CE / CME
Pharmacists: 0.50 contact hour (0.05 CEUs)
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Nurses: 0.50 Nursing contact hour
Released: May 19, 2022
Expiration: May 18, 2023
Nicole Lamanna, MD:
Let’s begin our discussion by looking at AEs commonly associated with the BCL-2 inhibitor venetoclax. Along with the BTK inhibitors acalabrutinib and ibrutinib, venetoclax is part of standard-of-care treatment regimens for both previously untreated and previously treated CLL. This agent is approved for use in patients with CLL and is commonly combined with obinutuzumab for first-line therapy based on the CLL14 trial and with rituximab for later-line therapy based on the MURANO trial.1,2
BCL-2 overexpression occurs in patients with CLL and other lymphomas, with BCL-2 binding to BAX and BAK to prevent apoptosis.3
Nicole Lamanna, MD:
Compared with other targeted therapies, venetoclax can be more cumbersome to use initially, as there is a process to mitigate the potential occurrence of tumor lysis syndrome (TLS). Before targeted therapies were available, patients generally received chemoimmunotherapy, including fludarabine, cyclophosphamide, and rituximab; bendamustine and rituximab; pentostatin; or cyclophosphamide and rituximab, and we often saw tumor lysis, particularly in patients with very high white blood cell (WBC) counts or bulky lymphadenopathy. This would be managed with fluids, forced diuresis, and hospitalization if necessary, depending on the bulk of the patient’s disease or age and comorbidities.
Now let’s fast-forward to the approval of the BTK inhibitor ibrutinib, with which we did not see tumor lysis. Then, in the clinical trials of venetoclax, we once again saw TLS. This resulted in the development of a 5-week dose ramp-up schema to reduce the risk of TLS.4 Patients who begin receiving venetoclax are started with a 20-mg oral daily dose and then are moved to 50-mg, 100-mg, 200-mg, and 400-mg doses in subsequent weeks, with 400 mg being the targeted daily dose.
Patients are assessed for their risk of TLS based on tumor burden (Table); those at high risk are recommended to be hospitalized for dosing and monitoring with the 20-mg and 50-mg doses during the ramp-up period.
Table. TLS Risk Stratification and Management Considerations4
Nichole Fisher, RN, BSN:
For the first 2 weeks of the ramp‑up period (with the 20 mg and 50 mg dosing), patients are required to have 3 clinic visits each week for monitoring. For patients who live farther away from the clinic or have transportation issues, this sometimes can be problematic, so prior to treatment, nurses should educate them on the requirements. Nurses also should educate on the timing of blood draws. During the first 2 weeks of the ramp-up period, blood draws are done predose and postdose to assess the risk for TLS. Patients who have a high tumor burden are often put in the hospital for that initial 20-mg and 50-mg dose ramp‑up period due to the high risk for tumor lysis.
Another thing that nurses will educate on is the importance of hydration. We recommend at least 2‑3 liters per day, although we caution against overhydration in patients who have congestive heart failure. Allopurinol also is given prior to initiating venetoclax and is taken throughout the ramp‑up period.
Nicole Lamanna, MD:
Debulking strategies also are used. As discussed above, venetoclax may be administered with the anti-CD20 antibodies obinutuzumab or rituximab. Per the CLL14 study and the prescribing information, obinutuzumab can be given on Days 1, 8, and 15 of treatment cycle 1, with venetoclax being given on Day 22 of cycle 1.1,4 Using another agent prior to initiating venetoclax can assist in debulking and makes treatment easier because the disease burden has been reduced by the time the patient receives venetoclax. The debulking process can be cumbersomeness for patients in the beginning because labs are still checked frequently, even in the outpatient setting. Once a patient gets beyond the first 5 weeks of treatment with venetoclax, treatment becomes less cumbersome and more commonplace for patients.
Anthony Perissinotti, PharmD, BCOP:
I do find that many healthcare professionals who do not use venetoclax often are fearful of TLS. I would say that if we follow the prescribing information recommendations for high-risk patients and monitor them appropriately, I am very confident that tumor lysis will not cause substantial issues. If patients are adequately hydrated and receiving the appropriate prophylaxis and monitoring, most patients will tolerate venetoclax very well.
Nicole Lamanna, MD:
Another thing to monitor for in patients receiving venetoclax is myelosuppression. With single-agent venetoclax, grade 3/4 neutropenia may be experienced by up to 40% of patients.5 In combination with anti‑CD20 antibodies, neutropenia can occur in up to 60% of patients. If a patient develops a grade 3/4 neutropenia or febrile neutropenia, venetoclax treatment should be paused and resumed when the neutropenia is resolved to grade ≥1. Granulocyte colony-stimulating factor (G-CSF) also should be used when clinically indicated. These measures are very important, as we do not want to cause increased incidences of infectious complications with our patients with CLL, who already are more prone to infectious complications at baseline, and we want patients to remain on treatment with venetoclax as long as possible.
Anthony Perissinotti, PharmD, BCOP:
I will manage neutropenia differently depending on when it occurs. If neutropenia occurs early in treatment, I usually recommend treating through it because I know that the venetoclax is ridding the bone marrow of the CLL cells, such that the bone marrow will be opened up for normal hematopoiesis; in this case, the absolute neutrophil count will gradually rise. If a patient is experiencing neutropenia after a few months of therapy and has reached the target dose of venetoclax and had a normal WBC count at baseline, I would consider holding the venetoclax until the patient’s WBC counts recover, after which I would resume treatment with venetoclax.
Nichole Fisher, RN, BSN:
Another common AE with venetoclax is thrombocytopenia, which can increase a patient’s risk for bleeding, and so we continuously monitor platelet counts and administer platelet transfusions, if needed.
A lot of what we’re doing on the nursing side of AE management is monitoring, assessing, and educating, so we will work with the healthcare professional to discuss any lab results that are out of range and then provide education to the patients on what these results mean and the potential next steps. With neutropenia, we talk to patients about the risk for infection, good hand hygiene, avoiding crowds, and other key measures. With thrombocytopenia and bleeding risk, we talk about bleeding of the gums and cuts that may not stop bleeding.
Nicole Lamanna, MD:
With serious infections, we treat the infection accordingly and may hold venetoclax if clinically indicated. If an infection is mild, and the patient is at home and doing well, I will often continue treating with venetoclax.
Nichole Fisher, RN, BSN:
Gastrointestinal (GI) AEs also can occur with venetoclax. Mild diarrhea and nausea can occur in up to 40% of patients receiving venetoclax.5 I will recommend that patients have antinausea medicines at home and that they take them 30-60 minutes prior to taking venetoclax; if they are experiencing nausea, I will recommend making sure they also have food in their stomach. For patients who experience mild diarrhea, we will treat accordingly with antidiarrheal agents as needed (assuming they do not have infectious diarrhea) and discuss hydration and antimotility agents, depending on the severity of their GI issues.
Anthony Perissinotti, PharmD, BCOP:
To illustrate some of these points, let’s look at a case. A 69-year-old man with CLL currently taking ibrutinib reports increasing fatigue during routine follow-up. On examination, his axillary lymphadenopathy has increased from 2 cm to 6 cm. He has normal cardiac and kidney function, and lab results show hemoglobin of 13.6 g/dL, WBC count of 14,000/μL, a platelet count of 400,000/μL, and an ALC 10.5 x 109/L, with normal lactate dehydrogenase (LDH). CT imaging reveals generalized lymphadenopathy (largest 6 cm in maximal dimension); PET imaging indicates lymphadenopathy with fluorodeoxyglucose uptake slightly above hepatic reference. After consultation, the patient decides on treatment with venetoclax for his progressive disease.
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