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
VIALE-A: Safety Summary
Courtney DiNardo, MD, MSCE:
In terms of safety, the important thing to recognize is that venetoclax interruptions are quite common in patients with AML. In the VIALE-A trial, 73.1% of patients required dose interruptions with venetoclax.
VIALE-A was designed with continuous venetoclax at 400 mg daily on Days 1-28 of each cycle along with azacitidine until disease progression, and this was not particularly well tolerated. The longer a patients is on venetoclax, the more on‑target neutropenia and cytopenias can develop, and so we realized fairly quickly that venetoclax dose interruptions are very important in order to enable patients to optimally tolerate this therapy long-term.18
VIALE-A: AEs With Azacitidine ± Venetoclax
Courtney DiNardo, MD, MSCE:
The most common AEs with venetoclax-based combinations in patients with AML included gastrointestinal issues, thrombocytopenia, neutropenia, febrile neutropenia, fatigue, edema, pyrexia, and pneumonia.
TLS was not a major issue for patients with AML, as opposed to what was seen with CLL and other more bulky lymphomas. By proactively managing the TLS risk by ensuring that the WBC count is under 25,000 when beginning therapy, using a uric acid–reducing agent, and monitoring electrolytes, there is not any significant TLS with AML or myeloid malignancies.16,18
Treatment Duration and VEN Dosing Schedule Among CR + CRi Responders
Courtney DiNardo, MD, MSCE:
As mentioned, venetoclax dose interruptions are very important for maintaining the longevity of treatment in patients with AML who receive it long-term. In VIALE‑A, patients who had a sustained remission had a duration of treatment with a median of 13 cycles. These data show that patients are able to tolerate venetoclax for many cycles if they are well managed. Determining the best dosing schedule for individual patients can take some trial and error, but it is important to optimize it so that it will be well tolerated for a long period of time. For an average patient enrolled in VIALE‑A, the median duration of each cycle was 5 weeks instead of 4 weeks, with 2 weeks off venetoclax therapy. So, patients were receiving 3 weeks on therapy and 2 weeks off therapy over a 5‑week cycle. This altered dosing regimen was associated with better tolerability while allowing patients to maintain a durable response.17
Venetoclax Dose Ramp-up and TLS Prevention and Assessment
Courtney DiNardo, MD, MSCE:
Although TLS is less common in patients with AML, dose ramp-up and TLS prophylaxis remain an important part of beginning therapy with venetoclax.
It is important for HCPs to assess individual patient risk factors for TLS before beginning therapy with venetoclax for AML by evaluating if the patient has circulating blasts, high burden of leukemia bone marrow involvement, high pretreatment LDH, and/or reduced renal function. Patients should have a WBC count <25 x 109/L prior to initiating venetoclax, and cytoreduction may be required prior to treatment. Prior to initiating venetoclax, all patients should receive prophylactic measures including adequate hydration and antihyperuricemic agents. Typically, allopurinol should be given prior to the first dose of venetoclax to reduce risk of TLS, and then continued through the ramp-up phase. For patients with rapidly increasing blast counts, high uric acid, or impaired renal function, consider rasburicase as initial treatment. When possible, glucose-6-phosphate dehydrogenase deficiency should be checked prior to rasburicase administration.
HCPs should assess blood chemistry before treatment and any preexisting abnormalities should be corrected prior to venetoclax initiation. Blood chemistries should also be monitored predosing, 6-8 hours after each new dose during ramp-up, and 24 hours after reaching the final dose of venetoclax for signs of TLS, including increased potassium, uric acid, phosphorus, and creatinine and decreased calcium. HCPs should also monitor blood chemistries for TLS at follow-up visits.
For patients with risk factors for TLS, additional measures should be considered, including increased laboratory monitoring and reducing the venetoclax starting dose.8
The dose ramp-up for venetoclax in AML is different than the ramp-up in CLL. As opposed to a weekly ramp-up, it is daily over the course of 3‑4 days, with the dose increasing from 100 mg once daily to 200 mg once daily, and then 400 mg once daily. The final dose of venetoclax should be 400 mg in combination with azacitidine or decitabine or 600 mg in combination with low-dose cytarabine, unless dose adjustments are needed for AEs, renal impairment, or drug–drug interactions. The risk of TLS is highest in the initial 3 days of treatment and so we do monitor labs daily during that period.8,20
Now, let’s consider another patient case.
Venetoclax: Drug Interactions and Dose Adjustments
Courtney DiNardo, MD, MSCE:
There are a number of drug–drug interactions with venetoclax. The specific guidelines on management depend on whether you are in the US or different European countries, because there are different recommended dose reductions. However, the key is if you are using a moderate CYP3A4 inhibitor, you should be reducing the dose of venetoclax by approximately 50% and at least three quarters if you are using a strong CYP3A4 inhibitor like voriconazole, and posaconazole carries even stronger risks.
It is very important to be aware of what medications your patient is taking, advise them to let you know if anything changes, and ensure that you are reducing the venetoclax dose appropriately. Otherwise, you will have very high venetoclax concentrations and more toxicity, which is primarily cytopenias in patients with AML.
Caitlin Rausch, PharmD, BCOP:
These are some examples of commonly used CYP3A4 inducers and inhibitors. As mentioned, since azoles are frequently used in this population, HCPs should be aware of these recommendations for dose adjustment. However, HCPs should also be aware that strong and moderate CYP3A4 inducers should be avoided, if possible, because they will reduce the level of venetoclax in the system. In addition, P-gp inhibitors and P-gp substrates can cause drug–drug interactions. For P-gp inhibitors, the venetoclax dose should be reduced and concomitant use of P-gp substrates should be avoided.8
These drug–drug interactions should also be considered during the ramp-up stage of dosing. In patients who are receiving an azole antifungal where the goal dose of venetoclax is lower, the dose ramp-up should be done at lower doses. For example, if your patient is receiving isavuconazonium sulfate or fluconazole, 200 mg is your goal dose of venetoclax, so you would do 50 mg, 100 mg, and then 200 mg to get to that dose.
Anti-infectious Prophylaxis With Venetoclax: Recommended Dose Reductions in VIALE and US Label
Courtney DiNardo, MD, MSCE:
Patients with AML beginning therapy with a venetoclax-based regimen face an increased risk of infections due to their disease and the risk of prolonged neutropenia, which is a common AE with venetoclax. This risk is particularly heightened in the early phase of treatment, necessitating close monitoring and the use of prophylaxis.
Regarding anti-infectious prophylaxis with venetoclax, we tend to start all patients on an antibiotic, an antiviral, and an antifungal. For the antibiotic, we typically recommend levofloxacin. It is important to note that ciprofloxacin is a moderate inhibitor of CYP3A4, so concomitant use of ciprofloxacin necessitates a dose reduction for venetoclax.
At my institution, we do see fungal infections frequently and so ‘triple antimicrobial prophylaxis’ is recommended for patients with AML until they are in a durable remission.8,16,22-24
Supportive Management: G-CSF Use With AZA + VEN in VIALE-A
Courtney DiNardo, MD, MSCE:
Granulocyte-colony stimulating factor (G-CSF) use is very effective in patients with AML who are experiencing neutropenia due to venetoclax while in remission. Historically, there was concern that giving G-CSF to patients with myeloid malignancies may stimulate myeloid blasts and exacerbate their cancer, but for patients in remission, data suggest that this is not the case. In an analysis from VIALE-A, patients who had received G-CSF were compared to those who had not received G-CSF and not only were there fewer days of grade 3 neutropenia and fewer days of febrile neutropenia, patients receiving G-CSF had similar, or slightly improved, survival to those patients who did not.
Overall, use of G-CSF is safe and appropriate in patients in remission with ongoing neutropenia using venetoclax combinations.25
Venetoclax: Hematologic Toxicity Management in AML
Courtney DiNardo, MD, MSCE:
As mentioned, cytopenias, particularly neutropenia, are common in patients with AML receiving venetoclax-based therapy. Managing these cytopenias is crucial to keeping patients on therapy long-term. In VIALE-A, 43% of patients with AML experienced grade ≥3 neutropenia when treated with venetoclax in combination with azacitidine.18,24
Patients should be monitored by assessing complete blood counts throughout the treatment period. According to the venetoclax prescribing information and clinical guidelines, the management of grade 4 neutropenia (with or without fever or infection) or grade 4 thrombocytopenia should be tailored based on the occurrence timing relative to achieving remission.
Prior to remission, treatment with venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine should not be held. For these patients, bone marrow evaluation is recommended. For patients who do achieve remission, if grade 4 cytopenias recur, HCPs should consider holding the venetoclax regimen until the AE resolves and then continue therapy at the same dose. For recurrent grade 4 cytopenia, the venetoclax regimen should be held until the AE resolves and then resumed with a reduction in duration of venetoclax in subsequent cycles, typically shortening the venetoclax administration from 28 days to 21 days in combination regimens. The use of supportive measures, such as G-CSF, can be considered to mitigate prolonged neutropenia, alongside monitoring and adjusting venetoclax dosing to balance efficacy and tolerability.
In most patients receiving 6 or more cycles of venetoclax in combination with azacitidine in ongoing remission, patients received 21 days of venetoclax over 5-week cycles, and about 50% of patients received G-CSF support.18
Now, let’s go back to our patient case.
Conclusions
Courtney DiNardo, MD, MSCE:
In both AML and CLL, the use of venetoclax requires careful management to mitigate the risk of TLS, particularly during the initial ramp-up phase of therapy. In CLL, a more gradual weekly dose escalation is necessary due to the higher risk of TLS from bulky disease, making hospitalization and intensive monitoring important in high-risk patients. Prophylaxis with hydration and allopurinol, or rasburicase in some cases, is recommended, with labs closely monitored during the ramp-up.
In AML, the ramp-up is quicker (over 3-4 days) due to the lower TLS risk, but prophylaxis and dose adjustments based on TLS risk factors like high leukemic burden or impaired renal function are still essential. AE management, particularly neutropenia, is critical in both diseases. In CLL, venetoclax is often combined with CD20 mAbs, leading to frequent neutropenia, which may require dose interruptions and growth factor support. In AML, where venetoclax is used with hypomethylating agents, similar strategies are employed, with the added importance of adjusting venetoclax duration in each cycle to balance efficacy and toxicity for long-term treatment, along with supportive measures like G-CSF to manage cytopenias.
By implementing appropriate dose ramp-up strategies, prophylactic measures for TLS, and proactive management of AEs such as neutropenia, HCPs can optimize venetoclax therapy in both AML and CLL, improving patient outcomes while minimizing treatment-related complications. This comprehensive approach ensures that patients can maintain long-term therapy, enhancing both efficacy and quality of life.
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