Clinical Challenges: Complications of CLL

Chronic lymphocytic leukemia (CLL) is a disease of older age, diagnosed typically at age 70, but life expectancy has increased substantially, according to one expert.

“About 30% to 40% of patients will never require treatment. We tell them, ‘You’re going to die with CLL, not of it,'” explained Stanley Marks, MD, chair of the Hillman Cancer Center at the University of Pittsburgh School of Medicine.

Thanks to newer treatments, some patients will survive 10 years or more after diagnosis, but will deal with disease-specific consequences.

CLL, COVID, and More

“The most common serious complication is infection, because of the reduced immune function of CLL patients,” said Shuo Ma, MD, PhD, of Northwestern University Feinberg School of Medicine in Chicago. “So avoiding exposure to pathogens and taking protective measures against infection are very important, especially during the current COVID-19 pandemic.” The familiar precautions of sequestration during outbreaks, masking, and hand hygiene need to be observed.

And even if CLL patients are not on treatment and are vaccinated against COVID-19, they still do not make sufficient antibodies. “So if they get COVID, they get a more serious form and do very poorly, with a mortality rate of 20% to 30%,” Marks said.

A recent international study found CLL patients with symptomatic COVID-19 had a high mortality rate when requiring inpatient admission (37%), and that among patients who were discharged or died, the overall case fatality rate was 50%. In addition, watch-and-wait and treated patients had similar rates of admission (89% vs 90%), ICU admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%).

“We tell CLL patients to behave as if they were never vaccinated, and if they become exposed, they need to get monoclonal antibodies immediately to lessen the severity,” Marks said.

Another immunodeficiency-related complication is secondary malignancies, of which skin cancer is the most common. “So CLL patients need to have their skin checked every 6 months,” Marks said. A small percentage of CLLs will evolve into the aggressive lymphoma known as Richter’s transformation. “This is very difficult to treat and is usually fatal,” he added.

While occasionally a patient with CLL may require blood transfusion, owing to anemia from reduced red blood cell production, bone marrow transplantation is not done, according to Marks, who added that “Historically, this [transplantation] was typically done in young CLL patients.”

Autoimmune anemia is another notable complication of CLL, and the treatment is steroids, Marks noted.

Targeted Therapy

The basic complications of CLL have not changed much, but the treatments have, noted Ma: “We now have very effective targeted therapies for CLL.”

Current practice relies less on chemotherapy and more on targeted treatments, which can improve outcomes even for carriers of the high-risk genes TP53 or del(17p), but these patients can experience several adverse consequences from these treatments.

Brian T. Hill, MD, PhD, director of the Lymphoid Malignancies Program at the Cleveland Clinic Taussig Cancer Center, outlined the complications of some contemporary targeted agents in the three major classes.

First, there are the FDA-approved monoclonal antibodies, rituximab (Rituxan), ofatumumab (Arzerra), and obinutuzumab (Gazyva).

“Most oncologists are familiar and comfortable with the complications associated with monoclonal antibodies, which are mainly infusion reactions in the first day or so, but most patients get on fairly well with monoclonal antibodies,” Hill said.

Side effects are mainly flu-like symptoms such as chills, fever, headaches, and nausea, typically treated with fluids and acetaminophen, while less common complications include tachycardia, rash, and dyspnea.

Novel inhibitors are effective in both treatment-naive and refractory CLL, and these include the Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). However, BTK inhibitors can cause diarrhea, bruising, and potentially minor bleeding to varying degrees.

In 2020, the American Society of Hematology published guidance on dealing with the complications of BTK inhibitors.

“The majority of patients don’t experience these toxicities, but there are nuanced differences in potential side effects between the various drugs in this class,” Hill said. “Patients on these agents need to be followed up within a day or two of starting treatment.”

“They should also avoid taking other blood thinners such as aspirin and Coumadin [warfarin],” Hill said. To prevent bruising they should take care not to fall or bang into objects. The medication should be withheld at least 3 days before biopsy or elective surgery. Some patients develop back pain owing to increased uric acid levels and should receive allopurinol, he said.

One potentially serious side effect of BTK inhibitors, particularly with ibrutinib, is cardiovascular distress, including atrial fibrillation and hypertension. “Not everyone has these, but those who do need to be closely monitored and treated by a cardiologist,” Hill said. In some high-risk cases, this class of drugs should not be used.

With the novel BCL2 inhibitor venetoclax (Venclexta), there is no bruising or bleeding, Hill said. Package guidance for this agent recommends a 5-week ramp-up, sometimes with a half dose for the first two doses, and appropriate monitoring. The main complication is too-rapid tumor lysis, a syndrome managed with IV hydration, which can often be done in the outpatient setting. “You don’t usually get this with the standard ramp-up, but if it occurs, you can interrupt treatment and resume at a lower dose,” he said.

Some recipients of this agent will develop back pain caused by excessive levels of uric acid and will need allopurinol to reduce concentrations.

“The newer treatments are significantly better and the toxicities are generally manageable,” said Hill. “But the side effects are different from those of traditional chemotherapy and it’s important to be aware of them.”