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VEN+LDAC: Summary of efficacy from the VIALE-C trial

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Study design
Baseline characteristics
Remission rates and time to first response

Study design1

The efficacy and safety of VENCLEXTA (venetoclax tablets) in combination with low-dose cytarabine (VEN+LDAC; N=143) vs placebo with low-dose cytarabine (PBO+LDAC; N=68) were evaluated in VIALE-C, a double-blind, randomized trial in patients with newly diagnosed AML.

At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria:

  • Baseline ECOG performance status of 2-3
  • Severe cardiac or pulmonary comorbidity
  • Moderate hepatic impairment
  • CLcr <45 mL/min, or
  • Other comorbidity

Dosing:

  • Patients received VENCLEXTA 600 mg orally once daily on Days 1-28 following completion of the ramp-up dosing schedule or placebo in combination with LDAC at 20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle beginning on Cycle 1, Day 1
  • During the 4-day ramp-up phase, patients received TLS prophylaxis and were hospitalized for monitoring

Bone marrow assessment:

  • A bone marrow assessment was performed following Cycle 1 of treatment. If 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 × 103/microliter
  • For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and was clinically indicated
  • LDAC was resumed on the same day as VENCLEXTA or placebo following interruption
  • Patients continued to receive treatment until disease progression or unacceptable toxicity

Baseline characteristics1

VEN+LDAC (N=143)

The median age of patients treated with VEN+LDAC was 76 years (range: 36-93 years). ECOG performance status at baseline was 0-1 for 52% of patients, 2 for 44% of patients, and 3 for 4.2% of patients.

Mutations identified were as follows:

  • 20% (22/112) with TP53
  • 19% (21/112) with IDH1 or IDH2
  • 18% (20/112) with FLT3
  • 16% (18/112) with NPM1

Intermediate or poor cytogenetic risk was present in 63% and 33% of patients, respectively.

LDAC (N=68)

The median age of patients treated with LDAC was 76 years (range: 41-88 years). ECOG performance status at baseline was 0-1 for 50% of patients, 2 for 37% of patients, and 3 for 13% of patients.

Mutations identified were as follows:

  • 23% (12/52) with IDH1 or IDH2
  • 17% (9/52) with FLT3
  • 17% (9/52) with TP53
  • 13% (7/52) with NPM1

Intermediate or poor cytogenetic risk was present in 63% and 29% of patients, respectively.

Remission rates and time to first response1

Efficacy was based on the rate of CR and duration of CR with supportive evidence of rate of CR+CRh, duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence.

CR

  • VEN+LDAC: 27% (95% CI: 20, 35); mDOCR: 11.1 months (95% CI: 6.1, –)
  • LDAC: 7.4% (95% CI: 2.4, 16); mDOCR: 8.3 months (95% CI: 3.1, –)

CR+CRh

  • VEN+LDAC: 47% (95% CI: 39, 55); mDOCR+CRh: 11.1 months
  • LDAC: 15% (95% CI: 7.3, 25); mDOCR+CRh: 6.2 months

TTFR

  • The median time to first response of CR or CRh was 1.0 month (range: 0.7-5.8 months) with VEN+LDAC treatment

Transfusion conversion

  • The rate of RBC and/or platelet transfusion dependence to independence* was 33% (37/111) in the VEN+LDAC arm vs 13% (7/55) in the LDAC arm

VEN+LDAC did not significantly improve OS vs LDAC. HR for OS was 0.75 (95% CI: 0.52, 1.07); P=0.114. The median OS for the VEN+LDAC arm was 7.2 months (95% CI: 5.6, 10.1) and for the LDAC arm was 4.1 months (95% CI: 3.1, 8.8).

*Transfusion independence was defined as no RBC and no platelet transfusion during any consecutive ≥56-day post-baseline period.

Complete remission (CR) was defined as ANC >1,000/microliter, platelets >100,000/microliter, red blood cell transfusion independence, and bone marrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease.

Complete remission with partial hematologic recovery (CRh) was defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

ANC=absolute neutrophil count; CI=confidence interval; CLcr=creatinine clearance; ECOG=Eastern Cooperative Oncology Group; FLT=fms-like tyrosine kinase; IDH=isocitrate dehydrogenase; mDOCR+CRh=median duration of complete remission and complete remission with partial hematologic recovery; NPM=nucleophosmin; TLS=tumor lysis syndrome; TP53=tumor protein 53; TTFR=time to first response.

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Safety Data

Review a summary of safety data for patients treated with VEN+LDAC from the VIALE-C trial

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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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