VENCLEXTA-based regimens offer well-studied safety profiles with exposure limited to 1 and 2 years1*

The fixed duration of VENCLEXTA-based regimens results in limited treatment exposure. There is no additional VENCLEXTA-based regimen exposure after completing treatment.1

1L

VEN+G safety from the CLL14 trial

  • In the VEN+G arm, 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 compared to 1% (3/214) of patients in the GCIb arm1,4
  • Serious adverse reactions were reported in 49% of patients in the VEN+G arm, most often due to febrile neutropenia and pneumonia (5% each)
  • The median duration of exposure to VENCLEXTA was 10.5 months (range: 0-13.5 months). The median number of cycles was 6 for obinutuzumab

Rates of discontinuation, dose reduction, and dose interruption

  • In the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%
  • Neutropenia led to discontinuation of VENCLEXTA in 2% of patients, reduction in 13%, and dose interruption in 41%

Adverse reactions (≥10%) in patients treated with VEN+G

Adverse reaction by body system VEN+G (N=212) GClb (N=214)
Any Grade
(%)
Grade ≥3
(%)
Any Grade
(%)
Grade ≥3
(%)
Blood and lymphatic system disorders
Neutropenia 60 56 62 52
Anemia 17 8 20 7
Gastrointestinal disorders
Diarrhea 28 4 15 1
Nausea 19 0 22 1
Constipation 13 0 9 0
Vomiting 10 1 8 1
General disorders and administration site conditions
Fatigue 21 2 23 1
Infections and infestations
Upper respiratory tract infection 17 1 17 1

Includes multiple adverse reaction terms.

VEN+G=VENCLEXTA + GAZYVA; GClb=GAZYVA + chlorambucil.

For laboratory abnormalities data, please see Table 10 in the VENCLEXTA full Prescribing Information.

During treatment with single-agent VENCLEXTA after completion of VEN+G combination treatment1:

  • The adverse reaction that occurred in ≥10% of patients was neutropenia (26%)
  • The Grade ≥3 adverse reactions that occurred in ≥2% of patients were neutropenia (23%) and anemia (2%)
0% clinical TLS.  The dose ramp-up was designed to gradually debulk tumor burden and mitigate TLS risk.  By implementing the TLS prophylaxis and monitoring protocol, 0% incidence of clinical TLS was observed in the 1L CLL trial.  Laboratory TLS occurred in 1% (3/212) of patients treated with VEN+G.  All 3 TLS events resolved and did not lead to withdrawal from the study.  GAZYVA administration was delayed in 2 cases in response to the TLS events.

New incidence of Grade 3 and 4 adverse events (AEs) decreased after the combination treatment period4

Comparison chart showing adverse events for patients within the VEN+G combination treatment period and the VENCLEXTA single-agent treatment period

Incidence of ≥2% during combination period.4
AST=aspartate aminotransferase.

  • VEN+G combination-therapy period: includes treatment-emergent adverse events occurring on or before last exposure date of GAZYVA® (obinutuzumab) + 29 days4
  • VENCLEXTA single-agent period: includes treatment-emergent adverse events occurring after start of VENCLEXTA monotherapy period to last exposure date of VENCLEXTA + 29 days4
  • Multiple occurrences of the same adverse event in an individual during the same treatment period are counted only once for that treatment period4

*From Cycle 1, Day 1 of rituximab.

R/R

VEN+R safety from the MURANO trial

At the time of data analysis, the median duration of exposure was 22 months in the VEN+R arm compared with 6 months in the BR arm
 

  • In the VEN+R arm, 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 last rituximab treatment were reported in 2% (4/194) of patients. Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with the most frequent (≥5%) being pneumonia (9%)
  • 93% (173/187) of patients in the VEN+R arm and 68% (127/188) of patients in the BR arm completed 6 combination treatment cycles8
    • 7 patients in each arm did not receive combination therapy: in the VEN+R arm, 7 patients did not receive rituximab, and in the BR arm, 7 patients did not receive either bendamustine or rituximab6
    • Patients needed to receive at least 90% of the target dose to be counted as receiving a full cycle8

Rates of discontinuation, dose reduction, and dose interruption

  • In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%
  • Neutropenia led to discontinuation of VENCLEXTA in 3% of patients and dose interruption in 46%. Thrombocytopenia led to discontinuation in 3% of patients

Adverse reactions (≥10%) in patients treated with VEN+R

Adverse reaction by body system VEN+R (N=194)
BR (N=188)
All Grades
(%)
Grade ≥3
(%)
All Grades
(%)
Grade ≥3
(%)
Blood and lymphatic system disorders
Neutropenia 65 62 50 44
Anemia 16 11 23 14
Gastrointestinal disorders
Diarrhea 40 3 17 1
Nausea 21 1 34 1
Constipation 14 <1 21 0
Infections and infestations
Upper respiratory tract infection 39 2 23 2
Lower respiratory tract infection 18 2 10 2
Pneumonia 10 7 14 10
General disorders and administration site conditions
Fatigue 22 2 26 <1

Includes multiple adverse reaction terms.

VEN+R=VENCLEXTA + rituximab; BR=bendamustine + rituximab.

For laboratory abnormalities data, please see Table 12 in the VENCLEXTA full Prescribing Information.

Select important adverse reactions6

Adverse reaction (%)
VEN+R (N=194)
BR (N=188)
Grade 3 or 4 febrile neutropenia
4 10
Grade 3 or 4 infections and infestations
18 22

Adverse reactions during treatment with single-agent VENCLEXTA after completion of VEN+R combination treatment1

  • Adverse reactions that occurred in ≥10% of patients were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%)
  • The Grade 3 or 4 adverse reactions that occurred in ≥2% of patients were neutropenia (12%) and anemia (3%)

Hear Dr. Crane discuss safety data from the MURANO trial.

Stop sign icon - No additional VEN+R drug exposure after stopping treatment after 2 years.  From cycle 1, day 1 of rituximab

New incidence of Grade ≥3 AEs decreased after the combination treatment period8,9

Comparison chart showing adverse events for patients within the VEN+R combination treatment period and the VENCLEXTA single-agent treatment period

Incidence of ≥2% during combination period.8
TLS=tumor lysis syndrome; AIHA=autoimmune hemolytic anemia.

  • VEN+R combination-therapy period: includes treatment-emergent AEs with an onset date from initiation of the VENCLEXTA dose ramp-up to within 90 days after last rituximab dose8
  • VENCLEXTA single-agent period: includes patients who had at least 1 VENCLEXTA dose more than 90 days after last rituximab dose and treatment-emergent AEs with an onset date more than 90 days after last rituximab dose8
  • Multiple occurrences of the same AE in an individual during the same treatment period are counted only once for that treatment period8

*From Cycle 1, Day 1 of rituximab.

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Initiation

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PFS results

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Dosing video

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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 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.

Please see full Prescribing Information.

VENCLEXTA®, VENCOMPASS® and their designs are registered trademarks of AbbVie Inc.
GAZYVA® is a registered trademark of Genentech, Inc.

    • VENCLEXTA Prescribing Information.

      VENCLEXTA Prescribing Information.

    • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236.

      Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236.

    • GAZYVA Prescribing Information, January 2021.

      GAZYVA Prescribing Information, January 2021.

    • Data on file, AbbVie Inc. ABVRRTI69608.

      Data on file, AbbVie Inc. ABVRRTI69608.

    • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23)(suppl):2225-2236.

      Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23)(suppl):2225-2236.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12)(suppl):1107-1120.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12)(suppl):1107-1120.

    • Data on file, AbbVie Inc. ABVRRTI69609.

      Data on file, AbbVie Inc. ABVRRTI69609.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO trial establishes feasibility of time-limited venetoclax–rituximab combination therapy in relapsed/refractory chronic lymphocytic leukemia. Presented at: 60th American Society of Hematology Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA.

      Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO trial establishes feasibility of time-limited venetoclax–rituximab combination therapy in relapsed/refractory chronic lymphocytic leukemia. Presented at: 60th American Society of Hematology Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA.

    • Data on file, AbbVie Inc. ABVRRTI69785.

      Data on file, AbbVie Inc. ABVRRTI69785.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. V.2.2021. National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed January 7, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. V.2.2021. National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed January 7, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Data on file, AbbVie Inc. ABVRRTI71322.

      Data on file, AbbVie Inc. ABVRRTI71322.

    • Owen C, Christofides A, Johnson N, Lawrence T, MacDonald D, Ward C. Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia [published online ahead of print May 16, 2017]. Leuk Lymphoma. 2017;58(12):2777-2785.

      Owen C, Christofides A, Johnson N, Lawrence T, MacDonald D, Ward C. Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia [published online ahead of print May 16, 2017]. Leuk Lymphoma. 2017;58(12):2777-2785.

    • Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286.

      Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286.

    • US Food and Drug Administration. Hematologic malignancies: regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hematologic-malignancies-regulatory-considerations-use-minimal-residual-disease-development-drug-and. January 2020. Accessed February 28, 2020.

      US Food and Drug Administration. Hematologic malignancies: regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hematologic-malignancies-regulatory-considerations-use-minimal-residual-disease-development-drug-and. January 2020. Accessed February 28, 2020.

    • Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL [published online ahead of print March 14, 2018]. Blood. 2018;131(25):2745-2760.

      Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL [published online ahead of print March 14, 2018]. Blood. 2018;131(25):2745-2760.

    • Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax–rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

      Seymour JF, Kipps TJ, Eichhorst B, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax–rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

    • Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. Oncologist. 2016;21(3):354-376.

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      Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56-66.

    • Giacomini KM, Huang S-M, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236.

      Giacomini KM, Huang S-M, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236.

    • Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495-2502.

      Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495-2502.

    • CRESEMBA Prescribing Information. December 2019.

      CRESEMBA Prescribing Information. December 2019.

    • Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes. Updated November 14, 2017. Accessed March 11, 2021.

      Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes. Updated November 14, 2017. Accessed March 11, 2021.

    • Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes. Updated November 14, 2017. Accessed February 20, 2019.

      Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes. Updated November 14, 2017. Accessed February 20, 2019.

    • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236

      Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236