CE / CME
Nurses: 1.00 Nursing contact hour
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Released: October 01, 2024
Expiration: March 31, 2025
Venetoclax: Adverse Events and Management
Caitlin Rausch, PharmD, BCOP:
The most common AEs associated with venetoclax in patients with CLL include cytopenias, gastrointestinal adverse effects, and infections. Although typically lower grade, these AEs can be relatively frequent. Neutropenia is seen more frequently in combination with a CD20 mAb, particularly obinutuzumab.
Tumor lysis syndrome (TLS) is also a concern, but the incidence has been reduced with the use of ramp-up dosing. TLS can occur when cellular by-products are released during tumor cell lysis. When cell by-products such as potassium, phosphorus, and nucleic acids (metabolized into uric acid) are released by large amounts of tumor cell lysis, it can overwhelm the body’s homeostatic mechanisms. The risk of TLS and severity depends on several factors, including the type of malignancy, cancer mass, potential for lysis of the cancer cells, patient characteristics, and implementation of appropriate supportive care measures.
TLS is always something to consider as patients with CLL begin venetoclax treatment. To help reduce the potential for TLS in patients with CLL, venetoclax dose ramp-up is employed, with dosing beginning at 20 mg once daily for the first week and ramping up weekly until Week 5 at 400 mg once daily dosing. For patients at high risk for TLS (eg, if they have bulky adenopathy), they should receive the first dose of the first 2 ramp-up doses while inpatient.
TLS is diagnosed when 2 or more laboratory abnormalities (hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia) present within 3 days before or 7 days after therapy initiation. Clinical or overt symptoms of TLS occur when laboratory signs are accompanied by increased serum creatinine levels, seizures, cardiac dysrhythmia, or death.7 Healthcare professionals (HCPs) should monitor for TLS using appropriate laboratory assessments as per the prescribing information and take preventative measures by using adequate hydration and antihyperuricemic agents.8
Patient Case
Let’s take a moment to consider a patient case example. A 73-year-old man was diagnosed with CLL and began first-line treatment with venetoclax plus obinutuzumab. He has already received 3 weeks of obinutuzumab and is about to start treatment with venetoclax. His previous medical history includes hypertension, GERD, hyperlipidemia, and asthma and his current medications include lisinopril/HCTZ, omeprazole, and atorvastatin.
After receiving obinutuzumab treatment, a CT scan shows improvement in his lymphadenopathy (largest lymph node being 7 cm) and his blood counts have improved with a white blood cell (WBC) count of 21 K/mm3 (absolute lymphocyte count [ALC]: 18.7) from his baseline of 163 K/mm3 (ALC: 158.6), hemoglobin of 11.1 g/dL from baseline of 10.9 g/dL, and platelet count of 101 K/mm3 from baseline of 68 K/mm3. His current labs also show serum creatinine of 1.4 mg/dL and CrCl of 55 mL/min.
Based on this information, let’s discuss venetoclax administration considerations.
Venetoclax: TLS Management
Caitlin Rausch, PharmD, BCOP:
Multiple factors contribute to the risk of TLS, including tumor burden, ALC, renal function (CrCl <80 mL/min), and splenomegaly. This algorithm outlines how to initiate and escalate venetoclax therapy by assessing patient risk based on the presence of bulky adenopathy and lymph node size, and to aid in determining whether you should initiate therapy in an inpatient or outpatient setting. Prior to the initiation of venetoclax, assessments of tumor burden and blood chemistry should be completed; any blood chemistry abnormalities should be corrected.
This reference slide is adapted from the prescribing information and can be useful for HCPs to determine what is typically done in clinical practice.8
For patients with low risk of TLS—those with lymph nodes less than 5 cm and ALC less than 25 x 109/L—venetoclax administration can be done on an outpatient basis with prophylactic oral hydration (1.5-2.0 L) and prophylactic allopurinol. Laboratory monitoring should be done predose, at 6-8 hours, and at 24 hours for the first dose of 20 mg and 50 mg venetoclax and then prior to the first dose of the subsequent ramp-up doses.
For patients with intermediate risk of TLS—those with lymph nodes between 5 cm and less than 10 cm or ALC ≥25 x 109/L—venetoclax administration should be done on an outpatient basis, with prophylactic oral hydration (1.5-2.0 L) or consideration for IV hydration, if indicated, and prophylactic allopurinol. Laboratory monitoring should be done predosing, at 6-8 hours, and at 24 hours for the first dose of 20 mg and 50 mg venetoclax and then prior to the first dose of the subsequent ramp-up doses.
For patients with intermediate risk of TLS and CrCl less than 80 mL/min or those with high risk of TLS—those with lymph nodes ≥10 cm or lymph nodes ≥5 cm and ALC ≥25 x 109/L—venetoclax administration can be done on an inpatient basis with prophylactic oral hydration (1.5-2.0 L), IV hydration (150-200 mL/hour as tolerated), and prophylactic allopurinol (or consider rasburicase if elevated baseline uric acid). Laboratory monitoring should be done at first dose of 20 mg and 50 mg predose, 4 hours, 8 hours, 12 hours, and 24 hours and then outpatient for subsequent ramp-up doses predose, 6-8 hours, and 24 hours.
Applying this algorithm to our patient case above, the recommendation would be to admit this patient to the hospital for the initial administration of venetoclax since he has intermediate risk for TLS with his largest lymph node being 7 cm and his CrCl being poor at 55 mL/min. He should begin allopurinol and intravenous fluids with 0.9% sodium chloride at 200 mL/hr and TLS labs should be obtained predosing, and at 4, 8, 12, and 24 hours after venetoclax is administered.
For patients with CLL who experience signs of TLS, immediately hold venetoclax dosing. If TLS resolves within 24 to 48 hours of the last dose, venetoclax can be resumed at same dose. For any blood chemistry changes requiring more than 48 hours to resolve, venetoclax should be resumed at reduced dose. For any events of clinical TLS, resume at reduced dose following resolution. Clinical TLS is defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, seizures and/or sudden death.8
If TLS occurred with anti-CD20 antibody, hold the anti-CD20 antibody as well.
Venetoclax: Hematologic Toxicity Management
Caitlin Rausch, PharmD, BCOP:
In CLL/SLL, some of the most common AEs with venetoclax include neutropenia, thrombocytopenia, anemia, diarrhea, nausea, and upper respiratory tract infection. According to the prescribing information for venetoclax, if grade 3 neutropenia with infection or fever or grade 4 hematologic AE occurs, venetoclax should be held until resolution to grade ≤1.8 Consider growth factor support and/or additional supportive care such as antimicrobials, if indicated. Growth factor support may be considered while holding venetoclax. Because this is the first occurrence of neutropenia, venetoclax can be resumed at the same dose once the AE resolves.
For the second or subsequent occurrence of grade 3 neutropenia with infection or fever or grade 4 hematologic AE, HCPs should interrupt treatment, and resume venetoclax at the next lower dose once resolved to grade ≤1 or baseline and consider growth factor support.8
Similar dose holds and reductions can be considered for nonhematologic AEs that are grade ≥3.8
If the dose of venetoclax needs to be reduced because of AEs for patients with CLL/SLL, the recommended dose reductions are from 400 mg to 300 mg, then 300 mg to 200 mg, 200 mg to 100 mg, 100 mg to 50 mg, 50 mg to 20 mg, and 20 mg to 10 mg. If the dose interruption occurs during the ramp-up period, continue the reduced dose for 1 week before increasing the dose. For dose interruptions lasting longer than 1 week during the ramp-up period or 2 weeks after completion of the ramp-up, reassess risk of TLS and determine whether reinitiation at a reduced dose is necessary.8
HCPs should also consider discontinuation for patients who require dose reductions to less than 100 mg for more than 2 weeks.8
Collaborative Care
Caitlin Rausch, PharmD, BCOP:
There are a number of different treatment options available for patients with CLL and the side effect profile for each available agent can substantially dictate choice of therapy. Further, patients are often on therapy for a prolonged period. With these considerations in mind, it is helpful to have an interdisciplinary care team available for patients with CLL. This team can ensure that patients are able to receive their medication, understand how to take it properly, and that they are not experiencing side effects months down the line.9,10
Factors Leading to Poor Patient Outcomes
Caitlin Rausch, PharmD, BCOP:
Interdisciplinary teams are needed because we know that there are several factors that contribute to poor outcomes in these patients. Many of these therapies are highly effective, but if patients are unable to access these medications, are not taking them correctly, and/or are not able to come to appointments as needed, then it can be very difficult to administer the medications as they should be given, which can impact their efficacy and safety. It is important to provide education to patients so they understand what is expected during treatment, what they can do to help stay adherent to therapy, and what it is going to cost them and their family, both financially and in time commitment (eg, bringing them back and forth for appointments).
Significant coordination is required from the patient’s care team for optimal interdisciplinary care, but it also requires the patient to have some support from family or friends, too, to be successful.11-14
Now, let’s go back to our patient case question.
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