Download Dasatinib 140 mg once daily versus 70 mg twice daily in patients

Research Article
Dasatinib 140 mg once daily versus 70 mg twice daily in patients
with Ph-positive acute lymphoblastic leukemia who failed imatinib:
Results from a phase 3 study
Michael B. Lilly,1* Oliver G. Ottmann,2 Neil P. Shah,3 Richard A. Larson,4 Josy J. Reiffers,5
Gerhard Ehninger,6 Martin C. Müller,7 Aude Charbonnier,8 Eduardo Bullorsky,9 Herve Dombret,10
Mary Brigid Bradley-Garelik,11 Chao Zhu,11 and Giovanni Martinelli12
Dasatinib 70 mg twice daily is indicated for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1 ALL) intolerant or resistant to imatinib. In patients with chronic-phase chronic myelogenous leukemia, once-daily dosing has similar efficacy with improved safety, compared with twice-daily dosing. A
phase 3 study (n 5 611) assessed the efficacy and safety of dasatinib 140 mg once daily versus 70 mg
twice-daily in patients with advanced phase chronic myelogenous leukemia or Ph1 ALL resistant or intolerant to imatinib. Here, results from the Ph1 ALL subset (n 5 84) with a 2-year follow-up are reported.
Patients were randomly assigned to receive dasatinib either 140 mg once daily (n 5 40) or 70 mg twice daily
(n 5 44). The rate of confirmed major hematologic response with once-daily dosing (38%) was similar to
that with twice-daily dosing (32%). The rate of major cytogenetic response with once-daily dosing (70%)
was higher than that with twice-daily dosing (52%). Compared with the twice-daily schedule, the once-daily
schedule had longer progression-free survival (median, 3.0 months versus 4.0 months, respectively) and
shorter overall survival (median, 9.1 months versus 6.5 months, respectively). Overall safety profiles were
similar between two groups, with nonhematologic adverse events being mostly grade 1 or 2. Pleural effusion was less frequent with once-daily dosing than with twice-daily dosing (all grades, 18% versus 32%).
Notably, none of the differences between the two schedules was statistically significant. Compared with the
70 mg twice daily, dasatinib 140 mg once daily had similar overall efficacy and safety in patients with imatinib-resistant or intolerant Ph1 ALL. (clinicaltrials.gov identifier: NCT00123487). Am. J. Hematol. 85:164–170,
C 2009 Wiley-Liss, Inc.
2010. V
Introduction
Approximately 30% of adult acute lymphoblastic leukemia
(ALL) and up to 5% of childhood ALL are characterized by
the presence of the Philadelphia (Ph) chromosome [1]. The
Ph chromosome is formed by a reciprocal translocation
t(9;22)(q34;q11) and results in a chimeric BCR-ABL oncogene [1]. BCR-ABL fusion proteins encoded by the oncogene
are constitutively active tyrosine kinases promoting leukemogenesis [1,2]. The prognosis of patients with Ph-positive ALL
(Ph1 ALL) treated with chemotherapy alone is exceptionally
poor with a less than 10% probability of long-term survival [3].
Imatinib, a selective BCR-ABL kinase inhibitor currently
recommended as a front-line therapy for chronic myelogenous leukemia (CML) in chronic phase (CML-CP), shows
significant antileukaemic activity in patients with refractory
or relapsed Ph1 ALL, including patients who had prior
transplantation [4,5]. However, up to 30% of these patients
are refractory to imatinib, and in responders, relapse occurs
after a median of 2.2 months of imatinib therapy, reflecting
rapid development of resistance to imatinib [5]. Imatinib-resistance is attributed primarily to intrinsic or acquired BCRABL kinase domain mutations resistant to imatinib inhibition
[6–8]. The Src family of kinases (SFKs) that are involved in
the pathophysiology of ALL, but not inhibited by imatinib,
have also been implicated in imatinib-resistance [9,10].
Dasatinib is a multikinase inhibitor, targeting both BCR-ABL
and SFKs [11]. It is 325-fold more potent in vitro than imatinib at inhibiting unmutated BCR-ABL expressed in cells
and is active against all known imatinib-resistant BCR-ABL
mutations except T315I [11,12]. Dasatinib has demonstrated notable clinical efficacy in patients with Ph1 ALL or
CML-blast phase (CML-BP), CML-accelerated phase
(CML-AP), or CML-CP who are resistant or intolerant to
imatinib [4,13–17].
The initially approved dosing schedule of dasatinib for all
phases of CML and Ph1 ALL was 70 mg twice daily. A
large phase 3 study in patients with CML-CP showed that
dasatinib 100 mg once-daily regimen had similar efficacy
1
Chao Family Comprehensive Cancer Center, University of California, Irvine,
Orange, California; 2Hematology and Oncology, Universitatsklinik Frankfurt,
Frankfurt, Germany; 3San Francisco School of Medicine, University of California, San Francisco, California; 4University of Chicago Medical Center, Chicago, Illinois; 5CRLCC Institut Bergonié, Bordeaux, France; 6Medizinische
Klinik, Universitatsklinikum Carl Gustav Carus Dresden, Dresden, Germany;
7
III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany; 8Institut Paoli Calmettes, Marseille, France;
9
Department of Hematology, Hospital Britanico, Buenos Aires, Argentina;
10
Department of Hematology, Hopital Saint Louis, Paris, France; 11BristolMyers Squibb, Wallingford, Connecticut; 12Institute of Hematology and Medical Oncology, University of Bologna, Bologna, Italy
Statement of prior presentation: Presented at the 50th annual meeting of
the American Society of Hematology, San Francisco, CA, December 6–9,
2008 (Larson R, et al., Blood 2008; 112:abstract 2926) and at the 12th Congress of the European Haematology Association, Vienna, Italy, June 7-10,
2007 (Dombret H, et al., Haematologica 2007;92 (Suppl. 1):abstract 859).
Conflict of interest: MBL received research grant from Bristol-Myers Squibb;
OGO received honoraria/consulting fee and research grant from BristolMyers Squibb; NPS received consulting fee from Bristol-Myers Squibb; RAL
received consulting fee and research grant from Bristol-Myers Squibb; JJR,
GE, MCM, and AC have no financial relationships to disclose; EB received
honoraria from Bristol-Myers Squibb; HD received honoraria/consulting fee
from Bristol-Myers Squibb; MBB-G and CZ are employees of Bristol-Myers
Squibb; GM has no financial relationships to disclose.
Contract grant sponsor: Bristol-Myers Squibb.
*Correspondence to: Michael B. Lilly, University of California, 101 The City
Drive, Orange, CA 92868, USA. E-mail: [email protected]
Received for publication 2 December 2009; Accepted 11 December 2009
Am. J. Hematol. 85:164–170, 2010.
Published online 15 December 2009 in Wiley InterScience (www.interscience.
wiley.com).
DOI: 10.1002/ajh.21615
C 2009 Wiley-Liss, Inc.
V
American Journal of Hematology
164
http://www3.interscience.wiley.com/cgi-bin/jhome/35105
research article
with improved safety compared with the 70 mg twice-daily
dosing, forming the basis for approval of the 100 mg oncedaily regimen for CML-CP [18]. A phase 3 dose optimization study was, therefore, undertaken to assess the efficacy
and safety of dasatinib140 mg once daily relative to 70 mg
twice daily in patients with Ph1 ALL, CML-BP, or CML-AP
resistant or intolerant to imatinib. Regimens employing
lower total daily doses of dasatinib (e.g., 100 mg daily)
were not tested in this study due to the theoretical risk of
compromising efficacy in a patient population with aggressive hematologic disease. Data for a minimum of 2 years of
follow-up are now available, and here, we report the results
for the Ph1 ALL subset.
Methods
Study design
This was a randomized, open-label, international phase 3 trial. The
objective of the trial was to compare the efficacy and safety of dasatinib
140 mg once daily with dasatinib 70 mg twice daily in patients with
CML-AP or CML-BP, or Ph1 ALL. A total of 609 patients were stratified
by disease type (CML-AP, n 5 316; CML-BP, n 5 209; or Ph1 ALL,
n 5 84) and imatinib status (resistance or intolerance). Patients within
each stratum were randomly assigned with equal probability to receive
dasatinib either 140 mg once daily (once-daily group) or 70 mg twice
daily (twice-daily group) using a permuted block randomization procedure. The study was conducted in accordance with the Declaration of
Helsinki and was approved by the appropriate local ethics committee at
each trial center. Written, informed consent was obtained from each
patient before enrollment.
Patient eligibility
Patients with Ph1 ALL who had primary or acquired hematologic resistance to imatinib or who were intolerant to imatinib were eligible for
enrollment. Definitions of resistance and intolerance and criteria for
patient eligibility were as described previously [13].
Treatment with dasatinib
Dasatinib was administered orally to patients with Ph1 ALL at either
140 mg once daily or 70 mg twice daily. Treatment continued until disease progression, unacceptable toxicity, or withdrawal at the request of
patient or investigator. Patients were followed for at least 30 days after
the last dose, or until recovery from all toxic effects, whichever was longer. Follow-up visits occurred at least every 4 weeks until all studyrelated toxicities resolved to baseline or to grade 1, stabilized, or were
considered irreversible.
Therapies other than dasatinib were not allowed during the study,
with the exception of hydroxyurea for elevated white blood cell counts.
Colony-stimulating factors and recombinant erythropoietin were permitted at the discretion of the investigator. Patients were supported with
platelet transfusions as required.
Efficacy assessment
Primary efficacy endpoint was major hematologic response (MaHR).
Secondary endpoints included overall hematologic response (OHR),
major cytogenetic response (MCyR), time to and duration of MaHR and
MCyR, progression-free survival (PFS), overall survival (OS), and
safety. Definitions of hematologic responses as described previously
were used [13]. Hematologic responses were assessed by complete
blood count on all patients within 72 hr of initiating treatment, weekly
during weeks 126, at weeks 8 and 12, and monthly thereafter. A
MaHR was defined as a complete hematologic response (CHR) or no
evidence of leukemia (NEL). An OHR was defined as CHR, NEL, or
minor hematologic response (MiHR). A hematologic response was confirmed if all criteria as defined [13] were met consistently for at least 28
days. During this interval, two consecutive assessments showing nonresponse were interpreted as response not achieved, whereas a single
nonresponse between two assessments did not preclude a response
being achieved. Responses that did not meet the above confirmation
criteria were listed as unconfirmed hematologic responses. Patients
with absolute neutrophil count <500/mm3 or platelet count <20,000/
mm3 were classified as not achieving a hematologic response. Hematologic response duration was measured from the first day the criteria
were met until the date treatment was discontinued due to progression
or death.
Cytogenetic responses were assessed by bone-marrow aspirates/
biopsies conducted every month for the first 3 months and every 3
months thereafter. Standard definitions of cytogenetic response (CyR)
American Journal of Hematology
were used as follows: complete CyR (CCyR), 0% Ph1 metaphases;
partial CyR (PCyR), >0–35% Ph1 metaphases; minor CyR, >35265%
Ph1 metaphases; minimal CyR, >65295% Ph1 metaphases; and no
CyR, >95–100% Ph1 metaphases. A minimum of 20 metaphase cells
was required. A major CyR (MCyR) was defined as either a CCyR or
PCyR.
Patients were considered to have undergone a progression if, after
starting the maximum dasatinib dose, any of the following had
occurred: (a) failure to meet the criteria for the best confirmed OHR
over 2 consecutive weeks; (b) no decrease from baseline blast levels in
peripheral blood or bone-marrow over 4 weeks; (c) an increase of 50%
or higher in peripheral blood blast count over 2 weeks; or (d) death
without a report of prior progression.
Progression-free survival (PFS) was defined as the time from randomization until disease progression, death, or treatment discontinuation due to progression. Overall survival (OS) was defined as the time
from randomization until the time of death.
Safety assessment
Assessment of adverse events was carried out every week for the
first 8 weeks of treatment and every other week thereafter and graded
according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Dose modifications
A dose increase to 180 mg once daily or 90 mg twice daily was permitted for patients with any of the following: (a) a rising percentage of
blasts on two consecutive hematologic assessments at least 1 week
apart; (b) lack of OHR within 1 month of treatment initiation; (c) no
MCyR after 3 months; (d) no CCyR after 6 months of treatment; and
(e) loss of OHR achieved with dasatinib. Stepwise dose reduction to
100 mg, then to 80 mg once daily or to 50 mg, then to 40 mg twice
daily was allowed for patients with grade 2 nonhematologic toxicity or
for patients having absolute neutrophil count <500/mm3 and/or platelet
count <10,000/mm3 for >6 weeks and bone-marrow cellularity <10%
with blasts <5%. Treatment was interrupted for patients having absolute neutrophil count <500/mm3 and/or platelet count <10,000/mm3 for
>6 weeks and bone-marrow cellularity >10% with blasts >5%, or febrile neutropenia with signs and symptoms of sepsis.
Mutation analysis
RNA from peripheral blood collected at baseline was extracted with
PAXgene reagent, and reverse transcriptase-polymerase chain reaction
(RT-PCR) was performed to amplify the kinase domain of BCR-ABL
fusion transcript as described [19]. BCR-ABL point mutations were then
analyzed by direct sequencing of both strands of the BCR-ABL amplicon.
Statistical analysis
Two-sided 95% confidence intervals (CIs) for response rates were
calculated using Clopper-Pearson method [20]. PFS, OS, and the time
to and duration of MaHR and MCyR were estimated using KaplanMeier product limit method. For descriptive purpose only, log-rank test
was conducted for PFS and OS on a post-hoc basis. Two-sided 95%
CIs for median values were calculated using the Brookmeyer and
Crowley method [21]. Selected efficacy and adverse event rates were
compared using Fisher’s exact test.
Results
Patient disposition and characteristics
Of the 85 patients enrolled in 44 sites worldwide between
June 2005 and March 2006, 40 patients were randomized
to dasatinib 140 mg once daily and 44 patients to dasatinib
70 mg twice daily; one patient was ineligible (Fig. 1). At 2year follow-up, two patients in the once-daily group and
three patients in the twice-daily group were still on treatment (Fig. 1). The remaining patients discontinued treatment due to multiple causes with disease progression
being the most common cause in both once-daily and
twice-daily dosing groups (Fig. 1). Each group had two discontinuations due to drug-related toxicity with one each for
pleural effusion and gastrointestinal bleeding. There were
two discontinuations for stem cell transplantation in the
once-daily group and three in the twice-daily group. One
treatment-related death was reported in the twice-daily
group.
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TABLE I. Patient Demographics and Disease Characteristics
140 mg once
daily (n 5 40)
Characteristics
Figure 1. The CONSORT flowchart for Ph1 ALL subgroup in study 180-035, a
randomized, open-label, multicenter, international phase 3 trial.
The randomization between the two dosing regimens
was balanced in terms of demographics, disease history
and duration, BCR-ABL mutation, imatinib status, treatment
history, performance status, and hematologic parameters
(Table I). Patients in both groups received extensive prior
treatment, and substantial numbers underwent prior stem
cell transplantation.
Hematologic and cytogenetic responses
Hematologic and cytogenetic response rates are presented in Table II. The rate of confirmed MaHR (primary efficacy endpoint) in the once-daily group (38%) was not significantly different than that in the twice-daily group (32%)
(P 5 0.650). The rates of confirmed CHR and OHR were
similar between once-daily (33% and 48%, respectively)
and twice-daily (25% and 41%, respectively) groups. The
rates of CHR, MaHR, and OHR observed on at least one
occasion during therapy were 50%, 55%, and 66%, respectively, in the once-daily group and 38%, 43%, and 52%,
respectively, in the twice-daily group. Excluding seven
patients whose baseline hematologic status did not permit
standard calculations of response, the rates of confirmed
MaHR and CHR were also similar between the two dosing
schedules (Table III).
A MCyR was more frequent (70%) in the once-daily
group than in the twice-daily group (52%) (P 5 0.120), as
was a CCyR (50% vs. 39%) (Table II). Excluding 32
patients with 0–35% Ph1 cells at study entry, the rates of
MCyR and CCyR in the once-daily group were also higher
than those in the twice-daily group (Table III).
Response by imatinib status
In the imatinib-resistant cohort, the rates of hematologic
and cytogenetic responses in the once-daily group were
similar to the respective responses in the twice-daily group
(Table II). In the imatinib-intolerant cohort, MaHR and
MCyR were both achieved by all six patients in the oncedaily group and by three out of 10 patients in the twicedaily group (Table II). Excluding six imatinib-intolerant
patients in whom at least one valid on-study cytogenetic
assessment could not be made, the MCyR rates were similar for both groups.
Response by BCR/ABL mutation
Baseline mutation data were available for 31 patients in
the once-daily group (26 imatinib-resistant and five imati-
166
Median age (range), years
Male, n (%)
BCR-ABL mutation, n/total (%)
Median disease duration (range), months
Prior imatinib dose, n (%)
400–600 mg/day
Higher than 600 mg/day
Prior imatinib therapy duration, n (%)
Less than1 year
1–3 years
Longer than 3 years
Imatinib status, n (%)
Primary resistance
Acquired resistance
Intolerance
Prior treatment other than imatinib, n (%)
Stem Cell transplant, n (%)
Radiotherapy, n (%)
Chemotherapy, n (%)
Interferon-a, n (%)
ECOG score, n (%)
0
1
2
White blood cell count
Median (range), 31023/mm3
At least 20,000/mm3, n (%)
Platelet count
Median (range), 31023/mm3
Higher than 100,000/mm3, n (%)
Blast in peripheral blood
Median (range), %
At least 15%, n (%)
Blast in bone marrow,
Median (range), %
Extramedullary leukemia, n (%)
Number of disease sitesa
a
51.8
18
17/31
11.5
(17–73)
(45)
(55)
(7.6–49.8)
70 mg twice
daily (n 5 44)
51.0
22
18/34
19.1
(15–80)
(50)
(53)
(4.6–181.9)
11 (29)
28 (73)
16 (28)
36 (64)
21 (52)
19 (48)
0
26 (59)
15 (34)
3 (7)
4
30
6
40
12
11
38
3
3
31
10
44
11
12
42
3
(10)
(75)
(15)
(100)
(30)
(28)
(95)
(8)
16 (40)
14 (35)
10 (25)
(7)
(71)
(23)
(100)
(25)
(27)
(96)
(7)
14 (32)
20 (45)
10 (23)
10.4 (1–189)
10 (25)
9.4 (1–126)
13 (30)
119 (6–425)
19 (48)
73 (5–297)
28 (63)
54 (0–100)
15 (38)
41 (0–92)
19 (43)
56 (0–100)
7 (18)
10
77 (0–100)
7 (18)
7
Some patients had more than one site.
nib-intolerant) and 34 patients in the twice-daily group (26
imatinib-resistant and eight imatinib-intolerant) (Table IV).
Patients with BCR-ABL mutations were equally distributed
between the once-daily (55%) and twice-daily (53%)
groups. Mutations were detectable in 65% (17/26 in each
group) of imatinib-resistant patients, but in one out of 13
imatinib-intolerant patients. Y253H (six in the once-daily
group and eight in the twice-daily group) and E459K (five in
the once-daily group and two in the twice-daily group) were
the most common mutations. The rates of MCyR were similar for patients with or without BCR-ABL mutations, irrespective of dose schedule (Table IV). Mutations were
located predominantly in the P-loop and marked proportions of these patients achieved MCyR in both groups. As
expected, three patients with the T315I mutation had no
response to dasatinib. Patients with other specific mutations that are highly resistant to imatinib achieved MCyR
(Table IV).
Response duration
All confirmed MaHRs were achieved within the first 4
months of treatment with the median time to MaHR of 1.2
months (95% CI: 0.9–1.8 months) in the once-daily group
and 1.0 month (95% CI: 1.0–2.8 months) in the twice-daily
group. The median duration of MaHR in responders was
4.6 months in the once-daily group and 11.5 months in the
twice-daily group (Fig. 2A). This notable difference in
MaHR was likely due to the variability resulting from a small
number of patients at risk in the later time points (Fig. 2A)
and was not associated with significant differences in PFS
or OS (Fig. 2C and D below).
Most MCyRs were achieved within the first 3 months of
treatment with the median time to MCyR of 1 month in both
American Journal of Hematology
research article
TABLE II. Best Hematologic and Cytogenetic Responses to Dasatinib
All patients (n 5 84)
Imatinib-intolerant (n 5 16)
Twice daily (n 5 44)
Once daily (n 5 34)
Twice daily (n 5 34)
Once daily (n 5 6)
Twice daily (n 5 10)
Confirmed hematologic responses , n (%)
MaHR
15 (38)
95% CI
23–54
OHR
19 (48)
95% CI
32–64
CHR
13 (33)
NEL
2 (5)
MiHR
4 (10)
14 (32)
19–48
18 (41)
26–57
11 (25)
3 (7)
4 (9)
9 (27)
13–44
13 (39)
22–56
8 (24)
1 (3)
4 (12)
11 (32)
17–51
15 (44)
27–62
9 (27)
2 (6)
4 (12)
6 (100)
54–100
6 (100)
54–100
5 (83)
1 (17)
0
3 (30)
7–65
3 (30)
7–65
2 (20)
1 (10)
0
All hematologic responsesb, n (%)
MaHR
22 (55)
OHR
26 (65)
CHR
20 (50)
NEL
2 (5)
MiHR
4 (10)
No response
14 (35)
19
23
15
4
4
21
16
20
15
1
4
14
15
19
12
3
4
15
6
6
5
1
4
4
3
1
Cytogenetic responses, n (%)
MCyR
28 (70)
95% CI
54–83
CCyR
20 (50)
PCyR
8 (20)
Otherc
3 (8)
d
9 (23)
Unable to determine
23 (52)
37–68
17 (39)
6 (14)
3 (7)
18 (41)
Response
Once daily (n 5 40)
Imatinib-resistant (n 5 68)
a
(43)
(52)
(38)
(9)
(9)
(48)
(47)
(59)
(44)
(3)
(12)
(41)
22 (65)
47–80
15 (44)
7 (21)
3 (9)
9 (27)
(44)
(56)
(35)
(9)
(12)
(44)
20 (59)
41–75
14 (41)
6 (18)
1 (3)
12 (35)
(100)
(100)
(83)
(17)
0
0
(40)
(40)
(30)
(10)
0
6 (60)
6 (100)
54–100
5 (83)
1 (17)
0
0
3 (30)
7–65
3 (30)
0
1 (10)
6 (60)
a
Best hematologic response lasting for at least 28 consecutive days.
Best hematologic response at any time during therapy.
c
Includes minor and minimal cytogenetic responses.
d
Represents patients lacking a valid on-study cytogenetic assessment.
MaHR, major hematologic response; OHR, overall hematologic response; CHR, complete hematologic response; NEL, no evidence of leukemia; MiHR, minor hematologic response; MCyR, major cytogenetic response; CCyR, complete cytogenetic response; PCyR, partial cytogenetic response.
b
TABLE III. Best Hematologic and Cytogenetic Responses After
TABLE IV. Response to Dasatinib by Baseline BCR-ABL Mutations
Exclusion of Patients with MaHRa or 0–35% Ph1 cellsb at Study
Entry
All patients
Response
Once daily
Twice daily
Patients excluding those with
MaHR or 0-35% Ph1 cells
at entry
Once daily
Twice daily
Confirmed hematologic responses, n (%)
MaHR
CHR
NEL
n 5 40
15 (38)
13 (33)
2 (5)
Cytogenetic responses, n (%)
n 5 40
MCyR
28 (70)
CCyR
20 (50)
PCyR
8 (20)
n 5 44
14 (32)
11 (25)
3 (7)
n 5 35
13 (37)
11 (31)
2 (6)
n 5 42
13 (31)
10 (25)
3 (7)
n 5 44
23 (52)
17 (39)
6 (14)
n 5 20
14 (70)
12 (60)
2 (10)
n 5 32
15 (47)
9 (28)
6 (19)
140 mg once daily n 5 31a
Mutation
70 mg twice daily n 5 34a
Total n (%)
MCyR n/total
Total n (%)
MCyR n/total
14 (45)
17 (55)
9/14
13/17
16 (47)
18 (53)
10/16
9/18
None
Any
Specific mutationb,c
G250E
Y253H
E255K
T315I
F359C/L/V
E459K
F486S
3
6
1
1
2
5
2
3
4
0
0
1
5
2
2
8
3
2
2
2
0
1
5
1
0
1
0
0
a
Patients with valid analysis.
Reported in at least two patients.
c
Patients may have more than one specific mutation.
MCyR, major cytogenetic response.
b
a
Six CHR and one NEL.
20 with 0% Ph1 cells and 12 with >0–35% Ph1 cells.
MaHR, major hematologic response; CHR, complete hematologic response;
NEL, no evidence of leukemia; MCyR, major cytogenetic response; CCyR, complete cytogenetic response; PCyR, partial cytogenetic response; Ph, Philadelphia
chromosome.
b
once-daily (95% CI: 1.0–1.3 months) and twice-daily (95%
CI: 1.0–1.2 months) groups. The median duration of MCyR
for the once-daily group (4.1 months) was similar to that for
the twice-daily group (4.4 months) (Fig. 2B). The median
duration of CCyR for the once-daily group (4.3 months;
95% CI, 3.7–6.9) was also similar to that for the twice-daily
group (5.5 months; 95% CI, 3.3–13.4). Of patients with
CCyR, 16 out of 20 in the once-daily group and 12 out of
17 in the twice-daily group progressed.
Progression-free survival and overall survival
The median length of PFS in the once-daily group (4.0
months) was not significantly different from that in the
twice-daily group (3.1 months) (P 5 0.735) (Fig. 2C). The
most common cause of progression was the loss of hema-
American Journal of Hematology
tologic response occurring in 30% of patients in each
group. The median length of OS in the once-daily group
(6.5 months) was less than that in the twice-daily group
(9.1 months) with the difference being statistically insignificant (P 5 0.336) (Fig. 2D).
Safety
Drug-related adverse events occurring in 10% of
patients were generally similar between the two schedules
(Table V). The incidences of grade 3/4 neutropenia (oncedaily, 67% vs. twice-daily, 72%) or thrombocytopenia (oncedaily, 72% vs. twice-daily, 60%) were similar between two
groups (Table V). Nonhematologic adverse events were
mostly grade 1 or 2 for both schedules with gastrointestinal
events (e.g., diarrhea, nausea, and vomiting) being the
most common (Table V). Fewer patients experienced a
pleural effusion when dasatinib was administered once
daily (all grades, 18%; grade 3–4, 5%) versus twice daily
(all grades, 32%; grade 3–4, 14%) (Table V). The incidence
of other fluid-related events was also lower in the once-
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a
TABLE V. Dasatinib-Related Adverse Events
140 mg once daily
(n 5 40)
All grades
Cytopenia, n (%)
Anemia
Leukocytopenia
Neutropenia
Thrombocytopenia
Fluid retention, n (%)
Pleural effusion
Superficial edema
Other fluid-related events
Ascites
Generalized edema
Pericardial effusion
Pulmonary edema
Other adverse events, n (%)d
Diarrhea
Nausea
Vomiting
Infection
Hemorrhage
Gastrointestinal bleeding
Central nervous system
Other
Pyrexia
Febrile neutropenia
Musculoskeletal pain
Dyspnea
Fatigue
Gastritis
Headache
Anorexia
Rash
39
33
33
36
12
7
7
1
(100)
(85)
(85)
(92)
(30)
(18)b
(18)
(3)
0
1 (3)
1 (3)
0
14
11
8
7
6
2
4
6
5
5
4
4
4
4
3
2
(35)
(28)
(20)
(18)
(15)
(5)
0
(10)
(15)
(13)
(13)
(10)
(10)
(10)
(10)
(8)
(5)
Grade 3/4
14
21
26
28
1
1
70 mg twice daily
(n 5 44)
All grades
(35)
(53)
(67)
(72)
(3)
(3)c
0
0
0
0
0
0
43
35
34
38
19
14
8
7
1
4
1
3
2 (5)
1 (3)
0
3 (8)
2 (5)
2 (5)
0
0
0
5 (13)
0
1 (3)
0
1 (3)
0
0
0
12
11
8
4
7
5
1
4
7
3
3
10
6
(98)
(81)
(79)
(88)
(43)
(32)b
(18)
(16)
(2)
(9)
(2)
(7)
(27)
(25)
(18)
(9)
(16)
(11)
(2)
(9)
(16)
(7)
(7)
(23)
(14)
0
3 (7)
5 (11)
8 (18)
Grade 3/4
16
30
31
26
7
6
1
2
(36)
(70)
(72)
(60)
(16)
(14)c
(2)
(5)
0
1 (2)
0
1 (2)
2
2
1
2
3
3
1
3
1
1
(5)
(5)
(2)
(5)
(7)
(7)
0
(2)
0
(7)
(2)
0
0
0
(2)
0
0
a
Graded according to the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) Version 3.0. Cytopenia values were based on
clinical laboratory measurements on available samples. All other events were
based on adverse reaction reports.
b
P 5 0.207.
c
P 5 0.115.
d
Adverse events experienced by 10% of patients in any group.
daily (3%) versus twice-daily (16%) group. Neither of these
differences was statistically significant.
Dose modifications
Median average daily doses were similar between oncedaily (140 mg) and twice-daily (138 mg) groups, as were
the median treatment durations (3.4 months vs. 2.5
months). The median treatment durations were longer in
patients who achieved a MaHR in both once-daily (5.9
months; range 2.9–11.1) and twice-daily (6.8 months;
range 2.0–23.5) groups. Fewer patients in the once-daily
group compared with the twice-daily group required dose
reductions (n 5 4, 10% vs. n 5 10, 23%) with nearly all
reductions being due to nonhematologic toxicities (8% vs.
21%). The rate of dose interruption in the once-daily group
(n 5 13, 33%) was similar to that in the twice-daily group
(n 5 15, 34%) with nearly all interruptions being due to
nonhematologic toxicities. Dose escalation was performed
for 12 patients (30%) in the once-daily and for 13 patients
(30%) in the twice-daily group with major reasons being rising blast percentage (13% vs. 21%) and loss of hematologic response (18% vs. 5%).
Figure 2. Kaplan-Meier analyses. A: Major hematologic response computed on
responding patients only. Patients who neither progressed nor died were censored
on the date of last assessment. B: Major cytogenetic response computed on
responding patients only. Patients who neither progressed nor died were censored
on the date of last assessment. C: Progression-free survival computed on all
randomized patients. Patients who neither progressed nor died were censored on
the date of last cytogenetic or hematologic assessment. D: Overall survival computed on all randomized patients. Patients who had not died or who were lost to
follow-up were censored on the last date on which they were known to have been
alive. CI, confidence interval; NA, not available.
168
Discussion
In this study, we evaluated the efficacy and safety of
dasatinib administered at either 140 mg once daily or 70
mg twice daily to patients with imatinib-resistant or -intolerant Ph1 ALL. At 2-year follow-up, the once-daily schedule
was generally similar to the twice-daily schedule in terms of
hematologic and cytogenetic response rates and survival.
Both dosing schedules were similarly effective irrespective
American Journal of Hematology
research article
of baseline BCR-ABL mutation status. The study was not
powered to detect the small differences between the dosing
schedules. However, consistently similar efficacy between
these schedules was seen across other CML subgroups
including CML-CP, CML-AP, and CML-BP [18,22,23], supporting the conclusion that 140 mg once-daily regimen has
clinical efficacy similar to that of the currently approved 70
mg twice-daily regimen in Ph1 ALL patients resistant or
intolerant to imatinib.
There were minimal differences in myelosuppression
between the two schedules. However, pleural effusions, a
significant toxicity of dasatinib needing medical intervention, occurred less frequently with once-daily dosing compared with twice-daily dosing. Although the difference was
not statistically significant (possibly due to the small number of patients), these findings are consistent with similar
results for CML-AP and CML-BP subgroups studied in the
present trial [22,23]. In a separate phase 3 study involving
CML-CP patients, the incidence of pleural effusion with
100 mg once daily was lower than that with 70 mg twice
daily, but the incidence rates were similar between 140 mg
once-daily and 70 mg twice-daily regimens [18]. A recent
analysis has concluded that the twice-daily schedule is a
risk factor for pleural effusion in CML patients treated with
dasatinib [24]. The once-daily regimen also resulted in a
lower incidence of dose reduction for toxicity in various
subgroups including Ph1 ALL [22,23]. The consistently
lower incidences of fluid retention and dose reduction with
once-daily dosing across all patient subgroups support the
view that dasatinib administered once daily may have an
improved safety profile. While it is possible that a dosing
regimen of 100 mg once daily would achieve significantly
lower rates of pleural effusion while preserving efficacy,
this regimen has only been studied in chronic-phase
patients and was not studied in advanced phase patients
due to the concern that efficacy might have been compromised in these patients.
Importantly, this study demonstrates that potent transient
BCR-ABL inhibition is sufficient to effect rapid and deep
clinical remissions in patients with aggressive leukemias.
Oral dasatinib has a human plasma terminal half-life of 3 to
4 hr [25] and BCR-ABL kinase inhibition, as assessed by
substrate phosphorylation, was more sustained across a
24-hr period with the twice-daily schedule than with the
once-daily dosing [26,27]. This persistent exposure of targets to inhibitory drug concentrations may drive certain
adverse events providing a possible explanation for
increased incidence of fluid retention with the twice-daily
dosing [27,28]. Transient exposure of CML cell lines in vitro
to clinically relevant dasatinib, on the other hand, induced
apoptosis that was still evident at 48 hr later, suggesting
that the peak plasma concentration of dasatinib achieved
with either dosing schedule produces a persistent inhibition
of cell proliferation [27,28].
MCyR rates (52–70%) were higher than confirmed
MaHR rates (32–38%) in the present patient population, a
finding also noted in an earlier study [13]. This observation
was attributed to patients who achieved a cytogenetic
response but who either had severe residual cytopenias or
did not meet the criteria for a confirmed hematologic
response. Such patients were, therefore, precluded from
being classified as having attained a confirmed hematologic
response. In support of this, counting hematologic
responses observed at least once during the course of
therapy gave higher rates (43–55%).
Sixty-five percent of the imatinib-resistant patients in this
study possessed BCR-ABL kinase domain mutations, a
finding in agreement with published results in Ph1 ALL
patients [6–8]. Attainment of both hematologic and cytoge-
American Journal of Hematology
netic responses in patients containing imatinib-resistant
mutations is consistent with the ability of dasatinib to inhibit
a spectrum of BCR-ABL mutants [12], and some of these
mutations, particularly those at Y253, E255, and F359, are
substantially more sensitive to dasatinib than to nilotinib, an
approved drug for imatinib-intolerant- or resistant CML that
is 30-fold more potent than imatinib at inhibiting BCR-ABL
kinase [29,30]. One-third of imatinib-resistant patients had
no detectable BCR-ABL mutations at baseline, and the efficacy of dasatinib in this patient population may be attributed to its ability to potently inhibit both BCR-ABL kinase
and SFKs. However, it remains plausible that a resistant
mutation in some of these patients was no longer detectable because imatinib was not the most recently administered therapy. Only one out of 13 imatinib-intolerant
patients had a BCR-ABL mutation, an observation consistent with the view that mutants emerge under selection
pressure induced by imatinib treatment [8].
Given the relative rarity of Ph1 ALL, the population (n 5
84) studied here is a large series. These patients received
extensive prior treatment including chemotherapy and
bone-marrow transplantation, and the poor clinical status of
these patients may explain the rapid progression or relapse
observed in this study. Nevertheless, patients in this series
still achieved a very high cytogenetic response rate (oncedaily 70%; twice-daily, 52%) and a reasonable overall survival (once-daily, 6.5 months; twice-daily, 9.1 months). The
median time to MaHR and MCyR was 1.0 month, indicating that the disease control was rapidly achieved with dasatinib in these patients. Notably, five patients (once-daily, two
patients; twice-daily, three patients) discontinued treatment
to pursue stem cell transplantation (SCT) with four patients
(two patients in each group) having achieved a CCyR and
one patient a PCyR (twice-daily group). This observation
suggests a role of dasatinib in stabilizing and preparing
Ph1 ALL subjects for SCT. Also, of note, of six patients
who had a dasatinib-induced MaHR or MCyR lasting longer
than 12 months, three had previously undergone SCT, indicating the possibility that the use of dasatinib could benefit
Ph1 ALL patients progressing after SCT. Thus, the 140 mg
daily schedule, with its equivalent efficacy and possibly
improved toxicity profile, would appear to represent the
optimal dasatinib regimen in patients who are eligible for
curative therapy with SCT.
Dasatinib therapy was also well tolerated; nonhematologic adverse events were mostly grade 1 or 2, and only
four patients (5%) discontinued therapy due to dasatinibrelated toxicity. Myelosuppression, neutropenia, and thrombocytopenia in particular, and fluid retention remain important safety concerns and continue to be managed effectively with dose interruptions and reductions. Additionally,
dasatinib is vulnerable to a comparatively small number of
resistance-conferring mutations [31,32], and a small proportion of patients presented herein remain on dasatinib without progression after 2 years. Taken together, these results
suggest that dasatinib should be evaluated now as part of
front-line therapy and in combination with cytotoxic agents
for patients with newly diagnosed Ph1 ALL.
Results presented here confirm the data from the earlier
registrational phase 2 study [13] that oral dasatinib is efficacious and well tolerated in patients with imatinib-resistant
Ph1 ALL whose disease otherwise is destined to follow a
rapid and aggressive course. This study further demonstrates that compared with the 70 mg twice-daily dosing
schedule, dasatinib 140 mg once daily has similar efficacy
and may have improved safety in this patient group, a conclusion supported by similar results across other subgroups
including CML-CP, CML-AP, and CML-BP. The present data
formed the basis for the recent approval of dasatinib 140
169
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mg once daily as a dosing option for imatinib-resistant or
-intolerant Ph1 ALL patients.
Acknowledgments
Professional medical writing and editorial assistance was
provided by Motasim Billah, an employee of Bristol-Myers
Squibb.
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