For Treatment-Naïve CLL: The Risks & Benefits of Time-Limited Therapy vs. Continuous Therapy

Chronic lymphocytic leukemia (CLL) stands out as one of the most diverse and unpredictable hematologic malignancies. However, the landscape of CLL management has undergone a remarkable transformation over the past two decades. Breakthroughs in therapeutic options, combined with a profound understanding of disease biology, have not only revolutionized treatment strategies but have also paved the way for the development of critical prognostic markers.

These advancements are not just milestones; they represent a new era in which we can offer more personalized and effective care to our patients.

Dr. Adam Kittai, an associate professor at the Icahn School of Medicine at Mount Sinai and a practicing malignant hematologist, tells SurvivorNet Connect that a patient-centered therapeutic approach, which aligns with the patient’s goals and values, represents the best practice in managing care.

“What I really take in consideration is what the patient wants. Do they want a time-limited therapy, or do they want a continuous therapy? And really, patient preference is what I use as my determining decision about what to treat that patient with,” he says. 

When Should Therapy Begin? Key Indications

CLL is currently treated at the onset of marrow failure or symptoms related to the disease, as established by the International Working Group. This approach is grounded in the findings of several randomized phase 3 trials, which have not shown a survival benefit for initiating treatment early. The indication for therapy includes:

• Progressive marrow failure
• Advanced Stage (Binet C, Rai 3 or 4)
• Massive, enlarging, or symptomatic splenomegaly
• Massive, enlarging, and/or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of > 50% over a 2-month period or lymphocyte doubling time < 6 months
• Autoimmune hemolytic anemia and/or thrombocytopenia inadequately responsive to glucocorticoids
• Symptomatic or functional extranodal involvement
• Disease-related symptoms: weight loss ≥10% over 6 mo, significant fatigue, fevers for 2 or more weeks without infection, night sweats ≥1 mo without infection

Selecting the Optimal Therapeutic Strategy

Estimating survival outcomes with contemporary CLL therapies that include novel agents remains challenging due to the relatively short follow-up periods in trials evaluating these combinations. With the advent of these innovative treatments, expected OS can vary widely, ranging from a few years to several decades, influenced by the disease’s characteristics, patient-specific factors, and the therapeutic strategies employed.

There is no universally accepted standard regimen for front-line treatment of chronic lymphocytic leukemia (CLL), leading to variations in clinical practice. This choice should be guided according to:

• Genetic risk stratification of the tumor
• Patient comorbidities and concurrent medications
• Patient preferences and treatment objectives
• Practical considerations and logistics

Management Strategies: Time-Limited Therapy 

The choice among targeted agents is strongly dependent upon patient comorbidities and preferences. Fixed-duration therapy is more intensive and logistically complicated but offers a treatment-free interval. In this context, the current options are venetoclax plus obinutuzumab, administered over one year, or ibrutinib plus venetoclax, administered over 15 months.

“If a patient wants time-limited therapy, they have to understand that the first couple of weeks of this time-limited therapy, they have to come into clinic weekly in order to get their infusion of obinutuzumab for the first three weeks in a row, and we have to monitor their labs when we start Venetoclax to make sure that we’re not running into the issues with tumor lysis syndrome,” Dr. Kittai says. 

Venetoclax combined with obinutuzumab may be favored over Bruton tyrosine kinase (BTK) inhibitors in patients with cardiovascular disorders, uncontrolled hypertension, or a high risk of bleeding, such as those with low platelet counts or conditions necessitating anticoagulation. Additionally, venetoclax should be avoided in patients using a nephrotoxic drug and those taking a strong  CYP3A inhibitor due to the increased risk of developing tumor lysis syndrome (TLS).

Venetoclax paired with obinutuzumab provides a concentrated treatment regimen over the course of one year, followed by a planned break from therapy. For patients who show disease progression after a sustained response, a second cycle of this treatment may be considered.

Venetoclax is administered orally, while obinutuzumab is given intravenously. The initiation of this treatment necessitates frequent monitoring for TLS, requiring regular clinic visits. The most commonly observed toxicities include neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infections, cough, musculoskeletal pain, fatigue, and edema.

Conversely, the combination of ibrutinib and venetoclax offers an all-oral treatment regimen. While initiation includes TLS prophylaxis and monitoring, the logistics are simpler compared to the venetoclax and obinutuzumab regimen. The most frequently reported toxicities include neutropenia, diarrhea, and hypertension. The occurrence of clinically significant TLS remains rare.

Management Strategies: Continuous Therapy 

The main treatment option for most patients is a BTK inhibitor, with acalabrutinib or zanubrutinib being preferred over ibrutinib.

In this setting, Dr. Kittai shares that “if somebody comes in and they’re saying, wait a minute, I don’t really need to have time-limited therapy. I’d rather have an easier option where it doesn’t require so much therapy upfront, where it doesn’t require so much monitoring upfront, then I usually air towards a covalent BTK inhibitor with acalabrutinib or zanubrutinib.”

BTK inhibitors are administered orally and are typically continued until either disease progression or the emergence of unacceptable toxicity. Although the highest toxicity levels are observed within the first six months of treatment, these adverse effects can persist throughout the course of therapy. Significant toxicities associated with BTK inhibitors include bleeding, atrial fibrillation, and hypertension. Additional side effects may involve fatigue, rash, infections, and musculoskeletal pain. The toxicity profile is a critical factor in selecting among the various BTK inhibitors available.

In the treatment-naïve setting, acalabrutinib has shown superior progression-free survival (PFS). It can be administered as a monotherapy or in combination with obinutuzumab. It is suitable as a single agent for patients across all age groups, with a standard oral dosage of 100 mg twice daily, continued until disease progression or the emergence of unacceptable toxicity.

Acalabrutinib has multiple drug interactions that may require either avoidance or dose adjustments. For instance, acalabrutinib and other BTK inhibitors are typically avoided in patients on anticoagulation therapy, particularly those taking warfarin. Additionally, acalabrutinib should be avoided in patients with severe hepatic impairment.

The most common adverse effects associated with acalabrutinib include anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infections, and diarrhea. However, there are also serious, potentially life-threatening toxicities, such as opportunistic infections, bleeding, arrhythmias, and the development of secondary primary malignancies.

The second alternative option, zanubrutinib, has also demonstrated an improvement in PFS in treatment-naïve patients. Zanubrutinib is taken orally, with dosing options of either 160 mg twice daily or 320 mg once daily and is continued until there is either disease progression or the development of unacceptable toxicity.

The most frequently encountered toxicities with zanubrutinib include bleeding, upper respiratory tract infections, diarrhea, joint pain, and cardiac events. Consequently, zanubrutinib and other BTK inhibitors are typically avoided in patients with cardiovascular conditions, uncontrolled hypertension, or a heightened risk of bleeding, such as those with a history of major bleeding events.

It is important to note that these two agents have not been compared directly. Nevertheless, if the main goal is the best efficacy with acceptable tolerability, zanubrutinib should be offered. On the other hand, if the goal is best tolerability with good efficacy, acalabrutinib should be considered as the first choice. 

Choosing the right drug for your patient is a complex process.

“These two drugs are very similar, have similar side effect profiles, and similar efficacy,” Dr. Kittai adds. “And ultimately, it’s your choice about which drug you think you want to use for your patients and get familiar with one and how to use it.”