Initiation of Venetoclax for Adult Patients with Chronic Lymphocytic Leukemia (CLL)

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Venetoclax is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax initiation begins with a 5- week ramp-up period designed to gradually reduce tumor burden and decrease the risk of tumor lysis syndrome (TLS). This video will describe the 5-week ramp-up period and discuss the administration of venetoclax for first-line treatment of CLL/SLL in combination with obinutuzumab and for the treatment of relapsed/refractory CLL/SLL in combination with rituximab.

Venetoclax Indication and Safety Overview

Indication

Venetoclax is a BCL-2 inhibitor indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Contraindications

Strong CYP3A Inhibitors: Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated.

Warnings and Precautions

• TLS: Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax. Anticipate TLS: assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases.
• Neutropenia: Monitor blood counts. Interrupt dosing and resume at same or reduced dose. Consider supportive care measures.
• Infections: Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with venetoclax. Monitor patients for signs and symptoms of infection and treat promptly. Withhold venetoclax for Grade 3 and 4 infection until resolution and resume at same or reduced dose.
• Immunization: Do not administer live attenuated vaccines prior to, during, or after venetoclax treatment until B-cell recovery.
• Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.
• Increased mortality in patients with multiple myeloma (MM) when venetoclax is added to bortezomib and dexamethasone. In a randomized trial in patients with relapsed or refractory MM, the addition of venetoclax to bortezomib plus dexamethasone, a use for which venetoclax is not indicated, resulted in increased mortality. Treatment of patients with MM with venetoclax in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions

• In CLL/SLL, the most common adverse reactions for venetoclax when given in combination with obinutuzumab or rituximab or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

Review full prescribing information for additional information at www.rxabbvie.com or contact AbbVie Medical Information at 1-800-633-9110 or go to abbviemedinfo.com.

Low or Medium Tumor Burden Patients with CLL

High Tumor Burden Patients with CLL

Transcript

(00:04): The content of this video has been developed by AbbVie US Medical Affairs. Venetoclax is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during the 5-week ramp-up phase in patients with CLL or SLL is contraindicated.

(00:29): Venetoclax is a first-in-class treatment to help restore apoptotic pathways in cancer cells. Venetoclax is a selective, potent, oral BCL-2 inhibitor that binds to BCL-2 and frees pro-apoptotic proteins.

(00:45): Venetoclax should be administered according to a 5-week ramp-up dosing schedule. This 5-week ramp-up schedule is designed to gradually reduce tumor burden, or debulk and decrease the risk of tumor lysis syndrome (TLS). The dosing schedule for the 5-week ramp-up for venetoclax is 20 milligrams by mouth daily in week 1, 50 milligrams by mouth daily in week 2, 100 milligrams by mouth daily in week 3, 200 milligrams by mouth daily in week 4, and 400 milligrams by mouth daily in week 5 and beyond. Dose levels should not be skipped.

(01:23): We will review the ramp-up dosage schedule for first-line treatment of CLL using venetoclax in combination with obinutuzumab. Start obinutuzumab at 100 milligrams intravenously on cycle 1, day 1. This is followed by 900 milligrams intravenously on cycle 1, day 2. Administer 1000 milligrams intravenously on day 8 and day 15 of cycle 1. Administer 1000 milligrams intravenously on day 1 of each subsequent 28-day cycle for a total of 6 cycles. Refer to the obinutuzumab label for more information. Start the 5-week venetoclax ramp-up schedule on cycle 1, day 22. After completing the ramp-up phase on cycle 2, day 28, continue venetoclax at a dose of 400 milligrams by mouth daily from cycle 3, day 1 until the last day of cycle 12.

(02:17): We will now review the ramp-up dosage schedule for relapse refractory treatment of CLL using venetoclax in combination with rituximab. Start rituximab administration after the patient has completed the 5-week venetoclax ramp-up and has received venetoclax 400 milligrams orally once daily for 7 days. Administer rituximab on day 1 of each 28-day cycle for 6 cycles at a dose of 375 milligrams per meter squared intravenously for cycle 1 and 500 milligrams per meter squared intravenously for cycles 2 through 6. Refer to the rituximab label for more information. Venetoclax is taken for 24 months at the recommended dose of 400 milligrams orally daily from cycle 1, day 1 of rituximab.

(03:09): There are potentially serious adverse events to monitor for and to counsel patients on when starting treatment with venetoclax. In patients with CLL, the most common adverse reactions greater than or equal to 20% for venetoclax when given in combination with obinutuzumab or rituximab or as monotherapy are neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. Tumor lysis syndrome, or TLS, is a less common but potentially serious adverse reaction. TLS, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax. Venetoclax can cause rapid reduction in tumor cells and thus poses a risk for TLS early in therapy and during re-initiation after dosage interruption. Healthcare providers must assess patient-specific factors for the level of TLS risk and plan to provide prophylactic hydration and anti-hyperuricemics to patients prior to their first dose of venetoclax.

(04:18): In the clinical trials that led to the approval of venetoclax in previously untreated and relapsed refractory CLL, the incidence of TLS was 1% and 3%, respectively. The risk of TLS is a continuum based on multiple factors, particularly reduced renal function and tumor burden. Tumor burden assessment considers lymph node measurements and absolute lymphocyte count.

(04:43): Educate your patients on the signs and symptoms of TLS. These can include fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, muscle or joint pain. Review things patients can do to help decrease the risk of TLS. These include staying hydrated, watching for previously listed signs and symptoms, keeping all bloodwork appointments, and taking medications exactly as prescribed. The mainstays of prophylaxis are hydration and anti-hyperuricemics. Based on a patient's risk stratification, you will instruct them on appropriate hydration strategies and anti-hyperuricemics dosing.

(05:27): All patient comorbidities should be considered in determining risk and appropriate setting for treatment initiation—inpatient, or outpatient. Perform tumor burden assessments, including radiographic evaluation such as a CT scan; assess blood chemistry, including potassium, uric acid, phosphorus, calcium, and creatinine in all patients; and correct preexisting abnormalities prior to initiation of treatment with venetoclax. Patients with reduced renal function (creatinine clearance less than 80 milliliters per minute) require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with venetoclax.

(06:10): The table included below this video can help you determine your patient's individual risk stratification for TLS, and in doing so, can help guide whether inpatient or outpatient treatment initiation is appropriate, as well as what prophylactic measures to consider. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose, and at each dose increase. Dose modifications depend on a patient's specific scenario. If a patient has blood chemistry changes or symptoms suggestive of TLS, the next day's dose will be held. If the chemistry abnormality and/or symptoms resolve within 24 to 48 hours, the patient can restart at the current dose. If it takes more than 48 hours for resolution of chemistries or symptoms, the patient will resume venetoclax treatment at a reduced dose.

(07:06): If a patient experiences Grade 3 or 4 nonhematologic toxicities, or Grade 3 neutropenia with infection, or Grade 4 hematologic toxicities (other than lymphopenia), venetoclax is held. If this is a first occurrence, venetoclax can be resumed at the same dose once the toxicity is resolved to baseline or Grade 1 level. If this is a second or subsequent occurrence, venetoclax is resumed at a reduced dose once the toxicity has resolved. A larger dose reduction may occur per physician discretion. Reassess the risk of TLS when reinitiating venetoclax 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.

(07:54): Always assess for the possibility of drug interactions prior to initiation of venetoclax. Avoid concomitant use of venetoclax with moderate CYP3A inhibitors and P-glycoprotein inhibitors at initiation and during the dose titration phase. Consider alternative medications or reduce the venetoclax dose. Concomitant use of venetoclax with strong or moderate CYP3A inhibitors or P-glycoprotein inhibitors increases venetoclax exposure, which may increase venetoclax toxicities, including the risk of TLS. Patients should be monitored more frequently for adverse reactions, and the dose may need to be further adjusted.

(08:35): Medications to pay particular attention to include, but are not limited to, clarithromycin, itraconazole, ketoconazole, posaconazole, ritonavir, voriconazole, ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil, amiodarone, cyclosporine, dronedarone, and quinidine. Foods such as grapefruit, some oranges, and starfruit are also CYP3A inhibitors. The venetoclax dose that was used prior to initiating the CYP3A inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor. For special situations, including patients with severe hepatic impairment, pregnancy or lactation, or with questions on vaccinations, please refer to the prescribing information.

(09:25): Patients should be advised to take their venetoclax tablets exactly as prescribed and to not change or interrupt their doses unless advised by their medical team. Take venetoclax by mouth, once daily, at about the same time each day. Swallow the tablet whole with a meal and water. Do not chew, crush, or break apart the tablets. If vomiting occurs after taking venetoclax, do not take another tablet. Instead, take the next dose at the usual time the following day. If a patient forgets or misses a dose, if it was within 8 hours of the usual time when the patient remembers, they can take the missed dose as soon as possible, and take the next dose at the usual time. If it has been more than 8 hours from the time they usually take their venetoclax, the patient should not take the missed dose; they can take the next scheduled dose at the usual time. You may find it helpful to refer back to the visual aids provided below the video player: Determining Tumor Lysis Syndrome Risk Stratification and the 5-week Venetoclax Initiation Calendar.

(10:32): Please see full prescribing information for additional information at www.rxabbvie.com or contact AbbVie Medical Information at abbviemedinfo.com.

•This content is intended for US/PR Healthcare Professionals.

•AbbVie US Medical Affairs is the sole author and copyright owner of this presentation and has paid Aggrego Oncology to host this content. AbbVie is solely responsible for all written and oral content within this presentation. © 2023 AbbVie Inc. All rights reserved.

BCL2-US-00061-MC

V 1.0, Approved April 2023