell transplantation. The adverse events that led to treatment discontinuation were pleural effusion (3), diarrhea (2), rash, renal impairment, auricular fibrillation and liver enzyme elevation one patient each.  Overall, bosutinib was well tolerated. Grade 3-4 hematological toxicities were 3%, 6% and 6% for anemia, thromboctytopenia and neutropenia. Most common non hematological side effects were diarrhea (39%, nauseas 13% and liver alterations 14% and pleural effusion 14%.

CONCLUSIONS: Little is known about the therapeutic role of Bosutinib in 4th line. The series presented here is, to our knowledge, the largest being presented. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKIs.

 Table 1

 

			IM+NI-I+DA-R (N=4)	IM+NI-R+DA-R (N=18)	IM+NI-I+DA-I (N=30)	IM+NI-R+DA-I (N=7)	Total (N=59)
Sex, N   (%) Male			2 (50)	11 (61.1)	16 (53.3)	2 (28.6)	31   (52.5)
Median age of diagnosis,   yr (range)			57.32 (50-64)	49.19 (23-73)	54.95 (21-89)	48.87 (26-68)	53.15 (21-89)
Median age of Bosutinib   initiation, yr (range)			69.13 (61-70)	62.27 (39-79)	64.85 (25-90)	64.79(35-74)	63.7 (25-9)
Median follow up, months   (range)			18.5(7.8-34.1)	8.4(1.22-36.1)	16.3(0.5-34.7)	23.4(3.3-28.9)	14.3(0.7-36.1)
SOKAL Index at   diagnosis, N (%)	High		2(50.0)	4 (23.5)	1 (4.3)	1 (20)	8 (16.3)
	Intermediate		1 (25.0)	5 (29.4)	10(43.5)	2 (40)	18 (36.7)
	Low		1 (25.0)	8 (47.1)	12 (52.2)	2 (40)	23 (46.9)
Median Time from first   TKI to BOS, (yr, range)			10.3 (4.8-11.9)	9.3 (2.0-11.4)	8.8 (0.7-13.6)	8.2 (5.1-12.3)	8.8 (0.7-13.6)
Median duration of prior therapy, months (range)		Imatinib	38.8 (11.8-69.8)	32.6 (6.3-96.8)	26.2 (1.6-102.6)	23.1 (8.3-66.8)	28.8 (1.6-102.6)
		Dasatinib	21.5 (12.6-75)	21.8 (7.7-69)	31.4 (0.4-87.1)	23.7 (10.3-53.6)	23.44 (0.4-87.1)
		Nilotinib	19.1 (2.1-46.2)	16.7 (5-65.6)	8.9 (0.2-58.5)	30.9 (6.9-49.3)	14.3 (0.2-65.6)

BOS: bosutinib, IM, imatinib; DA, dasatinib; NI, nilotinib, I: Intolerance, R: Resistant, Yr: year