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

12 th Congress of the European Hematology Association
-intolerant Philadelphia-positive (Ph + ) chronic myelogenous leukemia
(CML). Results of a subset of pts with Ph + CML-chronic phase (CP) or -
accelerated phase (AP) who received nilotinib for imatinib-intolerance are
reported. All pts signed an informed consent and received nilotinib for an
unapproved indication. Methods. Pts were part of a phase II open-label
study evaluating the safety and efficacy of nilotinib in imatinib-resistant
or -intolerant Ph + CML-CP. Imatinib resistance was defined using standard
criteria. Imatinib intolerance was defined as the absence of a prior
major cytogenetic response (MCyR) and discontinuation of imatinib due
to grade 3/4 adverse event (AE) or persistent (>1 mo) or recurrent grade
2 AE (recurred >3 times) despite optimal supportive care. The proportion
of pts achieving MCyR was the primary endpoint; safety and toxicity
were secondary endpoints. Planned starting dose was nilotinib 400 mg
BID, but could be escalated to 600 mg BID for lack of response. Nilotinib
cross-intolerance was defined as pts who experienced any grade 3/4 AE
with the same preferred term that was identified for their imatinib-intolerance.
All pts signed an informed consent and received nilotinib for an
unapproved indication. Results. Of 318 pts with CML-CP enrolled (median
duration of exposure 245 days), 95 pts were enrolled for imatinibintolerance
for either nonhematologic and/or hematologic AEs. Of the
120 pts with CML-AP enrolled (median duration of exposure 137.5 days),
22 pts were enrolled for imatinib-intolerance. Some pts had >1 AE satisfying
the criteria for intolerance. The frequency of grade 3/4 AEs in both
CP and AP pts for imatinib and nilotinib is shown (Table 1). Only 2/109
(3%) pts with nonhematologic imatinib-intolerance experienced a recurrence
of similar grade 3/4 AEs during nilotinib therapy. 42 pts were
enrolled with hematologic intolerance to imatinib (neutropenia, thrombocytopenia)
and only 7/42 (17%) pts developed similar events during
nilotinib therapy and discontinued nilotinib. All 7 pts experienced a recurrence
of grade 3/4 thrombocytopenia and discontinued nilotinib. Of 117
pts with imatinib intolerance, 103 had at least 6 mos of follow-up and
50% of these pts achieved MCyR, which is similar to that reported for
imatinib-resistant pts (45%), presumably because these pts also had imatinib-resistance.
Conclusions. These results demonstrate that nilotinib has
a very low rate of cross-intolerance with imatinib and can be used effectively
in both CML-CP and -AP pts with imatinib-intolerance. Thrombocytopenia
appears to be the only intolerant AE that may recur with
nilotinib. Although imatinib and nilotinib are chemically similar with an
identical target and mechanism of action in CML, there is minimal clinical
overlap in terms of intolerant symptoms. Overall, these results support
the excellent tolerability of nilotinib.
Table 1. Occurrence of Nilotinib Intolerance in Imatinib-Intolerant Pts.
320 | haematologica/the hematology journal | 2007; 92(s1)
0861
IN PATIENTS WITH CHRONIC MYELOGENEOUS LEUKEMIA (CML), RESPONSE DYNAMICS
TO NILOTINIB AFTER IMATINIB FAILURE DEPEND ON THE TYPE OF BCR-ABL MUTATIONS
S. Soverini, 1 G. Saglio, 2 S. Branford, 3 J. Radich, 4 D.W. Kim, 5
T. Hughes, 3 M. Mueller, 6 P. Erben, 6 A. Hochhaus, 6 Y. Shou, 7
A. Weitzman, 7 M. Baccarani, 1 G. Martinelli1 1 2 University of Bologna, BOLOGNA, Italy; University of Turin, OBASSANO,
Italy; 3Institute of Medical and Veterinary Sci, ADELAIDE, Australia; 4Fred Hutchinson Cancer Research Center, SEATTLE, USA; 5Catholic University of
Korea, SEOUL, South-Korea; 6Med. Fakultaet Mannheim, Uni Heidelberg,
MANNHEIM, Germany; 7Novartis Pharmaceuticals Corporation, EAST
HANOVER, USA
Background. Nilotinib (AMN107) is an orally bioavailable inhibitor of
the BCR-ABL tyrosine kinase with improved potency and specificity
over imatinib. In preclinical models, activity of nilotinib was also demonstrated
in 32/33 imatinib-resistant mutant cell lines. Aims. We sought to
investigate the efficacy of nilotinib in patients (pts) according to the type
of preexisting BCR-ABL mutations associated with imatinib resistance.
Methods. We have investigated peripheral blood samples from 183 chronic
phase (CP) and 51 accelerated phase (AP) CML pts who had been
enrolled in a phase II study investigating the efficacy and safety of 400
mg nilotinib BID after imatinib failure. Screening for BCR-ABL mutations
was performed by direct sequencing of the BCR-ABL tyrosine
kinase domain ranging from amino acid 230 to 490 (GenBank accession
no. M14752) and its surrounding regions. Results. Prior to nilotinib, 31 different
BCR-ABL mutations involving 23 amino acids were detected
affecting 43% of CP and 57% of AP pts. After 6 months of therapy, complete
hematologic response (CHR) was achieved in 57%, major cytogenetic
response (MCyR) in 42%, and complete cytogenetic response
(CCyR) in 24% of pts with mutations vs 79%, 57%, and 39% of pts
without mutations, respectively. Response dynamics were associated
with preclinical activity of nilotinib: MCyR was achieved in 17/32 pts
with mutations associated with preclinical IC50 to nilotinib of