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

6520 Poster Discussion Session (Board #12), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
A randomized phase II study of sapacitabine in MDS refractory to
hypomethylating agents. Presenting Author: Guillermo Garcia-Manero,
University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Sapacitabine is an orally administered nucleoside analogue
which causes single-strand DNA breaks and induces G2 cell cycle arrest. A
multi-center, randomized phase 2 study was conducted to evaluate 3 dose
regimens in older patients with MDS refractory to hypomethylating agents.
The primary endpoint is 1-year survival. Secondary endpoints include the
rate of CR, CRp, PR, major hematological improvement (HI) or stable
disease and their corresponding durations. The study uses a selection
design to identify a dose regimen which produces a better 1-year survival
rate in the event that all three dose regimens are active. The planned
sample size is 60 patients (20 patients in each arm). Methods: Eligible
patients must be � 60 years with intermediate-2 or higher risk MDS
previously treated with hypomethylating agents and 6 - � 20% blasts in
bone marrow, ECOG 0-2, adequate renal and hepatic functions. Patients
were randomized 1:1:1 to receive sapacitabine every 4 weeks at 200 mg
b.i.d. x 7 days (Arm G), 300 mg q.d. x 7 days (Arm H), or 100 mg q.d. x 5
days per week x 2 weeks (Arm I). The number of cycles is not limited.
Results: As of January 2012, 61 patients were enrolled and 56 had � 30
days of follow-up. Mean follow-up was 173 days. Median age was 71. Two
or 3 cytopenias were present in 42 patients and 14 have received both
azacitidine and decitabine. Baseline bone marrow had 6-10% blasts in 31
patients and 11-19% blasts in 25 patients. Median number of cycles was 2
and 18 patients received � 4 cycles. To date, 8 patients have responded (2
CRs, 2 CRp, and 4 major HIs): 15% (Arm G), 16% (Arm H) and 12% (Arm
I). Time to response is 1-3 cycles. Additionally, 6 patients achieved stable
disease lasting longer than 16 weeks. More than 50% of patients have lived
16 weeks or longer. Three deaths occurred within 30 days of randomization
and 1 death was considered to be related to sapacitabine. Common adverse
events (all grades, regardless of causality) included fatigue, nausea,
diarrhea, constipation, edema, dyspnea, pyrexia, pneumonia, febrile neutropenia,
anemia, neutropenia and thrombocytopenia, most of which were
mild to moderate. Conclusions: Sapacitabine appears to be safe and active
across all 3 dose regimens. Updated data will be presented at the meeting.
6522 Poster Discussion Session (Board #14), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Efficacy and tolerability of lenalidomide (LEN) in patients (pts) 75 and older
versus those younger than 75 with RBC transfusion-dependent low/int-1-risk
MDS and del 5q. Presenting Author: Pierre Fenaux, Hopital Avicenne, Bobigny,
France
Background: LEN is the approved treatment for pts with RBC transfusiondependent
Low/Int-1-risk MDS and del 5q. In 2 multicenter trials (MDS-003/-
004) LEN lead to RBC transfusion independence (TI) for � 26 wks in 35–58% of
pts and cytogenetic response (CyR) in 25–73%. Most common grade (G) 3–4
adverse events (AE) were neutropenia and thrombocytopenia, a safety concern in
elderly pts. We evaluated efficacy and tolerability of LEN in pts � 75yvs�75 y
in MDS-003/-004 trials. Methods: Pts received LEN 5 mg � 28 d, 10 mg � 21 d,
or 10 mg � 28 d (all 28 d cycles). Dose reductions were required for G4
neutropenia (both trials) and platelet counts � 30x109 /L (MDS-003) or � 25 x
109 /L (MDS-004). Results: 32% of the 286 pts were � 75 y. Baseline (BL)
characteristics, LEN treatment, and optional G-CSF use are shown in Table. In
pts � 75yvs�75 y: RBC-TI � 26 wks was 39 vs 47% (P � NS); CyR was 64 vs
54% (P � NS); 2-y AML progression rates were 10 vs 19% (P � NS); 2-y overall
survival rates were 62 vs 73% (P � .001); G3–4 AE: neutropenia (63 vs 76%; P
� .024), thrombocytopenia (56 vs 49%; P � NS), infection (36 vs 20%; P �
.003); median time to recovery to ANC � 1x109 /L was 0.7 vs 0.7 mo (P � NS)
and to platelet counts � 100x109 /L was 3.3 vs 1.7 mo (P � NS). 59% pts � 75
y and 49% pts � 75 y discontinued LEN due to AE (33 vs 26%; P � NS), lack of
effect (32 vs 49%; P � NS), or death (15 vs 6%; P � NS). Dose reduction and
discontinuation rates are shown in Table. Conclusions: Pts � 75 y and � 75 y
had comparable response and AML progression rates. In pts � 75 y, LEN
appears to be well tolerated but the higher infection rate justifies close follow-up.
< 75 y > 75 y P value
BL characteristics
Female, %
Median time from diagnosis, y
Median RBC transfusion burden, units/8 wks
Neutropenia (< 1x10
65
3
6
79
3
6
.019
NS
NS
9 /L), %
Thrombocytopenia (< 100x10
11 8 NS
9 /L), %
del 5q, %
Isolated
Plus > 1 abnormality
IPSS risk, %
Low
Int-1
ECOG, %
0
1/2
LEN treatment
Median duration, mo
Median total dose per cycle, mg
Median % of assigned dose cycle 1–4
Reason for dose reduction, %
Neutropenia
Thrombocytopenia
Reason for discontinuation, %
Neutropenia
Thrombocytopenia
Optional G-CSF use
Pts treated, %
14
71
24
27
45
25
26
14
126
68
33
17
2
4
37
13
67
31
40
37
12
42
9
108
56
25
30
3
3
30
NS
NS
NS
.003
.009
NS
NS
NS
.019
NS
NS
NS
Leukemia, Myelodysplasia, and Transplantation
421s
6521 Poster Discussion Session (Board #13), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Use of single polymorphism arrays (SNP-A) to modify prognostic scoring
systems for myelodysplastic syndromes. Presenting Author: Manojkumar
Bupathi, Cleveland Clinic Foundation/MetroHealth Medical Center-
Department of Translational Hematology and Oncology Research, Cleveland,
OH
Background: MDS are hematologic neoplasms characterized by dysplasia
and cytopenias. Two commonly used risk stratifications, IPSS (Greenberg
et al Blood 1997) and IPSS-R are based on clinical factors (marrow blasts,
number of cytopenias and genetic abnormalities determined by conventional
karyotyping), with the IPSS based on 4 cytogenetic risk groups and
the IPSS-R based on 5 cytogenetic risk groups defined by Schanz et al JCO
2012. A drawback to metaphase cytogenetics (MC) is its inability to detect
small cryptic chromosomal defects and uniparental disomy (UPD). SNP-A
can identify these small cytogenetic lesions/UPD and has been shown to be
of prognostic value in MDS. The goal of this investigation was to determine
if SNP-A detected defects could be used to refine the IPSS and IPSS-R.
Methods: SNP-A karyotyping was performed as previously described (Tiu et
al, Blood, 2011). We reviewed data from 327 patients idenfitying SNP-A
results, MC, and the IPSS/IPSS-R-related clinical factors were identified.
Overall survival (OS) measured from the date of sampling for SNP-A
karyotyping was the primary endpoint. Data were analyzed using Cox
proportional hazards models. Results: SNP-A lesions not detected by MC
were grouped as 1) none or only gains/losses; 2) UPD only or gains�losses
but no UPD; and 3) UPD�other defects. The frequencies/median os in
months (mo) of the groups were: 66%/20.0, 23%/12.7 and 11%/5.8,
respectively, p�.0001 for OS. Combining the SNP-A groups with MC resulted
in revised definitions of cytogenetic risk that had better discrimination than
the underlying models; and when combined with the relevant clinical
factors resulted in refined IPSS (IPSSSNP-A ) and IPSS-R (IPSS-RSNP-A ) risk
stratifications (Table). Conclusions: Detection of chromosomal gains, losses,
and UPD by SNP-A has prognostic value in MDS and can be used to refine
current risk stratifications.
Median os in mo (% of pts) for each model.
Risk groups
Model 1 2 3 4 5
IPSS 39.1 (21%) 20.0 (37%) 8.9 (21%) 4.6 (21%) ---
IPSSSNP-A 47.0 (15%) 27.1 (30%) 15.3 (26%) 7.2 (18%) 2.5 (12%)
IPSS-R 39.1 (9%) 30.4 (32%) 17.6 (12%) 16.7 (14%) 4.6 (28%)
IPSS-R SNP-A 41.8 (23%) 27.7 (14%) 15.1 (34%) 6.6 (17%) 2.6 (12%)
6523 Poster Discussion Session (Board #15), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Results of a phase II trial of azacitidine (AZA) with or without epoetin beta
(EPO) in lower-risk MDS. Presenting Author: Claude Gardin, Hematology,
Hopital Avicenne APHP, University of Paris 13, Bobigny, France
Background: Although anemia of IPSS low and int-1 (LR) MDS initially
responds to erythroid stimulating agents (ESA) in 40-50% of patients (pts),
response is generally transient. Anemia recurrence with RBC cell transfusion
dependency (RBC-TD) is an indicator of poor prognosis, even in
absence of progression to higher risk MDS. AZA leads to RBC transfusion
independence (RBC-TI) in 30–40% of LR-MDS (Lyons, JCO, 2009), but it
has not been prospectively tested in LR-MDS patients resistant to ESA. It
also remains unknown if the addition of ESA to AZA would be useful in such
pts. Methods: In this randomized phase-II trial (GFMAzaEpo-2008-1 trial,
NCT01015352), the Groupe Francophone des Myélodysplasies (GFM)
compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm)
to the same treatment plus EPO 60000U/week (AZA�EPO arm). Inclusion
criteria were LR-MDS resistant to at least 12 weeks of ESA, with RBC-TD �
4 RBC units in the previous 8 weeks. Responders in both arms were eligible
for maintenance up to 12 monthly cycles, unless progression or loss of
erythroid response occurred. The primary endpoint was RBC-TI (HI-E major
using IWG 2000 criteria) after 6 courses. Results: Between 2009 and
2010, the 98 planned pts were included: M/F 65/28; median age 71y
(41-84); 5 pts were excluded (one consent withdrawal, 2 early unrelated
events and 2 with exclusion criteria). In the remaining 93 pts, IPSS risk was
low in 69 and int-1 in 23 pts, with no imbalance between arms. Five pts
received � 4 cycles and 16 received only 4 or 5 cycles, mainly due to
toxicity or progression. RBC-TI after 6 courses was observed in 16.7%
(8/48) in the AZA arm and 18 % (8/45) in the AZA�EPO arm (P�1), and in
19.5% (8/41) and 26 % (8/31) respectively, in the 72 pts who received �
6 cycles (P�.57). Overall best response rate (at least HI-E minor using IWG
2000 criteria) was 35 and 33% in the AZA and AZA�EPO arms,
respectively (P�0.99). Of note, only 9 pts in the AZA�EPO arm required at
least one hospitalization for a SAE, compared to 22 pts in the AZA arm
(P�0.015). Conclusions: Erythroid response to AZA, in LR MDS with
demonstrated ESA resistance, appears lower than expected, with no
improved outcome when combined with an ESA. The latter may however
improve tolerance of AZA in LR MDS.
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