Annual Meeting Proceedings Part 1 - American Society of Clinical ...

6504 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia
in chronic phase (CML-CP): DASISION 3-year follow-up. Presenting
Author: Andreas Hochhaus, Universitätsklinikum Jena, Jena, Germany
Background: In the phase 3 DASISION trial of dasatinib v IM in patients
(pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates
of complete cytogenetic response (CCyR) and major molecular response
(MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed
CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P�0.001,
meeting the primary endpoint. Methods: Pts were randomized to receive
dasatinib 100 mg once daily (QD; n�259) or IM 400 mg QD (n�260).
Results: Minimum 24-month follow-up (median 26.6 months) is reported
here. 24-month molecular response rates were higher for dasatinib v IM:
MMR (BCR-ABL �0.1%) 64% v 46%, P�0.0001; MR4 (BCR-ABL
�0.01%) 29% v 19%, P�0.0053; MR4.5 (BCR-ABL �0.0032%) 17% v
8%, P�0.0032. MMR rates were higher for dasatinib in all Hasford risk
groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of
pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had
maintained their MMR at 24 months, respectively. Pts receiving dasatinib v
IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and
15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts
receiving dasatinib (n�9; 3.5%) transformed to accelerated/blast phase v
IM (n�15; 5.8%) on study or during follow-up after discontinuation.
24-month overall and progression-free survival were similar for dasatinib v
IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few
additional adverse events (AEs) were reported between 12 and 24 months
in both arms, with grade 3/4 nonhematologic AE rates �1%. In each arm,
10 pts had a BCR-ABL mutation detected at time of discontinuation. For
dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs
(7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v
�1%), death (2% v �1%), and other (4% v 8%). Few pts discontinued
between 12 and 24 months for dasatinib (n�19; 7%) and IM (n�16; 6%).
Conclusions: Updated data with minimum 36-month follow-up will be
presented, including mutation analyses in pts who discontinued, progressed,
or had suboptimal response. Pts receiving dasatinib had a lower
transformation rate and higher molecular responses v pts receiving IM,
supporting the use of dasatinib in newly diagnosed CML-CP.
6506 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant
chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib.
Presenting Author: Neil P. Shah, University of California, San Francisco,
San Francisco, CA
Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as
1st- and 2nd-line therapy for CML pts with newly diagnosed disease or
resistance/intolerance to imatinib. This ongoing study in pts with imatinibresistant/-intolerant
CML provides the longest follow-up of a secondgeneration
BCR-ABL inhibitor. Methods: Study design has been described
(Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML
(N�670) were randomized to dasatinib 100 mg once daily (QD), 50 mg
twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are
reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151
pts (74%) remain on QD dosing, 85 of whom (56%) are on �100 mg QD
dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%)
originally randomized to BID dosing having switched to QD dosing. For pts
randomized to the 100 mg QD arm (n�167), progression-free survival
(PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate
of transformation to advanced disease. In exploratory analyses, 42% and
60% of pts had BCR-ABL levels �10% (International Scale) at 1 and 3
months (mos), respectively. In a landmark analysis, BCR-ABL �10% at 1
or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD,
nonhematologic adverse events (AEs; all grades) generally first occurred in
�24 mos. Cumulative rates of AEs in the 100 mg QD arm were headache
(33%), diarrhea (28%), fatigue (26%), and pleural effusion (24%). For
dasatinib 100 mg QD, cytopenias (grades 3/4) generally first occurred in
�12 mos. The most common hematologic AEs (grades 3/4) in the 100 mg
QD arm were neutropenia (36%) and thrombocytopenia (24%). AEs were
managed by dose/schedule modifications. Conclusions: Five-yr follow-up of
pts who switched to dasatinib 100 mg QD after imatinib-resistance/
intolerance shows high rates of PFS, and OS with an overall low rate of
transformation. Exploratory analyses suggest that achievement of a fast and
deep response (�10% BCR-ABL) at 1 or 3 mos after initiation of dasatinib
100 mg QD may be associated with a higher PFS. Dasatinib 100 mg QD
was generally well tolerated over 5 yrs. Six-yr data will be presented.
Leukemia, Myelodysplasia, and Transplantation
6505^ Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Switch to nilotinib versus continued imatinib in patients (pts) with chronic
myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL
after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up.
Presenting Author: Jeffrey Howard Lipton, Princess Margaret Hospital,
Toronto, ON, Canada
Background: Nilotinib induced significantly faster and deeper molecular
responses vs imatinib in the ENESTnd trial. Achieving these deeper
molecular responses may increase patient eligibility for future TKI discontinuation
studies. Methods: CML-CP pts (N � 207) who achieved a
complete cytogenetic response but were still BCR-ABL positive by RQ-PCR
after � 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg
BID (n � 104) or to continue their imatinib dose (400 or 600 mg QD [n �
103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL
by RQ-PCR with a sample sensitivity of � 4.5 logs in 2 consecutive
samples). Other endpoints included molecular responses (MMR � 0.1% IS ,
MR4 � 0.01% IS , and MR4.5 � 0.0032% IS ) and BCR-ABL ratio over time.
Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib
by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL
in at least 1 sample) by 12 mo was significantly higher on nilotinib vs
imatinib (23.1% vs 10.7%; P � .02). Rates of MMR, MR4 ,MR4.5 , and
CMR were also superior in pts switched to nilotinib, and these pts had
significantly shorter times to achieve these responses. Imatinib-treated pts
had minimal evidence of improvement in molecular response vs a median
0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With
12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib.
The nilotinib safety profile was consistent with prior studies. Both drugs
were well tolerated. Conclusions: Twice as many pts achieved deeper
molecular responses after switching to nilotinib vs staying on imatinib.
Nilotinib
400 mg BID
(n � 104)
Molecular response by 12 mo (ITT population), %
Confirmed CMR 12.5
P � .108*
CMR 23.1
P � .02*
Molecular response by 12 mo (in pts without the response at baseline), %
MMR n � 24
75.0
MR
P � .006**
4 n � 74
48.6
MR
P � .006**
4.5 n � 94
33.0
P � .008**
CMR
*Stratified Cochran-Mantel-Haenszel test. **Stratified log-rank test.
n � 101
20.8
P � .03**
417s
Imatinib
400 or 600 mg QD
(n � 103)
5.8
10.7
n � 28
35.7
n � 78
25.6
n � 91
16.5
n � 100
10.0
6507 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatmentnaive
(TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim
results of a phase Ib/II study. Presenting Author: John C. Byrd, The Ohio
State University Comprehensive Cancer Center and Arthur G. James Cancer
Hospital and Solove Research Institute, Columbus, OH
Background: Fludarabine based therapy, while effective, carries significant
risk of morbidity and mortality in the elderly pts. As such, older CLL pts
represent a high priority for new therapeutic approaches. PCI-32765 (P) an
oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation,
migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses
of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts.
Mature follow-up of the TN pts is reported. Methods: Pts �65 yrs old with
active CLL requiring Tx by IWCLL guidelines were treated with oral P at
doses of 420 mg or 840 mg administered daily for 28-day cycles until
disease progression (PD). Response was evaluated according to 2008
IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts
(840 mg). The 840 mg cohort was terminated after comparable activity and
safety between doses was shown in R/R pts. Median age 71 yrs (range
65-84) with 74% of pts �70 yrs. 19/31 (61%) had baseline cytopenias
(Hgb � 11g/dl or plts �100,000). Unmutated IgVH was present in 43% of
pts. The majority of AEs have been Gr��2 in severity, most commonly
diarrhea, nausea, and fatigue. Gr �3 non-heme AEs potentially related to P
in 19% of pts. 10% of pts experienced Gr �3 infections or cytopenias. With
a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a
response by IWCLL criteria with 65% partial responses (PR) and 8%
complete remissions with no morphologic evidence of CLL on marrow. An
additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis.
Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle
assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of
high risk factors. 84% of pts remain on study, reasons for discontinuation
� AE (3), investigator decision (1) and PD (1). There have been no deaths.
Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions:
PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The
high ORR, including marrow clearance and very low PD rate with the single
agent suggests that P warrants further study as a first-line treatment
approach in elderly pts.
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