Drugs DOI 10.1007/s40265-016-0677-x
ADIS DRUG EVALUATION
Dasatinib: A Review in Chronic Myeloid Leukaemia and Ph+ Acute Lymphoblastic Leukaemia Gillian M. Keating1
Ó Springer International Publishing Switzerland 2016
Abstract Dasatinib (SprycelÒ) is an orally administered, small molecule inhibitor of multiple tyrosine kinases. In the phase 3 DASISION trial, dasatinib 100 mg once daily resulted in deeper and faster cytogenetic and molecular responses than imatinib 400 mg once daily in patients with newly diagnosed, chronic-phase chronic myeloid leukaemia (CML), although there was no significant betweengroup difference in progression-free survival (PFS) or overall survival (OS) in the longer term. In the phase 3 CA180-034 trial, a regimen of dasatinib 100 mg once daily provided the most favourable benefit-risk profile in patients with imatinib-resistant or -intolerant chronic-phase CML. In the phase 3 CA180-035 trial, a regimen of dasatinib 140 mg once daily demonstrated efficacy in patients with accelerated- or blast-phase CML or Ph? acute lymphoblastic leukaemia (ALL) resistant or intolerant to imatinib. Dasatinib had an acceptable tolerability profile. In conclusion, dasatinib is an important option for the treatment of patients with newly diagnosed chronic-phase CML and for imatinib-resistant or -intolerant patients with chronic- or advanced-phase CML or Ph? ALL.
The manuscript was reviewed by: R. Hehlmann, Medizinische Fakulta¨t Mannheim, Universita¨t Heidelberg, Mannheim, Germany; R.A. Larson, Section of Hematology/Oncology, Department of Medicine, and Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA; G. Saglio, Department of Clinical and Biological Sciences, University of Turin, Division of Hematology, Mauriziano University Hospital, Turin, Italy. & Gillian M. Keating
[email protected] 1
Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand
Dasatinib: clinical considerations in CML and Ph1 ALL Small molecule inhibitor of multiple tyrosine kinases, including BCR-ABL1 and the SRC family of kinases Dasatinib 100 mg once daily was associated with deeper and faster cytogenetic and molecular responses than imatinib in newly diagnosed, chronicphase CML, with no significant between-group difference in longer-term PFS or OS Dasatinib 100 mg once daily provided the most favourable benefit-risk profile in imatinib-resistant or -intolerant chronic-phase CML Dasatinib 140 mg once daily demonstrated efficacy in imatinib-resistant or -intolerant advanced-phase CML or Ph? ALL Acceptable tolerability profile
1 Introduction Chronic myeloid leukaemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, which is formed by a reciprocal translocation fusing the ABL1 gene from chromosome 9 to the BCR gene on chromosome 22 [1]. The Ph chromosome encodes the BCR-ABL1 fusion protein, a constitutively active, oncogenic tyrosine kinase that plays a critical role in the pathogenesis of CML [1]. In addition, Ph? acute lymphoblastic leukaemia (ALL) is the
G. M. Keating
most common ALL subtype in adults and has a poor prognosis [2]. The development of tyrosine kinase inhibitors (TKIs) [e.g. dasatinib (SprycelÒ), imatinib, nilotinib, bosutinib, ponatinib] has transformed the treatment of CML, with chronic-phase CML now considered a manageable chronic disease [3]. Dasatinib is an orally administered small molecule inhibitor of multiple tyrosine kinases. This narrative review discusses the efficacy and tolerability of dasatinib in newly diagnosed chronic-phase CML and in imatinib-resistant or -intolerant chronic- and advancedphase CML and Ph? ALL, as well as summarizing its pharmacological properties.
The occurrence of lymphocytosis in patients with CML receiving dasatinib has been linked with improved response rates and pleural effusion (Sect. 5) [19]. The mechanism underlying this lymphocytosis is unclear, although dasatinib-induced inhibition of STAT3 and STAT5B signalling downstream of the BCR-ABL1 and SRC pathways may be a possible mechanism [19]. Dasatinib has the potential to prolong the QT interval, according to in vitro data [20, 21], although prolongation of the corrected QT (QTc) interval was reported infrequently in patients receiving dasatinib in clinical trials (Sect. 5.2). Reversible inhibition of platelet aggregation was seen in patients with CML receiving dasatinib [22] (see Sect. 5).
2 Pharmacodynamic Properties of Dasatinib
3 Pharmacokinetic Properties of Dasatinib
Dasatinib inhibits multiple tyrosine kinases at nanomolar concentrations, including BCR-ABL1, c-KIT, EPHA2, platelet-derived growth factor receptor-b and the SRC family of kinases (e.g. SRC, LCK, YES, FYN) [4–6]. Dasatinib is structurally unrelated to imatinib and is 325-fold more potent than imatinib at inhibiting wild-type BCR-ABL1 in vitro [7]. Imatinib only binds to the inactive conformation of the BCR-ABL1 kinase domain; point mutations in BCR-ABL1, most of which destabilize the inactive conformation of the BCR-ABL1 kinase domain, are the most common mechanism of acquired imatinib resistance [7–9]. By contrast, dasatinib binds to the BCRABL1 kinase domain in both the inactive and active conformations [4, 7, 8, 10]. Because of this, dasatinib demonstrated in vitro activity against imatinib-resistant BCR-ABL1 mutants (with the exception of T315I), including when mutations were located in the phosphatebinding loop of BCR-ABL1 kinase, the activation loop and other sites [7, 9–11]. In vitro, potent, transient inhibition of BCR-ABL1 kinase activity was sufficient to result in apoptosis in CML cell lines [12]. Dasatinib demonstrated activity in murine models of CML [4, 13] and in murine models of imatinib-resistant BCR-ABL1-dependent disease [10]. Activation of BCR-ABL1-independent pathways, such as the SRC family of kinases, is also implicated in CML and Ph? ALL progression and imatinib resistance [14]. Dasatinib blocked signalling by the SRC family of kinases, resulting in the inhibition of cell adhesion, migration and invasion of prostate cancer cells [15]; imatinib does not inhibit the activity of the SRC family of kinases [14]. Dasatinib induced the mobilization and activation of lymphocytes (preferentially natural killer/T cells) in patients with Ph? leukaemia [16, 17]. Large granular lymphocyte lymphocytosis has also been reported in patients with CML or Ph? ALL receiving dasatinib [18].
Following oral administration, peak plasma concentrations of dasatinib were reached in 0.5–6 h [20] or 0.5–3 h [21]. Dose-proportional increases in the area under the plasma concentration–time curve (AUC) and linear elimination characteristics were seen with dasatinib 15–240 mg/day [20]. The active metabolite of dasatinib is equipotent to dasatinib; however, the active metabolite represents only about 5% of the dasatinib AUC, meaning that it is unlikely to play a major role in the activity of dasatinib. A high-fat meal did not affect dasatinib pharmacokinetics to a clinically relevant extent [20, 21]. Dasatinib has an apparent volume of distribution of 2505 L, indicating extensive extravascular distribution [20, 21]. In vitro, plasma protein binding of dasatinib and its active metabolite was &96 and 93% [20, 21]. Dasatinib is extensively metabolized by multiple enzymes, with CYP3A4 primarily responsible for the formation of the active metabolite [20, 21]. The parent drug accounted for &26% of circulating radioactivity in plasma 2 h after administration of radiolabelled dasatinib 100 mg [23]. Dasatinib is mainly eliminated in faeces, with &85 and 4% of radioactivity recovered in the faeces and urine following administration of a radiolabelled dose of dasatinib [20, 21, 23]. The parent drug accounted for 19 and 0.1% of the administered dose in faeces and urine [20, 21, 23]. The mean elimination terminal half-life of dasatinib was reported as 3–5 h [20] and &5–6 h [21]. Dasatinib exposure appeared similar in Japanese and non-Japanese patients [24], and did not significantly differ between east Asian and non-east Asian patients [25]. Age, gender and moderate to severe hepatic impairment did not affect the pharmacokinetics of dasatinib to a clinically relevant extent [20, 21]. However, the EU summary of product characteristics (SPC) states that dasatinib should be administered with caution to patients with hepatic impairment [21].
Dasatinib: A Review
Coadministration of a strong CYP3A4 inducer [e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbtial, hypericum (St. John’s wort)] may decrease dasatinib concentrations and coadministration of a strong CYP3A4 inhibitor (e.g. ketoconazole, clarithromycin, atazanavir, indinavir, nefazodone, ritonavir, saquinavir) may increase dasatinib concentrations [20, 21]. Local prescribing information should be consulted for recommendations regarding the coadministration of dasatinib with strong CYP3A4 inducers or inhibitors [20, 21]. Dasatinib is a weak inhibitor of CYP3A4 [20, 21]. CYP3A4 substrates with a narrow therapeutic index (e.g. alfentanil, astemizole, terfenadine, cisapride, ciclosporin, fentanyl, sirolimus, tacrolimus) should be administered with caution to patients receiving dasatinib [20, 21]. Given that the solubility of dasatinib is pH dependent, simultaneous administration of dasatinib and antacids should be avoided [20]. If antacid therapy is needed, an interval of C2 h should separate the administration of dasatinib and the antacid [20, 21]. The coadministration of dasatinib and H2-receptor antagonists or proton pump inhibitors is not recommended [20, 21].
4 Therapeutic Efficacy of Dasatinib 4.1 In Newly Diagnosed Chronic-Phase CML Results of a phase 2 trial demonstrated the potential beneficial effects of dasatinib 100 mg/day in the treatment of patients with newly diagnosed CML in early chronic phase [26]. In addition, a phase 2b trial in patients with newly diagnosed Ph? chronic-phase CML reported a 3-year progression-free survival (PFS) rate of 93% in patients randomized to dasatinib 100 mg once daily and 90% in patients randomized to imatinib 400 mg once daily; the 3-year overall survival (OS) rate was 97% in both treatment groups [27]. The focus of this section is the randomized, open-label, multinational, phase 3 DASISION trial which compared the efficacy of dasatinib 100 mg once daily with that of imatinib 400 mg once daily in patients with newly diagnosed Ph? chronic-phase CML [28]. Patients were eligible for inclusion in DASISION if they had Ph? chronic-phase CML, had received no prior treatment for CML except for anagrelide or hydroxyurea, had an Eastern Co-operative Oncology Group (ECOG) performance status of 0–2 and had adequate hepatic and renal function. At baseline, 80.5, 19.1 and 0.4% of patients had an ECOG performance status of 0, 1 and 2, respectively, and 33.3, 47.6 and 19.1% had a low, intermediate and high Hasford score, respectively. Patients were stratified by Hasford score and continued treatment until disease progression or unacceptable toxicity
occurred [28]. Dose interruptions/reductions and dose increases were permitted for adverse events and suboptimal response, respectively [28, 29]. The primary endpoint was the confirmed complete cytogenetic response (CCyR) rate by 12 months after the start of treatment [28]. Secondary endpoints were the major molecular response (MMR) rate at any time (defined as a BCR-ABL1 transcript level of B0.1%), the time to confirmed CCyR and the time to MMR. Efficacy was assessed in the intent-to-treat (ITT) population [28]. The confirmed CCyR rate by 12 months and the MMR rate at any time were significantly higher in patients receiving dasatinib than in those receiving imatinib (Table 1) [28]. Significantly higher CCyR and MMR rates were also seen by 12 months with dasatinib versus imatinib (Table 1). The times to both confirmed CCyR and MMR were significantly (p \ 0.0001) shorter with dasatinib than with imatinib [28]. The median time to confirmed CCyR was 3.1 months in dasatinib recipients and 5.8 month in imatinib recipients [30] and the median time to MMR was 15 and 36 months in the corresponding treatment groups [29]. Cumulative MMR rates by 2, 3 and 5 years were 64, 69 and 76%, respectively, with dasatinib and 46, 55 and 64%, respectively, with imatinib (Table 1) [29–31]. Progression to the accelerated or blast phases of CML had occurred in 1.9% of dasatinib recipients versus 3.5% of imatinib recipients by 12 months [28], in 2.3 vs. 5.0% by 2 years [29], in 3.1 vs. 5.0% by 3 years [30] and in 4.6 vs. 7.3% by 5 years [31]. Estimated PFS and OS rates at 12 months, 2 years and 3 years in patients receiving dasatinib and imatinib are shown in Table 1 (statistical analysis not reported) [28–30]. At 5 years, the estimated PFS (85 vs. 86%) and OS (91 vs. 90%) rates did not significantly differ between dasatinib and imatinib recipients (Table 1) [31]. After 3 months’ treatment, significantly more dasatinib than imatinib recipients had a BCR-ABL1 transcript level of B10% (84 vs. 64%; p\0.0001) [30]. In both dasatinib and imatinib recipients, 5-year PFS and OS rates were significantly (p \ 0.01) higher in patients who had a BCR-ABL1 transcript level of B10 vs. [10% at 3 months [31]. In patients with a BCR-ABL1 transcript level of B10 vs. [10% at 3 months, the 5-year CCyR rate was 94 vs. 41% in dasatinib recipients and 92 vs. 59% in imatinib recipients and the 5-year MMR rate was 87 vs. 38% in dasatinib recipients and 81 vs. 41% in imatinib recipients. Transformation rates also appeared numerically lower in patients with a BCR-ABL1 transcript level of B10 vs. [10% at 3 months [31]. In patients with low-, intermediate- and high-risk Hasford scores, MMR rates were 73, 61 and 57%, respectively, with dasatinib and 56, 50 and 38%, respectively, with imatinib after a minimum 2 years of follow-up [29].
G. M. Keating Table 1 Efficacy of dasatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results of the phase 3 DASISION trial Minimum follow-up
Treatmenta (mg od)
Confirmed CCyR rate by time point (% of pts)
CCyR rate by time point (% of pts)
MMR rate by time point (% of pts)
12 months [28]
DAS 100
77*,b
83**,c
46***,c
52***
96
97
IMA 400
b
66
72
28
34
97
99
DAS 100
80d
86**,c,d
64***,c,d
94
95
IMA 400
d
74
46d
92
95
DAS 100
82d
69***,c,d
91
94
IMA 400
77d
55d
91
93
DAS 100
83d,e
76*,c,d
85
91
IMA 400
79d,e
64d
86
90
2 years [29] 3 years [30] 5 years [31]
d
82
MMR rate at any time (% of pts)
Estimated PFS rate (% of pts)
Estimated OS rate (% of pts)
CCyR complete cytogenetic response, DAS dasatinib, IMA imatinib, MMR major molecular response, od once daily, OS overall survival, PFS progression-free survival, pts patients * p \ 0.01, ** p B 0.001, *** p \ 0.0001 vs. IMA a
259 pts were randomized to receive DAS and 260 pts were randomized to receive IMA
b
Primary endpoint
c
Post hoc statistical analysis
d
Cumulative rate
e
Data obtained from the US prescribing information [20]
After a minimum 3 years’ follow-up, mutations were detected in 10% of dasatinib recipients and 9% of imatinib recipients, according to the results of a retrospective mutational analysis [32]. Mutations affected 4 sites in dasatinib recipients and 12 sites in imatinib recipients, multiple mutations affected one dasatinib recipient and six imatinib recipients, and the T315I mutation was detected in 11 dasatinib recipients and in no imatinib recipients [32]. Subgroup analyses revealed that the efficacy profile of dasatinib in east Asian [25] and Japanese [33] patients appeared consistent with that seen in the overall DASISION population. 4.2 In Chronic- or Advanced-Phase CML or Ph1 ALL Resistant or Intolerant to Imatinib Based on the results of phase 2 trials, a dasatinib regimen of 70 mg twice daily was initially approved for use in imatinib-resistant or -intolerant patients with chronic-phase CML [34], accelerated-phase CML [35], blast-phase CML [36] or Ph? ALL [37]. Although once-daily administration of dasatinib is associated with only transient inhibition of BCR-ABL1, a phase 1 dose-escalating trial demonstrated that once-daily dasatinib induced haematological and cytogenetic responses in patients with CML or Ph? ALL resistant or intolerant to imatinib [38]. Once-daily administration of dasatinib also appeared to be better tolerated than twice-daily dasatinib (Sect. 5). Subsequently, phase 3 trials (CA180-034 [39] and CA180-035 [40–42]) examined the use of once-daily dasatinib regimens in patients with
CML or Ph? ALL resistant or intolerant to imatinib. These phase 3 trials, which led to the approval of dasatinib regimens of 100 mg once daily in chronic-phase CML and 140 mg once daily in advanced-phase CML and Ph? ALL (Sect. 6), are the focus of this section. 4.2.1 Chronic-Phase CML The randomized, open-label, multinational, dose-optimization CA180-034 trial examined the efficacy of dasatinib 100 mg once daily, dasatinib 50 mg twice daily, dasatinib 140 mg once daily and dasatinib 70 mg twice daily in imatinib-resistant or -intolerant patients with chronic-phase CML [39]. Patients were stratified by imatinib status (resistant or intolerant) and continued treatment until disease progression or unacceptable toxicity occurred; dose interruptions and reductions were permitted to manage adverse events and dose increases were permitted for suboptimal response [39]. After 2 years, patients receiving twice-daily dasatinib regimens were permitted to switch to once-daily dasatinib regimens [43]. At baseline, 41% of patients had received prior imatinib therapy for[3 years, 74% of patients were imatinib resistant and 52, 26 and 5% of patients had received prior interferon-a, chemotherapy or haematopoietic stem cell transplantation (HSCT), respectively [39]. The primary endpoint was the major cytogenetic response (MCyR) rate in imatinib-resistant patients (minimum follow-up of 6 months), with the primary analysis examining if once-daily dasatinib was noninferior to twicedaily dasatinib and the secondary analysis examining the
Dasatinib: A Review Table 2 Efficacy of dasatinib in chronic-phase chronic myeloid leukaemia resistant or intolerant to imatinib: results of the phase 3 CA180-034 trial Minimum follow-up 6 months [39]
2 years [44]
6 years [45]
7 years [43]
Treatmenta (mg)
Response rates [IMA resistant/intolerant] (% of pts) MCyR
CCyR
CHR
MMR
DAS 100 od
59 [53/74]
41 [34/63]
90 [86/100]
DAS 50 bid
54 [47/73]
42 [35/61]
92 [91/93]
DAS 140 od
56 [50/70]
44 [36/68]
86 [85/86]
DAS 70 bid
55 [51/68]
45 [39/61]
87 [87/85]
b
Estimated PFS rate (% of pts)
Estimated OS rate (% of pts)
DAS 100 od
63 [59/77]
50 [44/67]
92 [89/100]
37 [35/43]
80
91
DAS 50 bid
61 [56/77]
50 [42/73]b
92 [92/93]
38 [32/54]
76
90
DAS 140 od
63 [58/77]
50 [42/73]b
87 [86/89]
38 [30/67]
75
94
DAS 70 bid
61 [57/74]
54 [48/69]b
88 [89/86]
38 [34/51]
76
88
DAS 100 od
43 [40/49]
49
71
DAS 50 bid
40 [35/55]
51
74
DAS 140 od
40 [30/68]
40
77
DAS 70 bid
40 [37/50]
47
70
DAS 100 od
46 [43/55]
42
65
DAS 50 bid
44 [39/59]
NR
70
DAS 140 od DAS 70 bid
44 [34/75] 46 [42/57]
NR 44
73 68
bid twice daily, CCyR complete cytogenetic response, CHR complete haematological response, DAS dasatinib, IMA imatinib, MCyR major cytogenetic response, MMR major molecular response, NR not reported, od once daily, OS overall survival, PFS progression-free survival, pts patients a b
167, 168, 167 and 168 pts were randomized to receive DAS 100 od, DAS 50 bid, DAS 140 od and DAS 70 bid, respectively Post hoc analysis
noninferiority of dasatinib 100 vs. 140 mg/day [39]. Efficacy was assessed in the ITT population [39]. In terms of the MCyR rate after a minimum 6 months’ follow-up in imatinib-resistant patients, once-daily dasatinib was noninferior to twice-daily dasatinib (52 vs. 49%), with the lower limit of the 95% CI for the between-treatment difference (2.8%; 95% CI -6.0 to 11.6) exceeding the noninferiority margin of -15% [39]. Dasatinib 100 mg/day was also noninferior to dasatinib 140 mg/day in terms of the MCyR rate in imatinib-resistant patients (50 vs. 51%), with a between-treatment difference of -0.8% (95% CI -9.6 to 8.0) [39]. In general, cytogenetic and haematological response rates appeared consistent across treatment groups, regardless of schedule (once or twice daily) or dosage (100 or 140 mg/day), after 6 months [39] and 2 years’ [44] followup (Table 2). Cytogenetic response rates appeared deeper in imatinib-intolerant patients than in imatinib-resistant patients (Table 2) [39, 44]. BCR-ABL1 mutation status did not appear to affect cytogenetic or haematological response rates [39, 44], although all patients with dasatinib-resistant mutations had discontinued treatment by 6 years [45]. The MMR rate was 37, 43 and 46% after 2, 6 and 7 years’ follow-up, respectively, in patients receiving dasatinib 100 mg once daily (Table 2) [43–45].
Progression to the accelerated or blast phases of CML had occurred in four and ten evaluable patients receiving dasatinib 100 mg once daily after 2 and 6 years’ follow-up, respectively [44, 45]. In patients receiving dasatinib 100 mg once daily, estimated PFS rates at 2, 6 and 7 years were 80, 49 and 42%, respectively, and estimated OS rates at these time points were 91, 71 and 65%, respectively (Table 2) [43–45]. Achieving a molecular [43, 45] or cytogenetic [45] response with dasatinib 100 mg once daily at 3 or 6 months was predictive of longer-term PFS and OS. For example, 6-year PFS and OS rates were significantly (p \ 0.0001) higher in patients achieving BCR-ABL1 transcript level of B10 vs. [10% at 3 months [45]. 4.2.2 Advanced-Phase CML or Ph? ALL The randomized, open-label, multinational CA180-035 trial compared the efficacy of dasatinib 140 mg once daily with that of dasatinib 70 mg twice daily in patients with accelerated-phase CML (n = 317) [40], blast-phase CML (n = 210) [41] or Ph? ALL (n = 84) [42] resistant or intolerant to imatinib. Patients had to have an ECOG performance status of 0–2 and adequate hepatic and renal function to be eligible for inclusion [40–42]. Among
G. M. Keating Table 3 Efficacy of oral dasatinib in patients with advanced-phase chronic myeloid leukaemia or Ph? acute lymphoblastic leukaemia resistant or intolerant to imatinib: results of the phase 3 CA180-035 trial Cohort
Accelerated-phase CML [40] Myeloid blast-phase CML [41] Lymphoid blast-phase CML [41] Ph? ALL [42]
Treatment (mg)
No. of pts
Confirmed haematological response rates (% of pts)
Cytogenetic response rates (% of pts)
MaHRa
OHR
CHR
NEL
MCyR
CCyR
DAS 140 od
158
66
75
47
19
39
32
DAS 70 bid
159
68
76
52
16
43
33
DAS 140 od
75
28
17
11
25
14
DAS 70 bid
74
28
18
11
28
21
DAS 140 od
33
42
21
21
50
38
DAS 70 bid
28
32
14
18
40
36
DAS 140 od
40
38
48
33
5
70
50
DAS 70 bid
44
32
41
25
7
52
39
ALL acute lymphoblastic leukaemia, bid twice daily, CCyR complete cytogenetic response, CHR complete haematological response, CML chronic myeloid leukaemia, DAS dasatinib, MaHR major haematological response, MCyR major cytogenetic response, NEL no evidence of leukaemia, od once daily, OHR overall haematological response, pts patients a
Primary endpoint
patients with accelerated-phase CML, 52% had received prior imatinib for [3 years, 74% were imatinib resistant and 54, 44 and 9% had received prior interferon-a, chemotherapy or HSCT, respectively [40]. Among patients with blast-phase CML, 27% had received prior imatinib for [3 years, 84% were imatinib resistant and 60, 36, 16 and 10% had received prior chemotherapy, interferon-a, HSCT or radiotherapy, respectively [41]. Among patients with Ph? ALL, 4% had received prior imatinib for [3 years, 81% were imatinib resistant and 95, 27 and 27 and 7% had received prior chemotherapy, HSCT, radiotherapy or interferon-a, respectively [42]. Patients were stratified by the phase and type of disease and imatinib status (resistant or intolerant) and randomized to receive dasatinib 140 mg once daily or 70 mg twice daily until disease progression, unacceptable toxicity or study withdrawal [40–42]. Dose interruptions and reductions were permitted to manage adverse events and dose increases were permitted for suboptimal response [40–42]. The median durations of treatment with once-daily versus twice-daily dasatinib were 15.4 vs. 12 months in accelerated-phase CML [40], 3.3 vs. 3.1 months in myeloid blastphase CML [41], 3.4 vs. 3.6 months in lymphoid blastphase CML [41] and 3.4 vs. 2.5 months in Ph? ALL [42]. The primary endpoint was the major haematological response (MaHR) rate [40–42]. The CA180-035 trial was powered to assess the noninferiority of once- versus twicedaily dasatinib for the primary endpoint across the entire study population [40, 41]. Formal statistical analyses were generally not conducted for subgroups, although post hoc statistical analysis was reported for some PFS and OS outcomes [40, 41]. Efficacy was assessed in the ITT population [41]. The median duration of follow-up was 15 months in accelerated-phase CML [40]; patients with blast-
phase CML or Ph? ALL were followed for a minimum of 2 years [41, 42]. Across the entire study population, dasatinib 140 mg once daily was shown to be noninferior to dasatinib 70 mg twice daily in terms of MaHR (primary endpoint) [20]. In patients with accelerated-phase CML, the MaHR rate with once-daily versus twice-daily dasatinib was 66 vs. 68% (Table 3) [40]. Most MaHRs were achieved within 4 months, with a median time to MaHR of 1.9 months. The median duration of MaHR had not been reached at the time of data analysis; it was estimated that MaHR would be sustained for 24 months in 65 vs. 60% of patients receiving once-daily versus twice-daily dasatinib [40]. In patients with myeloid blast-phase CML, the MaHR rate with both once- and twice-daily dasatinib was 28% (Table 3) [41]. The median time to MaHR with onceversus twice-daily dasatinib was 2 vs. 3 months, with a median duration of MaHR of 8 vs. 9 months [41]. In patients with lymphoid blast-phase CML, the MaHR rate with once- versus twice-daily dasatinib was 42 vs. 32% (Table 3), with a median time to MaHR of 2 vs. 2 months and a median duration of MaHR of 5 vs. 8 months [41]. In patients with Ph? ALL, the MaHR rate with oncedaily versus twice-daily dasatinib was 38 vs. 32% (Table 3) [42]. All MaHRs were achieved within 4 months, with a median time to MaHR with once-daily versus twicedaily dasatinib of 1.2 vs. 1.0 months and a median duration of MaHR of 4.6 vs. 11.5 months [42]. Other haematological and cytogenetic response rates in patients with advanced-phase CML and Ph? ALL resistant or intolerant to imatinib are shown in Table 3 [40–42]. MaHR and MCyR rates were not affected by baseline mutation status (i.e. no BCR-ABL1 mutation, any BCRABL1 mutation or excluding T315I mutations) in patients
Dasatinib: A Review
with accelerated-phase CML [40]. The presence of baseline BCR-ABL1 mutations did not appear to affect the MaHR rate in patients with blast-phase CML [41] or the MCyR rate in patients with Ph? ALL [42], although none of the patients with T315I achieved MaHR [41] or MCyR [42]. In patients receiving once- versus twice-daily dasatinib, median PFS was 25.1 vs. 26.0 months in accelerated-phase CML [40], 3.8 vs. 3.7 months in myeloid blast-phase CML [41] and 4.7 vs. 4.8 months in lymphoid blast-phase CML [41]. Median PFS did not significantly differ between onceand twice-daily dasatinib in Ph? ALL (4.0 vs. 3.1 months) [42]. Estimated 24-month PFS rates did not significantly differ between once- and twice-daily dasatinib in accelerated-phase CML (51 vs. 55%) [40]. Estimated 24-month PFS rates with once- versus twice-daily dasatinib were 11 vs. 18% in myeloid blast-phase CML and were not estimable in lymphoid blast-phase CML [41]. In patients with accelerated-phase CML, median OS had not yet been reached with once-daily dasatinib and was 30.7 months with twice-daily dasatinib [40]. In patients receiving once- versus twice-daily dasatinib, median OS was 7.9 vs. 7.7 months in myeloid blast-phase CML [41] and 11.4 vs. 9.0 months in lymphoid blast-phase CML [41]. Median OS did not significantly differ between once- and twice-daily dasatinib in Ph? ALL (6.5 vs. 9.1 months) [42]. Estimated 24-month OS rates did not significantly differ between once- and twice-daily dasatinib in accelerated-phase CML (63 vs. 72%) [40]. Estimated 24-month OS rates with once- versus twice-daily dasatinib were 24 vs. 28% in myeloid blast-phase CML and 21 vs. 16% in lymphoid blast-phase CML [41].
5 Tolerability and Safety of Dasatinib 5.1 General Adverse Event Profile In patients with newly diagnosed [30] or imatinib-resistant or -intolerant [43] chronic-phase CML, most adverse events first occurred within 12 [30] or 24 [43] months of treatment with dasatinib 100 mg once daily. Over longerterm follow-up (5 [31] or 7 [43] years), no new safety signals emerged [31] and most adverse events were of grade 1 or 2 severity [31, 43]. In patients with imatinibresistant or -intolerant advanced-phase CML or Ph? ALL who received dasatinib 140 mg once daily, most nonhaematological drug-related adverse events were of grade 1 or 2 severity [40–42]. Discontinuation because of drug-related adverse events occurred in 16% of dasatinib recipients and 7% of imatinib recipients after 5 years’ follow-up in patients with newly diagnosed chronic-phase CML in the DASISION trial [31], in 24% of imatinib-resistant or -intolerant patients with
chronic-phase CML who received dasatinib 100 mg once daily in the 7-year analysis of the CA180-034 trial [43] and in 9–20% of imatinib-resistant or -intolerant patients with advanced-phase CML who received dasatinib 140 mg once daily in the CA180-035 trial [40, 41]. Myelosuppression was the most commonly reported drug-related adverse event in dasatinib recipients [31, 40–42, 45]. In patients with newly diagnosed, chronic-phase CML who received dasatinib 100 mg once daily or imatinib 400 mg once daily in the DASISION trial, grade 3 or 4 neutropenia occurred in 29 and 24% of patients, grade 3 or 4 thrombocytopenia occurred in 22 and 14%, and grade 3 or 4 anaemia occurred in 13 and 9% after 5 years’ follow-up [31]. Grade 3 or 4 neutropenia, thrombocytopenia and anaemia occurred in 36, 24 and 13% of patients, respectively, with imatinib-resistant or -intolerant chronic-phase CML who received dasatinib 100 mg once daily in the 6-year analysis of the CA180-034 trial [45]. Significantly (p \ 0.05) lower incidences of all-grade neutropenia (64 vs. 73–77%) and grade 3 or 4 thrombocytopenia (23 vs. 36–41%) were seen with dasatinib 100 mg once daily than with the other dasatinib regimens after 2 years’ follow-up in the CA180034 trial [44]. Among patients with imatinib-resistant or -intolerant advanced-phase CML or Ph? ALL who received dasatinib 140 mg once daily in the CA180-035 trial, grade 3 or 4 neutropenia occurred in 59–79% of patients, grade 3 or 4 thrombocytopenia occurred in 64–85% and grade 3 or 4 anaemia occurred in 35–76% [40–42]. It should be noted that the myelosuppression that occurs during TKI therapy reflects both the suppression of the leukaemic clone and inhibition of non-leukaemic haematopoiesis [46]. Following TKI-induced reduction of leukaemic haematopoiesis, normal stem and progenitor cells need time to recover and repopulate the bone marrow [46]. Thus, the myelosuppression seen during dasatinib therapy was generally reversible and could be managed with dose interruption or reduction [20, 21, 39], with growth factors and/or transfusions also administered if necessary [39]. Given that grade 3 or 4 myelosuppression appeared more frequent in advanced-phase CML or Ph? ALL than in chronic-phase CML, it is recommended that complete blood counts be performed weekly for the first 2 months and then monthly or as clinically indicated in patients with advanced-phase CML or Ph? ALL, and every 2 weeks for 12 weeks then every 3 months or as clinically indicated in patients with chronic-phase CML [20, 21]. The most common nonhaematological drug-related adverse events (all grades; incidence of C10%) occurring within the first 5 years of follow-up in patients with newly diagnosed, chronic-phase CML in the DASISION trial were fluid retention (38% of dasatinib recipients vs.
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45% of imatinib recipients), diarrhoea (22 vs. 23%), rash (14 vs. 18%), musculoskeletal pain (14 vs. 17%), headache (14 vs. 11%), fatigue (11 vs. 12%), abdominal pain (11 vs. 8%), nausea (10 vs. 25%), myalgia (7 vs. 12%), arthralgia (7 vs. 10%), muscle spasms (5 vs. 21%) and vomiting (5 vs. 12%) [20, 28]. All-grade pleural effusion was reported in 28% of dasatinib recipients and 0.8% of imatinib recipients and all-grade superficial localized oedema was reported in 14 and 38% of patients in the corresponding treatment groups [20, 28]. Few dasatinib recipients (B5%) experienced nonhaematological drugrelated adverse events of grade 3 or 4 severity in the 5-year DASISION analysis [20]. A generally similar profile of nonhaematological drugrelated adverse events was seen in patients with imatinibresistant or -intolerant chronic-phase CML who received dasatinib 100 mg once daily in the CA180-034 trial [45]. After a minimum 7 years of follow-up, the most common nonhaematological drug-related adverse events (all grades; reported in [20% of patients) were fluid retention (48%), headache (33%), diarrhoea (28%), fatigue (26%), dyspnoea (24%) and musculoskeletal pain (22%); pleural effusion, superficial localized oedema and pericardial effusion were reported in 28, 22 and 3% of patients, respectively [20]. A significantly (p\0.05) lower incidence of all-grade pleural effusion (14 vs. 23–25%) was seen with dasatinib 100 mg once daily than with the other dasatinib regimens after 2 years’ follow-up [44]. In the CA180-035 trial, the most common nonhaematological drug-related adverse events (all grades; incidence of C10%) reported in patients with imatinib-resistant or -intolerant advanced-phase CML or Ph? ALL who received dasatinib 140 mg once daily included fluid retention (21–34%), diarrhoea (18–35%), nausea (19–28%), vomiting (11–20%), infection (10–18%), haemorrhage (15–26%), pyrexia (11–15%), febrile neutropenia (4–13%), musculoskeletal pain (11–13%), dyspnoea (10–20%), fatigue (9–20%), headache (10–27%) and rash (5–21%); pleural effusion was reported in 18–21% of patients [40–42]. Patients with accelerated-phase CML who received dasatinib 140 mg once daily were significantly less likely than those receiving dasatinib 70 mg twice daily to experience all-grade pleural effusion (20 vs. 39%; p \ 0.001) [40]. Death had occurred in 10% of dasatinib recipients and 10% of imatinib recipients after 5 years’ follow-up in patients with newly diagnosed chronic-phase CML in the DASISION trial; infection was the cause of death in 11 dasatinib recipients and one imatinib recipient [31]. Death had occurred in 31% of dasatinib 100 mg once daily recipients after 7 years’ follow-up in imatinib-resistant or -intolerant patients with chronic-phase CML in the CA180-034 trial [43].
5.2 Specific Adverse Events of Interest Most cases of pleural effusion reported in dasatinib recipients were of mild to moderate severity [20, 31, 40]. Grade 3 or 4 drug-related pleural effusion occurred in 3–7% of patients receiving dasatinib 100 or 140 mg once daily [31, 40–43]. Pleural effusion was usually managed with dose interruption or reduction, administration of diuretics or corticosteroids, and/or thoracentesis [31, 39]. Discontinuation of treatment because of pleural effusion was reported in 4–7% of patients receiving dasatinib 100 or 140 mg once daily [31, 40, 43]. Patients with symptoms of pleural effusion or fluid retention (e.g. new or worsened dyspnoea, pleuritic chest pain, dry cough) should be promptly evaluated [20, 21]. The risk of pulmonary arterial hypertension (PAH) may be increased by dasatinib [20], and there may be an association between pleural effusion and pulmonary hypertension (PH) [31]. More information is needed concerning the mechanism underlying dasatinib-related PAH; inhibition of SRC kinase by dasatinib has been suggested as a possible mechanism, although PAH may also represent an idiosyncratic reaction or be related to pre-existing conditions or prior therapies causing vascular damage or inflammation [47]. PH was reported in 5% of dasatinib 100 mg once daily recipients in the 5-year DASISION analysis; however, right heart catheterization was performed in only one dasatinib recipient, and findings did not support a diagnosis of PAH [31]. PH occurred in 2% of patients receiving dasatinib 100 mg once daily in the 7-year CA180-034 analysis, with PAH confirmed by right heart catheterization reported in one patient [43]. Cases of confirmed PAH have also been reported in the postmarketing setting in patients receiving dasatinib [47]. PAH was usually completely or partially reversible following discontinuation of dasatinib [47], although fatal outcomes have also been reported [48]. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease before starting and during dasatinib treatment [20, 21]. Dasatinib should be permanently discontinued if PAH is confirmed [20, 21]. Low rates of arterial ischaemic events were reported with dasatinib [31, 43]. Cardiovascular ischaemic events, transient ischaemic attack and peripheral arterial disease were reported in 4, 1 and 0%, respectively, of patients receiving dasatinib 100 mg once daily in the 5-year DASISION analysis [31], and cardiovascular ischaemic events, cerebrovascular events and peripheral vascular events were reported in 4, 3 and 0%, respectively, of patients receiving dasatinib 100 mg once daily in the 7-year CA180-034 analysis [43].
Dasatinib: A Review
QTc interval prolongation was reported infrequently in dasatinib recipients in clinical trials [20, 21, 28]. For example, a QTc interval of [500 ms occurred in one (0.4%) dasatinib recipient and one (0.4%) imatinib recipient in the 12-month DASISION analysis [28]. It should be noted that the DASISION [28], CA180-034 [39] and CA180-035 [40] trials excluded patients with uncontrolled or significant cardiovascular disease, including a QTc interval of [450 ms at baseline [28, 39] or a history of congenital long QT syndrome [39]. The risk of QTc interval prolongation may be increased in patients with hypokalaemia or hypomagnesaemia, in patients with congenital long QT syndrome, in patients taking antiarrhythmics or other agents that lead to QT interval prolongation and in patients who have received cumulative high-dose anthracycline therapy [20, 21]. Hypokalaemia and hypomagnesaemia should be corrected prior to the administration of dasatinib [20, 21], and the EU SPC recommends that dasatinib be administered with caution to patients who have or who may develop QTc interval prolongation [21]. Dasatinib may induce platelet dysfunction [22] (see Sect. 2). Most bleeding-related adverse events occurred in patients receiving dasatinib who had grade 3 or 4 thrombocytopenia [20, 21]. The EU SPC recommends that caution be exercised in dasatinib recipients required to take platelet inhibitors or anticoagulants [21]. Reactivation of hepatitis B has been reported in patients who are chronic carriers of hepatitis B virus (HBV) who have received BCR-ABL1 TKIs [21], including dasatinib [49]. The EU SPC recommends that patients be tested for HBV infection before starting treatment with dasatinib [21]. HBV carriers who require treatment with dasatinib should be closely monitored for signs and symptoms of active HBV infection during dasatinib therapy and for several months after treatment has stopped [21].
6 Dosage and Administration of Dasatinib In the EU, dasatinib is approved for the treatment of adults with newly diagnosed Ph? chronic-phase CML; chronic-, accelerated- or blast-phase CML with resistance or intolerance to prior therapy including imatinib; and Ph? ALL or lymphoid blast-phase CML with resistance or intolerance to prior therapy [21]. In the US, dasatinib is approved for the treatment of adults with newly diagnosed Ph? CML in the chronic phase; chronic-, accelerated- or myeloid or lymphoid blast-phase Ph? CML with resistance or intolerance to prior therapy including imatinib; or Ph? ALL with resistance or intolerance to prior therapy [20]. The recommended starting dosage of dasatinib is 100 mg once daily in chronic-phase CML and 140 mg once daily in accelerated-phase CML, myeloid or lymphoid blast-phase
CML and Ph? ALL [20, 21]. Dose escalation may be considered in patients with a suboptimal response to dasatinib [20, 21]. Dose interruption, dose reduction and/or discontinuation may be needed to manage myelosuppression, and dose interruption and/or dose reduction may be needed to manage nonhaematological adverse reactions [20, 21]. Dasatinib can be taken without regard to food [20]. Dasatinib therapy was continued until disease progression or unacceptable toxicity in clinical trials. It is not known how stopping dasatinib therapy after a cytogenetic response (including CCyR) or MMR has been achieved might affect long-term outcomes [20, 21]. Local prescribing information should be consulted for more information concerning precautions and warnings related to dasatinib and dosage adjustments for suboptimal response, adverse reactions and drug interactions.
7 Place of Dasatinib in the Management of CML and Ph1 ALL US National Comprehensive Cancer Network (NCCN) [1] and European LeukemiaNet [3] guidelines recommend the use of dasatinib, imatinib or nilotinib for the first-line treatment of chronic-phase CML. The goal of TKI therapy is to achieve CCyR within 12 months of starting treatment and to prevent progression to the accelerated or blast phase [1]. The response to TKI therapy should be monitored during treatment; the BCR-ABL1 transcript level and/or cytogenetic response should be assessed every 3 months. Factors such as patient adherence, drug interactions and mutational status should be assessed in patients with a suboptimal response to treatment, and treatment should be adjusted as necessary. Options for patients with accelerated- or blast-phase CML who have progressed following prior TKI therapy include any TKI that was not used before progression, followed by HSCT, if feasible [1, 3]. In patients with CML and cytogenetic or haematological resistance to primary treatment with imatinib or nilotinib, dasatinib is recommended as a second-line and subsequent therapy option (depending on the results of mutational analysis) [1, 50]. NCCN guidelines also recommend that the use of dasatinib be considered in patients with relapsed/refractory Ph? ALL (depending on the results of mutational analysis) [2]. In the DASISION trial, deeper and faster cytogenetic and molecular responses were seen with first-line dasatinib 100 mg once daily than with first-line imatinib 400 mg once daily in patients with newly diagnosed chronic-phase CML (Sect. 4.1). An early response to first-line treatment (e.g. achieving a BCR-ABL1 transcript level of B10% by 3 months) was predictive of 5-year PFS and OS in this trial. Despite the higher confirmed CCyR and MMR rates achieved by 12 months with dasatinib 100 mg once daily
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versus imatinib 400 mg once daily in DASISION, no significant between-group difference in PFS or OS was seen in the longer term (Sect. 4.1) [31]. One factor that may have contributed to the lack of survival advantage seen with dasatinib is that following discontinuation of imatinib, patients could receive rescue therapy with dasatinib (16% of patients) or nilotinib (9%) [31]. Compared with twice-daily regimens, a regimen of dasatinib 100 mg once daily provided the most favourable benefit-risk profile in imatinib-resistant or -intolerant patients with chronic-phase CML (Sects. 4.2.1, 5), with dasatinib 140 mg once daily also demonstrating efficacy in patients with imatinib-resistant or -intolerant advancedphase CML or Ph? ALL (Sect. 4.2.2). These results show that despite its short elimination half-life (Sect. 3), oncedaily administration of dasatinib is sufficient to induce a clinical response, supporting in vitro findings that continuous BCR-ABL1 inhibition is not required (Sect. 2). Therapeutic drug monitoring has been suggested as a way to optimize efficacy and tolerability in patients receiving dasatinib (and other TKIs) [51]. A dasatinib regimen of 100 mg once daily was associated with the lowest trough plasma concentrations (Ctrough) of dasatinib [52], providing an explanation as to why the risk of pleural effusion was minimized with the dasatinib 100 mg once daily regimen in the CA180-034 trial [53]. The OPTIMdasatinib trial successfully used a dose optimization strategy based on Ctrough values to minimize the risk of pleural effusion in patients considered at high risk (i.e. those with Ctrough values of C3 nmol/L) [54]. Several trials have demonstrated the feasibility of discontinuing dasatinib therapy in patients with chronic-phase CML who have achieved a deep molecular response, including DADI [55], DASFREE [56], D-STOP [57] and OPTIM-STOP [58]. For example, DADI included patients with chronic-phase CML who had maintained a deep molecular response on dasatinib therapy for C1 year [55]. Following discontinuation of dasatinib, the treatment-free remission rate was 49% at 6 months (primary endpoint) and 48% at 12 months [55]. NCCN guidelines state that discontinuation of TKI therapy with careful monitoring is feasible in selected patients with chronic-phase CML [1]. The TKIs differ in terms of their molecular mechanisms of action and target profiles, which may explain in part the differences between these agents in terms of their tolerability and resistance profiles [5]. For example, mild to moderate pleural effusion and (rarely) PAH are mainly associated with dasatinib, whereas nilotinib is particularly associated with QTc interval prolongation and peripheral arterial occlusive disease [1, 3]. Myelosuppression was the most commonly occurring grade 3 or 4 adverse event in patients receiving dasatinib (Sect. 5). In patients receiving dasatinib, adverse events were usually managed with dose
interruption or reduction and appropriate medical intervention or supportive measures. Dose interruption or reduction appeared to have minimal impact on outcomes and survival in dasatinib recipients [59]. Similar to imatinib, point mutations in the BCR-ABL1 kinase domain are the most frequent mechanism of resistance to dasatinib and nilotinib [1]. Besides T315I, the BCR-ABL1 mutations F317L/V/I/C, T351A and V299L are associated with dasatinib resistance and E255K/V, F359V/C/I and Y253H are associated with nilotinib resistance [1, 9, 50]. Given these differences, patients with imatinib-resistant CML who develop nilotinib resistance may still respond to dasatinib (and vice versa) [5]; therefore, mutational analysis is a useful tool when selecting subsequent TKI therapy in patients with a suboptimal response to first- or second-line TKI therapy [1, 50]. For example, dasatinib is recommended as second-line or subsequent therapy in patients who have previously received imatinib and/or nilotinib and have the mutations E255K/V, F359V/C/I and Y253H, nilotinib is recommended as second-line or subsequent therapy in patients who have previously received imatinib and/or dasatinib and have the mutations F317L/V/I/C, T351A and V299L, bosutinib is recommended as second-line or subsequent therapy in patients who have previously received imatinib, nilotinib and/ or dasatinib and have the mutations E255K/V, F317L/V/I/C, F359V/C/I, T351A or Y253H, and ponatinib is recommended in patients with the T315I mutation or who have not responded to at least two prior TKIs [1]. In conclusion, dasatinib is an important option for the treatment of patients with newly diagnosed chronic-phase CML and for imatinib-resistant or -intolerant patients with chronic- or advanced-phase CML or Ph? ALL. Data Selection Dasatinib: 334 records identified Duplicates removed
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Excluded by author (e.g. not randomized trials; review; duplicate data; small patient number; phase 1/2 trials)
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Search Strategy: Embase, MEDLINE and PubMed from 2011 to present. Previous Adis Drug Evaluation published in 2011 was hand-searched for relevant data. Clinical trial registries/databases and websites were also searched for relevant data. Key words were Dasatinib, Sprycel, BMS-354825, chronic, myeloid, myelogenous, myelocytic, granulocytic, CML, Philadelphia, acute. Records were limited to those in English language. Searches last updated 5 December 2016.
Dasatinib: A Review Acknowledgements During the peer review process, the manufacturer of dasatinib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit. Compliance with Ethical Standards Funding The preparation of this review was not supported by any external funding. Conflict of interest Gillian M. Keating is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
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