Greater Understanding of CLL Pathophysiology Spurs Small Molecules Development

William Wierda, MD, PhD

Small Molecules Background

During the 10th Annual Meeting of the Society of Hematologic Oncology, William Wierda, MD, PhD, will explore the emergence of small molecule-inhibitor targeted therapies. His presentation, “Workup of CLL in the Era of Small Molecules,” is scheduled for Friday, September 30, 2022, at 6:45 am. Wierda is a professor; section chief, chronic lymphocytic leukemia (CLL); and center medical director, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, where he is also executive medical director. He will address the role of Bruton tyrosine kinase (BTK) inhibitors, PI3K inhibitors, and inhibitors of BCL2 during the session.

CLL is the most common leukemia in adults in Western countries; estimates indicate more than 20,000 individuals in the United States will receive CLL diagnoses and approximately 4410 will die of CLL in 2022.^1,2 Improved knowledge of the B-cell receptor (BCR) signaling pathway and its relationship to the behavior and pathophysiology of CLL has resulted in substantial advances in therapeutic options.^1,2 The BCR is responsible for an antigenindependent survival signal involving PI3K and an antigen-dependent signal involving intracellular molecules such as LYN, SYK, BTK, and PI3K leading to proliferation and activation of the cells.¹ CLL B cells are “stuck” in a later stage of development characterized by the inability to further differentiate, impaired immune function, and prolonged life span due to overexpression of antiapoptotic proteins (primarily BCL2).^1,3 Downstream components of the BCR signaling pathway continue to be expressed in CLL B cells, propagating signaling.1 Increased understanding of the role of BCR in CLL pathophysiology led to the development of small molecule inhibitor-targeted therapies with tyrosine kinase inhibitors against BTK and PI3K and inhibitors of BCL2.¹

BTK Inhibitors

BTK inhibitors block the adenosine triphosphate–binding site by binding irreversibly via covalent bonds with the sulfhydryl group of Cys481 or reversibly with noncovalent bind ing affinity, disrupting the ability of the CLL cells to interact with the microenvironment, resulting in death of the malignant cells.¹ Current BTK inhibitors approved by the FDA for treatment of CLL are irreversible and include acalabrutinib (Calquence) and ibrutinib (Imbruvica).²

Results from the phase 3 ELEVATE CLL TN trial (NCT02475681) showed acalabrutinib plus or minus obinutuzumab (Gazyva) produced improved progression-free survival (PFS) compared with chlorambucil (Leukeran) plus obinutuzumab in patients with treatment-naïve CLL.² The combination of acalabrutinib and obinutuzumab also produced a longer PFS than acalabrutinib alone at 48 months (87% vs 78%), but the study was not powered to compare the PFS between the acalabrutinib arms.²

The phase 3 RESONATE-2 trial (NCT01722487) in CLL patients without del(17p) who were 65 years or older resulted in approval of ibrutinib as first-line therapy for all patients.² In 2 separate studies (ECOG-ACRIN Cancer Research Group (E1912) study [NCT02048813] and FLAIR study [ISRCTN01844152]) ibrutinib with rituximab (Rituxan) proved more effective than fludarabine/cyclophosphamide/rituximab in patients lacking del(17p)/TP53 mutations.² Results also indicated ibrutinib is a good option for younger patients with unmutated IGHV.² Ibrutinib plus rituximab or obinutuzumab proved more effective than chemoimmunotherapy for treatment-naïve CLL without del(17p) or TP53 mutations across several randomized phase 3 trials; however, the clinical outcomes were not improved with the addition of rituximab compared to ibrutinib monotherapy.² Therefore, ibrutinib is recommended as monotherapy in first-line or relapsed/refractory CLL.²

Zanubrutinib (Brukinsa) is another irreversible BTK inhibitor, but is highly selective/specific and has FDA approval for Waldenström macroglobulinemia and relapsed/refractory mantle cell lymphoma.² The phase 3 SEQUOIA trial (NCT03336333) evaluated zanubrutinib vs bendamustine plus rituximab and found a greater overall response rate (95% vs 85%) with zanubrutinib in patients with untreated CLL without del(17p)/TP53 mutation along with significantly improved PFS (HR, 0.42; P < .0001).² However, patients with mutated IGHV did not experience a significant improvement in PFS (HR, 0.67; P = .0929).²

PI3K Inhibitors

PI3K activation results in greater B-lymphocyte proliferation, apoptosis, adhesion, and migration.³ Approved PI3K inhibitors for treatment of CLL include idelalisib (Zydelig) and duvelisib (Copiktra).^2,3 Idelalisib received FDA approval in 2014 for R/R CLL and duvelisib was approved in 2018 for the treatment of R/R CLL.³ Due to poorer toxicity profiles including autoimmune complications such as colitis, pneumonitis, and increased susceptibility of infections, BTK inhibitors are preferred to PI3K inhibitors.^2,3 Additionally, acalabrutinib monotherapy proved more effective with fewer adverse events than idelalisib plus rituximab in the phase 3 randomized ASCEND trial (NCT02970318).³

BCL2 Inhibitors

The BCL2 family of proteins are important regulators of apoptosis, containing proteins that support apoptosis and others that support survival.⁴ Cancer cells avoid apoptosis by shifting toward more proteins in support of survival.⁴ Venetoclax (Venclexta) is the only FDA-approved BCL2 inhibitor for the treatment of CLL and is a fixed-duration treatment option.⁴ Venetoclax plus obinutuzumab significantly improved PFS compared with chlorambucil plus obinutuzumab in patients 65 years or older or patients younger than 65 years with comorbidities in the CLL14 study (NCT02242942).² Venetoclax also resulted in a greater rate of undetectable minimal residual disease (74% vs 34%; P < .0001) along with a lower rate of conversion to MRD-positive status 1 year after treatment.² Recently presented results from the phase 3 CLL13 trial (NCT02950051) indicate superior PFS with venetoclax plus obinutuzumab plus ibrutinib (HR, 0.32; 97.5% CI, 0.19-0.5; P < .0001) and venetoclax plus obinutuzumab (HR, 0.42; 97.5% CI, 0.26-0.68; P < .0001) over chemotherapy.⁵

Recommended Therapies

Given the advantages of specific therapies in patients with particular gene mutations and characteristics, the National Comprehensive Cancer Network (NCCN) recommends certain treatments depending upon the findings during work-up.² For patients with CLL without del(17p) or TP53 mutations, the NCCN guidelines give the strongest recommendation for acalabrutinib plus or minus obinutuzumab followed by zanubrutinib.² Venetoclax and obinutuzumab is a recommended option for patients 65 years or older or younger patients with significant comorbidities and is included as a lesser recommended option for patients younger than 65 years without comorbidities due to a lack of current available evidence.²

For patients with del(17p) or TP53 mutations there are limited data for recommendations and the NCCN recommends enrolling these patients in an appropriate clinical trial.² However, currently available data suggest acalabrutinib plus Obinutuzumab; ibrutinib; venetoclax plus Obinutuzumab; and zanubrutinib are preferred treatment options for first-line therapy.²

REFERENCES

1. Tambaro FP, De Novellis D, Wierda WG. The role of BTK inhibition in the treatment of chronic lymphocytic leukemia: a clinical view. J Exp Pharmacol. 2021;13:923-935. doi:10.2147/JEP.S265284

2. Wierda WG, Brown J, Abramson JS, et al. NCCN Guidelines Insights: chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2022. J Natl Compr Canc Netw. 2022;20(6):622-634. doi:10.6004/jnccn.2022.0031

3. Hus I, Pula B, Robak T. PI3K inhibitors for the treatment of chronic lymphocytic leukemia: current status and future perspectives. Cancers (Basel). 2022;14(6):1571. doi:10.3390/cancers14061571

4. Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021;96(12):1679-1705. doi:10.1002/ajh.26367

5. Eichhorst B, Niemann C, Kater A, et al. Time-limited venetoclax-obinutuzumab +/- ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia (CLL): PFS co-primary end point of the randomized phase 3 GAIA/CLL13 trial. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. https://library.ehaweb.org/eha/2022/eha2022-congress/366209/barbara.eichhorst.time-limited.venetoclax-obinutuzumab.2B.-.ibrutinib.is.html