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

12 th Congress of the European Hematology Association
11% and lipase elevations in 15% of nilotinib pts (1 patient developed
Grade 1/2 pancreatitis; no Grade 3/4 pancreatitis), while dasatinib abnormalities
are hypophosphatemia in 11% and hypocalcemia in 22%. Rates
of Grade 3/4 non-hematologic AEs such as pleural effusion, GI bleeding,
arrhythmia, and pneumonia/infection are >2-7 times higher for dasatinib
than nilotinib. Summary and Conclusions. The toxicity profiles of the second
generation TKIs for imatinib resistant/intolerant CML-CP appear to
be different and favor nilotinib with its reduced rates of Grade 3/4 AEs
even with longer median duration of drug exposure compared to dasatinib.
Further analysis is required to understand the cost impact to health
care payers of the differences in safety profiles among the new TKIs.
Table 1.
0553
WITHIN THE P-LOOP GROUP, THE Y253H AND E255K/V ABL KINASE DOMAIN
MUTATIONS ARE OF PARTICULAR SEVERE PROGNOSIS IN CHRONIC MYELOGENOUS
LEUKEMIA PATIENTS RESISTANT TO IMATINIB MESYLATE
F. Nicolini, 1 F.E. Nicolini, 1 S. Corm, 2 S. Hayette, 3 Q.H. Le,1 D. Bories, 4
S. Giraudier, 4 M. Tulliez, 4 N. Sorel, 5 F. Guilhot, 5 D. Rea, 6
J-M. Cayuela, 6 P. Rousselot, 7 M.P. Gaub, 8 F. Maloisel, 8 F.X. Mahon, 9
L. Legros, 10 P. Cony-Makhoul, 11 J.J. Kiladjian, 12 O. Tournilhac, 13
D. Guyotat, 14 M. Delain, 15 V. Leblond, 16 B. Varet, 17 M. Michallet, 1
C. Roche-Lestienne, 18 C. Preudhomme18 1 Edouard Herriot Hospital, LYON; 2 Hôpital Huriez, LILLE; 3 Centre Hospitalier
Lyon Sud, PIERRE-BENITE; 4 Hôpital Henri Mondor, CRETEIL; 5 Hôpital
Jean Bernard, POITIERS; 6 Hôpital Saint Louis, PARIS; 7 Hospital Jean Mignot,
LE CHESNAY; 8 Hôpital Civil, STRASBOURG; 9 Hôpital Pellegrin, BOR-
DEAUX; 10 Hôpital de l'Archet, NICE; 11 Centre Hospitalier, ANNECY; 12 Hôpital
Avicenne, BOBIGNY; 13 Hôtal Dieu, CLERMONT-FERRAND; 14 ICL,
SAINT-ETIENNE; 15 Hôpital Bretonneau, TOURS; 16 Pitié Salpêtrière Hospital,
PARIS; 17 Hôpital Necker, PARIS; 18 Hôpital Calmette, LILLE, France,
Despite its remarkable efficacy in chronic myelogenous leukemia
(CML) resistance to imatinib mesylate (IM) may arise, and the onset of
BCR-ABL point mutations remains the main cause identified, being
responsible for resistance. Among these mutations, some located in the
ATP binding loop (P-loop: residues 248-255) or at residue 315 seem particularly
critical by disturbing IM binding or by altering the flexibility of
the ABL kinase domain. The poor clinical prognosis of these mutations
is generally accepted but still debatable. Among the P-loop group, biochemistry
and cellular assays suggest that there is some heterogeneity
in impairing the response to IM and mutations located at residues 253
and 255 are responsible for particularly high IC50 values in vitro. In a vast
retrospective study from 5 different French centers, we analysed and
compared the features and clinical outcomes of 75 CML patients treated
with IM and presenting either clinical, cytological, cytogenetical
resistance or molecular progression. Progression has been defined as a
loss of any previous response, progression to a more advanced phase and
a ≥2-fold increase in BCR-ABL/ABL ratio confirmed on 2 assessments 3
months apart. Fourty-six patients (32M/14F, median age 52) harboured
49 P-loop mutations [Group 1 (G1)] and 29 patients (19M/10F, median
age 52) harboured 37 mutations with at least a T315I mutation (± other)
[Group 2 (G2)], as detected by direct sequencing. At mutation discov-
206 | haematologica/the hematology journal | 2007; 92(s1)
ery 24 patients (52%) were in chronic phase (CP), 12 (26%) in accelerated
phase (AP), 10 (22%) in blast crisis (BC) in G1 and 12 (41%), 4
(14%), 13 (45%) in G2 respectively. The median duration of IM was 16
months (1.3-65.6) for G1 and 19 (0-57.6) for G2 (p=ns). In patients who
had received IFN prior to IM, duration of IFN was similar between the
2 groups (5 months (0-89) for G1 vs 9 months (0-131) for G2, p=ns). The
median interval between diagnosis and day 1 of IM was 16 months (0-
61.5) for G1 and 13 months (0-49.5) (p=ns) for G2. Univariate analysis
for gender, age, sokal, prior treatment with IFN, initial dose of IM, intervals
between diagnosis-IM start, diagnosis-mutation detection, IMmutation
detection and major cytogenetic response with IM, did not
show any significant impact of these variables. Multivariate analysis
demonstrated a significantly worse PFS since IM start for E255K/
V+Y253H mutants vs other P-loop mutants (p=0.016, HR:2.96, 95%CI:
1.22-7.16). IFN treatment prior to IM was associated with better survival
rates (p=0.00013, HR:0.12, 95%CI: 0.04-0.35). Progression free survival
(PFS) Kaplan Meier curves for all phases, since IM start showed a significant
better survival for other P-loop mutations than Y253H, E255K/V
and T315I groups (p=0.03) (See Figure 1). In conclusion, our results confirm
that P-loop and T315I mutations are associated with poor prognosis,
but they show that Y253H and E255K mutations are of particularly
severe prognosis within the P-loop group as suggested by in vitro data.
Those mutations would require early therapeutic intervention in order
to improve survival
Figure 1. PFS, CML all phases according to mutation status.
0554
NILOTINIB THERAPY AFTER DASATINIB FAILURE IN PATIENTS WITH IMATINIB-RESIS-
TANT OR-INTOLERANT CHRONIC PHASE AND ACCELERATED PHASE PHILADELPHIA-POS-
ITIVE CHRONIC MYELOGENOUS LEUKEMIA
F. Giles, 1 P. Le Coutre, 2 K. Bhalla, 3 G. Rosti, 4 G. Ossenkoppele, 5
G. Alimena, 6 A. Weitzman, 7 A. Haque, 7 Y. Shou, 7 H. Kantarjian1 1 MD Anderson Cancer Center, HOUSTON, USA; 2 Campus Virchow
Klinikum, Charite, BERLIN, Germany; 3 University of South Florida, TAMPA,
USA, 4 Institute of Hematology and Oncology, BOLOGNA, Italy; 5 Department
of Pathology, Free University, AMSTERDAM, Netherlands; 6 University La
Sapienza, ROME, Italy; 7 Novartis Pharmaceuticals Corporation, EAST
HANOVER, USA
Background. Nilotinib is a potent, highly selective, aminopyrimidine
inhibitor which is 30-fold more potent in vitro than imatinib and active
against 32/33 imatinib-resistant cell lines with Bcr-Abl mutations. Aims.
These results are from an ongoing phase II study evaluating the efficacy
and safety, as defined by hematologic and cytogenetic response rates
(HR/CyR), of nilotinib administered at a daily dose of 400 mg BID to
patients (pts) with Philadelphia-positive (Ph + ) chronic myelogenous
leukemia (CML) in chronic phase (CP), accelerated phase (AP), and blast
crisis (BC) who were resistant or intolerant to imatinib and dasatinib.
Methods. All pts signed an informed consent and received nilotinib for
an unapproved indication. Results. Data from 42 pts are available. Included
were 16 CP, 9 AP, and 17 BC; 13 myeloid; 4 lymphoid) pts were
included. Median age 58 (19 -78) years; median time since first diagnosis
of CML was 18 (0.1-166) mos. Of the 42 pts, 10 (24%) had
extramedullary involvement. Median exposure was 81 (4-420) days with