SCIENTIFIC PROGRAMME
SESSION I
THE GENOMIC AND
EPIGENOMIC LANDSCAPE
OF CLL AND CLINICAL
CONSEQUENCES
SESSION II
THE ROLE OF BCR
ACTIVATION AND
SIGNALLING FOR CLL
SESSION III
THERAPEUTIC OPTIONS
FOR CLL
SESSION IV
LONG TERM FOLLOW
UP OF CLINICAL TRIALS
VERSUS REAL WORLD
DATA (OUTSIDE CLINICAL
TRIALS DATA-OCT)
SESSION V
THE INCREASING ROLE
OF THE LEUKAEMIC
MICROENVIRONMENT
SESSION VI
THERAPEUTIC OPTIONS 2 :
THE USE OF CELLULAR
AND NON-CELLULAR
IMMUNOTHERAPIES IN
CLL
SESSION VII
EFFICACY THROUGH
SAFETY
SESSION VIII
CLONAL HETEROGENEITY,
CLONAL EVOLUTION AND
MECHANISMS OF DRUG
RESISTANCE
SESSION IX
CONTRASTING
THERAPEUTIC CONCEPTS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES
PHENOTYPIC CHANGES IN CLL CELLS IN A PATIENT ACQUIRING VENETOCLAX
RESISTANCE
Ferenc Takács1, Gábor Mikala2, Dóra Aczél1, Andrea Reszegi3, Ágnes Czeti1, Donát Alpár1, Csaba Bödör1,
Gábor Szalóki1, Ilona Kardos1 and Gábor Barna1
(1)MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and
Experimental Cancer Research, Semmelweis University, Budapest, Hungary, (2)South-Pest Central
Hospital- National Institute of Hematology and Infectious Diseases, Budapest, Hungary, (3)1st
Department of Pathology and Experimental Cancer Research-Molecular Pathology Research Group,
Budapest, Hungary
Chronic lymphoid leukemia (CLL) is the most common adult leukemia in the western world
representing an indolent and biologically heterogeneous disease. In addition to conventional
chemo-immuno therapy, new targeted therapies including the selective Bcl-2 inhibitor
venetoclax were introduced in recent years. Although venetoclax is a highly effective drug,
acquired drug resistance may make long-term treatment challenging. The role of response
predictive factors is becoming therefore of paramount importance. Here, we present the case
of a patient who developed venetoclax resistance with phenotyping changes of CLL cells
during therapy. Our aim was to investigate the signal transduction and immunophenotypic
changes emerging during venetoclax therapy. Furthermore, we compared the phenotype of
resistant CLL cells in bone marrow and peripheral blood.
We collected peripheral blood (PB) samples at the time of initiation of venetoclax therapy and
at 180th, 270th, 360th, and 450th day of treatment. Furthermore PB and bone marrow (BM)
samples were available at the time of overt clinical resistance (450th day). Cell surface
molecules CD49d, CD38, ROR1, CD69, CD86, CD27, CD184 and, CD185 were measured by flow
cytometry. We also investigated the most common Bcl-2 resistance mutation (G101V) by
digital droplet PCR. Protein and apoptosis arrays were performed from PB samples at the day
0 and the day 360 day of venetoclax therapy, and from PB and BM samples at the onset of
resistance.
We observed that the expression of surface markers CD184, CD185 and CD86 decreased
during venetoclax therapy until the onset of the resistance with CD69 and ROR1 showing
bimodal distribution. With higher CD69 expression documented in BM and CD185 expression
was higher in PB. The G101V Bcl-2 resistance mutation was not detected in any of the samples
analysed. Levels of BAD, BAX, XIAP, Bcl-XL and, p-CREB proteins were elevated during therapy
and decreased at the time of venetoclax resistance. Expression of Bcl-2 decreased during
therapy, however in the resistance sample the Bcl-2 expression was higher compared to the
initial presentation. In the BM sample XIAP, Bcl-XL, and p-CREB expression were higher
compared to the PB sample at the time of resistance.
Based on our results, development of venetoclax resistance is associated with changes in
expression of surface proteins and phospho-proteins in CLL cells. Monitoring of these markers
during the disease course may be helpful in the early detection of acquired venetoclax
resistance.
Supporting grants: EFOP-3.6.3-VEKOP-16-2017-00009, NVKP_16-1-2016-0004; NKFIH K16-
119950, KH17-126718 and ÚNKP-19-3-I-SE-33, ÚNKP-19-4-SE-77; HAS LP95021; János Bolyai
Scholarship Program;
POSTER 36