For Patients and Caregivers

VENCLEXTA efficacy results: undetectable minimal residual disease (uMRD)

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Achieving uMRD in CLL means a patient has no detectable cancer cells, at a threshold of <1 detectable CLL cell per 10,000 leukocytes13

Tumor burden
Decreasing detectable CLL cells in peripheral blood and/or bone marrow

uMRD rates with VEN+G

CLL14: In a randomized (1:1), multicenter, actively controlled, open-label, phase 3 trial (CLL14), VEN+G was studied against GClb in 432 patients with previously untreated CLL with comorbid medical conditions (total CIRS score >6 or CrCl <70 mL/min). The primary endpoint was progression-free survival (PFS). See full study design.1,2

CLL=chronic lymphocytic leukemia; CR=complete remission; MRD=minimal residual disease.

IRC-assessed PFS (primary endpoint) in 1L CLL

After a median follow-up of 28 months (range: 0-36 months):

  • There were 29 events in the VEN+G arm (14 progressions and 15 deaths without disease progression) compared with 79 events in the GClb arm (71 progressions and 8 deaths without disease progression)*
  • Median PFS was not reached in either arm

Undetectable MRD (uMRD) rates with VEN+G1

  • The rate of uMRD in bone marrow was 57% (123/216) for VEN+G (95% CI: 50-64) and 17% (37/216) for GClb (95% CI: 12-23) in the ITT population; P<0.0001

91% concordance: Of the 134 patients in the VEN+G arm with uMRD in peripheral blood who had matching bone marrow specimens, 122 patients had uMRD in bone marrow.

  • In patients with a CR, the rate of uMRD 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
  • MRD was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) 3 months after treatment ended. uMRD was defined as having achieved <1 CLL cell per 10,000 leukocytes1
  • While uMRD 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
  • The FDA does not yet consider MRD an established surrogate endpoint for clinical outcomes in patients with CLL15
  • Of evaluable GClb patients, 42% achieved uMRD (76/182)4
  • The population with evaluable results (n=369) excludes results missing due to progressive disease (PD), withdrawal (including withdrawal due to toxicity), deaths without disease progression, MRD status unknown, and other missing samples or assessments
  • Not prespecified or tested for statistical significance

*Number of events based on earliest event of disease progression or deaths without disease progression due to any cause.
†Assessed 3 months after treatment completion.2
‡Evaluable patients.4

Review a summary of safety data for patients treated with VEN+G from the CLL14 trial

View data

CI=confidence interval; CrCl=creatinine clearance; CR=complete remission; GClb=GAZYVA + chlorambucil; HR=hazard ratio; IRC=Independent Review Committee; ITT=intent to treat; PFS=progression-free survival; uMRD=undetectable minimal residual disease; VEN+G=VENCLEXTA + GAZYVA.

NEXT: Additional Data

US-VENC-240262

Important Safety Information & Indication

Indication

  • VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Important Safety Information

Contraindication

  • 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/SLL 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 reduction.

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. Interrupt dosing for severe neutropenia and resume at same or reduced dose. 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 and resume at same or reduced dose.

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 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 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.

Please see full Prescribing Information.

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VENCLEXTA® and its design are registered trademarks of AbbVie Inc.
GAZYVA® is a registered trademark of Genentech, Inc.

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