For Patients and Caregivers

VEN+DEC: Summary of efficacy from Study M14-358

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Study design
Baseline characteristics
Remission rates and mutational/cytogenetic risk subgroups

Study design1

Study M14-358 was a non-randomized, open-label trial (NCT02203773) that evaluated the efficacy and safety of VENCLEXTA (venetoclax tablets) in combination with azacitidine (VEN+AZA; N=84) or decitabine (VEN+DEC; N=31) in patients with newly diagnosed acute myeloid leukemia (AML).

Of those patients, 67 who received AZA combination and 13 who received DEC combination were 75 years or older, 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 400 mg orally once daily following completion of the ramp-up dosing schedule in combination with azacitidine (75 mg/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1, Day 1) or decitabine (20 mg/m2 was administered intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1, Day 1)
  • During the ramp-up phase, patients received TLS prophylaxis and were hospitalized for monitoring
  • Treatment was continued until disease progression or unacceptable toxicity

Baseline characteristics1

The median age of patients treated with VEN+DEC was 75 years (range: 68-86 years). ECOG performance status at baseline was 0-1 for 92% of patients and 2 for 7.7% of patients.

Of the 13 patients in the VEN+DEC arm, those who had mutations identified were as follows:

  • 31% with TP53
  • 23% with FLT3
  • 15% with NPM1
  • No patients with IDH1 or IDH2

Intermediate or poor cytogenetic risk was present in 38% and 62% of patients, respectively.

First-line efficacy and fast remissions with VEN+DEC1

  • Complete remission (CR) was 54% (n=7); 95% CI: (25, 81)
  • Complete remission with partial hematologic recovery (CRh) was 7.7% (n=1); 95% CI: (0.2, 36)
  • Median duration of response of CR was 12.7 months; 95% CI: (1.4, -)
  • Median time to first response (CR or CRh) was 1.9 months (range: 0.8-4.2 months)

Descriptive prespecified exploratory analysis of CR+CRh rates in different mutational and cytogenetic risk subgroups6

CR+CRh rates were:

  • 33% (n=1/3; 95% CI: [0.8, 91]) for FLT3
  • 100% (n=2/2; 95% CI: [16, 100]) for NPM1
  • 75% (n=3/4; 95% CI: [19, 99]) for TP53
  • 60% (n=3/5; 95% CI: [15, 95]) for the intermediate cytogenetic risk group, and
  • 63% (n=5/8; 95% CI: [25, 92]) for the poor cytogenetic risk group

CR rates were:

  • 50% (n=2/4; 95% CI: [7, 93]) for TP53, and
  • 50% (n=4/8; 95% CI: [16, 84]) for the poor cytogenetic risk group

CR rates for FLT3, NPM1, and the intermediate cytogenetic risk group were the same as rates seen for CR+CRh. No patients had an IDH1/2 mutation.

Four patients had insufficient sample for analysis. Patients could have expressed one or more, or none of the identified mutations. The subgroup analyses were not powered or tested to demonstrate a statistically significant difference in outcomes for any subgroup examined.1

CR was defined as absolute neutrophil count (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.1

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).1

CI=confidence interval; CLcr=creatinine clearance; ECOG=Eastern Cooperative Oncology Group; FLT=fms-like tyrosine kinase; IDH=isocitrate dehydrogenase; NPM=nucleophosmin; TP53=tumor protein 53; TLS=tumor lysis syndrome; VEN=VENCLEXTA.

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Safety Data

Review a summary of safety data for patients treated with VEN+DEC from Study M14-358

Review safety data
NEXT: VEN+LDAC Study Design

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.

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      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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