Venclexta Drug Information
Generic name: VENETOCLAX
BCL-2 Inhibitor [EPC]
Uses of Venclexta
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Acute Myeloid Leukemia 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.
Dosage & Administration of Venclexta
Important Safety Information
Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to reduce risk of TLS.
Recommended Dosage for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA dosing begins with a 5-week ramp-up. The 5-week ramp-up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS. VENCLEXTA 5-week Dose Ramp-Up Schedule Administer VENCLEXTA according to the 5-week ramp-up dosing schedule to the recommended dosage of 400 mg orally once daily as shown in Table 1.
Table 1. Dosing Schedule for 5-Week Ramp-up Phase for Patients with Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up schedule. Each cycle is 28 days.
Refer to the acalabrutinib prescribing information for additional dosing information. Cycle 3 Day 1: start VENCLEXTA according to the 5-week ramp-up dosing schedule (see Table 1 ). After completing the ramp-up phase, continue VENCLEXTA at a dose of 400 mg orally once daily until disease progression, unacceptable toxicity, or until the last day of Cycle 14.
Refer to the obinutuzumab prescribing information for additional dosing information. In Combination with Rituximab Start rituximab administration after the patient has completed the 5-week ramp-up dosing schedule for VENCLEXTA (see Table 1 ) and has received VENCLEXTA at the recommended dosage of 400 mg orally once daily for 7 days. Refer to the rituximab prescribing information for additional dosing information.
Monotherapy The recommended dosage of VENCLEXTA is 400 mg once daily after completion of the 5-week ramp-up dosing schedule (see Table 1 ).
Recommended Dosage for Acute Myeloid Leukemia
The recommended dosage and ramp-up of VENCLEXTA depends upon the combination agent. Follow the dosing schedule, including the 3-day or 4-day dose ramp-up, as shown in Table 2. Table 2.
Dosing Schedule for 3- or 4-Day Ramp-up Phase in Patients with Continue VENCLEXTA, in combination with azacitidine or decitabine or low-dose cytarabine, until disease progression or unacceptable toxicity. Refer to Clinical Studies and Prescribing Information for azacitidine, decitabine, or cytarabine for additional dosing information.
Risk Assessment and Prophylaxis for Tumor Lysis Syndrome
Patients treated with VENCLEXTA may develop tumor lysis syndrome (TLS). Refer to the appropriate section below for specific details on management. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week ramp-up phase.
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. TLS can also occur upon resumption of VENCLEXTA following a dosage interruption. See Table 4, Table 5, and Table 6 for dose modifications of VENCLEXTA after interruption.
The risk of TLS is a continuum based on multiple factors, particularly reduced renal function (creatinine clearance <80 mL/min) and tumor burden; splenomegaly may also increase the risk of TLS. Perform tumor burden assessments, including radiographic evaluation (e.g., CT scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of treatment with VENCLEXTA. The risk may decrease as tumor burden decreases.
Table 3 below describes the recommended TLS prophylaxis and monitoring during VENCLEXTA treatment based on tumor burden determination from clinical trial data. Consider all patient comorbidities before final determination of prophylaxis and monitoring schedule. Reassess the risk of TLS when reinitiating VENCLEXTA after a dosage interruption lasting more than 1 week during the ramp-up phase, or more than 2 weeks after completion of ramp-up.
Institute prophylaxis and monitoring as needed. Table 3. Recommended TLS Acute Myeloid Leukemia All patients should have white blood cell count less than 25 × 10 9 /L prior to initiation of VENCLEXTA.
Cytoreduction prior to treatment may be required. Prior to first VENCLEXTA dose, provide all patients with prophylactic measures including adequate hydration and anti-hyperuricemic agents and continue during ramp-up phase. 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.
For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase levels, or reduced renal function), consider additional measures, including increased laboratory monitoring and reducing VENCLEXTA starting dose.
Dosage Modifications for Adverse Reactions Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma The recommended dose reductions for VENCLEXTA for adverse reactions are provided in Table 4. The recommended dosage modifications for VENCLEXTA for adverse reactions are provided in Table 5 and Table 6. For patients having a dosage interruption lasting more than 1 week during the ramp-up phase, or more than 2 weeks after completion of ramp-up, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule).
Table 4. Recommended Dose Reduction for a During the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. b If a dosage interruption lasts more than 1 week during the ramp-up phase or more than 2 weeks after completion of ramp-up, reassess the risk of TLS and determine if reinitiation at a reduced dosage is necessary. Table 5.
Recommended VENCLEXTA Dosage Modifications for Adverse Reactions a in Patients with CLL/SLL Receiving VENCLEXTA in Combination with Obinutuzumab, with Rituximab or as Monotherapy Adverse Reaction Occurrence Dosage Modification Tumor Lysis Syndrome Blood chemistry changes or symptoms suggestive of TLS Grade 3 or 4 non-hematologic toxicities Grade 3 neutropenia with infection or fever; or Grade 4 hematologic toxicities (except lymphopenia) 1 st occurrence Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. 2 nd and subsequent occurrences Interrupt VENCLEXTA. Consider discontinuing VENCLEXTA for patients who require dose reductions to less than 100 mg for more than 2 weeks. a Adverse reactions were graded using NCI CTCAE version 4.0. b Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures.
Table 6: Recommended Dosage Modifications for Adverse Reactions in Patients with CLL/SLL Receiving VENCLEXTA in Combination with Acalabrutinib Acute Myeloid Leukemia Monitor blood counts frequently through resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status. Dose modifications of VENCLEXTA for adverse reactions are provided in Table 7.
Table 7. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. a Recommend bone marrow evaluation.
Dosage Modifications for Drug Interactions Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors Table 8 describes VENCLEXTA contraindication or dosage modification based on concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor at initiation, during, or after the ramp-up phase. Resume the VENCLEXTA dosage that was used prior to concomitant use of a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. Table 8.
Management of Potential VENCLEXTA Interactions with CYP3A and P-gp Inhibitors s for Patients with Severe Hepatic Impairment Reduce the VENCLEXTA once daily dose by 50% for patients with severe hepatic impairment (Child-Pugh C); monitor these patients more closely for adverse reactions.
Administration
Instruct patients of the following: Take VENCLEXTA with a meal and water. Take VENCLEXTA at approximately the same time each day. The recommended dosage of VENCLEXTA may be delivered using any of the approved tablet strengths.
For patients who are unable to swallow a VENCLEXTA tablet whole, the tablets can be crushed. Mix the entire dose with 120 mL (4 ounces) of water, apple juice, apple sauce, or yogurt. Take the entire dose immediately with a meal and water.
Do not crush more than one dose at a time. If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, instruct the patient to take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 8 hours, instruct the patient not to take the missed dose and resume the usual dosing schedule the next day.
If the patient vomits following dosing, instruct the patient to not take an additional dose that day and to take the next prescribed dose at the usual time.
| VENCLEXTA Oral Daily Dose | |
| Week 1 | 20 mg |
| Week 2 | 50 mg |
| Week 3 | 100 mg |
| Week 4 | 200 mg |
| Week 5 and beyond | 400 mg |
| VENCLEXTA Oral Daily Dose | ||
| Day 1 | 100 mg | |
| Day 2 | 200 mg | |
| Day 3 | 400 mg | |
| Days 4 and beyond | 400 mg orally once daily of each 28-day cycle in combination with azacitidine or decitabine | 600 mg orally once daily of each 28-day cycle in combination with low-dose cytarabine |
| Tumor Burden | Prophylaxis | Blood Chemistry Monitoring c,d | ||
|---|---|---|---|---|
| Hydration a | Anti- hyperuricemics b | Setting and Frequency of Assessments | ||
| Low | All LN <5 cm AND ALC <25 x10 9 /L | Oral (1.5 to 2 L) | Allopurinol | Outpatient For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours For subsequent ramp-up doses: Pre-dose |
| Medium | Any LN 5 to <10 cm OR ALC ≥25 x10 9 /L | Oral (1.5 to 2 L) and consider additional intravenous | Allopurinol | Outpatient For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours For subsequent ramp-up doses: Pre-dose For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CLcr <80ml/min; see below for monitoring in hospital |
| High | Any LN ≥10 cm OR ALC ≥25 x10 9 /L AND any LN ≥5 cm | Oral (1.5 to 2 L) and intravenous (150 to 200 mL/hr as tolerated) | Allopurinol; consider rasburicase if baseline uric acid is elevated | In hospital For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12, and 24 hours Outpatient For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours |
| ALC = absolute lymphocyte count; CLcr = creatinine clearance; LN = lymph node. a Administer intravenous hydration for any patient who cannot tolerate oral hydration. b Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA. c Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. d For patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose. | ||||
| Dose at Interruption, mg | Restart Dose, mg a,b |
|---|---|
| 400 | 300 |
| 300 | 200 |
| 200 | 100 |
| 100 | 50 |
| 50 | 20 |
| 20 | 10 |
| a During the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. b If a dosage interruption lasts more than 1 week during the ramp-up phase or more than 2 weeks after completion of ramp-up, reassess the risk of TLS and determine if reinitiation at a reduced dosage is necessary [see Dosage and Administration ( 2.2, 2.4 )]. | |
| Adverse Reaction | Occurrence | Dosage Modification |
|---|---|---|
| Tumor Lysis Syndrome | ||
| Blood chemistry changes or symptoms suggestive of TLS [see Warnings and Precautions ( 5.1 )] | Any | Withhold the next day’s dose. If resolved within 24 to 48 hours of last dose, resume at same dose. |
| For any blood chemistry changes requiring more than 48 hours to resolve, resume at reduced dose (see Table 4 ). | ||
| For any events of clinical TLS, b resume at reduced dose following resolution (see Table 4 ). | ||
| Non-Hematologic Adverse Reactions | ||
| Grade 3 or 4 non-hematologic toxicities [see Adverse Reactions ( 6.1 )] | 1 st occurrence | Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. |
| 2 nd and subsequent occurrences | Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTA after resolution. A larger dose reduction may occur at the discretion of the physician. | |
| Hematologic Adverse Reactions | ||
| Grade 3 neutropenia with infection or fever; or Grade 4 hematologic toxicities (except lymphopenia) [see Warnings and Precautions ( 5.2 )] | 1 st occurrence | Interrupt VENCLEXTA. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. |
| 2 nd and subsequent occurrences | Interrupt VENCLEXTA. Follow dose reduction guidelines in Table 4 when resuming treatment with VENCLEXTA after resolution. A larger dose reduction may occur at the discretion of the physician. | |
| Consider discontinuing VENCLEXTA for patients who require dose reductions to less than 100 mg for more than 2 weeks. a Adverse reactions were graded using NCI CTCAE version 4.0. b Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures [see Adverse Reactions ( 6.1 )]. | ||
| Adverse Reaction a | Adverse Reaction Occurrence | Dose Modification |
|---|---|---|
| Grade 3 or 4 neutropenia with or without fever and/or infection; Grade 4 neutropenia lasting more than 7 days | First occurrence | Interrupt VENCLEXTA and/or acalabrutinib. b Once toxicity resolves to Grade ≤ 1 or baseline, restart VENCLEXTA and/or acalabrutinib at same dose. |
| Second occurrence | Interrupt VENCLEXTA and/or acalabrutinib. b Once toxicity resolves to Grade ≤ 1 or baseline, restart VENCLEXTA at one lower dose level and restart acalabrutinib at same dose. | |
| Subsequent occurrence | Withhold VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1 or baseline. b,c | |
| Grade 3 or 4 thrombocytopenia and/or bleeding e | First occurrence | Interrupt VENCLEXTA and/or acalabrutinib. When bleeding resolves and thrombocytopenia is Grade ≤ 1 or baseline without transfusion support for 5 consecutive days, restart VENCLEXTA and/or acalabrutinib at same dose. |
| Second occurrence | Interrupt VENCLEXTA and acalabrutinib until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart VENCLEXTA at one lower dose level and restart acalabrutinib at same dose. d | |
| Subsequent occurrences of severe thrombocytopenia | Interrupt VENCLEXTA and acalabrutinib until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart VENCLEXTA at one lower dose level and resume acalabrutinib at a reduced frequency of 100 mg once daily. c,d | |
| Grade 3 or 4 tumour lysis syndrome (TLS) | First and subsequent episodes | If a patient experiences blood chemistry changes suggestive of TLS, the following day’s VENCLEXTA and acalabrutinib dose should be withheld. If resolved within 24–48 hours of last dose, treatment can be resumed at the same dose. For events of clinical TLS or blood chemistry changes requiring more than 48 hours to resolve, resume VENCLEXTA at one lower dose level. When resuming treatment after interruption due to TLS, monitor for TLS and provide prophylaxis. |
| Grade 3 other non-hematologic events f | First occurrence | Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1. Restart VENCLEXTA and/or acalabrutinib at same dose. |
| Second occurrence | Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1 c. | |
| Grade 4 other non-hematologic events f | First occurrence | Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1. Restart VENCLEXTA at one lower dose level and restart acalabrutinib at a reduced frequency of 100 mg once daily. e |
| Second occurrence | Interrupt VENCLEXTA and/or acalabrutinib until toxicity resolves to Grade ≤ 1 c. | |
| a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Growth factor may be used at physician discretion. c Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with VENCLEXTA in combination with acalabrutinib. d Acalabrutinib dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. e Platelets may be used at physician discretion. f Certain treatment-emergent non-hematologic AEs (e.g., venous thromboembolic events) may be managed and become clinically stable following medical intervention but may not improve to Grade ≤ 1 according to the NCI CTCAE definitions. In such cases, if a subject is clinically stable, resumption of VENCLEXTA may be possible based on clinical judgement of the treating physician. | ||
| Adverse Reaction | Occurrence | Dosage Modification |
|---|---|---|
| Hematologic Adverse Reactions | ||
| Grade 4 neutropenia with or without fever or infection; or Grade 4 thrombocytopenia [see Warnings and Precautions ( 5.2 )] | Occurrence prior to achieving remission a | In most instances, do not interrupt VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine due to cytopenias prior to achieving remission. |
| First occurrence after achieving remission and lasting at least 7 days | Delay subsequent cycle of VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine and monitor blood counts. Upon resolution to Grade 1 or 2, resume VENCLEXTA at the same dose in combination with azacitidine, decitabine, or low-dose cytarabine. | |
| Subsequent occurrences in cycles after achieving remission and lasting 7 days or longer | Delay subsequent cycle of VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine and monitor blood counts. Upon resolution to Grade 1 or 2, resume VENCLEXTA at the same dose in combination with azacitidine, decitabine, or low-dose cytarabine, and reduce VENCLEXTA duration by 7 days during each of the subsequent cycles, such as 21 days instead of 28 days. | |
| Non-Hematologic Adverse Reactions | ||
| Grade 3 or 4 non-hematologic toxicities [see Adverse Reactions ( 6.1 )] | Any occurrence | Interrupt VENCLEXTA if not resolved with supportive care. Upon resolution to Grade 1 or baseline level, resume VENCLEXTA at the same dose. |
| a Recommend bone marrow evaluation. | ||
| Coadministered Drug | Initiation and Ramp-Up Phase | Steady Daily Dose (After Ramp-Up Phase) a | |
|---|---|---|---|
| Posaconazole | CLL/SLL | Contraindicated | Reduce VENCLEXTA dose to 70 mg. |
| AML | Day 1 – 10 mg Day 2 – 20 mg Day 3 – 50 mg Day 4 – 70 mg | ||
| Other strong CYP3A inhibitor | CLL/SLL | Contraindicated | Reduce VENCLEXTA dose to 100 mg. |
| AML | Day 1 – 10 mg Day 2 – 20 mg Day 3 – 50 mg Day 4 – 100 mg | ||
| Moderate CYP3A inhibitor | Reduce the VENCLEXTA dose by at least 50%. | ||
| P-gp inhibitor | |||
| a In patients with CLL/SLL, consider alternative medications or reduce the VENCLEXTA dose as described in Table 8. | |||
Side Effects of Venclexta
Clinical Trials Experience
Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. In CLL/SLL, the safety population reflects exposure to VENCLEXTA as monotherapy in patients in M13-982, M14-032, and M12-175 and in combination with obinutuzumab or rituximab in patients in CLL14 and MURANO. In this CLL/SLL safety population, the most common adverse reactions (≥20%) for VENCLEXTA were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.
In the CLL/SLL safety population that reflects exposure to VENCLEXTA in combination with acalabrutinib, the most common adverse reactions (≥20%) were neutropenia, headache, diarrhea, musculoskeletal pain, and COVID-19. In AML, the safety population reflects exposure to VENCLEXTA in combination with decitabine, azacitidine, or low-dose cytarabine in patients in M14-358, VIALE-A, and VIALE-C. In this safety population, the most common adverse reactions (≥30% in any trial) were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma VENCLEXTA in Combination with Acalabrutinib The safety of VENCLEXTA in combination with acalabrutinib (VEN+A) (N=291) versus fludarabine plus cyclophosphamide plus rituximab or bendamustine plus rituximab (FCR/BR) (N=259) was evaluated in AMPLIFY, a randomized, multicenter, open-label study in patients with previously untreated CLL. Among patients who received VEN+A, 96% were exposed for 6 months or longer and 91% were exposed for greater than one year. Serious adverse reactions were reported in 25% of patients receiving VEN+A.
Fatal adverse events occurred in 3.4% of patients. The most common fatal adverse events included COVID-19 and COVID-19 pneumonia. In the VEN+A arm, adverse reactions led to treatment discontinuation in 8% of patients.
Neutropenia led to discontinuation of VENCLEXTA in 0.3% of patients, dose reduction in 7%, and dose interruption in 21%. Table 10 presents adverse reactions identified in AMPLIFY. Table 10.
Adverse Reactions (≥15% Any Grade) in Patients with Previously Untreated CLL Who Received VEN+A in AMPLIFY Other clinically relevant adverse reactions reported in <15% of patients receiving VEN+A included upper respiratory tract infections, lower respiratory tract infection, arthralgia, pneumonia, hemorrhage, dizziness, constipation, vomiting, second primary malignancy and hypertension. Table 11 presents laboratory abnormalities in AMPLIFY. Table 11.
New or Worsening Clinically Important Laboratory Abnormalities (≥15% Any Grade) in Patients with Previously Untreated CLL Who Received VEN+A in AMPLIFY Grade 4 laboratory abnormalities that developed in ≥15% of patients treated with VEN+A include absolute neutrophil count decreased (15%). VENCLEXTA in Combination with Obinutuzumab The safety of VENCLEXTA in combination with obinutuzumab (VEN+G) (N=212) versus obinutuzumab in combination with chlorambucil (GClb) (N=214) was evaluated in CLL14, a randomized, open-label, actively controlled trial in patients with previously untreated CLL. Patients randomized to the VEN+G arm were treated with VENCLEXTA and obinutuzumab in combination for six cycles, then with VENCLEXTA as monotherapy for an additional six cycles.
The trial required a total Cumulative Illness Rating Scale (CIRS) >6 or CLcr <70 mL/min, hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system. Serious adverse reactions were reported in 49% of patients in the VEN+G arm, most often due to febrile neutropenia and pneumonia (5% each). Fatal adverse reactions that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.
In the VEN+G arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 21%, and dose interruption in 74%. Neutropenia led to discontinuation of VENCLEXTA in 2% of patients, dose reduction in 13%, and dose interruption in 41%. Table 12 presents adverse reactions identified in CLL Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+G are presented below: Blood and lymphatic system disorders: febrile neutropenia (6%) Infection and infestations (all include multiple adverse reaction terms): pneumonia (9%), urinary tract infection (6%), sepsis (4%) Metabolism and nutrition disorder: tumor lysis syndrome (1%) During treatment with VENCLEXTA monotherapy after completion of VEN+G, the adverse reaction that occurred in ≥10% of patients was neutropenia (26%).
Table 13 presents laboratory abnormalities CLL14. Table 13. VENCLEXTA in Combination with Rituximab The safety of VENCLEXTA in combination with rituximab (VEN+R) (N=194) versus bendamustine in combination with rituximab (B+R) (N=188) was evaluated in MURANO.
Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily, in combination with rituximab for 6 cycles followed by VENCLEXTA monotherapy, for a total of 24 months after ramp-up. At the time of analysis, the median duration of exposure to VENCLEXTA was 22 months and the median number of cycles of rituximab was 6 in the VEN+R arm. Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%).
In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. Neutropenia and thrombocytopenia each led to discontinuation of VENCLEXTA in 3% of patients. Table 14 presents adverse reactions identified in MURANO.
Table 14. Adverse Reactions (≥10%) in Patients Treated with VEN+R in MURANO Other clinically important adverse reactions (All Grades) reported in <10% of patients treated with VEN+R are presented below:: tumor lysis syndrome (3%) During treatment with VENCLEXTA monotherapy after completion of VEN+R combination treatment, adverse reactions that occurred in ≥10% of patients were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%). Table 15 presents laboratory abnormalities identified in MURANO.
Table 15. VENCLEXTA as Monotherapy The safety of VENCLEXTA was evaluated in pooled data from three single-arm trials (M13-982, M14-032, and M12-175). Patients received VENCLEXTA 400 mg orally once daily after completing the ramp-up phase (N=352).
The median duration of treatment with VENCLEXTA at the time of data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent of patients received VENCLEXTA for more than 60 weeks. The median number of prior therapies was 3 (range: 0 to 15).
Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the VENCLEXTA monotherapy studies, most often (2 patients) from septic shock. Adverse reactions led to treatment discontinuation in 9% of patients, dose reduction in 13%, and dose interruption in 36%. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia.
The most frequent adverse reaction (≥5%) leading to dose reductions or interruptions was neutropenia (8%). Table 16 presents adverse reactions identified in these trials. Table 16.
Adverse Reactions Reported in ≥10% (All Grades) or ≥5% (Grade ≥3) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy presents laboratory abnormalities reported throughout treatment that were new or worsening from baseline. Table 17. New or Worsening Laboratory Abnormalities in ≥40% (All Grades) or ≥10% (Grade 3 or 4) of Patients with Previously Treated CLL/SLL Who Received VENCLEXTA Monotherapy s in CLL/SLL Tumor Lysis Syndrome Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA.
CLL14 The incidence of TLS was 1% (3/212) in patients treated with VEN+G. All three events of TLS resolved and did not lead to withdrawal from the trial. Obinutuzumab administration was delayed in two cases in response to the TLS events.
MURANO The incidence of TLS was 3% (6/194) in patients treated with VEN+R. After 77/389 patients were enrolled in the trial, the protocol was amended to incorporate the current TLS prophylaxis and monitoring measures described in sections 2.2 and 2.4. All events of TLS occurred during the VENCLEXTA ramp-up period and were resolved within two days.
All six patients completed the ramp-up and reached the recommended daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in patients who followed the current 5-week ramp-up schedule and TLS prophylaxis and monitoring measures. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 14.
All events resolved within 5 days. No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures was observed in these patients. All patients had CLcr ≥50 mL/min.
After this experience, TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised. Acute Myeloid Leukemia VENCLEXTA in Combination with Azacitidine The safety of VENCLEXTA in combination with azacitidine (VEN+AZA) (N=283) versus placebo in combination with azacitidine (PBO+AZA) (N=144) was evaluated in VIALE-A, a double-blind, randomized trial, in patients with newly diagnosed AML. At baseline, patients were ≥75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity.
Patients were randomized to receive VENCLEXTA 400 mg orally once daily after completion of the ramp-up phase in combination with azacitidine (75 mg/m 2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle) or placebo in combination with azacitidine. Among patients who received VEN+AZA, the median duration of exposure to VENCLEXTA was 7.6 months (range: <0.1 to 30.7 months). Adverse reactions led to permanent discontinuation of VENCLEXTA in 24% of patients, dose reductions in 2%, and dose interruptions in 72%.
Adverse reactions which led to discontinuation of VENCLEXTA in ≥2% of patients were sepsis (excluding fungal; 3%) and pneumonia (2%). The most frequent adverse reaction leading to dose reduction was pneumonia (0.7%). Among patients who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for absolute neutrophil count (ANC) <500/microliter.
Table 18 presents adverse reactions identified in VIALE-A. Table 18. 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 in VIALE-A Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 18 or <10% are presented below: Hepatobiliary disorders: cholecystitis/cholelithiasis a (4%) %. a Includes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis chronic. b Includes pneumonia, lung infection, pneumonia fungal, pneumonia klebsiella, atypical pneumonia, lower respiratory tract infection, pneumonia viral, lower respiratory tract infection fungal, pneumonia hemophilus, pneumonia pneumococcal, and pneumonia respiratory syncytial viral. c Includes headache and tension headache.
Table 19 presents laboratory abnormalities identified in VIALE-A. Table 19. New or Worsening Laboratory Abnormalities (≥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 in VIALE-A VENCLEXTA in Combination with Azacitidine or Decitabine The safety of VENCLEXTA in combination with azacitidine (N=67) or decitabine (N=13) was evaluated in M14-358, a non-randomized trial of patients with newly diagnosed AML.
Azacitidine The median duration of exposure to VENCLEXTA when administered in combination with azacitidine was 6.5 months (range: 0.1 to 38.1 months). The safety of VENCLEXTA in combination with azacitidine in this trial is consistent with that of VIALE-A. Decitabine The median duration of exposure to VENCLEXTA when administered in combination with decitabine was 8.4 months (range: 0.5 to 39 months).
One (8%) fatal adverse reaction of bacteremia occurred within 30 days of starting treatment. Permanent discontinuation of VENCLEXTA due to adverse reactions occurred in 38% of patients. The most frequent adverse reaction leading to permanent discontinuation (≥5%) was pneumonia (8%).
Dosage reductions of VENCLEXTA due to adverse reactions occurred in 15% of patients. The most frequent adverse reaction leading to dose reduction (≥5%) was neutropenia (15%). Dosage interruptions of VENCLEXTA due to adverse reactions occurred in 69% of patients.
The most frequent adverse reactions leading to dose interruption (≥ %). VENCLEXTA in Combination with Low-Dose Cytarabine VIALE-C The safety of VENCLEXTA in combination with low-dose cytarabine (VEN+LDAC) (N=142) versus placebo with low-dose cytarabine (PBO+LDAC) (N=68) was evaluated in VIALE-C, a double-blind randomized trial in patients with newly diagnosed AML. Patients were randomized to receive VENCLEXTA 600 mg orally once daily after completion of a 4-day ramp-up phase in combination with low-dose cytarabine (20 mg/m 2 subcutaneously once daily on Days 1-10 of each 28-day cycle) or placebo in combination with low-dose cytarabine.
Among patients who received VEN+LDAC, the median duration of exposure to VENCLEXTA was 3.9 months (range: <0.1 to 17.1 months). Adverse reactions led to permanent discontinuation of VENCLEXTA in 25% of patients, dose reductions in 9%, and dose interruptions in 63%. The most frequent adverse reaction (>2%) which resulted in permanent discontinuation of VENCLEXTA was pneumonia (6%).
Table 20 presents adverse reactions identified in VIALE-C. Table 20. Adverse Reactions (≥10%) in Patients with AML Who Received VEN+LDAC with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Compared with PBO+LDAC in VIALE-C Other clinically important adverse reactions (All Grades) at ≥10% that did not meet criteria for Table 20 or <10% are presented below: Hepatobiliary disorders: cholecystitis/cholelithiasis a (1%) % Investigations: weight decreased (9%). a Includes cholecystitis and cholecystitis acute. b Includes sepsis, bacteremia, septic shock, neutropenic sepsis, staphylococcal bacteremia, streptococcal bacteremia, bacterial sepsis, Escherichia bacteremia, pseudomonal bacteremia, and staphylococcal sepsis. c Includes urinary tract infection and escherichia urinary tract infection. d Includes dizziness and vertigo. e Includes dyspnea and dyspnea exertional.
Table 21 describes laboratory abnormalities identified in VIALE-C. Table 21. New or Worsening Laboratory Abnormalities (≥10%) in Patients with AML Who Received VEN+LDAC with Difference Between Arms of ≥5% for All Grades or ≥2% for Grade 3 or 4 Reactions Compared with PBO+LDAC in VIALE-C The safety of VENCLEXTA in combination with low-dose cytarabine (N=61) was evaluated in M14-387, a non-randomized, open- label trial of patients with newly diagnosed AML.
The safety of VENCLEXTA in combination with low-dose cytarabine is consistent with that of VIALE-C.
| Body System Adverse Reactions* | VENCLEXTA plus acalabrutinib (N = 291) | Investigator’s choice of FCR or BR (N = 259) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Nervous system disorders | ||||
| Headache | 35 | 1.4 | 8 | 0.4 |
| Gastrointestinal disorders | ||||
| Diarrhea | 33 | 1.7 | 11 | 0.4 |
| Nausea | 15 | 0 | 36 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain a | 25 | 0.7 | 14 | 0.8 |
| Infections | ||||
| COVID-19 | 21 | 6 | 3.9 | 1.5 |
| General disorders | ||||
| Fatigue b | 18 | 0.3 | 17 | 1.5 |
| Skin and subcutaneous tissue disorders | ||||
| Bruising c | 17 | 0 | 1.5 | 0 |
| Rash d | 16 | 1 | 16 | 1.5 |
| *Excludes laboratory terms. a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain, non-cardiac chest pain and pain in jaw. b Includes fatigue and asthenia. c Includes increased tendency to bruise, contusion, and ecchymosis. d Includes rash, dermatitis, and other related terms. | ||||
| Laboratory Abnormality | VENCLEXTA plus acalabrutinib a | Investigator’s choice of FCR or BR a | ||
|---|---|---|---|---|
| All grade (%) | Grade 3 or 4 (%) | All grade (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Neutropenia | 78 | 38 | 80 | 53 |
| Lymphopenia | 56 | 12 | 92 | 73 |
| Thrombocytopenia | 43 | 5 | 59 | 15 |
| Anemia | 35 | 7 | 56 | 8 |
| Chemistry | ||||
| Glucose increased | 74 | 0 | 84 | 0 |
| Calcium decreased | 30 | 0.7 | 25 | 2.3 |
| ALT increased | 26 | 3.1 | 28 | 1.6 |
| Urate increased | 25 | 25 | 23 | 23 |
| LDH increased | 24 | 0 | 40 | 0 |
| Potassium increased | 22 | 2.4 | 12 | 3.1 |
| AST increased | 22 | 1.4 | 28 | 1.6 |
| ALP increased | 20 | 0 | 15 | 0 |
| Glucose decreased | 20 | 0.3 | 5 | 0 |
| Creatinine increased | 19 | 0.3 | 12 | 0.8 |
| Sodium increased | 15 | 0.3 | 9 | 0.4 |
| a The denominator used to calculate the rate varied between 256 and 290 based on the number of patients with a baseline value and at least one post-treatment value. | ||||
| Adverse Reaction | VENCLEXTA + Obinutuzumab (N = 212) | Obinutuzumab + Chlorambucil (N = 214) | ||
|---|---|---|---|---|
| All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥3 (%) | |
| Blood and lymphatic system disorders | ||||
| Neutropenia a | 60 | 56 | 62 | 52 |
| Anemia a | 17 | 8 | 20 | 7 |
| Gastrointestinal disorders | ||||
| Diarrhea | 28 | 4 | 15 | 1 |
| Nausea | 19 | 0 | 22 | 1 |
| Constipation | 13 | 0 | 9 | 0 |
| Vomiting | 10 | 1 | 8 | 1 |
| General disorders and administration site conditions | ||||
| Fatigue a | 21 | 2 | 23 | 1 |
| Infections and infestations | ||||
| Upper respiratory tract infection a | 17 | 1 | 17 | 1 |
| a Includes multiple adverse reaction terms. | ||||
| Laboratory Abnormality a | VENCLEXTA + Obinutuzumab (N = 212) | Obinutuzumab + Chlorambucil (N = 214) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Leukopenia | 90 | 46 | 89 | 41 |
| Lymphopenia | 87 | 57 | 87 | 51 |
| Neutropenia | 83 | 63 | 79 | 56 |
| Thrombocytopenia | 68 | 28 | 71 | 26 |
| Anemia | 53 | 15 | 46 | 11 |
| Chemistry | ||||
| Blood creatinine increased | 80 | 6 | 74 | 2 |
| Hypocalcemia | 67 | 9 | 58 | 4 |
| Hyperkalemia | 41 | 4 | 35 | 3 |
| Hyperuricemia | 38 | 38 | 38 | 38 |
| a Includes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown. | ||||
| Adverse Reaction | VENCLEXTA + Rituximab (N = 194) | Bendamustine + Rituximab (N = 188) | ||
|---|---|---|---|---|
| All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥3 (%) | |
| Blood and lymphatic system disorders | ||||
| Neutropenia a | 65 | 62 | 50 | 44 |
| Anemia a | 16 | 11 | 23 | 14 |
| Gastrointestinal disorders | ||||
| Diarrhea | 40 | 3 | 17 | 1 |
| Nausea | 21 | 1 | 34 | 1 |
| Constipation | 14 | <1 | 21 | 0 |
| Infections and infestations | ||||
| Upper respiratory tract infection a | 39 | 2 | 23 | 2 |
| Lower respiratory tract infection a | 18 | 2 | 10 | 2 |
| Pneumonia a | 10 | 7 | 14 | 10 |
| General disorders and administration site conditions | ||||
| Fatigue a | 22 | 2 | 26 | <1 |
| a Includes multiple adverse reaction terms. | ||||
| Laboratory Abnormality | VENCLEXTA + Rituximab (N = 194) | Bendamustine + Rituximab (N = 188) | ||
|---|---|---|---|---|
| All Grades a (%) | Grade 3 or 4 (%) | All Grades a (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Leukopenia | 89 | 46 | 81 | 35 |
| Lymphopenia | 87 | 56 | 79 | 55 |
| Neutropenia | 86 | 64 | 84 | 59 |
| Anemia | 50 | 12 | 63 | 15 |
| Thrombocytopenia | 49 | 15 | 60 | 20 |
| Chemistry | ||||
| Blood creatinine increased | 77 | <1 | 78 | 1 |
| Hypocalcemia | 62 | 5 | 51 | 2 |
| Hyperuricemia | 36 | 36 | 33 | 33 |
| Hyperkalemia | 24 | 3 | 19 | 2 |
| a Includes laboratory abnormalities that were new or worsening, or with worsening from baseline unknown. | ||||
| Adverse Reaction | VENCLEXTA (N = 352) | |
|---|---|---|
| All Grades (%) | Grade ≥3 (%) | |
| Blood and lymphatic system disorders | ||
| Neutropenia a | 50 | 45 |
| Anemia a | 33 | 18 |
| Thrombocytopenia a | 29 | 20 |
| Lymphopenia a | 11 | 7 |
| Febrile neutropenia | 6 | 6 |
| Gastrointestinal disorders | ||
| Diarrhea | 43 | 3 |
| Nausea | 42 | 1 |
| Abdominal pain a | 18 | 3 |
| Vomiting | 16 | 1 |
| Constipation | 16 | <1 |
| Mucositis a | 13 | <1 |
| Infections and infestations | ||
| Upper respiratory tract infection a | 36 | 1 |
| Pneumonia a | 14 | 8 |
| Lower respiratory tract infection a | 11 | 2 |
| General disorders and administration site conditions | ||
| Fatigue a | 32 | 4 |
| Edema a | 22 | 2 |
| Pyrexia | 18 | <1 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain a | 29 | 2 |
| Arthralgia | 12 | <1 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Cough a | 22 | 0 |
| Dyspnea a | 13 | 1 |
| Nervous system disorders | ||
| Headache | 18 | <1 |
| Dizziness a | 14 | 0 |
| Skin and subcutaneous tissue disorders | ||
| Rash a | 18 | <1 |
| Adverse reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. a Includes multiple adverse reaction terms. | ||
| Laboratory Abnormality | VENCLEXTA (N = 352) | |
|---|---|---|
| All Grades a (%) | Grade 3 or 4 (%) | |
| Hematology | ||
| Leukopenia | 89 | 42 |
| Neutropenia | 87 | 63 |
| Lymphopenia | 74 | 40 |
| Anemia | 71 | 26 |
| Thrombocytopenia | 64 | 31 |
| Chemistry | ||
| Hypocalcemia | 87 | 12 |
| Hyperglycemia | 67 | 7 |
| Hyperkalemia | 59 | 5 |
| AST increased | 53 | 3 |
| Hypoalbuminemia | 49 | 2 |
| Hypophosphatemia | 45 | 11 |
| Hyponatremia | 40 | 9 |
| a Includes laboratory abnormalities that were new or worsening, or worsening from baseline unknown. | ||
| Adverse Reaction | VENCLEXTA + Azacitidine (N = 283) | Placebo + Azacitidine (N = 144) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Gastrointestinal disorders | ||||
| Nausea | 44 | 2 | 35 | <1 |
| Diarrhea a | 43 | 5 | 33 | 3 |
| Vomiting b | 30 | 2 | 23 | <1 |
| Stomatitis c | 18 | 1 | 13 | 0 |
| Abdominal pain d | 18 | <1 | 13 | 0 |
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 42 | 42 | 19 | 19 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain e | 36 | 2 | 28 | 1 |
| General disorders and administration site conditions | ||||
| Fatigue f | 31 | 6 | 23 | 2 |
| Edema g | 27 | <1 | 19 | 0 |
| Vascular disorders | ||||
| Hemorrhage h | 27 | 7 | 24 | 3 |
| Hypotension i | 12 | 5 | 8 | 3 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite j | 25 | 4 | 17 | <1 |
| Skin and subcutaneous tissue disorders | ||||
| Rash k | 25 | 1 | 15 | 0 |
| Infections and infestations | ||||
| Sepsis l (excluding fungal) | 22 | 22 | 16 | 14 |
| Urinary tract infection m | 16 | 6 | 9 | 6 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Dyspnea n | 18 | 4 | 10 | 2 |
| Nervous system disorders | ||||
| Dizziness o | 17 | <1 | 8 | <1 |
| a Includes diarrhea and colitis. b Includes vomiting and hematemesis. c Includes stomatitis, mouth ulceration, mucosal inflammation, cheilitis, aphthous ulcer, glossitis, and tongue ulceration. d Includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. e Includes arthralgia, back pain, pain in extremity, musculoskeletal pain, bone pain, myalgia, neck pain, non-cardiac chest pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, spinal pain, and musculoskeletal discomfort. f Includes fatigue and asthenia. g Includes edema peripheral, edema, generalized edema, eyelid edema, face edema, penile edema, periorbital edema, and swelling. h Includes epistaxis, hematuria, conjunctival hemorrhage, hemoptysis, hemorrhoidal hemorrhage, gingival bleeding, mouth hemorrhage, hemorrhage intracranial, vaginal hemorrhage, cerebral hemorrhage, gastrointestinal hemorrhage, muscle hemorrhage, skin hemorrhage, upper gastrointestinal hemorrhage, anal hemorrhage, eye hemorrhage, gastritis hemorrhagic, hemorrhage, hemorrhage urinary tract, hemorrhagic diathesis, hemorrhagic stroke, hemorrhagic vasculitis, lower gastrointestinal hemorrhage, mucosal hemorrhage, penile hemorrhage, post procedural hemorrhage, rectal hemorrhage, retinal hemorrhage, shock hemorrhagic, soft tissue hemorrhage, subdural hemorrhage, tongue hemorrhage, urethral hemorrhage, vessel puncture site hemorrhage, vitreous hemorrhage, and wound hemorrhage. i Includes hypotension and orthostatic hypotension. j Includes decreased appetite and hypophagia. k Includes rash, rash maculo-papular, rash macular, drug eruption, rash papular, rash pustular, eczema, rash erythematous, rash pruritic, dermatitis acneiform, rash morbilliform, dermatitis, eczema asteatotic, exfoliative rash, and perivascular dermatitis. l Includes sepsis, escherichia bacteremia, escherichia sepsis, septic shock, bacteremia, staphylococcal bacteremia, klebsiella bacteremia, staphylococcal sepsis, streptococcal bacteremia, enterococcal bacteremia, klebsiella sepsis, pseudomonal bacteremia, pseudomonal sepsis, urosepsis, bacterial sepsis, clostridial sepsis, enterococcal sepsis, neutropenic sepsis, and streptococcal sepsis. m Includes urinary tract infection, escherichia urinary tract infection, cystitis, urinary tract infection enterococcal, urinary tract infection bacterial, pyelonephritis acute, and urinary tract infection pseudomonal. n Includes dyspnea, dyspnea exertional, and dyspnea at rest. o Includes dizziness and vertigo. | ||||
| Laboratory Abnormality | VENCLEXTA + Azacitidine | Placebo + Azacitidine | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Neutrophils decreased | 98 | 98 | 88 | 81 |
| Platelet decreased | 94 | 88 | 94 | 80 |
| Lymphocytes decreased | 91 | 71 | 72 | 39 |
| Hemoglobin decreased | 61 | 57 | 56 | 52 |
| Chemistry | ||||
| Bilirubin increased | 53 | 7 | 40 | 4 |
| Calcium decreased | 51 | 6 | 39 | 9 |
| Sodium decreased | 46 | 14 | 47 | 8 |
| Alkaline phosphatase increased | 42 | 1 | 29 | <1 |
| Blood bicarbonate decreased | 31 | <1 | 25 | 0 |
| The denominator used to calculate the rate varied from 85 to 144 in the PBO+AZA arm and from 125 to 283 in the VEN+AZA arm based on the number of patients with at least one post-treatment value. | ||||
| Adverse Reaction | VENCLEXTA + Low-Dose Cytarabine (N = 142) | Placebo + Low-Dose Cytarabine (N = 68) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Gastrointestinal disorders | ||||
| Nausea | 42 | 1 | 31 | 0 |
| Diarrhea | 28 | 3 | 16 | 0 |
| Vomiting | 25 | <1 | 13 | 0 |
| Abdominal pain a | 15 | <1 | 9 | 3 |
| Stomatitis b | 15 | 1 | 6 | 0 |
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 32 | 32 | 29 | 29 |
| Infections and infestations | ||||
| Pneumonia c | 29 | 19 | 21 | 21 |
| Vascular Disorders | ||||
| Hemorrhage d | 27 | 8 | 16 | 1 |
| Hypotension e | 11 | 5 | 4 | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain f | 23 | 3 | 18 | 0 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue g | 22 | 2 | 21 | 0 |
| Nervous System Disorders | ||||
| Headache | 11 | 0 | 6 | 0 |
| a Includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. b Includes stomatitis, mouth ulceration, aphthous ulcer, glossitis, mucosal inflammation, and tongue ulceration. c Includes pneumonia, lung infection, lower respiratory tract infection, pneumonia fungal, lower respiratory tract infection fungal, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia cytomegaloviral, and pneumonia pseudomonal. d Includes epistaxis, conjunctival hemorrhage, hemoptysis, gastrointestinal hemorrhage, gingival bleeding, mouth hemorrhage, upper gastrointestinal hemorrhage, hematuria, retinal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, gastric hemorrhage, gastritis hemorrhagic, hemorrhage intracranial, hemorrhage subcutaneous, lip hemorrhage, mucosal hemorrhage, pharyngeal hemorrhage, post procedural hemorrhage, pulmonary alveolar hemorrhage, pulmonary hemorrhage, tooth pulp hemorrhage, uterine hemorrhage, and vascular access site hemorrhage. e Includes hypotension and orthostatic hypotension. f Includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, arthritis, bone pain, musculoskeletal chest pain, and spinal pain. g Includes fatigue and asthenia. | ||||
| Laboratory Abnormality | VENCLEXTA + Low-Dose Cytarabine | Placebo + Low-Dose Cytarabine | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Platelets decreased | 97 | 95 | 92 | 90 |
| Neutrophils decreased | 95 | 92 | 82 | 71 |
| Lymphocytes decreased | 92 | 69 | 65 | 24 |
| Hemoglobin decreased | 63 | 57 | 57 | 54 |
| Chemistry | ||||
| Bilirubin increased | 61 | 7 | 38 | 7 |
| Albumin decreased | 61 | 6 | 43 | 4 |
| Potassium decreased | 56 | 16 | 42 | 14 |
| Calcium decreased | 53 | 8 | 45 | 13 |
| Glucose increased | 52 | 13 | 59 | 9 |
| AST increased | 36 | 6 | 37 | 1 |
| Alkaline phosphatase increased | 34 | 1 | 26 | 1 |
| ALT increased | 30 | 4 | 26 | 1 |
| Sodium increased | 11 | 3 | 6 | 1 |
| The denominator used to calculate the rate varied from 38 to 68 in the PBO+LDAC arm and from 65 to 142 in the VEN+LDAC arm based on the number of patients with at least one post-treatment value. | ||||
Warnings & Cautions for Venclexta
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, and during reinitiation after dosage interruption in patients with CLL/SLL. 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.
TLS, including fatal cases, has been reported after a single 20 mg dose of VENCLEXTA. In patients with CLL/SLL who followed the current (5-week) dose ramp-up and the TLS prophylaxis and monitoring measures, the rate of TLS was 2% in the VENCLEXTA CLL/SLL monotherapy trials. The rate of TLS remained consistent with VENCLEXTA in combination with obinutuzumab or rituximab.
With a 2- to 3-week dose ramp-up and higher starting dose in patients with CLL/SLL, the TLS rate was 13% and included deaths and renal failure. 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 (VIALE-A). 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 (VIALE-C).
The risk of TLS is a continuum based on multiple factors, particularly reduced renal function, tumor burden, and type of malignancy. Splenomegaly may also increase the risk of TLS in patients with CLL/SLL. 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 (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. Interrupt dosing if needed; when restarting VENCLEXTA, follow dose modification guidance.
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 of VENCLEXTA. For patients with CLL/SLL, coadministration of VENCLEXTA with strong CYP3A inhibitors at initiation and during the 5-week ramp-up phase is contraindicated. For patients with AML, reduce the dose of VENCLEXTA when coadministered with strong CYP3A inhibitors at initiation and during the 3- or 4-day ramp-up phase.
Febrile neutropenia occurred in 4% to 6% of patients treated with VENCLEXTA in monotherapy studies and in combination studies with obinutuzumab or rituximab. Febrile neutropenia occurred in 2% of patients treated with VENCLEXTA in combination with acalabrutinib. In patients with AML, baseline neutrophil counts worsened in 95% to 100% of patients treated with VENCLEXTA in combination with azacitidine, decitabine, or low-dose cytarabine.
Neutropenia can recur with subsequent cycles. Monitor complete blood counts throughout the treatment period. For interruption and dose resumption of VENCLEXTA for severe neutropenia, see Table 5 and Table 6 for CLL and Table 7 for AML.
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.
In AMPLIFY, a randomized study in patients with previously untreated CLL/SLL, serious or grade 3 or higher infections occurred in 14% of patients who received VENCLEXTA in combination with acalabrutinib (VEN+A), most commonly due to COVID-19. In an additional cohort of patients receiving VENCLEXTA in combination with acalabrutinib and obinutuzumab (AVO) (an unapproved regimen for previously untreated CLL/SLL in AMPLIFY), serious or Grade 3 or higher infections occurred in 25% receiving AVO compared to 14% in patients receiving VEN+A. Fatal infections occurred in 6% receiving AVO compared to 3.1% of patients receiving VEN+A, most commonly due to COVID-19.
The safety and effectiveness of AVO has not been established in patients with previously untreated CLL/SLL.
Immunization
Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise patients that vaccinations may be less effective.
Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, administration of venetoclax to pregnant animals at exposures equivalent to that observed in patients at a dose of 400 mg daily resulted in post-implantation loss and decreased fetal weight. Advise pregnant women of the potential risk to a fetus.
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.
Drug Interactions with Venclexta
Effects of Other Drugs on VENCLEXTA Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp inhibitor increases venetoclax C max and AUC 0-INF, which may increase VENCLEXTA toxicities, including the risk of TLS. Concomitant use with a strong CYP3A inhibitor at initiation and during the ramp-up phase in patients with CLL/SLL is contraindicated. In patients with CLL/SLL taking a steady daily dosage (after ramp-up phase), 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 with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A. Strong or Moderate CYP3A Inducers Concomitant use with a strong CYP3A inducer decreases venetoclax C max and AUC 0-INF, which may decrease VENCLEXTA efficacy.
Avoid concomitant use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A inducers.
Effect of VENCLEXTA on Other Drugs Warfarin
Concomitant use of VENCLEXTA increases warfarin C max and AUC 0-INF, which may increase the risk of bleeding. Monitor international normalized ratio (INR) more frequently in patients using warfarin concomitantly with VENCLEXTA. P-gp Substrates Concomitant use of VENCLEXTA increases C max and AUC 0-INF of P-gp substrates, which may increase toxicities of these substrates.
Avoid concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before VENCLEXTA.
Pregnancy Safety for Venclexta
Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VENCLEXTA use in pregnant women to inform a drug-associated risk. Administration of venetoclax to pregnant mice during the period of organogenesis was fetotoxic at exposures 1.2 times the human exposure at the recommended dose of 400 mg daily based on AUC.
Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal data In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human exposure at the recommended dose of 400 mg once daily).
No teratogenicity was observed in either the mouse or the rabbit.
Pediatric Use of Venclexta
Pediatric Use The safety and effectiveness of VENCLEXTA have not been established in pediatric patients. Clinical signs of toxicity included decreased activity, dehydration, skin pallor, and hunched posture at ≥30 mg/kg/day. In addition, mortality and body weight effects occurred at 100 mg/kg/day.
Contraindications for Venclexta
Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during the ramp-up phase is contraindicated in patients with CLL/SLL due to the potential for increased risk of tumor lysis syndrome.
Overdosage Information for Venclexta
There is no specific antidote for VENCLEXTA. For patients who experience overdose, closely monitor and provide appropriate supportive treatment; during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs and symptoms of TLS along with other toxicities. Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.
Clinical Studies of Venclexta
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma In Combination with Acalabrutinib AMPLIFY (ACE-CL-311) was a randomized, multi-center, open-label study (NCT03836261) that evaluated the efficacy and safety of VENCLEXTA in combination with acalabrutinib (VEN+A). The study included patients previously untreated for CLL without del(17p) or TP53 mutation that were 18 years of age and older. Patients were randomized to receive: VENCLEXTA plus acalabrutinib (VEN+A): Acalabrutinib 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles or until disease progression or unacceptable toxicity.
VENCLEXTA was administered for a total of 12 cycles. Each cycle was 28 days. An additional investigational combination regimen.
Patients were stratified by age (>65 years or ≤65), IgVH mutational status (mutated versus unmutated), Rai stage (high risk versus non-high risk) and geographic region (North America and Europe versus other). The major efficacy outcome was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) of the VEN+A arm versus the Investigator’s choice (FCR/BR) arm. The median duration of follow-up for PFS was 42.6 months (range: 1 to 59 months) in the VEN+A arm.
Efficacy results are presented in Table 22. The Kaplan-Meier curve for IRC-assessed PFS is shown in Figure 1. Table 22.
Efficacy Results in AMPLIFY – ITT Population Figure 1. Kaplan-Meier Curve of IRC-Assessed Progression-free Survival in AMPLIFY With a median follow-up of 41.0 months, a total of 60 death events were reported with 18 in the VEN+A arm and 42 in the FCR/BR arm. In Combination with Obinutuzumab CLL14 (BO25323) was a randomized (1:1), multicenter, open-label, actively controlled trial (NCT02242942) that evaluated the efficacy and safety of VENCLEXTA in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) for patients with previously untreated CLL with coexisting medical conditions (total Cumulative Illness Rating Scale score >6 or CLcr <70 mL/min).
The trial required hepatic transaminases and total bilirubin ≤2 times upper limit of normal and excluded patients with Richter’s transformation or any individual organ/system impairment score of 4 by CIRS except eye, ear, nose, and throat organ system. A total of 432 patients were randomized, 216 to each arm. Baseline demographic and disease characteristics were similar between the arms.
The median duration of follow-up for PFS was 28 months (range: 0 to 36 months). Efficacy results for CLL14 are shown in Table 23. Table Figure 2.
Kaplan-Meier Curve of IRC-Assessed Progression-free Survival in CLL14 At the time of analysis, median overall survival (OS) had not been reached, with fewer than 10% of patients experiencing an event. Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The definition of negative status was less than one CLL cell per 10 4 leukocytes.
Rates of MRD negativity 3 months after the completion of treatment regardless of response and in patients who achieved CR are shown in Table 24. At this assessment, 134 patients in the VEN+G arm who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 122 patients (91%) were MRD negative in both peripheral blood and bone marrow. Table 24.
Minimal Residual Disease Negativity Rates Three Months After the Completion of Treatment in CLL14 Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 58% (126/216) in patients treated with VEN+G and 9% (20/216) in patients treated with GClb. In Combination with Rituximab MURANO was a randomized (1:1), multicenter, open-label trial (NCT02005471) that evaluated the efficacy and safety of VENCLEXTA in combination with rituximab (VEN+R) versus bendamustine in combination with rituximab (B+R) in patients with CLL who had received at least one line of prior therapy. Patients in the VEN+R arm completed the VENCLEXTA 5-week ramp-up dosing schedule and received VENCLEXTA 400 mg orally once daily for 24 months from Cycle 1 Day 1 of rituximab in the absence of disease progression or unacceptable toxicity.
A total of 389 patients were randomized: 194 to the VEN+R arm and 195 to the B+R arm. The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months). Efficacy results for MURANO are shown in Table 25.
Table 25. IRC-Assessed Efficacy Results in MURANO Figure 3. Median OS had not been reached in either arm.
The Kaplan-Meier curve for OS is shown in Figure 4. Figure 4. Kaplan-Meier Curve of Overall Survival in MURANO Monotherapy The efficacy of VENCLEXTA monotherapy in previously treated CLL or SLL is based on three single-arm trials.
M13-982 M13-982 (NCT01889186) was an open-label, multicenter trial that enrolled 106 patients with CLL with 17p deletion who had received at least one prior therapy. In the trial, 17p deletion was confirmed in peripheral blood specimens from patients using Vysis CLL FISH Probe Kit, which is FDA approved for selection of patients for VENCLEXTA treatment. Patients received VENCLEXTA 400 mg orally once daily following completion of the ramp-up dosing schedule.
Efficacy was based on overall response rate (ORR) as assessed by an IRC. Table 26 summarizes the baseline demographic and disease characteristics of the trial population. Table The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months).
Efficacy results are shown in Table 27. Table 27. Efficacy Results per IRC for Patients with Previously Treated CLL with 17p Deletion in M The median time to first response was 0.8 months (range: 0.1 to 8.1 months).
Based on a later data cutoff date and investigator-assessed efficacy, the duration of response (DOR) ranged from 2.9 to 32.8+ months. The median DOR has not been reached with median follow-up of 22 months. Minimal residual disease was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with VENCLEXTA.
Three percent (3/106) achieved MRD negativity in the peripheral blood and bone marrow (less than one CLL cell per 10 4 leukocytes). M12-175 M12-175 (NCT01328626) was an open-label, multicenter trial that enrolled previously treated patients with CLL or SLL, including those with 17p deletion. Patients continued this dose until disease progression or unacceptable toxicity.
The median duration of treatment at the time of evaluation was 22.1 months (range: 0.5 to 71.7 months). The median number of prior treatments was 3 (range: 1 to 11). Efficacy was based on 2008 IWCLL guidelines and assessed by an IRC.
The.2 months (range: 2.4 to 52.4 months). M14-032 M14-032 (NCT02141282) was an open-label, multicenter trial that enrolled patients with CLL who had been previously treated with and progressed on or after ibrutinib or idelalisib. At the time of analysis, the median duration of treatment was 19.5 months (range: 0.1 to 39.5 months).
The median number of prior treatments was 4 (range: 1 to 15). The ORR was with a CR + CRi rate of 5% and PR rate of 65%. The median DOR was not reached with a median follow-up time of 19.9 months (range: 2.9 to 36 months).
Acute Myeloid Leukemia VENCLEXTA was studied in adult patients with newly diagnosed AML who were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr <45 mL/min, or other comorbidity. In Combination with Azacitidine or Decitabine VIALE-A was a randomized (2:1), double-blind, placebo-controlled, multicenter trial (NCT02993523) that evaluated the efficacy and safety of VENCLEXTA in combination with azacitidine (VEN+AZA) versus placebo with azacitidine (PBO+AZA). During the ramp-up, patients received TLS prophylaxis and were hospitalized for monitoring.
For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated. Azacitidine was resumed on the same day as VENCLEXTA or placebo following interruption. Azacitidine dose reduction was implemented in the clinical trial for management of hematologic toxicity.
Patients continued treatment until disease progression or unacceptable toxicity. A total of 431 patients were randomized: 286 to the VEN+AZA arm and 145 to the PBO+AZA arm. The baseline demographic and disease characteristic are shown in Table Efficacy was based on overall survival (OS), measured from the date of randomization to death from any cause.
The combination of VEN+AZA was superior in OS to PBO+AZA. The efficacy results of VIALE-A are shown in Table 29. Figure 5.
Kaplan-Meier Curve for Overall Survival in VIALE-A Table Among the patients treated with VEN+AZA, 155 were dependent on red blood cell (RBC) and/or platelets transfusions at baseline; of these patients, 49% (76/155) became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period. Of the patients treated with VEN+AZA, 131 were independent of both RBC and platelet transfusions at baseline, 69% (90/131) remained transfusion independent during any consecutive ≥56-day post-baseline period. Among the patients treated with PBO+AZA, 81 were dependent on RBC and/or platelets transfusions at baseline; of these patients, 27% (22/81) patients became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period.
Of the patients treated with PBO+AZA, 64 were independent of both RBC and platelet transfusions at baseline, 42% (27/64) remained transfusion independent during any consecutive ≥56-day post-baseline period. The median time to first response of CR or CRh was 1.0 months (range: 0.6 to 14.3 months) with VEN+AZA treatment. M14-358 M14-358 (NCT02203773) was a non-randomized, open-label trial that evaluated the efficacy of VENCLEXTA in combination with azacitidine (N=84) or decitabine (N=31) in patients with newly diagnosed AML.
Of those patients, 67 who received azacitidine combination and 13 who received decitabine combination were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy. Dose reductions for decitabine were not implemented in the clinical trial. Table 30.
Baseline Patient Characteristics for Patients with AML Treated with VENCLEXTA in Combination with Azacitidine or Decitabine ECOG = Eastern Cooperative Oncology Group. a Includes 6 patients with insufficient sample for analysis in the azacitidine group and 4 in the decitabine group. b As defined by the National Comprehensive Cancer Network (NCCN) risk categorization v2014. c No mitosis in 1 patient in azacitidine group (excluded favorable risk by Fluorescence in situ Hybridization analysis). d Patients may have had more than one comorbidity. The efficacy results are shown in Table 31. Table 31.
Efficacy Results for Patients with Newly Diagnosed AML Treated with VENCLEXTA in Combination with Azacitidine or Decitabine.3 months for VENCLEXTA in combination with azacitidine. The median follow-up was 11.0 months (range: 0.7 to 38.8 months) for VENCLEXTA in combination with decitabine. The median duration of is defined as time from the first documentation of CR to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest.
Median time to first CR or CRh for patients treated with VENCLEXTA in combination with azacitidine was 1.0 month (range: 0.7 to 8.9 months). Median time to first CR or CRh for patients treated with VENCLEXTA in combination with decitabine was 1.9 months (range: 0.8 to 4.2 months). Of patients treated with VENCLEXTA in combination with azacitidine, 12% (8/67) subsequently received stem cell transplant.
The trial enrolled 35 additional patients (age range: 65 to 74 years) who did not have known comorbidities that precluded the use of intensive induction chemotherapy and were treated with VENCLEXTA in combination with azacitidine (N=17) or decitabine (N=18). For the 17 patients treated with VENCLEXTA in combination with azacitidine, the CR rate was The CRh rate was Nine (53%) patients subsequently received stem cell transplant. For the 18 patients treated with VENCLEXTA in combination with decitabine, the CR rate was The CRh rate was Four (22%) patients subsequently received stem cell transplant.
In Combination with Low-Dose Cytarabine VIALE-C was a randomized (2:1), double-blind, placebo-controlled, multicenter trial (NCT03069352) that evaluated the efficacy and safety of VENCLEXTA in combination with low-dose cytarabine (VEN+LDAC) versus placebo with low-dose cytarabine (PBO+LDAC). Table 32. Baseline Demographic and Disease h, and the rate of conversion from transfusion dependence to transfusion independence.
The h of 11.1 months with VEN+LDAC treatment and 6.2 months with PBO+LDAC treatment. The median time to first response of CR or CRh was 1.0 month (range: 0.7 to 5.8 months) with VEN+LDAC treatment. Among the patients treated with VEN+LDAC, 111 were dependent on RBC and/or platelets transfusions at baseline; of these patients, 33% (37/111) patients became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period.
Of the patients treated with VEN+LDAC, 32 were independent of both RBC and platelet transfusions at baseline, 50% (16/32) remained transfusion independent during any consecutive ≥56-day post-baseline period. Among the patients treated with PBO+LDAC, 55 were dependent on RBC and/or platelets transfusions at baseline; of these patients, 13% (7/55) patients became independent of RBC and platelet transfusions during any consecutive ≥56-day post-baseline period. Of the patients treated with PBO+LDAC, 13 were independent of both RBC and platelet transfusions at baseline, 31% (4/13) remained transfusion independent during any consecutive ≥56-day post-baseline period.
VEN+LDAC did not significantly improve OS versus PBO+LDAC. The hazard ratio (HR) for OS was p-value 0.114. M14-387 M14-387 (NCT02287233) was a non-randomized, open-label trial that evaluated the efficacy of VEN+LDAC (N=82) in patients with newly diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder.
Table 33. Baseline Patient Characteristics for Patients with AML Treated with VENCLEXTA in Combination with Low-Dose Cytarabine The median follow-up was 7.3 months (range: 0.3 to 54.0 months). The h for patients treated with VEN+LDAC was 1.0 month (range: 0.8 to 9.4 months).
The trial enrolled 21 additional patients (age range: 67 to 74 years) who did not have known comorbidities that precluded the use of intensive induction chemotherapy and were treated with VEN+LDAC. The CR rate was The CRh rate was One patient (4.8%) subsequently received stem cell transplant.
| VENCLEXTA + acalabrutinib N = 291 | FCR/BR b N = 290 | ||
|---|---|---|---|
| Progression-free survival a | |||
| Number of events, n (%) | 89 (31) | 95 (33) | |
| Disease progression, n (%) | 77 (26) | 66 (23) | |
| Death events (%) | 12 (4) | 29 (10) | |
| Median, months (95% CI) | Not Reached (51.1, Not Reached) | 47.6 (43.3, Not Reached) | |
| HR c (95% CI) | 0.65 (0.49, 0.87) | ||
| p-value d | 0.0038 | ||
| Overall Response Rate (CR, CRi, nPR, PR) e | |||
| ORR n (%) | 270 (93) | 218 (75) | |
| (95% CI) | (89, 95) | (70, 80) | |
| CR | 26 (9) | 15 (5) | |
| CRi, n (%) | 0 | 1 (0.3) | |
| nPR, n (%) | 1 (0.3) | 1 (0.3) | |
| PR n (%) | 243 (84) | 201 (69) | |
| CR = complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response a Per IRC assessment. b Approximately 50% of patients were treated with FCR and 50% were treated with BR per investigator's choice. c Based on stratified Cox-Proportional-Hazards model. d Based on stratified log-rank test. The pre-specified type I error rate (α) for this interim analysis is 0.0469 derived from a Lan-DeMets alpha spending function with O’Brien-Fleming boundary. e Per iwCLL 2018 criteria | |||
| Endpoint | VENCLEXTA + Obinutuzumab (N = 216) | Obinutuzumab + Chlorambucil (N = 216) |
|---|---|---|
| Progression-free survival a | ||
| Number of events, n (%) | 29 (13) | 79 (37) |
| Disease progression | 14 (6) | 71 (33) |
| Death | 15 (7) | 8 (4) |
| Median, months | Not Reached | Not Reached |
| HR (95% CI) b | 0.33 (0.22, 0.51) | |
| p-value b | <0.0001 | |
| Response rate c, n (%) | ||
| ORR d | 183 (85) | 154 (71) |
| 95% CI | (79, 89) | (65, 77) |
| CR | 100 (46) | 47 (22) |
| CR+CRi d | 107 (50) | 50 (23) |
| PR | 76 (35) | 104 (48) |
| CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery; HR = hazard ratio; ORR = overall response rate (CR + CRi + PR); PR = partial remission. a From randomization until earliest event of disease progression or death due to any cause. IRC-assessed; Kaplan-Meier estimate. b HR estimate is based on Cox-proportional hazards model stratified by Binet Stage and geographic region; p-value based on log rank test stratified by the same factors. c Per 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) guidelines. d p-values based on Cochran-Mantel-Haenszel test; p=0.0007 for ORR; p<0.0001 for CR+CRi. | ||
| VENCLEXTA + Obinutuzumab | Obinutuzumab + Chlorambucil | |
|---|---|---|
| MRD negativity rate (ITT population) | ||
| N | 216 | 216 |
| Bone marrow, n (%) | 123 (57) | 37 (17) |
| 95% CI | (50, 64) | (12, 23) |
| p-value a | <0.0001 | |
| Peripheral blood, n (%) | 163 (76) | 76 (35) |
| 95% CI | (69, 81) | (29, 42) |
| p-value a | <0.0001 | |
| MRD negativity rate in patients with CR | ||
| N | 100 | 47 |
| Bone marrow, n (%) | 69 (69) | 21 (45) |
| 95% CI | (59, 78) | (30, 60) |
| p-value a | 0.0048 | |
| Peripheral blood, n (%) | 87 (87) | 29 (62) |
| 95% CI | (79, 93) | (46, 75) |
| p-value a | 0.0005 | |
| CI = confidence interval; CR = complete remission. a p-value based on Chi-square test. | ||
| Endpoint | VENCLEXTA + Rituximab (N = 194) | Bendamustine + Rituximab (N = 195) |
|---|---|---|
| Progression-free survival a | ||
| Number of events, n (%) | 35 (18) | 106 (54) |
| Disease progression, n | 26 | 91 |
| Death events, n | 9 | 15 |
| Median, months (95% CI) | Not Reached | 18.1 (15.8, 22.3) |
| HR (95% CI) b | 0.19 (0.13, 0.28) | |
| p-value b | <0.0001 | |
| Response rate c, n (%) | ||
| ORR | 179 (92) | 141 (72) |
| 95% CI | (88, 96) | (65, 78) |
| CR+CRi | 16 (8) | 7 (4) |
| nPR | 3 (2) | 1 (1) |
| PR | 160 (82) | 133 (68) |
| CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery; HR = hazard ratio; nPR = nodular partial remission; ORR = overall response rate (CR + CRi + nPR + PR); PR = partial remission. a Kaplan-Meier estimate. b HR estimate is based on Cox-proportional hazards model stratified by 17p deletion, risk status, and geographic region; p-value based on log-rank test stratified by the same factors. c Per 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) guidelines. | ||
| Characteristic | N = 106 |
|---|---|
| Age, years; median (range) | 67 (37-83) |
| White; % | 97 |
| Male; % | 65 |
| ECOG performance status; % 0 1 2 | 40 52 8 |
| Tumor burden; % Absolute lymphocyte count ≥25 x 10 9 /L One or more nodes ≥5 cm | 50 53 |
| Number of prior therapies; median (range) | 2.5 (1-10) |
| Time since diagnosis, years; median (range) a | 6.6 (0.1-32.1) |
| ECOG = Eastern Cooperative Oncology Group. a N=105. | |
| Endpoint | VENCLEXTA N = 106 |
|---|---|
| ORR, n (%) a (95% CI) | 85 (80) (71, 87) |
| CR + CRi, n (%) CR, n (%) CRi, n (%) | 8 (8) 6 (6) 2 (2) |
| nPR, n (%) | 3 (3) |
| PR, n (%) | 74 (70) |
| CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery; IRC = independent review committee; nPR = nodular partial remission; ORR = overall response rate (CR + CRi + nPR + PR); PR = partial remission. a Per 2008 IWCLL guidelines. | |
| Characteristic | VENCLEXTA + Azacitidine N = 286 | Placebo + Azacitidine N = 145 |
|---|---|---|
| Age, years; median (range) | 76 (49, 91) | 76 (60, 90) |
| Race | ||
| White; % | 76 | 75 |
| Black or African American; % | 1 | 1.4 |
| Asian; % | 23 | 23 |
| Males; % | 60 | 60 |
| ECOG performance status; % | ||
| 0-1 | 55 | 56 |
| 2 | 40 | 41 |
| 3 | 5.6 | 3.4 |
| Bone marrow blast; % | ||
| <30% | 30 | 28 |
| ≥30% to <50% | 21 | 23 |
| ≥50% | 49 | 49 |
| Disease history; % | ||
| De Novo AML | 75 | 76 |
| Secondary AML | 25 | 24 |
| Cytogenetic risk detected a, % | ||
| Intermediate | 64 | 61 |
| Poor | 36 | 39 |
| Mutation analyses detected; n/N b (%) | ||
| IDH1 or IDH2 | 61/245 (25) | 28/127 (22) |
| IDH1 | 23/245 (9.4) | 11/127 (8.7) |
| IDH2 | 40/245 (16) | 18/127 (14) |
| FLT3 | 29/206 (14) | 22/108 (20) |
| NPM1 | 27/163 (17) | 17/86 (20) |
| TP53 | 38/163 (23) | 14/86 (16) |
| a Per the 2016 National Comprehensive Cancer Network (NCCN) Guidelines. b Number of evaluable BMA specimens received at baseline. | ||
| Endpoint | VENCLEXTA + Azacitidine (N = 286) | Placebo + Azacitidine (N = 145) |
|---|---|---|
| Overall survival | ||
| Median a, months (95% CI) | 14.7 (11.9, 18.7) | 9.6 (7.4, 12.7) |
| Hazard ratio b (95% CI) | 0.66 (0.52, 0.85) | |
| p-value b | <0.001 | |
| Response rate | ||
| CR, n (%) | 105 (37) | 26 (18) |
| (95% CI) | (31, 43) | (12, 25) |
| p-value c | <0.001 | |
| Median DOCR a,d (months) | 18.0 | 13.4 |
| 95% CI | (15.3, -) | (8.7, 17.6) |
| CR+CRh, n (%) | 185 (65) | 33 (23) |
| (95% CI) | (59, 70) | (16, 30) |
| p-value c | <0.001 | |
| Median DOCR+CRh a,e (months) | 17.8 | 13.9 |
| 95% CI | (15.3, -) | (10.4, 15.7) |
| CI = confidence interval; CR = complete remission; CRh = complete remission with partial hematologic recovery; DOCR = duration of CR; HR = hazard ratio; - = not reached. CR (complete remission) was defined as absolute neutrophil count >1,000/microliter, platelets >100,000/microliter, red blood cell transfusion independence, and bone marrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. CRh (complete remission with partial hematological recovery) 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). a Kaplan-Meier estimate. b Hazard ratio estimate (VEN+AZA vs. PBO+AZA) is based on Cox-proportional hazards model stratified by cytogenetics (intermediate risk, poor risk) and age (18 to <75, ≥75 years) as assigned at randomization; p-value based on log-rank test stratified by the same factors. c p-value is from Cochran-Mantel-Haenszel test stratified by age and cytogenetics risk. d 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. e 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. | ||
| Characteristic | VENCLEXTA + Azacitidine N = 67 | VENCLEXTA + Decitabine N = 13 |
|---|---|---|
| Age, years; median (range) | 76 (61-90) | 75 (68-86) |
| Race; % | ||
| White | 87 | 77 |
| Black or African American | 4.5 | 0 |
| Asian | 1.5 | 0 |
| Native Hawaiian or Pacific Islander | 1.5 | 15 |
| American Indian/Alaskan Native | 0 | 7.7 |
| Unreported other | 6 | 0 |
| Male; % | 60 | 38 |
| ECOG performance status; % 0-1 2 3 | 64 33 3 | 92 7.7 0 |
| Disease history; % De Novo AML Secondary AML | 73 27 | 85 15 |
| Mutation analyses detected a; % | ||
| TP53 | 15 | 31 |
| IDH1 or IDH2 | 27 | 0 |
| FLT3 | 16 | 23 |
| NPM1 | 19 | 15 |
| Cytogenetic risk detected b,c; % | ||
| Intermediate | 64 | 38 |
| Poor | 34 | 62 |
| Baseline comorbidities d; % | ||
| Severe cardiac disease | 4.5 | 7.7 |
| Severe pulmonary disease | 1.5 | 0 |
| Moderate hepatic impairment | 9 | 0 |
| Creatinine clearance <45 mL/min | 13 | 7.7 |
| ECOG = Eastern Cooperative Oncology Group. a Includes 6 patients with insufficient sample for analysis in the azacitidine group and 4 in the decitabine group. b As defined by the National Comprehensive Cancer Network (NCCN) risk categorization v2014. c No mitosis in 1 patient in azacitidine group (excluded favorable risk by Fluorescence in situ Hybridization [FISH] analysis). d Patients may have had more than one comorbidity. | ||
| Efficacy Outcomes | VENCLEXTA + Azacitidine N = 67 | VENCLEXTA + Decitabine N = 13 |
|---|---|---|
| CR, n (%) | 29 (43) | 7 (54) |
| (95% CI) | (31, 56) | (25, 81) |
| CRh, n (%) | 12 (18) | 1 (7.7) |
| (95% CI) | (9.6, 29) | (0.2, 36) |
| CI = confidence interval; CR = complete remission; CRh = complete remission with partial hematological recovery. | ||
| Characteristic | VENCLEXTA + Low-Dose Cytarabine N = 143 | Placebo + Low-Dose Cytarabine N = 68 |
|---|---|---|
| Age, years; median (range) | 76 (36, 93) | 76 (41, 88) |
| Race; % | ||
| White | 71 | 69 |
| Black or African American | 1.4 | 1.5 |
| Asian | 27 | 29 |
| Male; % | 55 | 57 |
| ECOG performance status; % 0-1 2 3 | 52 44 4.2 | 50 37 13 |
| Disease history; % De Novo AML Secondary AML | 59 41 | 66 34 |
| Mutation analyses detected; n/N a (%) | ||
| TP53 | 22/112 (20) | 9/52 (17) |
| IDH1 or IDH2 | 21/112 (19) | 12/52 (23) |
| FLT3 | 20/112 (18) | 9/52 (17) |
| NPM1 | 18/112 (16) | 7/52 (13) |
| Cytogenetic risk detected b; % | ||
| Favorable | <1 | 4 |
| Intermediate | 63 | 63 |
| Poor | 33 | 29 |
| a Number of evaluable BMA specimens received at baseline. b Per the 2016 National Comprehensive Cancer Network (NCCN) Guidelines. | ||
| Characteristic | VENCLEXTA in Combination with Low-Dose Cytarabine N = 61 |
|---|---|
| Age, years; median (range) | 76 (63-90) |
| Race; % | |
| White | 92 |
| Black or African American | 1.6 |
| Asian | 1.6 |
| Unreported | 4.9 |
| Male; % | 74 |
| ECOG performance status; % 0-1 2 3 | 66 33 1.6 |
| Disease history; % De Novo AML Secondary AML | 54 46 |
| Mutation analyses detected a; % | |
| TP53 | 8.2 |
| IDH1 or IDH2 | 23 |
| FLT3 | 21 |
| NPM1 | 9.8 |
| Cytogenetic risk detected b; % | |
| Intermediate | 59 |
| Poor | 34 |
| No mitoses | 6.6 |
| Baseline comorbidities c; % | |
| Severe cardiac disease | 9.8 |
| Moderate hepatic impairment | 4.9 |
| Creatinine clearance ≥30 or <45 mL/min | 3.3 |
| a Includes 7 patients with insufficient sample for analysis. b As defined by the National Comprehensive Cancer Network (NCCN) risk categorization v2014. c Patients may have had more than one comorbidity. | |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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