Annual Meeting Proceedings Part 1 - American Society of Clinical ...

440s Leukemia, Myelodysplasia, and Transplantation
6596 General Poster Session (Board #21G), Mon, 1:15 PM-5:15 PM
Omacetaxine mepesuccinate in chronic-phase chronic myeloid leukemia
(CML) in patients resistant, intolerant, or both to two or more tyrosinekinase
inhibitors (TKIs). Presenting Author: Luke Paul Akard, Indiana
Blood and Marrow Transplantation, Indianapolis, IN
Background: Omacetaxine mepesuccinate (“omacetaxine”) is a first-inclass,
reversible, transient inhibitor of protein elongation that facilitates
tumor cell death without depending on BCR-ABL signaling. Clinical activity
was shown in two phase 2, open-label, multicenter studies of patients with
treatment-resistant CML who had failed at least prior imatinib, many of
whom were also resistant to or intolerant of dasatinib and/or nilotinib.
Methods: A subset of data from the phase 2 studies included patients in
chronic phase who were resistant/intolerant to �2 approved TKIs. Omacetaxine
1.25 mg/m2 was given subcutaneously twice daily: �14 consecutive
days/28-day cycle for induction, �7 days/cycle as maintenance.
Patients had never achieved or lost response to �2 TKIs (R group), were
intolerant of �2 TKIs (I), or resistant to 1 and intolerant of another (R/I)
were evaluated. Results: Of 81 patients (median age, 58 years), 69 were R,
7 I, and 5 R/I. Major cytogenetic response occurred in 13 (19%) in the R
group (median duration not reached), 2 (29%) I (median duration 7.4
months), and 1 (20%) R/I (duration 17.7 months). For all patients, cycles
of exposure and study duration were 7 cycles and 9.1 months (R); 4 cycles,
7.3 months (I); and 2 cycles, 2.3 months (R/I). Median overall survival in
months were 33.9 (R), not reached (I), and 25.0 (R/I). Of 66 (81%)
patients with treatment-related grade 3/4 adverse events (AEs), the most
common were thrombocytopenia in 44 R, 6 I, and 4 R/I patients and
neutropenia in 32 R, 4 I, and 1 R/I. Fifteen patients had an AE leading to
discontinuation (10 R, 2 I, 3 R/I), primarily disease progression. There were
9 deaths (the most common were disease progression, sepsis), 8 I, 1 R/I; 2
were considered related to treatment (both sepsis). Conclusions: This
subset analysis of patients with chronic-phase CML and prior therapy with
�2 TKIs shows that omacetaxine provides efficacy and tolerability across
TKI-R, I, and R/I groups. Interpretation of the I and the R/I group data was
limited by small sample sizes. Support: Teva Pharmaceutical Industries
Ltd.
6598 General Poster Session (Board #22A), Mon, 1:15 PM-5:15 PM
Comparison of fludarabine (F), cyclophosphamide (C), and rituximab (R)
versus FCR plus bevacizumab (B) in relapse chronic lymphocytic leukemia
(CLL). Presenting Author: Hun Ju Lee, University of Texas M. D. Anderson
Cancer Center, Houston, TX
Background: There is significant data to show that vascular endothelial
growth factor (VEGF) is important in the development and progression of
CLL. Bevacizumab (B) is an anti-VEGF monoclonal antibody associated
with improvement in progression free survival (PFS) when combined with
chemotherapy in pts with solid malignancies. FCR is the most active
chemoimmunotherapy in treatment of CLL. We report data on a phase II
trial combining FCR-B and comparing the results to those seen in a trial
with FCR for pts with relapsed CLL (Badoux et al. Blood, March 2011).
Methods: FCR consisted of F: 25 mg/m2 and C: 250 mg/m2 on D2-4; R: 375
mg/m2 on D1 (for the first course) and 500 mg/m2 for courses 2-6, every 4
weeks for 6 courses. FCR-B consisted as above for FCR and (B) 10 mg/kg
was given on D3 of each cycle. Indications for treatment and response
assessment were according to 1996 NCI-WG guidelines for both groups.
Results: Baseline characteristics, complete remission (CR), overall response
rate (ORR), PFS and OS of relapsed CLL pts are shown (Table).
Conclusions: In relapsed pts with CLL, FCR-B showed a trend toward
improved PFS compared to FCR.
Characteristics FCR-B (%)[range] FCR (%)[range] P-value
N 62 284
Median age, yrs 64 [30-84] 60 [31-84]
Median # of prior treatments 2 [1-5] 2 [1-10]
Alkylating agent and (F) refractory 5 (8) 33 (11)
Prior exposure to FCR 52 (84) 78 (27)
Rai stage
0-II 26 (42) 154 (54)
III 9 (14) 34 (12)
IV 27 (44) 96 (34)
Karyotype/FISH
Diploid/13q- 22 (36) 97 (34)
11q- 25 (40) 16(6)
� 12 3 (5) 13 (5)
Complex 1 (2) 22 (8)
Abn 17p 11 (18) 20 (7)
Others 0 14 (5)
Response
CR 13 (21) 85 (30)
ORR 44 (71) 210 (74)
Overall Median (mo) [95% CI]
PFS 34 [Not reached (NR)] 23 [18-27] Not significant (NS)
OS NR 47 [40-53] NS
Prior chemoimmunotherapy (FCR)
PFS 34 [16-52] 20 [17-22] NS
OS 38 [NR] 43 [36-49] NS
6597 General Poster Session (Board #21H), Mon, 1:15 PM-5:15 PM
FLT3 mutations in myelodysplastic syndromes (MDS) and chronic myelomonocytic
leukemia (CMML). Presenting Author: Pavan Kumar Bhamidipati,
Synergy Medical Education Alliance/Michigan State University,
Saginaw, MI
Background: FLT3 mutations occur in one third of acute myeloid leukemia
(AML) patients (pts) and predict poor outcome. The incidence and impact
of FLT3 in MDS/ CMML is unknown. Methods: We conducted a retrospective
review at MDACC to identify FAB MDS/ CMML pts with FLT3 mutations at
diagnosis. Results: From 1996 to 2010; 2052 MDS/ CMML pts had
mutation analysis. 45 (2.2%) had FLT3 mutations (internal tandem
duplication-ITD or D835) at diagnosis. 29 pts had MDS and 16 had CMML.
Median (Med) age was 64 years (21 to 83) and 69% were males. FAB
groups: 3 pts with refractory anemia (RA), 11 pts with refractory anemiaexcess
blasts (RAEB), 18 pts with refractory anemia-excess blasts in
transformation (RAEB-T) and 13 pts with CMML. IPSS: 3 in Low (7%), 16
in Int-1 (36%), 11 in Int-2 (24%), and 15 in High (33%). Med white count,
hemoglobin, platelet count and marrow blast percent at diagnosis were 5.2
x109 /l (1.2 to 211), 10.0 g/l (6.8 to 14.9), 78 x 109 /l (8 to 429), and 14%
(1 to 28), respectively. FLT3 ITD and FLT3 D835 mutations were present
in 32 (71%) and 13 pts (29%), respectively. Karyotype was diploid in 30
(66%); -5/-7 in 5 (11%), 11q in 1 (2%), and others in 9 pts (19%). All 5
pts with -5/ -7 had the ITD mutation. Concurrent mutations were identified
in RAS, NPM1 and C-Kit in 6 (13%), 3 (7%) and 1 (2%) pt, respectively.
Med overall survival (OS) for FLT3 pts was 15 months compared to 17
months for non FLT3 pts (P�0.9). 18 pts had RAEB-T: 13 (72%) received
AraC-based therapy and 3 (17%) received hypomethylating therapy (HMT)
with complete remission (CR) in 14 pts (78%). 14 pts had RA/ RAEB: 5
(36%) received AraC-based therapy and 7 (50%) received HMT with CR in
5 (37%) and hematological improvement (HI) in 4 (28%). 13 pts had
CMML: 4 (31%) received AraC-based therapy and 6 (46%) received HMT
with CR in 3 (23%) and HI in 3 (23%). Repeat FLT3 was available on 16
pts achieving any response and was absent/ decreased in 14 (88%), stable
in 1 (6%) and increased in 1 (6%). Notably, the 14 pts with absent/
decreased FLT3 had med OS of 27 months versus 12 months for remaining
group (P�0.004). Conclusions: FLT3 occurs in MDS/ CMML at a lower
frequency than AML and does not predict poor outcome. Pts who achieve
absent/ decreased FLT3 seem to have significantly improved overall
survival.
6599 General Poster Session (Board #22B), Mon, 1:15 PM-5:15 PM
Expression levels of nucleoside transporter hENT1 and dCK enzyme, as
prognostic factors in patients with AML treated with cytarabine. Presenting
Author: Carmen Corrales-Alfaro, Instituto Nacional de Cancerologia, Mexico
City, Mexico
Background: Cytarabine has been set as the main drug included in different
schemas for the treatment of AML patients. This drug requires inflow to the
cell by the nucleoside transporter hENT1 and its activation rate is limited
by dCK enzyme. Therefore decreased expression levels of these genes may
influence response rate to this drug. Methods: AML patients � 15 years,
without previous treatment were included. After informed consent signature,
peripheral blood was obtained and DNA was extracted by standard
methodology. Amplification of hENT1 and dCK genes was done by RT-PCR.
Clinical parameters were registered. All patients received cytarabine �
doxorrubicine as induction regimen (7 � 3 schema). Descriptive statistics
was used. Uni- and multivariate analysis was done to determine factors
influencing on response and overall survival. This protocol was approved by
local IRB. Results: From January till December 2011, 22 patients have
been included. Median age was 36 years (15-72 y), 52.3 % were male.
According with FAB classification, M2 subtype was the most frequent
(28.5 %). All patients had an adequate performance status (ECOG 1 & 2 �
34 & 66 %, respectively). Cytogenetic risk was considered as intermediate
risk in 38 %, followed by unfavorable in 28 %. Complete response was
achieved in 58 %. Higher hENT1 expression levels was the only factor
influencing on response and survival by Spearmen correlation analysis.
Conclusions: These are preliminary results but are highly suggestive that
pharmacogenetic analysis regarding cytarabine inflow may be decisive in
AML patients. Our results require to be confirmed with a larger sample, and
a longer follow-up.
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