- Data from two studies continue to show the long-term
efficacy and safety of fixed-duration venetoclax combination
regimens across different lines of therapy in CLL
- Six-year median follow-up from the Phase 3 CLL14 study shows
continued PFS after treatment with venetoclax plus obinutuzumab
compared to treatment with chlorambucil plus obinutuzumab in
previously untreated patients with CLL and co-existing
- Final seven-year follow-up results of the Phase 3 MURANO
trial demonstrate sustained PFS and overall survival (OS) with
venetoclax and rituximab compared to bendamustine and rituximab in
patients with relapsed/refractory (R/R) CLL
CHICAGO, Ill., June 9, 2023
/PRNewswire/ -- AbbVie (NYSE: ABBV) today announced new findings
demonstrating sustained long-term safety and efficacy of
VENCLYXTO®/ VENCLEXTA® (venetoclax)-based
combination therapies in patients with previously untreated CLL
with co-existing conditions, as well as R/R CLL. The results are
being presented during oral sessions at the European Hematology
Association (EHA) Annual Congress in Frankfurt, Germany.
"Results from the CLL14 and MURANO studies demonstrate the
long-term benefits of fixed-duration venetoclax combinations for
patients living with CLL," said Mariana
Cota Stirner, M.D., Ph.D., vice president, hematology,
AbbVie. "These results underscore our commitment to transform how
blood cancers are treated today and show that venetoclax can give
patients lasting results with time off treatment."
CLL14 Long-Term Analysis
New six-year follow-up results from the Phase 3 CLL14 study
showcase updated outcomes in previously untreated patients with CLL
and co-existing conditions. Patients treated with fixed-duration
venetoclax plus obinutuzumab continued to experience improved PFS
(95% Confidence Interval (CI) 0.31-0.52; Hazard Ratio (HR) 0.40)
and higher rates of undetectable minimal residual disease (uMRD)
when treated with fixed-duration venetoclax plus obinutuzumab
compared to those who received chlorambucil plus obinutuzumab
(53.1% vs 21.7%, respectively).
The data also showed significantly improved rates of time to
next treatment (TTNT) with venetoclax plus obinutuzumab at 65.2
percent (95% CI 0.33-0.58; HR 0.44) compared to chlorambucil plus
obinutuzumab at 37.1 percent.1 The observed differences
in PFS and TTNT benefits between venetoclax-based treatment and
chemoimmunotherapy were maintained across all risk groups,
including patients with high-risk molecular features of CLL.
No new safety signals were observed in this six-year analysis.
The most frequently occurring Grade 3 (≥2%) adverse events (AEs) in
patients receiving the venetoclax-based combination were
neutropenia, thrombocytopenia, infusion-related reaction (during
treatment), anemia, febrile neutropenia, pneumonia and
"The latest findings show that patients can experience long-term
disease control, five years after stopping treatment," said Othman
Al-Sawaf, M.D., investigator in the CLL14 study,
hematologist-oncologist at the University Hospital Cologne
in Germany, and study physician at the German CLL Study Group.
"These results confirm the treatment benefits of fixed-duration
venetoclax and obinutuzumab for previously untreated CLL patients
with co-existing conditions."
Results will also be featured at EHA's Press Briefing.
MURANO Long-Term Analysis
Final data from the Phase 3 MURANO trial showcase that R/R CLL
patients treated with two-year fixed-duration venetoclax plus
rituximab sustained significantly longer median PFS at 54.7 months
(95% CI 52.3, 59.9), the study's primary endpoint, compared to 17.0
months (95% CI 15.5, 21.7; HR 0.23) with bendamustine plus
rituximab after 7 years of median follow-up.2
Seven-year OS rates were 69.6 percent (95% CI 62.8, 76.5) for
patients treated with the venetoclax-based combination versus 51
percent (95% CI 43.3, 58.7) for study participants who received
bendamustine-based combination (HR 0.53).2 Furthermore,
most of the patients treated with the full two-year
venetoclax-based combination achieved uMRD (70.3%) at the end of
their treatment course, and those patients were shown to have
improved PFS and OS compared to patients with detectable MRD
The safety profile of the venetoclax-rituximab combination is
consistent with the known safety profile of each individual therapy
alone. No new serious safety issues were observed in the MURANO
updated analysis. The most common adverse reactions (ARs) (≥20%) of
any grade were neutropenia, diarrhea, upper respiratory tract
infection, fatigue, and nausea.
"We are pleased to find that uMRD was associated with prolonged
PFS in R/R CLL patients after seven years," said study investigator
Prof. John Seymour, Director of the
Integrated Haematology Department of the Peter MacCallum Cancer
Center and the Royal Melbourne Hospital in Melbourne. "Overall, these findings continue
to support the use of treatment with venetoclax plus rituximab in
this patient population."
VENCLYXTO/VENCLEXTA is being developed by AbbVie and Roche. It
is jointly commercialized by AbbVie and Genentech, a member of the
Roche Group, in the U.S. and by AbbVie outside of the U.S.
About the CLL14 Phase 3 Trial1,3
prospective, multicenter, open-label, randomized Phase 3 CLL14
trial, which was conducted in close collaboration with the German
CLL Study Group (GCLLSG), evaluated the efficacy and safety of a
combined regimen of VENCLYXTO/VENCLEXTA and obinutuzumab (n=216)
versus obinutuzumab and chlorambucil (n=216) in previously
untreated patients with CLL and co-existing medical conditions
(total Cumulative Illness Rating Scale [CIRS] score >6 or
creatinine clearance <70 mL/min). The therapies were
administered for a fixed-duration of 12 months for
VENCLYXTO/VENCLEXTA in combination with six cycles of obinutuzumab.
The trial enrolled 432 patients, all of whom were previously
untreated, according to the International Workshop on Chronic
Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on PFS,
as assessed by an independent review committee.
Key secondary endpoints were rates of MRD in peripheral blood
and bone marrow, overall and complete response rates, MRD in
complete response in peripheral blood and bone marrow, and OS.
In patients with CLL receiving venetoclax combination therapy
with obinutuzumab, the most frequently occurring ≥ Grade 3 AEs
(≥2%) were neutropenia (51.9%), thrombocytopenia (14.2%),
infusion-related reaction (9.0%), anemia (7.5%), febrile
neutropenia (4.2%), pneumonia (3.8%) and leukopenia (2.4%). Serious
ARs were most often due to febrile neutropenia and pneumonia (5%
each). The most common ARs (≥20%) of any grade were neutropenia
(60%), diarrhea (28%), and fatigue (21%). Fatal ARs that occurred
in the absence of disease progression and with onset within 28 days
of the last study treatment were reported in 2 percent (4/212) of
patients, most often from infection.
About the MURANO Phase 3 Trial2,4
of 389 patients with R/R CLL who had received at least one prior
therapy were enrolled in the international, multicenter,
open-label, randomized Phase 3 MURANO trial. The trial was designed
to evaluate the efficacy and safety of VENCLYXTO/VENCLEXTA and
rituximab (n=194) compared with bendamustine and rituximab (n=195).
The median age of patients in the trial was 65 years (range: 22 to
The trial met its primary efficacy endpoint of investigator
(INV)-assessed PFS. At the time of the primary analysis, median PFS
with VENCLYXTO/VENCLEXTA and rituximab was not reached compared
with 17.0 months for bendamustine and rituximab (HR: 0.17; 95% CI:
0.11- 0.25; p<0.0001). In the primary efficacy analysis, the
median follow-up for PFS was 23.8 months (range: 0 to 37.4).
Additional efficacy endpoints included independent review committee
(IRC)-assessed PFS, INV- and IRC-assessed overall response rate
(defined as complete response + complete response with incomplete
marrow recovery + partial response + nodular partial response), OS
and rates of MRD-negativity.
In patients with CLL receiving combination therapy with
rituximab, the most frequent serious adverse reaction (AR; ≥5%) was
pneumonia (9%). The most common ARs (≥20%) of any grade were
neutropenia (65%), diarrhea (40%), upper respiratory tract
infection (39%), fatigue (22%), and nausea (21%). Fatal ARs that
occurred in the absence of disease progression and within 30 days
of the last venetoclax treatment and/or 90 days of the last
rituximab were reported in 2% (4/194) of patients.
About VENCLYXTO® (venetoclax)
VENCLYXTO® (venetoclax) is a first-in-class
medicine that selectively binds and inhibits the B-cell lymphoma-2
(BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells
from undergoing their natural death or self-destruction process,
called apoptosis. VENCLYXTO targets the BCL-2 protein and works to
help restore the process of apoptosis.
VENCLYXTO is being developed by AbbVie and Roche. It is jointly
commercialized by AbbVie and Genentech, a member of the Roche
Group, in the U.S. and by AbbVie outside of the U.S. Together, the
companies are committed to BCL-2 research and to studying
venetoclax in clinical trials across several blood and other
cancers. Venetoclax is approved in more than 80 countries,
including the U.S.
Indication and Important VENCLYXTO (venetoclax) EU Safety
Venclyxto in combination with obinutuzumab is indicated for the
treatment of adult patients with previously untreated chronic
lymphocytic leukaemia (CLL).
Venclyxto in combination with rituximab is indicated for the
treatment of adult patients with CLL who have received at least one
Venclyxto monotherapy is indicated for the treatment of CLL:
- In the presence of 17p deletion
or TP53 mutation in adult patients who are
unsuitable for or have failed a B-cell receptor pathway inhibitor,
- In the absence of 17p deletion
or TP53 mutation in adult patients who have failed
both chemoimmunotherapy and a B-cell receptor pathway
Venclyxto in combination with a hypomethylating agent is
indicated for the treatment of adult patients with newly diagnosed
acute myeloid leukaemia (AML) who are ineligible for intensive
Hypersensitivity to the active substance or to any of the
excipients is contraindicated. Concomitant use of strong CYP3A
inhibitors at initiation and during the dose-titration phase due to
increased risk for tumour lysis syndrome (TLS). Concomitant use of
preparations containing St. John's wort as Venclyxto
efficacy may be reduced.
Special Warnings & Precautions for Use
Tumour Lysis syndrome, including fatal events, has occurred in
patients when treated with Venclyxto. For CLL and AML, please refer
to the indication-specific recommendations for prevention of TLS in
the Venclyxto summary of product characteristic (SmPC).
Patients should be assessed for risk and should receive
appropriate prophylaxis, monitoring, and management for
TLS. The risk of TLS is a continuum based on multiple factors,
including comorbidities. Venclyxto poses a risk for TLS at
initiation and during the dose-titration phase. Changes in
electrolytes consistent with TLS that require prompt management can
occur as early as 6 to 8 hours following the first dose of
Venclyxto and at each dose increase.
Neutropenia (grade 3 or 4) has been reported. Complete
blood counts should be monitored throughout the treatment
In patients with AML, neutropenia (grade 3 or 4) is common
before starting treatment. The neutrophil counts can worsen with
Venetoclax in combination with a hypomethylating agent. Neutropenia
can recur with subsequent cycles of therapy. Dose modification and
interruptions for cytopenias are dependent on remission status.
For CLL and AML, please refer to the indication-specific
recommendations for dose modifications for toxicities in the
Serious infections including sepsis with fatal outcome have been
reported. Monitoring of any signs and symptoms of infection is
required. Suspected infections should receive prompt treatment
including antimicrobials and dose interruption or reduction as
Live vaccines should not be administered during treatment or
thereafter until B-cell recovery.
In CLL and AML CYP3A inhibitors may increase Venclyxto plasma
In CLL, at initiation and dose-titration phase, Strong CYP3A
inhibitors are contraindicated due to increased risk for TLS and
moderate CYP3A inhibitors should be avoided. If moderate CYP3A
inhibitors must be used, please refer to the recommendations for
dose modifications in the Venclyxto SmPC.
In AML, please refer to the AML-specific recommendation for dose
modifications for potential interactions with CYP3A inhibitors, in
the VENCLYXTO SmPC.
Avoid concomitant use of P-gp and BCRP inhibitors at initiation
and during the dose titration phase.
CYP3A4 inducers may decrease Venclyxto plasma
concentrations. Avoid coadministration with strong or
moderate CYP3A inducers. These agents may decrease venetoclax
Co-administration of bile acid sequestrants with VENCLYXTO is
not recommended as this may reduce the absorption of VENCLYXTO.
The most commonly occurring adverse reactions (>=20%) of any
grade in patients receiving venetoclax in the combination studies
with obinutuzumab or rituximab were neutropenia, diarrhoea, and
upper respiratory tract infection. In the monotherapy studies,
the most common adverse reactions were neutropenia/neutrophil count
decreased, diarrhoea, nausea, anaemia, fatigue, and upper
respiratory tract infection.
The most frequently occurring serious adverse reactions
(>=2%) in patients receiving venetoclax in combination with
obinutuzumab or rituximab were pneumonia, sepsis, febrile
neutropenia, and TLS. In the monotherapy studies, the most
frequently reported serious adverse reactions (>=2%) were
pneumonia and febrile neutropenia.
Discontinuations due to adverse reactions occurred in 16% of
patients treated with venetoclax in combination with obinutuzumab
or rituximab in the CLL14 and Murano studies, respectively.
In the monotherapy studies with venetoclax, 11% of patients
discontinued due to adverse reactions.
Dosage reductions due to adverse reactions occurred in 21% of
patients treated with the combination of venetoclax and
obinutuzumab in CLL14, in 15% of patients treated with the
combination of venetoclax and rituximab in Murano, and in 14% of
patients treated with venetoclax in the monotherapy studies. The
most common adverse reaction that led to dose interruptions was
The most commonly occurring adverse reactions (>=20%) of any
grade in patients receiving venetoclax in combination with
azacitidine or decitabine in the VIALE-A and M14-358, respectively,
were thrombocytopenia, neutropenia, febrile neutropenia, nausea,
diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and
decreased appetite, haemorrhage, dizziness/syncope, hypotension,
headache, abdominal pain, and anaemia.
The most frequently reported serious adverse reactions (≥5%) in
patients receiving venetoclax in combination with azacitidine were
febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358,
the most frequently reported serious adverse reactions (≥5%) were
febrile neutropenia, pneumonia, bacteraemia and sepsis.
Discontinuations due to adverse reactions occurred in 24% of
patients treated with venetoclax in combination with azacitidine in
the VIALE-A study, and 26% of patients treated with venetoclax in
combination with decitabine in the M14-358 study, respectively.
Dosage reductions due to adverse reactions occurred in 2% of
patients in VIALE-A, and in 6% of patients in M14-358. Venetoclax
dose interruptions due to adverse reactions occurred in 72% and 65%
of patients, respectively. The most common adverse reaction that
led to dose interruption (>10%) of Venetoclax in VIALE-A, were
febrile neutropenia, neutropenia, pneumonia, and
thrombocytopenia. The most common adverse reactions that led
to dose interruption (≥5%) of venetoclax in M14-358 were febrile
neutropenia, neutropenia/neutrophil count decreased, pneumonia,
platelet count decreased, and white blood cell count decreased.
Patients with reduced renal function (CrCl <80 mL/min) may
require more intensive prophylaxis and monitoring to reduce the
risk of TLS at initiation and during the dose-titration
phase. Safety in patients with severe renal impairment (CrCl
<30 mL/min) or on dialysis has not been established, and a
recommended dose for these patients has not been determined.
For patients with severe (Child-Pugh C) hepatic
impairment, a dose reduction of at least 50% throughout treatment
Venclyxto may cause embryo-fetal harm when administered to a
pregnant woman. Advise nursing women to discontinue breastfeeding
This is not a complete summary of all safety information. See
Venclyxto (venetoclax) SmPC at www.ema.europa.eu.
Globally, prescribing information varies; refer to the individual
country product label for complete information.
About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for
multiple blood cancers while advancing a dynamic pipeline of
investigational therapies across a range of cancer types. Our
dedicated and experienced team joins forces with innovative
partners to accelerate the delivery of potentially breakthrough
medicines. We are evaluating more than 20 investigational medicines
in over 300 clinical trials across some of the world's most
widespread and debilitating cancers. As we work to have a
remarkable impact on people's lives, we are committed to exploring
solutions to help patients obtain access to our cancer medicines.
For more information, please
visit http://www.abbvie.com/oncology and our Blood
Cancer Press Kit page.
AbbVie's mission is to discover and deliver innovative medicines
that solve serious health issues today and address the medical
challenges of tomorrow. We strive to have a remarkable impact on
people's lives across several key therapeutic areas: immunology,
oncology, neuroscience, eye care, virology and gastroenterology, in
addition to products and services across our Allergan Aesthetics
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AbbVie Forward-Looking Statements
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considered, forward-looking statements for purposes of the Private
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revisions to forward-looking statements as a result of subsequent
events or developments, except as required by law.
- Al-Sawaf O, et al. Venetoclax-Obinutuzumab for previously
untreated chronic lymphocytic leukemia: 6-year results of the
randomized CLL14 study. Abstract No. S145. Presented orally at
European Hematology Association 2023 Hybrid Congress, Frankfurt, Germany, June 8-11.
- Arnon P Kater, et al. Final seven-year follow-up and
retreatment substudy analysis of MURANO: Venetoclax-rituximab
(VenR)-treated patients with relapsed with relapsed/refractory
chronic lymphocytic leukemia (R/R CLL). Abstract No. S201.
Presented orally at European Hematology Association 2023 Hybrid
Congress, Frankfurt, Germany,
- Fischer K, et al. Venetoclax and obinutuzumab in patients with
CLL and coexisting conditions. N Engl J Med.
- Seymour JF, et al. Venetoclax-rituximab in relapsed or
refractory chronic lymphocytic leukemia. N Engl J Med.
- Summary of Product Characteristics for VENCLYXTO (venetoclax).
Ludwigshafen, Germany: AbbVie
Deutschland GmbH & Co. KG.