A Review of Selected Presentations From the ASCO Meeting • June 3-7, 2022 •
Chicago, Illinois
Acalabrutinib ± Obinutuzumab vs Obinutuzumab + Chlorambucil in Treatment-Naive Chronic Lymphocytic Leukemia: Five-Year Follow-Up of ELEVATE-TN
Bruton’s tyrosine kinase (BTK) is an essential component of B-cell receptor signaling. Many small-molecule BTK inhibitors have been developed, and BTK inhibition is now a standard of care for the treatment of patients with chronic lymphocytic leukemia (CLL).1 Acalabrutinib is a next-generation, highly selective BTK inhibitor that is approved by the US Food and Drug Administration (FDA) for the treatment of patients with CLL/small lymphocytic lymphoma (SLL) or with previously treated mantle cell lymphoma (MCL). The approval of acalabrutinib in patients with previously untreated CLL was based on results from the randomized phase 3 ELEVATE-TN trial, which enrolled patients ages 65 years or older (or ages 18-65 years with comorbidities) without significant cardiovascular disease. A total of 535 patients were randomly assigned to acalabrutinib plus obinutuzumab (n=179), single-agent acalabrutinib (n=179), or obinutuzumab plus chlorambucil (n=177). The median age of enrolled patients was 70 years. Deletion 17p (del[17p]) and/or TP53 mutations were found in 14%.
The improvements seen with acalabrutinib in the original report were maintained at a 4-year analysis.2,3 After a median follow-up of 46.9 months, the median progression-free survival (PFS) as assessed by the investigators was not reached in both acalabrutinib arms vs 27.8 months with obinutuzumab plus chlorambucil (P<.0001).2,3
At the 2022 American Society of Clinical Oncology (ASCO) annual meeting, Jeff Sharman, MD, presented results from a 5-year follow-up analysis of the ELEVATE-TN study.4 The median follow-up was 58.2 months (range, 0-72.0 months). The rates of treatment discontinuation were 35.2% for acalabrutinib plus obinutuzumab and 40.2% for acalabrutinib alone. Adverse events (AEs) were the most common reason for treatment discontinuation. AEs led to discontinuation in 17.3% of patients receiving acalabrutinib plus obinutuzumab and in 15.6% of those receiving acalabrutinib. Among patients in the control arm, 72 (41%) crossed over to the single-agent acalabrutinib arm.
The previously reported PFS benefit reported with acalabrutinib-based therapy was maintained after approximately 5 years. The median PFS was not reached in either acalabrutinib-containing arm vs 27.8 months in the obinutuzumab-plus-chlorambucil arm (hazard ratio [HR] for acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil, 0.11; 95% CI, 0.07-0.16; HR for acalabrutinib vs obinutuzumab plus chlorambucil, 0.21; 95% CI, 0.15-0.30; Figure 1). The estimated 5-year PFS rates were 84% with acalabrutinib plus obinutuzumab and 72% with acalabrutinib monotherapy. Among patients with del(17p) and/or TP53 mutations, the median PFS was not reached in either acalabrutinib-containing arm vs 17.5 months with obinutuzumab plus chlorambucil (HR for acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil, 0.19; 95% CI, 0.08-0.45; HR for acalabrutinib vs obinutuzumab plus chlorambucil, 0.21; 95% CI, 0.09-0.50; Figure 2).
At this analysis, the median overall survival (OS) had not been reached in any arm. However, there was an improvement in OS with acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil (HR, 0.55; 95% CI, 0.30-0.99; P=.0474). Response rates were higher in the acalabrutinib-containing arms, with an overall response rate (ORR) of 96.1% with acalabrutinib plus obinutuzumab, 89.9% with acalabrutinib alone, and 83.1% with obinutuzumab plus chlorambucil. The rates of complete response (CR) or CR with incomplete count recovery (CRi) have continued to increase with additional follow-up, reaching 32.4% with acalabrutinib plus obinutuzumab vs 14.5% with acalabrutinib alone at the current analysis. Among patients with a CR/CRi, rates of undetectable minimal residual disease were higher with acalabrutinib plus obinutuzumab (42%) compared with single-agent acalabrutinib (10%) or obinutuzumab plus chlorambucil (9%).
Safety findings were similar to previous analyses. AEs that occurred more frequently in the acalabrutinib-containing arms included headache, diarrhea, and arthralgia. AEs that were more frequent with obinutuzumab plus chlorambucil included neutropenia, nausea, and infusion-related reactions. Cardiac events occurred in 24.2% of patients receiving acalabrutinib plus obinutuzumab, 21.8% of patients receiving acalabrutinib, and 7.7% of patients receiving obinutuzumab plus chlorambucil. Atrial fibrillation occurred in 6.2%, 7.3%, and 0.6% of patients, respectively. Major bleeding occurred in 6.7%, 4.5%, and 1.2% of patients. Hypertension was reported in 9.6%, 8.9%, and 3.6%. Grade 3 or higher infections were more common with acalabrutinib plus obinutuzumab (28%) than with acalabrutinib alone (20%). The investigators concluded that acalabrutinib administered as a single agent or as a component of combination therapy is associated with durable disease control and tolerability.
References
1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated June 3, 2022. Accessed June 22, 2022.
2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
3. 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.
4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 5-year follow-up of ELEVATE-TN [ASCO abstract 7539]. J Clin Oncol. 2022;40(16 suppl).
Influence of Racial and Ethnic Identity on Overall Survival in Patients With Chronic Lymphocytic Leukemia
The incidence of CLL varies substantially by race and ethnicity, with White individuals accounting for most CLL diagnoses in the United States. According to publicly available data from the Surveillance, Epidemiology, and End Results program, the incidence of CLL is 4.7 per 100,000 White Americans, 3.2 per 100,000 Black Americans, 2.1 per 100,000 Hispanic Americans, and 1.1 per 100,000 Asian Americans.1 Data for CLL characteristics and outcomes according to race and/or ethnicity are limited. Previous studies indicate that outcomes are worse among CLL patients who are not White. In a 2011 study, OS outcomes were significantly worse in Black patients (n=2059) compared with White patients (n=27,703).2 The 5-year OS was 63.9% vs 77.1%, respectively (P<.01). In a 2013 publication, Black patients with CLL receiving care at 2 institutions (n=84) had higher rates of disease-related complications at diagnosis and higher-risk molecular features compared with a reference non-Black population of 1571 patients.3 Event-free survival and OS were both significantly shorter in Black patients vs non-Black patients (P=.007 and P=.0001, respectively).3 More recently, an analysis of data from the Connect CLL registry showed that OS was shorter among 98 non-White patients vs 1333 White patients (HR, 1.34; P=.0445).4
To obtain additional knowledge about CLL demographics, treatment, and outcomes based on race/ethnicity, Victoria Vardell, MD, and colleagues analyzed the National Cancer Database for Chronic Lymphocytic Leukemia, which includes approximately 70% of patients with CLL in the United States.1 The analysis focused on 97,804 evaluable patients diagnosed between 2004 and 2018 who had racial/ethnic data available. Approximately 91% of patients identified as White, 8% as Black, 3% as Hispanic, 1% as Asian, and 1% as another race. The median age at diagnosis was lower for Black and other racial minority patients (66 years) compared with White patients (70 years). Comorbidity burden as assessed by the Charlson-Deyo Comorbidity Index was also significantly higher among Black patients compared with White patients (0.43 vs 0.31 points).
Compared with White patients, Black patients were more likely to be female (42.8% vs 39.3%), uninsured (6.6% vs 2.1%), or Medicaid-insured (9.9% vs 3.4%), and to reside in low-income areas (47.7% vs 13.1%) or areas with a low high-school graduation rate (41.3% vs 14.3%). Black patients were more likely than White patients to receive systemic CLL-directed therapy at diagnosis (35.9% vs 23.6%). In a multivariate analysis adjusted for age and comorbidity score, the risk of death was significantly higher in Black patients than White patients, with a median OS of 7.0 years and 9.1 years, respectively (HR, 1.51; 95% CI, 1.46-1.57; P<.001; Figure 3). Survival over time is shown in Figure 4.
The investigators noted several limitations to the analysis. The racial/ethnic categories may not reflect the complexity of the racial/ethnic background of all patients. In addition, the database does not include staging and molecular risk information, has limited treatment data, and lacks information about the cause of death. However, this analysis—the largest of its kind to date—provides insights into disparities among patients with CLL based on race/ethnicity. CLL appeared to present at a younger age in Black and other racial minority patients compared with White patients. Black patients had significantly more comorbidities and often had increased socioeconomic disadvantages. They were also more likely to receive treatment at diagnosis, which may reflect more advanced disease.
In the era of targeted therapies, OS was significantly shorter in Black patients compared with White patients and those of other races. This discrepancy persisted even after the study investigators adjusted for the patient’s age and comorbidity score. The disparity in OS has appeared to improve in the past 15 years. The investigators concluded that the findings should lay the groundwork for strategies to reduce these differences in outcomes. Possible approaches include targeted education to improve early detection and management, as well as additional research to understand disease characteristics and disparities in access to treatment. There is also a need for broader action to address racism, reduce disparities, and build trust between minority patients and the medical community.
References
1. Vardell VA, Ermann DA, Shah H, et al. Impact of racial and ethnic identity on overall survival in patients with chronic lymphocytic lymphoma [ASCO abstract 7508]. J Clin Oncol. 2022;40(16 suppl).
2. Shenoy PJ, Malik N, Sinha R, et al. Racial differences in the presentation and outcomes of chronic lymphocytic leukemia and variants in the United States. Clin Lymphoma Myeloma Leuk. 2011;11(6):498-506.
3. Falchi L, Keating MJ, Wang X, et al. Clinical characteristics, response to therapy, and survival of African American patients diagnosed with chronic lymphocytic leukemia: joint experience of the MD Anderson Cancer Center and Duke University Medical Center. Cancer. 2013;119(17):3177-3185.
4. Mato A, Nabhan C, Lamanna N, et al. The Connect CLL Registry: final analysis of 1494 patients with chronic lymphocytic leukemia across 199 US sites. Blood Adv. 2020;4(7):1407-1418.
Acalabrutinib vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia: ASCEND Results at ∼4 Years of Follow-Up
The FDA approval of acalabrutinib in patients with relapsed/refractory CLL was based on its demonstrated efficacy and safety in the randomized phase 3 ASCEND trial, which compared acalabrutinib vs the investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in patients with relapsed/refractory CLL. The trial enrolled 310 patients, whose median age was 67 years (range, 32-90). The patients had received a median of 2 prior therapies (range, 1-10). The patients were randomly assigned to acalabrutinib or the investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab. Crossover from the control arm to acalabrutinib was allowed after confirmed disease progression.
In the primary analysis of the ASCEND trial, after a median follow-up of 16.1 months, treatment with acalabrutinib led to a significant 69% decrease in the risk of disease progression or death compared with idelalisib plus rituximab or bendamustine plus rituximab.1 The median PFS was not reached with acalabrutinib vs 16.5 months in the control arm (HR, 0.31; 95% CI, 0.20-0.49; P<.001). Acalabrutinib was also associated with an acceptable safety profile. Serious AEs occurred in 29% of patients treated with acalabrutinib, 56% of patients treated with idelalisib plus rituximab, and 26% of patients treated with bendamustine plus rituximab.
After a median follow-up duration of approximately 3 years, the PFS advantage reported with acalabrutinib compared with idelalisib plus rituximab or bendamustine plus rituximab was maintained (HR, 0.29; 95% CI, 0.21-0.41; P<.0001).2 At that time, the median OS was not reached in either arm. No new safety signals were reported.
At the 2022 ASCO meeting, Wojciech Jurczak, MD, presented the final analysis of the study.3 After a median follow-up of approximately 4 years, the median PFS was still not reached among patients treated with acalabrutinib vs 16.8 months in those treated with idelalisib plus rituximab or bendamustine plus rituximab (HR, 0.28; 95% CI, 0.20-0.38; P<.0001). The estimated 42-month PFS rates were 62% vs 19%, respectively (Figure 5). Among patients with del(17p), the median PFS was not reached in the acalabrutinib arm vs 13.8 months in the control arm (HR, 0.13; 95% CI, 0.06-0.29; P<.0001; Figure 6). The PFS benefit of acalabrutinib was also maintained in patients with the unmutated immunoglobulin heavy-chain variable region (IGHV) gene (HR, 0.20; P<.0001) and other subgroups. In the overall population, the median OS was not reached in either arm. The 42-month OS rates were 78% with acalabrutinib vs 65% in the control arm.
In this follow-up analysis, the rates of AEs and events of clinical interest were similar to those reported in the primary analysis. The rates of grade 3 or higher AEs, serious AEs, and AEs leading to dose adjustment or treatment discontinuation were lower with acalabrutinib and bendamustine plus rituximab compared with idelalisib plus rituximab. The most frequent any-grade AEs reported with acalabrutinib were neutropenia, headache, diarrhea, and upper respiratory tract infection. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia. Serious AEs reported in at least 5% of patients in any group consisted of pneumonia (9% with acalabrutinib, 10% with idelalisib plus rituximab, and 3% with bendamustine plus rituximab), diarrhea (1%, 16%, and 0%), and pyrexia (3%, 7%, and 3%). The incidence of bleeding events was higher with acalabrutinib than with idelalisib plus rituximab or bendamustine plus rituximab (31%, 8%, and 6%), as was the incidence of atrial fibrillation (8%, 3%, and 3%). Hypertension was reported in 8%, 6%, and 0% of patients, respectively, and major hemorrhage occurred in 3% of patients in all 3 arms.
The investigators concluded that these data show a continued efficacy benefit and a consistent safety profile for acalabrutinib among patients with relapsed/refractory CLL. These data support the long-term use of acalabrutinib in this population, including in patients with high-risk disease.
References
1. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861.
2. Jurczak W, Pluta A, Wach M, et al. Three-year follow-up of the ASCEND trial: acalabrutinib vs rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia [ASH abstract 393]. Blood. 2021;138(suppl 1).
3. Jurczak W, Pluta A, Wach M, et al. Acalabrutinib vs rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia: ASCEND results at ~4 years of follow-up [ASCO abstract 7538]. J Clin Oncol. 2022;40(16 suppl).
Fixed-Duration Ibrutinib + Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Three-Year Follow-Up From the Fixed-Duration Cohort of the Phase 2 CAPTIVATE Study
The international, multicenter phase 2 CAPTIVATE study evaluated a targeted strategy of ibrutinib plus venetoclax as frontline treatment in patients with CLL who were ages 70 years or younger.1 The study included a fixed-duration cohort, in which patients received 3 cycles of ibrutinib lead-in followed by 12 cycles of ibrutinib plus venetoclax, and a cohort in which treatment discontinuation was guided by minimal residual disease (MRD). The fixed-duration cohort included 159 patients with previously untreated CLL/SLL requiring treatment, with an Eastern Cooperative Oncology Group performance status of 0 to 2. The primary analysis of the fixed-duration cohort was performed after a median time on study of 27.9 months. The trial met its primary endpoint, with 56% of patients attaining CR/CRi.1 Response rates were consistent in patients with high-risk features.
At the 2022 ASCO meeting, William G. Wierda, MD, presented an updated analysis from the CAPTIVATE fixed-duration cohort.2 The patients’ median time on study was 38.7 months, including a median of 24.9 months after the end of treatment. The patients’ median age was 60 years (range, 33-71), 67% were male, and 86% did not have del(17p). Most patients (92%) completed treatment with ibrutinib and venetoclax. The median treatment duration was 13.8 months, reflecting the planned 15 cycles lasting 28 days each.
In this updated analysis, the CR rate in all treated patients increased from 55% to 57%. The results were similar for the primary endpoint population of patients without del(17p). An estimated 94% of CRs were maintained after 24 months. Among patients with a response, the median duration was not reached. The CR rate was similar among patients with del(17p) or TP53 mutations (56%) and with unmutated IGHV (64%; Figure 7). Undetectable MRD in the blood and/or bone marrow was reported among 79% of patients (125/159). MRD responses appeared to be durable (Figure 8). Among 85 patients with undetectable MRD in the blood at 3 months post-treatment, 66 (78%) maintained undetectable levels of MRD through 12 months post-treatment.
The 36-month PFS and OS rates were 88% and 98%, respectively. OS rates were similar among patients with high-risk features. Among 22 patients with disease progression, no BTK, PLCG2, or BCL2 mutations associated with resistance to ibrutinib or venetoclax were detected.
The most frequent treatment-emergent adverse events (TEAEs) consisted of diarrhea (62%; 3% grade 3), nausea (42%; 1% grade 3), and arthralgia (33%; 1% grade 3). Most TEAEs were grade 1/2 in severity. A notable exception was neutropenia, which occurred in 41% of patients, with 32% developing grade 3/4 cases. Frequent TEAEs generally occurred within 4 months of starting treatment. The median time from onset to resolution or improvement ranged from 16.5 days for diarrhea, to 40.5 days for nausea, to 42.5 days for arthralgia. No new serious AEs or secondary malignancies were reported since the primary analysis.
Twelve patients who developed progressive disease after fixed-duration ibrutinib plus venetoclax were re-treated with single-agent ibrutinib. Treatment led to a partial response in 9 patients and a partial response with lymphocytosis in 1 patient. The study investigators concluded that treatment with fixed-duration ibrutinib plus venetoclax is an efficacious, oral, once-daily chemotherapy-free fixed-duration regimen for patients with previously untreated CLL/SLL.
References
1. Tam CS, Allan JN, Siddiqi T, et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood. 2022;139(22):3278-3289.
2. 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 [ASCO abstract 7519]. J Clin Oncol. 2022;40(16 suppl).
Four-Year Follow-Up From a Phase 2 Study of Obinutuzumab, Ibrutinib, and Venetoclax in CLL
Clinical trials are evaluating combinations of BTK inhibitors plus the BCL2 inhibitor venetoclax to identify a time-limited, chemotherapy-free treatment regimen. At the 2022 ASCO meeting, Kerry A. Rogers, MD, presented a 4-year follow-up analysis from a phase 2 study evaluating the combination regimen of obinutuzumab, ibrutinib, and venetoclax, administered for up to 14 cycles, among patients with treatment-naive or relapsed/refractory CLL.1 As reported in 2020, the primary endpoint—the rate of CR with undetectable MRD by flow cytometry in the blood and bone marrow 2 months after completion of treatment—was reached by 28% of patients in both the treatment-naive (n=25) and relapsed/refractory (n=25) cohorts (Figure 9).2 At the 2022 ASCO meeting, Dr Rogers presented additional data from those 2 cohorts after a median follow-up of approximately 56 months, as well as from a second treatment-naive cohort of 25 patients with a median follow-up of approximately 30 months.
The median age of the enrolled patients was 58 years (range, 24-77 years), and 36% of the patients were female. IGHV-unmutated CLL was reported in 75% of patients, and 36% of patients had a complex karyotype. In the relapsed/refractory cohort, the patients had received a median of 1 prior therapy (range, 1-3). Deletion 11q22.3 was detected in 28% of patients, and 8% had del(17p13.1).
At the end of treatment, the ORR was 88% in the relapsed/refractory cohort, 84% in treatment-naive cohort 1, and 96% in treatment-naive cohort 2 (Figure 9). (Among 9 patients [38%] in treatment-naive cohort 2, end-of-treatment assessments were delayed and occurred at a median of 21 weeks, owing to the COVID-19 pandemic.) The median PFS and OS were not reached at the time of the analysis. The estimated rates of 4-year PFS and OS were both 96% for treatment-naive cohort 1, and 85% and 100%, respectively, for the relapsed/refractory cohort. The estimated 2-year PFS and OS rates for treatment-naive cohort 2 were both 96%. During the follow-up period, 3 patients died (1 in each cohort) and 6 patients developed disease progression (4 in the relapsed/refractory cohort and 2 in treatment-naive cohort 1).
Assessments conducted at the end of treatment showed MRD negativity in the blood and bone marrow in 50% of patients (11 of 22) in the relapsed/refractory cohort, 67% of patients (14 of 21) in treatment-naive cohort 1, and 65% of patients (10 of 22) in treatment-naive cohort 2. The investigators noted that a substantial proportion of patients had sustained MRD negativity in the blood more than 1 year after completing treatment.
The most common AEs consisted of neutropenia (95% any-grade; 73% grade ≥3), leukopenia (95%; 45%), lymphopenia (93%; 40%), thrombocytopenia (91%; 28%), hypertension (85%; 39%), hypocalcemia (79%; 0%), and diarrhea (77%; 8%). Atrial fibrillation was reported in 11% of patients (8 of 75); grade 3 or higher cases occurred in 3%. Palpitations occurred in 19% of patients. Tumor lysis syndrome and febrile neutropenia each occurred in 1 patient. The investigators stated that based on the demonstrated efficacy and safety of obinutuzumab, ibrutinib, and venetoclax, this regimen is being evaluated as first-line therapy in two phase 3 trials.3,4
References
1. Rogers KA, Huang Y, Abruzzo LV, et al. Four-year follow up from a phase 2 study of obinutuzumab, ibrutinib, and venetoclax in CLL [ASCO abstract 7540]. J Clin Oncol. 2022;40(16 suppl).
2. Rogers KA, Huang Y, Ruppert AS, et al. Phase II study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naïve and relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(31):3626-3637.
3. ClinicalTrials.gov. Assessing the ability of combination treatment with venetoclax to permit time limited therapy in chronic lymphocytic leukemia. https://clinicaltrials.gov/ct2/show/NCT03701282. dentifier: NCT03701282. Accessed June 22, 2022.
4. ClinicalTrials.gov. 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. https://clinicaltrials.gov/ct2/show/NCT03737981. dentifier: NCT03737981. Accessed June 22, 2022.
A Phase 1b/2 Study of Lisaftoclax (APG-2575), a Novel BCL2 Inhibitor, in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
The BCL2 inhibitor venetoclax can lead to tumor lysis syndrome. To address this risk, administration incorporates an extended 5-week ramp-up period. Other challenges associated with the use of venetoclax include thrombocytopenia and severe neutropenia.1 Lisaftoclax is a novel BCL2 inhibitor in development. In a first-in-human study of lisaftoclax, a daily ramp-up schedule appeared to be feasible.2
At the 2022 ASCO meeting, Jianyong Li, MD, PhD, presented results of a multicenter open-label phase 1b/2 trial evaluating lisaftoclax in patients with relapsed/refractory CLL/SLL in China.3 Lisaftoclax was administered orally once daily at 400 mg, 600 mg, or 800 mg, with 15 patients in each cohort. Overall, the median age of the 45 enrolled patients was 58 years (range, 38-80), 76% were male, 20% had complex chromosomal abnormalities, and 33% had del(17p)/TP53 mutations.
Lisaftoclax was generally well tolerated at doses up to 800 mg per day, with no dose-limiting toxicities. The maximum tolerated dose was not reached. A pharmacokinetics analysis found an approximately dose-proportional increase in exposure at dose levels of 400 mg to 800 mg (Figure 10).
Grade 3 or higher TEAEs were reported in 56% of patients, and 20% of patients developed treatment-emergent serious AEs. Fourteen patients (31%) discontinued treatment, with no discontinuations owing to TEAEs. The most frequent TEAEs of any grade included neutrophil count decrease (56%), anemia (42%), white blood cell count decrease (40%), platelet count decrease (38%), hyperuricemia (31%), hypokalemia (24%), blood bilirubin increase (22%), diarrhea (20%), and hypertriglyceridemia (20%). The most frequent grade 3 or higher TEAEs were neutrophil count decrease (31%), platelet count decrease (24%), and anemia (9%). One case of clinical tumor lysis syndrome was reported.
After a median of 7 cycles, lisaftoclax was associated with an ORR of 67%, with 1 CR (2%). The median time to response was 1 cycle (range, 1-13). The recommended phase 2 dose of single-agent lisaftoclax was identified as 600 mg. The investigators concluded that lisaftoclax may offer an alternative for the treatment of relapsed/refractory CLL/SLL that provides a more patient-friendly daily ramp-up schedule.
References
1. Davids MS, Hallek M, Wierda W, et al. Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res. 2018;24(18):4371-4379.
2. Ailawadhi S, Chanan-Khan AA, Chen Z, et al. First-in-human study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i) in patients (pts) with relapsed/refractory (R/R) CLL and other hematologic malignancies (HMs) [ASCO abstract 7502]. J Clin Oncol. 2021;39(15 suppl).
3. Li J, Zhou K, Gong Y, et al. A phase Ib/II study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor, in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma [ASCO abstract 7543]. J Clin Oncol. 2022;40(16 suppl).
Phase 1/2 Study of Zilovertamab and Ibrutinib in Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia
Zilovertamab is a humanized monoclonal antibody that is directed against ROR1, an onco-embryonic tyrosine kinase–like receptor that is expressed in hematologic cancers, including CLL, but not in healthy adult tissues. At the 2022 ASCO meeting, Hun Ju Lee, MD, presented results of a phase 1/2 study evaluating the combination of zilovertamab (previously known as cirmtuzumab) and ibrutinib in patients with MCL or CLL.1 The dose-finding cohort, which included 18 patients with CLL, evaluated a range of zilovertamab doses, with ibrutinib added after 1 month. The dose-expansion cohort, which included 16 patients with CLL, confirmed the recommended zilovertamab dose of 600 mg, which was administered with ibrutinib at approved doses. Another 31 patients with CLL were enrolled in a phase 2 randomized cohort that compared zilovertamab plus ibrutinib (n=18) with ibrutinib alone (n=10). Among the patients with CLL enrolled across the study cohorts, the median age was 66 to 68 years. The patients had received a median of 2 prior systemic regimens (range, 1-9).
The regimen was generally well tolerated, with a safety profile similar to ibrutinib alone. Among patients with CLL who received zilovertamab plus ibrutinib in the dose-finding and dose-expansion cohorts, the most frequent TEAEs of any grade included platelet decrease (74%), hemoglobin decrease (74%), neutropenia (47%), contusion (47%), hypertension (47%), diarrhea (44%), upper respiratory tract infection (44%), fatigue (41%), muscle spasms (32%), and onycholysis (32%). The most common grade 3 or higher TEAEs included hypertension (21%), neutropenia (18%), and diarrhea (6%). In the randomized controlled cohort, the most common TEAEs of any grade reported with zilovertamab plus ibrutinib and ibrutinib alone were hemoglobin decrease (occurring in 89% vs 70%, respectively), platelet decrease (72% vs 80%), contusion (39% vs 40%), neutropenia (33% vs 30%), back pain (33% vs 40%), and fatigue (33% vs 30%). The grade 3 or higher TEAEs reported in more than 1 patient receiving zilovertamab plus ibrutinib consisted of back pain (2 patients; 11%) and pneumonia (2 patients; 11%). The most common grade 3 or higher TEAEs in patients receiving ibrutinib alone were pneumonia (2 patients; 20%) and neutropenia (2 patients; 20%).
Clinical responses were observed among heavily pretreated patients with CLL. In the dose-finding and dose-expansion cohorts, zilovertamab plus ibrutinib was associated with an ORR of 91% (including a CR rate of 9%) in the overall population (n=34) and 88% (all partial responses) in patients who had received 3 or more prior regimens (n=8). In the randomized cohort, the ORR was 94% (all partial responses) with zilovertamab plus ibrutinib and 100% (all partial responses) with ibrutinib monotherapy. Responses were observed in pretreated patients. The median response duration was 33.5 months in the dose-finding and dose-expansion cohorts, and not reached in the randomized cohort.
The median PFS was not reached in any study cohort after a median follow-up ranging from 24 months to 33.5 months. The median PFS was also not reached among patients with TP53 mutations after a median follow-up duration of at least 33 months. The median PFS was not reached in treatment-naive patients or in those treated with 1 or 2 prior regimens. The median PFS was 36 months among those who had received 3 or more prior regimens. Among the previously treated patients, landmark 3-year PFS rates with zilovertamab plus ibrutinib were approximately 100% in patients who had received 1 or 2 prior regimens and approximately 70% in patients who had received more than 2 prior regimens. The study investigators noted that these data compare favorably to historical control data for ibrutinib monotherapy, in which 3-year PFS rates were approximately 73% in patients who had received 1 to 2 prior regimens and approximately 50% in those who had received more than 2 prior regimens.2 The median OS was not reached in any CLL cohort.
References
1. Lee HJ, Choi MY, Siddiqi T, et al. Phase 1/2 study of zilovertamab (formerly cirmtuzumab) and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [ASCO abstract 7520]. J Clin Oncol. 2022;40(16 suppl).
2. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031-2042.
Phase 1 Dose Escalation of LAVA-051, a Novel Bispecific Gamma-Delta T-Cell Engager (Gammabody), in Relapsed/Refractory Hematologic Malignancies
The novel bispecific γδ T-cell engager LAVA-051 targets CD1D, which is expressed in CLL and multiple myeloma cells, and the Vδ2 T-cell receptor chain of Vg9Vδ2 T cells, an innate-like T-cell population with antitumor activity. Preclinical data suggest that LAVA-051 has a low potential for inducing cytokine release syndrome, and therefore is expected to have a broad therapeutic window.1 At the 2022 ASCO meeting, Annemiek Broijl, MD, PhD, presented results of a phase 1 dose-escalation study of LAVA-051 in a small cohort of 3 patients with CLL and 3 patients with multiple myeloma.1
Using an open-label, accelerated titration design, the study evaluated a range of LAVA-051 doses administered via intravenous infusion or subcutaneous injection. The 3 patients with CLL had received between 3 and 5 prior therapies. As of the analysis, the starting dose of LAVA-051 had been increased by 100-fold in both disease cohorts. There were no cases of cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, or of significant increases in levels of interleukin 6. No dose-limiting toxicities were reported. No patients developed anti-drug antibodies. Most observed AEs were not considered treatment-related. No grade 2 or higher TEAEs were reported in more than 1 patient. One patient developed a grade 2 infusion-related reaction, and 1 patient developed grade 3 neutropenia.
The investigators noted that the drug’s pharmacodynamic parameters reflected the mechanism of action. The concentration of Vg9Vδ2 in the peripheral blood decreased early after drug administration but subsequently recovered. Administration of LAVA-051 was associated with consistent increased expression of the activation markers CD25 and CD69, indicating activation of Vg9Vδ2 T-cells. Moreover, there was a dose-dependent increase in Vg9Vδ2 T-cell receptor occupancy with increasing LAVA-051 doses. In this early analysis, there were potential signs of antitumor activity, including signs of a tumor flare reaction and a reduction in the percentage of clonal B cells in the blood in a patient with CLL who had stable disease. The patient stopped treatment after cycle 5 owing to a COVID diagnosis. Clinical investigations of LAVA-051 are ongoing.
Reference
1. Broijl A, van de Donk NW, Bosch F, et al. Phase I dose escalation of LAVA-051, a novel bispecific gamma-delta T-cell engager (Gammabody), in relapsed/refractory hematological malignancies [ASCO abstract 2577]. J Clin Oncol. 2022;40(16 suppl).
Highlights in Chronic Lymphocytic Leukemia From the 2022 American Society of Clinical Oncology Annual Meeting: Commentary
At the 2022 American Society of Clinical Oncology (ASCO) annual meeting, several presentations evaluated treatments for chronic lymphocytic leukemia (CLL). Follow-up analyses of phase 3 trials provided long-term data for the Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib. Another follow-up analysis evaluated fixed-duration treatment with venetoclax and ibrutinib. Two network meta-analyses compared data for BTK inhibitors and other treatments. Another important study provided insights into the epidemiology of the disease.
The Influence of Racial and Ethnic Identity on Overall Survival in CLL
Dr Daniel Ermann and colleagues presented interesting results of a study that examined the influence of racial and ethnic identity on overall survival in patients with CLL.1 The field of CLL needs more real-world data, as well as data evaluating disparities in care and outcome among various subgroups of patients. This retrospective review examined records from the National Cancer Database (NCDB) and identified approximately 97,800 patients who were diagnosed with CLL from 2004 to 2018. The aim was to evaluate outcomes for patients based on their racial groups, such as White, Black, Asian, and Hispanic. The first noteworthy observation from the study was that approximately 90% of the patients in the database were White. Black and Hispanic patients constituted a small subset of patients with CLL. This finding is consistent with previous studies showing that CLL is predominantly a disease of older White men.2 The analysis provides evidence to support observations from clinical experience and previous reports suggesting that outcome is worse in Black patients.3-5 The median age at diagnosis was 66 years for Black patients vs 70 years for White patients. Black patients had a higher burden of comorbidity at diagnosis and were more likely to be uninsured.
There were other important findings in this analysis. Treatment for CLL is typically initiated once patients develop disease progression that causes symptoms or abnormalities in blood counts, lymph nodes, or the spleen. Black patients were more likely than white patients to begin early treatment. Treatment began immediately after diagnosis in 35% of Black patients vs 23% of White patients.1 This difference might reflect the type of settings in which Black patients tend to seek care. More importantly, Black patients might have more aggressive disease that requires earlier treatment.
The most important finding of this analysis was that overall survival was much worse in Black patients as compared with all other ethnic groups, including White and Hispanic patients. The median overall survival was 7 years for Black patients, 9.1 years for White patients, and 10.4 years for Hispanic patients. A multivariate analysis found that Black ethnicity was independently associated with poor outcomes. There was no other variable that could explain why these patients did poorly. Essentially all outcomes were significantly worse among Black patients compared with the other ethnic groups.
Studies in cancers consistently show that Black patients have worse outcomes than other racial groups.6,7 This analysis highlights a need in CLL that community awareness organizations and clinicians can address. Hopefully, it will be possible to improve outcomes for patients across all ethnic and racial groups.
Acalabrutinib
At the 2022 ASCO meeting, investigators presented updates for 2 studies of acalabrutinib in CLL. The large, randomized phase 3 ELEVATE-TN trial evaluated acalabrutinib alone, acalabrutinib plus obinutuzumab, and chlorambucil plus obinutuzumab in patients with previously untreated CLL.8 The study randomly assigned 535 patients into 3 groups. Group 1 received acalabrutinib alone (n=179). Group 2 received acalabrutinib plus obinutuzumab (n=179). Group 3 received chlorambucil plus obinutuzumab (n=177). Initial reports of the ELEVATE-TN study showed improved outcomes among patients in the acalabrutinib arms compared with those in the chlorambucil/obinutuzumab arm.8 Dr Jeff Sharman and colleagues presented results from an updated 5-year analysis, which continued to show that outcomes were superior in the acalabrutinib arms.9 An important finding from this analysis was that patients who received acalabrutinib plus obinutuzumab had better outcomes compared with patients who received acalabrutinib alone. The ELEVATE-TN study was not designed to detect a difference between the 2 acalabrutinib-containing arms. However, these data indirectly answer an important question in the field, which is whether the addition of a CD20 antibody to a BTK inhibitor improves long-term outcomes. The rate of progression-free survival (PFS) at 5 years was 72% with acalabrutinib alone vs 84% with acalabrutinib plus obinutuzumab. This improvement in PFS was noted in the earlier reports and has continued to increase over the years, suggesting that combining BTK inhibitors with obinutuzumab might be an effective and viable strategy.
There were no new safety signals or adverse events reported in the updated analysis.9 The toxicities in both acalabrutinib arms were expected. They included bleeding and headache. Atrial fibrillation, an adverse event of interest, occurred at fairly similar rates in the acalabrutinib arms (6.2% with acalabrutinib plus obinutuzumab, 7.3% with acalabrutinib alone, and 0.6% with obinutuzumab plus chlorambucil).
This important 5-year analysis of the ELEVATE-TN study provides promising data.9 Throughout the COVID-19 pandemic, physicians aimed to minimize the use of CD20 antibodies because of the associated risk of infectious complications. In the future, however, it may be possible to justify this risk based on the long-term improvement in PFS. It remains to be seen whether the addition of obinutuzumab to acalabrutinib will become the standard of care.
Dr Wojciech Jurczak and colleagues presented data from a 4-year follow-up analysis of the ASCEND trial, which evaluated acalabrutinib in 310 patients with relapsed/refractory CLL.10,11 The trial compared acalabrutinib (n=155) vs idelalisib plus rituximab (n=119) or bendamustine plus rituximab (n=36). Earlier results showed a significant improvement in PFS among patients treated with acalabrutinib vs those treated with idelalisib plus rituximab or bendamustine plus rituximab.10 This significant improvement in PFS was maintained in the 4-year analysis.11 The median PFS was not reached in the acalabrutinib arm vs 16.8 months in the control arm.
Importantly, this analysis also showed that acalabrutinib significantly improved outcome among patients with deletion 17p (del[17p]). In the acalabrutinib arm, the median PFS was not reached for patients with or without del(17p). Other treatments, notably venetoclax, are less effective in patients with del(17p).12 In the ASCEND study, among patients treated with idelalisib plus rituximab or bendamustine plus rituximab, the median PFS was 20.3 months for patients without del(17p) and 13.8 months for patients with del(17p).
This analysis of the ASCEND trial raised another important point. No head-to-head trial has compared a BTK inhibitor and a phosphoinositide 3-kinase (PI3K) inhibitor in patients with CLL. There has been some debate regarding the relative efficacy of a BTK inhibitor compared with a PI3K inhibitor. The ASCEND trial did not address this question directly. However, the trial provides a comparison between a fairly large group comprising patients treated with idelalisib plus rituximab and a smaller group of patients treated with bendamustine plus rituximab. These treatments led to similar outcomes, and acalabrutinib was shown to be superior to both.
In the modern era, it is difficult to demonstrate an improvement in overall survival among patients with CLL. Patients have access to many effective therapies, and if one therapy is unsuccessful, another novel therapy is utilized. Therefore, in this analysis of the ASCEND trial, acalabrutinib did not significantly improve overall survival. However, there was a trend toward improvement.
Treatment with BTK inhibitors must be continued indefinitely, which can be challenging if patients develop problematic side effects. Chemotherapy can be stopped after 6 months. An important finding of this analysis was that the rate of adverse events, including infections, was significantly lower in the acalabrutinib arm vs the control arms and fairly similar to previous reports.10 This 4-year analysis of the ASCEND trial shows promising results for acalabrutinib in the setting of relapsed/refractory CLL.
Network Meta-Analyses
Dr Asher Chanan-Khan and colleagues provided data from studies that can be considered surrogates for clinical trials.13,14 Generating data for direct comparisons of BTK inhibitors with various available therapeutic options requires large, randomized trials that take years to complete. There are data available from 2 head-to-head trials comparing acalabrutinib and zanubrutinib, respectively, with ibrutinib.15,16 However, given the similar efficacy and variable toxicity results, it is difficult to identify the best option among the various treatments that are available. To address the question of which BTK inhibitor is potentially the best, Dr Chanan-Khan and colleagues performed 2 network meta-analyses of trials that evaluated the most common treatments in CLL.13,14 An analysis of treatment-naive patients included trials evaluating zanubrutinib; ibrutinib; bendamustine plus rituximab; chlorambucil plus obinutuzumab; and chlorambucil plus rituximab. Among patients with relapsed/refractory disease, the trials evaluated zanubrutinib; ibrutinib; acalabrutinib; bendamustine plus rituximab; and venetoclax plus rituximab.
In the analysis of patients in the frontline setting, there was a statistically significant improvement in PFS with the use of zanubrutinib vs bendamustine plus rituximab.13 Zanubrutinib was also superior to chlorambucil plus obinutuzumab and chlorambucil plus rituximab. PFS was comparable between zanubrutinib and ibrutinib. It should be stated that cross-trial comparisons typically should not be considered proof that one treatment is better than another. However, this analysis suggests that the efficacy of BTK inhibitors is fairly similar and superior to the alternative options, such as bendamustine plus rituximab.
The meta-analysis of studies in the relapsed/refractory setting showed that zanubrutinib significantly improved PFS as compared with acalabrutinib, ibrutinib, and bendamustine/rituximab.14 There was a trend toward improved PFS for zanubrutinib compared with venetoclax plus rituximab, although the difference did not reach statistical significance.
These types of analyses, although not traditional phase 3 randomized clinical trials, provide evidence that can inform treatment selection. However, an important element missing from these analyses was an examination of toxicity. Agents might have similar efficacy, but different rates of adverse events. It would be difficult to justify switching treatment to an agent with similar efficacy but higher toxicity. If a meta-analysis were to demonstrate that a particular agent improved efficacy with better tolerability, this finding could be considered a compelling reason to use this agent, even in the absence of randomized clinical trial data.
Ibrutinib Plus Venetoclax
The multicenter phase 2 CAPTIVATE study evaluated ibrutinib plus venetoclax for the frontline treatment of patients with CLL.17 Dr William Wierda and colleagues presented 3-year follow-up data from the fixed-duration cohort (n=159).18 Previous reports of the CAPTIVATE study showed that frontline treatment with ibrutinib and venetoclax is very effective.17 This regimen is also effective in the relapsed/refractory setting.19 In the fixed-duration cohort of the CAPTIVATE study, ibrutinib was administered as a lead-in drug for the first 3 cycles. Venetoclax was then administered, using the standard ramp-up dose, along with concomitant ibrutinib. Combination therapy was given for 12 months, for a total treatment duration of 15 months. Subsequently, patients with progressive disease could receive re-treatment with single-agent ibrutinib. Patients with a durable response could receive fixed-duration ibrutinib plus venetoclax.
Previous data showed that this regimen had a very high success rate in terms of depth of response.17 In this analysis, all patients had good outcomes with the use of ibrutinib and venetoclax. The 3-year rate of PFS was 88%. This outcome is comparable with other studies of BTK inhibitors, which have shown a 4-year PFS rate of approximately 80%.8 Undetectable minimal residual disease as measured in the peripheral blood or bone marrow biopsy was reported in 79% of patients.18 These promising results also showed good tolerability of the fixed-duration treatment.
The study analyzed outcome according to high-risk subtypes. Immunoglobulin heavy-chain variable region (IGHV) mutational status did not appear to impact outcome. Patients with del(17p) or TP53 mutations had a slightly inferior outcome as compared with patients without these abnormalities.
This analysis of the fixed-duration cohort also evaluated outcome when patients stopped treatment after 15 months.18 Among the 159 patients in this cohort, 26 patients developed progressive disease. The rate of disease progression was fairly low, and progression did not appear to impact overall survival. Twelve of the patients who progressed after fixed-duration therapy received further treatment with single-agent ibrutinib. Ten of these patients had a partial response, and 1 patient had stable disease. (Outcome was unavailable for 1 patient.)
This analysis highlights several findings. A finite duration of treatment can result in deep responses. A substantial percentage of these patients may not require treatment for a fairly long period. When treatment is needed, single-agent ibrutinib is effective.
Toxicities can be a concern with the doublet of ibrutinib plus venetoclax. The predominant adverse events consisted of neutropenia, diarrhea, arthralgia, and nausea.18 Ibrutinib is associated with a significant incidence of cardiovascular side effects,21 which can be an issue for patients who restart ibrutinib after the initial 15 months of therapy. However, these results from the CAPTIVATE study show that CLL can be controlled for a fairly long period with a finite duration of therapy.
Disclosure
Dr Awan has provided consultancy services to Genentech, AstraZeneca, AbbVie, Janssen, Pharmacyclics, Gilead Sciences, Kite Pharma, Celgene, Karyopharm, MEI Pharma, Verastem, Incyte, BeiGene, Johnson & Johnson, DAVA Oncology, BMS, Merck, Cardinal Health, ADC Therapeutics, Epizyme, and Caribou Biosciences. He has received research funding from Pharmacyclics.
References
1. Vardell V, Ermann DA, Shah H, et al. Influence of racial and ethnic identity on overall survival in patients with chronic lymphocytic lymphoma [ASCO abstract 7508]. J Clin Oncol. 2022;40(16 suppl).
2. Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl). 2004;13(3):279-287.
3. Shenoy PJ, Malik N, Sinha R, et al. Racial differences in the presentation and outcomes of chronic lymphocytic leukemia and variants in the United States. Clin Lymphoma Myeloma Leuk. 2011;11(6):498-506.
4. Falchi L, Keating MJ, Wang X, et al. Clinical characteristics, response to therapy, and survival of African American patients diagnosed with chronic lymphocytic leukemia: joint experience of the MD Anderson Cancer Center and Duke University Medical Center. Cancer. 2013;119(17):3177-3185.
5. Mato A, Nabhan C, Lamanna N, et al. The Connect CLL Registry: final analysis of 1494 patients with chronic lymphocytic leukemia across 199 US sites. Blood Adv. 2020;4(7):1407-1418.
6. Esnaola NF, Ford ME. Racial differences and disparities in cancer care and outcomes: where’s the rub? Surg Oncol Clin N Am. 2012;21(3):417-437, viii.
7. Jemal A, Siegel R. Social inequalities in cancer burden between Black and White populations in the USA. In: Vaccarella S, Lortet-Tieulent J, Saracci R, Conway DI, Straif K, Wild CP, eds. Reducing Social Inequalities in Cancer: Evidence and Priorities for Research. Lyon, France: International Agency for Research on Cancer; 2019.
8. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
9. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 5-year follow-up of ELEVATE-TN [ASCO abstract 7539]. J Clin Oncol. 2022;40(16 suppl).
10. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861.
11. Jurczak W, Pluta A, Wach M, et al. Acalabrutinib vs rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia: ASCEND results at ~4 years of follow-up [ASCO abstract 7538]. J Clin Oncol. 2022;40(16 suppl).
12. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236.
13. Chanan-Khan A, Yang K, Liu T, et al. Efficacy of first-line treatment for chronic lymphocytic leukemia: a Bayesian network meta-analysis [ASCO abstract e19526]. J Clin Oncol. 2022;40(16 suppl).
14. Chanan-Khan A, Liu T, Yang K, et al. Network meta-analysis of progression free survival in the treatment of relapsed or refractory chronic lymphocytic leukemia [ASCO abstract e19514]. J Clin Oncol. 2022;40(16 suppl).
15. 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.
16. 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 [EHA abstract LB1900]. HemaSphere. 2021;5(suppl).
17. Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865.
18. 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 [ASCO abstract 7519]. J Clin Oncol. 2022;40(16 suppl).
19. 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.
20. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103.
21. Abdel-Qadir H, Sabrie N, Leong D, et al. Cardiovascular risk associated with ibrutinib use in chronic lymphocytic leukemia: a population-based cohort study. J Clin Oncol. 2021;39(31):3453-3462.