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

430s Leukemia, Myelodysplasia, and Transplantation
6556 General Poster Session (Board #16G), Mon, 1:15 PM-5:15 PM
Maintenance therapy with arsenic after induction in an alternative and
long-term case for the prevention of recurrence of acute promyelocytic
leukemia during the period between November 2005 and December 2011.
Presenting Author: Mozaffar Aznab, Kermanshah University of Medicine,
Kermanshah, Iran
Background: Arsenic trioxide has been used in the first line treatment of
acute promyelocytic leukemia and also for recurrence after ATRA and
chemotherapy. In this study, it we used it in induction of remission and
maintenance therapy Methods: Between November 2005 to December
2011, 42 patients admitted in our department with APL diagnosis. There
were 27 male and 15 women with a median age of 28 years. Arsenic
trioxide started at 0.15 mg/kg intravenous infusion till patient’s bone
marrows achieve to complete remission. Then, after 28 days rest, we did
consolidation with Arsenic trioxide with the same dosage for 28 more days.
We continued treatment with 14 days courses of Arsenic trioxide every 3-4
months for 2 years, as maintenance therapy Results: Four patients died
during the first 20 days of treatment. Thirty-eight patients achieved to
remission. Two patients refused to continue treatment after achieving to
remission and excluded from this study. Thirty-six patients finished whole
treatment. After a median follow-up of 54 months, 4 patients died due to
disease relapse and one patient relapsed and initiated treatment with
Arsenic and ATRA. Five patients faced leukocytosis over 100,000/ml. In
these cases we were obligated to discontinue Arsenic for 3-4 days and did
chemotherapy by Danourobicin for 2 days. Totally 8 patients died during
remission induction and long-term follow up. One year, 3 and 5 years RFS
were 97%, 87.1% and 79.4 respectively and we didn’t observe any relapse
for patients who remained in remission after 5 years. Finally, 31 patients
are alive and free of disease. The overall survival was 79.5% for our cohort.
Conclusions: Arsenic trioxide is an effective treatment as the first line
therapy for new cases of APL and long term therapy with will reduce the risk
of diseases recurrence without any major toxicity in long time.
6558 General Poster Session (Board #17A), Mon, 1:15 PM-5:15 PM
Response rates in patients with relapsed/refractory acute myeloid leukemia
with FLT3-ITD mutation using 5-azacitadine plus sorafenib. Presenting
Author: Mona Lisa Alattar, University of Texas at Houston Health Science
Center, Houston, TX
Background: The outcome of patients with relapsed acute myeloid leukemia
(AML) with FLT3-ITD mutation is poor. Sorafenib is an inhibitor of FLT-3
kinase activity in nanomolar concentrations. We conducted this phase II
study to evaluate the efficacy and tolerability of the combination of
Sorafenib and 5-Aza for the treatment of patients with refractory or
relapsed AML with the particular emphasis on those with FLT3-ITD
mutation. Methods: Patients were eligible if they had relapsed or refractory
AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 daily
x 7 together with Sorafenib 200 mg BID X 28 days; cycles were repeated in
approximately 1-month intervals. Responses were assessed after first cycle
and then at the discretion of the treating physician at the time of the best
peripheral blood response. Results: 32 patients with AML with a median age
of 61 years (range, 24-87) were enrolled. They included 13 (41%) with
diploid cytogenetics, 9 (28%) with complex cytogenetics, and 10 (31%)
with miscellaneous chromosomal abnormalities. FLT-3-ITD was detected
prior to the initiation of treatment in 30/32 patients. Patients had received
a median of 2 prior treatments (range, 1-6). 12 (38%) patients had
received �3 prior regimens and 11 had failed therapy with a FLT3 kinase
inhibitor (6 with AC220, 1 with PKC412, and 5 with sorafenib, either as
monotherapy or with plerixafor); 2 had failed 2 prior FLT3 inhibitors. 10
patients were inevaluable as they never received therapy or discontinued it
before response assessment at one month. The overall CR/CRi rate among
the 22 evaluable patients is 50%, including 9 (41%) with CRi and 2 (9%)
with CR; with a median of 3 (range, 1-9) treatment cycles. The median time
to achieving CR/CRi was 3 months (range, 1-4) and the median duration of
CR/CRi was 3 months (range, �1–5.5). Three patients proceeded to
allogeneic stem cell transplant. The most common study drug-related
adverse events were rash and fatigue with no deaths attributable to study
medications. Conclusions: Combination of 5-Aza and Sorafenib is promising
for the treatment of patients with relapsed and refractory AML with
FLT-3-ITD mutation and may allow them to proceed to stem cell transplant.
6557 General Poster Session (Board #16H), Mon, 1:15 PM-5:15 PM
Effect of ROR1-targeting small molecules on chronic lymphocytic leukemia
(CLL) cells. Presenting Author: Hakan Mellstedt, Karolinska University
Hospital Solna, Stockholm, Sweden
Background: There is a great interest to develop targeting drugs for CLL,
both MAbs and small molecules, to improve the outcome for the disease.
ROR1, a receptor tyrosine kinase, is overexpressed on CLL cells but not on
normal cells. ROR1 is constitutively phosphorylated and siRNA transfection
induces leukemic cell death. The aim of the study is to produce small
molecules inhibiting the cytoplasmic tyrosine kinase activity of ROR1,
which could induce specific killing of leukemic cells. Methods: A highthroughput
screening assay in 384-format has been developed measuring
phosphorylation of a substrate peptide by human recombinant intracellular
ROR-1 kinase domain. A collection of 80.000 small molecules has been
screened generating two chemical series. Novel leads have been synthesized
and structure-activity-relationship has been developed using the
assay. Results: Three compounds were selected (KAN0173631,
KAN0438063, KAN0438175T). Freshly isolated leukemic CLL cells were
used as targets in addition to PBMC from healthy donors to test cytotoxicity.
The three compounds induced specific apoptosis of CLL cells (Annexin V/PI
and MTT) both at 24 and 48h. Efficacy index (EI), i.e. killing of leukemic
cells in relation to normal PBMC was favourable. The most promising drug
KAN0438063 had an EI of 40 i.e. killed 40 times more CLL cells than
PBMC at an IC50 of 10�M. The compounds induced PARP cleavage and
cleavage of caspases 8 and 9 as well as down regulation of Mcl-1 and Bcl-xl
(Western Blot). ROR1 was dephosphorylated (Western Blot). The selective
apoptotic effect was compared to other small molecules targeting non-
ROR1 structures in CLL (PCI-32765, CAL-101, R406, R788, STK-
156485, STK-156133) and our compounds were significantly more
effective (EI) (p�0.001). Conclusions: We have developed effective and
selective series of compounds targeting ROR1 with promising ADMET
properties. ROR1 targeting small molecules might also be effective for
other tumor cells expressing ROR1 as has been noted for e.g. pancreatic
carcinoma cells. Our model molecules will be further optimized and tested
in animal tumor models. These molecules represent the first small
molecules targeting ROR1 – a “survival factor” in CLL.
6559 General Poster Session (Board #17B), Mon, 1:15 PM-5:15 PM
Post hoc analysis of relationship between baseline white blood cell count
and survival outcome in a randomized phase III trial of decitabine in older
patients with newly diagnosed acute myeloid leukemia. Presenting Author:
Chris Arthur, Royal North Shore Hospital, St. Leonards, Australia
Background: In a large phase III trial (N�485), patients (pts) �65y with
newly diagnosed acute myeloid leukemia (AML) received 1-h IV infusion of
decitabine (DAC) 20 mg/m2 for 5 consecutive days every 4 wk or treatment
choice (TC) with supportive care or cytarabine 20 mg/m2 subcutaneous
injection for 10 consecutive days every 4 wk (NCT00260832; Kantarjian et
al. JCO, in press). Enrolled pts had white blood cell (WBC) count �40
x109 /L; baseline WBC counts were relatively low (median [range] DAC: 3.1
x109 /L [0.3-127.0]; TC: 3.7 x109 /L [0.5-80.9]). This post hoc analysis
assessed baseline WBC count and survival outcome. Methods: Overall
survival (OS) and progression-free survival (PFS) were summarized by
baseline WBC subgroups (�1, 1-5, �5 x109 /L). Results: Mature survival
data (2010) were based on intent-to-treat (ITT) population (446 deaths:
TC, n�227; DAC, n�219). OS was 5.0 mo for TC vs 7.7 mo for DAC
(nominal P�.037). For each WBC subgroup, differences in OS for TC vs
DAC were not significant (NS), but hazard ratios (HR) favored DAC for all
subgroups (Table). There was a significant difference in PFS in favor of DAC
for patients with baseline WBC 1–5 x109 /L (P�.005; HR�0.67) and �5
x109 /L (P�.027; HR�0.71). Conclusions: These data are consistent with
overall results, with a trend toward improved outcome with DAC regardless
of baseline WBC count in older pts with newly diagnosed AML. Further
analyses are warranted.
Outcome WBC x10 9 /L
TC
Median, a mo
Event/n
OS All pts 5.0
227/243
�1 4.9
20/22
1-5 5.9
106/115
�5 4.3
94/99
PFS All pts 2.1
221/243
�1 2.2
20/22
1-5 2.9
110/115
�5 2.1
98/99
DAC
Median, a mo
Event/n
7.7
219/242
8.6
22/25
9.5
104/119
6.3
88/93
3.7
221/242
5.5
24/25
3.8
111/119
3.4
89/93
Nominal P value b
HR (95% CI) c
P�.037
HR�0.82 (0.68, 0.99)
P�NS
HR�0.85 (0.42, 1.70)
P�NS
HR�0.78 (0.58, 1.03)
P�NS
HR�0.82 (0.60, 1.10)
P�.003
HR�0.75 (0.62, 0.91)
P�NS
HR�1.05 (0.56, 1.97)
P�.005
HR�0.67 (0.51, 0.89)
P�.027
HR� 0.71 (0.53, 0.97)
a Kaplan-Meier product limit estimates. b 2-sided log-rank test. c Stratified Cox regression
model (age and cytogenetic risk as strata; treatment group as covariate). HR �1 means
advantage for DAC.
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