Patients
From February 20, 2021, to July 8, 2024, 358 patients were screened for eligibility (detailed reasons for screening failure are provided in supplementary Table 1) and 192 patients were randomized to receive either orelabrutinib (91 patients) or chlorambucil plus rituximab (101 patients), comprising the intention-to-treat (ITT) population (Fig. 1). Among these, 91 patients in the orelabrutinib group and 98 patients in the chlorambucil-rituximab group received the assigned treatments, and were included for the safety analysis.
Fig. 1
Baseline demographics and disease characteristics were generally balanced between treatment groups (Table 1). The median age of patients was 67.0 years (interquartile range [IQR], 61.5–71.0), with the majority being over 65 years old (69.3%) and male (64.6%). Del(13q) was present in 93 (48.4%) patients, del(11q) in 27 (14.1%), and trisomy 12 in 52 (27.1%). 58 (36.5%) of 159 patients with evaluable results had an unmutated immunoglobulin heavy-chain variable-region (IGHV) gene. Complex karyotypes were identified in 29 (15.1%) patients.
Table 1 Demographics and disease characteristics
At data cutoff for the interim analysis on May 17, 2024, the median follow-up duration was 22.4 months (range, 1.9–40.3) for the orelabrutinib group and 19.7 months (range, 0.03–38.7) for the chlorambucil-rituximab group (for all patients, 21.4 months [range, 0.03–40.3]). In the orelabrutinib group, 22 (24.2%) patients discontinued treatment early, primarily due to disease progression (n = 12), and treatment remained ongoing in 69 (75.8%) patients. Detailed characteristics and outcomes for patients with early progression are provided in Supplementary Table 2. In the chlorambucil-rituximab group, 84 of 101 (83.2%) patients completed the planned six cycles of protocol treatment. In total, 9 (9.9%) patients in the orelabrutinib group and 33 (32.7%) patients in the chlorambucil-rituximab group received at least one subsequent systemic therapy during follow-up (supplementary Table 3).
Efficacy
As of the cutoff date (May 17, 2024), with a median follow-up of 21.4 months (range, 0.03–40.3), disease progression as assessed by the independent review committee (IRC) or death occurred in 55 patients in the ITT population (16 [17.6%] in the orelabrutinib group vs 39 [38.6%] in the chlorambucil–rituximab group). The median IRC-assessed PFS was not reached (NR; 95% CI, not estimable [NE]–NE) with orelabrutinib, and 19.4 months (95% CI, 16.6–NE) with chlorambucil plus rituximab (Fig. 2a). Orelabrutinib demonstrated a 68% reduction in the risk of disease progression or death compared to chlorambucil plus rituximab (hazard ratio [HR], 0.32; 95% CI, 0.18–0.58; p < 0.0001), crossing the prespecified efficacy boundary for PFS. Kaplan–Meier estimates of PFS rates at 12 months were 93.1% (95% CI, 85.2–96.8) in the orelabrutinib group and 76.1% (95% CI, 65.7–83.8) in the chlorambucil-rituximab group; and at 24 months were 81.6% (95% CI, 69.9–89.1) and 48.4% (95% CI, 35.8–59.8), respectively. In the prespecified subgroup analyses, PFS favored orelabrutinib over chlorambucil plus rituximab in multiple analyzed subgroups, including those based on advanced age, Rai stage III/IV, bulky disease (tumor lesions ≥5 cm), del(11q) positivity, or unmutated IGHV status (Fig. 2b; supplementary Figs. 1, 2). Investigator-assessed PFS results were consistent with the primary analysis as per IRC assessment (supplementary Fig. 3).
Fig. 2
Progressive-free survival as assessed by the independent review committee in the intention–to–treat population. a Kaplan-Meier curve for progressive-free survival. b Analyses of progression-free survival in key subgroups. The tick marks indicate censored data. Between-group difference was evaluated with the log-rank test. P values were two-sided. The Cox proportional-hazards model was used to assess the HRs and associated 95% CIs. PFS progressive-free survival, mo months, NR not reached, NE not estimable, HR hazard ratios, CI confidence interval
As assessed by the IRC, the confirmed ORR was higher with orelabrutinib (90.1%; 95% CI, 82.1–95.4) than with chlorambucil plus rituximab (79.2%; 95% CI, 70.0–86.6), corresponding to an odds ratio of 2.41 (95% CI, 1.03–5.65; p = 0.041; Table 2). In the orelabrutinib group, complete response (CR) was achieved in 2 (2.2%) patients, partial response in 72 (79.1%), and PR with lymphocytosis (PR-L) in 8 (8.8%). In the chlorambucil–rituximab group, CR was achieved in 4 (4.0%) patients and PR in 76 (75.2%). The median IRC-assessed duration of response (DoR) was NR in either treatment group and was significantly longer with orelabrutinib compared to chlorambucil plus rituximab (HR = 0.30; 95% CI, 0.15–0.60; p = 0.0003; Fig. 3a). The DoR rates at 12 and 24 months were estimated to be 90.3% (95% CI, 80.7–95.3) and 84.3% (95% CI, 72.4–91.4) for orelabrutinib, compared with 71.2% (95% CI, 58.7–80.6) and 51.7% (95% CI, 36.9–64.7) for chlorambucil plus rituximab. According to investigator assessment, the data on tumor response and DoR reaffirmed the benefits of orelabrutinib (Table 2; supplementary Fig. 4).
Fig. 3
IRC-assessed DoR and overall survival in the intention–to–treat population. a Kaplan-Meier curve for IRC-assessed DoR. b Kaplan-Meier curves for overall survival. The tick marks indicate censored data. Between-group difference was evaluated with the log-rank test. P values were two-sided. The Cox proportional-hazards model was used to assess the HRs and associated 95% CIs. DoR duration of response, OS overall survival, mo months, NR not reached, NE not estimable, HR hazard ratios, CI confidence interval
Table 2 Tumor response as assessed by the independent review committee and investigators
In the ITT population, OS data were immature at the time of interim analysis, with a total of 16 deaths: 5 (5.5%) in the orelabrutinib group and 11 (10.9%) in the chlorambucil–rituximab group. The median OS has not yet been reached in either group (HR, 0.45; 95% CI, 0.16–1.31; p = 0.13; Fig. 3b). The estimated OS rates were 96.7% (95% CI, 90.1–98.9) with orelabrutinib versus 96.9% (95% CI, 90.7–99.0) with chlorambucil plus rituximab at 1 year; 95.1% (95% CI, 87.1–98.2) versus 83.3% (95% CI, 70.3–91.0) at 2 years; 92.1% (95% CI, 80.4–96.9) versus 78.7% (95% CI, 62.1–88.6) at 3 years, respectively.
Exposure and safety
In the safety population, the median duration of treatment was 19.3 months (IQR, 11.6–27.6) for orelabrutinib, 5.2 months (IQR, 5.1–5.9) for chlorambucil, and 4.7 months (IQR, 4.6–5.3) for rituximab, respectively. 6.6% (6/91) of patients had a dose reduction of orelabrutinib, and 10.2% (10/98) of patients had a dose reduction of chlorambucil. Detailed treatment exposure is summarized in Supplementary Table 4.
Treatment-emergent adverse events (TEAEs) were reported in 90 (98.9%) patients in the orelabrutinib group and 96 (98.0%) patients in the chlorambucil–rituximab group. The incidence of grade 3 or worse TEAEs was respectively 58.2% versus 69.4% as per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0), and 15.4% versus 33.7% as per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria (supplementary Tables 5, 6, 7). 82 of 91 (90.1%) patients receiving orelabrutinib and 89 of 98 (90.8%) patients receiving chlorambucil plus rituximab experienced any grade treatment-related adverse events (TRAEs), with grade 3 or worse events occurring in 35.2% versus 60.2% per NCI-CTCAE (Table 3). The frequent grade ≥3 TRAEs (≥10% incidence) were neutrophil count decrease (7.7% [7/91] in the orelabrutinib group vs. 30.6% [30/98] in the chlorambucil–rituximab group), white-cell count decrease (1.1% vs. 23.5%), lymphocyte count decreased (1.1% vs. 14.3%), and infectious pneumonia (6.6% vs. 6.1%). Grade ≥3 treatment-related hematologic toxicities as assessed by the iwCLL criteria were more frequent in the chlorambucil–rituximab group (33 [33.7%]) than in the orelabrutinib group (13 [14.3%]; supplementary Table 7), mostly including neutrophil count decrease (7.7% vs. 30.6%) and platelet count decrease (5.5% vs. 5.1%). As of the data cutoff date, no treatment-related atrial fibrillation or second primary malignancies were reported.
Table 3 Treatment-related adverse events in the safety population
TEAEs led to dose reduction of orelabrutinib or chlorambucil in 6.6% (6/91) and 9.2% (9/98) of patients; led to treatment discontinuation in 5.5% (5/91) and 7.1% (7/98) of patients; and led to the dose interruption in 44.0% (40/91) and 61.2% (60/98) of patients, respectively (supplementary Table 5). Among these, TRAE-related dose reductions occurred in 4.4% versus 8.2% of patients; treatment discontinuations in 1.1% versus 6.1%; and dose interruption in 17.6% versus 49.0%, for orelabrutinib and chlorambucil plus rituximab, respectively (supplementary Table 5). Serious TEAEs occurred in 43 patients (47.3%) receiving orelabrutinib and 23 patients (23.5%) receiving chlorambucil plus rituximab; of which 17 (18.7%) and 13 (13.3%) were considered serious TRAEs, respectively (supplementary Table 5). A total of 6 deaths due to TEAEs were reported: 5 (5.5%) in the orelabrutinib group and 1 (1.0%) in the chlorambucil–rituximab group. One death (1.0%) in the orelabrutinib group, attributed to febrile neutropenia, was considered possibly related to the treatment (supplementary Table 5).
Predefined events of special interest (defined as grade ≥ 3 infection, Hepatitis B virus reactivation, and grade ≥ 3 bleeding) occurred in 32 (35.2%) patients receiving orelabrutinib and 21 (21.4%) patients receiving chlorambucil plus rituximab, regardless of treatment causality (supplementary Table 8). The most common TEAEs of special interest were grade ≥ 3 infection (34.1% vs. 21.4%) in both groups. No grade ≥ 3 bleeding was observed in either group.
Hematological variables
Both the orelabrutinib and chlorambucil plus rituximab increased the hemoglobin concentrations, platelet count, and absolute neutrophil count during treatment (supplementary Fig. 5a). No difference between treatment groups was observed in the proportion of patients with sustained improvement in hemoglobin concentrations, platelet count, and absolute neutrophil count. Kaplan–Meier analysis of time to sustained hematologic improvement (supplementary Fig. 5b) showed earlier or a trend toward earlier recovery with orelabrutinib than with chlorambucil plus rituximab in hemoglobin concentrations (4.7 months vs. 7.2 months; p = 0.33), platelet count (7.9 months vs. 11.1 months; p = 0.085), and absolute neutrophil count (5.3 months vs. 11.0 months; p = 0.031).
In addition, changes in lymphocyte count, reflecting treatment-related lymphocytosis, over time are shown in supplementary Fig. 5c. In the orelabrutinib group, lymphocyte count increased after baseline, peaked at 2 weeks, and then declined over time.
Patients–reported quality of life (QoL)
In the QoL exploratory analysis, a total of 191 patients completed at least one valid QoL questionnaire: 91 in the orelabrutinib group and 100 in the chlorambucil–rituximab group, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), EuroQol 5-Dimension 3-Level questionnaire (EQ-5D-3L), and Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16).
EORTC QLQ-C30–global health status/quality of life (GHS/QoL) scale and EQ-5D-3L visual analogue scale (VAS) were maintained or improved from baseline in both groups across most visits (supplementary Fig. 6a, b). With comparable baseline scores, least-squares mean (LSM) changes from baseline in the EORTC QLQ-C30-GHS/QoL and EQ-5D-3L VAS did not differ significantly between treatment groups at each visit, except at cycle 37. The LSM change from baseline to cycle 37 in EORTC QLQC30 GHS/QoL scores was 10.2 (95% CI, 2.8–17.7) for orelabrutinib versus −5.2 (95% CI, −18.2 to 7.9) for chlorambucil plus rituximab (LSM difference, 15.4 [95% CI, 0.4–30.4]; nominal p = 0.044; supplementary Fig. 6a), Similarly, difference in LSM change from baseline to cycle 37 in EQ-5D-3L VAS favored orelabrutinib (LSM difference, 11.3 [95% CI, 1.5–21.1]; nominal p = 0.024; supplementary Fig. 6b). Descriptive analysis for QLQ-CLL16 showed that scores remained stable throughout the study, with no clinically meaningful deterioration observed in either group (supplementary Fig. 6c).
In the responder analysis, the proportion of patients with clinically meaningful improvement was higher than that of those with deterioration for the EORTC QLQ-C30 GHS/QoL (10-point threshold) and EQ-5D-3L VAS (7-point threshold) at all visits in both groups. During the first 13 cycles, the proportion of patients achieving clinically meaningful improvement was similar between the two groups. From cycle 16 onward, more patients had clinically meaningful improvement with orelabrutinib versus chlorambucil plus rituximab, with the numerical difference increasing over time (supplementary Table 9).
