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
MATTHEW DAVIDS (BOSTON)
VENETOCLAX TRIALS
The oral BCL-2 inhibitor venetoclax first entered the clinic in 2011 in a first in human phase 1
study for patients with relapsed or refractory CLL and non-Hodgkin lymphoma (Roberts et al.,
NEJM, 2016). The drug was immediately noted to be highly active in CLL, but also associated
with a risk of tumor lysis syndrome. After adjusting the dosing, venetoclax was shown in this
and other early studies to be safe, tolerable, and effective for the treatment of relapsed or
refractory CLL, including for high risk patients such as those with TP53 aberrant disease. More
recently, venetoclax has been approved in both the relapsed/refractory and frontline settings
in combination with anti-CD20 antibodies, and is also being studied in combination with novel,
small molecule partners. Though promising, the follow-up for these combination studies
remains relatively short at the present time.
In this presentation, we will review the long term follow-up of the initial venetoclax clinical
trials in CLL, with a focus primarily on studies of venetoclax monotherapy in the
relapsed/refractory population. We will discuss the favorable long-term safety profile that
has emerged with this drug when given at the approved dose and schedule, with a specific
focus on the low incidence of cytopenias and gastrointestinal toxicities (Davids et al., Clin
Cancer Res, 2018).
We will review an analysis of four of the early-phase venetoclax trials with extended follow-up
to assess the rates of response over time, including rates of complete remission and
undetectable minimal residual disease (Roberts et al., Blood, 2019). We will review factors
such as bulky lymphadenopathy and refractoriness to B-cell receptor inhibitor therapy that
are associated with a shorter duration of response. We will also discuss the genetic factors
that may predispose to a shorter duration of response, such as TP53 aberrant disease and
NOTCH1 mutation. Additionally, we will discuss the kinetics of developing undetectable
peripheral blood MRD over time with venetoclax monotherapy (Lew et al., Blood Adv, 2020).
We will examine how peripheral blood undetectable MRD commonly correlates with bone
marrow undetectable MRD, and how both of these are associated with a comparable long-term
prognosis. We will also review the long term data on the initial phase 1b trial of
venetoclax with rituximab, including the most recent information available on patients who
electively discontinued venetoclax in remission and their response to retreatment with
venetoclax (Brander et al., ASH Annual Meeting, 2019).
Collectively, the data discussed will provide an overview of what we can expect with long term
treatment using venetoclax monotherapy in CLL, with an aim to spark a discussion about the
potential pros and cons of long term venetoclax monotherapy versus newer strategies
exploring time-limited venetoclax-based combination therapy.
References
Danielle M. Brander, MD, John F. Seymour, MBBS, PhD, FRACP, Thomas J. Kipps, MD, PhD, Shuo Ma,
MD, PhD, Mary Ann Anderson, MBBS, PhD, FRACP, FRCPA, Michael Y. Choi, MD, Kathryn Humphrey,
BSc, Abdullah Al Masud, PhD, Ruby Nandam, RN, MSN, Amanda Jacobson, PhD and Andrew W. Roberts,
MBBS, PhD. Durability of Responses on Continuous Therapy and Following Drug Cessation with
Venetoclax and Rituximab: Long-Term Follow-up Analysis of a Phase 1b Study in Patients with Relapsed
CLL. Abstract 3036, ASH Annual Meeting, 2019
Davids MS, Hallek M, Wierda W, Roberts AW, Stilgenbauer S, Jones JA, Gerecitano JF, Kim SY, Potluri J,
Busman T, Best A, Verdugo ME, Cerri E, Desai M, Hillmen P, Seymour JF. Comprehensive Safety Analysis
of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Clin
Cancer Res. 2018 Sep 15;24(18):4371-4379.