Introduction
Chronic lymphocytic leukemia (CLL) accounts for nearly 1.1% of new cancer cases in the United States in 2022.1 Novel fixed-duration single-agent and combination therapies are under investigation for the treatment of CLL and being compared against monotherapy with Bruton tyrosine kinase (BTK) inhibitors.2 At the 2022 American Society of Clinical Oncology (ASCO®) Annual Meeting, which was held in person but offered live streaming and on-demand features for virtual attendees, investigators presented results of meta-analyses and retrospective studies as well as updated clinical trials on combination therapies and/or monotherapies that highlighted progression-free survival (PFS) benefits of these treatments.
The following presentations are a sampling of the research presented at this year’s meeting.
Efficacy of First-Line Treatment for CLL: A Bayesian Network Meta-Analysis3
The SEQUOIA (ClinicalTrials.gov Identifier: NCT03336333) is a network meta-analysis of randomized controlled trials (RCTs) that compared the efficacy of the second-generation BTK inhibitor zanubrutinib with frontline therapies usually administered to adults patients with CLL who are treatment-naive.3 Patients who received zanubrutinib achieved a statistically significant improvement in PFS compared with patients randomly assigned to bendamustine plus rituximab (hazard ratio [HR], 0.42; 95% CI, 0.27-0.65).
In the CLL11 study (ClinicalTrials.gov Identifier: NCT01010061), patients treated with zanubrutinib achieved a statistically significant PFS improvement compared with those treated with obinutuzumab plus chlorambucil (HR, 0.45; 95% CI, 0.23-0.86). In the ALLIANCE trial (ClinicalTrials.gov Identifier: NCT01886872), patients who received zanubrutinib achieved a statistically significant improvement in PFS compared with those who received chlorambucil plus rituximab (HR, 0.22; 95% CI, 0.12-0.41). In the MaBLe trial (ClinicalTrials.gov Identifier: NCT01056510),treatment with zanubrutinib achieved PFS outcomes comparable to those seen with ibrutinib (HR, 1.07; 95% CI, 0.59-1.94).
Clinical Impact
In recent RCTs, zabrutinibdemonstrated greater efficacy than the 3 combination regimens currently used to treat CLL. The study findings suggest that, in terms of PFS, it is as promising a therapy as ibrutinib, the standard first-line treatment for CLL.
Survival Outcomes in Patients With CLL Treated at Academic Centers4
In a retrospective analysis of data from the National Cancer Database, researchers from Huntsman Cancer Institute-University of Utah in Salt Lake City investigated whether patients with CLL in the United States would have better survival when treated at academic vs nonacademic centers. Approximately 33.3% of the 98,186 patients with CLL analyzed were treated in academic centers between 2004 and 2018. Patients who received treatment at an academic center were slightly younger overall than their counterparts treated at a nonacademic center (median age, 67 years vs 71 years, respectively; P <.001). Patients in the academic center group included more Black patients compared with the nonacademic center group (9.7% vs 6.3%; P <.001). Additionally, academic centers were more likely than nonacademic centers to treat privately-insured patients.
At a median follow-up of 4.3 years, median overall survival (OS) of patients treated at academic centers was 11 years and nonacademic centers was 8.2 years (P <.001). Patients with CLL treated at academic centers enjoyed a higher survival benefit than those treated at nonacademic centers, with 73% vs 66% survival at 5 years and 53% vs 43% survival at 10 years, respectively (P <.001).
Clinical Impact
Better OS outcomes were observed in patients with CLL treated in academic centers rather than nonacademic centers, most likely due to factors such as differences in treatment, clinical trial availability and access, and supportive-care management.
Safety and Efficacy of Ibrutinib in Indian Patients With CLL5
Unlike in the United States and other Western countries, the prevalence of CLL in India is low. Therefore, there is a lack of real-world data on the safety and efficacy of ibrutinib as a treatment for CLL in both treatment-naive and relapsed/refractory settings. In a retrospective study, investigators from the All India Institute of Medical Sciences in New Delhi recruited all consecutive patients diagnosed with CLL from April 2016 through December 2021. The median follow-up period was 15 months (range, 4-60 months).
Study authors examined the toxicity profile of ibrutinib, patients’ responses to treatment with this agent, and survival outcomes. Among the 90 patients recruited, 33 were treatment-naive and 57 had relapsed/refractory CLL. Study authors documented an overall response rate (ORR) of 84.4% (n=76) and a complete response rate of 20% (n=18). Partial response was observed in 54.4% of patients (n=49) and 9 patients in the trial experienced a partial response with lymphocytosis. Grade 3 and 4 adverse events were reported for 3 patients who had treatment-naive CLL and 17 patients who had relapsed/refractory CLL.
Clinical Impact
In India’s largest study of the clinical impact of ibrutinib on CLL, treatment with ibrutinib yielded a 2-year PFS rate of 80% for the entire cohort. First approved for use in India in 2015, ibrutinib is likely to become the treatment of choice for both treatment-naive and relapsed/refractory CLL.
Real-World Data on Lebanese Patients With CLL6
This observational prospective study examined multiple aspects of CLL management of consecutively diagnosed patients in a single-center setting in Lebanon from 2004 through 2021. Investigators evaluated characteristics, diagnostic studies performed, indications for therapy, and the implication of new treatments such as BTK inhibitors in patients with CLL. Among the 128 patients in the registry (men, 82), the median age at diagnosis was 66 years. Approximately 73% of patients were asymptomatic at diagnosis whereas 25% had lymphadenopathies.
The most common regimens used were fludarabine plus cyclophosphamide plus rituximab (38.5%), bendamustine plus rituximab (23%), and the BTK inhibitor ibrutinib (19.2%). PFS, defined as the time from initiation of first-line treatment to disease progression from any cause, could not be established due to the small number of cases. For the same reason, a correlation between genetic features and survival could not be established.
Clinical Impact
Patients with CLL in Lebanon generally share the same epidemiologic characteristics as patients with CLL from other countries. Following the 2016 approval of ibrutinib in Lebanon, there has been an upward trend in its use in both frontline and relapsed settings for patients with CLL.
Real-World Clinical Outcomes in Patients Receiving Either Ibrutinib or Chemo-Immunotherapy as First-Line Treatment for CLL/SLL: A Retrospective Analysis7
In a retrospective analysis, investigators compared outcomes of first-line treatments for either CLL or small lymphocytic lymphoma (SLL) within the clinical setting. These first-line treatments were ibrutinib — the sole targeted treatment that has consistently shown PFS and OS benefits in multiple phase 3 CLL/SLL clinical trials — and chemo-immunotherapy. A total of 3064 patients with CLL or SLL were classified as either patients with high-risk cytogenetic markers or patients without immunoglobulin heavy-chain variable region gene (IGHV) testing. Patients treated with first-line ibrutinib had a 51% lower risk of needing subsequent treatment when compared with patients receiving chemo-immunotherapy.
Clinical Impact
Overall, these real-world-setting outcomes are consistent with clinical trial results supporting use of ibrutinib in CLL/SLL, namely evidence that ibrutinib is safe and effective even for patients with high cytogenetic risk features and those without IGHV testing.
Characteristics and Clinical Outcomes Among Patients Receiving Either Ibrutinib or Anti-CD20 Monotherapy as First-Line Treatment for CLL/SLL: A Retrospective Analysis in Community Oncology Practice8
In a retrospective study, investigators compared outcomes between first-line ibrutinib and anti-CD20 monotherapy with rituximab or obinutuzumab in the community setting. The 3226 patients with CLL or SLL included in the analysis were classified as either patients who had high-risk cytogenetic markers or patients without IGHV testing. Patients treated with ibrutinib were more likely to have high-risk cytogenic markers (42.6%) compared with patients who received an anti-CD20 antibody (27.9%). Additionally, patients who received ibrutinib as first-line treatment had a 70% reduced risk of initiating a subsequent treatment compared with patients who received an anti-CD20 antibody.
Clinical Impact
First-line treatment with ibrutinib rather than anti-CD20 therapy will likely remain the choice of community oncology practitioners, due not only to its ability to statistically significantly reduce the risk of subsequent treatment but also because of its safety benefit especially among patients without IGHV testing and those with high cytogenetic risk features.
Four-Year Follow-Up From a Phase 2 Study of Obinutuzumab, Ibrutinib, and Venetoclax in CLL9
This study was conducted by researchers from The Ohio State University in Columbus and the University of Cincinnati in Ohio. A total of 75 patients were randomly assigned into 3 cohorts. Patients were placed into the relapsed/refractory cohort, treatment-naive 1 cohort — both of which were previously reported — or into the treatment-naive 2 cohort, a new, previously unreported group of patients who were given the same treatment as the treatment-naive 1 cohort.
The treatment-naive 2 cohort received treatment for 14 cycles lasting 28 days each with a standard dose escalation. Obinutuzumab was started in cycle 1, ibrutinib was started in cycle 2, and venetoclax was started in cycle 3. Response was assessed 2 months after cycle 14. The combined ORR and complete remission rate for the treatment-naive 1 and treatment-naive 2 cohorts were 90% and 24%, respectively. In the relapsed/refractory cohort, 100% OS was demonstrated compared with 85% (95% CI, 60-95) for the treatment-naive cohort. For treatment-naive 2, the 24-month PFS and OS estimates were both 96% (95% CI, 75-99).
Clinical Impact
Having demonstrated safety and yielding durable remission rates, fixed-duration combination therapy with obinutuzumab, ibrutinib, and venetoclax can potentially become a preferred treatment for the management of relapsed/refractory CLL.
Fixed-Duration Ibrutinib + Venetoclax for First-Line Treatment of CLL/SLL: Three-Year Follow-Up From the FD Cohort of the Phase 2 CAPTIVATE Study10
In the multicenter phase 2 CAPTIVATE trial (ClinicalTrials.gov Identifier: NCT02910583), a regimen of ibrutinib plus venetoclax was evaluated as a first-line treatment for CLL and SLL. A total of 159 patients with previously untreated CLL or SLL received 3 cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. Of these, 147 (92%) and 149 (94%) patients completed treatment with ibrutinib and venetoclax, respectively. At 36 months across all treated populations, PFS was 88% and OS was 98%, with similar results seen in patients with high-risk features. An oral, chemotherapy-free regimen given once daily showed durable responses for patients with CLL or SLL who were all previously untreated.
Clinical Impact
Given the efficacy findings and itsmanageable safety profile, fixed-duration combination therapy with ibrutinib plus venetoclax offers clinically meaningful PFS, OS, CR, and ORR outcomes for patients with CLL/SLL, including those with high-risk features such as TP53 mutation and a complex karyotype. Successful responses to single-agent retreatment with ibrutinib may also be expected.
Summary
The treatment landscape for CLL has changed dramatically over the past few years, with novel therapies replacing the once-standard chemo-immunotherapy.11 As evidenced by data reported at the 2022 ASCO Annual Meeting, options among fixed-duration, non-chemo-immunotherapy regimens are expanding, with more single-agent and combination therapies consistently demonstrating safety and efficacy in the clinical setting. Among these new treatment options, the first-generation BTK inhibitor ibrutinib remains the preferred first-line treatment for CLL, although the second-generation BTK inhibitor zanubrutinib has been found to be comparable to ibrutinib.
In terms of combination therapy for CLL, bendamustine plus rituximab and chlorambucil plus obinutuzumab are only 2 of various tried-and-tested approaches for previously untreated patients. The growing availability of these new therapies has already translated to improved outcomes and a brighter outlook for patients with CLL, including those with high-risk cytogenetic markers. Further investigation is needed to maximize PFS for treatment-naive and relapse/remitting patients with CLL and further improve their quality of life.
Disclosures
Several study authors declared affiliations with the pharmaceutical industry. Please see the original references for a full list of authors’ disclosures.
References
1. National Cancer Institute. Cancer stat facts: leukemia—chronic lymphocytic leukemia (CLL). US Department of Health and Human Services. Accessed June 20, 2022. https://seer.cancer.gov/statfacts/html/clyl.html
2. Hallek MJ, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021;96(31). doi:10.1002/ajh.26367
3. Chanan-Khan A, Yang K, Liu T, et al. Efficacy of first-line treatment for chronic lymphocytic leukemia: a Bayesian network meta-analysis. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract e19526.
4. Vardell V, Ermann DA, Shah H, Fitzgerald L, Hu B, Stephens DM. Survival outcomes in patients with chronic lymphocytic leukemia treated at academic centers. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 7544.
5. Gogia A, Sharma A, Gupta R, Rani L, Mallick S. Safety and efficacy of ibrutinib in Indian patients with chronic lymphocytic leukemia. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract e19585.
6. Nasr L, Yahia I, Diab S, Ghoche A, Nasr FL. Real-world data of Lebanese patients with chronic lymphocytic leukemia. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract e19512.
7. Wu L, Ran T, He J, Panjabi S, Lu X. Real-world clinical outcomes in patients receiving either ibrutinib or chemo-immunotherapy (CIT) as first-line (1L) treatment for chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL): a retrospective analysis. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract e19057.
8. Vose J, He J, Lu X, Wu L, Ran T, Panjabi S. Characteristics and clinical outcomes among patients receiving either ibrutinib or anti-CD20 monotherapy as first-line (1L) treatment for chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL): a retrospective analysis in community oncology practice. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract e19056.
9. Rogers KA, Huang Y, Abruzzo L, et al. Four-year follow-up from a phase 2 study of obinutuzumab, ibrutinib, and venetoclax in CLL. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 7540.
10. Wierda WG, Barr PM, Siddiqi T, et al. Fixed-duration (FD) ibrutinib (I) + venetoclax (V) for first-line (1L) treatment (tx) of chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL): three-year follow-up from the FD cohort of the phase 2 CAPTIVATE study. Abstract presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 7519.
11. Bewarder M, Stilgenbauer S, Thruner L, Kaddu-Mulindwa D. Current treatment options in CLL. Cancers (Basel). 2021;13(10):2468. doi:10.3390/cancers13102468
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Reviewed June 2022
