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

530s Lymphoma and Plasma Cell Disorders
8082 General Poster Session (Board #36G), Mon, 1:15 PM-5:15 PM
Disruption of the eIF4F translation initiation complex as a determinant of
diffuse large B-cell lymphoma responsiveness to enzastaurin
(LY317615.HCl) and its primary metabolite (LY326020). Presenting
Author: Jeremy Richard Graff, Lilly Research Labs Cancer Biology and
Patient Tailoring Lilly, Indianapolis, IN
Background: Enzastaurin (enza) is in ph 3 registration trials for DLBCL
patients at high risk of relapse following R-CHOP therapy. In a phase 2
DLBCL study, 4 of 55 treated patients were progression- free after
prolonged, continuous oral enza therapy with 3 of these 4 confirmed as
complete responders (Robertson et al., JCO, 2007). The molecular mechanism
for this differential response is unclear. Methods: In clinical trials,
Enza yields 2-4 �M total circulating drug, comprised of ~50% enza, ~50%
primary metabolite, LY326020. We therefore evaluated the sensitivity of a
DLBCL cell panel representing both Activated B Cell (ABC) and Germinal
Center (GC) subtypes to enza and LY326020. Gene expression analyses,
western blotting to explore intracellular signaling and mRNA cap analogue
co-capture assays were used to identify the critical effectors of drug
sensitivity. Results: For the first time, we show the profound biological
activity of LY326020, the primary metabolite that accounts for ~ 50% of
circulating drug in patients. Like Enza, though more potently, LY326020
inhibits PKC and PI3K-AKT-TOR pathway signaling and robustly induces
apoptosis in both ABC and GC DLBCL cells. In both sensitive and resistant
cells, enza and LY326020 reduced phosphorylation of numerous proteins
in the PI3K-AKT-TOR pathway (e.g. pGSK3�ser9 ) in a dose and timedependent
manner. However, only sensitive DLBCL cells showed reduced
4EBP1ser65 phosphorylation. Accordingly, we show a dose and timedependent
increase in 4EBP1: eIF4E binding. This increase is most
pronounced by LY326020. Moreover, cells selected for resistance to enza
show reduced 4EBP1 expression and cells lacking 4EBP1 are insensitive to
the pro-apoptotic effects of enza and LY326020. Conclusions: These data
demonstrate that sensitivity of DLBCL to both enza and LY326020 is
critically dependent upon 4EBP1 modulation and subsequent disruption of
the eIF4F translation complex. Moreover, these data are the first to show
the potent biologic activity of LY326020, the primary metabolite of enza
that accounts for ~50% of total circulating drug in patients and in
preclinical models.
8084 General Poster Session (Board #37A), Mon, 1:15 PM-5:15 PM
An update on gemcitabine, rituximab, and oxaliplatin in combination for
relapsed/refractory non-Hodgkin lymphomas. Presenting Author: Robert M.
Crescentini, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Background: Relapsed/refractory non-Hodgkin lymphomas (NHL) have no
standard of care. A variety of salvage chemotherapy options are available.
We previously reported results of our phase II trial using gemcitabine,
rituximab and oxaliplatin (GROC) in the salvage setting for relapsed/
refractory NHL in which we observed an overall response rate of 58% with
an incidence of grade 3-4 thrombocytopenia of 9% and neutropenic fever
of 3.5%, but no grade 3-4 non-hematologic toxicities. Here we update
progression free survival (PFS) and overall survival (OS) data. Methods: This
phase II, single-arm, multicenter study evaluated safety and efficacy of
GROC in patients with relapsed/refractory NHL. Patients were treated on a
14 day cycle. On day 1, patients with CD20� NHL received rituximab (375
mg/m2 ). On day 2, patients received gemcitabine (1000 mg/m2 ) and
oxaliplatin (100 mg/m2 ). Granulocyte colony stimulating factor was given.
Stem cell transplant (SCT) was considered after a minimum of 6 cycles.
Results: A total of 58 patients were enrolled from the H. Lee Moffitt and the
Auxilio Mutuo Cancer Centers. Ages ranged from 24 to 88 years (median 72
years). The majority of patients had an ECOG performance status of 0-1
(89%). Lymphoid neoplasms included large B-cell (79%), follicular (7%),
lymphoblastic (1.8%), Burkitt (1.8%), primary mediastinal large B-cell
(3.5%), and peripheral T-cell lymphoma (7%). Eighty-one percent of
patients had stage III-IV disease, median IPI was 3, 40% had B-symptoms,
43% had bulky disease and 74% had an elevated LDH. Anthracyclinebased
therapy had been used in 91% of patients and 66% had received
rituximab. Median PFS was 134 days (95% CI 115-153) and median OS
was 296 days (95% CI 164-428). No difference in response was observed
based on age �60, IPI, LDH or albumin levels. Prior therapy with rituximab
(p�0.02) and initial response to front-line therapy (p�0.04) appear to
correlate with improved outcomes. Nine patients went on for SCT.
Conclusions: GROC is a useful salvage regimen for relapsed/refractory NHL
with minimal toxicities and good clinical efficacy. Several patients were
able to be successfully mobilized, collected and transplanted post GROC
therapy.
8083 General Poster Session (Board #36H), Mon, 1:15 PM-5:15 PM
Use of the cumulative amount of serum-free light chains (sFLC) at
diagnosis and PET2 for the early identification of high risk of treatment
failure in Hodgkin lymphoma (cHL). Presenting Author: Rosaria De Filippi,
Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale
Tumori, Fondazione �G.Pascale�, Naples, Italy
Background: Since early identification of patients (pts) at risk of failure is
the mainstay of a risk-adapted therapy, we explored the prognostic impact
of the sFLC assay in cHL, whose biology involves ongoing activation of
polyclonal B-cells. Methods: Serum samples from 248 untreated cHL pts
were tested by the Freelite assay. Median age was 32 yrs (r 15-85), males
47%, stages: I (5%), II (51%), III (17%), IV (27%); B-sympt. 60%,
E-disease, 38%; bulky �10 cm, 44%; ESR � 65, 42%; IPS �3, 39%.
Early unfavorable disease (GHLSG/ EORTC) was respectively found in 33%
and 42% of cases. ABVD was given to 89% of pts. Results: Absolute FLC
levels were summed into a sFLC(���) variable and ROC analysis indicated
57.1 mg/mL as the threshold to discriminate outcomes. CR rates were 96%
and 67% for pts below and above the cutoff, respectively (p�.0001). Cox
univariate analysis disclosed a HR of 16.70 (95% CI, 8.5-32.9) of events
for sFLC(���) � 57.1 mg/mL, by far higher than for PET2 positivity (HR
10.8), PS �1 (HR 4.2), IPS �3 (HR 2.8) and all other predictors (HR
0.54-2.4). In a multivariaye model only sFLC(���) and PET2 remained
independent predictors. A dismal 8-yrs EFS characterized pts with
sFLC(���) above threshold (20% vs 89%; �2 119, p�.0001). Pts with
sFLC(���) below cutoff and a negative PET2 had an EFS of 93% as
compared to 36% of those with sFLC(���) above cutoff or a positive PET2.
Pts with sFLC(���) above cutoff and positive PET2, had the worse
outcome with an EFS �10% and a median survival �12 mo.s (�2 65.4;
p�.0001). sFLC assay was even more valuable in identifying poor risk pts
within the early unfavorable category (5-yrs EFS �25%, �2 51 p�.0001).
By immunoistochemistry small B cells and plasmacytoid lymphocytes were
identified as the main source of sFLC in HL tissues while a strong sFLC
uptake by mast cells was documented. Conclusions: A cumulative amount
of sFLC �57.1 mg/mL, is the strongest independent predictor of failure in
cHL. Combining sFLC(���) and PET2 outcomes can timely discriminate
poor risk pts subsets, who may benefit from upfront treatment escalation or
early salvage. Our data also support that sFLC might endorse immunobiologic
activities relevant to cHL pathobiology.
8085 General Poster Session (Board #37B), Mon, 1:15 PM-5:15 PM
Prevention of adverse events during treatment of HIV-associated Hodgkin
lymphoma with ritonavir and zidovudine. Presenting Author: Sonia Sandhu,
John H. Stroger Jr. Hospital of Cook County, Chicago, IL
Background: In response to very high rates of neurologic and hematologic
adverse events (AE) when ABVD was used in combination with ritonavir
(RTV) or zidovudine (AZT) in HIV-associated Hodgkin (HL) we instituted a
policy to use alternative antiretroviral agents during HL therapy in our HIV
patients. In this study, we examined all AE in HIV-HL since the exclusion of
RTV and AZT over 2 years ago. We also evaluated the AEs when HAART and
chemotherapy for NHL were taken together in an expanded cohort of 52
pts. Methods: A screen of pharmacy and hospital databases between
1998-2012 identified all HIV-associated HL and NHL patients. Adverse
events during chemotherapy were assessed by chart review and graded per
the NCI Common Terminology Criteria for Adverse Events. Statistics:
Fisher’s exact test was used to examine the differences in AE incidence
associated with use of specific antiretrovirals. Results: HAART use during
chemotherapy was identified in 35/36 (96%) pts with HL and 52/108
(48%) of pts with NHL. Before RTV and AZT were prohibited, G3/4
neuropathy, neutropenia, and anemia developed in 31, 68, and 57% of 23
pts with HIV-HL respectively. Since then, 12 patients were treated with
non-RTV and AZT based HAART. 0% neuropathy and only 20% G3/4
neutropenia and 10% anemia was observed, each statistically significant
(p�0.01). Of the 54 patients with NHL, 64% received CHOPR like,
HYPERCVADR (18%), and daEPOCHR (11%). All AEs for each NHL
regimen were similar to historical controls and no anti HIV medication was
found to correlate with any AE, despite 28% of the HAART regimens
containing RTV. Conclusions: No relationship between any AE and anti HIV
medications was identified during treatment for NHL. But, excluding RTV
or AZT-based HIV therapy during HL treatment, decreased neuropathy,
neutropenia, and anemia by 100%, 38%, and 28% respectively. We
suggest that exclusion of ritonavir and zidovudine from HAART regimens
used with ABVD become the standard.
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