Chronic lymphocytic leukemia (CLL) is a lymphoproliferative B-cell disorder prevalent in the aging population.¹ In 2018, an estimated 195,000 people were living with CLL in the United States, and the annual incidence is approximately 20,100 new cases per year.² The median age at diagnosis for CLL ranges from 70 to 72 years, with only 9.1% of patients being younger than 45 years of age.¹ Although mostly indolent in nature, CLL is characterized by the clonal proliferation and accumulation of mature B-cells that is usually initiated by the loss or addition of large chromosomal material (deletion 13q, deletion 11q, and trisomy 12).¹ Additional mutations following the initiating events can mediate an aggressive disease course, and high-risk disease has been associated with 17p deletions or TP53 gene mutations or unmutated immunoglobulin heavy chain genes (IGHV) or 11q deletion.

Although a watch-and-wait approach is suitable for asymptomatic patients, those presenting with Rai stages 2–4, bulky adenopathy, constitutional symptoms, immune-mediated complications related to CLL, or repeated infections will require antileukemic therapy.¹ Until recently, standard first-line treatment for CLL consisted of a combination of chemotherapeutic agents and anti-CD20 antibodies such as fludarabine, cyclophosphamide, and rituximab (FCR); bendamustine and rituximab (BR); or chlorambucil and obinutuzumab.³ The advent of Bruton’s tyrosine kinase (BTK) inhibitors and of the BCL2 inhibitor venetoclax has transformed the treatment paradigm for CLL in the front-line as well as relapsed/refractory settings.⁴ Indeed, the U.S. Food & Drug Administration (FDA) approval of ibrutinib, a first-generation irreversible BTK inhibitor, in 2014 marked the beginning of the era of targeted therapies in CLL.⁵

Hagop Kantarjian, MD, Professor and Chair of the Leukemia Department at The University of Texas MD Anderson Cancer Center, echoed that “The introduction of BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, and of venetoclax has provided oral targeted therapy options for our patients with CLL, as well as the potential of cure for CLL with a time-limited combination approach, thereby revolutionizing the treatment of this disease.”

BTK Signaling in CLL

BTK is an important component of the signaling cascade mediated by the B-cell receptor that is critical for the survival of both normal and malignant B cells.⁵ Upon antigen binding to the surface immunoglobulin, BTK is activated by upstream Src-family kinases and the Syk kinase, which further signals through phosphorylation and activation of the phospholipase Cγ2.⁶ This process is accompanied by calcium mobilization that ultimately leads to activation of the nuclear factor kappa B, Akt serine/threonine kinase, and mitogen-activated kinase pathways, followed by proliferation and migration of B cells.⁶ In CLL cells, BTK is known to mediate interaction with the tumor microenvironment and promote their survival and progression.⁷ BTK deficiency in a CLL-like mouse model led to delayed development of lymphogenesis and reduced leukemia infiltration.⁸ Similarly, inhibition of BTK in vivo was associated with diminished tumor formation. On the other hand, overexpression of BTK correlated with an increased incidence of cancer and poor outcomes.⁸ It was therefore not surprising that pharmacologic inhibition of BTK activity in CLL resulted in increased apoptosis of cancer cells.⁷ Consequently, small-molecule BTK inhibitors have been developed in an effort to target B-cell signaling in CLL and treat it.

Three BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of B-cell malignancies.^4,5 Although ibrutinib and acalabrutinib are approved for CLL and are in clinical use, zanubrutinib has shown similar efficacy in clinical trials and is currently under review by the FDA for the treatment of CLL.^4,5

BTK Inhibition Monotherapy in the Front Line

Single-agent ibrutinib initially showed clinical efficacy and tolerability in a phase I study of patients with relapsed/refractory B-cell lymphoma and CLL with an overall response rate of 60%, complete remission rate of 16%, and median progression-free survival of 13.6 months.⁹ Subsequently, in a phase Ib/II study, an overall response rate of 87%, complete remission of 35%, and estimated 7-year progression-free survival of 83% were reported for first-line single-agent ibrutinib in elderly patients with treatment-naive CLL.¹⁰ In the Alliance A041202 trial, monotherapy with ibrutinib was compared to chemoimmunotherapy with BR and resulted in a higher progression-free survival at 2 years (87% vs 74%). The toxicity profiles of ibrutinib and BR differed markedly, in that ibrutinib was associated with more nonhematologic adverse effects (ie, atrial fibrillation, hypertension, and infection) as compared to BR.¹¹

The approval of ibrutinib was based on data from the phase III RESONATE-2 trial that randomly assigned 269 older adults with CLL to receive either once-daily single-agent ibrutinib until disease progression or unacceptable toxicity or chlorambucil up to 12 cycles.¹² Recently, up to 8 years of follow-up data were presented that continued to demonstrate the superiority of ibrutinib, with an overall response rate of 92% and a progression-free survival of 59% for ibrutinib vs 9% for chlorambucil treatment at 7 years (Table 1).^13,14 According to Kerry Rogers, MD, a hematologist-oncologist at The Ohio State University Comprehensive Cancer Center, “Ibrutinib is a well-studied BTK inhibitor with the longest follow-up evidence. While acalabrutinib and zanubrutinib have better toxicity profiles due to minimal off-target effects, they are associated with more limited but promising phase III trial data.”

The ELEVATE-TN trial evaluated acalabrutinib monotherapy vs acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab in 535 treatment-naive elderly patients with CLL and reported an estimated 30-month progression-free survival of 90%, 82%, and 34%, respectively.¹⁵ Acalabrutinib has been studied for up to 4 years of follow-up with an estimated progression-free survival of 77.9% and an overall response rate of 89.9%; in the ELEVATE-TN trial, it was less commonly associated with grade 3 or higher atrial fibrillation (1.1%) and hypertension (2.8%) and had an increased incidence of transient headache (38%, any grade).^16,17 Similarly, zanubrutinib monotherapy is currently being studied in cohort 1 of the SEQUOIA trial and has been associated with an overall response rate of 94.6% and progression-free survival of 85.5% with a follow-up of 2 years.¹⁸

In light of this evidence, the most recent National Comprehensive Cancer Network (NCCN) Guidelines have listed all three BTK inhibitors as preferred regimens for the front-line setting of CLL treatment, with a category 1 recommendation for ibrutinib and acalabrutinib.¹⁹ However, since single-agent BTK inhibitor therapy in the first-line setting is intended be continued indefinitely, the issues of medication adherence as well as higher costs have led to interest in combining BTK inhibitors with other agents.²⁰

Combination Therapy With BTK Inhibition

BTK Inhibitors With Anti-CD20 Agents

The third arm of the Alliance A041202 trial compared the efficacy of ibrutinib plus rituximab with ibrutinib monotherapy and BR among elderly patients with untreated CLL and indicated that the addition of rituximab to ibrutinib did not provide any advantage (Table 2).¹¹ The addition of obinutuzumab to ibrutinib appeared to show a benefit in the iLLUMINATE trial as opposed to obinutuzumab plus chlorambucil.²¹ In contrast, acalabrutinib plus obinutuzumab treatment in the first line was associated with improved overall response rate (96.1% vs 89.9% vs 82.5%) and complete remission rates (27.7% vs 11.2% vs 13%) vs acalabrutinib alone and chlorambucil plus obinutuzumab, based on data from the ELEVATE-TN trial.^15,16 To that end, acalabrutinib in combination with obinutuzumab has a category 1 recommendation in the latest NCCN Guidelines for front-line therapy of CLL.¹⁹ Dr. Rogers noted that “The only significant progression-free survival difference is with obinutuzumab added to acalabrutinib, and this small improvement must be weighed against the increased toxicity of the anti-CD20 monoclonal antibody.”

BTK Inhibitors With Venetoclax

“The introduction of the BCL2 inhibitor venetoclax is another crucial milestone in CLL treatment paradigms,” emphasized Dr. Kantarjian. “This paved the way for fixed-duration combination therapy regimens in CLL,” he added. The CLL14 phase III study corroborated that a time-limited regimen of 6 cycles of obinutuzumab with 12 cycles of venetoclax among untreated patients with CLL led to a 50% complete remission rate and undetectable measurable residual disease (uMRD) in the bone marrow (BM, 57%) and peripheral blood (PB, 76%) 3 months after completion of venetoclax treatment.²² This doublet is also listed in the latest NCCN Guidelines for front-line therapy of CLL as preferred therapy for front-line CLL, with a category 1 recommendation.¹⁹ Dr. Rogers cautioned, “The combination of venetoclax and obinutuzumab, however, necessitates infusions for obinutuzumab and monitoring for tumor-lysis syndrome, which could be cumbersome for many patients.” She agreed that oral therapy, even if continued indefinitely, is usually preferred by most patients and so a fixed-duration combination of BTK inhibitors with venetoclax is an attractive option. In a phase II trial, the combination of ibrutinib and venetoclax showed 75% BM uMRD as a best response among patients with untreated high-risk CLL.²³ Dr. Kantarjian confirmed, “Achievement of uMRD correlates with prolonged progression-free survival and overall survival. Although remission with uMRD is uncommon with ibrutinib treatment, this has been observed with venetoclax… I believe fixed-duration combinations of BTK inhibitors with venetoclax have a lot of potential in front-line CLL.”

Based on results to date, the fixed-duration combination of BTK inhibitor plus venetoclax can be suggested for all patients with CLL. HAGOP KANTARJIAN, MD

The CAPTIVATE study included treatment-naive patients with CLL who were less than 70 years of age and received 3 cycles of ibrutinib followed by 12 cycles of combined fixed-duration ibrutinib plus venetoclax.²⁴ The best uMRD rate for this fixed-duration cohort was 75% in PB and 68% in BM.²⁵ After the 12 cycles of venetoclax, patients with confirmed uMRD were randomly assigned to placebo or ibrutinib, and those without uMRD were randomly assigned to either ibrutinib or ibrutinib plus venetoclax. Interestingly, the 30-month progression-free survival is estimated to be more than 95% across all arms with tolerable adverse events²⁶ (Table 3).

Data from the phase III GLOW trial comparing the efficacy of ibrutinib plus venetoclax with obinutuzumab plus chlorambucil among elderly unfit untreated patients with CLL have also been reported recently.²⁷  The 30-month progression-free survival was 80.5% in the ibrutinib plus venetoclax arm vs 35.8% in the obinutuzumab plus chlorambucil arm. The best uMRD rates were also higher in the ibrutinib plus venetoclax arm (43.4% in PB and 40.6% in BM).²⁷ Cohort 3 of the SEQUOIA trial is currently investigating the efficacy of zanubrutinib in combination with venetoclax among patients with untreated CLL and high-risk features.²⁸ A 1-year analysis reported an overall response rate of 97.2% and a complete remission rate of 13.9% for the combination of zanubrutinib plus venetoclax.²⁸ Triplet regimens combining BTK inhibitors with obinutuzumab and venetoclax have also been investigated in early-phase studies and have reported promising uMRD rates (Table 3).²⁰ Ongoing phase III trials are expected to clarify the utility of adding obinutuzumab to the doublet of BTK inhibitors and venetoclax.

Perspectives on Front-Line Therapy

The introduction of BTK inhibitors and venetoclax have heralded the possibility of chemotherapy-free regimens for the upfront treatment of CLL. The latest version of the NCCN Guidelines suggests acalabrutinib with or without obinutuzumab, or ibrutinib or venetoclax plus obinutuzumab for most patients with treatment-naive CLL.¹⁹ Since zanubrutinib is not yet approved by the FDA for CLL, it can only be provided in a clinical trial setting despite it being listed as a preferred front-line therapy. Importantly, the guidelines do not recommend one BTK inhibitor over another and in the absence of head-to-head trials, these treatment decisions require an individualized approach based on patient-, therapy- and disease-related factors.

Patient preference plays a key role in front-line therapy decisions for CLL. The route of administration and toxicity profiles of treatment regimens need to be carefully weighed among patients with frailty and comorbidities. KERRY ROGERS, MD

“Patient preference plays a key role in front-line therapy decisions for CLL,” Dr. Rogers noted. “The route of administration and toxicity profiles of treatment regimens need to be carefully weighed among patients with frailty and comorbidities.” For instance, BTK inhibitor therapy can be suggested for patients who have reservations against intravenous infusions and frequent clinic visits to start treatment. For those with cardiovascular comorbidities where BTK are needed, acalabrutinib or zanubrutinib can be suggested due to the lower cardiovascular events compared to ibrutinib. For those taking proton-pump inhibitors, ibrutinib should be recommended. “Based on results to date, the fixed-duration combination of BTK inhibitor plus venetoclax can be suggested for all patients with CLL,” said Dr. Kantarjian. “With overall response rates and molecular responses above 90% with BTK inhibitors plus venetoclax therapy—which are quite sustained in most patients after stopping therapy—I believe that we are now closer than ever to achieving a functional cure in CLL,” he concluded.