30] Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML)
in Early Chronic Phase (CML-CP). Session Type: Oral Session
Jorge Cortes, Susan O'Brien, Dan Jones, Charles Koller, Gautam Borthakur, Claude Nicaise, Laverne Henderson,
Alessandra Ferrajoli, Hagop Kantarjian Leukemia, UT MD Anderson Cancer Center, Houston, TX, USA;
Bristol-Myers Squibb Co., Wallingford, CT, USA
Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high
level of activity in pts with CML-CP who are resistant to or intolerant of imatinib (IM), we initiated a phase II trial to
study the 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 (BCR-ABL/ABL ratio 0.05% in our lab) at 12
months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily (BID) or
a 100 mg-once-daily (QD) schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose
reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Thirty-seven pts
have been enrolled between November 2005 and June 2007 (19 on the QD schedule, 18 BID). Median age was 41
years (yrs) (range 18-76 yrs). Nine (24%) of the pts were Sokal intermediate-risk and 3 (8%) were high-risk. Median
baseline WBC count was 29.1 x 109/L (range 3.4-300.0). Three pts had clonal evolution at start of therapy. At 3 mo,
complete hematologic response (CHR) was achieved in all pts,major cytogenetic response occurred 31/33 (94%), and
complete cytogenetic response (CCyR) in 26/33 (79%) evaluable pts. After 6 mo of therapy, 30/32 (94%) evaluable pts
had achieved CCyR. This compares favorably with results obtained in historical controls with IM at standard (400 mg)
and high-dose (800 mg) at our institution:
Percent with CCyR (No. Evaluable)
Months on Therapy Dasatinib Imatinib 400 mg Imatinib 800 mg P value
3mo 79 (33) 37 (49) 62 (202) 0.0003
6mo 94 (32) 54 (48) 82 (199) <0.0001
12mo 100 (24) 65 (48) 86 (197) 0.0001
At 12 mo, 8/25 (32%) evaluable pts had achieved a major molecular response. Responses are similar in both treatment
schedule groups. The most common non-hematologic adverse events (AE) included fatigue (n=22), musculoskeletal pain
(n=20), headache (n=19), and dizziness (n=14), and were predominantly grade (grade 1-2). Grade 3-4 non-hematologic
toxicity (regardless of causality) included headache, pain, rash, neuropathy and memory impairment (1 each). Pleural
effusion occurred in 5 (14%) pts (all grade 1-2). Grade 3-4 hematologic toxicity (transient) included neutropenia in 4
(11%) pts, thrombocytopenia in 4 (11) pts, and anemia in (5%). With a median duration of therapy of 10 mo, 18 (49%)
pts required transient treatment interruption, 14 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1
due to both. Sixteen pts (43%) have required dose reductions. The actual median daily dose for all pts was 100 mg; it
was 100 mg for pts treated on the QD schedule, and 90 mg for those in the BID schedule. There is no significant
difference in grade 3-4 toxicity by treatment schedule. Conclusion: Rapid, complete cytogenetic responses to dasatinib
100 mg/day occur in a high percentage of patients with previously untreated CML-CP. Once daily dosing appears to be
associated with less toxicity. Accrual to this trial continues.
Abstract #30 appears in Blood, Volume 110, issue 11, November 16, 2007
734] Efficacy of Dasatinib in Patients with Chronic-Phase Chronic Myelogenous Leukemia with Resistance or
Intolerance to Imatinib: 2-Year Follow-Up Data from START-C (CA180-013). Session Type: Oral Session
Richard M. Stone, Hagop M. Kantarjian, Michele Baccarani, Jeffrey H. Lipton, Timothy Hughes, Rana Ezzeddine, Eric
Bleickardt, Andreas Hochhaus Dana-Farber Cancer Institute, Boston, MA, USA; MD Anderson Cancer Center,
Houston, TX, USA; S. Orsola-Malpighi University Hospital, Bologna, Italy; Princess Margaret Hospital, Toronto,
Canada; Institute of Medical and Veterinary Science, Adelaide, Australia; Bristol-Myers Squibb, Wallingford, CT, USA;
Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Dasatinib (SPRYCEL ) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both
the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for
patients with imatinib-resistant or -intolerant chronic-phase chronic myelogenous leukemia (CP-CML). Here we report
the extended follow-up of START-C, a 75-center, international study of dasatinib in 387 patients with CP-CML with
resistance (n=288) or intolerance (n=99) to imatinib. Recruitment took place from February to July 2005. Dasatinib was
administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) were allowed for
lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 mo (range 32-50). Prior therapy
included interferon- in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses
>600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete
hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%,
respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87-93%), major
cytogenetic response (MCyR) in 59% (95% CI 54-64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in
49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a
MCyR with dasatinib. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses
were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who
had achieved a MCyR with dasatinib losing this response. Major molecular response rate (ie, a BCR-ABL/ABL ratio of
<0.1% according to the international scale by RQ-PCR) at 12 mo was 25%. Progression-free survival at 15 mo was
90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%;
the average daily dose administered was 101 mg (range 11-171). Reports of grade 3-4 thrombocytopenia and
neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily
of diarrhea (37%), headache (32%), fatigue (31%), and dyspnea (30%). Pleural effusion was experienced by 27% of
patients; this was categorised as grade 1-2 in 21% and grade 3-4 in 6%. Dasatinib-induced cytogenetic responses remain
durable in patients with CP-CML resistant or intolerant to imatinib. Updated analyses corresponding to a minimum
follow-up of 2 years on all patients will be presented.
Abstract #734 appears in Blood, Volume 110, issue 11, November 16, 2007
736] Dasatinib or High-Dose Imatinib for Patients with Chronic-Phase Chronic Myeloid Leukemia Resistant
to Standard-Dose Imatinib: 2-Year Follow-Up Data from START-R (CA180-017). Session Type: Oral Session
Hagop M. Kantarjian, Philippe Rousselot, Ricardo Pasquini, Nelson Hamerschlak, Jerzy Holowiecki, David Dejardin,
Eric Bleickardt, Neil P. Shah MD Anderson Cancer Center, Houston, TX, USA; Hopital Saint Louis, Paris Cedex,
France; Hospital de Clinicas de Curitiba, Parana, Brazil; Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Katedra i
Klinika Hematologii i Transplantacji Szpiku, Katowice, Poland; Bristol-Myers Squibb, Wallingford, CT, USA; UCSF
School of Medicine, San Francisco, CA, USA
Resistance to imatinib is a well-recognized problem in chronic-phase chronic myeloid leukemia (CP-CML). Increased
potency of BCR-ABL inhibition by escalating imatinib doses to 800 mg/d ( high-dose imatinib ) can be effective in some
cases that are resistant to lower doses, but tolerability and durability of response limit the utility of this approach. Dasatinib
(SPRYCEL ) has been shown to be effective in imatinib-resistant CML and its potency against BCR-ABL relative to
imatinib (325-fold more potent against BCR-ABL in vitro) as well as its activity against nearly all imatinib-resistant
BCR-ABL kinase domain mutations auger its potential in this setting. In this international phase-II study, 150 patients with
CP-CML resistant to imatinib 400-600 mg/d were randomized on a 2:1 basis to dasatinib 70 mg BID (n=101) or
imatinib 800 mg/d (n=49). Crossover was permitted for confirmed progression, lack of major cytogenetic response
(MCyR) at 12 weeks, or intolerance despite dose reduction (grade 3-4 non-hematologic toxicity). Dasatinib dose could
be escalated to 90 mg BID for inadequate response at 12 weeks, or reduced to 50 or 40 mg BID for toxicity. Dose
reduction of imatinib to 600 mg/d was allowed for patients who had not previously received that dose. Median treatment
duration with dasatinib was 13.7 mo and 3.1 mo with imatinib. With a median follow-up of 15 mo, complete hematologic
response (CHR) rates were 93% and 82% for patients receiving dasatinib and high-dose imatinib, respectively
(p=0.034). Dasatinib was also associated with higher MCyR rates (52% vs 33%, p=0.023); the difference being
attributable to complete cytogenetic responses (40% vs 16%, p=0.004). For patients with no prior CyR to imatinib, 49%
achieved a MCyR with dasatinib vs 7% with high-dose imatinib. Major molecular responses were also more frequent
with dasatinib (16% vs 4%, p=0.038). Responses achieved with dasatinib were highly durable, and superior to historic
experience with imatinib. Analyses of progression-free survival (PFS) favored dasatinib (hazard ratio [HR] 0.14,
p<0.0001). Results were consistently in favor of dasatinib for PFS irrespective of the prior imatinib dose received (400
mg/d - HR 0.10, p=0.0177; 600 mg/d - HR 0.15, p=0.0005). Grade 3-4 non-hematologic toxicity was minimal for both
treatment groups. All-grade superficial edema (15% vs 43%) and fluid retention (30% vs 45%) were less common with
dasatinib than imatinib, whereas pleural effusion (17% vs 0%; grade 3-4, 4% vs 0%) was more common. Cytopenia was
more frequent and severe with dasatinib. Treatment discontinuation attributable to toxicity occurred in 7% of patients
receiving dasatinib and 18% treated with imatinib. The overall benefit-risk assessment favors dasatinib relative to
high-dose imatinib in CP-CML patients with resistance to 400-600 mg imatinib. Updated results reflecting a minimum
follow-up of 2 years will be presented.
Abstract #736 appears in Blood, Volume 110, issue 11, November 16, 2007
1945] BCR-ABL Transcript Levels at Time of Complete Cytogenetic Remission Achieved after Salvage with
Dasatinib or Nilotinib. Session Type: Poster Session, Board #135-II
Michael J. Mauro, Richard D. Press, Michael W. Deininger, Brian J. Druker Center for Hematologic Malignancies,
Oregon Health Science University, Portland, OR, USA
Achievement of a CCyR is a favorable threshold response in CP CML, associated with an expected degree of
BCR-ABL transcript reduction. Transcript level at the time of CCyR has been reported for late CP (post-IFN) and
IRIS trial cases as median reductions of 2 2.5 logs below a standard baseline. The level of BCR-ABL transcripts at the
time of CCyR may be predictive of subsequent relapse risk, and expectations and relative levels of BCR-ABL transcript
reduction may differ in patients with imatinib refractory CML. 28 CP CML patients were treated at our center with
nilotinib (n=1) or dasatinib (n=26) or both (n=1), 27/28 on phase II clinical trials for imatinib refractory or intolerant CP
CML. 15 of 28 patients received nilotinib or dasatinib for imatinib failure, achieved subsequent CCyR, and had a
quantitative PCR (qPCR) result at the time of CCyR and were analyzed. 8/28 who did not achieve CCyR, 2/28 without a
paired qPCR sample, and 3/28 switched for imatinib intolerance were excluded. 20-cell karyotype of BM metaphases
was used to determine CCyR and qPCR was expressed as % BCR-ABL/G6PDH RNA ratio and log reduction below
standard baseline. The median reduction of BCR-ABL transcripts at time of CCyR for this cohort was 1.6 logs (range 0
4.2, mean 1.7). Patient characteristics are shown in Table 1. One case had no reduction below standard baseline and
only a 3-fold reduction (19 to 6.6%) in BCR-ABL transcripts at time of CCyR; cytogenetics prior to salvage therapy
demonstrated duplication of the Ph chromosome in 100% of metaphases. Another case with a 4.2 log reduction (nested
qPCR (+) only) in transcripts at time of CCyR had undergone prior allografting and received dasatinib for imatinib
refractory cytogenetic relapse post transplant. BCR-ABL transcript reduction in the setting of salvage therapy after
imatinib failure may have different kinetics than the setting of de novo CML and primary imatinib exposure, as the median
reduction at time of CCyR in this cohort is noticeably lower that expected for late CP ( 2 log reduction) and newly
diagnosed CP ( 2.5 log reduction) cases. Transcript level reduction may be variably affected by different mechanisms of
resistance such as BCR-ABL amplification in the setting of duplication of the Ph chromosome. Further study in larger
cohorts is warranted to better describe kinetics of transcript reduction in the salvage setting.
Table 1. Patient Characteristics
Age / Sex Therapy (@CCyR) Time to CCR %BCR-ABL/G6PD Log Reduction Mutation Status
61/M Nilotinib 400 mg QD 5 mo 0.04 2.0 Not evaluated
60/M Dasatinib 80 mg QD 17 mo 0.10 1.6 M388L
69/M Dasatinib 70 mg BID 3 mo 0.039 2.0 None found
47/M Dasatinib 70 mg BID 11 mo 0.10 1.6 Deletion ABL exon 7
49/M Dasatinib 70 mg BID 3mo Undetectable 4.2 None found
54/F Dasatinib 40 mg BID 14 mo 0.20 1.3 Y253F
74/F Dasatinib 50 mg BID 6 mo 0.073 1.8 F486S
57/F Dasatinib 100 mg QD 6 mo 0.096 1.6 Not evaluated
62/M
Nilotinib 400 mg BID 6 mo 0.17 1.4 M244V
56/F Dasatinib 50 mg BID 6 mo 0.12 1.5 None found
65/M Dasatinib 70 mg BID 3 mo 0.01 2.6 M351T, E279K
86/F Dasatinib 40 mg BID 3 mo 0.17 1.4 Not evaluated
55/F Dasatinib 140 mg QD 6 mo 0.32 1.1 None found
57/M Dasatinib 100 mg QD 3 mo 0.04 2.0 F359V
42/M
Dasatinib 100 mg QD 3 mo 6.6 0 None found
post Dasatinib; non-trial patient
Abstract #1945 appears in Blood, Volume 110, issue 11, November 16, 2007