Managing Venetoclax for CLL

Danielle Brander, MD:The key toxicities when considering venetoclax therapy are primarily focused on TLS, or tumor lysis syndrome, management. That is, when you target BCL-2 and take away that antiapoptosis, there can be a lot of cell turnover and death, particularly if patients have bulkier disease. Bulkier disease is defined not only in the size of the lymph node, but also in the presence of high white blood cell count for CLL patients. Therefore, when you consider this as the most important toxicity to consider when you’re treating patients with venetoclax, it helps to understand why the dosing strategies through the clinical trials have been established.

All patients who initiate venetoclax are recommended to start in the dose ramp-up phase over the period of 5 weeks to achieve the targeted daily dose, which for CLL is 400 mg. Therefore, all patients will start at 20 mg and each week progress through the recommended ramp-up phase.

Whether patients are starting their venetoclax in the outpatient or clinic setting, versus whether they start in a monitoring inpatient hospital setting, really depends on their burden of disease. For patients with moderate or high burden of disease, these are the patients with increasing size of their lymph nodes or white blood cell count that is approaching over 25. It’s recommended that these patients be admitted for tumor lysis monitoring. That is, patients start on allopurinol or another medication to lower their uric acids. They’re given IV fluids and cardiac monitoring prior and subsequent to their first dose. Patients who do well during their initial phases can then move to the outpatient setting where labs are checked prior to the dose ramp up, 6 to 8 hours after the dose ramp up, and the following morning. Again, you’re checking the tumor lysis labs to ensure that patients are not having any change in their electrolytes, their renal function, or any other markers of tumor lysis that would require active intervention and be prone to intervention.

The dosing guidelines and labeling for venetoclax outline what is considered a low, an intermediate or moderate, or a high tumor burden. And these are great guidelines to use when assessing a patient to consider whether they can start their treatment inpatient or outpatient. They’re also very helpful in understanding, even if the first dose escalations are required inpatient, patients who do well who can then move their third, fourth, or fifth week escalation to the outpatient setting.

The portion of this that I would point out is just that these are rough guidelines to consider. And any patient who has additional factors, such as lower renal function or are coming directly from another targeted inhibitor where the risk of switching directly from one therapy to the next is high, you may consider this patient for an inpatient evaluation and monitoring while they’re treated, even if they currently fall at a lower tumor burden.

The second factor to consider in terms of toxicity management for venetoclax is, even for patients without tumor lysis, some patients can develop cytopenias, and this does appear in multiple studies to be a true treatment of fact. The most common of this is neutropenia. And while patients can be managed through this period, it’s important to recognize that this may develop and to manage patients accordingly.

Transcript edited for clarity.

Case: An Older Patient with Relapsed CLL

March 2015

• A 70-year-old female reported symptoms of weight loss, fatigue, and pain in the upper left portion of her abdomen
• PE showed moderate axillary lymphadenopathy and splenomegaly, spleen palpated 7 cm below the costal margin
• Otherwise, the patient is overall well-appearing and continues to exercise
• Laboratory results:
  • WBC, 48,000; 73% lymphocytes
  • Hb, 10 g/dL (1 year ago Hb, 12 m/dL)
  • Platelets, 125,000/mm³(1 year ago platelets, 165,000/mm³)
  • ANC 1,800/mm³(WNL)
  • LDH, 250 U/L
  • Beta-2-microglobulin, 4.2 µg/L
• Cytogenetics by FISH showed 17p deletion in 56%
• IgVH unmutated
• Bone marrow biopsy; diffuse infiltration by CLL
• The patient was enrolled in a clinical trial and was treated with ibrutinib 420 mg daily
• After 18 months, she achieved complete remission of her disease and resolution of her symptoms

November 2017

• The patient developed had developed atrial fibrillation and despite cardiology interventions could not restart ibrutinib
• During routine follow up, the patient reported increasing fatigue
• PE: cervical lymphadenopathy, ~4 cm; spleen, palpable 8 cm below the costal margin
• Normal kidney function
• Laboratory results:
  • ALC; 112,000 cells/mL
  • Hb; 10.8 g/dL
  • Platelets; 105,000 cells/mm³
• The patient was started on venetoclax