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

420s Leukemia, Myelodysplasia, and Transplantation
6516^ Poster Discussion Session (Board #8), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Phase II trial of the combination of ofatumumab and lenalidomide in
patients with relapsed chronic lymphocytic leukemia (CLL). Presenting
Author: Lorenzo Falchi, University of Texas M. D. Anderson Cancer Center,
Houston, TX
Background: Based on the activity of ofatumumab and lenalidomide as
monotherapy, we evaluated efficacy and tolerability of the combination in
pts with relapsed CLL. Methods: Thirty-six pts entered this phase II study.
All pts had an indication for therapy, adequate liver/renal function and
received prior fludarabine. Ofatumumab IV was given weekly for 4 weeks
(300mg w 1; 1,000 mg w 2-4), monthly during months 2-6, and every
other month during months 7-24. Lenalidomide 10 mg PO/day started on
day 9 and continued for 24 months. Responses were assessed (2008 IWG
criteria) at month 3, 6 and every 6 months. Results: Thirty-four pts are
evaluable. Median age was 64 yrs (34-82), 59 % of the pts had Rai stage
III-IV disease, median �-2M level was 4.1 mg/dL (1.7-16), 62 % of the pts
had unmutated IgHV, 26% del(17p) and 12% del(11q). Median number of
prior treatments was 2 (1-8), all pts had been treated with FCR and 29%
were fludarabine-refractory. The overall response (OR) rate is 65% (22 pts);
7 pts (21%) achieved a complete response (CR) including 4 MRD-negative
CR, and 15 pts (44%) achieved a partial response (PR). Twelve pts are still
on therapy. Median duration of response has not been reached with a
median follow up of 13 months. Seven pts discontinued therapy despite
ongoing response: HSCT (3 pts), toxicity (2 pts) and physician choice (2
pts); 3 pts discontinued therapy because of loss of response (at 12, 16 and
16 months). Eighty-two % of the pts are alive. No deaths occurred on
therapy, 6 deaths occurred after therapy discontinuation: CLL (4), HSCT
(1) and CLL/lung cancer (1). Lenalidomide daily dose was 10 mg (9 pts),
7.5 mg (4 pts), 5 mg (13 pts), �5 mg (8 pts). G3-4 toxicities included
neutropenia (16 pts, 47%), thrombocytopenia (3 pts, 9%) and anemia (2
pts, 6%). One pt (3%) experienced G4 pulmonary embolism while on ESAs.
One pt (3%) had G3 infusion reaction to ofatumumab. Fourteen G3
infections occurred: pneumonia (4), fever/bacteremia (5), parotitis (1),
cellulitis (2), HZV (1), and CNS toxoplasmosis (1). G1-2 tumor flare
reaction occurred in 8 pts (24%). Conclusions: The combination of
ofatumumab and lenalidomide was well tolerated. It induced durable
responses in 65% of FCR pre-treated pts with relapsed CLL.
6518^ Poster Discussion Session (Board #10), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
A phase I/II study of the selective phosphatidylinositol 3-kinase-delta
(PI3K�) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with
previously treated chronic lymphocytic leukemia (CLL). Presenting Author:
Richard R. Furman, Weill Cornell Medical College, New York, NY
Background: PI3K� is expressed in cells of hematopoietic origin where it
regulates the survival and proliferation of malignant B-cells. GS-1101 is an
orally bioavailable, small-molecule inhibitor that selectively targets PI3K�
and is highly active in patients with hematologic malignancies. Methods:
This Phase 1/2 study evaluated repeated 28-day cycles of GS-1101 in
combination with ofatumumab. GS-1101 (150mg BID) was co-administered
with a total of 12 infusions of ofatumumab over 24 weeks (300mg
initial dose either on Day 1 or Day 2 (relative to the first dose of GS-1101),
followed 1 week later by 1,000mg weekly for 7 doses, followed 4 weeks
later by 1,000mg every 4 weeks for 4 doses). Thereafter, each subjects
received single-agent GS-1101 as long as the subject was benefitting.
Results: Accrual is complete with 21 subjects enrolled and 11 evaluable.
Six subjects started ofatumumab treatment on Day 1 and 5 on Day 2.
Median [range] age was 63 [54-76] years. The majority (9/11; 82%) of
patients had bulky adenopathy. The median [range] number of prior
therapies was 3 [1-6], including prior exposure to alkylating agents (10/11;
90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab
(3/11; 28%) and/or ofatumumab (2/11;18%). At the data cutoff, the
median [range] treatment duration was 5 [0-7] cycles. Almost all subjects
(9/11;82%) experienced marked and rapid reductions in lymphadenopathy
within the first 2 cycles. The lymphocyte mobilization that is expected with
PI3K� inhibition was significantly reduced in magnitude and duration and
persisted past Cycle 1 in only 1 patient. Early follow up data support a
favorable safety profile and confirm a lack of clinically significant myelosuppression.
Elevated baseline levels of CCL3, CCL4, CXCL13, and TNFa were
significantly reduced after 28 days of treatment. Conclusions: GS-1101/
ofatumumab offers a well-tolerated noncytotoxic combination regimen with
substantial activity in previously treated patient with bulky adenopathy.
Data on the complete cohort of 21 subjects will be presented.
6517 Poster Discussion Session (Board #9), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Pretreatment prognostic factors associated with outcomes for first-line
FCR-based treatments in previously untreated CLL. Presenting Author:
William G. Wierda, University of Texas M. D. Anderson Cancer Center,
Houston, TX
Background: First-line chemoimmunotherapy with fludarabine, cyclophosphamide,
and rituximab (FCR) demonstrated improved outcomes, including
survival, for fit patients (pts) with CLL. Modifications of this regimen,
including intensified rituximab (FCR3), addition of mitoxantrone (FCMR) or
addition of alemtuzumab fir high-risk CLL (CFAR), were evaluated but did
not improve outcomes in historic comparisons. Methods: We correlated
outcomes, including complete remission (CR), time-to-treatment failure
(TTF) and overall survival (OS), with new and traditional pretreatment
prognostic factors to identify high-risk pts. Results: All pts (N�473) had an
NCI-WG indication for treatment and received a first-line FCR-based
regimen on trial; the intended treatment was 6 courses. Patient characteristics
correlated with outcomes are presented in the table. Factors not
associated with outcomes included absolute lymphocyte count; platelet
count; performance status; spleen size; liver size; and number of involved
lymph node sites. Conclusions: We identified the following as high-risk
pretreatment features for patients going on first-line FCR-based therapy:
advanced age, presence of 17p del, high B2M (�4mg/l), and unmutated
IGHV gene. Pts with these features should be pursued with new treatment
modalities and novel agents in order to improve outcomes.
Pretreatment
characteristic Higher CR Longer TTF Longer OS
Younger age UVA UVA UVA; MVA
Female - UVA; MVA -
Earlier Rai stage UVA; MVA - UVA
Lower ß-2 microglobulin (