12th Congress of the European Hematology ... - Haematologica

median dose intensity being 800 (216-1195) mg/day. 13 (31%) pts have
ongoing treatments and 29 (69%) pts discontinued treatment (16 disease
progression, 6 adverse event, 5 other reasons, and 2 deaths). The primary
endpoint for CP pts was CyR, while the primary endpoint for AP pts was
HR. 13/16 CP pts had no baseline complete hematologic response (CHR).
4/13 (31%) pts had major cytogenetic response (MCyR); 2 (15%) complete
and 2 (15%) partial cytogenetic response: 1 minor, 2 minimal, 3
none, 1 not assessable, and 2 disease progression. 5/13 had CHR. Of the
9 AP pts, 2 (22%) returned to CP, 6 (67%) were not available and there
was 1 (11%) death. Of the 17 BC pts, 3 (18%) had CHR 1 (6%) returned
to chronic phase, 5 (29%) had stable disease, 4 (24%) were not available,
and 4 (24%) had progressive disease. Overall, thrombocytopenia (33%),
pyrexia (29%), anemia (24%), and neutropenia (24%) were the most
common adverse events including all grades. The most common grade
3/4 adverse events were thrombocytopenia (26%), neutropenia (24%),
and anemia (7%). Any hematologic and/or cytogenetic responses were
observed in 4/8 CP and 3/7 AP patients with baseline mutations vs. 6/7
CP and 2/3 AP patients without baseline mutations. Summary and Conclusions.
Nilotinib has clinical activity in CML-CP, -AP, and -BC pts who
were resistant or intolerant to imatinib and have also previously failed
dasatinib therapy. In these heavily pre-treated pts, nilotinib administration
has acceptable safety and tolerability similar to that previously profiled.
Updated information will be presented at the meeting.
0555
A PHASE II STUDY OF NILOTINIB, A NOVEL TYROSINE KINASE INHIBITOR ADMINISTERED
TO IMATINIB-RESISTANT AND -INTOLERANT PATIENTS WITH PHILADELPHIA-POSITIVE
CHRONIC MYELOGENOUS LEUKEMIA IN CHRONIC PHASE
G. Martinelli, 1 G. Rosti, 1 P. Le Coutre, 2 K. Bhalla, 3 F. Giles, 4
G. Ossenkoppele, 5 A. Hochhaus, 6 N. Gatterman, 7 A. Haque, 8
D. Resta, 8 A. Weitzman, 8 M. Baccarani, 1 H. Kantarjian4 1 Institute of Hematology and Oncology, BOLOGNA, Italy; 2 Campus Virchow
Klinikum, Charite, BERLIN, Germany; 3 University of South Florida, TAMPA,
USA; 4 MD Anderson Cancer Center, HOUSTON, USA; 5 Department of
Pathology, Free University, AMSTERDAM, Netherlands; 6 III Medizinische
Klinik, MANNHEIM, Germany; 7 University of Dusseldorf, DUSSELDORF,
Germany; 8 Novartis Pharmaceuticals Corporation, EAST HANOVER, USA
Background. Nilotinib is a potent, highly selective, aminopyrimidine
inhibitor that in vitro is 30-fold more potent than imatinib and active
against 32/33 imatinib-resistant BCR-ABL mutations. Aims. This openlabel
study was designed to evaluate the safety and efficacy of nilotinib,
as defined by hematologic/cytogenetic response rates (HR/CyR), administered
at a daily dose of 400 mg BID to patients (pts) with imatinibresistant
or -intolerant Philadelphia-positive (Ph + ) chronic myelogenous
leukemia (CML) in chronic phase (CP). Methods. Nilotinib could be escalated
to 600 mg BID for pts who did not adequately respond to treatment.
All pts signed an informed consent and received nilotinib for an
unapproved indication. Results. 318 pts were enrolled including 223
(70.1%) with imatinib resistance and 95 (29.9%) with imatinib intolerance.
Median age was 58 (21-85) years and the median time since CML
diagnosis was 57.3 mos. 50.6% were men. Treatment with nilotinib is
ongoing for 221 (69.5%) pts. A total of 97 (30.5%) pts have discontinued
treatment. The median duration of nilotinib exposure was 245 (1-
502) days. The median average dose intensity for all pts was 796.6 (151-
1111.5) mg/day. The nilotinib dose was escalated for 41 (12.9%) pts.
Efficacy data are available for 280 pts with ″6 months of follow-up.
Major CyR (MCyR) was observed in 145 (51.8%) pts, of which 96
(34.3%) were complete and 49 (17.5%) partial. 10 (3.6%) pts had disease
progression. The median time to MCyR was 2.8 (0.9-11.1) months. 95
(33.9%) had a CHR at baseline and 185 (66.1%) did not. 137 (74.1%) of
the 185 pts without baseline CHR achieved CHR. The median time to
CHR was 1 (0.9-8.3) mo. Of 101 pts with baseline mutation analysis
performed, 45 (44.6%) had BCR-ABL mutations. Of the 318 pts included
in the safety analysis, overall the most frequent grade 3/4 adverse
events included thrombocytopenia (n=70, 22%), neutropenia (n=49,
15.4%), anemia (n=22, 6.9%), and elevated serum lipase (n=22, 6.9%).
3 (0.9) pts experienced QTcF >500 msec. Overall, there were 4 deaths (1
myocardial infarction and ventricular rupture, 1 coronary artery disease
and sudden death, 2 sepsis). Summary and conclusions. Nilotinib has
demonstrated significant clinical activity as defined by 51.8% MCyR
rate and 74.1% CHR rate, and an acceptable safety and tolerability profile
in pts with imatinib-resistant or -intolerant CML-CP.
12 th Congress of the European Hematology Association
0556
NILOTINIB MONOTHERAPY IN PATIENTS WITH IMATINIB-RESISTANT OR -INTOLERANT
PH+ CHRONIC MYELOGENOUS LEUKEMIA IN BLAST CRISIS OR RELAPSED/
REFRACTORY PH + ACUTE LYMPHOBLASTIC LEUKEMIA
O. Ottmann, 1 R. Larson, 2 H. Kantarjian, 3 P. Le Coutre, 4 M. Baccarani, 5
A. Weitzman, 6 F. Giles3 1 University of Frankfurt, FRANKFURT, Germany; 2 University of Chicago Hospital,
CHICAGO, USA; 3MD Anderson Cancer Center, HOUSTON, USA;
4 Campus Virchow Klinikum, BERLIN, Germany; 5 Institute of Hematology and
Oncology, BOLOGNA, Italy; 6 Novartis Pharmaceuticals Corporation, EAST
HANOVER, USA
Background. Nilotinib is a potent, highly selective, aminopyrimidine
inhibitor of BCR-ABL that in vitro is 30-fold more potent than imatinib.
It is active against 32/33 imatinib-resistant BCR-ABL mutations. Aims.
This open-label phase II study was designed to evaluate the safety and
efficacy of nilotinib at a dose of 400 mg BID in adult patients (pts) with
imatinib-resistant or -intolerant CML-BC or in pts with relapsed/refractory
Ph+ALL. The primary endpoints were investigator assessments of
best hematologic response (HR) and complete remission, respectively.
Methods. Daily doses of nilotinib could be escalated to 600 mg BID for
pts who did not adequately respond to treatment, and in the absence of
safety concerns. All pts signed an informed consent and received nilotinib
for an unapproved indication. Results. Safety and efficacy data are
reported for 120 BC (87 myeloid, 27 lymphoid, 6 unknown) and 41 Ph +
ALL pts (37 active disease, 4 residual disease; 38 relapsed, 3 refractory).
60% of pts had >35% Ph + metaphases for BC and 31% for Ph + ALL.
Median ages were 54 yrs for BC and 46 yrs for Ph + ALL pts. Chromosomal
abnormalities other than Ph + were noted in 64 (53%) BC and 12
(29%) Ph + ALL pts. Extramedullary involvement was present in 44 (37%)
BC and 3 (7%) Ph + ALL pts. Median treatment duration was 53 (1-441)
and 72 (3-363) days for BC and Ph + ALL, respectively. Median dose intensity
was 800 mg/day for both pt groups. Treatment is ongoing for 21
(18%) BC and 4 (10%) Ph + ALL pts. Most discontinuations were due to
disease progression (61 [51%] in BC; 26 [63%] in Ph + ALL). Hematologic
responses (HR) were observed in 42 (35%) BC pts. Of the 120 BC pts,
complete HR was reported in 25 (21%) pts, marrow responses (no evidence
of leukemia) in 7 (6%) pts, and return to chronic phase in 10 (8%)
pts. Complete remission was reported in 10 (24%) Ph + ALL pts, of which
1 pt had minimal residual disease. The most common grade 3/4 AEs
were thrombocytopenia (41%), neutropenia (28%), pneumonia (11%),
and anemia (27%) in BC and thrombocytopenia (24%) in Ph + ALL pts.
During the study period, death occurred in 9 (8%) BC and 3 (7%) Ph +
ALL pts. No Ph + ALL pt developed CNS disease while on therapy. Summary
and conclusions. Nilotinib monotherapy has significant clinical activity
and is well tolerated in pts with imatinib-resistant or -intolerant BC
and pts with relapsed/refractory Ph+ ALL. Nilotinib represents an important
new treatment option for these pts, in which there remains a high
unmet medical need. Given the safety and efficacy of nilotinib
monotherapy, the combination of nilotinib with systemic chemotherapy
warrants investigation in Ph + CML-BC or ALL. Updated data will be
presented at the meeting.
0557
A PHASE II STUDY OF NILOTINIB, A NOVEL TYROSINE KINASE INHIBITOR ADMINISTERED
TO IMATINIB-RESISTANT OR -INTOLERANT PATIENTS WITH PHILADELPHIA-
POSITIVE CHRONIC MYELOGENOUS LEUKEMIA IN ACCELERATED PHASE
P. Le Coutre, 1 R. Larson, 2 H. Kantarjian, 3 N. Gattermann, 4
A. Hochhaus, 5 A. Haque, 6 D. Resta, 6 A. Weitzman, 6 F. Giles, 3
S. O' Brien7 1 Campus Virchow Klinikum, BERLIN, Germany; 2 University of Chicago Hospital,
CHICAGO, USA; 3 MD Anderson Cancer Center, HOUSTON, USA;
4 University of Dusseldorf, DUSSELDORF, Germany; 5 III Medizinische Klinik,
MANNHEIM, Germany; 6 Novartis Pharmaceuticals Corporation, EAST
HANOVER, USA; 7 University of Newcastle, TYNE, United Kingdom
Background. Nilotinib is a potent, highly selective, aminopyrimidine
inhibitor of BCR-ABL that in vitro is 30-fold more potent than imatinib.
It is active against 32/33 imatinib-resistant BCR-ABL mutations. Aims.
This open-label study was designed to evaluate the safety and efficacy
of nilotinib, as defined by hematologic/cytogenetic response (HR/CyR)
rates, at a dose of 400 mg BID in patients (pts) with Philadelphia-positive
(Ph + ) imatinib-resistant or -intolerant chronic myelogenous leukemia
(CML) in accelerated phase (AP). Methods. Nilotinib could be escalated
to 600 mg BID for pts who did not adequately respond to treatment. All
haematologica/the hematology journal | 2007; 92(s1) | 207