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Associate Professor of Medicine
Division of Hematology-Oncology
Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center
Shuo Ma, MD, PhD, has disclosed that she has received consulting fees from AbbVie, AstraZeneca, BeiGene, Janssen, and Pharmacyclics and funds for research support from AbbVie, AstraZeneca, BeiGene, Janssen, Juno, Loxo, Pharmacyclics, and TG Therapeutics.
The treatment landscape for chronic lymphocytic leukemia (CLL) continues to evolve at a rapid pace. In this commentary, Shuo Ma, MD, PhD, discusses emerging therapeutic strategies for patients with CLL, including novel BTK inhibitors and PI3 kinase (PI3K) inhibitors, BTK plus BCL-2 inhibitor combinations, and chimeric antigen receptor (CAR) T-cell therapy.
Combining Targeted Therapies: Ibrutinib Plus Venetoclax
Ibrutinib (a BTK inhibitor) and venetoclax (a BCL-2 inhibitor) are currently approved by the FDA for treating CLL and are now standard of care therapies for patients with this disease. Because of their high efficacy and nonoverlapping mechanisms of action, it was hypothesized that the benefits of combining these agents may include a synergy of efficacy and a reduction in venetoclax-related tumor lysis syndrome (TLS) with initial ibrutinib treatment. We now have data on this approach from earlier-phase studies, as well as 2 phase III studies (GLOW and CAPTIVATE).
GLOW is an ongoing, randomized phase III study comparing ibrutinib plus venetoclax (given as fixed-duration therapy with a 3-month ibrutinib lead-in) with chlorambucil plus obinutuzumab as frontline therapy in patients with treatment-naive CLL who are aged ≥65 years or <65 year with comorbidities. At a median follow-up of 27.7 months, ibrutinib plus venetoclax significantly prolonged progression free survival (PFS) compared with chlorambucil plus obinutuzumab, reducing the risk of progression or death by almost 80% (median PFS: not reached vs 21.0 months; HR: 0.216; P <.0001). Complete response (CR)/CR with incomplete blood count recovery (CRi) and undetectable measurable residual disease (uMRD) rates at end of treatment also were improved with ibrutinib plus venetoclax. Of note, the frequency of grade ≥3 TLS was lower with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab (no patients vs 5.7% of patients, respectively).
The ongoing phase II CAPTIVATE trial also is examining ibrutinib plus venetoclax as frontline therapy for patients with treatment-naive CLL. This trial differed in design from GLOW, including a fixed-duration cohort and a measurable residual disease (MRD)-guided cohort. MRD is an emerging response endpoint in CLL and may have particular importance with limited-duration therapies (eg, venetoclax-based treatment). Prior studies have shown that patients who achieve uMRD have longer PFS compared with patients who have low or high MRD, suggesting uMRD as an important surrogate marker predicting favorable long-term outcome.
In the fixed-duration cohort of CAPTIVATE, patients received 3 cycles of ibrutinib during a lead-in phase, followed by 12 cycles of ibrutinib plus venetoclax. In the MRD-guided cohort, patients received the initial fixed-duration therapy and then were randomized based on MRD status. Patients with confirmed uMRD were randomized to receive placebo or additional cycles of ibrutinib. Patients without confirmed uMRD were randomized to continue receiving ibrutinib plus venetoclax or to receive ibrutinib monotherapy.
In the fixed-duration cohort, the 24-month PFS and overall survival with combination therapy were 95% and 98%, respectively, with 55% achieving CR/CRi. Among patients in the MRD-guided cohort who achieved peripheral blood uMRD, 93% also achieved bone marrow uMRD. This finding is important because it demonstrates good response concordance and implies that peripheral blood uMRD is a reliable surrogate marker for predicting bone marrow uMRD. The 1-year disease-free survival (DFS) rate after randomization was high among patients with uMRD after initial ibrutinib plus venetoclax therapy, regardless of whether they received additional ibrutinib treatment (95.3%) or placebo (100%).
Among patients in the MRD-guided cohort who did not achieve uMRD after the initial 15 treatment cycles, 66% who received ibrutinib plus venetoclax ultimately achieved uMRD compared with 42% who received ibrutinib monotherapy. In other words, combining ibrutinib with venetoclax conveyed a 24% increase in the potential for converting to a deep response in bone marrow compared with ibrutinib alone. The key takeaway from these results is that, regardless of whether patients receive additional treatment, once they finish their initial fixed-duration regimen, the PFS and DFS appear to be relatively favorable in short-term follow-up.
Numerous studies are ongoing that examine ibrutinib, acalabrutinib, and zanubrutinib in combinations with venetoclax with or without an anti-CD20 monoclonal antibody. Of particular interest is the ongoing randomized phase III CLL17 trial, which is assessing ibrutinib plus venetoclax vs venetoclax plus obinutuzumab vs ibrutinib monotherapy in patients with treatment-naive CLL.
Novel BTK Inhibitors
Ibrutinib is a first-generation BTK inhibitor that targets several other tyrosine kinases in addition to BTK; this can lead to “off-target” adverse events. Second-generation BTK inhibitors (ie, acalabrutinib and zanubrutinib) are more selective and have been associated with a lower incidence of some adverse events based on randomized phase III head-to-head comparison studies.
The randomized phase III SEQUOIA trial is comparing zanubrutinib vs bendamustine plus rituximab in patients with previously untreated CLL/small lymphocytic lymphoma (SLL). Results from the randomized arms with patients without del(17p) CLL were recently presented and showed that zanubrutinib improved PFS vs bendamustine plus rituximab (24-month PFS: 85.5% vs 69.5%; HR: 0.42; P <.0001).
First- and second-generation BTK inhibitors covalently bind to BTK. Over time, patients may acquire mutations in BTK that result in them becoming resistant to covalent inhibitors. For example, more than 50% of patients who are resistant to a covalent BTK inhibitor have CLL with a BTK C481S mutation. Because covalent binding occurs at residue C481, when this residue is mutated, BTK inhibitors that covalently bind the C481 residue can no longer bind to and inhibit the BTK enzyme, leading to resistance.
Pirtobrutinib (formerly known as LOXO-305) is a next-generation, highly selective, noncovalent BTK inhibitor that acts independently of residue C481 by reversibly binding to a BTK pocket. Laboratory findings have demonstrated that pirtobrutinib inhibits BTK even in patients with mutations that affect the BTK covalent binding site.
The BRUIN trial is an ongoing, first-in-human phase I/II trial examining pirtobrutinib in patients with relapsed/refractory (R/R) CLL and other lymphomas. In the CLL/SLL cohort, overall response rate (ORR) was 63% among all patients. Among patients who had received ≥10 treatment cycles, ORR was 86%, suggesting that it will likely continue to improve over time.
The importance of pirtobrutinib for patients with previous BTK inhibitor exposure cannot be understated. In the BRUIN trial, among patients who had received various prior therapies (BTK inhibitors, BCL-2 inhibitors, PI3K inhibitors, or chemotherapy), all responded similarly to pirtobrutinib. ORR was similar among patients with CLL with and without the BTK C481 mutation, confirming that pirtobrutinib overcomes the resistance mechanism of the BTK C481 mutation.
Also exciting is the favorable safety profile of pirtobrutinib. Pirtobrutinib had low rates of adverse events of special interest, including hemorrhage (5% any grade; <1% grade ≥3), bruising (16% any grade; 0% grade ≥3), hypertension (5% any grade; 1% grade ≥3), and atrial fibrillation (1% any grade; 0% grade ≥3). Overall, the favorable safety profile of pirtobrutinib and its ability to overcome resistance make it a very exciting agent.
Novel PI3K Inhibitor Combinations
Umbralisib is a novel, next-generation PI3K δ inhibitor that has been studied in combination with ublituximab, a novel anti-CD20 antibody (the combination is known as U2), for patients with CLL. Umbralisib is currently approved to treat R/R marginal zone lymphoma after ≥1 prior anti-CD20–based regimen and R/R follicular lymphoma after ≥3 prior lines of systemic therapy. Compared with previous generations of PI3K inhibitors, umbralisib appears to have an improved toxicity profile, particularly with regard to liver toxicity and colitis.
The randomized, open-label phase III UNITY CLL trial compared the U2 combination vs chlorambucil plus obinutuzumab in patients with treatment-naive R/R CLL. U2 improved PFS in both treatment-naive patients (median: 38.5 vs 26.1 months; HR: 0.482; P <.001) and patients with R/R disease (median: 19.5 vs 12.9 months; HR: 0.601; P <.01). U2 also significantly improved ORR (83.3%) compared with chlorambucil plus obinutuzumab (68.7%) in the overall population. ORR was 57% with U2 among patients previously exposed to BTK inhibitors, suggesting that these patients also may benefit from this combination.
The U2 combination was associated with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation that was mostly low grade (rates of any-grade ALT/AST elevation were 17%/14%; rates of grade ≥3 ALT/AST elevation were 8%/5%). Among patients receiving the U2 combination, any-grade noninfectious colitis occurred in 5% (2% grade ≥3), and any-grade pneumonitis occurred in 3% (0.5% grade ≥3).
Because the U2 combination and venetoclax target different pathways, a combination of these agents was postulated to produce synergistic effects. In a phase I/II trial, patients initially received the 3 cycles of U2 during a debulking period, followed by 9 cycles of U2 plus venetoclax. After 12 treatment cycles, the ORR was 100% (37% CR rate), and peripheral blood and bone marrow uMRD were achieved by 91% and 72% of patients, respectively.
Several trials are planned. In the randomized phase II/III ULTRA V trial, patients with treatment-naive or R/R CLL are randomized to receive the U2 combination or a combination of U2 and venetoclax. It should be noted that as of February 2022, the FDA is investigating a possible increased risk of death with umbralisib based on initial findings from the UNITY trial. While the FDA evaluates the results from UNITY, it has suspended enrollment of new patients on ongoing clinical trials of umbralisib.
CAR T-Cell Therapy
In addition to targeted therapies, the emerging CLL treatment landscape includes a new, exciting, and completely different type of therapy: CD19-targeted CAR T-cell therapy. CAR T-cell therapy currently has FDA approval for treating several different lymphomas, but it is still an experimental therapy for treating CLL and does not have FDA approval for this disease.
Among the clinical trials for CAR T-cell therapy in CLL, the open-label phase I/II TRANSCEND CLL 004 trial was a multicohort study examining the CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel) for treating R/R CLL. The monotherapy cohort included 2 dose levels. Patients were ineligible for a BTK inhibitor therapy or had failed BTK inhibitor therapy and were either at standard risk and had failed ≥3 prior lines of therapy or had high-risk disease and failed ≥2 prior lines of therapy.
In the monotherapy cohort, ORR—both in total population or when examined by dose level—was in the 80% range, with the CR rate up to 56% depending on dose. The peripheral blood and bone marrow uMRD rates were up to 75%. Many responses were quite durable, even among patients who had failed multiple lines of previous conventional or targeted therapies.
Adverse events of interest associated with CAR T-cell therapy are cytopenias (both those resulting from lymphodepleting chemotherapy and those arising from CAR T-cell–associated immune effects), cytokine-release syndrome (CRS), and neurotoxicity. Among patients in the TRANSCEND monotherapy cohort, grade ≥3 CRS and neurotoxicity rates were 9% and 17%, respectively. CRS and neurotoxicity were managed with standard treatment regimens of tocilizumab, steroids, or a combination.
The TRANSCEND study also examined a combination of ibrutinib and 2 dose levels of liso-cel. Among patients receiving ibrutinib and liso-cel, ORRs were 95% in the overall population (n = 19), with 63% of patients achieving a CR/CRi and 89%/79% achieving peripheral blood/bone marrow uMRD.
It is likely that CAR T-cell therapy will have a role in salvage therapy for patients with CLL, especially for those who have already failed standard targeted therapies.
Emerging Therapy Landscape for CLL/SLL
The future CLL treatment landscape will likely provide patients with many excellent options, with the potential for highly efficacious continuous or fixed-duration regimens and MRD-guided fixed-duration options. We will eagerly await the data from the next several years of trials that will assist us in selecting among the myriad CLL treatment options.
What investigational CLL treatment strategies are you most excited about? How do you anticipate using these strategies should they be approved? Answer the polling question and join the conversation by posting a comment in the discussion section below.