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

12 th Congress of the European Hematology Association
malignancies in vivo. Results. Inactivation of Icmt reduced splenomegaly
(Figure 1 C), the amount of immature myeloid cells in peripheral blood
(Figure 1 B), and tissue infiltration. Moreover, in the absence of Icmt
there was a dramatic reduction in the ability of K-RAS-expressing
hematopoietic cells to form colonies in methylcellulose in the absence
of exogenous growth factors (Figure 1D). Interestingly, the absence of
Icmt had no impact on the proliferation and differentiation of normal,
non-malignant hematopoietic cells. Finally, inactivation of Icmt reduced
lung tumor development and myeloproliferation phenotypes in a second
mouse model of K-RAS-induced cancer (Figure 1E-G). Conclusion. We
conclude that inhibition of Icmt significantly ameliorates phenotypes of
K-RAS-induced malignancies in vivo and that ICMT may be an attractive
therapeutic target.
Figure 1. Knockout of Icmt and K-RAS-induced malignancies. Bergo et al.
0925
PROGNOSTIC IMPACT OF CHROMOSOMAL ABNORMALITIES IN ELDERLY PATIENTS WITH
MULTIPLE MYELOMA TREATED WITH HIGH-DOSE MELPHALAN (MEL140) AND
AUTOLOGOUS STEM CELL TRANSPLANTATION
P. Liebisch, 1 C. Straka, 2 A. Wimmer, 1 C. Wendl, 1 A. Hinke, 3 S. Ibach, 3
H. Döhner1 1 University Hospital of Ulm, ULM; 2 Interne Klinik Dr. Argirov, BERG; 3 Wissenschaftlicher
Service Pharma (WiSP), LANGENFELD, Germany
Background. Although chromosomal aberrations (CA) have emerged as
important outcome predictors in multiple myeloma (MM), the prognostic
significance of many recurring genomic changes is still unknown.
Moreover, there is only scarce data on the implication of chromosomal
abnormalities in elderly patients (pts.) receiving high-dose chemotherapy
(HD-CTX) followed by autologous stem cell transplantation (ASCT).
Aims. To evaluate the prognostic relevance of recurring chromosomal
aberrations as detected by cIg-FISH for elderly pts. with MM receiving
HD-CTX and ASCT. Materials. Between 05/2001 and 08/2006, 549 pts.
60-70 yrs. of age with newly diagnosed symptomatic MM entered the
DSMM II trial of the Deutsche Studiengruppe Multiples Myelom to
346 | haematologica/the hematology journal | 2007; 92(s1)
receive two cycles of HD-CTX (melphalan 140 mg/sqm) followed by
ASCT after 3-4 cycles of dexamethason-based induction chemotherapy
(IC; arm A1) or no IC (arm A2). cIg-FISH and DNA probes mapping to
chromosome bands 1q21.2, 9q34, 11q25, 13q14, 14q32, 17p13, and
22q11 were applied to all pts. from whom sufficient bone marrow specimen
were obtained. 110 pts. with a median age of 64 yrs. for that information
on all genomic loci was available were included in the present
analysis. The clinical database was last updated in 01/2006. Results. The
median follow-up of time in the present series was 68 (0-238) weeks. Univariate
analysis showed significantly shorter EFS in 11 out of 110 pts.
(10%) with chromosome 17p13 deletion (17p'; 58 vs. 93 weeks, p=0.011)
and 16 out of 110 pts. (14.5%) with translocation t(4;14) (78 vs. 93 weeks,
p=0.027). Clinical and laboratory variables as well as all other CA had no
significant impact on EFS. Most likely due to the short follow-up time,
overall survival was not influenced by any parameter. Conclusions. 17p'
and t(4;14), but not 13q' or +1q were associated with a significantly shorter
EFS in elderly pts. receiving HD-CTX and ASCT. The next interim
analysis of the DSMM II trial will take place in 04/2007 and molecular
cytogenetic analysis of further cases is ongoing. This data (including multivariable
analysis) will be presented at the meeting.
Supported by grants from the Deutsche José Carreras Leukämie-Stiftung
(DJCLS-R04/04), the Deutsche Krebshilfe (70-3899-Li I), and the Wilhelm
Sander-Stiftung (No. 2002.098.1) to P.L. and H.D. The first two authors contributed
equally to this work.
0926
A NEW APPROACH TO MRD MONITORING IN AML, REAL-TIME QUANTIFICATION
OF MULTIPLE AML-UPREGULATED GENES
K. Tobal, G.J. Mufti
King's College Hospital, LONDON, United Kingdom
MRD monitoring in AML plays an important role in assessing the
effectiveness of treatment and identifying patients at high risk of relapse,
which enable intervention to prevent its onset. Several chromosomal
translocations have been identified in AML, but are only detected in
approximately 30% of patients. It is therefore vital to identify other type
of MRD markers, such as those that are either have a restricted expression
to or significantly upregulated in leukaemic cells, an example is WT1
gene, which is overexpressed at levels exceeding 104 copies in approximately
60% of AML patients. The main criterion of such markers is that
they should be upregulatde by at least 3 logs, to enable accurate and sensitive
protocols for MRD monitoring capable of detecting early increases
in MRD level and therefore enable clinical intervention. We have
examined a number of genes, using the above criterion (WT1, PRAME
and CA9, XAGE1, CCL23, CLL1, ST18, RHAMM, and SPAG6). Using
real-time RT-PCR (RQ-PCR) protocols for the quantification of these
transcripts, we examined their levels in 214 samples from 103 AML
patients at different phases of the disease (160 BM and 54 PB) and 15 normal
BM and 7 normal PB samples. Presentation samples were (60 BM, 21
PB), post induction chemotherapy (27 BM, 6 PB), stable remission (42 BM,
12 PB), poor remission/before the onset of relapse (18 BM, 10 PB), and at
haematological relapse (13 BM, 5 PB ). Of the above genes, only WT1,
PRAME, CA9, XAGE1, ST18 and SPAG6 conformed to the above criterion,
and as such could be suitable as MRD markers in AML. These markers
were able to offer accurate MRD monitoring for all 103 patients. Of
the presentation samples from 60 patients WT1, PRAME, CA9, XAGE1,
ST18, SPAG6 were shown as suitable for monitoring MRD in 43, 34, 12,
18, 21, and 18 patients respectively. The combination of WT1, PRAME
with any third marker is sufficient to provide MRD monitoring for all 60
patients examined at presentation. However, the combination of all these
6 markers provided multiple markers for each of 52/60 patients. The levels
of all transcripts decreased significantly in remission samples. Relapse
samples showed levels corresponding to those detected at diagnosis,
while patients examined 2-3 months before the onset of relapse showed
a significant increase in the levels of the chosen markers, compared to
those detected at remission. In 5 patients a single marker (WT1, PRAME,
or XAGE1) did not show a significant increase before the onset of haematological
relapse. However, in these patients, the second and third marker
showed the significant increase in their levels to indicate imminent
relapse. This finding shows the shortcoming of having a single AMLupregulated
transcript, such as WT1, for MRD monitoring, as compared
to having multiple AML-upregulated transcripts as MRD markers. These
data show the value of this alternative approach to MRD monitoring in
AML. These genes, taken together, were able to offer accurate MRD
monitoring for all patients examined and were able to distinguish patients
at high risk of relapse up to 3 months before its onset. This approach
could simplify MRD monitoring with a choice of few markers only.