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VEN+AZA: Summary of safety data from the VIALE-A trial

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Adverse reactions
Additional safety info

A tolerable, manageable, and predictable safety profile1

No additional warnings or precautions were observed in the AML trials for VENCLEXTA (venetoclax tablets). The safety profile of VEN+AZA was consistent with the known side effect profile of both agents.

Adverse reactions (≥10%) in patients with AML who received VEN+AZA with a difference between arms of ≥5% for all grades or ≥2% for Grade 3 or 4 reactions compared with PBO+AZA1*

Adverse reaction by body system
  VEN+AZA
(N=283)		 PBO+AZA
(N=144)
Body system Adverse reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%)
Gastrointestinal disorders  Nausea 44 2 35 <1
Diarrhea† 43 5 33 3
Vomiting† 30 2 23 <1
Stomatitis† 18 1 13 0
Abdominal pain† 18 <1 13 0
Blood and lymphatic system disorders Febrile neutropenia 42 42 19 19
Musculoskeletal and connective tissue disorders Musculoskeletal pain† 36 2 28 1
General disorders and administration site conditions Fatigue† 31 6 23 2
Edema† 27 <1 19 0
Vascular disorders Hemorrhage† 27 7 24 3
Hypotension† 12 5 8 3
Metabolism and nutrition disorders Decreased appetite† 25 4 17 <1
Skin and subcutaneous tissue disorders Rash† 25 1 15 0
Infections and infestations   Sepsis†
(excluding fungal)		 22 22 16 14
Urinary tract infection† 16 6 9 6
Respiratory, thoracic, and mediastinal disorders Dyspnea† 18 4 10 2
Nervous system disorders Dizziness† 17 <1 8 <1

*Patients who received at least one dose of either treatment.
†Includes multiple adverse reaction terms.

Hematologic laboratory abnormalities1

New or worsening Grade 3 or 4 hematologic laboratory abnormalities (≥10%) in VIALE-A with a difference between arms of ≥2% for VEN+AZA vs PBO+AZA, respectively:

  • Neutrophils decreased 98% vs 81%
  • Platelets decreased 88% vs 80%
  • Lymphocytes decreased 71% vs 39%
  • Hemoglobin decreased 57% vs 52%

Duration of exposure and occurrence of serious adverse reactions

Patients maintained treatment with VEN in the VEN+AZA arm for a median of 7.6 months1

Median duration of exposure
to VEN or PBO1,5

Median number
of treatment cycles3

Median duration of exposure
to VEN or PBO1,5

Median number
of treatment cycles3

Rate of serious adverse reactions
  VEN+AZA (N=283)1 PBO+AZA (N=144)3,5
  (%) occurrence Most frequent adverse reaction(s) (%) occurrence Most frequent adverse reaction(s)
Serious ARs 83 ≥5%: febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), hemorrhage (6%)
 73 ≥5%: pneumonia (22%), febrile neutropenia (10%), sepsis (8%)
Fatal ARs 23 >2%: pneumonia (4%), sepsis (excluding fungal; 3%), hemorrhage (2%) 20 ≥2%: sepsis (4%), pneumonia (2%)
Discontinuation, reduction, and interruption rates of VEN or PBO
  VEN VEN+AZA (N=283) PBO PBO+AZA (N=144)
ARs leading to permanent drug  discontinuation 24 >2%: sepsis (excluding fungal; 3%), pneumonia (2%) 20 ≥2%: sepsis (4%), pneumonia (3%), thrombocytopenia (2%), malignant neoplasm progression (2%)
Most frequent AR leading to dose reductions 35 pneumonia (0.7%) 4 pneumonia (1%)
ARs leading to dose interruptions 72 ≥5%: febrile neutropenia (20%), neutropenia (20%), pneumonia (14%), sepsis (excluding fungal; 11%), thrombocytopenia (10%) 57 ≥5%: pneumonia (13%), neutropenia (10%)
• In the VEN+AZA arm, among patients who achieved bone marrow clearance of leukemia, 53% (114/216)‡ underwent dose interruptions for ANC <500/microliter1,7
• Once bone marrow assessment confirmed a remission, defined as less than 5% leukemia blasts with cytopenia, VENCLEXTA or placebo was interrupted up to 14 days or until ANC ≥500/microliter and platelet count ≥50 x 103/microliter1
• Azacitidine was resumed on the same day as VENCLEXTA or placebo following interruption1
• Azacitidine dose reduction was implemented in the clinical trial for management of hematologic toxicity1

‡Of patients who achieved a morphologic leukemia-free state of response or better.7

Long-term follow-up safety17

  • The most common adverse events of any grade (≥20%) were:
    • Hematologic (VEN+AZA vs PBO+AZA): thrombocytopenia (47% vs 42%); febrile neutropenia (43% vs 19%); neutropenia (43% vs 29%); anemia (31% vs 23%); leukopenia (21% vs 14%)
    • Non-hematologic (VEN+AZA vs PBO+AZA): diarrhea (45% vs 34%); nausea (45% vs 37%); constipation (44% vs 40%); hypokalemia (30% vs 30%); vomiting (30% vs 24%); decreased appetite (28% vs 19%); pyrexia (27% vs 23%); peripheral edema (25% vs 19%); fatigue (22% vs 17%); pneumonia (26% vs 30%)
  • Grade ≥3 adverse events (≥10%) were:
    • Hematologic (VEN+AZA vs PBO+AZA): thrombocytopenia (46% vs 40%); febrile neutropenia (43% vs 19%); neutropenia (43% vs 29%); anemia (28% vs 22%); leukopenia (21% vs 12%)
    • Non-hematologic (VEN+AZA vs PBO+AZA): hypokalemia (12% vs 11%); pneumonia (23% vs 28%)
  • Serious adverse events occurred in 86% of patients with VEN+AZA vs 77% of patients with PBO+AZA
  • Fatal adverse events occurred in 25% of patients with VEN+AZA vs 22% of patients with PBO+AZA
  • Overall safety profiles were comparable between VEN+AZA and PBO+AZA with no new findings

Data cutoff date: December 1, 2021.

Rates of treatment-emergent adverse reactions of any grade are consistent with previous analyses1,17

AML=acute myeloid leukemia; ANC=absolute neutrophil count; AR=adverse reaction; AZA=azacitidine; PBO=placebo; VEN=VENCLEXTA.

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Dosing & Administration

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Important Safety Information & Indication

Indication

VENCLEXTA is indicated in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Important Safety Information

Tumor Lysis Syndrome

  • Tumor lysis syndrome (TLS), 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. 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.
  • In patients with AML who followed the current 3-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 1.1% in patients who received VENCLEXTA in combination with azacitidine. In patients with AML who followed a 4-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 5.6% and included deaths and renal failure in patients who received VENCLEXTA in combination with low-dose cytarabine.
  • The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy.
  • 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 AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles.
  • Monitor complete blood counts. Interrupt dosing for severe neutropenia. Resume at same dose then reduce duration based on remission status and first or subsequent occurrence of 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 and resume at same 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 with VENCLEXTA 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 AML receiving combination therapy with azacitidine, the most frequent serious adverse reactions (≥5%) were febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were neutrophils decreased (98%), platelets decreased (94%), lymphocytes decreased (91%), hemoglobin decreased (61%), nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with azacitidine, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%).
  • In patients with AML receiving combination therapy with decitabine, the most frequent serious adverse reactions (≥10%) were sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were neutrophils decreased (100%), lymphocytes decreased (100%), white blood cells decreased (100%), platelets decreased (92%), hemoglobin decreased (69%), febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexia (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%), and vomiting (31%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment.
  • In patients with AML receiving combination therapy with low-dose cytarabine, the most frequent serious adverse reactions (≥10%) were pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were platelets decreased (97%), neutrophils decreased (95%), lymphocytes decreased (92%), hemoglobin decreased (63%), nausea (42%), and febrile neutropenia (32%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%).

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 nursing 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 signs of 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.

    • VENCLEXTA Prescribing Information.

      VENCLEXTA Prescribing Information.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed May 17, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed May 17, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

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