BTKIs for the treatment of CLL/SLL: The Patient Journey

Introduction

Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) is the most common adult leukemia and represents a significant clinical burden.^1-4 The incidence of CLL/SLL increases with age, and the median age at diagnosis is 70 years.⁵ Coupled with an improved understanding of disease biology and more available effective therapy options, treatment for CLL across the disease continuum has rapidly evolved to include non-chemotherapy-based regimens that disrupt B cell receptor signaling.² The increased availability of multiple active treatment regimens has led to a more complex management landscape.⁶ Current guideline-preferred frontline therapy options include Bruton’s tyrosine kinase (BTK) inhibitors and the BCL2 inhibitors with anti-CD20 antibodies.⁶

Selecting Therapy for Treatment-Naïve CLL

BTK Inhibitors

Bruton’s tyrosine kinase is a nonreceptor tyrosine kinase that plays a central role in B cell receptor signaling. There are currently 3 BTK inhibitors included in the National Comprehensive Cancer Network (NCCN) guidelines for CLL: ibrutinib, acalabrutinib, and zanubrutinib. Several studies have demonstrated a benefit of continuous BTK inhibitor therapy over chemoimmunotherapy in both the frontline and relapsed or refractory (R/R) settings.^{4, 7}

Ibrutinib is a first-generation BTK inhibitor and is the only BTK inhibitor to show an overall survival (OS) benefit in phase 3 prospective studies. Several randomized studies comparing ibrutinib to chemotherapy or chemoimmunotherapy have demonstrated a benefit with ibrutinib in progression-free survival (PFS), OS, or both (Table 1).^8-13 In treatment-naïve patients ibrutinib was initially compared to chlorambucil (Clb) in older patients without del(17p)/TP53 mutation in the RESONATE-2 study. With long-term follow-up, the 7-year PFS was 59% with ibrutinib and 9% with Clb. Median OS was also longer with ibrutinib (median OS not reached with ibrutinib vs 89 months with Clb).⁸ The ECOG 1912 study was the first study to compare fludarabine, cyclophosphamide, and rituximab (FCR) to ibrutinib with rituximab in patients 70 years or younger with untreated CLL and no del(17p)/TP53. With 5.8 years’ median follow-up, ibrutinib and rituximab demonstrated superior PFS (HR = 0.27; P < 0.001) in mutated and unmutated IGHV CLL as well as overall OS improvement (HR = 0.47; P = 0.018).^{12, 13} The ALLIANCE study evaluated ibrutinib with or without rituximab compared with bendamustine/rituximab (BR) in patients who were 65 years or older with untreated CLL. Ibrutinib-based treatment resulted in significantly improved PFS compared with BR (not reached vs 43 months). There was no significant difference in PFS between ibrutinib and ibrutinib with rituximab.¹⁰

Table 1: Phase 3 studies comparing ibrutinib-based therapy to control chemotherapy or chemoimmunotherapy in patients with untreated CLL/SLL.^8-12

Acalabrutinib and zanubrutinib are second-generation BTK inhibitors. In the phase 3 ELEVATE-TN study, acalabrutinib was compared to obinutuzumab and chlorambucil (O-Clb) in patients 65 years or older with untreated CLL/SLL or patients under 65 years with coexisting conditions. At a median follow-up of 46.9 months, PFS for acalabrutinib with or without obinutuzumab was superior to O-Clb (Table 2).¹⁴ 

Zanubrutinib was compared to BR in patients 65 years or older or those under 65 with coexisting conditions in the SEQUOIA study. With a median of 26.2 months’ follow-up, PFS was significantly improved for patients treated with zanubrutinib compared with BR (Table 2).¹⁵

Table 2: Second-generation BTK inhibitors evaluated as treatment for CLL/SLL in phase 3 studies.

While BTK inhibitors have not been compared directly in the frontline setting, both second-generation BTK inhibitors have been compared directly to ibrutinib in the relapsed setting. In the ELEVATE-RR study, acalabrutinib was compared to ibrutinib in a phase 3 noninferiority study in previously treated patients with CLL/SLL. With a median follow-up of 40.9 months, median PFS was 38.4 months in both arms, and the noninferiority endpoint was met (Figure 1). Importantly, rates of atrial fibrillation and discontinuations due to treatment were lower with acalabrutinib compared with ibrutinib (Table 3).¹⁶

Table 3: Key safety results from ELEVATE-RR of acalabrutinib vs ibrutinib in patients with previously treated CLL/SLL.¹⁶

Zanubrutinib was directly compared to ibrutinib in the phase 3 ALPINE study in patients with previously treated CLL. With a median follow-up of 24 months, the 12-month landmark event-free rate was 94.9% in zanubrutinib-treated patients compared with 84% in the ibrutinib-treated patients (HR = 0.40; P = 0.0007) (Figure 2). The rate of atrial fibrillation was also lower with zanubrutinib vs ibrutinib (2.5% vs 10.1%) (Table 4) .^{17, 18}

Figure 2: ALPINE Study – Head-to-Head BTKi Study

Table 4: Key safety results from ELEVATE-RR of acalabrutinib vs ibrutinib in patients with previously treated CLL/SLL.¹⁶

BCL2 Inhibitors

B cell lymphoma 2 (BCL2) is a proapoptotic protein that supports cell survival. Fixed-duration treatment with the BCL2 antagonist venetoclax in combination with obinutuzumab has demonstrated deep and durable responses in both the frontline setting and R/R treatment.^{4, 7} In the CLL14 study, venetoclax with obinutuzumab as a fixed-duration treatment was compared to O-Clb.¹⁹ The study included untreated patients with a cumulative illness rating scale (CIRS) score above 6 and showed the combination of venetoclax and obinutuzumab improved PFS over O-Clb (median PFS not reached vs 35.6 months for O-Clb).^{19, 20} In fit patients without del(17p)/TP53, venetoclax with obinutuzumab has demonstrated superior PFS over standard chemoimmunotherapy (FCR or BR) (Table 5).²¹ The study is ongoing and evaluating several combinations of venetoclax including venetoclax with rituximab, obinutuzumab, and ibrutinib.²² Venetoclax-containing regimens have not been compared directly to BTK inhibitors in any prospective studies. 

Table 5: Phase 3 study outcomes with venetoclax-based regimens as initial therapy for CLL/SLL. 

Managing Patients with del(17p)/TP53 CLL

CLL with del(17p)/TP53 is an aggressive subtype, and patients have inferior outcomes. There are limited data of BTK inhibitors in del(17p)/TP53⁴. In a pooled analysis of 89 patients with del(17p/TP53) treated with ibrutinib, the 4-year OS rate was 88%.²³ Analysis of a real-world evidence study evaluating patients who would have been excluded from the key clinical studies found no differences in response rates in 110 patients with del(17p)/TP53 treated with ibrutinib. However, PFS and OS were lower compared with patients who did not have del(17p)/TP53 CLL.²⁴ The 4-year PFS for patients with del(17p)/TP53 on the ELEVATE-TN study was 75% with acalabrutinib and 76% with acalabrutinib with obinutuzumab.¹⁴ The effect of zanubrutinib on del(17p)/TP53 CLL was evaluated in a nonrandomized cohort of SEQUOIA, yielding an overall response rate of 95%, an 18-month PFS of 89%, and OS of 95%.^{15, 25} An evaluation of the effect of venetoclax on del(17p) suggested that responses were less durable in patients with this mutation (Table 6). Patients with high-risk disease will eventually progress, and ongoing prospective studies are further evaluating therapy options for these patients.

Table 6: The impact of BTK and BCL2 inhibitors on patients with del(17p)/TP53-mutated CLL. 

Current Guidelines

Patients with CLL who require treatment have several active treatment options.²⁶ The preferred regimens for first-line CLL were recently simplified in the NCCN guidelines and age parameters were removed. Currently, patients are differentiated by deletion (del) of chromosome 17p or mutations in the TP53 gene.²⁶ Preferred regimens regardless of del(17p)/TP53 status include acalabrutinib with or without obinutuzumab, venetoclax with obinutuzumab, or zanubrutinib (Table 7). Ibrutinib with or without an anti-CD20 monoclonal antibody (mAb) is now listed under “other recommended regimens,” and ibrutinib with venetoclax is a category 2B recommended regimen.²⁶ Ibrutinib, acalabrutinib, and venetoclax are FDA-approved for CLL.^27-29 Zanubrutinib is FDA-indicated for mantle cell lymphoma and Waldenström’s macroglobulinemia, but does not have a current indication in CLL.³⁰

Table 7: NCCN preferred first-line treatment options for patients with CLL.

Toxicities

Class- and drug-specific treatment-emergent adverse events do occur.^{2, 6} Class effects for BTK inhibitors include atrial fibrillation, hypertension, and bleeding risk, as well as the risk of infection.³¹ Patients should be counseled to report palpitations, chest pressure, shortness of breath, and if they notice blood anywhere (sputum, stool, urine, etc.) or plan to have any type of medical procedure. Blood pressure should be monitored closely and managed.

Drug-specific effects of ibrutinib include myalgias, arthralgias, and rash.^{8, 27} Acalabrutinib is associated with headaches, which generally occur at the beginning of therapy and reduce over time.¹⁴ Zanubrutinib is associated with gastrointestinal toxicity and cytopenias.¹⁵

Tumor lysis syndrome can occur with venetoclax.²⁰ Patients are given ramp-up dosing beginning with 20 mg and building to the final dose of 400 mg over 5 weeks.²⁹ Each dose requires pre-dose labs as well as post-dose monitoring and appropriate hydration based on the patient's tumor lysis risk. Infusion-related reactions and cytopenias can occur with obinutuzumab.³²

Selecting and Sequencing Therapies

Important factors when selecting initial treatment for CLL are patient comorbidities (eg, preexisting atrial fibrillation, uncontrolled hypertension, use of blood thinners, or renal impairment), disease factors like del(17p) or a TP53 mutation, and how time-limited or continuous therapy fits with individual patient goals.⁴

Selecting therapy for patients who relapse depends on prior treatment exposure and the reason for discontinuation (intolerance or progression). If discontinuation is due to intolerance, it is reasonable to try another BTK inhibitor. For patients who discontinue a BTK inhibitor due to progression, changing to a venetoclax-based regimen should be considered.⁷ If a patient received frontline venetoclax and obinutuzumab, switching class to a BTK inhibitor is an effective option. For patients completing frontline fixed-duration therapy who had an extended period of benefit, venetoclax retreatment can be considered. PI3K inhibitors are FDA-approved for the treatment of CLL and can be used in the third-line setting or beyond, but patients should be monitored closely for treatment-related toxicity.⁷ 

Summary

• BTK inhibitors (acalabrutinib, ibrutinib, and zanubrutinib), venetoclax, and obinutuzumab are effective treatment options for patients with CLL.
• BTK inhibitors, venetoclax, and obinutuzumab have not been studied head-to-head in the frontline setting.
• Treatment decision-making is dependent upon patient preferences, comorbidities, and genetic features of the disease.
• The adverse event profiles and duration of treatment for BTK inhibitors, venetoclax, and obinutuzumab are very different and should be discussed with each patient to determine the best fit. 

References

1. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(1):23-33.
2. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473.
3. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA: Cancer J Clin. 2022;72(1):7-33.
4. Kutsch N, Fink AM, Fischer K. Management of front line chronic lymphocytic leukemia. Am J Hematol. 2022;97 Suppl 2:S3-S10.
5. NIH. National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER). Cancer stat facts: leukemia — chronic lymphocytic leukemia (CLL). Accessed Nov 11, 2022. https://seer.cancer.gov/statfacts/html/clyl.html
6. Wierda WG, Brown J, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 1.2023). © 2022 National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org. 
7. Woyach JA. Management of relapsed/refractory chronic lymphocytic leukemia. Am J Hematol. 2022;97 Suppl 2:S11-S18.
8. Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440-3450.
9. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56.
10. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
11. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib plus rituximab is superior to FCR in previously untreated CLL: results of the phase III NCRI FLAIR trial. Blood. 2021;138(Supplement 1):642.
12. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
13. Shanafelt TD, Wang XV, Hanson CA, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022;140(2):112-120.
14. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175.
15. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043.
16. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.
17. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of alpine study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2021;62(SUPPL 1):S127‐S129.
18. Brown JR, Hillmen P, Eichhorst B, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Clin Lymphoma Myeloma Leuk. 2022;22(Supplemet 2):S266.
19. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.
20. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Hematol Oncol. 2021:39(S2):201-203.
21. Eichhorst BNC, Kater A, Fürstenau M, et al. Time-limited venetoclax-obinutuzumab +/- ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia (CLL): PFS co-primary endpoint of the randomized phase 3 GAIA/CLL13-trial. Abstract presented at: EHA 2022; Palermo, Italy; October 17-20, 2022. Abstract LB2365.
22. Eichhorst B, Niemann C, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments (RVe, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia (CLL) of fit patients: first co-primary endpoint analysis of the International Intergroup GAIA (CLL13) trial. Blood. 2021;138(Supplement 1):71.
23. Allan JN, Shanafelt T, Wiestner A, et al. Long‐term efficacy of first‐line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196(4):947-953.
24. Mato AR, Roeker LE, Allan JN, et al. Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial. Am J Hematol. 2018;93(11):1394-1401.
25. Tam CS, Robak T, Ghia P, et al. Zanubrutinib monotherapy for patients with treatment-naïve chronic lymphocytic leukemia and 17p deletion. Haematologica. 2020;106(9):2354-2363.
26. Kumar SK, Callander NS, Adekola K, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma (Version 2.2023). © 2022 National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org.
27. IMBRUVICA® (ibrutinib). Prescribing information. Janssen Biotech, Inc.; 2022.
28. CALQUENCE® (acalabrutinib). Prescribing information. AstraZeneca Pharmaceuticals LP; 2022.
29. VENCLEXTA® (venetoclax tablets). Prescribing information. AbbVie Inc.; 2022.
30. BRUKINSA™ (zanubrutinib). Prescribing information. Bei Gene, Ltd.; 2021.
31. Pineda-Gayoso R, Alomar M, Lee DH, Fradley MG. Cardiovascular toxicities of Bruton’s tyrosine kinase inhibitors. Curr Treat Options Oncol. 2020;21(8):67.
32. GAZYVA® (obinutuzumab). Prescribing information. Genentech, Inc.; 2022.