Text on Screen: This video is sponsored by AbbVie and Genentech, Inc. The physicians included in this video are presenting information on behalf of AbbVie and Genentech, Inc., and received compensation.

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

Text on Screen: 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.

Continue viewing this video for Important Safety Information at the end of video.

Text on Screen: Treatment Management with VENCLEXTA in Newly Diagnosed AML

This video provides Prescribing Information–based direction for initiation, assessment, and management for select VENCLEXTA regimens, including safety, dosing, dose adjustments, and management of select cytopenias

Dr. Erba: I’m Harry Erba, academic hematologist, caring for people with acute myeloid leukemia.

Text on Screen: Harry Erba, MD, PhD Academic Hematologic Oncologist

Dr. Erba: VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine in 431 adults with newly diagnosed AML who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy.

Text on Screen: • 3-day ramp-up of 100 mg to 200 mg and then to a final dose of 400 mg orally once daily. Patients received TLS prophylaxis and were hospitalized for monitoring VENCLEXTA 400 mg (orally once daily) Days 1-28

AZA 75 mg/m² (IV or subcutaneous) Days 1-7 Beginning Day 1 of each 28-day cycle vs | Placebo (orally once daily) Days 1-28

AZA 75 mg/m² (IV or subcutaneous) Days 1-7 Beginning Day 1 of each 28-day cycle Treatment was continued until disease progression or unacceptable toxicity

 

Comorbidities 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
• Other comorbidities

TLS=tumor lysis syndrome; AZA=azacitidine; IV=intravenous; ECOG=Eastern Cooperative Oncology Group; CLcr=creatinine clearance.

Dr. Erba: When treating patients with AML who are ineligible for intensive induction chemotherapy due to age, or comorbidities with a VENCLEXTA regimen, there are things to consider, such as…

…evaluating for tumor lysis syndrome prior to initiation, dose ramp-up schedules, dose reductions based on certain drug-drug interactions . . .

Text on Screen: INITIATION

• Evaluate tumor lysis syndrome (TLS) risk in all patients and provide prophylactic measures
• 3-day dose ramp-up for VEN+HMA or 4-day dose ramp-up for VEN+LDAC. Monitor blood chemistries
• Dose-reduce for concomitant use with P-gp inhibitors or strong or moderate CYP3A inhibitors or for severe hepatic impairment

VEN=VENCLEXTA; HMA=hypomethylating agent; LDAC=low-dose cytarabine.

This is a summary and is not an exhaustive list of all treatment considerations.

Dr. Erba: …assessing for certain adverse reactions . . .

Text on Screen: ASSESSMENT

• Assess and monitor for common and serious adverse reactions (ARs)
• Bone marrow assessment as clinically indicated
  • In AML clinical trials, bone marrow assessment was conducted following Cycle 1 treatment to assess for remission

Dr. Erba: . . . and management of hematologic and nonhematologic adverse reactions.

Text on Screen: MANAGEMENT

• Manage hematologic ARs with dose modifications based on remission status*
  • May include VENCLEXTA pause or change in VENCLEXTA duration
• Manage non-hematologic ARs with dose modifications*

*See Table 6 in the full Prescribing Information for dose modifications.

Dr. Erba: Understanding these treatment considerations can help you as you start your patients on a VENCLEXTA regimen.

Text on Screen: INITIATION, ASSESSMENT, MANAGEMENT
This content is not a substitute for independent medical judgment.

Dr. Erba: Let’s begin with initiation. Patients treated with VENCLEXTA may develop tumor lysis syndrome.

Text on Screen: Initiation

Pretreatment TLS risk assessment and prophylaxis
TLS=tumor lysis syndrome.

Dr. Erba: Because of this, there are specific details on management to help assess and reduce the risk of tumor lysis syndrome. So, prior to VENCLEXTA initiation, the physician wants to ensure that the patient has a white blood cell count less than 25,000 per microliter.

Text on Screen: All patients should have white blood cell count less than 25 x10⁹/L prior to initiation of VENCLEXTA. Cytoreduction prior to treatment may be required

Dr. Erba: The physician also needs to provide prophylactic measures prior to the first VENCLEXTA dose, including adequate hydration and anti-hyperuricemic agents, and continue that through the ramp-up.

Text on Screen: Prior to first VENCLEXTA dose, provide all patients with prophylactic measures including adequate hydration and anti-hyperuricemic agents and continue during ramp-up phase

Dr. Erba: Prior to initiation of treatment, assess blood chemistry and correct any pre-existing abnormalities.

Text on Screen: Assess blood chemistry and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA

Blood chemistry

- Potassium | - Uric acid
- Phosphorus | - Calcium | - Creatinine

Dr. Erba: Be sure to monitor blood chemistries for tumor lysis syndrome.

Text on Screen: Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during ramp-up, and 24 hours after reaching final dose

Dr. Erba: For patients with TLS risk factors, you may consider additional measures.

Text on Screen: For patients with risk factors for TLS, consider additional measures, including increased laboratory monitoring and reducing VENCLEXTA starting dose

TLS risk factors

- Circulating blasts | - High burden of leukemia involvement in bone marrow

- Elevated pretreatment lactate dehydrogenase [LDH] levels | - Reduced renal function

Dr. Erba: The recommended dosage and ramp-up of VENCLEXTA depends upon the combination agent.

Text on Screen: Initiation

VEN+AZA

Dr. Erba: When in combination with azacitidine, VENCLEXTA is taken orally via a 3-day ramp-up designed to help patients safely attain the recommended daily dose.

Text on Screen: Orally once daily

Dr. Erba: So, on Day 1, we initiate VENCLEXTA at 100 mg, then 200 mg…

Text on Screen: • If using VENCLEXTA in combination with decitabine, follow the 3-day dose ramp-up schedule, up to 400 mg of VENCLEXTA, and administer decitabine at 20 mg/m² intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1, Day 1

Dr. Erba: . . . on Day 2, and 400 mg once daily on Day 3 . . .

Text on Screen: • If using VENCLEXTA in combination with low-dose cytarabine, follow the 4-day dose ramp-up schedule, up to 600 mg of VENCLEXTA, and administer low-dose cytarabine at 20 mg/m² subcutaneously once daily on Days 1-10 of each 28-day cycle beginning on Cycle 1, Day 1

Dr. Erba: . . . and beyond for each 28-day cycle.

The combination agent, azacitidine, is administered once daily intravenously . . .

Text on Screen: 75 mg/m² DAYS 1-7
once daily

Dr. Erba: …or subcutaneously at 75 mg/m² on Days 1-7 of each 28-day treatment cycle.

Once treatment begins, patients should continue treatment until disease progression or unacceptable toxicity is observed.

Text on Screen: Continue VENCLEXTA, plus combination agent, until disease progression or unacceptable toxicity is observed

Dr. Erba: In AML, there is a risk of infection. Because of this, antibiotic and antifungal therapy may be used.

Text on Screen:  Initiation Drug-drug interactions

Dr. Erba: However, concomitant use of VENCLEXTA…

…with strong or moderate CYP3A inhibitors or P-gp inhibitors may…

Text on Screen:  Initiation Drug-drug interactions (posaconazole)
VEN+AZA/DEC/LDAC

Dr. Erba: . . . increase the risk of tumor lysis syndrome at initiation and during the ramp-up phase…

Text on Screen: Initiation Drug-drug interactions (other strong CYP3A inhibitors)

Dr. Erba: …and requires VENCLEXTA dose adjustment . . .

Text on Screen: Initiation Drug-drug interactions (moderate CYP3A inhibitors or P-gp inhibitors) VEN+AZA/DEC

Dr. Erba: …due to increases in exposure.

Text on Screen: Initiation For VEN+LDAC, the recommended reduced maintenance dose for VEN would be 300 mg or less.

Dr. Erba: It is important to note that patients may experience certain adverse reactions when treated with VENCLEXTA.

By being equipped with safety information, physicians can confidently start and manage their patients on a VENCLEXTA regimen.

Voiceover: Serious and sometimes fatal adverse reactions occurred with VENCLEXTA treatment. Warnings and precautions include tumor lysis syndrome, neutropenia, infections, immunization, embryo-fetal toxicity, and increased mortality in patients with multiple myeloma when VENCLEXTA is added to bortezomib and dexamethasone. Appropriate precautions should be taken by the healthcare provider.

Text on Screen: Assessment

PBO=placebo.

Voiceover: 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%) . . .

Text on Screen: 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+AZA*

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

Voiceover: …nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%).

Dr. Erba: Throughout treatment, physicians should assess and monitor for cytopenias as well as common and serious adverse reactions.

Text on Screen:  Hematologic laboratory abnormalities

Dr. Erba: In VIALE-A, bone marrow assessment was conducted at the end of Cycle 1, by Day 28.

For patients with resistant disease, that is having >5% blasts, at the end of Cycle 1, bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated.

Text on Screen: Assessment

In VIALE-A: bone marrow assessment following Cycle 1

Dr. Erba: Knowing when remission is achieved is important, because it can help determine how to manage certain cytopenias.

For example, management of Grade 4 neutropenia, will differ based on if remission is achieved and if it is the first or subsequent occurrence of the Grade 4 neutropenia.

So, for a patient who experiences Grade 4 neutropenia before remission is achieved, in most instances physicians would not interrupt the VENCLEXTA regimen because of neutropenia—and we actually encourage the patient to stay on the VENCLEXTA regimen.

Text on Screen: Management Grade 4 neutropenia with or without fever or infection, or Grade 4 thrombocytopenia | Before remission*^† is achieved | STAY ON VENCLEXTA REGIMEN In most instances, do not interrupt the VENCLEXTA regimen due to cytopenias

^*Recommend bone marrow evaluation.
^†Remission is defined as achieving a CR or CRh.
CR=complete remission; CRh=complete remission with partial hematologic recovery.

Dr. Erba: For patients who experience Grade 4 neutropenia after remission is achieved, management will involve dose interruptions, which is quite common with this treatment.

For example, in VIALE-A, of patients in the VENCLEXTA + azacitidine arm who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for absolute neutrophil count <500/microliter.

Text on Screen: In VIALE-A:
Of patients that achieved bone marrow clearance

53%* (114/216)

dose interruptions for ANC <500/microliter

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

ANC=absolute neutrophil count.

Dr. Erba: So, for patients who experience their first occurrence of Grade 4 neutropenia, lasting at least 7 days, after remission is achieved, we would delay the subsequent cycle of the VENCLEXTA regimen and monitor blood counts.

Text on Screen: After remission*^† is achieved (1st occurrence lasting at least 7 days)

DELAY subsequent cycle of VENCLEXTA regimen and monitor blood counts

*Recommend bone marrow evaluation.

^†Remission is defined as achieving a CR or CRh.

Dr. Erba: Upon resolution to Grade 1 or Grade 2, we would resume the VENCLEXTA regimen.

Text on Screen: 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

^*Recommend bone marrow evaluation.
^†Remission is defined as achieving a CR or CRh.
^‡Dose may vary based on drug-drug interactions or severe hepatic impairment.

Dr. Erba: For subsequent occurrences after remission is achieved, we would again delay the subsequent cycle of the VENCLEXTA regimen, monitor blood counts . . .

Text on Screen: After remission*^† is achieved (subsequent occurrences lasting at least 7 days) DELAY subsequent cycle of VENCLEXTA regimen and monitor blood counts
*Recommend bone marrow evaluation.
^†Remission is defined as achieving a CR or CRh.

Dr. Erba: …and resume the VENCLEXTA regimen upon resolution to Grade 1 or 2. We would also reduce the duration of VENCLEXTA treatment by 7 days for each subsequent cycle.

Text on Screen: 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

^*Recommend bone marrow evaluation.
^†Remission is defined as achieving a CR or CRh.
^‡Dose may vary based on drug-drug interactions or severe hepatic impairment.

Dr. Erba:  So for example, for a second occurrence of Grade 4 neutropenia, VENCLEXTA would be dosed for 21 days of a 28-day cycle.

For any occurrence of a non-hematologic Grade 3 or 4 adverse reaction, we would interrupt VENCLEXTA if supportive care does not provide resolution.

Text on Screen: Management Grade 3 or 4 non-hematologic toxicities Before or after remission is achieved (any occurrence) INTERRUPT VENCLEXTA if not resolved with supportive care

Dr. Erba: Once toxicity resolves to Grade 1 or baseline level, we would resume VENCLEXTA at the same dose.

Text on Screen: RESUME VENCLEXTA at the same dose* upon resolution to Grade 1 or baseline level

*Dose may vary based on drug-drug interactions or severe hepatic impairment.

Dr. Erba: As we see, when treating AML, there are a number of considerations, such as…

…evaluating tumor lysis syndrome risk in all patients and providing prophylactic measures, following the appropriate dose ramp-up schedule for the VENCLEXTA regimen, dose-reducing for concomitant use with certain medications…

Text on Screen: INITIATION

• Evaluate TLS risk in all patients and provide prophylactic measures
• 3-day dose ramp-up for VEN+HMA or 4-day dose ramp-up for VEN+LDAC. Monitor blood chemistries
• Dose-reduce for concomitant use with P-gp inhibitors or strong or moderate CYP3A inhibitors or for severe hepatic impairment

This is a summary and is not an exhaustive list of all treatment considerations.

Dr. Erba: . . . assessing and monitoring for common and serious adverse reactions, bone marrow assessment as clinically indicated . . .

Text on Screen: ASSESSMENT

• Assess and monitor for common and serious adverse reactions (ARs)
• Bone marrow assessment as clinically indicated
  • In AML clinical trials, bone marrow assessment was conducted following Cycle 1 treatment to assess for remission

Dr. Erba: …and managing certain hematologic adverse reactions with dose modifications based on remission status and adverse reaction occurrence, as well as dose modifications for management of non-hematologic adverse reactions.

Text on Screen: MANAGEMENT

• Manage hematologic ARs with dose modifications based on remission status*
  • May include VENCLEXTA delay or change in VENCLEXTA duration • Manage non-hematologic ARs with dose modifications*

*See Table 6 in the full Prescribing Information for dose modifications.

Dr. Erba: By leveraging this video, the Prescribing Information, and other VENCLEXTA resources for guidance, I believe this approach can aid healthcare providers in both the academic and community setting as they treat their AML patients with a VENCLEXTA regimen.

Text on Screen: Continue viewing for Important Safety Information.

Voiceover: [Indication and Important Safety Information (ISI)]

Text on Screen: [Indication and ISI]

Voiceover: [ISI]

Text on Screen: [ISI]

Voiceover: [ISI and Please see line]

Text on Screen: [ISI, Please see line, references, and job code]

References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. Vazquez L. Antifungal prophylaxis in immunocompromised patients. Mediterr J Hematol Infect Dis. 2016;8(1):e2016040. 3. Beaton M, Peterson GJ, O’Brien K. Acute myeloid leukemia: advanced practice management from presentation to cure. J Adv Pract Oncol. 2020;11(8):836-844. 4. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. 5. Data on file, ABVRRTI71272. AbbVie Inc. 6. Data on file, ABVRRTI71500. AbbVie Inc.

US-VENA-210088

Text on Screen: This video is sponsored by AbbVie and Genentech, Inc. The physicians included in this video are presenting information on behalf of AbbVie and Genentech, Inc., and received compensation.

 

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

Text on Screen: 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.

Continue viewing this video for Important Safety Information at the end of video.

 

Dr. Erba: Serious and sometimes fatal adverse reactions occurred with VENCLEXTA treatment. Warnings and precautions include tumor lysis syndrome, neutropenia, infections, immunization, embryo-fetal toxicity, and increased mortality in patients with multiple myeloma when VENCLEXTA is added to bortezomib and dexamethasone. Appropriate precautions should be taken by the healthcare provider.

Text on Screen: IN THE VIALE-A TRIAL TRANSFUSION INDEPENDENCE
Continue viewing this video for Important Safety Information at the end of video

In our patients with acute myeloid leukemia, at the time of diagnosis they are often already dependent on red blood cell and/or platelet transfusion due to the bone marrow failure state.

Text on Screen: Harry Erba, MD, PhD Academic Hematologic Oncologist

Dr. Erba: This is a burden for many of our patients, requiring them to travel to the clinic or the hospital to receive those transfusions.

 

And so, in my opinion, the achievement of transfusion independence in my patients with any bone marrow failure state, such as acute myeloid leukemia, is important.

 

VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine in 431 adults with newly diagnosed AML who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy.

Text on Screen: • 3-day ramp-up of 100 mg to 200 mg and then to a final dose of 400 mg orally once daily. Patients received TLS prophylaxis and were hospitalized for monitoring VENCLEXTA 400 mg (orally once daily) Days 1-28 AZA 75 mg/m² (IV or subcutaneous) Days 1-7 Beginning Day 1 of each 28-day cycle vs   |   Placebo (orally once daily) Days 1-28 AZA 75 mg/m² (IV or subcutaneous)   Days 1-7 Beginning Day 1 of each 28-day cycle  Treatment was continued until disease progression or unacceptable toxicity Comorbidities 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  • Other comorbidities

TLS=tumor lysis syndrome; AZA=azacitidine; IV=intravenous; ECOG=Eastern Cooperative Oncology Group; CLcr=creatinine clearance.

 

Dr. Erba: In the VIALE-A trial, the median overall survival of patients treated with venetoclax with azacitidine was 14.7 months.

Text on Screen: PRIMARY ENDPOINT: OVERALL SURVIVAL Median Overall Survival

VEN+AZA     |     14.7 months     |     95% CI: (11.9, 18.7)

 

Dr. Erba: The median overall survival of patients treated with placebo and azacitidine was 9.6 months.

Text on Screen: AZA     |     9.6 months     |     95% CI: (7.4, 12.7)

OS: HR=0.66; 95% CI: (0.52, 0.85); P<0.001 VEN=VENCLEXTA; CI=confidence interval; OS=overall survival; HR=hazard ratio.

 

Dr. Erba: In the VIALE-A trial, more patients were able to convert from transfusion dependence to independence with the combination of venetoclax with azacitidine.

Text on Screen: TRANSFUSION INDEPENDENCE CONVERSION*

 

Dr. Erba: 49% of patients treated with the combination of venetoclax with azacitidine became transfusion independent, compared to 27% treated with placebo and azacitidine.

Text on Screen: Transfusion independence conversion (conversion from dependent to independent)

VEN + AZA    |    49% (76/155)    |    AZA     |    27% (22/81) RBC and PLATELET

Patients were dependent on RBC and/or platelet transfusions at baseline

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms. Transfusion independence was defined as no RBC and platelet transfusion during any consecutive ≥56-day post-baseline period. Transfusion dependence was defined as requiring RBC or platelet transfusion at baseline (within 8 weeks prior to the first dose of study drug or randomization).

RBC=red blood cell.

 

Dr. Erba: Maintenance of transfusion independence is also an important clinical endpoint for my patients with acute myeloid leukemia.

Text on Screen: TRANSFUSION INDEPENDENCE MAINTENANCE*

 

Dr. Erba: In the VIALE-A trial, 69% of patients were transfusion independent at study entry, maintained independence from both red blood cell and platelet transfusion when treated with the combination of venetoclax and azacitidine compared with 42% of patients treated with the combination placebo with azacitidine.

 

Text on Screen: Transfusion independence maintenance (independent from baseline to post-baseline period)    |    VEN + AZA    |    69% (90/131)    |    AZA     |    42% (27/64) RBC and PLATELET

Patients were independent of both RBC and platelet transfusions at baseline.

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms.

Transfusion independence was defined as no RBC and platelet transfusion during any consecutive ≥56-day post-baseline period. Transfusion dependence was defined as requiring RBC or platelet transfusion at baseline (within 8 weeks prior to the first dose of study drug or randomization). RBC=red blood cell.

 

Dr. Erba: 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%) . . .

Text on Screen: SAFETY DATA

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+AZA* PBO=placebo.

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

 

Dr. Erba: . . . nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%).

Text on Screen: Hematologic laboratory abnormalities

 

Dr. Erba: We also saw additional data for the VENCLEXTA + low-dose Ara-C regimen in the VIALE-C trial.

Text on Screen: VIALE-C: VEN+LDAC vs LDAC

VIALE-C phase 3 trial: VEN + low-dose cytarabine (LDAC): Efficacy of VEN+LDAC regimen was based on CR rate 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=complete remission; CRh=complete remission with partial hematologic recovery; Ara-C=cytarabine.

 

Dr. Erba: For VENCLEXTA plus low-dose Ara-C, the rate of red blood cell and/or platelet transfusion dependence to independence was 33% vs 13% for placebo plus low-dose Ara-C.

Text on Screen: Transfusion independence conversion

VEN+LDAC   |   33%   |   (37/111) LDAC   |   13%   |   (7/55) In the VIALE-C trial, VEN+LDAC did not significantly improve OS vs placebo+LDAC.

 

Based on the results of the phase 3 VIALE-A trial, I am confident in the selection of the oral BCL-2 inhibitor venetoclax in combination with azacitidine as the initial treatment of my older patients who are ineligible for intensive induction chemotherapy.

Text on Screen: Continue viewing for Important Safety Information.

Voiceover: [Indication and ISI]

Text on Screen: [Indication and Important Safety Information (ISI)]

 

Voiceover: [ISI]

 

Text on Screen: [ISI]

 

Voiceover: [ISI and Please See Line]

Text on Screen: [ISI and Please See line]

References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. Chen L, Zhou H, Guo B, et al. Clinical efficacy of platelet transfusion therapy in patients with leukemia and analysis of risk factors for ineffective transfusion. Oncol Lett. 2020;19(3):2554-2561. 3. Getting a Blood Transfusion. American Cancer Society. 2021. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/blood-transfusion-and-donation/how-blood-transfusions-are-done.html. Accessed October 5, 2021. 4. Corey-Lisle PK, Desrosiers M-P, Collins H, et al. Transfusions and patient burden in chemotherapy-induced anaemia in France. Ther Adv Med Oncol. 2014;6(4):146-153.

US-VENA-230067

Text on Screen: This video is sponsored by AbbVie and Genentech, Inc. The physicians included in this video are presenting information on behalf of AbbVie and Genentech, Inc., and received compensation.

 

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

Text on Screen 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.

Continue viewing this video for Important Safety Information at the end of video.

Dr. Erba: Serious and sometimes fatal adverse reactions occurred with VENCLEXTA treatment. Warnings and precautions include tumor lysis syndrome, neutropenia, infections, immunization, embryo-fetal toxicity, and increased mortality in patients with multiple myeloma when VENCLEXTA is added to bortezomib and dexamethasone. Appropriate precautions should be taken by the healthcare provider.

Text on Screen: IN THE VIALE-A TRIAL OVERALL SURVIVAL IN NEWLY DIAGNOSED AML

Continue viewing this video for Important Safety Information at the end of video.

Dr. Erba: For most of my 30-year career caring for people with acute myeloid leukemia, we had very limited therapeutic options . . .

Text on Screen: Harry Erba, MD, PhD Academic Hematologic Oncologist

Dr. Erba: . . . basically limited to intensive chemotherapy. Or we typically have used the hypomethylating agents: azacitidine, decitabine, or even low-dose cytarabine for those who are ineligible to receive intensive chemotherapy.

This intensive chemotherapy regimen leads to higher rates of induction mortality in our older patients, those with comorbidities, those with poor organ function, and those with poor performance status.

This is a relentless, unforgiving disease with very short median overall survival and very few patients living more than 6 to 12 months.

But we have other options for them. In terms of initial therapy, we have the combination of venetoclax, an oral BCL-2 inhibitor, with hypomethylating agents, such as azacitidine.

VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine in 431 adults with newly diagnosed AML who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy.

Text on Screen: • 3-day ramp-up of 100 mg to 200 mg and then to a final dose of 400 mg orally once daily. Patients received TLS prophylaxis and were hospitalized for monitoring VENCLEXTA 400 mg (orally once daily)    Days 1-28 AZA 75 mg/m² (IV or subcutaneous)   Days 1-7 Beginning Day 1 of each 28-day cycle vs   |   Placebo (orally once daily)   Days 1-28 AZA 75 mg/m² (IV or subcutaneous)   Days 1-7 Beginning Day 1 of each 28-day cycle  Treatment was continued until disease progression or unacceptable toxicity

Comorbidities 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   
• Other comorbidities

TLS=tumor lysis syndrome; AZA=azacitidine; IV=intravenous; ECOG=Eastern Cooperative Oncology Group; CLcr=creatinine clearance.

Dr. Erba: In the VIALE-A trial . . .

Text on Screen: PRIMARY ENDPOINT: OVERALL SURVIVAL

Dr. Erba: . . . the median overall survival of patients treated with . . .

Text on Screen: VEN=VENCLEXTA

Dr. Erba: . . . venetoclax with azacitidine was 14.7 months.

Text on Screen: VEN=VENCLEXTA; CI=confidence interval.

 

Dr. Erba: The median overall survival of patients treated with placebo and azacitidine was 9.6 months…

Text on Screen: • Median follow-up for OS was approximately 20.5 months (range: <0.1-30.7 months)

• Median follow-up was estimated using reverse Kaplan-Meier methodology

OS=overall survival.

Dr. Erba: . . . the median overall survival of patients treated with . . .

Text on Screen: VEN=VENCLEXTA

Dr. Erba: …an improvement in the median survival by 5.1 months.

Text on Screen: mOS=median overall survival.

 

Dr. Erba: The hazard ratio for survival favored the combination of venetoclax with azacitidine, with a hazard ratio of 0.66. This translates to a 34% reduction in the risk of mortality.

Text on Screen: HR=hazard ratio.

 

Dr. Erba: I believe that the improvement in the median overall survival by 5.1 months is meaningful to my patients with acute myeloid leukemia.

Text on Screen: 5.1 months

 

Dr. Erba: That’s what they want to know from me. “Doc, am I going to see that granddaughter graduate from college or that grandson get married in a year?” That they understand, and that’s what’s important to them.

 

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%) . . .

Text on Screen: SAFETY DATA 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+AZA*

PBO=placebo.

*Patients who received at least one dose of either treatment. 

^†Includes multiple adverse reaction terms.

 

Dr. Erba: . . . nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%).

Text on Screen: Hematologic laboratory abnormalities

We also saw additional data for the VENCLEXTA + low-dose Ara-C regimen in the VIALE-C trial.

Text on Screen:  VIALE-C: VEN+LDAC vs LDAC VIALE-C phase 3 trial: VEN + low-dose cytarabine (LDAC): Efficacy of VEN+LDAC regimen was based on CR rate 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. In the VIALE-C trial, VEN+LDAC did not significantly improve OS vs placebo+LDAC.

CR=complete remission; CRh=complete remission with partial hematologic recovery; Ara-C=cytarabine.

 

Dr. Erba: Based on the results of the phase 3 VIALE-A trial, I am confident in the selection of the oral BCL-2 inhibitor venetoclax in combination with azacitidine as the initial treatment of my older patients who are ineligible for intensive induction chemotherapy.

Text on Screen: Continue viewing for Important Safety Information.

 

Voiceover: [Indication and ISI]

 

Text on Screen: [Indication and Important Safety Information (ISI)]

 

Voiceover: [ISI]

Text on Screen: [ISI]

 

Voiceover: [ISI and Please See Line]

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References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. New treatment options lead to new questions in acute myeloid leukemia. ASH Clinical News. 2019. Accessed October 4, 2021. https://www.ashclinicalnews.org/acute-leukemias/new-treatment-options-lead-new-questions-acute-myeloid-leukemia/ 3. Zhang RJ, Zhai JH, Zhang ZJ, et al. Hypomethylating agents for elderly patients with acute myeloid leukemia: a PRISMA systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25(6):2577-2590. 4. DiNardo CD. Hypomethylating agents and venetoclax in acute myeloid leukemia. Clin Adv Hematol Oncol. 2021;19(2):82-83. 5. Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422-4429. 6. Wass M, Hitz F, Schaffrath J, et al. Value of different comorbidity indices for predicting outcome in patients with acute myeloid leukemia. PLoS One. 2016;11(10):e0164587. 7. Kadia TM, Ravandi F, O’Brien S, et al. Progress in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15(3):139-151. 8. Finn L, Dalovisio A, Foran J. Older patients with acute myeloid leukemia: treatment challenges and future directions. Ochsner J. 2017;17(4):398-404. 9. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.

US-VENA-210235

Text on Screen: This video is sponsored by AbbVie and Genentech, Inc. The physicians included in this video are presenting information on behalf of AbbVie and Genentech, Inc., and received compensation. 

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

Text on Screen: 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

Continue viewing this video for Important Safety Information at the end of video.

Dr. Erba: Serious and sometimes fatal adverse reactions occurred with VENCLEXTA treatment. Warnings and precautions include tumor lysis syndrome, neutropenia, infections, immunization, embryo-fetal toxicity, and increased mortality in patients with multiple myeloma when VENCLEXTA is added to bortezomib and dexamethasone. Appropriate precautions should be taken by the healthcare provider.

 

Text on Screen: IN THE VIALE-A TRIAL REMISSIONS IN NEWLY DIAGNOSED AML

 

Dr. Erba: For most of my 30-year career caring for people with acute myeloid leukemia, we had very limited therapeutic options, basically limited to intensive chemotherapy . . .

 

Text on Screen: Harry Erba, MD, PhD Academic Hematologic Oncologist

 

Dr. Erba: . . . the so-called three plus seven or seven plus three schedule. We know that this combination of chemotherapy can induce remissions. However, we also learned during this time that this intensive chemotherapy regimen leads to higher rates of induction mortality in our older patients, those with comorbidities, those with poor organ function, those with poor performance status.

 

Now, we did have regimens that were available for patients ineligible to receive intensive chemotherapy during this time, the hypomethylating agents azacitidine, or decitabine, or low-dose cytarabine.

 

Without therapy, this is a relentless, unforgiving disease with very short median overall survival and very few patients living more than 6 to 12 months.

 

I’m happy to say that we have multiple regimens that are available to our patients that have been shown to improve the remission rates.

 

In terms of initial therapy, we have the combination of venetoclax an oral BCL-2 inhibitor with hypomethylating agents such as azacitidine.

 

VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine in 431 adults with newly diagnosed AML who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy.

 

Text on Screen: • 3-day ramp-up of 100 mg to 200 mg and then to a final dose of 400 mg orally once daily. Patients received TLS prophylaxis and were hospitalized for monitoring VENCLEXTA 400 mg (orally once daily)  Days 1-28 AZA 75 mg/m² (IV or subcutaneous)   Days 1-7 Beginning Day 1 of each 28-day cycle vs   |   Placebo (orally once daily)   Days 1-28 AZA 75 mg/m² (IV or subcutaneous)   Days 1-7 Beginning Day 1 of each 28-day cycle  Treatment was continued until disease progression or unacceptable toxicity

 

Comorbidities 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  
• Other comorbidities

 

TLS=tumor lysis syndrome; AZA=azacitidine; IV=intravenous; ECOG=Eastern Cooperative Oncology Group; CLcr=creatinine clearance.

 

Dr. Erba: In the VIALE-A trial, the median overall survival of patients treated with venetoclax with azacitidine was 14.7 months.

 

Text on Screen: PRIMARY ENDPOINT: OVERALL SURVIVAL

Median Overall Survival

VEN+AZA     |     14.7 months     |     95% CI: (11.9, 18.7)

 

Dr. Erba: The median overall survival of patients treated with placebo and azacitidine was 9.6 months.

 

Text on Screen: AZA     |     9.6 months     |     95% CI: (7.4, 12.7) OS: HR=0.66; 95% CI: (0.52, 0.85); P<0.001 VEN=VENCLEXTA; CI=confidence interval; OS=overall survival; HR=hazard ratio.

 

Dr. Erba: The value of a regimen in the treatment of acute myeloid leukemia is not just in its ability to clear bone marrow blasts but also a regimen’s ability to allow the recovery of normal hematopoiesis. And typically, we have defined this as a complete remission, less than 5% marrow blasts, no peripheral blood blasts, and a neutrophil count over 1000 per microliter, and a platelet count over 100,000 per microliter. This is what a complete remission is.

 

What those levels represent are levels that hematologists have generally considered safe values.

 

Complete remission was achieved in 37% of patients in the VIALE-A trial treated with the combination of azacitidine and venetoclax . . .

 

Text on Screen: SECONDARY ENDPOINTS: REMISSIONS

 

Dr. Erba: . . . compared to only 18% complete remission in patients treated with azacitidine and placebo.

 

Text on Screen: VEN+AZA N=286 I CR (n=105) 37% I CRh 28%• CR, 95% CI: (31, 43); P<0.001• CR+CRh, 95% CI: (59, 70); P<0.001 CR was defined as absolute neutrophil count (ANC) >1,000/microliter, platelets >100,000/microliter, RBC transfusion independence, and bone marrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CR=complete remission; CRh=complete remission with partial hematologic recovery.

 

Dr. Erba: It’s important also to focus on the rate of complete remission with complete blood count recovery or partial hematologic recovery in patients treated in the VIALE-A trial. In patients receiving venetoclax with azacitidine 65% of patients achieved a CR plus a CRh. In patients treated with azacitidine and placebo the CR+CRh rate was 23%. Nearly three times as many patients achieved a CR+CRh with the combination of venetoclax and azacitidine.

 

Text on Screen: VEN+AZA I CR+CRh 65% (n=185) AZA I N=145 I CR (n=26) 18% I CRh 5% I CR+CRh 23% (n=33)

• CR, 95% CI: (12, 25)
• CR+CRh, 95% CI: (16, 30)

 

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). CR=complete remission; CRh=complete remission with partial hematologic recovery.

 

Dr. Erba: The duration of these complete remissions is also important to my patients with acute myeloid leukemia. So it’s important to me that the median duration of complete remission with the combination of azacitidine with venetoclax was 18 months . . .

 

Text on Screen: PRESPECIFIED EXPLORATORY ENDPOINTS: MEDIAN DURATION CR* VEN+AZA  I  18 months 95% CI: (15.3, -)  I  mDOCR

 

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms. 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. mDOCR=median duration of complete remission.

 

Dr. Erba: . . . compared to 13.4 months with azacitidine and placebo.

 

Text on Screen: AZA  I  13.4 months 95% CI: (8.7, 17.6)  I  mDOCR

 

Dr. Erba: Now let’s include CRh with the responses. It was 17.8 months with the combination of venetoclax plus azacitidine versus 13.9 months with the combination of placebo with azacitidine.

 

Text on Screen: PRESPECIFIED EXPLORATORY ENDPOINTS: MEDIAN DURATION CR+CRh*

VEN+AZA I 17.8 months 95% CI: (15.3, -) I mDOCR+CRh AZA I 13.9 months 95% CI: (10.4, 15.7) I mDOCR+CRh 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.

 

mDOCR+CRh=median duration of complete remission and complete remission with partial hematologic recovery.

 

Dr. Erba: One thing that impresses me is the time to response. It was a median time to response of a month with the combination of azacitidine and venetoclax.

 

Text on Screen: TIME TO FIRST RESPONSE

VEN+AZA 1.0 month   |   (range: 0.6-14.3 months)   |   TTFR

(CR or CRh)

TTFR=time to first response.

 

Voiceover: 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%) . . .

 

 Text on Screen: SAFETY DATA

 

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+AZA*

 

PBO=placebo.

 

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

 

Voiceover: . . . nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%).

 

Text on Screen:  Hematologic laboratory abnormalities

 

Dr. Erba: We also saw additional data for the VENCLEXTA + low-dose Ara-C regimen in the VIALE-C trial.

 

Text on Screen: VIALE-C: VEN+LDAC VS LDAC

 

VIALE-C phase 3 trial: VEN + low-dose cytarabine (LDAC): Efficacy of VEN+LDAC regimen was based on CR rate 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.

 

In the VIALE-C trial, VEN+LDAC did not significantly improve OS vs placebo+LDAC.

 

Ara-C=cytarabine.

 

Dr. Erba: For VIALE-C, we saw 27% CR with VENCLEXTA with low-dose Ara-C vs 7.4% with placebo plus low-dose Ara-C.

 

Text on Screen:  Remissions

VEN+LDAC   |   CR: 27% (95% CI: 20, 35)  

LDAC   |   CR: 7.4% (95% CI: 2.4, 16)

 

Dr. Erba: And 47% CR+CRh with VENCLEXTA with low-dose Ara-C vs 15% with placebo plus low-dose Ara-C.  

 

Text on Screen:  Remissions VEN+LDAC   |   CR: 27% (95% CI: 20, 35)   |   CR+CRh: 47% (95% CI: 39, 55)

 

LDAC   |   CR: 7.4% (95% CI: 2.4, 16)   |   CR+CRh: 15% (95% CI: 7.3, 25)

 

Dr. Erba: Median duration of CR was 11.1 months with VENCLEXTA with low-dose Ara-C and 8.3 months with placebo plus low-dose Ara-C. 

 

Text on Screen: Remissions

VEN+LDAC   |   mDOCR: 11.1 months (95% CI: 6.1, -) LDAC   |   mDOCR: 8.3 months (95% CI: 3.1, -) 

 

Dr. Erba: And median duration of CR+CRh was 11.1 months with VENCLEXTA plus low-dose Ara-C vs 6.2 months with placebo plus low-dose Ara-C.

 

Text on Screen: Remissions

 

VEN+LDAC   |   mDOCR: 11.1 months (95% CI: 6.1, -)   |   mDOCR+CRh: 11.1 months

 

LDAC   |   mDOCR: 8.3 months (95% CI: 3.1, -)   |   mDOCR+CRh: 6.2 months

 

In patients with AML receiving combination therapy with low-dose cytarabine, 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%).

 

Dr. Erba: The median time to first response of CR or CRh was 1 month.

 

Text on Screen: Remissions 1.0 month   |   (range: 0.7-5.8 months)   |   TTFR

 

(CR or CRh)

 

Dr. Erba: VIALE-A showed that with the combination of the oral BCL-2 inhibitor, with the same drugs we had been using for 10 to 20 years, there was improvements in complete remission rate compared to those drugs alone with placebo. Based on the results of the phase 3 VIALE-A trial, I am confident in the selection of the oral BCL-2 inhibitor venetoclax in combination with azacitidine as the initial treatment of my older patients who are ineligible for intensive induction chemotherapy.

 

Text on Screen: VEN+AZA   |   CR: 37% 105/286 patients 95% CI: (31, 43)

 

CR+CRh: 65% 185/286 patients 95% CI: (59, 70)   P<0.001 AZA   |   CR: 18% 26/145 patients 95% CI: (12, 25)

 

CR+CRh: 23% 33/145 patients 95% CI: (16, 30)   P<0.001

 

Voiceover: [Indication and Important Safety Information (ISI)]

Text on Screen: [Indication and ISI]

 

Voiceover: [ISI]

 

Text on Screen: [ISI]

 

Voiceover: [ISI and Please See Line]

 

Text on Screen: [ISI, Please See Line, references, and job code]

 

References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. New treatment options lead to new questions in acute myeloid leukemia. ASH Clinical News. 2019. Accessed October 4, 2021. https://www.ashclinicalnews.org/acute-leukemias/new-treatment-options-lead-new-questions-acute-myeloid-leukemia/ 3. Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422-4429. 4. Wass M, Hitz F, Schaffrath J, et al. Value of different comorbidity indices for predicting outcome in patients with acute myeloid leukemia. PLoS One. 2016;11(10):e0164587. 5. Kadia TM, Ravandi F, O’Brien S, et al. Progress in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15(3):139-151. 6. Zhang RJ, Zhai JH, Zhang ZJ, et al. Hypomethylating agents for elderly patients with acute myeloid leukemia: a PRISMA systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25(6):2577-2590. 7. DiNardo CD. Hypomethylating agents and venetoclax in acute myeloid leukemia. Clin Adv Hematol Oncol. 2021;19(2):82-83. 8. Finn L, Dalovisio A, Foran J. Older patients with acute myeloid leukemia: treatment challenges and future directions. Ochsner J. 2017;17(4):398-404. 9. Øvlisen AK, Oest A, Bendtsen MD, et al. Stringent or nonstringent complete remission and prognosis in acute myeloid leukemia: a Danish population-based study. Blood Advances. 2018;2(5):559-564.

US-VENA-210223

Text on Screen: This video is sponsored by AbbVie and Genentech, Inc. The physicians included in this video are presenting information on behalf of AbbVie and Genentech, Inc., and received compensation. 

 

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

 

Text on Screen: 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.

Continue viewing this video for Important Safety Information at the end of video.

 

Dr. Erba: Serious and sometimes fatal adverse reactions occurred with VENCLEXTA treatment. Warnings and precautions include tumor lysis syndrome, neutropenia, infections, immunization, embryo-fetal toxicity, and increased mortality in patients with multiple myeloma when VENCLEXTA is added to bortezomib and dexamethasone. Appropriate precautions should be taken by the healthcare provider.

 

Text on Screen: Continue viewing this video for Important Safety Information at the end of video.

 

Text on Screen: IN THE VIALE-A TRIAL EFFICACY IN NEWLY DIAGNOSED AML

 

Dr. Erba: For most of my 30-year career caring for people with acute myeloid leukemia, we had very limited therapeutic options . . .

 

Text on Screen: Harry Erba, MD, PhD Academic Hematologic Oncologist

 

Dr. Erba: . . . basically limited to intensive chemotherapy. Or we typically have used the hypomethylating agents: azacitidine, decitabine, or even low-dose cytarabine for those who are ineligible to receive intensive chemotherapy.

This intensive chemotherapy regimen leads to higher rates of induction mortality in our older patients, those with comorbidities, those with poor organ function, and those with poor performance status.

This is a relentless unforgiving disease with very short median overall survival and very few patients living more than 6 to 12 months.

This led to a very difficult decision for our patients who are older or ineligible to receive that intensive induction chemotherapy.

But we have other options for them. In terms of initial therapy, we have the combination of venetoclax an oral BCL-2 inhibitor with hypomethylating agents, such as azacitidine.

 

VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine in 431 adults with newly diagnosed AML who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy.

 

Text on Screen: • 3-day ramp-up of 100 mg to 200 mg and then to a final dose of 400 mg orally once daily. Patients received TLS prophylaxis and were hospitalized for monitoring VENCLEXTA 400 mg (orally once daily) Days 1-28 AZA 75 mg/m² (IV or subcutaneous)  Days 1-7 Beginning Day 1 of each 28-day cycle   |   Placebo (orally once daily)   Days 1-28 AZA 75 mg/m² (IV or subcutaneous)   Days 1-7 Beginning Day 1 of each 28-day cycle Treatment was continued until disease progression or unacceptable toxicity

 

Comorbidities 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
• Other comorbidities

 

TLS=tumor lysis syndrome; AZA=azacitidine; IV=intravenous; ECOG=Eastern Cooperative Oncology Group; CLcr=creatinine clearance.

 

Text on Screen: PRIMARY ENDPOINT: OVERALL SURVIVAL

 

Dr. Erba: In the VIALE-A trial…the median overall survival . . .

 

Text on Screen: VEN=VENCLEXTA;

 

Dr. Erba: of patients treated with venetoclax with azacitidine was 14.7 months.

 

Text on Screen: VEN=VENCLEXTA; CI=confidence interval.

 

Dr. Erba: The median overall survival of patients treated with placebo and azacitidine was 9.6 months…

 

 

Text on Screen: AZA | 9.6 months | 95% CI: (7.4, 12.7) VEN+AZA | 14.7 months | 95% CI: (11.9, 18.7)

• Median follow-up for OS was approximately 20.5 months (range: <0.1-30.7 months)
  • Median follow-up was estimated using reverse Kaplan-Meier methodology

OS=overall survival.

 

Dr. Erba:…an improvement in the median survival by 5.1 months.

 

Text on Screen: mOS=median overall survival.

 

Dr. Erba:  The hazard ratio for survival favored the combination of venetoclax with azacitidine, with a hazard ratio of 0.66. This translates to a 34% reduction in the risk of mortality.

 

Text on Screen:  34% REDUCTION IN RISK OF MORTALITY HR=0.66 I 95% CI: (0.52, 0.85); P<0.001 HR=hazard ratio.

 

Dr. Erba: I believe that the improvement in the median overall survival by 5.1 months is meaningful to my patients with acute myeloid leukemia. We need to remember that these are older patients who are not eligible for intensive therapies.

 

Text on Screen: 5.1 months

 

Dr. Erba: And so, they do not have potentially curative options. So improving survival by 5.1 months is meaningful for these patients. It gives them more time to spend with their family, to see a granddaughter graduate from college, see a grandson finally get married.

 

This is important. That’s what they want to know from me. “Doc, am I going to see that granddaughter graduate from college or that grandson get married in a year?” That they understand, and that’s what’s important to them.

 

Text on Screen: SECONDARY ENDPOINTS: REMISSIONS

 

Dr. Erba: Complete remission was achieved…

 

…in 37% of patients in the VIALE-A trial treated with the combination of azacitidine and venetoclax . . .

 

Text on Screen:  VEN+AZA N=286 I CR (n=105) 37% I CRh 28%

• CR, 95% CI: (31, 43); P<0.001
• CR+CRh, 95% CI: (59, 70); P<0.001

 

CR was defined as absolute neutrophil count (ANC) >1,000 microliter, platelets >100,000/microliter, RBC transfusion independence, and bone marrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease.

 

CR=complete remission; CRh=complete remission with partial hematologic recovery.

 

Dr. Erba: …compared to only 18% complete remission in patients treated with azacitidine and placebo.

 

Text on Screen: AZA N=145 I CR (n=26) 18% I CRh 5%

• CR, 95% CI: (12, 25)
• CR+CRh, 95% CI: (16, 30)

 

Dr. Erba: It’s important also to focus on the rate of complete remission with complete blood count recovery or partial hematologic recovery in patients treated in the VIALE-A trial. 

 

Text on Screen: 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). CR=complete remission; CRh=complete remission with partial hematologic recovery.

 

So what is this CRh or partial hematologic recovery? Well, for me, this is an important endpoint for my older patients with acute myeloid leukemia. In patients receiving venetoclax with azacitidine 65% of patients achieved a CR plus a CRh. In patients treated with azacitidine and placebo the CR+CRh rate was 23%, nearly three times as many patients achieved a CR+CRh with the combination of venetoclax and azacitidine.

 

Text on Screen: VEN+AZA I CR+CRh 65% (n=185) AZA I CRh 5% I CR+CRh 23% (n=33)

 

Dr. Erba: The combination of CR and CRh I believe is a very valuable endpoint in this trial.

 

The duration of these complete remissions is also important to my patients with acute myeloid leukemia. So it’s important to me that the median duration of complete remission with the combination of azacitidine with venetoclax was 18 months . . .

 

Text on Screen: PRESPECIFIED EXPLORATORY ENDPOINTS: MEDIAN DURATION CR*

VEN+AZA I 18 months 95% CI: (15.3, -)  I mDOCR

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms.

 

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.

mDOCR=median duration of complete remission.

 

Dr. Erba: …compared to 13.4 months with azacitidine and placebo.

 

Text on Screen: AZA I 13.4 months 95% CI: (8.7, 17.6) I mDOCR

 

Dr. Erba: Now let’s include CRh with the responses. It was 17.8 months with the combination of venetoclax plus azacitidine versus 13.9 months with the combination of placebo with azacitidine.

 

Text on Screen: PRESPECIFIED EXPLORATORY ENDPOINTS: MEDIAN DURATION CR+CRh*

VEN+AZA I 17.8 months 95% CI: (15.3, -) I mDOCR+CRh

AZA I 13.9 months 95% CI: (10.4, 15.7) I mDOCR+CRh

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms.

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.

mDOCR+CRh=median duration of complete remission and complete remission with partial hematologic recovery.

 

Dr. Erba: One thing that impresses me is the time to response. It was a median time to response of a month with the combination of azacitidine and venetoclax.

 

Text on Screen: TIME TO FIRST RESPONSE

VEN+AZA 1.0 month   |   (range: 0.6-14.3 months)   |   TTFR

(CR or CRh)

TTFR=time to first response.

 

Voiceover: 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%) . . .

 

Text on Screen: SAFETY DATA

 

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+AZA*

PBO=placebo.

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

 

Voiceover: . . . nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%).

 

Text on Screen: Hematologic laboratory abnormalities

 

Dr. Erba: One of the complications of acute myeloid leukemia is bone marrow failure. Our patients with acute myeloid leukemia quite frequently at the time of diagnosis are going to be requiring red blood cell transfusion or platelet transfusion support. This is a burden on patients…

 

Text on Screen: TRANSFUSION INDEPENDENCE

 

…it requires coming into the clinic or the hospital for those transfusions. And so, in my opinion, the achievement of transfusion independence in my patients with any bone marrow failure state, such as acute myeloid leukemia, is important.

 

In the VIALE-A trial, 49% of patients treated with the combination of venetoclax and azacitidine became transfusion independent from a state of transfusion dependence compared to…

 

Text on Screen: TRANSFUSION INDEPENDENCE CONVERSION*

Transfusion independence conversion (conversion from dependent to independent)

RBC and PLATELET

Patients were dependent on RBC and/or platelet transfusions at baseline

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms.

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

Transfusion dependence was defined as requiring RBC or platelet transfusion at baseline (within 8 weeks prior to the first dose of study drug or randomization).

RBC=red blood cell.

 

Dr. Erba: …27% of patients treated with the combination of placebo with azacitidine.

 

Text on Screen: VEN + AZA   |   49%   |   (76/155) AZA   |   27%   |   (22/81)

 

Dr. Erba: Maintenance of transfusion independence is also an important clinical endpoint for my patients with acute myeloid leukemia. In the VIALE-A trial, 69% of patients who were transfusion independent at study entry, maintained independence from both red blood cell and platelet transfusion when treated with the combination of venetoclax and azacitidine, compared with 42% of patients treated with the combination placebo with azacitidine.

 

Text on Screen: TRANSFUSION INDEPENDENCE MAINTENANCE*

Transfusion independence maintenance (independent from baseline to post-baseline period)

VEN + AZA   |   69%   |   (90/131)

AZA   |   42%   |   (27/64) RBC and PLATELET

Patients were independent of both RBC and platelet transfusions at baseline

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms.

Transfusion independence was defined as no RBC and platelet transfusion during any consecutive ≥56-day post-baseline period. Transfusion dependence was defined as requiring RBC or platelet transfusion at baseline (within 8 weeks prior to the first dose of study drug or randomization).

RBC=red blood cell.

 

Dr. Erba: We also saw additional data for the VENCLEXTA + low-dose Ara-C regimen in the VIALE-C trial.

 

Text on Screen: VIALE-C: VEN+LDAC vs LDAC

 

VIALE-C phase 3 trial: VEN + low-dose cytarabine (LDAC): Efficacy of VEN+LDAC regimen was based on CR rate 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.

In the VIALE-C trial, VEN+LDAC did not significantly improve OS vs placebo+LDAC.

Ara-C=cytarabine.

 

Dr. Erba: For VIALE-C, we saw 27% CR with VENCLEXTA with low-dose Ara-C vs 7.4% with placebo plus low-dose Ara-C. 

 

Text on Screen: Remissions VEN+LDAC   |   CR: 27% (95% CI: 20, 35)   LDAC   |   CR: 7.4% (95% CI: 2.4, 16)

 

And 47% CR+CRh with VENCLEXTA with low-dose Ara-C vs 15% with placebo plus low-dose Ara-C.  

 

Text on Screen: Remissions VEN+LDAC   |   CR: 27% (95% CI: 20, 35)   |   CR+CRh: 47% (95% CI: 39, 55) LDAC   |   CR: 7.4% (95% CI: 2.4, 16)   |   CR+CRh: 15% (95% CI: 7.3, 25)

 

Dr. Erba: Median duration of CR was 11.1 months with VENCLEXTA with low-dose Ara-C and 8.3 months with placebo plus low-dose Ara-C. 

 

Text on Screen: Remissions VEN+LDAC   |   mDOCR: 11.1 months

(95% CI: 6.1, -) LDAC   |   mDOCR: 8.3 months (95% CI: 3.1, -) 

 

And median duration of CR+CRh, was 11.1 months with VENCLEXTA plus low-dose Ara-C vs 6.2 months with placebo plus low-dose Ara-C.

 

Text on Screen: Remissions VEN+LDAC   |   mDOCR: 11.1 months (95% CI: 6.1, -)   |   mDOCR+CRh: 11.1 months

LDAC   |   mDOCR: 8.3 months (95% CI: 3.1, -)   |   mDOCR+CRh: 6.2 months

 

Dr. Erba: The median time to first response of CR or CRh was 1 month.

 

Text on Screen:  Remissions 1.0 month   |   (range: 0.7-5.8 months)   |   TTFR   |   (CR or CRh)

In patients with AML receiving combination therapy with low-dose cytarabine, 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%).

Dr. Erba: For VENCLEXTA plus low-dose Ara-C, the rate of red blood cell and/or platelet transfusion dependence to independence was 33% vs 13% for placebo plus low-dose Ara-C.

 

Text on Screen: Transfusion independence conversion VEN+LDAC: 33% (37/111) LDAC: 13% (7/55)

 

Dr. Erba: Overall survival benefit was not evaluated for VENCLEXTA in combination with decitabine.

 

Text on Screen: M14-358: VEN+AZA OR DEC M14-358 phase 1b trial: VEN+AZA or decitabine (DEC): VEN+AZA or decitabine (DEC): VENCLEXTA was studied in a non-randomized, open-label trial that evaluated the efficacy of VENCLEXTA in combination with AZA (N=84) or DEC (N=31) in patients with newly diagnosed AML. Overall survival benefit was not evaluated for VENCLEXTA in combination with decitabine.

 

Dr. Erba: For VENCLEXTA plus decitabine, the CR rate was 54% and CRh was 7.7%.

 

Text on Screen: VEN+DEC Remissions

CR   |   54%   |   95% CI: (25, 81)   |   (n=7) CRh   |   7.7%   |   95% CI: (0.2, 36)   |   (n=1)

 

Dr. Erba: Median duration of CR was 12.7 months . . .

 

Text on Screen: VEN+DEC mDOCR 12.7 months   |   95% CI: (1.4, –) In patients with AML receiving combination therapy with decitabine, 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%).

 

Dr. Erba: …and the median time to first response, CR or CRh, was 1.9 months.

 

Text on Screen: VEN+DEC TTFR (CR or CRh) 1.9 months   |   (range: 0.8-4.2)

 

Dr. Erba: Looking at the VIALE-A data, it was quite clear to me that we had a therapeutic option that can improve response rates, leading to a decrease in transfusion dependence, and also improving their survival over what we had had in the past.

 

Text on Screen: In patients with newly diagnosed AML who were ≥75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy

LONGER OVERALL SURVIVAL

LASTING IMPACT

*Endpoints were not powered or tested to demonstrate a statistically significant difference between the treatment arms.

 

Dr. Erba: Based on the results of the phase 3, VIALE-A trial, I am confident in the selection of the oral BCL-2 inhibitor venetoclax in combination with azacitidine as the initial treatment of my older patients who are ineligible for intensive induction chemotherapy.

 

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References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. New treatment options lead to new questions in acute myeloid leukemia. ASH Clinical News. 2019. Accessed October 4, 2021. https://www.ashclinicalnews.org/acute-leukemias/new-treatment-options-lead-new-questions-acute-myeloid-leukemia/ 3. Zhang RJ, Zhai JH, Zhang ZJ, et al. Hypomethylating agents for elderly patients with acute myeloid leukemia: a PRISMA systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25(6):2577-2590. 4. DiNardo CD. Hypomethylating agents and venetoclax in acute myeloid leukemia. Clin Adv Hematol Oncol. 2021;19(2):82-83. 5. Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422-4429. 6. Wass M, Hitz F, Schaffrath J, et al. Value of different comorbidity indices for predicting outcome in patients with acute myeloid leukemia. PLoS One. 2016;11(10):e0164587. 7. Kadia TM, Ravandi F, O’Brien S, et al. Progress in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15(3):139-151. 8. Finn L, Dalovisio A, Foran J. Older patients with acute myeloid leukemia: Treatment challenges and future directions. Ochsner J. 2017;17(4):398-404. 9. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. 10. Klepin HD, Estey E, Kadia T. More versus less therapy for older adults with acute myeloid leukemia: New perspectives on an old debate. Am Soc Clin Oncol Educ Book. 2019;39:421-432. 11. Chen L, Zhou H, Guo B, et al. Clinical efficacy of platelet transfusion therapy in patients with leukemia and analysis of risk factors for ineffective transfusion. Oncol Lett. 2020;19(3):2554-2561. 12. Cannas G, Thomas X. Supportive care in patients with acute leukaemia: historical perspectives. Blood Transfus. 2015;13(2):205-220. 13. Getting a blood transfusion. American Cancer Society. Updated February 7, 2021. Accessed October 5, 2021. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/blood-transfusion-and-donation/how-blood-transfusions-are-done.html.

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