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

2004 to January, 2006. At enrollment, 55 (12%) of them had der(9)
deletion and 387 (88%) had not. The 2 groups, with/without deletions,
were comparable (no significant difference in age, Sokal risk, imatinib
dose). Median observation time is 18 months (3-33 months). Fluorescence
in situ hybridization (FISH) analysis of bone marrow cells was
performed at diagnosis using BCR/ABL extra-signal, D-FISH or dualcolor
dual-fusion probes. Response monitoring was based on conventional
cytogenetic examination after 6 and 12 months on imatinib
(every 6 months thereafter) and quantitative molecular (Q-PCR) evaluations
(PB) after 3, 6 and 12 months on imatinib (every 6 months
thereafter). RESULTS At 6 months, complete cytogenetic response
(CCgR) rates were (deletions present/absent) 73%/67%, with a major
molecular response (MMR, defined as a Bcr-Abl/Abl x 100 ratio <
0.05%) rate of 44%/43%, respectively. At 12 months, CCgR rates were
85%/84% and MMR 58%/57% . No difference is statistically significant.
During the first year, no progression was reported among patients
with deletions, while 6 (1.5%) of non deleted patient progressed to
accelerated/blastic phase. Summary and Conclusions. The presence of
der (9) deletions do not constitute a poor prognostic factor for response
in early CP patients under imatinib treatment: the cytogenetic and
molecular response rates in the 2 groups, with and without der(9) deletions,
are superimposable. This finding is relevant to the long term
effect of imatinib treatment, since both the CCgR and the MMolR are
important and established indicator of long term survival. ACKNOWL-
EDGMENTS COFIN 2003, FIRB 2001, AIRC, CNR, Fondazione del
Monte di Bologna e Ravenna, European LeukemiaNet, AIL.
0907
THE INTRACELLULAR CONCENTRATIONS OF IMATINIB AND NILOTINIB, CAN BE
SUBSTANTIALLY ALTERED BY INTERACTION WITH OTHER DRUGS: STUDIES
WITH PROTON PUMP INHIBITORS
D. White, 1 V.A. Saunders, 1 P. Dang, 1 K. Lynch, 2 P. Manley, 2 T.P. Hughes1 1 2 IMVS and Hanson Institute, ADELAIDE; Novartis Pharmaceuticals, SYD-
NEY, Australia
Background. There is accumulating evidence that dose intensity is a
key determinant of molecular response in CML patients treated with
imatinib. Furthermore it has been demonstrated that trough imatinib
blood levels are predictive of cytogenetic and molecular response.
However, it is the concentration of imatinib within haemopoietic cells,
not plasma that is the major determinant of ABL kinase inhibition.
Factors that increase or reduce imatinib intracellular uptake and retention
(IUR) may therefore impact on response. Aims. To assess the
impact of drugs known to inhibit efflux pumps on the IUR of imatinib
and nilotinib. Proton Pump Inhibitors (PPIs) pantoprazole and
esomeprazole, were selected because they interact with efflux pumps,
and are commonly used in CML patients treated with either imatinib
or nilotinib. Methods. Using the IUR assay and [14C]-labelled nilotinib
or imatinib the effect of co administration of PPI’s were assessed after
2 hours exposure at 37oC. Further using the same approach the effect
of unlabelled imatinib on [14C]-nilotinib uptake, and unlabelled nilotinib
on [14C]-imatinib uptake were examined. Using cell lines, the
IC50 for imatinib and nilotinib were also assessed in the presence and
absence of PPI. Results. (Table 1). These results demonstrate a significant
decrease in the IUR for imatinib in the presence of either PPI. A
similar though not significant decrease was observed with the addition
of nilotinib. In contrast a statistically significant increase in the
IUR for nilotinib was observed when either PPIs or imatinib were
added. Furthermore serial IC50 experiments in K562 cells demonstrated
a dose dependant decrease in the IC50nilotinib when either PPI was
incorporated into the assay (IC50nilotinib:0 µM pantoprazole-350
nM, 200 µM pantoprazole-145 nM and 400 µM pantoprazole -83nM).
In contrast the IC50 for imatinib in the presence of PPI was increased
(IC50 0 µM pantoprazole-4.2 µM, 200 µM pantoprazole-10 µM and
400 µM pantoprazole -7 µM). Conclusions. Imatinib and nilotinib are
transported differently by haemopoietic cells. We have shown this
clearly with regard to influx mechanisms. 1 We now show that imatinib
increases nilotinib intracellular concentration significantly, but
the converse does not apply. The effects of PPIs are also contrasting
with both pantoprazole and esomeprazole significantly increasing
nilotinib, but not imatinib intracellular concentration. We speculate
that these interactions are due to competition and inhibition of efflux
pathways, most likely ABCB1 but possibly ABCG2. Monitoring plasma
concentrations of imatinib and nilotinib may not be sufficient to
ensure optimal intracellular concentrations of these kinase inhibitors.
Drug interactions are well recognised to alter plasma levels by affect-
ing hepatic metabolism. Our findings suggest such drug interactions
may also lead to excessive toxicity (in off-target cells) or reduced efficacy,
by significantly altering intracellular concentrations of these
kinase inhibitors. These effects will not be reflected in changes to
plasma drug levels.
Table 1.
Reference
12 th Congress of the European Hematology Association
1. White, D.L., et al. Blood 2006:108:697-704.
haematologica/the hematology journal | 2007; 92(s1) | 339