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VIALE-A OS long-term follow-up data and real-world evidence

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OS follow-up
ARC initiative study design
OS and CR in a real-world study

VIALE-A long-term follow-up data: VEN+AZA vs AZA17

VIALE-A study design

A randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of VENCLEXTA (venetoclax tablets) in combination with azacitidine (VEN+AZA; N=286) vs placebo with azacitidine (PBO+AZA; N=145) in adults with newly diagnosed AML who were ≥75 years of age, or with comorbidities (see baseline characteristics) that precluded the use of intensive induction chemotherapy.1
View full study design.

Primary endpoint data

VEN+AZA demonstrated superior overall survival (OS) vs AZA. Median OS: VEN+AZA: 14.7 months; 95% CI: (11.9, 18.7) vs AZA: 9.6 months; 95% CI: (7.4, 12.7). OS: HR=0.66; 95% CI: (0.52, 0.85); P<0.001.1 View KM curve.

Median follow-up for OS was approximately 43.2 months (range: <0.1-53.4)17

Data cutoff date: December 1, 2021

  • The rates shown are estimated and can be unreliable due to a large number of patients censored at the tail end of the curve
  • The rates were not powered to demonstrate a statistically significant difference in survival rates
  • No conclusions of efficacy or safety can be drawn from these data

VEN+AZA ARC Initiative study design18,19

An ongoing retrospective real-world analysis

data method

The AML Real-world EvidenCe (ARC) Initiative is an ongoing retrospective patient medical chart review from 10 US academic sites and 4 Israeli academic sites. While the ARC study population is broader, this subgroup analysis includes only patients from the population described in the next section.

Population
  • 90 adult patients
  • Newly diagnosed with AML
  • Ineligible for intensive induction chemotherapy, defined as patients ≥75 years of age, or with one of the comorbidities of interest per the Ferrara criteria and physician judgment from the study primary investigator
  • Treated with VEN+AZA
  • No prior treatment on venetoclax
  • Median age of the study population was 76 years (range: 34-89), and 24% had secondary AML
Study period
  • VEN+AZA treatment started on April 11, 2016. Follow-up was until May 30, 2022
  • Median follow-up: 10.2 months
Study outcomes
  • CR rate: complete response rate was calculated among the 87 patients with available physician-reported response data documented in patient medical records
  • mOS: median OS was estimated by the Kaplan-Meier survival analysis to summarize time to death
ARC study limitations
  • Patients in this study were treated in academic centers and results may not be generalizable to AML patients treated in the community setting
  • Results in this study are based on information as recorded in patient charts by the treating physician, which may have been subject to potential data entry errors and differences in record keeping practices across the different centers included in this study. However, a series of data quality checks were performed to ensure that data values followed reasonable logics and expected ranges to alleviate data entry errors
  • The response rate in this study was reported as recorded by the physician in the patient chart, may be subject to physician interpretation; however, the European LeukemiaNet (ELN) 2017 guidelines were provided as a guidance for definition of responses in the electronic case report form. It is unknown whether the ELN guidelines were routinely used in real-world practice to assess response
  • Safety outcomes were not part of the study objectives, and this study was not powered to detect clinical meaningful changes in the safety endpoints

Real-world evidence (ARC data): VEN+AZA18

 

Real-world data are observational in nature and are not based on controlled clinical studies. Results from this study may differ from those observed and are not in the VENCLEXTA Prescribing Information.

Real-world evidence ARC data
  • AML Real-world EvidenCe (ARC) data among intensive induction chemotherapy–ineligible VEN+AZA subgroup (n=90)
  • VEN patients ≥75 years old or with ≥1 comorbidity of interest regardless of age (based on the Ferrara criteria for patients ineligible for intensive chemotherapy)

1L=first line; AZA=azacitidine; CI=confidence interval; CR=complete response; CRh=complete remission with partial hematologic recovery; HR=hazard ratio; OS=overall survival; PBO=placebo; VEN=VENCLEXTA; VEN+AZA=VENCLEXTA + azacitidine.

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Safety Data

A summary of safety data for patients treated with VEN+AZA in the VIALE-A trial

Review safety data
NEXT: VEN+DEC Study Design

US-VENA-240002

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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