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

8029 Poster Discussion Session (Board #9), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
A multicenter phase II study of vorinostat in patients (pts) with relapsed or
refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell
lymphoma (MCL). Presenting Author: Kiyoshi Ando, Department of Hematology
and Oncology, Tokai University, Kanagawa, Japan
Background: Most pts with indolent B-NHL relapse even after rituximabcontaining
chemotherapy. Vorinostat is an orally active histone deacetylase
(HDAC) inhibitor, and is under investigation as monotherapy or in combination
regimens in various hematologic malignancies. It has been reported
that the histone acetyltransferase genes (EP300 and CREBBP) are frequently
mutated in NHL, suggesting the potential usefulness of HDAC
inhibitors in its treatment. Methods: We conducted a phase 2 study to
investigate the efficacy, safety and tolerability of vorinostat in pts with
indolent B-NHL or MCL with the overall response rate (ORR) against
follicular lymphoma (FL) as the primary endpoint. The primary hypothesis
was to demonstrate the efficacy in FL pts as measured by the ORR.
Assuming the true ORR with vorinostat of 50% and without vorinostat of
less than 25%, 39 pts will provide 90% power to demonstrate an
ORR�25%. Vorinostat was administered at the dose of 200 mg BID for 14
consecutive days in a 21-day cycle. The ORR and PFS were determined by
an independent review panel in the Full Analysis Set (FAS) population.
Results: A total of 56 pts with a median age of 60 years (range: 33 - 75)
were enrolled, and 50 of them (39 with FL, 11 with other subtypes of
indolent B-NHL or MCL) were included in the FAS population. The number
of prior therapeutic regimens was 2 (range: 1 - 4) and 41 pts have
previously received rituximab-based regimens.. The percentages of pts with
FLIPI at low risk, intermediate risk and high risk were 41%, 39%, and
21%, respectively. The ORR in 39 pts with FL was 49% (95% CI: 32, 65),
and the pre-specified statistical success criterion was met. The median
PFS in 39 pts with FL was 17.5 months (range: 2, 22�), especially the
median PFS in 19 responders with FL has not yet been reached. The major
toxicities were hematologic and gastrointestinal ones, which were reversible
and manageable. Grade 3/4 infection was observed in 2%. Conclusions:
This phase 2 study demonstrated that oral vorinostat is an agent with
sustained antitumor activity in pts with relapsed or refractory indolent
B-NHL, with acceptable safety profiles, warranting further investigations.
8031 Poster Discussion Session (Board #11), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
CNS-directed chemotherapy including high-dose chemotherapy with autologous
stem cell transplantation (HD-ASCT) for CNS relapse of aggressive
lymphomas: Final analysis of a phase II study. Presenting Author: Agnieszka
Korfel, Department of Hematology and Oncology, Charite Campus
Benjamin Franklin, Berlin, Germany
Background: The outcome of patients with CNS relapse of aggressive
lymphoma (secondary CNS lymphoma, SCNSL) is poor with no standard
therapy established thus far. Here we present the final analysis of a
prospective multicenter phase II study using an intensive induction
regimen followed by high-dose chemotherapy and autologous stem-cell
transplantation. Methods: Adult immunocompetent patients �65 years
with SCNSL were eligible. Induction chemotherapy consisted of two cycles
MTX/IFO (methotrexate 4g/m2 iv. d1, ifosfamide 2g/m2 iv. d3-5 and i.th.
liposomal cytarabine 50mg d6) and one cycle AraC/TT (cytarabine 3g/m2 d1-2, thiotepa 40mg/m2 iv. d2 and i.th. liposomal cytarabine 50mg d3).
Then, patients without progression received high-dose chemotherapy with
carmustine 400mg/m2 iv. d -5, thiotepa 2x5mg/kg iv. d -4 to -3 and
etoposide 150mg/m2 iv. d -5 to -3 followed by ASCT d0. Results: Thirty
eligible patients (median age 58 years) were enrolled. Three patients had
T-cell and 27 aggressive B-cell lymphoma. Pre-treatment was CHOP-like in
29 patients, including rituximab in 26. CNS relapse occurred after a
median of 8.5 (3-80) months and was intracerebral in 23 and meningeal
in13 patients (combined in 7); 6 had concomitant systemic lymphoma.
After induction therapy CNS response was found in 22 (73%) patients
(8xCR, 14xPR), 3 patients had SD, 4 patients PD and 1 patient no
response evaluation. HD-ASCT was performed in 24 patients; resulting in
15 CR (63%), 2 PR (8%) and 7 PD (29%). Myelotoxicity was the most
frequent WHO grade 3-4 adverse event with infections in 8/30 pts on
MTX/IFO (27%), 5/23 (22%) on AraC/TT and 11/20(55%) on HD-ASCT.
One patient died due to septic diverticulitis and one developed persisting
fecal incontinence. The median follow up was 21 months. The median PFS
was 12.1 months (95% CI 6.4-17.7) in all patients and 30.4 (95%CI
2.5-58.3) months after HD-ASCT, the median overall survival was 27.4
months and not reached, respectively. Conclusions: This first prospective
study on SCNSL demonstrates that lasting remissions can be achieved with
CNS-directed HD-ASCT in a large proportion of patients and probably cure
in some.
Lymphoma and Plasma Cell Disorders
517s
8030 Poster Discussion Session (Board #10), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Interim analysis of the largest prospective trial to date in adult CD20positive
post-transplant lymphoproliferative disorder (PTLD): Introducing
risk-stratified sequential treatment (RSST). Presenting Author: Ralf Ulrich
Trappe, Department of Internal Medicine II: Hematology and Oncology,
University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Background: The prospective, multicenter international phase II PTLD-1
trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4
cycles of CHOP-21 � G-CSF) in adult CD20-positive PTLD demonstrated
excellent efficacy (90% overall response rate, ORR) and safety (11%
treatment-related mortality, TRM). As the response to rituximab predicted
overall survival (OS), the trial was amended in 2007 introducing riskstratified
sequential treatment (RSST) according to the response to
rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15
and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy
for patients (pts) in complete remission (CR, low risk) while all others (high
risk) received 4 cycles of R-CHOP-21 � G-CSF. Key exclusion criteria were
CNS involvement, HIV infection, severe organ dysfunction not related to
PTLD, and ECOG � 2. Primary endpoint was ORR. This is an analysis of the
first 91 patients treated with RSST. Results: 79/91 pts had monomorphic,
12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or
heart�lung, 3 heart�kidney and 1 kidney�pancreas transplant recipients.
Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late
PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of
treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of
RSST was 7/90 (8%) including 5 deaths with unknown remission status.
ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90
pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up
of �3 years, relapse rate in low risk pts was not increased by rituximab
consolidation in RSST compared to CHOP consolidation in ST (3/23 vs.
5/14, p�0.104]). In patients in PD after rituximab, R-CHOP was more
effective than CHOP in achieving CR (15/23 vs. 3/11, p�0.038). OS at 3
years was higher with RSST (70%, 95% CI: 60-82%) compared to ST
(61%, 95%CI 49-72%) but this difference was not significant. Conclusions:
With RSST 27% of pts were classified as low risk and achieved durable
tumor control without chemotherapy while R-CHOP seems more efficient
than CHOP in in high risk patients.
8032 Poster Discussion Session (Board #12), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Phase Ib trial of AVL-292, a covalent inhibitor of Bruton’s tyrosine kinase
(Btk), in chronic lymphocytic leukemia (CLL) and B-non-Hodgkin lymphoma
(B-NHL). Presenting Author: Jennifer R. Brown, Dana-Farber
Cancer Institute, Boston, MA
Background: Btk supports activation, survival, and proliferation of malignant
B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 � 0.5nM),
selective small molecule covalent inhibitor of Btk. Methods: Patients (pts)
with previously treated CLL or B-NHL were administered AVL-292 in
escalating cohorts of 125, 250, or 400 mg po QD using a 3�3 design in
continuous 28 day cycles until progressive disease (PD) or toxicity. Key
objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma
AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292
was assessed by covalent probe assay in peripheral blood mononuclear
cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at
400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior
therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with
both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4
B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2
marginal zone (MZL)). Median time on treatment is 65 days, range 28-158.
Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD
after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or
grade 4 adverse events (AEs) have occurred and MTD has not been reached.
Most frequent AEs reported include transient diarrhea, rash/skin infection,
URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug
related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients
have stable disease (SD) with median 28% decrease from baseline lymph
node measurement (range 3-40% decrease). Six of 8 pts with CLL
experienced increased ALC in cycle 1: median increase 89.5% (range
50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1
not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose
levels � 250 mg. Multiple dose PK exposure (AUClast) was linear with no
accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated
from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL
shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was
achieved with � 250 mg QD and PK was predictable with no accumulation.
Dose escalation is ongoing and MTD cohort expansion is planned.
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