Venetoclax

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease that are managed in much the same way. The most common type of leukemia in adults,¹ CLL/SLL has traditionally been treated with a number of chemoimmunotherapy regimens, such as fludarabine, cyclophosphamide, and rituximab (FCR); chlorambucil and obinutuzumab; or bendamustine and rituximab (BR).² However, with the advent of targeted therapies and other novel agents, the role of chemoimmunotherapy in this hematologic malignancy is declining.³

Venetoclax (Venclexta), an inhibitor of BCL2, an antiapoptotic protein overexpressed in CLL,⁴ is one of those novel oral agents. It is currently approved for the treatment of adult patients with CLL or SLL.⁵ According to the NCCN Clinical Practice Guidelines in Oncology® (NCCN Guidelines®), venetoclax plus obinutuzumab is a preferred first-line regimen for frail patients with significant comorbidity or for patients 65 years of age or older as well as younger patients with significant comorbidities.⁶ Additionally, venetoclax plus rituximab is a preferred regimen (category 1) in the treatment of relapsed or refractory disease in all patient categories, including those younger than age 65 without significant comorbidities.⁶ Ongoing and planned clinical trials will continue to explore venetoclax-containing regimens in the front-line setting (ClinicalTrials.gov identifiers NCT03455517, NCT02950051, NCT03609593, NCT02242942).

According to Nitin Jain, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, other targeted options for patients with CLL in the relapsed or refractory setting include ibrutinib (Bruton’s tyrosine kinase [BTK] inhibitor), idelalisib (phosphatidylinositol 3-kinase [PI3K] delta inhibitor), and duvelisib (dual inhibitor of PI3K gamma and delta).⁶ However, all of these targeted agents are recommended for continuous use over an indefinite period.

In contrast, venetoclax, which is usually given in combination with obinutuzumab⁷ or rituximab but may also be given as a single agent, is administered for a shorter duration. In combination with rituximab, it is administered for 2 years (with rituximab for the first 6 months) and then stopped.⁴ In combination with obinutuzumab, it is given for 1 year (with obinutuzumab for the first 6 months). This use has been labeled “time-limited” or “fixed-duration” therapy and is associated with a number of important advantages, including reduced costs and toxicities over time, as well as a potentially lower risk for selected resistant mutations. Dr. Jain pointed out that only limited follow-up data are available about the durability of remissions in patients who have stopped venetoclax therapy at 2 years.

Evolution of First- and Next-Line Therapies for CLL/SLL

A number of presentations at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition and 2019 ASCO Annual Meeting are likely to be practice-changing, Dr. Jain pointed out, particularly in the first-line setting for CLL, and “may therefore have implications for the role of venetoclax in the relapsed setting.” The ECOG-ACRIN trial (E1912),⁸ which compared FCR vs ibrutinib plus rituximab in younger patients with CLL, showed that those who received the targeted therapy (plus rituximab) had improved progression-free and overall survival. However, these benefits were restricted to patients with unmutated immunoglobulin heavy chain gene (IgVH).

The Alliance North American Intergroup study (A041202)⁹ in older patients with CLL compared three treatment arms in the first-line setting: bendamustine plus rituximab, single-agent ibrutinib, and ibrutinib plus rituximab. The investigators found that both ibrutinib arms were better than the bendamustine arm in terms of progression-free survival, “but that rituximab did not add significantly to efficacy,” Dr. Jain told JNCCN 360.

These two trials add support to the use of ibrutinib in the front-line setting for patients with CLL, Dr. Jain said. “This means that more patients will have been exposed to targeted therapy when they experience disease relapse. Eventually, fewer patients will have received chemotherapy by the time they start treatment with venetoclax.”

In addition to the potential for delivering therapy for a fixed duration, venetoclax is extremely well tolerated.

Recently presented data showed that after 2 years of venetoclax therapy (combined with rituximab for the initial 6 months) in patients with relapsed and/or refractory CLL,¹⁰ patients who attained undetectable minimal residual disease in the peripheral blood have a low risk of further relapse, whereas those with higher levels of minimal residual disease at the 2-year mark are more likely to experience relapse in the future.

A ‘Well-Tolerated’ Regimen

In addition to the potential for delivering therapy for a fixed duration, venetoclax is extremely well tolerated, Josie Montegaard, MSN, AGNP-BC, with the CLL Center at the Dana-Farber Cancer Institute in Boston, told JNCCN 360.

The concept of tumor lysis syndrome can be daunting when it is first explained to patients, but prevention and monitoring are key. Ms. Montegaard noted, “We reassure patients that we are proactive about intervention, even when there has only been a tiny change in a lab result. The example I offer,” she added, “is about a slight increase in potassium level from 3.5 to 4.0 mEq/L, both of which are still normal results. However, that subtle change may indicate to the team the need to initiate more frequent monitoring or extra hydration.” The consequence, she explained, is there are rarely any clinical manifestations from tumor lysis syndrome.

For older patients who may have comorbidities such as cardiac dysfunction or who are at high risk for bleeding events, venetoclax remains an option, whereas a BTK inhibitor or chemotherapy probably is not.

Despite the risk for tumor lysis syndrome, “venetoclax is usually easier to tolerate than either the BTK inhibitors or chemoimmunotherapies,” Ms. Montegaard said. Therefore, “it is an attractive option for patients who prefer treatment to have as little impact on their daily lives and routines as possible. After the upfront time commitment [roughly a little more than 1 month] for dose escalation, therapy often proceeds smoothly, with few adverse effects. Patients live normal lives with follow-up visits every 2 to 3 months. As for older patients who may have comorbidities such as cardiac dysfunction or who are at high risk for bleeding events, venetoclax remains an option, whereas a BTK inhibitor or chemotherapy probably is not,” stated Ms. Montegaard.

Assessing Risk for Tumor Lysis Syndrome

Lymph Nodes and Lymphocytes

Assessment of risk for tumor lysis syndrome, according to the U.S. FDA guidance in the venetoclax prescribing information,⁵ is calculated on the basis of the absolute lymphocyte count in the blood and the size of the lymph nodes as measured on computed tomography scan.

“If all the lymph nodes are smaller than 5 cm and the lymphocyte count is less than 25,000 mL,” Dr. Jain explained, “the patient is classified as ‘low risk.’ In contrast, if any lymph node is 10 cm or larger or the lymphocyte count is 25,000 mL or higher and any lymph node is 5 cm or larger, the patient is classified as ‘high risk.’ Those who lie between these parameters are considered to be at ‘medium risk.’”

Patients who are classified as high risk will require hospitalization for the “ramp-up” period before and during each dose escalation, Ms. Montegaard explained. Hospitalization allows for close monitoring, as these patients are at highest risk for tumor lysis syndrome.

“After their baseline laboratory assessments are checked, they are admitted to the hospital with intravenous hydration the night before they take the initial dose. In the morning, their labs are checked again. If everything looks good, the patient takes his or her dose and is monitored sometimes as frequently as 4, 8, 12, and 24 hours after the dose. If there is no evidence of tumor lysis at the 24-hour mark, the patient may be discharged,” she said. This process, including brief hospitalization before and for the first 24 hours, is usually repeated until patients reach the 100-mg dose. “At that point, we move dose escalation to the outpatient setting, although in rare instances, patients may require brief admissions for dose escalation until the full dose is reached,” she explained.

Renal Function

The majority of patients with relapsed or refractory CLL are able to proceed safely with the dose-escalation process as outpatients.

Kidney function should be considered, and creatinine clearance should be checked. “Anyone with poor renal function is at higher risk of tumor lysis syndrome,” said Dr. Jain. In addition to patients considered to be at high risk because of lymph node size and/or lymphocyte count, “those with glomerular filtration rates less than 80 mL/minute require hospitalization for dose escalation.” Dr. Jain remarked that taken together, those at high risk—either because of tumor burden or poor renal function—represent roughly about 20% to 30% of patients; “the majority of patients with relapsed or refractory CLL are able to proceed safely with the dose-escalation process as outpatients,” he said.

Preparation and Premedication

Medications

Regardless of whether the dose ramp-up is inpatient or outpatient, Ms. Montegaard explained, “we start all patients with allopurinol about 3 to 7 days before the first venetoclax dose to prevent hyperuricemia, which is one of the elevated lab results in tumor lysis syndrome.” Additionally, due to the high risk for neutropenia in patients on venetoclax, anti-infection prophylaxis for herpes simplex virus may be started with acyclovir. The team at the Dana-Farber Cancer Institute also may start prophylaxis for Pneumocystis jirovecii pneumonia with trimethoprim-sulfamethoxazole.

Hydration

“When we first mention the option of venetoclax and begin the education process,” Ms. Montegaard noted, “we start talking about the importance of hydration, which includes 2 to 3 L/day, if possible, at home before the first dose. If the patient finds it difficult to consume a full 3 L, the minimum we recommend is 2 L during the ramp-up period. In fact, any type of fluid (water, juice, noncaffeinated soda) is acceptable as long as it is not caffeinated. That said, a morning cup of coffee is allowed, as long as fluid amounts are adjusted to compensate for caffeine’s dehydrating effect.”

Patient instructions by Dr. Jain’s team are slightly different compared with those described by Ms. Montegaard. “All patients, regardless of risk category, are encouraged to initiate vigorous oral hydration, with a goal of 1.5 to 2.0 L/day,” he said. This represents “about 6 to 8 glasses of water a day, so most patients are able to tolerate the increased fluid volume for a few weeks,” he said.

Venetoclax Dose Escalation

The teams at MD Anderson Cancer Center and the Dana-Farber Cancer Institute follow somewhat similar venetoclax administration procedures. For outpatients, blood is drawn in the clinic and “assuming that the results are satisfactory, the venetoclax dose is taken,” Ms. Montegaard said. The patient is then started on intravenous fluids, 150 mL to 200 mL/hour, for 7 to 8 hours. At that point, blood is drawn again. If there is no evidence of tumor lysis syndrome, the patient can go home. He or she will need to come to the clinic again the next morning to repeat the blood draw and do a 24-hour check for tumor lysis syndrome. “If everything still looks good, the patient can go back to his or her routines until the next week, when the process is repeated for the next dose increase,” she told JNCCN 360.

At MD Anderson Cancer Center, in contrast, only patients at intermediate and high risk for tumor lysis syndrome are given intravenous hydration; oral hydration is considered sufficient for those at low risk.

Venetoclax is supplied in 1-week blister packs for each dose. “This makes it easy for patients to know how much to take and whether they have taken each daily pill,” Ms. Montegaard pointed out. 

“We try to be transparent with patients about the initial ramp-up process and the time commitment that may be necessary. Although outpatients may expect to go home after a full day of hydration at each new dose level (checking back at the clinic on the next morning), abnormal lab results may mandate that they remain in the clinic or hospital until those values can be addressed and stabilized. Dealing with the unknown, namely, ‘Will the lab results be ok’ or ‘Will I have to stay in clinic?’ can be emotionally draining,” Ms. Montegaard noted.  

Monitoring During Dose Escalation

Fluid Status

The risk of tumor lysis is highest with the first two venetoclax dose levels, when tumor burden is highest. “If aggressive hydration (200 mL/hour) during the first 2 dose steps results in significant water weight gain,” Ms. Montegaard suggested that subsequent hydration can be reduced, perhaps to 150 mL/hour. “We don’t usually want to go below 150 mL/hour and might use furosemide to manage the fluid status rather than cutting too far back on hydration,” she added.

Potassium Level

These patients typically have a high white blood cell count, she explained, and sometimes “we see a sort of pseudohyperkalemia. We have to try to distinguish a true high potassium level—a sign of tumor lysis syndrome—from an artifact that occurs as a result of hemolysis due to the high white blood cell count. If we suspect that hemolysis is the culprit, we will take another sample with a direct stick, without a tourniquet, rather than from a preexisting intravenous site and then bring the blood on ice directly to the lab,” Ms. Montegaard explained. Another option if a high potassium reading is suspected to be pseudohyperkalemia is to “do another blood draw with a venous blood gas tube.”

Neutropenia

With the combination of venetoclax plus rituximab, the risk for grade 3 or 4 neutropenia is about 50% to 60%, Dr. Jain cautioned. “When this occurs as a first episode, we ask patients to hold the venetoclax dose and provide growth factor support. Once growth factor is on board, neutropenia should resolve quickly, within a few days, and venetoclax may be restarted at the same dose level. If neutropenia occurs again,” he noted, treatment may be restarted but at a lower dose.

Ms. Montegaard stressed the importance of alerting patients to the signs of infection and the need to report them promptly to the team. “We tell patients to take their temperature if they feel unwell or develop chills and to report whenever temperature is 100.5°F or higher. The neutrophil count can dip at any point during treatment. If the absolute neutrophil count is less than 1,000/mm³ or near that level but trending down, we may initiate growth factor support,” she told JNCCN 360.

Diarrhea

With regard to other adverse effects, Dr. Jain stated that loose stools are common with venetoclax. “In the clinical trials,^4,11,12 up to 30% of patients had all grades of diarrhea with venetoclax,” he said.

Nausea: Some patients report nausea with venetoclax, Ms. Montegaard said, “but we don’t usually provide antiemetics. In many cases, taking the drug with food and before bedtime can mitigate the nausea.” [Editor’s Note: The NCCN Guidelines for Antiemesis recommend providing antiemetic drugs for venetoclax, as needed.]

The First Days Are the Hardest

Acknowledging that some clinicians have concerns about the ramp-up period for venetoclax and the potential for triggering tumor lysis syndrome, Dr. Jain commented, “I would point out that although the 5-week dose escalation may seem somewhat intimidating, for patients at low risk, the most intensive monitoring and time commitment are required for the first 2 dose levels.” If there is no evidence of tumor lysis syndrome with the 20-mg and 50-mg doses, the process for subsequent dose escalations is streamlined.

“This is nicely outlined in the prescribing information for venetoclax,”⁵ Dr. Jain pointed out, “but many clinicians do not realize there is a difference between the first 2 weeks and the subsequent 3 weeks. It means that for the next 3 escalations—100 mg, 200 mg, and 400 mg—the patient will have his or her baseline lab assessments and take the medication in the clinic. But [the patient] is not required to have additional assessments that afternoon or the following morning, if they had no evidence of tumor lysis syndrome with the 20- and 50-mg doses,” he continued. In contrast, those at high risk will need to follow the more frequent monitoring process for each of the five dose escalations.

In conclusion, Ms. Montegaard advised other practitioners about the importance of “being transparent about the ramp-up schedule, so patients know exactly what kind of time commitment may be required before they reach the full dose. Once that initial period is completed, this is an easy regimen. It’s important to clarify everything that is done to prevent and monitor for tumor lysis syndrome and to reassure patients that clinical symptoms are rare.”

Disclosures

Nitin Jain, MD, has received research funding from AbbVie, Genentech, Pharmacyclics, BMS, and AstraZeneca and has received honoraria from AbbVie, Genentech, Pharmacyclics, and AstraZeneca.

Josie Montegaard, MSN, AGNP-BC, has served as an advisory board member for Janssen.

References

1. National Cancer Institute. Chronic lymphocytic leukemia treatment (PDQ)—health professional version. Available at: https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq. Accessed May 14, 2019.

2. American Cancer Society. Typical treatment of chronic lymphocytic leukemia. Available at: https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/treating/treatment-by-risk-group.html. Accessed May 14, 2019.

3. Jain N. Selecting frontline therapy for CLL in 2018. Hematology Am Soc Hematol Educ Program. 2018;2018:242–247.

4. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018;378:1107–1120.

5. Venclexta (venetoclax). FDA prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s013lbl.pdf Accessed July 23, 2019.

6. Wierda WG, Byrd JC, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 5.2019—May 23, 2019. Accessed July 23, 2019. To view the most recent version of these guidelines, visit NCCN.org.

7. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019;380:2225-2236.

8. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood 2018;132:LBA-4.

9. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression-free survival compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia: results of Alliance North American Intergroup Study A041202. Blood 2018;132:6.

10. Kater AP, Hillmen P, Eichhorst B, et al. First prospective data on impact of minimal residual disease on long-term clinical outcomes after venetoclax plus rituximab versus bendamustine plus rituximab: phase III MURANO study. Blood 2018;132:185.

11. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016;17:768–778.

12. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:311–322.