New Data and Approvals Are Changing the Chronic Lymphocytic Leukemia Treatment Landscape

¹and treatment guidelines have adapted. Developments in targeted therapies, monoclonal antibodies, and combination regimens have benefited those with high-risk disease, improving outcomes even for patients with del(17p) or TP53 mutations.^2,3

Treatments that have already been approved as monotherapies have been, and continue to be, combined in experiments to potentially benefit wider rang- es of patients and generate better outcomes. Over the past year in particular, new data have prompted the approvals of different targeted drugs and combina- tion therapies, most recently in November with the approval of acalabrutinib as initial or subsequent therapy for adults with CLL or small lymphocytic lym- phoma (SLL). With so many developments in the CLL treatment spectrum over a short amount of time, the National Comprehensive Cancer Network (NCCN) has issued multiple updates to its treatment guidelines in 2019.^4,5

As the therapeutic landscape continues to evolve, identifying treatment regimens that optimally align with individual patient profiles is essential. This article reviews significant developments in the CLL treatment landscape over the past year, including data presented and/or published that are related to ibrutinib, acalabrutinib, and venetoclax combination regimens.

Recent and Current Developments in CLL Treatment

Ibrutinib

Key findings from several phase III studies examining ibrutinib in different populations were presented at the 2018 American Society for Hematology Annual Meeting and helped shape new directions in treatment of CLL. The data had immediate impact, particularly for patients with untreated CLL, as the NCCN overhauled its guidelines to elevate ibrutinib to first-line treatment status.⁴

Findings from the iLLUMINATE trial demonstrated that, when compared with standard chemoimmunotherapy, ibrutinib combined with a monoclonal antibody was effective in patients with previously untreated CLL. This led to the FDA approval of ibrutinib plus obinutuzumab in January 2019. Participants were 65 years and older (median, 75 years) and had untreated CLL or small lymphocytic leukemia, were separated into 2 groups: those with significant comorbidities or high-risk cytogenetics, and those without.⁶Treatments were assigned randomly 1:1, with patients either given ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).⁷The trial met its primary endpoint and improved progression-free survival (PFS), with a median follow-up of 31.3 months. At 30 months, the PFS rate was 79% in the ibrutinib/obinutuzumab group and 31% in the chlorambucil/obinutuzumab group.⁷

Results also showed a 77% reduction in risk of progression or death in the ibrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm (HR, 0.23; 95% CI, 0.15-0.37), which ultimately led to the combination’s approval.⁸The patients with high-risk disease, representing 65% of the ibrutinib arm—those with del(17p)/TP53 mutation, del(11q), or unmutated IGHV— experienced an 85% reduction in risk of progression or death.⁸Additionally, patients in the ibrutinib/obinutuzumab group had an overall response rate (ORR) of 88%, compared with 73% in the chlorambucil/obinutuzumab cohort.⁷Grade 3 and 4 adverse events (AEs) were similar in both groups; the most common were pneumonia and febrile neutropenia.⁷

Results of the phase III ALLIANCE trial backed the choice of ibrutinib as a standard-of-care treatment in older patients with CLL.⁹The study analyzed the efficacy of ibrutinib alone (n = 182) and in combination with the monoclonal antibody rituximab (n = 182) against bendamustine plus rituximab (n = 183), which had been the standard-of-care chemotherapy for older patients with CLL.^4,10Patients were 65 years and older with previously untreated CLL, as defined by International Workshop on CLL criteria.¹⁰At 2 years, PFS was 87% with ibrutinib alone, compared with 88% with ibrutinib/rituximab and 74% for bendamustine/rituximab.¹⁰

Both ibrutinib monotherapy and the ibrutinib/rituximab combination showed favorable safety profiles compared with bendamustine plus rituximab. Grade 3, 4, and 5 hematologic AEs occurred at a higher rate in the bendamustine/rituximab group compared with the ibrutinib monotherapy and ibrutinib/rituximab groups (61% vs 41% and 39%, respectively).¹⁰Based on these findings, the investigators concluded that in this setting, no significant difference exists between ibrutinib-plus-rituximab and ibrutinib monotherapy treatments.^10,11

The randomized, open-label, phase III E1912 trial also evaluated the combination of ibrutinib plus rituximab; in this case, researchers compared it with the standard chemoimmunotherapeutic regimen of fludarabine, cyclosphosphamide, and rituximab (FCR) in patients 70 years or younger with previously untreated CLL.¹¹Between March 2014 and June 2016, patients were assigned 2:1 to ibrutinib/rituximab (n = 354) or to FCR (n = 175).¹¹Patients with del(17p) were excluded from the study. The primary and secondary endpoints were PFS and overall survival (OS), respectively.¹¹With a median follow-up of 33.6 months, patients in the ibrutinib-plus-rituximab arm experienced better PFS compared with those in the chemoimmunotherapy group (89.4% vs 72.9% at 3 years; HR for progression or death, 0.35; 95% CI, 0.22-0.56;P<.001).¹¹AEs of grade 3 or higher were comparable between the groups (80.1% vs 79.7%).¹¹While continuous ibrutinib/rituximab therapy resulted in superior PFS and OS compared with 6 months of chemoimmunotherapy, investigators questioned the practicality of indefinite use of ibrutinib therapy, as it has been associated with significant expense and potential long-term toxic effects, including risk of drug resis- tance.¹¹Based on these results, a supplemental new drug application (sNDA) for ibrutinib plus rituximab for first-line treatment of CLL or small lymphocytic leukemia in those aged 70 years or younger was submitted.¹²

Venetoclax Combination Regimens

In May 2019, the combination of venetoclax plus obinutuzumab was granted approval by the FDA for patients with previously untreated CLL. Venetoclax was initially approved by the FDA in 2016 for previously treated patients with CLL with 17p deletion genetic mutation, based on data from a single-arm clinical trial that showed 80% of patients achieved complete or partial remission.¹³The combination of venetoclax plus rituximab was then approved in 2018 for patients with or without 17p deletion, with at least 1 prior therapy.¹⁴

The recent approval of the combination regimen was based on efficacy outcomes from the open-label, multicenter, randomized, phase III CLL14 study, presented at the 2019 American Society of Clinical Oncology Annual Meeting. Results showed significant improvements in PFS in patients who were administered venetoclax plus obinutuzumab compared with patients who received chlorambucil plus obinutuzumab (HR, 0.33, 95% CI, 0.22-0.51;P<.0001). The venetoclax/obinutuzumab arm also showed a greater ORR of 85%, compared with 71% in the chlorambucil/obinutuzumab cohort.¹⁵As a result of these findings, the NCCN guidelines have been updated, making venetoclax plus obinutuzumab a preferred first-line regimen for patients with previously untreated CLL.⁵

Further combinations with venetoclax are also under investigation, including venetoclax plus ibrutinib. Findings from the phase II CLARITY study were published this year, showing that the venetoclax-plus-ibrutinib combination is effective and safe in patients with relapsed/refractory CLL. The primary endpoint of the study was the eradication of minimal residual disease (MRD) in the bone marrow and peripheral blood, such that there was fewer than 1 CLL cell in 10,000 leukocytes following 12 months of the combination treatment. Of the 53 patients included in the study, 28 patients reached MRD negativity in peripheral blood and 19 patients showed MRD negativity in the bone marrow. Results also demonstrated that after 12 months, 47 participants had responded to treatment and 27 patients had achieved complete remission. This regimen will be explored further in phase III studies.¹⁶

Other potential combinations with venetoclax have been explored in preclinical studies, some of which potentially may improve efficacy without significantly increasing tox- icity. Combinations of venetoclax with anti-CD20 immuno- therapy and B-cell signaling inhibitors, are being tested, with an eye to minimize patient exposure to cytotoxic che- motherapy.17 Other trials are actively testing whether could be efficacious in patients with CLL.^18,19

Acalabrutinib

Acalabrutinib, a BTK inhibitor that has been FDA approved since 2017 for previously treated adult patients with mantle cell lymphoma, was recently approved as initial or subsequent therapy in adults with CLL or SLL.²⁰The approval followed significant findings from the ELEVATE-TN and ASCEND trials that, earlier this year, led the FDA grant breakthrough designation to acalabrutinib for the treatment of CLL in adult patients.^21-23

ASCEND is a randomized, global, multicenter, open-label phase III trial evaluating the efficacy and safety of acalabrutinib compared with the investigator&rsquo;s choice of either rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL.^21-22Findings were presented at the 24th European Hematology Association Congress. The primary endpoint of the study was PFS, and the secondary endpoints were OS, independent review committee (IRC)-assessed ORR, and safety. Eligible patients (N = 310) were randomized to 100 mg of acalabrutinib twice daily until disease progression, 150 mg of idelalisib twice daily plus 8 intravenous infusions of rituximab (375 or 500 mg/m2), or 70 mg/m2 of intravenous bendamustine on days 1 and 2 of each cycle plus intravenous rituximab (375 or 500 mg/m2) on day 1 of each 28-day cycle for up to 6 cycles.²¹The IRC-assessed ORRs did not significantly differ between the acalabrutinib arm and the 2 other cohorts (81% vs 75%). However, at a median follow-up of 16.1 months, acalabrutinib showed significant prolonged PFS compared with rituximab/idelalisib and rituximab/bendamustine, representing a 69% reduction in risk of progression or death (median, not reached vs 16.5 months; HR, 0.31; 95% CI, 0.20-0.49;P<.0001).²²

ELEVATE-TN is a randomized, multicenter, open-label phase III study evaluating the safety and efficacy of acalabrutinib as a monotherapy or in combination with obinutuzumab compared with chlorambucil plus obinutuzumab in previously untreated CLL patients.²³The patient population consists of 535 patients, randomized 1:1:1 to 3 cohorts. The primary endpoint, PFS, was reached by the acalabrutinib-plus-obinutuzumab group, showing meaningful improvements compared with the chlorambucil-plus-obinutuzumab group.²³

Acalabrutinib has also shown promise in patients intolerant to ibrutinib. Investigators presented findings at the 15th International Conference on Malignant Lymphoma from a phase II trial in which patients (median age, 70 years) had relapsed/refractory CLL and had received at least 1 prior therapy. Investigator-assessed ORR was 72%, and median follow-up was 23 months, with 63% of patients remaining on acalabrutinib and 80% remaining on the study. Reasons for discontinuation of acalabrutinib included progressive disease, AEs, patient withdrawal, and investigator decision.²⁴

Because of these combined findings, acalabrutinib monotherapy for patients with relapsed/refractory CLL has been added as a first-line, category 1 therapy in the most recent NCCN guidelines.⁵

Conclusions

Given the many important developments emerging from new trial results and from approvals for numerous agents in the past year, the CLL treatment spectrum will likely continue to evolve at an accelerated rate. As new evidence continues to demonstrate the clinical benefits of targeted therapies, it is incumbent upon physicians to keep up with the data and integrate these agents into real-world settings.

References

1. Seymour C. Breakthrough therapies enrich evolving CLL paradigm. OncLive website. onclive.com/web-exclusives/breakthrough-therapies-enrich-evolving-cll-paradigm. Published September 19, 2019. Accessed October 21, 2019.
2. Sharma S, Rai KR. Chronic lymphocytic leukemia (CLL) treatment: so many choices, such great options.Cancer. 2019;125(9):1432-1440. doi: 10.1002/cncr.31931.
3. Jain N, O&rsquo;Brien S. Initial treatment of CLL: integrating biology and functional status.Blood. 2015;126(4):463-470. doi: 10.1182/blood-2015-04-585067.
4. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 4.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated March 15, 2019. Accessed May 10, 2019.
5. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 2.2020. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated October 8, 2019. Accessed October 30, 2019.
6. Loguidice CT. Experts dissect 3 practice-changing studies for newly diagnosed CLL. OncLive website. onclive.com/publications/Oncology-live/2019/vol-20-no-7/experts-dissect-3-practicechanging-studies-for-newly-diagnosed-cll. Published April 1, 2019. Accessed October 28, 2019.
7. 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. doi: 10.1016/S1470-2045(18)30788-5.
8. Columbus G. FDA approves ibrutinib plus obinutuzumab in frontline CLL/SLL. OncLive website. onclive.com/web-exclusives/fda-approves-ibrutinib-plus-obinutu-zumab-in-frontline-cllsll. Published January 28, 2019. Accessed October 28, 2019.
9. Helwick C. Ibrutinib vs standard of care in front-line treatment of older patients with chronic lymphocytic leukemia. The ASCO Post website. ascopost.com/issues/december-10-2018/ibrutinib-vs-standard-of-care-in-older-patients-with-cll. Published December 10, 2018. Accessed May 7, 2019.
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. doi: 10.1056/NEJMoa1812836.
11. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmuno-therapy for chronic lymphocytic leukemia.N Engl J Med. 2019;381(5):432-443. doi: 10.1056/NEJMoa1817073.
12. Tucker N. Ibrutinib/rituximab seeking approval as frontline treatment for CLL. Targeted Oncology website. https://www.targetedonc.com/news/ibrutinibritux-imab-seeking-approval-as-frontline-treatment-for-cll. Published November 12, 2019. Accessed November 15, 2019.
13. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality [news release]. Silver Spring, MD: FDA; April 11, 2016. fda.gov/news-events/press-announcements/fda-approves-new-drug-chronic-lymphocytic-leukemia-patients-specific-chromosomal-abnormality. Accessed October 21, 2019.
14. Lawrence L. Venetoclax/rituximab combo approved for CLL/SLL. Cancer Network website. cancernetwork.com/news/venetoclaxrituximab-combo-approved-cllsll#targetText=The%20United%20States%20Food%20and,at%20least%20one%20prior%20therapy. Published June 18, 2018. Accessed October 21, 2019
15. FDA approves chemotherapy-free regimen, venetoclax plus obinutuzumab, as first-line treatment for CLL/SLL. The ASCO Post website. ascopost.com/issues/ may-25-2019/fda-approves-chemotherapy-free-regimen-venetoclax-plus-obinutu-zumab-as-first-line-treatment-for-cllsll/. Published May 25, 2019. Accessed October 21, 2019.
16. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study.J Clin Oncol. 2019;37(30):2722-2729. doi: 10.1200/JCO.19.00894.
17. Schieber M, Ma S. The expanding role of venetoclax in chronic lymphocytic leukemia and small lymphocytic lymphoma.Blood Lymphat Cancer. 2019;9:9-17. doi: 10.2147/BLCTT.S177009.
18. Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia. clinicaltrials.gov/ct2/show/NCT03701282?term=NCT03701282&draw=2&rank=1. Updated November 8, 2019. Accessed November 15, 2019.
19. Testing the Addition of a New Anti-cancer Drug, Venetoclax, to the Usual Treatment (ibrutinib and obinutuzumab) in Untreated, Older Patients With Chronic Lymphocytic Leukemia. clinicaltrials.gov/ct2/show/NCT03737981?term=NCT0373798 1&draw=2&rank=1. Updated November 7, 2019. Accessed November 15, 2019.
20. FDA takes second action under international collaboration, approves new treatment option for patients with chronic lymphocytic leukemia. FDA website. Posted November 21, 2019. https://bit.ly/2s7EiSz. Accessed November 27, 2019.
21. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator&rsquo;s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapse/refractory (R/R) chronic lymphocytic leukemia (CLL) [abstract LB2606]. Presented at: 24th European Hematology Association Congress; June 13-16, 2019; Amsterdam, the Netherlands.
22. EHA 2019: ASCEND trial compares acalabrutinib vs investigator&rsquo;s choice in relapsed or refractory CLL. The ASCO Post website. ascopost.com/News/60168. Updated June 19, 2019. Accessed October 21, 2019.
23. Calquence phase III ELEVATE-TN trial met primary endpoint at interim analysis in previously-untreated chronic lymphocytic leukaemia [news release]. Cambridge, UK: AstraZeneca; June 6, 2019. astrazeneca.com/media-centre/press-releases/2019/calquence-phase-iii-elevate-tn-trial-met-primary-endpoint-at-interim-analysis-in- previously-untreated-chronic-lymphocytic-leukaemia06062019.html. Accessed October 21, 2019.
24. Powers V. Acalabrutinib shows high response, prolonged survival in ibrutinib-intolerant R/R CLL. Targeted OncologyTM website. targetedonc.com/publications/ targeted-therapy-news/2019/September-2019/acalabrutinib-shows-high-response-prolonged-survival-in-ibrutinibintolerant-rr-cll. Published September 24, 2019. Accessed October 29, 2019.