Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy

Abstract

Nilotinib is a highly selective Bcr-Abl inhibitor approved for imatinib-resistant chronic myeloid leukemia (CML). Nilotinib and dasatinib, a multi-targeted kinase inhibitor also approved for second line therapy in CML, have different patterns of kinase selectivity, pharmacokinetics, and cell uptake and efflux properties, and thus patients may respond to one following failure of the other. An international Phase II study of nilotinib was conducted in CML patients [39 chronic phase (CP), 21 accelerated phase (AP)] after failure of both imatinib and dasatinib. Median times from diagnosis of CP or AP to nilotinib therapy were 89 and 83 months, respectively. Complete hematologic response and major cytogenetic response (MCyR) rates in CP were 79% and 43% respectively. Of 17 evaluable patients with CML-AP, 5 (29%) had a confirmed hematologic response and 2 (12%) a MCyR. The median time to progression has not yet been reached in CP patients. At 18 months 59% of patients are progression-free. Median overall survival for both populations has not been reached and the estimated 18 month survival rate in CML-CP was 86% and 80% at 12 months for CML-AP. Nilotinib is effective therapy in CML-CP and -AP following failure of both imatinib and dasatinib therapy.

Introduction

Nilotinib and dasatinib are both approved for the treatment of patients with chronic phase (CP) and accelerated phase (AP) chronic myeloid leukemia (CML) with imatinib resistance and/or intolerance.(1) These agents have different adverse event (AE) profiles, thus one agent may “rescue” patients from the toxicities of the other. While both demonstrate clinical activity against the majority of imatinib-resistant BCR-ABL mutated leukemia clones, some mutated phenotypes are differentially sensitive to these agents.(2) As nilotinib and dasatinib have different patterns of kinase target selectivity, pharmacokinetic parameters, and cell uptake and efflux properties, one may be active in patients with imatinib-resistant CML with currently unknown mechanisms of resistance when the other is less so.(3) Therefore, we investigated the efficacy of nilotinib in patients with CML following failure of imatinib and dasatinib.

Methods and patients

Adults with Ph+ CML in CP or AP who had imatinib resistance or intolerance and had also failed to respond to dasatinib therapy received oral nilotinib at a starting dose of 400 mg twice daily on an empty stomach. For patients with CML-CP, the primary endpoint was major cytogenetic response (MCyR), defined as complete (CCyR, 0% Ph+ metaphase cells) and partial (PCyR, <35% Ph+cells).(4) For patients with CML-AP, the primary endpoint was confirmed hematologic response defined as complete hematologic response (CHR, normal blood counts with no splenomegaly) or no evidence of leukemia (NEL) or return to chronic phase (RTC); secondary endpoints were: MCyR, time to progression (TTP), time to treatment failure (TTF), and overall survival (OS).(4)

Results

Sixty patients with failure after both prior imatinib and dasatinib therapy were enrolled. Baseline characteristics are shown in Table 1. Although 67% of patients in CP and 33% of patients in AP discontinued dasatinib due to toxicity, most patients (80%) had not achieved MCyR during dasatinib therapy despite a median duration of exposure of more than 6 months (Table 1). The mean prior daily dasatinib doses were 99.5 mg (range 40 – 180) in CP and 98.5 mg (range 20 – 200) in AP patients. Immediately prior to study entry, 56% of CP and 67% of AP patients were receiving daily dasatinib doses of ≤ 100 mg, although the majority of patients had started at daily dasatinib doses > 100 mg. The most common reasons for dasatinib intolerance in patients with CP and AP (n = 26) were myelosuppression (n = 7), serosal inflammation (n = 6), and pulmonary infiltrates or pneumonia (n = 3).

Table 1.

Baseline Demographic and Disease Characteristics

	CML-CP	CML-AP
	N=39	N=21
	n (%)	n (%)
Median age, years (range)	62 (34–78)	58 (19–73)
WHO Performance Status
Grade 0	25 (64)	7 (33)
Grade 1	12 (31)	12 (57)
Grade 2	2 (5)	2 (10)
Median time since initial diagnosis of CML, months (range)	89 (8–262)	83 (8–214)
Median duration of prior imatinib, months (range)	41 (6–65)	42 (<1–64)
Median duration of prior dasatinib, months (range)	7 (<1 – 34)	8 (<1 – 17)
Best prior cytogenetic response to dasatinib
Complete	5 (13)	1 (5)
MCyR	8 (21)	4 (19)
Minor	1 (3)	1 (5)
Minimal	1 (3)	3 (14)
None	24 (64)	11 (52)
Missing	4 (10)	2 (10)
Prior responses to TKI therapy
Imatinib resistant	33 (85)	18 (86)
Imatinib intolerant	6 (15)	3 (14)
Dasatinib resistant	12 (31)	12 (57)
Dasatinib intolerant	26 (67)	7 (33)
Dasatinib failure undefined	1 (3)	2 (10)

At a median duration of 12 months follow-up, nilotinib treatment was ongoing in 22 patients (56%) with CP and 4 patients (19%) with AP. The most common reasons for discontinuation of nilotinib were: disease progression (11 CP, 8 AP), AEs (4 CP, 6 AP), and death (0 CP, 2 AP). The median durations of nilotinib exposure were 11 months (range, <1.0 – 29.2) in patients with CP (n = 39) and 3.4 months (range <1.0 – 13.5) in patients with AP (n = 21); 28 patients with CP (72%) received nilotinib for more than 6 months; 7 patients with AP (33%) received nilotinib for more than 6 months. The nilotinib dose was escalated to 600 mg twice daily in 9 patients (7 CP, 2 AP). Efficacy analyses included patients who had either completed at least 4 months of treatment with nilotinib or had discontinued the study. Thirty-seven CP and 17 AP patients were included in the efficacy analysis. Of the 37 patients with CP, 28 (76%) did not have CHR at baseline; 22 of those 28 patients (79%) achieved CHR, and all remained in CHR at the time of data cut off. Sixteen patients (43%) achieved MCyR, with 9 (24%) patients achieving CCyR (Table 2). MCyR duration ranged from 3.2 to 23 months. Minor and minimal cytogenetic responses occurred in 7 patients (19%). Median TTP has not yet been determined; estimated progression-free survival at 18 months was 59%. Median TTF was 19.5 (range, 0.9 – 28.8) months. Median survival has not yet been reached. The estimated 18-month survival rate was 86%.

Table 2.

Hematologic and Cytogenetic Responses to Nilotinib

	CP	AP
	N =37	N=17
	n (%)	n (%)
Hematologic Response	-	5 (29)
Complete hematologic remission (CHR)*	22 (79)	0
Marrow response/no evidence of leukemia (NEL)	-	3 (18)
Return to chronic phase (RTC)	-	2 (12)
Major cytogenetic response (complete + partial)	16 (43)	2 (12)
Complete	9 (24)	0
Partial	7 (19)	2 (12)
Minor	1 (3)	4 (24)
Minimal	6 (16)	1 (6)

^*Evaluation of CHR in patients without CHR at baseline (n=28)

Confirmed hematologic response was reported in 5 of 17 patients (29%) with AP included in the efficacy analysis; 3 had NEL and 2 had RTC. The MCyR was achieved in 2 (12%), both PCyR. Five patients had minor (n = 4) or minimal (n = 1) cytogenetic responses. Median TTP was 9 months; the estimated progression-free survival at 6 months was 57%. Median TTF was 4.1 (range, 0.5 – 13) months. Median survival has not been reached; 6 and 12 month estimated survival rates were both 80%.

At least one BCR-ABL mutation was present at baseline prior to receiving nilotinib therapy in 21 of 37 (57%) evaluable patients (12/25 CP; 9/12 AP). Four (11%) of these patients (1 CP, 3 AP) had multiple mutations at the start of nilotinib therapy. The most commonly identified baseline mutations were F317L in 7 (19%) patients (6 CP, 1 AP patients), and T315I in 4 (11%) patients (2 CP, 2 AP patients).Eleven patients (52%) with baseline mutations (8/12 CP, 3/9 AP) achieved CHR; 4(19%) achieved MCyR (3/12 CP, 1/9 AP), and 6 (28% minor or minimal cytogenetic response (2/12 CP, 4/9 AP). Of 15 patients without baseline mutations, 80% (11/12 CP, 1/3 AP) achieved CHR, 40% (4/12 CP, 0/3 AP) MCyR, and another 33% (4/12 CP, 1/3 AP) either minimal or minor cytogenetic responses. Eighty-six percent of patients with the F317L (5 CP, 1 AP) mutation at baseline achieved CHR, 14% MCyR, and 14% minimal or minor cytogenetic responses. None of the 4 patients with T315I responded to nilotinib.

The most commonly reported nonhematologic events possibly related to nilotinib, and of any grade severity, were rash (28% CP, 19% AP), nausea (15% CP, 10% AP), pruritus (15% CP, 10% AP), headache (13% CP, 5% AP), and fatigue (10% CP, 10% AP). The most commonly reported grade 3 or 4 hematologic AEs possibly related to nilotinib were neutropenia (23% CP, 33% AP) and thrombocytopenia (28% CP, 19% AP). Other commonly reported grade 3 or 4 laboratory abnormalities were hyperphosphatemia (13% CP, 24% AP), elevated total bilirubin levels (8% CP, 14% AP), elevated lipase levels (25% CP, 10% AP), hypokalemia (5% CP, 10% AP), hyperglycemia (13% CP, 5% AP), hypermagnesemia (11% CP, 11% AP), hypocalcemia (10% CP, 19% AP) and elevated ALT levels (8% CP, 14% AP). Cardiac events occurred in 6 patients with CP (atrial arrhythmia (n=1), ventricular arrhythmia (n=2), other arrhythmias (n=1), cardiac failure (n=1), myocardial ischemia (n=1), and myocardial infarction (n=1) and none in patients with AP. Three patients with CP and 1 with AP experienced QTcF increases from baseline > 60 msec. One patient with CP had a QTcF value >500 msec.

Discussion

The observation from this study that some patients achieved responses with nilotinib, a TKI with increased selectivity for bcr-abl, after failing to respond to dasatinib, a broader spectrum multi-kinase inhibitor, indicates that in these patients bcr-abl continues to be the primary kinase therapeutic target. We have previously reported on the activity of dasatinib in a smaller cohort of patients who had failed prior therapy with imatinib and dasatinib – thus failure of either dasatinib or nilotinib as a second line agent does not preclude response to the alternate agent as a third line approach in CML.(5) The failure of nilotinib in patients on this study who had T315I-phenotype disease is consistent with prior reports and the resistance of this phenotype to all current approved abl-inhibitors is one of the pressing reasons why bcr-abl mutation analysis should be performed in patients with imatinib-resistant disease and why consideration of allogeneic stem cell transplantation is an important component of the therapy of these patients.(3)

While nilotinib and dasatinib are similarly active when used to treat patients with CML who have failed prior therapy with imatinib, these agents have distinct adverse event profiles which may reflect their different kinase inhibition profiles.(1, 6) These agents also have different efficacy associated with some bcr-abl mutated phenotypes.(7) They also behave differently as substrates for various cellular influx and efflux pumps.(8–10) As both agents are now approved as therapy in patients with imatinib failure or intolerance, establishing the degree of cross-intolerance between them and assessing the potential of patients with imatinib failure to respond to therapy with a third abl inhibitor are important clinical issues. The data from the currently reported study indicates that some patients who have failed to respond to both imatinib and dasatinib may have meaningful durable responses to nilotinib therapy. The comparative efficacy and optimal sequencing of these agents as second or third-line therapies warrants prospective evaluation within randomized studies.