VENCLEXTA® | AML Assessment & Management of Select Adverse Reactions

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Assessment for remission

Management of adverse reactions

Responses for CR and CRh were reached at different times during treatment; management of Grade 4 hematologic adverse reactions differs before and after remission^1,3

Bone marrow assessment was conducted following Cycle 1 treatment in our AML clinical trials to assess for remission

Once bone marrow assessment confirmed a remission,* VENCLEXTA or placebo was interrupted up to 14 days or until ANC ≥500/microliter and platelet count ≥50 x 10³/microliter
- For patients with resistant disease after the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated

Median time to first response of CR or CRh^1,3

Some patients achieved CR or CRh in later cycles (VEN+AZA vs AZA)^1,3

For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated.¹

In VIALE-A:

Select secondary endpoints: CR, CR+CRh^1,3

CR: 37% (n=105/286), 95% CI: (31, 43) in VEN+AZA vs 18% (n=26/145), 95% CI: (12, 25) in AZA; P<0.001
Median DOCR: 18 months, 95% CI: (15.3, NR) in VEN+AZA vs 13.4 months, 95% CI: (8.7, 17.6) in AZA
CR+CRh: 65% (n=185/286), 95% CI: (59, 70) in VEN+AZA vs 23% (n=33/145), 95% CI: (16, 30) in AZA; P<0.001
Median DOCR+CRh^†: 17.8 months, 95% CI: (15.3, NR) in VEN+AZA vs 13.9 months, 95% CI: (10.4, 15.7) in AZA
- Median DOCR and median DOCR+CRh endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms

Some patients achieved CR or CRh in later cycles^1,3,4

Management: Recommended dose modifications for cytopenias and non-hematologic adverse reactions in AML¹

Monitor blood counts frequently through resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status

Managing Grade 4 neutropenia with or without fever or infection, or Grade 4 thrombocytopenia

STAY ON VENCLEXTA REGIMEN: In most instances, do not interrupt the VENCLEXTA regimen due to cytopenias.

DELAY subsequent cycle of VENCLEXTA regimen and monitor blood counts

For 1st occurrence

RESUME VENCLEXTA therapy at 400 mg^§in combination with azacitidine or decitabine or at 600 mg in combination with low-dose cytarabine upon resolution to Grade 1 or 2 and resume 28-day treatment cycle

For subsequent occurrences

RESUME VENCLEXTA therapy at 400 mg^§ in combination with azacitidine or decitabine or at 600 mg^§ in combination with low-dose cytarabine upon resolution to Grade 1 or 2 and reduce treatment cycle by 7 days for each subsequent cycle

(eg, for 2nd occurrence, VENCLEXTA would be dosed for 21 days of a 28-day cycle)

Grade 3 or 4 non-hematologic toxicities

Any occurrence

Interrupt VENCLEXTA if not resolved with supportive care. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose.

See Initiation: Dosing and Drug Interactions.

In VIALE-A:

Exploratory post hoc analysis: 75% of patients in remission* (139/186) had at least 1 interruption in dosing lasting 7+ days⁴
In the VEN+AZA arm, among patients who achieved bone marrow clearance of leukemia, 53% (114/216)^§ underwent dose interruptions for ANC <500/microliter¹
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 × 10³/microliter¹

*Defined as less than 5% leukemia blasts with cytopenia.¹
^†Recommend bone marrow evaluation.¹
^‡Dose may vary based on drug-drug interactions or severe hepatic impairment.¹
^§Of patients who achieved a morphologic leukemia-free state of response or better.⁷

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.¹

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).¹

DOCR (duration of CR) is defined as the number of days from the date of first response of CR to the date of earliest evidence of confirmed morphologic relapse, confirmed progressive disease, or death due to disease progression.¹

DOCR+CRh (duration of CR+CRh) is defined as the number of days from the date of first response of CR+CRh (the first of either CR or CRh) to the date of earliest evidence of confirmed morphologic relapse, confirmed progressive disease, or death due to disease progression.¹

AML=acute myeloid leukemia; ANC=absolute neutrophil count; AZA=azacitidine; ITT=intent to treat; PBO=placebo; VEN=VENCLEXTA.

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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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Remission assessment and management of adverse reactions