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

6512 Poster Discussion Session (Board #4), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
BELA trial update: Bosutinib (BOS) versus imatinib (IM) in patients (pts)
with newly diagnosed chronic phase chronic myeloid leukemia (CP CML)
after 30 months of follow-up. Presenting Author: Carlo Gambacorti-
Passerini, University of Milan-Bicocca, Monza, Italy
Background: The BELA study compared the efficacy and safety of BOS (dual
Src/Abl kinase inhibitor) with IM in newly diagnosed CP CML. Methods: 502
pts with newly diagnosed CP CML were randomized to BOS 500 mg/d (n �
250) or IM 400 mg/d (n � 252) and stratified by Sokal risk group and
geographic region. Efficacy analyses included all randomized pts (ITT);
safety analyses included all treated pts (BOS, n � 248; IM, n � 251). Data
described below are for �24 mo of follow-up; updated data for �30 mo of
follow-up will be presented. Results: Median treatment duration was 27.5
mo in both cohorts; 63% of BOS pts and 71% of IM pts were still receiving
treatment. The primary reason for BOS discontinuation was a treatmentemergent
adverse event (TEAE; 24% vs 7% with IM); the primary reason for
IM discontinuation was disease progression (13% vs 4% with BOS).
Cumulative complete cytogenetic response (CCyR) rates by 24 mo were
79% for BOS and 80% for IM. Cumulative major molecular response
(MMR) rates by 24 mo were 59% for BOS and 49% for IM (P � 0.019),
including 16% and 12% of pts with complete molecular response (4.0-log
sensitivity). On-treatment transformation to accelerated/blast phase occurred
in 4 (2%) BOS pts and 13 (5%) IM pts. Deaths were reported for 7
BOS pts (6 due to CML progression) and 13 IM pts (10 due to CML
progression); 24-mo Kaplan-Meier overall survival estimates were 97%
(BOS) and 95% (IM). BOS was associated with higher incidences of
gastrointestinal events than IM (diarrhea [70% vs 25%], vomiting [32% vs
16%]; primarily transient), but lower incidences of edema (13% vs 40%)
and musculoskeletal events (cramps [4% vs 22%], bone pain [4% vs
10%]). Grade �3 TEAEs in �2% of BOS or IM pts were diarrhea (12% vs
1%), vomiting (3% vs 0%), and rash (2% vs 1%). Grade �3 lab
abnormalities (�15% of pts) with BOS and IM were neutropenia (10% vs
24%), thrombocytopenia (14% vs 15%), elevated alanine aminotransferase
(23% vs 4%), and hypophosphatemia (6% vs 20%). Conclusions: BOS
was effective for newly diagnosed CP CML and had a distinct toxicity
profile. With continued follow-up both on-treatment transformation to
accelerated/blast phase and overall survival continue to favor BOS versus
IM.
6514^ Poster Discussion Session (Board #6), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Reductions in JAK2V617F allele burden with ruxolitinib treatment in
COMFORT-II, a phase III study comparing the safety and efficacy of
ruxolitinib to best available therapy (BAT). Presenting Author: Alessandro
M. Vannucchi, University of Florence, Florence, Italy
Background: Ruxolitinib is a potent and selective JAK1/2 inhibitor approved
for the treatment of myelofibrosis (MF) based on results of the phase 3
COMFORT studies. Ruxolitinib demonstrated rapid and durable reductions
in splenomegaly and improved MF-related symptoms and quality of life of
patients (pts) with MF. Since one measure of efficacy is molecular
response, this analysis correlates changes in mutant allele burden (%V617F)
with spleen size reduction in COMFORT-II. Methods: COMFORT-II is a
randomized, open-label, phase 3 study comparing ruxolitinib 15 or 20 mg
twice daily (BID) with BAT. The primary endpoint was a � 35% reduction in
spleen volume from baseline (BL) at week 48. Change in %V617F was
measured by allele specific qPCR. Pts were stratified by reduction in
%V617F (� 10%, 10-20%, � 20%) and results were correlated with
achievement of the primary endpoint. Results: More pts in the ruxolitinib
arm had � 10% V617F reductions compared with BAT (41% vs 5%; P �
.01; Table). The majority of reductions � 20% were gradual and progressive
over the course of the study; 2 pts had rapid reductions from 48% to
1% and 45% to 9% over 48 weeks. In the ruxolitinib arm, significantly
more pts with a � 20% V617F reduction achieved the primary endpoint
compared with pts with a � 10% reduction (79% vs 30%; P � .004); in
each group, gender did not affect spleen response. For pts with � 10%
reductions (15 mg BID, n � 16; 20 mg BID, n � 24), the average total daily
dose (TDD) was ruxolitinib 29.6 mg; pts with � 20% reductions (15 mg
BID, n � 3; 20 mg BID, n � 11) had a TDD of 35.3 mg. Conclusions: Pts
who received ruxolitinib had larger reductions in JAK2V617F allele burden
compared with BAT. %V617F reductions were gradual over the course of
the 48-week study; longer follow-up is needed to determine the extent of
allele burden reduction.
Ruxolitinib
(N � 145) a
BAT
(N � 69) a
n(%)
JAK2V617F � at BL 110 (76) 49 (71) b
Median (range) %V617F
JAK2V617F
84.5 (5-96) 81 (1-95)
� with week-48 data
%V617F reduction
68 (62) 22 (45)
Median
< 10%
-7.0% 0%
c
40 (59) 21 (95)
10-20% 14 (21) 1 (5)
> 20% 14 (21) 0
a b c
Pts with %V617F data. Unknown JAK-mutation status, n � 4. Includes pts with increased
%V617F (range, 0-7%).
Leukemia, Myelodysplasia, and Transplantation
419s
6513 Poster Discussion Session (Board #5), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Subcutaneous omacetaxine mepesuccinate in patients with chronic phase
(CP) or accelerated phase (AP) chronic myeloid leukemia (CML) resistant/
intolerant to two or three approved tyrosine-kinase inhibitors (TKIs).
Presenting Author: Franck E. Nicolini, Centre Hospitalier Lyon Sud, Pierre
Bénite, France
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 in treatmentresistant
CML. Methods: A subset from the phase 2 studies included
patients in CP or AP who were resistant/intolerant to �2 approved TKIs.
Omacetaxine 1.25 mg/m2 was given SC twice daily: �14 consecutive
days/28-day cycle for induction, �7 days/cycle as maintenance. Secondary
results were calculated for responses by number of prior TKIs. Results: Of
122 patients (median age, 60 years), 62 had received 2 TKIs (100%
imatinib; 76% dasatinib; 24% nilotinib) and 60 had received all 3
approved TKIs. Prior non-TKI therapies (eg, 52% hydroxyurea, 34%
interferon) were common. Of 45 CP patients in the 2 TKI group, 12 (27%)
had major cytogenetic response (MCyR; median duration of 17.7 mo), and
of 36 in the 3 TKI group, 4 (11%) had MCyR (median duration not
reached). Of 17 AP patients in the 2 TKI group, 6 (35%) had major
hematologic response (MaHR; median duration, 13.4 mo), and of 24 in the
3 TKI group, 5 (21%) had MaHR (median duration, 6.4 mo). Median
months of survival in the 2 and 3 TKI groups were 30.1 and not reached for
CP and 12.0 and 24.6 for AP. Treatment-related grade 3/4 adverse events
(AEs) occurred in 52 (84%) patients in the 2 TKI group and 42 (70%) in
the 3 TKI group (most common: thrombocytopenia [71%, 48%]). Fifteen
(24%) and 16 (27%) had an AE leading to discontinuation, primarily
disease progression. There were 20 deaths (primarily disease progression),
11 in the 2 TKI group and 9 in the 3 TKI group; 4 were considered related to
treatment (sepsis in 2, pancytopenia, febrile neutropenia). Conclusions: In
patients with heavily pretreated CML, response to omacetaxine therapy
occurred whether they had received 2 or 3 prior TKIs. The drug was well
tolerated. Tolerability was similar across the TKI groups in both CP and AP
patients. Support: Teva Pharmaceutical Industries Ltd.
6515^ Poster Discussion Session (Board #7), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Combination of the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765
with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/
refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a
phase Ib/II study. Presenting Author: Susan Mary O’Brien, University of
Texas M. D. Anderson Cancer Center, Houston, TX
Background: BTK is an essential mediator of B cell receptor signaling and a
critical kinase for lymphoma cell survival. PCI-32765 (P), an oral,
selective, irreversible inhibitor of BTK, inhibits proliferation, migration and
adhesion in CLL cells, and is highly active as a single agent for the
treatment of R/R CLL pts. (O’Brien ASH 2011). BR produces an overall
response rate (ORR) of 59% in R/R CLL (Fischer JCO 2011). We report
interim data on P combined with BR. Methods: R/R CLL pts received P 420
mg orally daily for 28-day (D) cycles (C) until disease progression (PD). B
was administered 70 mg/m2 on D1 and D2 combined with R 375 mg/m2 on
D0 for C1 and 500 mg/m2 on D1 for subsequent courses for a maximum of
6 cycles. Response was evaluated according to IWCLL criteria. Results: 30
pts were enrolled. Median age of pts was 62 yrs (range 41-82). 46% of pts
were Rai stage III/IV and the median # of prior therapies was 2 (range 1-4).
37% and 13% were considered refractory (treatment free interval �12 mo)
to a purine analog containing regimen or BR, respectively. Bulky disease
was present in 52%. Adverse events (AE) have been consistent with that
expected with BR. Gr 3/4 neutropenia and thrombocytopenia have been
noted in 47% and 10% of pts, respectively. Grade �3 non-hematologic
AEs potentially related to P included rash (3 pts) and fatigue and tumor
lysis reported in 2 pts each. There were no Gr 3/4 infusion reactions. There
have been no discontinuations (D/C) due to AE and no deaths on study. At a
median follow-up of 4.9 mos (range 2.7-8.3 mo) 16 pts have completed BR
and 14 pts are still receiving BR. The ORR is 90% (27/30 pts) (CR 10%,
PR 80%). 2 additional pts achieved a nodal response with residual
lymphocytosis. Responses appear independent of high-risk clinical or
genomic features. 90% of pts remain on study; reasons for D/C include PD
(n�2) and 1 pt pursuing SCT. Conclusions: PCI-32765, in combination
with BR, is highly active. The high ORR, low rate of PD, and good
tolerability compares very favorably with historical controls, warranting
additional investigation of this combination.
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