Achieving undetectable MRD in CLL means a patient has no detectable
cancer cells, at a threshold of <1 detectable CLL cell per 10,000
leukocytes12
MRD can be measured in the bone marrow and/or peripheral blood12
MRD status at the end of treatment can be used to help assess
the response to therapy11,12
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 positive13
FDA considers MRD as not yet an established surrogate for
clinical outcomes in patients with CLL14
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 area14
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.11,14,15
PR=partial remission; CR=complete remission;
FDA=US Food and Drug Administration; iwCLL=International Workshop on
Chronic Lymphocytic Leukemia.
1L
VEN+G achieved undetectable MRD with 12 months 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.
IRC-assessed PFS (primary endpoint)
*Number of events based on earliest event of
disease progression or death due to any cause. Events due to
progression may include deaths occurring post-progression.
Rates of undetectable MRD in peripheral blood in ITT population
(secondary endpoint)
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 leukocytes
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 CGlb patients (95% CI: 29-42)†
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)‡
Rates of undetectable MRD in peripheral blood in evaluable
patients2§
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 prespecified or tested for
statistical significance
†P<0.0001. ‡P=0.0005. §Assessed 3 months
after treatment completion.
PFS was assessed in evaluable patients who achieved undetectable
MRD in peripheral blood 3 months after treatment completion9
Post hoc analysis
From the 36-month post hoc analysis of
INV-assessed PFS (1-year update). The clinical data cutoff date was
August 23, 2019. Not tested for statistical significance.
VEN+R achieved undetectable MRD with ~24 months* 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.
Rates of undetectable MRD in peripheral blood in ITT population
(secondary endpoint)
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 leukocytes
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 BR
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
patients10†
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. Not prespecified or tested for
statistical significance
*From Cycle 1, Day 1 of rituximab. †Assessed 3 months after combination treatment. ‡The number of patients is based on the EoCT MRD status
from the 2017 CSR, where one patient wasn't categorized as negative
due to missing EoCT response visit. nPR=nodular partial
remission; NCI-WG=National Cancer Institute–sponsored Working Group;
CT=computed tomography; EoCT=end of combination treatment;
CSR=clinical study report.
PFS by MRD status
PFS was assessed in evaluable patients who achieved undetectable
MRD in peripheral blood 3 months after the end of combination
treatment1,10
Post hoc analysis
From the 48-month post hoc analysis of INV-assessed PFS (2-year
update). The clinical data cutoff date was May 8, 2019.
Not tested for statistical significance.
§The number of patients is based on the EoCT MRD status
from the 2017 CSR, where one patient wasn’t categorized as negative
due to missing EoCT response visit. IIThe end of
combination treatment assessment occurs 3 months after the end of
combination treatment.1
EoCT=end of combination treatment; CSR=clinical
study report.
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 with high tumor burden when treated with VENCLEXTA.
In patients with CLL 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 studies. 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.
VENCLEXTA poses a risk for TLS at initiation and during the ramp-up phase. 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.
Patients should be assessed for TLS risk, including evaluation of tumor burden and comorbidities, and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Reduced renal function further increases the risk. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases.
Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors may increase the risk of TLS at initiation and during the ramp-up phase, and requires dose adjustment due to increases in VENCLEXTA exposure.
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 treated with VENCLEXTA in combination and monotherapy studies. Febrile neutropenia occurred in 4% to 6% of patients treated with VENCLEXTA in combination and monotherapy studies.
Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of 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 closely for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and higher infection.
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 avoid pregnancy during treatment.
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%).
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%).
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%).
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. Adjust VENCLEXTA dosage and closely monitor patients for signs of VENCLEXTA toxicities. 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.
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.
Monitor international normalized ratio (INR) closely in patients receiving warfarin.
Lactation
Advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA.
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, male fertility may be compromised by treatment with VENCLEXTA.
Hepatic Impairment
Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more closely for signs of toxicity. 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 progression and 15 death events) in the VEN+G arm compared with 79 in the GClb arm (71 progression and 8 death events).* 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 progression and 9 death events) compared with 106 events in the BR arm (91 progression and 15 death events). The median PFS was not reached 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-mrd-desktop.jpg)
