Hear Harry Erba, MD, PhD, and Dan Greenwald, MD, discuss results from the phase 3 VIALE-A trial and share important information to consider when treating patients with AML. Dr. Erba and Dr. Greenwald have been compensated by AbbVie Inc., and Genentech, Inc., to participate in these videos.
Treatment Management With VENCLEXTA in Newly Diagnosed AML
Dr. Erba discusses various treatment considerations to help patients get started on a VENCLEXTA regimen.
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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
Transfusion Independence in the VIALE-A Trial
Dr. Erba discusses transfusion independence and maintenance data from the VIALE-A trial.
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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 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: 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-210247
Overall Survival in Newly Diagnosed AML
Dr. Erba speaks about overall survival rates from the VIALE-A trial.
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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]
Text on Screen: [ISI and Please See line]
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
Remissions in Newly Diagnosed AML
Dr. Erba shares results from the VIALE-A trial regarding overall survival and remissions in newly diagnosed patients with AML.
NOW PLAYING 4 of 7
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
The AML Treatment Journey
Dr. Greenwald explains various factors to consider before starting patients on VENCLEXTA.
NOW PLAYING 5 of 7
Text on Screen: VENCLEXTA® venetoclax tablets 10 mg, 50 mg, 100 mg
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. Greenwald: 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.
Text on Screen: 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: THE AML TREATMENT JOURNEY
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
Continue viewing this video for Important Safety Information at the end of video.
Dr. Greenwald: Much of my research in medical school focused on immunology and the role of apoptosis in immune cells resisting cell death. And as we know as oncologists, BCL-2 plays a key role in tumor cells across various tumor types.
Text on Screen: DAN GREENWALD, MD COMMUNITY ONCOLOGIST
Dr. Greenwald: I’ve been following the story of BCL-2 through the early therapeutic attempts and what eventually became the small molecule that led to development of venetoclax.
Dr. Greenwald: 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: N=286 RANDOMIZED 2:1 •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 N=145
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
- CrCl <45 mL/min
- Other comorbidities
TLS=tumor lysis syndrome; AZA=azacitidine; IV=intravenous; ECOG=Eastern Cooperative Oncology Group; CrCl=creatinine clearance.
Dr. Greenwald: I’ve been using venetoclax in treatment of AML since shortly after its approval in late 2018.
Text on Screen: For appropriate patients, newly diagnosed and ineligible for intensive induction chemotherapy.
Dr. Greenwald: It’s important when considering a venetoclax-containing regimen for frontline treatment of AML, to really understand the labeled usage, the indications, and potential toxicities.
Dr. Greenwald: To take you through these treatment considerations, I’ll be using the help of two hypothetical patients who might be similar to patients you would consider treating with a VEN+AZA regimen.
Text on Screen: LINCOLN | LISA
Not actual patients.
Dr. Greenwald: For both patients we will be taking into consideration dosing as well as drug interactions which can impact starting therapy and target dosing.
We will also look at bone marrow assessment as it pertains to the management of cytopenias—including grade 4 neutropenia with or without a fever, grade 4 thrombocytopenia—and how these relate to treatment before and after remission, as well as in subsequent episodes of cytopenias.
Text on Screen: This is a summary and is not an exhaustive list of all treatment considerations.
Dr. Greenwald: But before we begin, let’s get to know our two hypothetical patients, Lincoln and Lisa, and what might make them appropriate candidates for consideration of VEN+AZA.
Text on Screen: LINCOLN | LISA
Not actual patients.
Dr. Greenwald: Lincoln is 68 with moderate hepatic impairment. He has been newly diagnosed with AML, but due to having a comorbidity . . .
Text on Screen: CONSIDERATIONS FOR TREATMENT WITH VENCLEXTA REGIMENS
Lincoln
68 YEARS OLD
Comorbidity: Moderate hepatic impairment
Total serum bilirubin: 2.0 mg/dL
Dr. Greenwald: . . . he is ineligible for intensive induction chemotherapy.
I would consider starting a patient like Lincoln on NCCN Category 1 Preferred regimen, VEN+AZA.
Text on Screen: VEN | AZA
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommends venetoclax (VENCLEXTA®) combination regimens for AML patients*
- For patients ≥60 years of age who are not candidates for intensive induction chemotherapy in first-line AML
FOR PATIENTS WITH OR WITHOUT ACTIONABLE MUTATIONS† VENETOCLAX + AZACITIDINE: CATEGORY 1 PREFERRED | VENETOCLAX + DECITABINE: CATEGORY 2A PREFERRED | VENETOCLAX + LOW-DOSE CYTARABINE: CATEGORY 2A OTHER RECOMMENDED
*See NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for AML, Version 3.2022, for complete recommendations. 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.
†Actionable mutations include IDH1/2 and FLT3.
NCCN=National Comprehensive Cancer Network® (NCCN®).
Dr. Greenwald: Lisa is 79 and has been newly diagnosed with AML.
Text on Screen: Lisa | 79 YEARS OLD
Dr. Greenwald: Due to her age, she is an appropriate candidate for VEN+AZA.
Lisa also has an IDH1/2 mutation.
Text on Screen: Mutation status: IDH1/2
Dr. Greenwald: Based on these factors, I would also consider starting a patient like Lisa on an NCCN Category 1 Preferred regimen, VEN+AZA.
Text on Screen: VEN | AZA
NCCN Guidelines® recommends venetoclax (VENCLEXTA®) combination regimens for AML patients*
- For patients ≥60 years of age who are not candidates for intensive induction chemotherapy in first-line AML
FOR PATIENTS WITH OR WITHOUT ACTIONABLE MUTATIONS†
VENETOCLAX + AZACITIDINE: CATEGORY 1 PREFERRED | VENETOCLAX + DECITABINE: CATEGORY 2A PREFERRED | VENETOCLAX + LOW-DOSE CYTARABINE: CATEGORY 2A OTHER RECOMMENDED
*See NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for AML, Version 3.2022, for complete recommendations. 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.
†Actionable mutations include IDH1/2 and FLT3.
NCCN=National Comprehensive Cancer Network® (NCCN®).
Dr. Greenwald: VENETOCLAX is FDA-approved regardless of mutation status. Patients like Lincoln or Lisa can start treatment whether they have, for example, an IDH1 mutation, an IDH2 mutation, an IDH1/2 mutation, a FLT3 mutation, an NPM1 mutation, a TP53 mutation, or no mutation at all.
Text on Screen: INITIATION | STARTING VEN+AZA
IDH1
IDH2
IDH1/2
FLT3
NPM1
TP53
This is not an exhaustive list of all mutations.
Dr. Greenwald: Patients treated with venetoclax may develop tumor lysis syndrome. Because of this, there are specific details on management to help assess and reduce the risk of TLS. Before starting either patient on a VEN+AZA regimen, we should first perform a pretreatment TLS risk assessment.
Text on Screen: INITIATION | PRETREATMENT TLS RISK ASSESSMENT WBC 45 x 109/L | HIGH
Dr. Greenwald: So, prior to VEN initiation you want to ensure that the patient has a white blood cell count less than 25,000. Cytoreduction prior to treatment may be required in order to achieve this.
Text on Screen: WBC CYTOREDUCTION <25 X 109/L
Dr. Greenwald: Next, prior to the first VEN dose, as you continue to prepare each patient for therapy, you would provide prophylactic measures, including adequate hydration and anti-hyperuricemic agents, and continue that through the ramp-up phase.
Dr. Greenwald: You also want to assess the patient’s blood chemistries and correct any preexisting abnormalities prior to the treatment initiation.
Text on Screen: POTASSIUM
URIC ACID
PHOSPHORUS
CALCIUM
CREATININE
Dr. Greenwald: Be sure to 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.
Text on Screen:
- Pre-dose
- 6 to 8 hours after each new dose
- 24 hours after final dose
Dr. Greenwald: For patients with risk factors for TLS, consider additional measures, including increased laboratory monitoring and reducing the venetoclax starting dose.
Text on Screen: TLS RISK FACTORS
Circulating blasts
High burden of leukemia involvement in bone marrow
Elevated pretreatment lactate dehydrogenase (LDH) levels
Reduced renal function
Dr. Greenwald: At initiation, both patients will receive azacitidine intravenously or subcutaneously once daily at 75 mg/m2 on Days 1-7 of each 28-day treatment cycle.
Text on Screen: INITIATION | STARTING VEN+AZA
75 mg/m2
or
Days 1-7 once daily
Dr. Greenwald: So let’s start with our first patient Lincoln who will follow the standard dose ramp-up for venetoclax, which is designed to allow patients to safely attain the recommended daily dose.
Text on Screen: VEN | AZA
LINCOLN
68 YEARS OLD
Comorbidity: Moderate hepatic impairment
Total serum bilirubin: 2.0 mg/dL
Dr. Greenwald: So, on Day 1 of the ramp-up, Lincoln starts venetoclax at 100 mg, 200 mg on Day 2, and 400 mg once daily on Day 3 and beyond for each 28-day cycle.
Text on Screen:
DAY 1 100
DAY 2 100 100
DAY 3+ 100 100 100 100
For each 28-day cycle
Text on Screen: STARTING VEN+DEC
DAY 1 100
DAY 2 100 100
DAY 3+ 100 100 100 100
For each 28-day cycle
- 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 once daily on Days 1-5 of each 28-day cycle beginning on Cycle 1, Day 1
STARTING VEN+LDAC
DAY 1 100
DAY 2 100 100
DAY 3 100 100 100 100
DAY 4 100 100 100 100 100 100
For each 28-day cycle
- 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. Greenwald: Now let’s look at Lisa’s ramp-up schedule. To help reduce the risk of infection, Lisa receives antifungal prophylaxis at initiation and throughout treatment. Since Lisa is starting VEN+AZA along with antifungal prophylaxis—fluconazole, a moderate CYP3A inhibitor—her recommended dosage and ramp-up dose at initiation will be adjusted.
Text on Screen: INITIATION | STARTING VEN+AZA
VEN | AZA | FLUCONAZOLE
LISA
79 YEARS OLD
Mutation status: IDH1/2
Dr. Greenwald: For concomitant use with a moderate CYP3A inhibitor like fluconazole, we would reduce the venetoclax dose by at least 50%. So, on Day 1 of the initiation ramp-up, Lisa starts venetoclax at 50 mg or less, then 100 mg or less on Day 2, and 200 mg or less once daily on Day 3 and beyond.
Text on Screen: INITIATION | STARTING VEN+AZA+MODERATE CYP3A INHIBITOR
FLUCONAZOLE
Steady daily dose (after ramp-up phase)
Reduce the VENCLEXTA dose by at least 50%
- Adjust the VENCLEXTA dose and monitor more frequently for adverse reactions
- If using venetoclax in combination with decitabine plus a moderate CYP3A inhibitor, you would follow the same dose-reduced ramp-up as the VEN+AZA regimen.
- VEN+LDAC plus a moderate CYP3A inhibitor would also follow the same dose-reduced ramp-up as VEN+AZA and VEN+DEC, with the exception of Day 4, which would be reduced from 600 mg to 300 mg or less once daily.
Dr. Greenwald: And this dose ramp-up and initiation process can take place either in the hospital setting or an outpatient clinic, depending on which scenario is most appropriate.
Text on Screen: INITIATION | STARTING VEN+AZA
Dr. Greenwald: Once they begin their VEN+AZA regimens, they will continue treatment until disease progression or unacceptable toxicity is observed.
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
[RATE OF SERIOUS ADVERSE REACTIONS table]
[DISCONTINUATION, REDUCTION, AND INTERRUPTION RATES OF VEN OR PBO Table]
PBO=placebo; AR=adverse reaction.
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*
[ADVERSE REACTION BY BODY SYSTEM table]
*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. Greenwald: Throughout treatment, you should assess and monitor for cytopenia as well as common and serious adverse reactions.
Text on Screen: [(CONT’D) added to table header]
HEMATOLOGIC LABORATORY ABNORMALITIES
New or worsening Grade 3 or 4 hematologic laboratory abnormalities (≥10%) in VIALE-A with a difference between arms of ≥2% for VEN+AZA vs PBO+AZA, respectively: neutrophils decreased 98% vs 81%, platelets decreased 88% vs 80%, lymphocytes decreased 71% vs 39%, hemoglobin decreased 57% vs 52%.
Dr. Greenwald: In VIALE-A, bone marrow biopsy was conducted following Cycle 1 to assess for remission.
Text on Screen: ASSESSMENT | IN THE VIALE-A TRIAL Cycle 1 (28 days)
Dr. Greenwald: For patients with resistant disease, that is having >5% blasts, at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated.
Text on Screen: Cycle 1 (28 days)
Cycle 2 (28 days)
Cycle 3 (28 days)
Dr. Greenwald: Knowing when remission is achieved is important . . .
Text on Screen: ACUTE MYELOID LEUKEMIA
Neutrophils
Red blood cells
Platelets
Excess myeloblasts
Dr. Greenwald: . . . because it helps determine . . .
Text on Screen: REMISSION
Dr. Greenwald: . . . how to manage certain cytopenias.
Text on Screen: LOW BLOOD COUNTS (CYTOPENIA) Too few neutrophils (neutropenia) Too few platelets (thrombocytopenia)
Dr. Greenwald: For example, for Grade 4 neutropenia and thrombocytopenia, management will differ based on if remission was achieved.
Text on Screen: MANAGEMENT | BEFORE REMISSION | AFTER REMISSION
Dr. Greenwald: If Grade 4 neutropenia or thrombocytopenia occurs before remission is achieved, the patient should stay on venetoclax. And in most instances, we would not interrupt treatment due to cytopenias.
Text on Screen: MANAGEMENT | BEFORE REMISSION*† IS ACHIEVED
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
*Recommend bone marrow evaluation. †Remission is defined as achieving a CR or CRh.
Dr. Greenwald: For example, I would keep Lincoln on his VEN regimen because, for him, neutropenia occurs at Cycle 2, but he doesn’t achieve remission until Cycle 3.
Text on Screen: MANAGEMENT | BEFORE REMISSION IS ACHIEVED | GRADE 4 NEUTROPENIA + NO REMISSION
Remission achieved: Cycle 3
Neutropenia: Cycle 2
Dr. Greenwald: And when Lincoln does achieve remission at Cycle 3, if he experiences Grade 4 neutropenia, there are additional approaches for after remission is achieved, which typically requires dose holds during treatment.
Text on Screen: MANAGEMENT | AFTER REMISSION IS ACHIEVED GRADE 4 NEUTROPENIA
(lasting at least 7 days)
+ REMISSION
Dr. Greenwald: For example, in VIALE-A, in the VEN+AZA arm, among patients who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for an absolute neutrophil count of <500/microliter. So, we see that the dose delays are quite common, and dose delays are a part of PI-based guidance for cytopenia management.
Text on Screen: In VIALE-A: Of patients who 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. Greenwald: So, for Lisa, we see that she achieved remission in Cycle 1. But, shortly after, at Cycle 2, she experiences her first occurrence of Grade 4 neutropenia, lasting at least 7 days.
Text on Screen: MANAGEMENT | AFTER REMISSION IS ACHIEVED GRADE 4 NEUTROPENIA
(lasting at least 7 days)
+ REMISSION
Remission achieved: Cycle 1
Neutropenia: Cycle 2
Dr. Greenwald: Based on guidance from the PI for patients who experience their first occurrence of Grade 4 neutropenia after achieving remission, I would delay Lisa’s subsequent cycle of the venetoclax regimen and monitor blood counts for count recovery.
Text on Screen: Managing Grade 4 neutropenia with or without fever or infection, or Grade 4 thrombocytopenia (1st occurrence lasting at least 7 days)
Delay subsequent cycle of VEN regimen + monitor blood counts
Dr. Greenwald: Once the neutropenia resolves to Grade 1 or 2, I would allow Lisa to resume venetoclax therapy at the same dose. For Lisa, that would be 200 mg, or less, due to her dose adjustments at initiation for antifungal prophylaxis. And she would resume this dose in combination with AZA. We would also keep Lisa on the 28-day treatment cycle, with venetoclax being taken once daily each day of the 28-day cycle and azacitidine being received once daily on Days 1-7 of each 28-day cycle.
Text on Screen: Managing Grade 4 neutropenia with or without fever or infection, or Grade 4 thrombocytopenia (1st occurrence lasting at least 7 days)
Delay subsequent cycle of VEN regimen + monitor blood counts
Resolution to Grade 1 or 2
Resume VENCLEXTA therapy + AZA or DEC or LDAC
Resume 28-day treatment cycle
Dr. Greenwald: If Lisa experiences any subsequent occurrences of neutropenia, lasting at least 7 days, I would again, delay the subsequent cycle of venetoclax regimen and monitor blood counts. Once the neutropenia resolves to Grade 1 or 2, I would allow Lisa to resume venetoclax at 200 mg, or less, in combination with AZA. I would also reduce the venetoclax treatment cycle by 7 days for each subsequent occurrence.
Text on Screen: Managing Grade 4 neutropenia with or without fever or infection, or Grade 4 thrombocytopenia (Subsequent occurrence lasting at least 7 days)
Delay subsequent cycle of VEN regimen + monitor blood counts
Resolution to Grade 1 or 2 | Resume VENCLEXTA therapy + AZA or DEC or LDAC
Reduce VENCLEXTA 28-day treatment cycle by 7 days
Dr. Greenwald: For example, for a second occurrence, after achieving remission, we would have a patient like Lisa receive VEN for 21 days of the standard 28-day cycle and azacitidine would be received once daily on Days 1-7.
For patients experiencing any occurrence of a Grade 3 or a Grade 4 non-hematologic adverse reaction, we would interrupt venetoclax if not resolved with supportive care. Upon resolution to Grade 1 or baseline, we would resume venetoclax at the same dose.
Text on Screen: MANAGEMENT | BEFORE OR AFTER REMISSION IS ACHIEVED
Grade 3 or 4 non-hematologic adverse reactions (Any occurrence)
Supportive care
Interrupt VENCLEXTA if not resolved with supportive care
Resolution to Grade 1 or baseline
Resume VENCLEXTA therapy + AZA or DEC or LDAC
Dr. Greenwald: We see that there are a number of provided recommendations for these select areas in a patient’s treatment journey. That is evaluating TLS risk in patients and providing prophylactic measures, following the appropriate dose ramp-up schedule for the VEN 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. Greenwald: . . . 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
This is a summary and is not an exhaustive list of all treatment considerations.
Dr. Greenwald: and managing certain hematologic adverse reactions with dose modifications based on remission status and AR occurrence, as well as dose modifications for management of non-hematologic ARs.
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. This is a summary and is not an exhaustive list of all treatment considerations.
Dr. Greenwald: Lincoln and Lisa are just two examples of what a patient on a venetoclax-containing regimen could look like. Of course, all patient scenarios are different.
Text on Screen: This content is not a substitute for independent medical judgement.
This is a summary and is not an exhaustive list of all treatment considerations.
Dr. Greenwald: And so, I recommend referring to the full Prescribing Information to obtain and understand more detailed information about how to best initiate, assess, and manage patients undergoing therapy with a venetoclax-containing regimen. And remember that in addition to this video and the package insert, you can always reach out to your colleagues in the academic setting for help in understanding the best way of managing your patient with AML.
Voiceover: [Indication and Important Safety Information (ISI)]
Text on Screen: [Indication and Important Safety Information (ISI)]
Voiceover: [Important Safety Information (ISI)]
Text on Screen: [ISI]
Voiceover: [Important Safety Information (ISI) and Please See line]
Text on Screen: [ISI, references, and job code]
References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. Kirkin V, Joos S, Zörnig M. The role of Bcl-2 family members in tumorigenesis. Biochem Biophys. 2004;1644(2-3):229-249. 3. ABIM Laboratory Test Ranges–January 2020. ABIM. 2020. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2022. © National Comprehensive Cancer Network, Inc 2023. All rights reserved. Accessed January, 13, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 5. Riley LK, Rupert J. Evaluation of patients with leukocytosis. Am Fam Physician. 2015;92(11):1004-1011. 6. Vazquez L. Antifungal prophylaxis in immunocompromised patients. Mediterr J Hematol Infect Dis. 2016;8(1):e2016040. 7. 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. 8. Data on file, ABVRRTI71272. AbbVie Inc. 9. Data on file, ABVRRTI71500. AbbVie Inc.
US-VENA-230005
VENCLEXTA® venetoclax tablets 10 mg, 50 mg, 100 mg
Mutational Subgroup Data
Dr. Greenwald reviews clinical data from mutational and cytogenetic risk subgroups in the VIALE-A trial.
NOW PLAYING 6 of 7
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. Greenwald: 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. Greenwald: 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 the video.
Text on Screen: IN THE VIALE-A TRIAL
MUTATIONAL SUBGROUP DATA
Continue viewing this video for Important Safety Information at the end of video.
Dr. Greenwald: It’s well recognized that for an oncologist treating patients in the community, AML has become more complex than ever.
Text on Screen: Dan Greenwald, MD Community Oncologist
Dr. Greenwald: No two patients are alike.
We now recognize there are several actionable mutations and other biomarkers that affect not only prognosis but often selection of therapy.
Venetoclax-based regimens can be used for patients who are either ineligible for intensive chemotherapy due to age or comorbidities, regardless of their mutational status.
VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of venetoclax in combination with azacitidine in 431 adults with newly diagnosed AML who were 75 years or older, or who 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 RANDOMIZED 2:1 N=286 N=145 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 • CrCl <45 mL/min • Other comorbidities
TLS=tumor lysis syndrome; AZA=azacitidine; IV=intravenous; ECOG=Eastern Cooperative Oncology Group; CrCl=creatinine clearance.
Dr. Greenwald: This allows for an option for treatment in patients regardless of the mutational status.
Text on Screen: Baseline Characteristics Table
*Per the 2016 NCCN Guidelines®.
†Number of evaluable bone marrow aspirate (BMA) specimens received at baseline.
IDH=isocitrate dehydrogenase; FLT=fms-like tyrosine kinase; NPM=nucleophosmin; TP53=tumor protein p53.
Dr. Greenwald: Along with this, NCCN guidelines list venetoclax-containing regimens as treatments to consider for patients in the frontline setting, with or without actionable mutations. Such as venetoclax in combination with azacitidine. It is a Category 1 Preferred regimen.
Text on Screen: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommends venetoclax (VENCLEXTA®) combination regimens for AML patients*
- For patients ≥60 years of age who are not candidates for intensive induction chemotherapy in first-line AML
For patients with or without actionable mutations†
VENETOCLAX + AZACITIDINE: CATEGORY 1 PREFERRED | VENETOCLAX + DECITABINE: CATEGORY 2A PREFERRED | VENETOCLAX + LOW-DOSE CYTARABINE: CATEGORY 2A OTHER RECOMMENDED
*See NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for AML, Version 3.2022, for complete recommendations. 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.
†Actionable mutations include IDH1/2 and FLT3.
NCCN=National Comprehensive Cancer Network® (NCCN®).
Dr. Greenwald: When you look at overall survival in the full study population you see that the VEN+AZA provided a median overall survival of 14.7 months versus 9.6 months with placebo and AZA. There was also a 34% reduction in risk of mortality with VEN+AZA.
Text on Screen: PRIMARY ENDPOINT: OVERALL SURVIVAL
CI=confidence interval; OS=overall survival; HR=hazard ratio.
Dr. Greenwald: And when we take a deeper look at the overall survival . . .
Text on Screen: DESCRIPTIVE PRESPECIFIED ANALYSIS: OVERALL SURVIVAL IN MUTATIONAL & CYTOGENETIC RISK SUBGROUPS
Descriptive prespecified analysis of OS in secondary and exploratory endpoints
- OS in the IDH1/2 and FLT3 subgroups was a prespecified secondary endpoint. Other select biomarker subgroups (IDH1, IDH2, TP53, and NPM1) and cytogenetic risk were prespecified exploratory endpoints
Subgroup analyses were not powered to demonstrate a statistically significant difference in OS. Small patient numbers and lack of multiplicity adjustments for some subgroups can be a limitation of these analyses. No conclusions of efficacy or safety can be drawn from these data.
*The HR of overall survival was estimated using the unstratified log-rank test and the Cox proportional hazards model for OS.
n/N=total number of events per total number of patients; NR=not reached.
Dr. Greenwald: . . . we see data for certain biomarker subgroups, as well as the cytogenetic risk subgroups (intermediate and poor).
Voiceover: Subgroup analyses were not powered to demonstrate a statistically significant difference in OS.
Small patient numbers and lack of multiplicity adjustments for some subgroups can be a limitation of these analyses.
No conclusions of efficacy or safety can be drawn from these data.
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. Greenwald: We also saw additional data for the VEN+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. Greenwald: So in reviewing all of these data, venetoclax with azacitidine is a viable treatment consideration for older age-appropriate patients regardless of their mutational status.
Text on Screen: Continue viewing this video for Important Safety Information.
Voiceover: [Indication and ISI]
Text on Screen: [Indication and Important Safety Information (ISI)]
Voiceover: [ISI]
Text on Screen: [ISI]
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Super: [ISI and Please See line]
References: 1. VENCLEXTA [package insert]. North Chicago, IL: AbbVie Inc. 2. DiNardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematology Am Soc Hematol Educ Program. 2016;2016(1):348-355. 3. Jillella AP, Cortes JE, Kota VK. Optimizing management of acute leukemia in community centers and when to refer. Hematology Am Soc Hematol Educ Program. 2020;2020(1):123-128. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2022. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 13, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 5. Data on file, ABVRRTI71211. AbbVie Inc.
US-VENA-230004
Efficacy in Newly Diagnosed AML
Dr. Erba speaks about key efficacy and safety data from VIALE-A trial.
NOW PLAYING 7 of 7
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.
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. 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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AML=acute myeloid leukemia.
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Important Safety Information & Indication
Indication
VENCLEXTA is indicated in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.
Important Safety Information
Tumor Lysis Syndrome
- Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with VENCLEXTA.
- VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during the ramp-up phase in all patients. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase.
- In patients with AML who followed the current 3-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 1.1% in patients who received VENCLEXTA in combination with azacitidine. In patients with AML who followed a 4-day ramp-up dosing schedule and the TLS prophylaxis and monitoring measures, the rate of TLS was 5.6% and included deaths and renal failure in patients who received VENCLEXTA in combination with low-dose cytarabine.
- The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy.
- Assess all patients for risk and provide appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA follow dose modification guidance in the Prescribing Information.
- Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate CYP3A inhibitors increases venetoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase, and requires VENCLEXTA dose reduction.
Neutropenia
- In patients with AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine. Neutropenia can recur with subsequent cycles.
- Monitor complete blood counts. Interrupt dosing for severe neutropenia. Resume at same dose then reduce duration based on remission status and first or subsequent occurrence of neutropenia. Consider supportive measures including antimicrobials and growth factors (e.g., G-CSF).
Infections
- Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with VENCLEXTA. Monitor patients for signs and symptoms of infection and treat promptly. Withhold VENCLEXTA for Grade 3 and 4 infection until resolution and resume at same dose.
Immunization
- Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. Advise patients that vaccinations may be less effective.
Embryo-Fetal Toxicity
- VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose.
Increased Mortality in Patients with Multiple Myeloma when VENCLEXTA is Added to Bortezomib and Dexamethasone
- In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with VENCLEXTA in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.
Adverse Reactions
- In patients with AML receiving combination therapy with azacitidine, the most frequent serious adverse reactions (≥5%) were febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage (6%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were neutrophils decreased (98%), platelets decreased (94%), lymphocytes decreased (91%), hemoglobin decreased (61%), nausea (44%), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%), and vomiting (30%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with azacitidine, with the most frequent (≥2%) being pneumonia (4%), sepsis (excluding fungal; 3%), and hemorrhage (2%).
- In patients with AML receiving combination therapy with decitabine, the most frequent serious adverse reactions (≥10%) were sepsis (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were neutrophils decreased (100%), lymphocytes decreased (100%), white blood cells decreased (100%), platelets decreased (92%), hemoglobin decreased (69%), febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexia (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%), and vomiting (31%). One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment.
- In patients with AML receiving combination therapy with low-dose cytarabine, the most frequent serious adverse reactions (≥10%) were pneumonia (17%), febrile neutropenia (16%), and sepsis (excluding fungal; 12%). The most common adverse reactions including hematological abnormalities (≥30%) of any grade were platelets decreased (97%), neutrophils decreased (95%), lymphocytes decreased (92%), hemoglobin decreased (63%), nausea (42%), and febrile neutropenia (32%). Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with LDAC, with the most frequent (≥5%) being pneumonia (6%) and sepsis (excluding fungal; 7%).
Drug Interactions
- Concomitant use with a P-gp inhibitor or a strong or moderate CYP3A inhibitor increases VENCLEXTA exposure, which may increase VENCLEXTA toxicities, including the risk of TLS. Consider alternative medications or adjust VENCLEXTA dosage and monitor more frequently for adverse reactions. Resume the VENCLEXTA dosage that was used prior to concomitant use of a P-gp inhibitor or a strong or moderate CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.
- Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A.
- Avoid concomitant use of strong or moderate CYP3A inducers.
- Monitor international normalized ratio (INR) more frequently in patients receiving warfarin.
- Avoid concomitant use of VENCLEXTA with a P-gp substrate. If concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.
Lactation
- Advise nursing women not to breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.
Females and Males of Reproductive Potential
- Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for 30 days after the last dose.
- Based on findings in animals, VENCLEXTA may impair male fertility.
Hepatic Impairment
- Reduce the dose of VENCLEXTA for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more frequently for signs of adverse reactions. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
Please see full Prescribing Information.
VENCLEXTA® and its design are registered trademarks of AbbVie Inc.
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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.3.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed April 5, 2023. 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.3.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed April 5, 2023. 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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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.
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.
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Data on file, AbbVie Inc. ABVRRTI71211.
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CRESEMBA Prescribing Information.
CRESEMBA Prescribing Information.
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Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration website. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. Updated March 6, 2020. Accessed October 15, 2020.
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Data on file, Genentech, Inc. 07/2022.
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Pratz KW, Jonas BA, Pullarkat V, et al. Long-term follow-up of the phase 3 VIALE-A clinical trial of venetoclax plus azacitidine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Oral abstract presented at: 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, Louisiana. https://clin.larvol.com/abstract-detail/ASH%202022/61249960
Pratz KW, Jonas BA, Pullarkat V, et al. Long-term follow-up of the phase 3 VIALE-A clinical trial of venetoclax plus azacitidine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Oral abstract presented at: 64th ASH Annual Meeting and Exposition; December 10, 2022; New Orleans, Louisiana. https://clin.larvol.com/abstract-detail/ASH%202022/61249960
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