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

442s Leukemia, Myelodysplasia, and Transplantation
6604 General Poster Session (Board #22G), Mon, 1:15 PM-5:15 PM
Pooled safety analysis of omacetaxine mepesuccinate in patients with
chronic myeloid leukemia (CML) resistant to tyrosine-kinase inhibitors
(TKIs). Presenting Author: Meir Wetzler, Roswell Park Cancer Institute,
Buffalo, NY
Background: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”)
is a reversible, transient inhibitor of protein elongation that does not
depend on BCR-ABL signaling. It showed significant clinical activity in two
phase 2, open-label, multicenter studies of patients with CML who were
resistant/intolerant to prior TKI therapy. However, omacetaxine tolerability
data across the 3 phases of CML are limited. Methods: Safety data were
pooled from all patients in the 2 studies plus a small pilot study.
Omacetaxine 1.25 mg/m2 was given subcutaneously twice daily: �14
successive days per 28-day cycle for induction, �7 days/cycle as maintenance.
Days of dosing could be adjusted and recombinant growth factors
given, as clinically indicated. Results: Of 207 pooled patients (median age,
57 years), 108 were in chronic (CP), 55 in accelerated (AP), and 44 in blast
phase (BP). Median treatment was 4 cycles (range, 1–41). On study, 80%
of patients had �1 hematologic adverse event (AE), 60% had a serious AE
(SAE), 30% had a hematologic SAE, 34% had an SAE that resulted in
hospitalization, and 15% discontinued treatment due to an SAE (most
commonly disease progression). There were 49 (24%) deaths (15 CP, 11
AP, and 23 BP). Of the 8 that were treatment related (5 CP, 2 AP, 1 BP),
the most common cause was sepsis (3 patients). The most common AEs
were thrombocytopenia (60%), anemia (51%), diarrhea (40%), neutropenia
(37%), and nausea (30%). Injection site reactions (eg, injection site
pain, erythema) occurred in 32%, with the majority being low grade.
Infections (eg, pneumonia, bronchitis) occurred in 51%. Treatment-related
grade 3/4 hematologic AEs included thrombocytopenia (52%), neutropenia
(31%), anemia (30%), leukopenia (12%), and febrile neutropenia
(11%). The most common treatment-related grade 3/4 nonhematologic AE
was fatigue (4.3%). Overall, there were 34 (16%) grade 3/4 infections (12
CP, 11 AP, 11 BP). Conclusions: In the largest safety analysis to date,
subcutaneous omacetaxine 1.25 mg/m2 showed an acceptable safety
profile in all phases of CML. AEs were primarily hematologic, and grade 3/4
nonhematologic AEs were not common. Support: Teva Pharmaceutical
Industries Ltd.
6606 General Poster Session (Board #23A), Mon, 1:15 PM-5:15 PM
Prospective evaluation of serial 2-hydroxyglutarate in acute myeloid leukemia
(AML) to determine response to therapy and predict relapse. Presenting
Author: Amir Tahmasb Fathi, Massachusetts General Hospital/Harvard
Medical School, Boston, MA
Background: Mutations in isocitrate dehydrogenase (IDH1 and IDH2) occur
in 10-20% of AML patients and result in production of 2-hydroxyglutarate
(2-HG). We hypothesize that serial 2-HG quantification may be used to
monitor response and predict relapse in patients with AML. Methods: We
are conducting a prospective study at MGH and DFCI to (1) assess changes
in serum and urine 2-HG levels during treatment in patients with newly
diagnosed AML, (2) compare 2-HG levels in serum, urine, and bone marrow
and, (3) serially compare 2-HG levels with IDH1/2mutant allele burden. In
those with elevated serum 2-HG (�1000ng/ml), 2-HG is monitored serially
or at relapse. Results: To date, 20 patients have been enrolled, 5 (25%) of
whom had elevated baseline serum 2-HG. All 5 were found to have IDH1/2
mutations. The serum 2-HG for these patients was significantly higher than
for those who were IDH-wt (median 1933 vs 87ng/mL; p�0.001). Urine
2-HG was also higher in IDH-mutant patients (median 30500 vs 4230ng/
mL; p�0.021), as was bone marrow 2-HG (median 9870 vs 309ng/mL;
p�0.005). Serum 2-HG levels strongly correlated with that in urine (R2 0.987). Serum 2-HG decreased in all IDH mutant patients on therapy, but
more rapidly in those receiving induction chemotherapy (Table), all of
whom achieved remission, than those receiving hypomethylatingagents.
Conclusions: Patients with IDH-mutant AML have markedly elevated serum
and urine 2-HG. 2-HG levels decreased with therapy and there is a strong
correlation between serum and urine 2-HG. Data on the sensitivity of serial
2-HG monitoring as well as comparison with mutant IDH1/2allele burden
will be presented. This data suggests that serial 2-HG quantification may be
a valuable non-invasive biomarker in this genetically defined subset of
AML.
Serial analysis of serum 2HG (ng/mL) during therapy in IDH-mutant AML.
Patient 1 (5-azacitidine)
(IDH2 R140Q)
Patient 2 (induction)
(IDH1 R132H)
Patient 3 (induction)
(IDH1 R132H)
Patient 4 (induction)
(IDH2 R140Q)
Patient 5 (5-azacitidine)
(IDH2 R140Q)
Day 0 Day 7 Day 14 Day 30 Day 60 Day 110
1,933 2,125 2,006 1,599 2,077 60
2,070 1,019 295 363 195
66,207 1,477 1,043 407 154
1,054 249 60 84 106
1,296 786 935 503
6605 General Poster Session (Board #22H), Mon, 1:15 PM-5:15 PM
Analysis of imatinib (IM)-related, low-grade (LG), non-hematologic (heme)
adverse events (AEs) in patients (pts) with chronic myeloid leukemia (CML)
switched to nilotinib (NIL): ENRICH study update. Presenting Author:
Michael J. Mauro, Knight Cancer Institute at Oregon Health & Science
University, Portland, OR
Background: This study update assesses change in chronic LG non-heme
AEs in adult Ph� CML-CP pts switched from IM to NIL. Methods: Pts were
eligible if treated with IM 400 mg/d for �3 mo, and had IM-related grade
(G) 1/2 non-heme AEs persisting �2 mo or recurring �3 times and
persisting despite best supportive care. Pts received NIL 300 mg BID.
Primary endpoint is change in IM-related LG non-heme AEs at 3 mo.
Disease response was monitored by RQ-PCR and pt-reported outcomes
measured by 2 quality-of-life (QoL) questions and MD Anderson Symptom
Inventory (MDASI)-CML. Results: 47 pts were enrolled as of data cut-off
(11/14/2011). There were 168 baseline IM-related non-heme AEs: 121
G1, 47 G2. 37 pts completed 3 mo NIL, by 3 mo 103 of 154 IM-related
AEs (67%) improved (92 resolved, 11 improved from G2 to G1), 47
unchanged, 4 increased in severity. 13 pts were dose reduced for
NIL-related AEs; 8 pts re-escalated after AEs recovered to G1 or resolved.
34 G3 AEs occurred in 15 pts; investigators reported 19 AEs as suspected
NIL-related (increased bilirubin, lipase, or blood glucose; hypokalemia;
hypophosphatemia; pruritus; bronchitis; dehydration; rash; arthralgia;
pleural effusion). 8 pts discontinued NIL: 6 for AEs, 2 withdrew consent.
No G4 AEs were reported. 32 pts had MMR (3-log reduction of Bcr-Abl;
�0.1% IS) at entry; 16 additional pts achieved MMR on NIL. At entry, 18
pts had 4-log reduction and 10 pts 4.5-log reduction in Bcr-Abl. 16 and 13
additional pts achieved 4- and 4.5-log reduction, respectively, on NIL. At 3
mo (n�34) 62% and 53% pts reported QoL improvement from baseline in
the previous 24 h and 7 d, respectively. Reduction in MDASI-CML
severity/interference scores indicates symptom improvement. Mean reductions
in MDASI-CML from baseline at 3 mo: severity, 1.21 (n�34);
interference, 1.55 (n�33). Conclusions: 3 mo after switching to NIL,
~70% baseline chronic LG non-heme IM-related AEs improved and �53%
of pts reported improvement in QoL. Molecular responses were maintained
or improved in all patients. Switch from IM to NIL in majority of pts reduces
IM-related toxicities and preserves/induces molecular response in CML-CP.
6607 General Poster Session (Board #23B), Mon, 1:15 PM-5:15 PM
Interim results of a phase I/II randomized study of clofarabine, idarubicin,
and cytarabine (CIA) versus fludarabine, idarubicin, and cytarabine (FIA)
for newly diagnosed or relapsed patients (pts) with acute myeloid leukemia
(AML). Presenting Author: Michael Mathisen, University of Texas M. D.
Anderson Cancer Center, Houston, TX
Background: Outcomes of pts with AML remain suboptimal. The addition of
cladribine to 3�7 has been shown to improve complete remission (CR)
rates and 3-year survival. The aim of this study was to assess the efficacy
and safety of idarubicin � cytarabine (IA, idarubicin 10 mg/m2 on days
1-3, cytarabine 1 g/m2 on days 1-5) combined with two other nucleoside
analogs, clofarabine (C) or fludarabine (F), in pts with newly diagnosed and
relapsed/refractory (RR) AML. Methods: Pts with newly diagnosed or RR
non-M3 AML with normal organ function were eligible. Pts with RR disease
were treated in the phase I portion defining the MTD of C. The starting dose
of C was 15 mg/m2 with doses escalating to 25 mg/m2 on days 1-5 in
subsequent cohorts. During phase II, patients were randomized in a
Bayesian design to C at the MTD with IA or fludarabine (F) at 30 mg/m2 on
days 1-5 with IA. Up to 6 consolidation cycles were planned according to an
attenuated schedule using the same drugs. Dose adjustments were made
for elderly pts or pts with poor PS. Results: 9 pts were enrolled in the phase I
portion. The overall response rate (ORR) in this group was 44%. DLT were
observed at C 20 mg/m2 and included hand/foot syndrome (HFS), elevated
bilirubin, and prolonged myelosuppression. The MTD was 15 mg/m2 on
days 1-5. 50 evaluable pts were enrolled (16 newly diagnosed, 34 RR) in
the phase II. In the frontline cohort, median age was similar in both groups
(C 56, F 55), as were the cytogenetic profiles. The CR rate was 100% in
both groups (9 CIA, 7 FIA). Detailed efficacy information can be found in
the Table. More than half of the RR cohort were receiving therapy as salvage
2 or higher, and most had short first CR durations. Notable toxicities
included elevated liver function tests for both groups, and HFS in the C
group. There were 4 deaths on study, though most pts were receiving
therapy as second salvage and were over the age of 60. Conclusions: CIA
and FIA are effective regimens for newly diagnosed or RR AML with
manageable toxicity profiles. The ORR were 100% and 32% for newly
diagnosed and RR AML pts, respectively, with low early mortality rates. The
study is ongoing.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.