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

2023 Poster Discussion Session (Board #11), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Recurrent genetic alterations in primary central nervous system lymphoma
of immunocompetent patients. Presenting Author: Alberto Gonzalez, APHP,
UPMC, CRICM, UMR975, Hopital Pitié-Salpêtrière, Paris, France
Background: Little is known about the molecular pathogenesis of primary
central nervous system lymphoma (PCNSL) in immunocompetent patients.
Our objective was to identify the genetic changes involved in PCNSL
oncogenesis and evaluate their clinical relevance. Methods: Twenty nine
and four newly diagnosed, HIV-negative PCNSL patients were investigated
using high-resolution single nucleotide polymorphism (SNPa) arrays (Infinium
Illumina Human 610-Quad SNP array-Illumina; validated by realtime
quantitative polymerase chain reaction) and whole-exome sequencing
respectively. Molecular results were correlated with prognosis. Results: All
PCNSLs were diffuse large B-cell lymphomas, and the patients received
high-dose methotrexate-based polychemotherapy without radiotherapy as
an initial treatment.SNPa analysis revealed recurrent large and focal
chromosome imbalances that target candidate genes in PCNSL oncogenesis.
The most frequent genomic changes were (i) 6p21.32 loss (79%),
corresponding to the HLA locus; (ii) 6q loss (27-37%); (iii) CDKN2A
homozygous deletions (45%); (iv) 12q12-q22 (27%); (v) chromosome
7q21 and 7q31 gains (20%). Sequencing of matched tumor and blood
DNA samples identified novel somatic mutations in MYD88 (L265P hot
spot mutation) and TBL1XR1 in 38% and 14% of the cases, respectively.
The correlation of genetic abnormalities with clinical outcomes using
multivariate analysis showed that 6q22 loss (p�0.006 and p�0.01), and
CDKN2A homozygous deletion (p�0.02 and p�0.01) were significantly
associated with shorter progression free survival and overall survival.
Conclusions: Our study identified novel genetic alterations in PCNSL, such
as MYD88 and TBL1XR1 somatic mutations, which would both contribute
to the constitutive activation of the NFkB signaling pathway and represent
potential promising targets for future therapeutic strategies.
2025 Poster Discussion Session (Board #13), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Impact of adjuvant anti-VEGF therapy on treatment-related pseudoprogression
in patients with newly diagnosed glioblastoma receiving chemoradiation
with or without anti-VEGF therapy. Presenting Author: Marco C. Pinho,
Martinos Center for Biomedical Imaging, Massachusetts General Hopital,
Boston, MA
Background: Chemoradiation (CRT) can significantly modify the appearance
of glioblastoma (GBM) on MRI, especially within the 3-month window
after CRT. Pseudoprogression (PsP) is an increasingly recognized phenomenon
in this scenario, and is thought to be secondary to increased
permeability of the tumor vessels from irradiation, possibly enhanced by
temozolomide (TMZ). We sought to determine if the addition of a VEGF
signaling inhibitor (cediranib) during and after CRT had an impact on the
frequency of PsP, by comparing two groups of patients with newly
diagnosed GBMs. Methods: Two groups of patients enrolled in IRBapproved
trials underwent serial MRIs at baseline, weekly during CRT and
monthly thereafter. The control group received radiation plus TMZ, while
the other group (CED) also received cediranib until progression (which was
defined by RANO criteria) or toxicity. Patients that progressed up to 3
months after CRT were considered to have apparent progression (AP) and
kept on treatment. Lesions that subsequently stabilized/regressed were
classified as PsP, while those that maintained growth despite treatment
were classified as true early progression (EP). Results: Forty patients were
enrolled in CED and 11 as controls. Ten patients from CED and three
controls were excluded due to treatment discontinuation before 3 months
(drug-related toxicity and enrollment in post-CRT trials respectively). Three
patients in CED (6%) had AP (all confirmed as EP) and no patients fulfilled
criteria for PsP. Six patients from control (54%) had AP; 3 (27%) were
eventually classified as EP and 3 (27%) as PsP. The frequency of PsP was
significantly higher in the control group (p�0.0086). Conclusions: The
addition of a VEGF inhibitor as part of adjuvant treatment in this cohort of
glioblastoma patients prevented the development of early treatmentrelated
effects (PsP). Suppressing the edema and mass effect that
accompanies PsP may improve the tolerability of treatment. Additionally,
this effect may be exploited as a strategy to make chemoradiation feasible
in patients with large, unresectable tumors and/or poor baseline performance
status.
Central Nervous System Tumors
121s
2024 Poster Discussion Session (Board #12), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Blood alterations preceding clinical manifestation of glioblastoma. Presenting
Author: Aysegul Ilhan-Mutlu, Medical University of Vienna, Vienna,
Austria
Background: Glioblastoma is the most common and aggressive primary
brain tumour in adults. There is lack of knowledge on biochemical blood
alterations prior to clinical diagnosis of glioblastoma. We had the rare
opportunity to investigate selected blood markers from plasma samples
taken 12, 42 and 72 months before tumor manifestation in a glioblastoma
patient. This index patient was enrolled in the longitudinal population
based Vienna Transdanube Aging Study (VITA), which prospectively collects
blood plasma from 600 participants at baseline (age 75), 30 and 60
months thereafter. Methods: We determined plasma levels of S100B,
neuropeptide Y (NPY), secretagogin (SCGN), microRNA-21, microRNAlet7,
microRNA-128, and microRNA-342-3p in all three blood samples
from our index patient and in consecutive blood samples from five male and
five female controls from the VITA cohort. These proteins and microRNAs
were previously shown to be relevant for the pathobiology of glioblastomas.
None of the controls had a malignant or neurological disease. Protein
markers were analysed using commercially available ELISAs and microR-
NAs were quantified using RT-qPCR. Results: Compared to baseline values,
we found a significant increase of microRNA-21 (up to 4-fold) and
microRNA-let7 (up to 7-fold) levels in the blood samples of our index
patient, whereas control samples showed almost stable levels of these
markers. There was no significant difference in S100B, NPY, SCGN,
microRNA-128, and microRNA-342-3p plasma levels between the index
patient and controls. Conclusions: Increases of microRNA-21 and microRNAlet7
plasma levels may be associated with pre-clinical development of
glioblastoma.
2026 Poster Discussion Session (Board #14), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
A single-institution phase II trial of radiation (RT), temozolomide (TMZ),
erlotinib, and bevacizumab for initial treatment of glioblastoma (GBM).
Presenting Author: Jennifer Leigh Clarke, University of California, San
Francisco, San Francisco, CA
Background: Standard treatment for GBM includes surgery followed by RT
and TMZ, rarely a curative treatment. Both the EGFR and VEGF pathways
are frequently overactive in GBM; we previously added erlotinib, an EGFR
inhibitor, to RT and TMZ, with modest improvement in survival. The present
study combined bevacizumab, a VEGF inhibitor, and erlotinib with RT and
TMZ, with the goal of improving overall survival (OS). Methods: Treatment
consisted of fractionated RT to 60 Gy with daily TMZ at 75 mg/m2/d and
erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzymeinducing
antiepileptic drugs [EIAEDs]). Bevacizumab was given at 10
mg/kg every 2 wks, starting � 4 wks after surgery. After RT, adjuvant TMZ
was given at 200 mg/m2/d x 5d per 28d cycle, with unchanged erlotinib
and bevacizumab doses. Treatment was continued until progression or for
12 mo, with an option to continue for up to 24 mo. OS and progression-free
survival (PFS) from initial diagnosis were compared against institutional
historical controls (recent prior up-front clinical trials including RT and
TMZ). Results: 59 pts were enrolled; 12 were receiving EIAEDs. Median age
was 54 yrs; median KPS was 90. 33% underwent gross total resection and
53% subtotal resection. 16 pts had tumors with methylated MGMT
(mMGMT), 26 with unmethylated MGMT (umMGMT), and 17 with unknown
status. The most frequent related grade 3/4 AEs were lymphopenia
(68%) thrombocytopenia (24%), neutropenia (10%), diarrhea (14%),
weight loss (14%), and fatigue (12%). 1 pt died of aspergillosis. Median
OS and PFS were 19.8 mo and 13.5 mo, respectively, vs. 18 mo and 8.6
mo for the historical control. The hazard ratio (adj for age, KPS, and extent
of surgery) for PFS was 0.7 (95% CI 0.49-0.99, p�0.04). Median OS in
pts with mMGMT was 20.9 mo, vs. 17.5 mo in pts with umMGMT; median
PFS was 14 mo vs. 12.4 mo, respectively. Conclusions: The combination of
bevacizumab, erlotinib, TMZ, and RT showed improved PFS but not OS vs.
historical controls. Though the numbers were small, PFS and OS for pts
with umMGMT were not significantly different from pts with mMGMT,
suggesting that this combination may be more effective than standard
therapy alone for pts with unMGMT tumors.
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