1029] Nilotinib Therapy after Dasatinib Failure in Patients with Imatinib-Resistant or
-Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP), Accelerated Phase (AP)
or Blast Crisis. Session Type: Poster Session, Board #183-I
Francis J. Giles, Phillip le Coutre, Kapil N. Bhalla, Gert Ossenkoppele, Giuliana Alimena, Ariful
Haque, Neil Gallagher, Hagop M. Kantarjian Hematology and Medical Oncology, University of Texas
Health Science Center, San Antonio, TX, USA; Campus Virchow Klinikum, Charite, Humboldt
Universitat, Berlin, Germany; Cancer Biology, H. Lee Moffitt Cancer Center, University of South
Florida, Tampa, FL, USA; Hematology, VU University Medical Center, Amsterdam, Netherlands;
Cellular Biotechnology and Hematology, University La Sapienza, Rome, Italy; Novartis, East
Hanover, USA; Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Background: Nilotinib and dasatinib are the next generation of tyrosine kinase inhibitors (TKIs) which
have been developed for use in the treatment of imatinib-resistant/intolerant CML. Few therapeutic
options are available for patients (pts) with CML who fail to benefit from or to tolerate first, imatinib,
and then, a second generation TKI such as dasatinib and nilotinib. This phase II open-label study was
designed to evaluate the safety and efficacy of nilotinib in such pts who either failed or were intolerant
to imatinib and dasatinib. Methods: Nilotinib was administered at a dose of 400 mg twice daily (BID)
to pts with CML-CP, -AP, and -BC who previously received and either failed or were intolerant to
imatinib and dasatinib. Pts who had inadequate hematologic and/or cytogenetic responses at 28 days
or who had disease progression could be escalated to 600 mg BID in the absence of safety concerns.
Results: A total of 67 evaluable pts are reported with CML-CP (27), -AP (15), and -BC (25 total; 15
myeloid, 8 lymphoid). Overall, 25% of pts had extramedullary disease at baseline (14 spleen, 6 liver).
For all pts, median time from first diagnosis was 20 (<1-266) months. The median duration of
nilotinib exposure was 85 (2-542) days with median dose intensity of 800 (211-1093) mg/day. A total
of 22 (33%) pts with dasatinib failure remained on nilotinib and 45 (67%) discontinued (8 for adverse
events, 27 for disease progression). Of 17 pts with CML-CP who did not have a complete
hematologic response (CHR) at baseline, 11 (65%) achieved a CHR at 4-month follow-up. Of all 22
pts with CML-CP at 4-month follow-up, 7 (32%) had a major cytogenetic response (3 complete, 4
partial). Disease progression occurred in only 2 pts with CML-CP, both of whom had CHR at
baseline. Of 13 evaluable pts with CML-AP, 3 (23%) demonstrated no evidence of leukemia and 3
(23%) had a return to chronic phase (RTC) after 4 months of nilotinib therapy. No pts with CML-AP
had disease progression at 4 months. Of 20 evaluable pts with CML-BC, 3 (15%) achieved CHR, 1
(5%) had RTC, and 6 (30%) had disease progression. For all pts (N=67), the most common grade 3/4
hematologic adverse events reported were neutropenia (51%), thrombocytopenia (44%), and anemia
(21%). The most frequent grade 3/4 nonhematologic adverse events reported were pyrexia (8%),
anorexia and headache (3%), and diarrhea, asthenia, constipation, fatigue, and myalgia (2% each). 3
pts had pleural effusion and 1 had pericardial effusion during nilotinib therapy. Conclusion: Nilotinib
has impressive clinical activity in these heavily pretreated pts with CML-CP, -AP, or -BC in whom
both imatinib and dasatinib have failed. In addition, nilotinib tolerability and safety profile in this
subset of pts was similar to that reported for pts who failed only imatinib.
Abstract #1029 appears in Blood, Volume 110, issue 11, November 16, 2007
1040] Nilotinib Is Associated with Minimal Cross Intolerance to Imatinib in Patients with
Imatinib-Intolerant Philadelphia-Positive (Ph+) Chronic Myelogenous Leukemia (CML) in
Either Chronic Phase (CP) or Accelerated Phase (AP). Session Type: Poster Session, Board
#194-I
Jorge Cortes, Elias Jabbour, Andreas Hochhaus, Philipp le Coutre, Michele Baccarani, Kapil N.
Bhalla, Gert Ossenkoppele, Norbert Gattermann, Ariful Haque, Neil Gallagher, Francis Giles, Hagop
M. Kantarjian MD Anderson Cancer Center, Houston, TX, USA; Klinikum Mannheim der Univ.
Heidelberg, Mannheim, Germany; Humboldt-Universitat, Berlin, Germany; Univ Bologna Institute of
Hematology Medical Oncology Seragnoli, Bologna, Italy; H. Lee Moffit Cancer Center, Tampa, FL,
USA; Free University, Amsterdam, Netherlands; University of Dusseldorf, Dusseldorf, Germany;
Novartis; The Cancer Therapy Research Center, San Antonio, TX, USA
Nilotinib, a highly selective BCR-ABL tyrosine kinase inhibitor that is 30-fold more potent than
imatinib, represents an important treatment option for pts with imatinib-resistant or -intolerant
Ph+CML. Reported are results from a phase II, open-label study evaluating the safety and efficacy of
nilotinib in imatinib-resistant or intolerant Ph+CML. Imatinib resistance was defined as treatment
with imatinib 600 mg/d with disease progression ( 50% increase in WBCs, blasts, basophils, or
platelets) or no hematologic response after 4 wks. Imatinib intolerance was defined as no prior MCyR
and discontinuation of imatinib due to Grade 3/4 AE or persistent (>1 mo) or recurrent Grade 2 AE
(recurred >3x) despite optimal supportive care. Nilotinib-imatinib cross-intolerance was defined as
treatment with nilotinib and occurrence (regardless of causality) of Grade 3/4 of the same AE that led
to discontinuation of imatinib therapy. Planned starting dose was nilotinib 400 mg BID but could be
escalated to 600 mg BID for lack of response. Of 320 pts with CML-CP, 94 (29.4%) were enrolled
for imatinib-intolerance for either nonhematologic and/or hematologic AEs, of these, 71 (76%) had
Grade 3/4 AEs at study entry. Of 127 pts with CML-AP, 24 (18.9%) were enrolled for
nonhematologic and/or hematologic imatinib-intolerance; of these, 16 (67%) had Grade 3/4 AEs at
study entry. Some pts had >1 AE satisfying criteria for intolerance. Only 2/71 (3%) pts with
nonhematologic imatinib-intolerance experienced a recurrence of similar Grade 3/4 AEs during
nilotinib therapy. Of 37 pts with hematologic intolerance to imatinib, 19/37 (51%) did not develop
Grade 3/4 or similar events during nilotinib therapy. Median duration of nilotinib exposure was 350.5
days in CML-CP and 141.5 days in CML-AP with median dose intensities of 725.8 mg/d and 768.8
mg/d, respectively. Only 1 pt (CML-AP) required a dose escalation to 600 mg BID. Although nilotinib
and imatinib have some molecular similarities, these results support previous findings of minimal
occurrence of cross-intolerance. These results also suggest important differences in safety profiles
between imatinib and nilotinib. Thrombocytopenia appears to be the only intolerant AE that may
recur with nilotinib. These results support nilotinib s excellent tolerability and indicate that it can be
used effectively in both CML-CP and -AP pts with imatinib-intolerance.
CML-CP Pts with Intolerance (N=94) CML-AP Pts with Intolerance (N=24)
Intolerance AEs Imatinib Intolerance Grade 3/4 AE during Nilotinib Imatinib
Intolerance Grade 3/4 AE during Nilotinib
Non-hematologic 56 2 15 0
Rash/Skin 26 0 5 0
Fluid Retention 17 0 5 0
GI 16 1 1 0
Liver Toxicity 10 1 3 0
ALT 4 0 1 0
AST 4 1 0 0
Myalgia/arthralgia 9 0 2 0
Hematologic 29 16 8 3
Thrombocytopenia 24 13 5 1
Neutropenia 8 4 3 2
Anemia 2 1 1 0
Abstract #1040 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