EHA 2008
DASATINIB IS ASSOCIATED WITH DURABLE TREATMENT RESPONSES IN
CHRONIC PHASE CHRONIC MYELOID LEUKEMIA: LONG-TERM FOLLOW-UP
FROM THE PHASE I TRIAL (CA180002)
0119
J Cortes, CL Sawyers, HM Kantarjian, NP Shah, R Paquette, E Bleickardt, P Paliwal, M
Talpaz (Houston, United States of America)
Author
Cortes, Jorge, MD Anderson Cancer Center, Houston, United States of America (P)
Co-author(s)
Sawyers, Charles L, Memorial Sloan-Kettering Cancer Center, New York, United States of
America
Kantarjian, Hagop M, MD Anderson Cancer Center, Houston, United States of America
Shah, Neil P, University of California San Francisco School of Medicine, San Francisco,
United States of America
Paquette, Ronald, UCLA, Los Angeles, United States of America
Bleickardt, Eric, Bristol-Myers Squibb, Wallingford, United States of America
Paliwal, Prashni, Bristol-Myers Squibb, Wallingford, United States of America
Talpaz, Moshe, University of Michigan, Ann Arbor, United States of America
Topic
23. Chronic myeloid leukemia - clinical
Keywords
BCR-ABL, Chronic myeloid leukemia, Imatinib resistance, Tyrosine kinase inhibitor
Background: Dasatinib is a potent BCR-ABL inhibitor, approximately 325-fold more potent
than imatinib and 16-fold more potent than nilotinib for in vitro kinase inhibition. Dasatinib
was approved for the treatment of imatinib-resistant/-intolerant chronic myeloid leukemia
(CML) in any phase or Philadelphia chromosome-positive acute lymphoblastic leukemia
(Ph+ ALL) because of efficacy observed during a phase I trial (CA180002) and a series of
phase II studies (the START program). Long-term follow-up is now available for patients
with CML in chronic phase (CP) treated during the 002 study.
Aims: To investigate the durability of dasatinib treatment responses and long-term
tolerability of patients treated in a phase I study. Data have been assessed after a minimum
follow-up of 27 months.
Methods: Patients with CML-CP who had experienced hematologic resistance/relapse on
imatinib or who had discontinued imatinib following toxicity were enrolled from November
2003 to April 2005. Dasatinib was administered at 15-180 mg/d on a QD or BID schedule
according to a dose-escalation protocol, with most patients initially treated on a 5 d on/ 2 d
off schedule (dasatinib 100 mg QD is now the approved dose for patients with CML-CP
following imatinib resistance or intolerance). In addition to safety assessments, rates of
complete hematologic response (CHR) or major/complete cytogenetic response
(MCyR/CCyR), and duration of progression-free survival (PFS) or overall survival were
evaluated.
Results: Of 45 patients with late CML-CP, 91% had received prior interferon-alpha, 62% had
received imatinib at a dose >600 mg/d, and 58% had received imatinib for >3 years. Most
patients had responded initially to imatinib (CHR 78%, MCyR 42%, CCyR 18%), 80%
eventually became imatinib resistant (20% intolerant), and 73% had baseline BCR-ABL
mutations. Dasatinib was administered QD to 22 patients for a median of 31 months (range
3.6–38.5) and BID to 23 patients for median of 23 months (range 0.5-36.1). Response rates
were similar for QD vs BID treatment (CHR: 95.5% vs 87.0%; MCyR 45.5% vs 60.9%;
CCyR 45.5% vs 43.5%). Across all patients, median durations of CHR and MCyR were not
reached (71% of responding patients had maintained MCyR at 33 months), and at 36
months, the PFS rate was 64% and the overall survival rate was 82%. In a landmark analysis,
achieving a MCyR at any time on dasatinib was associated with higher 36-month PFS (87%
vs 37%) and overall survival (95% vs 66%). At last follow-up, 62% of patients remained on
dasatinib; 18% discontinued following disease progression, only 1 patient (2%) discontinued
for toxicity, and 11% died. Grade 3/4 neutropenia and thrombocytopenia were each noted in
47% of patients. Nonhematologic side effects were typically mild to moderate. The most
common grade 3/4 nonhematologic side effects were pleural effusion (11%), gastrointestinal
bleeding (7%), and dyspnea or pulmonary edema (4%).
Summary/Conclusions: Long-term follow-up from this early study confirms that dasatinib is
associated with high rates of hematologic and cytogenetic responses in CML-CP following
imatinib failure. Dasatinib treatment responses were durable and translated into favorable
PFS and overall survival. Side effects rarely led to treatment discontinuation.
ASCO 2008
Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous
leukemia (CML-CP) with resistance or intolerance to imatinib (START-C).
Sub-category: Leukemia
Category: Leukemia, Myelodysplasia, and Transplantation
Meeting: 2008 ASCO Annual Meeting
Abstract No: 7009
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7009)
Author(s): M. J. Mauro, M. Baccarani, F. Cervantes, J. H. Lipton, Y. Matloub, R.
Sinha, R. M. Stone
Abstract: Background: Dasatinib is 325-fold more potent than imatinib and 16-fold
more potent than nilotinib against BCR-ABL in vitro. Extended 2-year follow-up data are
available for the START-C study, an international, 75-center, phase II study in patients (pts)
with CML-CP resistant or intolerant to imatinib. Methods: Pts were required to be either
imatinib-resistant or -intolerant. The starting dose was dasatinib 70 mg BID, with dose
escalations (90 mg BID) or reductions (50 or 40 mg BID) allowed for lack of response or
toxicity. The primary endpoint was major cytogenetic response rate (MCyR). Results:
Median time from CML diagnosis at baseline was 61 mos (range 3- 251). Best response to
prior imatinib therapy was complete hematologic response (CHR) in 82%, complete
cytogenetic response (CCyR) in 19%, and MCyR in 37% of pts. After a minimum follow up
of 24 mos (LPFV to database closure; n=387, 288 imatinib-resistant, 99 imatinib-intolerant),
CHR was noted in 91% (95% CI 88-94%), MCyR in 62% (95% CI 57-67%), CCyR in 53%
and major molecular response (MMR) in 47% of pts. Rates of MCyR were 55% for imatinib-
resistant pts, and 63% for pts with baseline BCR-ABL mutations; responses were seen across
all mutations except T315I. In imatinib-intolerant pts, the CCyR (n=99) rate and MMR
(n=94 evaluable) rate were both 78%. MCyRs were durable, with 88% of pts maintaining
response at 24 mos. Progression-free survival (PFS) at 24 mos was 80% (75% in imatinib-
resistant and 94% in imatinib-intolerant pts). Overall survival at 24 mos was 94% (92% in
imatinib -resistant and 100% in imatinib-intolerant pts). Grade 3-4 toxicities included
thrombocytopenia (49%) and neutropenia (50%), pleural effusion (9%), dyspnea (6%),
bleeding (4%), diarrhea (3%), and fatigue (3%). 3% of imatinib-intolerant pts developed
similar grade 3-4 toxicities; all were able to continue treatment after dose reduction,
demonstrating lack of cross intolerance. The appearance of new higher grade toxicity
between 12 and 24 months was uncommon. Conclusions: Dasatinib is well-tolerated in pts
with CML-CP and induces cytogenetic responses that are highly durable and result in a PFS
of 80% at 24-mos.
Dasatinib or high-dose imatinib for patients with chronic myelogenous
leukemia chronic-phase (CML-CP) resistant to standard- dose imatinib: 2-
year follow-up data from START-R.
Sub-category: Leukemia
Category: Leukemia, Myelodysplasia, and Transplantation
Meeting: 2008 ASCO Annual Meeting
Abstract No: 7012
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7012)
Author(s): P. H. Rousselot, T. Facon, R. Paquette, E. Bleickardt, D. Dejardin, H. M.
Kantarjian
Abstract: Background: Resistance to imatinib is a well-recognized problem in CML-CP.
Dasatinib is 325-fold more potent than imatinib against BCR-ABL in vitro is effective in
imatinib-resistant CML patients. Prior to dasatinib, imatinib dose escalation to 800 mg/day
was the primary option for resistance to standard-dose imatinib. Methods: In this global
Phase II study, 150 patients (pts) with CML-CP resistant to imatinib 400-600 mg/d were
randomized 2:1 to dasatinib 70 mg BID (n=101) or imatinib 800 mg/d (n=49). The primary
endpoint of the study was major cytogenetic response (MCyR) at 12 wks. Crossover was
permitted for confirmed progression, lack of MCyR at 12 wks, or intolerance despite dose
reduction. MCyR rates at 12 weeks were 36% vs 29%; p=0.4025. Two-year follow-up is now
presented. Results: With a minimum follow-up (LPFV to database closure) of 24 mos, MCyR
rates were (53% vs 33%, p=0.017) for pts receiving dasatinib and high-dose imatinib,
respectively; the difference being attributable to complete cytogenetic responses (44%
dasatinib vs 18% imatinib, p=0.0025). Major molecular responses (MMR) were also more
frequent with dasatinib (29% vs 12%, p=0.028). Duration of MCyR was greater with
dasatinib; 90% of dasatinib pts maintained MCyR at 18 mos vs 74% of imatinib pts.
Analysis of progression-free survival at 24 mos favored dasatinib (86% vs 65%, p=0.0012);
results were consistent irrespective of the prior imatinib dose received (400 mg/d, p=0.0562;
600 mg/d, p=0.0033). Time to treatment failure also favored dasatinib (proportion of pts
without failure at 24 mos: 59% vs 18% p<0.0001). Grade 3-4 non-hematologic toxicity was
minimal for both treatment groups. Grade 3-4 cytopenia was more frequent with dasatinib.
Discontinuation attributable to toxicity occurred in 22% of pts receiving dasatinib and 20%
treated with imatinib. Conclusions: With an extended follow-up of 24 mos, the overall benefit-
risk assessment favors dasatinib over high-dose imatinib in CML-CP pts with resistance to
400-600 mg imatinib. The current labelled dose of 100 mg QD was approved based on a
subsequent Phase III dose optimization study which showed comparable efficacy with
improved tolerability compared with 70 mg BID.
Efficacy of dasatinib in patients (pts) with previously untreated chronic
myelogenous leukemia (CML) in early chronic phase (CML-CP).
Sub-category: Leukemia
Category: Leukemia, Myelodysplasia, and Transplantation
Meeting: 2008 ASCO Annual Meeting
Abstract No: 7013
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7013)
Author(s): G. Borthakur, H. M. Kantarjian, S. M. O'Brien, D. Jones, C. Koller, C.
Nicaise, G. Garcia-Manero, A. Ferrajoli, J. E. Cortes
Abstract: Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of
BCR-ABL and SRC with significant activity in pts with CML-CP resistant or intolerant of
imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts
with previously untreated CML-CP. Methods: The primary objective was to estimate the
proportion of pts attaining major molecular response at 12 months (mo). Pts with previously
untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50
mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Forty pts have been enrolled (21
on the QD schedule, 19 BID). Median age was 41 years (yrs) (range 18-76 yrs). The rate of
complete cytogenetic response [CCyR] at 3, 6 and 12 mo compares favorably to those
observed in historical controls treated with imatinib 400mg or 800 mg daily (Table 1). At 12
mo, 8/25 (32%) evaluable pts had achieved a major molecular response. There was a trend
for improved molecular response with the QD schedule. Grade 3-4 non-hematologic toxicity
(regardless of causality) included fatigue (5%), headache (3%), and rash (3%). Pleural
effusion occurred in 5 (13%) pts (all grade 1-2). Grade 3-4 hematologic toxicity (transient)
were thrombocytopenia 10%, neutropenia 5%, and anemia 3%. With median follow-up of 18
mo, 18 (46%) pts required transient treatment interruption and dose reduction. The actual
median daily dose for all pts was 100mg. There is no significant difference in grade 3-4
toxicity by treatment schedule. Conclusions: Rapid CCyR occurs in most patients with
previously untreated CML-CP treated with dasatinib frontline therapy with a favorable
toxicity profile. Accrual to this trial continues.
Months on therapy Percent with CCyR (No. evaluable) P value
Dasatinib Imatinib 400 mg Imatinib 800 mg
3 mo 72 (36) 37 (49) 62 (202) 0.0003
6 mo 94 (34) 54 (48) 82 (199) <0.0001
12 mo 100 (26) 65 (48) 86 (197) 0.0001