Achieving undetectable MRD in CLL means a patient has no detectable
cancer cells, at a threshold of <1 detectable CLL cell per 10,000
leukocytes13
13
MRD can be measured in the bone marrow and/or peripheral
blood13
MRD status
at the end of treatment can be used to help assess the response to
therapy11,13
MRD
negativity may also be referred to as “undetectable minimal residual
disease”11
While
undetectable MRD and response rates are both measures of disease, it
is possible for a patient with a PR to be MRD negative, and for a
patient with a CR to be MRD positive14
FDA
considers MRD as not yet an established surrogate for clinical
outcomes in patients with CLL15
FDA MRD
guidance indicates that the therapeutic paradigm with small molecule
inhibitors of the B-cell receptor signaling pathway and other novel
products is rapidly evolving in this area15
Updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) and iwCLL guidelines, as well as recent
guidance from the FDA, indicate that undetectable MRD is emerging as
an important measurement of disease.11,15,16
MRD=minimal residual disease; CLL=chronic
lymphocytic leukemia; PR=partial remission; CR=complete remission;
FDA=US Food and Drug Administration; NCCN=National Comprehensive
Cancer Network; iwCLL=International Workshop on Chronic Lymphocytic Leukemia.
1L
VEN+G achieved undetectable MRD with 1 year of treatment1
CLL14: In a randomized (1:1), multicenter, actively controlled,
open-label, phase 3 trial (CLL14), VEN+G was studied against
chlorambucil plus GAZYVA (GClb) in 432 patients with previously
untreated CLL with comorbid medical conditions (total CIRS score >6
or CLcr <70 mL/min). The primary endpoint was IRC-assessed
progression-free survival. See full study design.1,2
IRC-assessed PFS (primary endpoint)1
*Number of events based on earliest event of
disease progression or death due to any cause.1
Rates of undetectable MRD in peripheral blood in ITT population
(secondary endpoint)2
Undetectable MRD was evaluated using allele-specific
oligonucleotide polymerase chain reaction (ASO-PCR) 3 months after
treatment ended and was defined as having achieved <1 CLL cell
per 10,000 leukocytes1
Undetectable
MRD in peripheral blood (ITT population) was 76% (163/216) in VEN+G
patients (95% CI: 69-81), compared with 35% (76/216) in GClb
patients (95% CI: 29-42); P<0.00011
In patients with CR, the rate of undetectable MRD in
peripheral blood was 87% (87/100) for VEN+G (95% CI: 79-93) and
62% (29/47) for GClb (95% CI: 46-75); P=0.0005
Rates of undetectable MRD in peripheral blood in evaluable
patients (post hoc analysis)4†
The population with evaluable results (n=369) excludes results
missing due to progressive disease (PD), withdrawal (including
withdrawal due to toxicity), deaths, MRD status unknown, and other
missing samples or assessments. Not tested for statistical
significance4
VEN+R achieved undetectable MRD with 2 years* of treatment1
MURANO: In a randomized (1:1), multicenter, actively
controlled, open-label, phase 3 trial (MURANO), VEN+R was studied
against bendamustine in combination with rituximab (BR) in 389
patients with CLL who had received at least one line of prior therapy.
The primary endpoint was progression-free survival. See full study
design.1,6
Rates of undetectable MRD in peripheral blood in ITT population
(secondary endpoint)7†
Undetectable MRD was evaluated using allele-specific
oligonucleotide polymerase chain reaction (ASO-PCR) and was defined
as having achieved <1 CLL cell per 10,000 leukocytes7
Undetectable
MRD was assessed in peripheral blood 3 months after the last dose of
rituximab in the ITT population that achieved PR or better: 53%
(103/194) for VEN+R vs 12% (23/195) for BR1
In patients with CR/CRi, the rate of undetectable MRD in
peripheral blood was 3% (6/194) for VEN+R and 2% (3/195) for
BR
Rates of undetectable MRD in peripheral blood in evaluable patients
(post hoc analysis)12†
The population with evaluable results (n=233) excludes results
missing due to progressive disease (PD), withdrawal (including
withdrawal due to toxicity), deaths, MRD status unknown, and other
missing samples or assessments
*From Cycle 1, Day 1 of rituximab.1 †Assessed 3 months after end of combination treatment;
not tested for statistical significance.1,7,12 ‡The number of patients in the VEN+R arm with
undetectable MRD is based on the EoCT MRD status at the clinical
cutoff date of May 8, 2017, where 1 patient wasn't categorized as
negative due to missing EoCT response visit.12
PFS was assessed in evaluable patients who achieved undetectable
MRD in peripheral blood 3 months after the end of combination
treatment1,12
Post hoc analysis
Not tested for statistical significance.
From the 4-year post hoc analysis of INV-assessed PFS at the
clinical cutoff date of May 8, 2019.
§The number of patients with undetectable MRD is based on
the EoCT MRD status at the clinical cutoff date of May 8, 2017,
where 1 patient wasn’t categorized as negative due to missing EoCT
response visit. IIThe end of combination treatment
assessment occurred 3 months after the end of combination
treatment.1
INV=investigator; EoCT=end of combination treatment.
Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome (TLS).
Tumor Lysis Syndrome
Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA.
VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients, and during reinitiation after dosage interruption in patients with CLL/SLL. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase. TLS, including fatal cases, has been reported after a single 20 mg dose.
In patients with CLL/SLL who followed the current (5 week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL monotherapy trials. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab. With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure.
The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL.
Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA follow dose modification guidance in the Prescribing Information.
Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase, and requires VENCLEXTA dose adjustment.
Neutropenia
In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with VENCLEXTA in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients.
Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials and growth factors (e.g., G-CSF).
Infections
Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with VENCLEXTA. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution.
Immunization
Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective.
Embryo-Fetal Toxicity
VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after the last dose.
Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone
In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.
Adverse Reactions
In patients with CLL receiving combination therapy with obinutuzumab, serious adverse reactions were most often due to febrile neutropenia and pneumonia (5% each). The most common adverse reactions (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.
In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (≥5%) was pneumonia (9%). The most common adverse reactions (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.
In patients with CLL/SLL receiving monotherapy, the most frequent serious adverse reactions (≥5%) were pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). The most common adverse reactions (≥20%) of any grade were neutropenia (50%), diarrhea (43%), nausea (42%), upper respiratory tract infection (36%), anemia (33%), fatigue (32%), thrombocytopenia (29%), musculoskeletal pain (29%), edema (22%), and cough (22%). Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most often (2 patients) from septic shock.
Drug Interactions
Concomitant use with a P-gp inhibitor or a strong or moderate CYP3A inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions. Resume the VENCLEXTA dosage that was used prior to concomitant use of a P-gp inhibitor or a strong or moderate CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.
Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A.
Avoid concomitant use of strong or moderate CYP3A inducers.
Monitor international normalized ratio (INR) more frequently in patients receiving warfarin.
Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.
Lactation
Advise women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.
Females and Males of Reproductive Potential
Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose.
Based on findings in animals, VENCLEXTA may impair male fertility.
Hepatic Impairment
Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
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![67% reduction in risk of progression or death vs GClb (HR=0.33; 95% CI: 0.22-0.51 [P<0.0001]). After a median follow-up of 28 months (range: 0-36 month), there were 29 events (14 progressions and 15 deaths occuring without progression) in the VEN+G arm compared with 79 in the GClb arm (71 progressions and 8 deaths occuring without progression).* Median PFS was not reached in either arm](/content/dam/gene/venclextahcp-fullsite/images/venclexta-cll-1L-67-primary-endpoint-mrd-desktop.jpg)
![81% reduction in risk of progression or death vs BR (HR=0.19; 95% CI: 0.13-0.28 [P<0.0001]). After a median follow-up of 23.4 month (range: 0-37.4+ months): There were 35 events in the VEN+R arm (26 progressions and 9 deaths occuring without progression) compared with 106 events in the BR arm (91 progressions and 15 deaths occuring without progression). The median PFS was not reached (NR) with VEN+R vs 18.1 months (95% CI: 15.8-22.3) with BR](/content/dam/gene/venclextahcp-fullsite/images/venclexta-cll-rr-81-primary-endpoint-pfs-desktop.jpg)
