LETTER TO THE EDITOR
Secondary resistance to sorafenib in two patients
with acute myeloid leukemia (AML) harboring FLT3-ITD
mutations
Sebastian Scholl
&
Baerbel Spies-Weisshart
&
Anne Klink
&
Lars-Olof Muegge
&
Hans-Joerg Fricke
&
Andreas Hochhaus
Received: 4 March 2010 / Accepted: 30 June 2010 / Published online: 21 July 2010
#
Springer-Verlag 2010
Dear Editor,
We report on two patients with acute myeloid leukemia
(AML) initially presenting in 2007. Both patients were
tested positive for the FLT3-ITD mutation and were
therefore treated with the FLT3 tyrosine kinase inhibitor
sorafenib (400 mg/day) after progress of AML following
several protocols of conventional chemotherapy. Both
patients responded with a significant reduction of peripheral
blast counts after 10 to 17 days leading to hematological
response for 12 and 14 weeks, respectively. At the time of
relapse, molecular analysis investigating mutations of both
tyrosine kinase domains by sequencing of each individual
FLT3-ITD cDNA did not demonstrate any additional
mutations. We therefore suggest that the secondary resis-
tance to sorafenib is mediated by other mechanisms than
the acquisition of secondary mutations of FLT3 in these
patients.
FLT3-ITD mutations represent the second most frequent
molecular aberration in AML leading to a constitutive
activity of the class III receptor tyrosine kinase FLT3.
FLT3-ITD mutations can be found in 25–30% of all AML
patients and are associated with a reduced disease-free
survival and overall survival [1–3].
The bi-aryl urea sorafenib (BAY 43-9006, Bayer Schering,
Leverkusen, Germany) that has been approved for the
treatment of several solid tumors, e.g. renal and hepatocellular
carcinoma, is able to significantly inhibit FLT3 including
activating FLT3 mutations like FLT3-ITD at a nanomolar
concentration [4, 5]. Furthermore, in vitro analysis of several
FLT3 inhibitors revealed a different spectrum of additional
mutations that may confer resistance to these inhibitors [6].
Recently, several clinical studies investigating the feasibility
and efficacy of sorafenib in a small cohort of patients with
relapsed FLT3-ITD positive AML have been reported,
including a case report demonstrating even a molecular
complete remission following sorafenib treatment in a
patient with AML who relapsed after allogeneic stem cell
transplantation [5, 7–9]. So far, there is no report on analyses
of FLT3-ITD kinase domain sequences in patients with
progress of AML after treatment with sorafenib.
Patient #1 was a 59-year-old man with AML M2
according to the French American British (FAB) classifica-
tion presenting with a hyperleukocytosis at primary
diagnosis. Cytogenetic and molecular genetic analyses
revealed a normal karyotype and the presence of a FLT3-
ITD as well as a NPM1 mutation. The patient received an
induction chemotherapy consisting of idarubicin and
intermediate-dosed cytarabine resulting in a complete
hematologic remission of AML. Consolidation chemother-
apy consisted of three courses with alternating anthracy-
clines (idarubicin versus mitoxantrone) combined with
intermediate-dosed cytarabine due to a lack of availability
of a sibling or unrelated donor at this time point. Only
3 months after consolidation therapy has been completed,
disease reoccured not only in the bone marrow but also as
meningeosis leukemia. Furthermore, karyotype analysis
demonstrated a translocation t(9;18) at early relapse. This
patient was subsequently treated with high-dosed cytara-
bine and cyclophosphamide and received an additional
intrathecal therapy. After the first course of this salvage
protocol, a partial remission could be documented while
there was a second progress of AML shortly after
S. Scholl (*)
:
B. Spies-Weisshart
:
A. Klink
:
L.-O. Muegge
:
H.-J. Fricke
:
A. Hochhaus
Department of Hematology/ Oncology, Universitätsklinikum Jena,
Erlanger Allee 101,
07740 Jena, Germany
e-mail: sebastian.scholl@med.uni-jena.de
Ann Hematol (2011) 90:473–475
DOI 10.1007/s00277-010-1027-9