Abstract
Background
Covalent BTK inhibitors (cBTKis) are the cornerstone of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) therapy, yet real‐world data on dose modifications and their differential impact on long‐term outcomes remain incompletely defined. This study investigated the incidence, timing, and the effectiveness of drug switching in a real‐world CLL cohort.
Methods
In this 7‐year retrospective real‐world study, 324 CLL/SLL patients treated at a specialized Shanghai outpatient clinic (April 2018–April 2025; median follow‐up, 42 months) were analyzed. Dose modifications were classified as dose interruption (DI) or dose reduction (DR). Their prognostic impact on progression‐free (PFS) and overall survival (OS) was assessed by Kaplan–Meier analysis and multivariate Cox regression.
Results
The 42‐month PFS rate was 70.2%. Of 324 patients, 229 (70.7%) experienced dose reductions or interruptions; infections were the predominant cause (61.9%). The full‐dose (FD) group (n = 90) demonstrated superior 4‐year PFS (93% vs. 58%, p < .001) and OS (98% vs. 76%, p = .007). Early modifications (0–3 months) were independent predictors of inferior PFS (hazard ratio [HR], 3.93, p = .008) and OS (HR, 3.29, p = .014). Prolonged DI (>14 days) was associated with inferior PFS (HR, 2.64) and OS (HR, 2.15), whereas DR and short DI (≤14 days) had negligible impact. Early (0–3 months) prolonged DI was devastating (3‐year PFS, 41.2%; HR, 3.84, p < .001). cBTKi switching (n = 82; 100% nonprogression‐driven) shortened DI (median, 6 vs. 14 days) and was independently associated with superior OS (HR, 0.34, p = .018) and PFS (HR, 0.36, p = .022).
Conclusions
Early prolonged DI is the dominant adverse prognostic factor in cBTKi‐treated CLL/SLL. Proactive switching minimizes treatment gaps and improves survival, supporting a timing‐aware, DI‐ versus DR‐informed approach to dose management.
Keywords: BTKi switching, chronic lymphocytic leukemia, covalent BTK inhibitor, dose interruption, dose reduction, real‐world study
Short abstract
In a 7‐year real‐world cohort of 324 chronic lymphocytic leukemia/small lymphocytic leukemia patients receiving covalent BTK inhibitors, early prolonged dose interruption (>14 days within 0–3 months) was the dominant adverse prognostic factor for survival, whereas dose reduction had negligible impact on outcomes. Proactive BTKi switching shortened treatment gaps and was independently associated with superior progression‐free and overall survival, supporting a timing‐aware approach that distinguishes dose interruption from dose reduction in clinical management.
INTRODUCTION
Covalent BTK inhibitors (cBTKis) have become the cornerstone of frontline and relapsed treatment for chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL). 1 , 2 , 3 , 4 , 5 However, real‐world dose modifications are common and their prognostic impact remains incompletely defined. Some studies report that dose reductions and treatment interruptions are associated with inferior progression‐free survival (PFS) and overall survival (OS), 6 , 7 , 8 , 9 whereas others—notably the EVIdeNCE post hoc analysis—suggest that dose modifications do not independently impact survival after adjusting for comorbidities. 10 These divergent findings may reflect differences in patient populations, adverse event profiles, and analytical granularity across studies. Critical gaps persist: prior studies have not systematically distinguished dose interruption (DI) from dose reduction (DR)—modifications with fundamentally different pharmacodynamic implications—nor characterized their interaction with modification timing, the comparative outcomes of cBTKi switching, or minimal residual disease (MRD) dynamics following permanent discontinuation. To address these, we conducted a 7‐year retrospective real‐world study with particular attention to DI versus DR distinction, timing–duration interaction, and switching outcomes in a Chinese CLL/SLL cohort.
MATERIALS AND METHODS
Study design and patients
This retrospective cohort study enrolled patients ≥18 years old with CLL/SLL who initiated cBTKi therapy (ibrutinib, zanubrutinib, or orelabrutinib) at the specialized outpatient clinic of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (April 2018–April 2025). Acalabrutinib was excluded (no National Medical Products Administration approval for CLL during the study period). Eligible patients received ≥1 month of continuous cBTKi therapy; patients receiving cBTKi within clinical trials were excluded. All patients were cBTKi‐naive at baseline. Diagnosis, treatment indications, and response assessment followed the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines. 11 Adverse events (AEs) were graded per Common Terminology Criteria for Adverse Events v5.0. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). The study was approved by the Ruijin Hospital institutional review board (MR‐31‐26‐020829) and conducted per the Declaration of Helsinki.
Dose modification definitions
The full‐dose (FD) group comprised patients maintaining approved standard dose throughout treatment. The DI/DR group comprised patients with any treatment interruption ≥3 consecutive days or dose reduction below standard at any point. DI was defined as complete cBTKi cessation ≥3 days with subsequent resumption; DR as sustained reduction below standard dose. Prolonged DI was defined as >14 days. The DI/DR group included isolated DI, isolated DR, and DI + DR subgroups. Permanent discontinuation was defined as cBTKi cessation without resumption. Dose modification events were classified as nonswitching or switching events (involving transition to an alternative cBTKi). When a single modification involved multiple AEs, a predefined clinical hierarchy attributed the modification to the most severe event.
MRD assessment
MRD was assessed in peripheral blood using 10‐color flow cytometry (limit of detection, 2 × 10−5; limit of quantitation, 5 × 10−5) at clinically indicated time points.
Statistical analysis
PFS was defined from cBTKi initiation to iwCLL‐defined progression or death; OS from initiation to death. Survival was estimated by Kaplan–Meier method with log‐rank testing. Multivariate Cox regression covariates were selected a priori: sex, age (>65 vs. ≤65 years), TP53/del(17p), immunoglobulin heavy chain variable region (IGHV) status, treatment setting (treatment‐naive [TN] vs. relapsed or refractory [R/R]), DI/DR group, modification timing (0–3, 3–6, 6–12, 1–2, and 2–3 months), and BTKi switching. Results included hazard ratio (HR) (95% CI) and two‐sided p < .05 significant. Analyses used R v4.4.2.
RESULTS
Patient characteristics
Among 324 patients (225 TN [69.4%], 99 R/R [30.6%]; median follow‐up, 42 months), 90 (27.8%) were in the FD group and 229 (70.7%) in the DI/DR group; five (1.5%) were lost to follow‐up (Figure 1A). Initial BTKi agents included ibrutinib, 204 (TN, 118; R/R, 86); zanubrutinib, 100 (TN, 88; R/R, 12); and orelabrutinib, 20 (TN, 19; R/R, 1). The DI/DR group was older (mean 67.2 vs. 64.5 years; p = .034) and had higher TP53/del(17p) prevalence (48.3% vs. 28.6%; p = .020). TN/R/R distribution was balanced (FD: 75.6%/24.4%; DI/DR: 66.8%/33.2%; p = .165). CIRS >6 was comparable (36.7% vs. 41.5%; p = .354). Among 98 R/R patients, prior chemotherapy (50.0% vs. 56.6%) and anti‐CD20 chemoimmunotherapy (50.0% vs. 43.4%) were balanced (p = .589). Other characteristics were well‐matched (Table 1). Separate analysis confirmed significant TN versus R/R survival differences (PFS log‐rank p = .017; OS log‐rank p = .037).
FIGURE 1.
(A) Patient cohort Consolidated Standards of Reporting Trials style flow diagram. (B) Distribution of dose interruption/reduction duration at different treatment time points. (C) Distribution of reasons for dose modification at different treatment stages.
TABLE 1.
Baseline characteristics comparison between FD and DR/DI patient groups.
| Name | Levels | FD group, % (N = 90) | DR/DI group, % (N = 229) | p |
|---|---|---|---|---|
| Start BTKi age, years | Mean ± SD | 64.5 ± 9.6 | 67.2 ± 10.5 | .034 |
| Age, years | ≤65 years old | 46 (51.1) | 93 (40.6) | .115 |
| >65 years old | 44 (48.9) | 136 (59.4) | ||
| Sex | Female | 24 (26.7) | 66 (28.8) | .805 |
| Male | 66 (73.3) | 163 (71.2) | ||
| RAI stage | 0/I | 4 (4.4) | 7 (3.1) | .344 |
| II | 51 (56.7) | 131 (57.2) | ||
| III | 21 (23.3) | 39 (17) | ||
| IV | 14 (15.6) | 52 (22.7) | ||
| BINET stage | A | 3 (3.3) | 5 (2.2) | .510 |
| B | 63 (70) | 149 (65.1) | ||
| C | 24 (26.7) | 75 (32.8) | ||
| β2‐microglobulin | ≤3.5 mg/L | 75 (83.3) | 168 (73.4) | .083 |
| >3.5 mg/L | 15 (16.7) | 61 (26.6) | ||
| TP53 (and/or) del(17p) | Negative | 35 (71.4) | 78 (51.7) | .020 |
| Positive | 14 (28.6) | 73 (48.3) | ||
| Unknown | 41 of 90 (45.6) | 78 of 229 (34.1) | ||
| IGHV‐mutation status | Unmutated | 13 (27.7) | 57 (40.7) | .106 |
| Mutated | 34 (72.3) | 83 (59.3) | ||
| Unknown | 43 of 90 (47.8) | 89 of 229 (38.9) | ||
| Treatment status | TN | 68 (75.6) | 153 (66.8) | .165 |
| R/R | 22 (24.4) | 76 (33.2) | ||
| Line of BTKi therapy | 1st line | 68 (75.6) | 153 (66.8) | .089 |
| 2nd line | 22 (24.4) | 66 (28.8) | ||
| 3rd line | 0 (0.0) | 7 (3.1) | ||
| 4th line | 0 (0.0) | 3 (1.3) | ||
| Types of prior therapies (n = 98) | Chemotherapy | 11 (50.0) | 43 (56.6) | .589 |
| Anti–CD20‐based chemoimmunotherapy | 11 (50.0) | 33 (43.4) | ||
| CIRS score (n = 319) | ≤6, No. (%) | 57 (63.3) | 134 (58.5) | .354 |
| >6, No. (%) | 33 (36.7) | 95 (41.5) |
Abbreviations: BINET stage, BINET staging system, A clinical classification for chronic lymphocytic leukemia consisting of three stages (A, B, and C); BTKi, BTK inhibitor; CIRS, Cumulative Illness Rating Scale; DI, dose interruption; DR, dose reduction; FD, full‐dose; IGHV, Immunoglobulin heavy chain variable region; RAI stage, RAI staging system, A clinial classification for chronic lymphocytic leukemia consisting of five stages (0‐IV); R/R, relapsed/refractory; TN, treatment‐naive.
Dose modification patterns
Of 352 events, 68.8% were driven by nonhematologic AEs, 10.5% combined AEs, 10.8% physician‐guided proactive adjustments, 4.5% hematologic AEs alone, and 5.4% social factors. Early modifications (0–3 months) lasted >14 days in 50.7% of cases; beyond 3 years, only 20% exceeded 14 days (Figure 1B). AE‐driven modifications declined from ∼80% at 0–3 months to 42.5% beyond 3 years, whereas physician‐guided adjustments increased from 1.3% to 57.5% (Figure 1C).
Survival outcomes
The 42‐month PFS rate was 70.2%; median OS was not reached. The FD group demonstrated superior PFS (4‐year: 93% vs. 58%; p < .001) and OS (98% vs. 76%; p = .007) versus DI/DR (Figure 2A,B). Early DI/DR (first event 0–3 months; n = 37) versus late DI/DR (>3 months; n = 138) showed inferior PFS (p = .0047) and OS (p = .0013) (Figure 2C,D). Multivariate Cox regression identified 0–3 month modifications as independent predictors of inferior PFS (HR, 3.93; 95% CI, 1.46–10.59; p = .008) and OS (HR, 3.29; 95% CI, 1.28–8.46; p = .014); 3–6 month modifications were similarly significant (PFS: HR, 2.70, p = .035; OS: HR, 2.81, p = .026). Modifications beyond 6 months were not independently significant (Figure 3A,B).
FIGURE 2.
Kaplan–Meier estimates of PFS and OS stratified by FD versus DI/DR (A and B) and by early dose modification within the first 3 months (C and D). FD: 4‐year PFS 93%, OS 98%; DI/DR: 4‐year PFS 58%, OS 76%. Early DI/DR (0–3 months) versus late (>3 months): PFS p = .0047; OS p = .0013. DI indicates dose interruption; DR, dose reduction; FD, full‐dose; HR, hazard ratio; OS, overall survival; PFS, progression‐free survival.
FIGURE 3.
Forest plots for multivariate Cox regression analyses of PFS (A) and OS (B). Independent predictors: 0–3 months modification (PFS HR = 3.93, p = .008; OS HR = 3.29, p = .014); 3–6 months modification (PFS HR, 2.70, p = .035; OS HR, 2.81, p = .026); BTKi switching (OS HR, 0.34, p = .018; PFS HR, 0.36, p = .022). BTKi indicates BTK inhibitor; HR, hazard ratio; OS, overall survival; PFS, progression‐free survival.
Subgroup survival by IGHV and treatment setting
Although mutated IGHV predicted improved PFS (HR, 0.35; p = .009) and OS (HR, 0.37; p = .011) and TN status predicted improved OS (HR, 0.43; p = .044) in our cohort (Figure 3A,B), contemporary evidence consistently demonstrates that continuous cBTKi therapy negates the survival difference between IGHV‐mutated and IGHV‐unmutated subgroups. 12 , 13
DI versus DR: Timing and duration
When DI and DR were analyzed separately (Tables 2 and 3), isolated early DI (0–3 months) was the strongest adverse factor: median PFS 18.5 months (HR, 6.45; p < .001). In contrast, isolated late DR (>6 months) showed a trend toward benefit (PFS HR, 0.42). Short DI/DR (≤14 days) had limited PFS impact (HR, 1.02–1.18), whereas prolonged DI (>14 days) yielded median PFS 28 months (HR, 2.64; 95% CI, 1.42–4.91) and median OS 42 months (HR, 2.15; 95% CI, 1.04–4.45). Permanent discontinuation due to disease progression carried the worst prognosis (median OS, 18.5 months; HR, 5.85). A critical timing–duration interaction was identified (Table 4): among early modifiers (0–3 months, n = 102), prolonged DI >14 days was associated with 3‐year PFS of 41.20% (HR, 3.84; 95% CI, 2.12–6.95; p < .001) and 3‐year OS of 68.40% (HR, 2.95; 95% CI, 1.38–6.31; p = .005). Among late modifiers (>3 months, n = 111), prolonged DI >14 days showed a more modest PFS decrement (3‐year PFS 62.70%; HR, 1.72; p = .042) and nonsignificant OS impact (3‐year OS, 79.30%; HR, 1.41; p = .316).
TABLE 2.
Survival outcomes by timing of first dose modification.
| Subgroups | No. (%) | Median PFS (m) | PFS HR (95% CI) | p | Median OS (m) | OS HR (95% CI) | p |
|---|---|---|---|---|---|---|---|
| Overall group | 321 (100) | 39 | 1.00 (baseline) | — | NR | 1.00 (baseline) | — |
| FD group | 90 (28.0) | NR | 0.18 (0.05–0.62) | .006 | NR | 0.22 (0.07–0.68) | .009 |
| Isolated DI (only DI) | |||||||
| Early (0–3 m) | 24 (7.5) | 18.5 | 6.45 (2.12–19.64) | <.001 | 28 | 3.84 (1.42–10.38) | .005 |
| Intermediate (3–6 m) | 18 (5.6) | 24 | 3.88 (1.24–12.15) | .019 | 36.5 | 2.12 (0.74–6.05) | .16 |
| Late (>6 m) | 12 (3.7) | 38 | 1.15 (0.35–3.78) | .82 | NR | 0.65 (0.20–2.12) | .702 |
| Isolated DR (only DR) | |||||||
| Early (0–3 m) | 20 (6.2) | 32.5 | 2.05 (0.68–6.18) | .201 | NR | 1.35 (0.45–4.06) | .59 |
| Intermediate (3–6 m) | 12 (3.7) | 42 | 1.64 (0.42–6.42) | .473 | NR | 0.88 (0.22–3.52) | .854 |
| Late (>6 m) | 30 (9.3) | NR | 0.42 (0.12–1.45) | .17 | NR | 0.35 (0.09–1.38) | .136 |
| Permanent discontinuation | |||||||
| Because of disease progression (PD) | 16 (5.0) | 0 | 8.54 (3.12–23.36) | <.001 | 18.5 | 4.12 (1.85–9.18) | <.001 |
Abbreviations: DI, dose interruption; DR, dose reduction; FD, full‐dose; HR, hazard ratio; NR, not reached; OS, overall survival; PD, progressive disease; PFS, progression‐free survival.
TABLE 3.
Survival outcomes by duration of dose modification.
| Subgroups | No. (%) | Median PFS (months) | PFS HR (95% CI) | Median OS (months) | OS HR (95% CI) |
|---|---|---|---|---|---|
| FD group | 90 (28.0) | NR | 1.00 (Ref) | NR | 1.00 (Ref) |
| Isolated DI (only DI) | 54 (16.8) | ||||
| Short DI (≤7 days) | 22 (6.9) | NR | 1.02 (0.45–2.12) | NR | 1.01 (0.42–2.20) |
| Moderate DI (7–14 days) | 20 (6.2) | NR | 1.15 (0.60–2.15) | NR | 1.10 (0.48–2.35) |
| Prolonged DI (>14 days) | 12 (3.7) | 26.5 | 2.64 (1.42–4.91) | 42 | 2.15 (1.04–4.45) |
| Isolated DR (only DR) | 62 (19.3) | ||||
| Short DR (≤7 days) | 14 (4.4) | NR | 1.05 (0.50–2.18) | NR | 1.02 (0.45–2.30) |
| Moderate DR (7–14 days) | 18 (5.6) | NR | 1.08 (0.52–2.25) | NR | 1.05 (0.48–2.40) |
| Long‐term/permanent DR (>14 days) | 30 (9.3) | NR | 1.25 (0.68–2.42) | NR | 1.18 (0.55–2.65) |
| DI + DR (combined) | 99 (30.8) | ||||
| Short‐term combined (≤14 days) | 69 (21.5) | 46 | 1.45 (0.82–2.35) | NR | 1.25 (0.62–2.15) |
| Long‐term severe combined (>14 days) | 30 (9.3) | 32 | 2.05 (1.18–3.45) | 46.5 | 1.58 (0.82–2.85) |
| Permanent discontinuation | 16 (5.0) | 0 | N/A | 18.5 | 5.85 (3.12–9.45) |
Abbreviations: DI, dose interruption; DR, dose reduction; FD, full‐dose; HR, hazard ratio; N/A, not available; NR, not reached; OS, overall survival; PFS, progression‐free survival.
TABLE 4.
Timing × DI duration interaction: 3‐year PFS and OS.
| Timing | DI duration | 3‐year PFS, % | PFS HR (95% CI) | p | 3‐year OS, % | OS HR (95% CI) | p |
|---|---|---|---|---|---|---|---|
| Early (0–3 months, n = 102) | ≤14 days | 83.10 | 1.00 (ref) | — | 90.50 | 1.00 (ref) | — |
| >14 days | 41.20 | 3.84 (2.12–6.95) | <.001 | 68.40 | 2.95 (1.38–6.31) | .005 | |
| Late (>3 months, n = 111) | ≤14 days | 82.50 | 1.00 (ref) | — | 89.80 | 1.00 (ref) | — |
| >14 days | 62.70 | 1.72 (1.02–2.91) | .042 | 79.30 | 1.41 (0.72–2.76) | .316 |
Abbreviations: DI, dose interruption; HR, hazard ratio; OS, overall survival; PFS, progression‐free survival.
AE profile
Among 312 AE‐driven events, infections dominated (193 of 312, 61.9%), primarily COVID‐19 (n = 117, 36.1%) and pneumonia (n = 73, 18.6%). Hematologic AEs contributed 16.0% (neutropenia, 9.3%; thrombocytopenia, 6.5%). Cardiac events were rare (atrial fibrillation, 0.3%). No modifications were attributed to redistribution lymphocytosis. No HBV reactivation‐related modifications occurred despite hepatitis B surface antigen‐positive patients (5.6%), confirming effective antiviral prophylaxis.
BTKi switching
Among 82 switching events (79 unique patients, including three patients who switched twice), 100% were non‐progressive disease (PD) driven: 86.6% (68/79) AE intolerance and 13.4% (11/79) shared decisions (Figure 4). Median time to switching was 7.4 months (interquartile range [IQR], 3.2–12.5); 43.0% (34 of 79) occurred ≤6 months (100% AE‐driven). Post‐switching, only 7.3% (n = 6) experienced subsequent PD versus 25 PD events in nonswitchers. Switching shortened DI (median 6 [IQR, 3–10] vs. 14 [IQR, 7–21] days; χ2 = 50.8; p < .001). On multivariate analysis, switching was independently associated with superior OS (HR, 0.34; 95% CI, 0.14–0.83; p = .018) and PFS (HR, 0.36; p = .022).
FIGURE 4.
(A) Distribution of initial covalent BTK inhibitor agents by treatment setting. (B) BTK inhibitor switching trajectories: ibrutinib → zanubrutinib (57.1%); orelabrutinib → zanubrutinib; and ibrutinib → orelabrutinib.
Permanent discontinuation and MRD
Of 120 patients (37.6%) permanently discontinuing BTKi, PD accounted for 50.0% and AE‐related discontinuation for 44.2%. Among 14 PR patients discontinuing for AE‐related reasons, 64.3% maintained PR without salvage therapy at median 13 months post‐cessation. However, MRD increased from 0.28% at discontinuation to 0.625% at 6 months (p = .002), confirming subclinical disease re‐emergence despite clinical stability.
DISCUSSION
This 7‐year real‐world analysis yields three principal findings: 1) dose modifications are common (70.7%) and predominantly AE‐driven in the early phase; 2) the prognostic impact is critically dependent on both timing and DI duration—early prolonged DI being most devastating; and 3) proactive cBTKi switching during AE‐driven modifications is independently associated with shorter treatment gaps and superior survival.
Three baseline imbalances require consideration. The DI/DR group had greater age (p = .034), higher TP53/del(17p) prevalence (p = .020), and numerically more R/R patients (p = .165). TP53 dysfunction confers genomic instability and accelerates clonal evolution; in a real‐world ibrutinib cohort, progression‐driven discontinuation was significantly more frequent in del(17p) patients (20% vs. 6%; p < .001), whereas toxicity‐driven discontinuation was lower. 14 The balanced CIRS distribution (p = .354) excludes the possibility that DI/DR was driven by excessive baseline comorbidity.
The AE profile in our Chinese cohort differed substantially from Western data. Infections dominated (61.9%), with COVID‐19 alone accounting for 36.1%—inseparable from the pandemic exposure during 2021 to 2023 in China. The incidence of cardiac events that led to dose reduction or discontinuation in our cohort was significantly lower (atrial fibrillation/atrial flutter: 0.3%; hypertension: 2.8%). The significantly lower incidence rate is mainly attributed to the fact that our cohort data only show the cardiac events that led to dose adjustments. Other contributing factors include lower baseline cardiovascular comorbidity, younger median age, and the 37.3% proportion of second‐generation cBTKis with lower cardiac toxicity. 15 This geographic AE difference has prognostic implications: infection‐driven interruptions reflect treatment‐related immunosuppression and underlying immune dysfunction, potentially conferring different prognostic weight than cardiac toxicity‐driven reductions.
The timing–duration interaction is the most clinically significant finding. Early (0–3 months) prolonged DI was devastating (PFS HR, 3.84; OS HR, 2.95), whereas late prolonged DI showed modest impact (PFS HR, 1.72; OS, nonsignificant). This is mechanistically coherent: during early treatment, premature BTKi cessation permits BTK resynthesis and B Cell Receptor‐pathway reactivation before adequate cytoreduction, 16 whereas late modifications occur after durable remission, with less tumor re‐expansion capacity. Short DI (≤14 days) and DR had negligible impact, and late DR even showed a trend toward benefit (PFS HR, 0.42), which may be related to individualized dose optimization following long‐term treatment. 16 This observation is consistent with the pharmacodynamic rationale that maintained dose reduction preserves inhibition. The prospective TAILOR study demonstrated >99% median BTK occupancy at reduced ibrutinib doses (280 mg every day), 17 supporting the biological plausibility that DR—unlike prolonged DI—can maintain efficacy.
These AE‐driven prognostic differences help contextualize the EVIdeNCE study, 10 which found that composite RDI lost significance after adjustment for cardiovascular comorbidity. In a cardiac‐toxicity‐predominant Western cohort, dose modifications may indeed carry less independent prognostic weight; in our infection‐driven Chinese cohort—where DI is more frequent and pathophysiologically distinct from DR—the impact is demonstrable. By separating DI from DR and incorporating timing interactions, our analysis adds granularity to EVIdeNCE's composite RDI framework.
Beyond dose modification timing, the prognostic impact of established molecular markers is likewise modulated by treatment continuity. Although mutated IGHV predicted favorable PFS (HR, 0.35; p = .009) and OS (HR, 0.37; p = .011) in our cohort, this prognostic association is treatment‐context–dependent. Continuous cBTKi therapy negates this difference, 12 , 18 whereas it persists after chemoimmunotherapy and fixed‐duration venetoclax‐based regimens. 18 The IGHV signal observed in our real‐world cohort may partly reflect treatment heterogeneity—including dose interruptions and variable exposure—that compromises the IGHV‐neutralizing effect of uninterrupted cBTKi therapy. Therefore, IGHV status should be regarded as a treatment‐strategy selection factor rather than an immutable prognostic determinant. 13 , 18 This treatment‐context dependency further underscores the importance of maintaining continuous cBTKi exposure—a goal that proactive BTKi switching may help achieve.
The BTKi switching data provide complementary evidence for minimizing treatment‐free intervals. Switching shortened DI from median 14 to 6 days and was independently associated with superior OS (HR, 0.34) and PFS (HR, 0.36). With 100% non‐PD–driven switches and only 7.3% subsequent progression, proactive switching effectively extends BTKi exposure benefit. The ALPINE trial demonstrated superior PFS and safety for zanubrutinib versus ibrutinib in R/R CLL, 19 providing prospective support for selective agent transition. Combined with the timing–DI data, these findings underscore that minimizing the cBTKi exposure gap—whether through rapid switching, proactive DR rather than DI, or shortened DI—is prognostically critical, particularly in the first 3 months.
Fixed‐duration ibrutinib–venetoclax (I + V) represents an alternative that may circumvent cumulative cBTKi toxicity. The CAPTIVATE study demonstrated 5.5‐year PFS of 66% with I + V in first‐line CLL, 20 and a phase 2 study confirmed feasibility even in high genomic risk R/R patients (7‐year PFS, 63.3%). 21 These data contextualize our findings: for patients requiring continuous cBTKi therapy, timing‐aware dose management is essential; for eligible patients, fixed‐duration strategies may bypass long‐term toxicity.
The post‐discontinuation MRD data, whereas exploratory (n = 14), reveal an important biological insight. Despite 64.3% of PR patients maintaining clinical remission, MRD increased significantly (0.28% to 0.625%; p = .002), confirming subclinical disease re‐emergence following BTKi withdrawal. This supports continuous cBTKi therapy as the recommended standard of care, particularly for high‐risk patients with del(17p) and/or TP53 mutations, as specified by the European Hematology Association 2026 guidelines, 13 and systematic MRD monitoring to guide timely adjustments.
Longer prior BTKi exposure was associated with more prolonged post‐discontinuation remission, 22 and the FLAIR trial demonstrated MRD‐guided I + V achieving 5‐year PFS of 93.9%. 23
CONCLUSIONS
In this 7‐year real‐world analysis in cBTKi‐treated CLL/SLL, dose modifications were common and predominantly AE‐driven in the early treatment phase. Early prolonged DI—not DR—was the dominant adverse prognostic factor. Short DI (≤14 days) and DR had negligible impact, and late DR even showed a trend toward benefit. Proactive switching minimizes treatment gaps and is independently associated with superior survival. These findings support a timing‐aware, DI‐versus‐DR‐informed approach to cBTKi dose management and highlight the critical importance of early AE intervention to optimize durable disease control in CLL/SLL.
Limitations
The retrospective single‐center design limits generalizability. BTKi switching was not randomized; switching patients may represent a favorable subpopulation. The small FD (n = 90) and early DI/DR (n = 37) subgroups limit statistical power. The MRD analysis (n = 14) is hypothesis‐generating. Median follow‐up of 42 months may be insufficient for mature OS differences.
AUTHOR CONTRIBUTIONS
Jiaojiao Zhang: Conceptualization; data curation; formal analysis; methodology; writing—original draft; and writing—review and editing. Jing Luo: Resources. Xiaozhong Shen: Formal analysis and methodology. Jiayi Ren: Resources. Weiyang Liu: Resources. Li Chen: Resources. Lu Jiang: Resources. Xiangqin Weng: Data curation; formal analysis; resources; and writing—original draft. Jin Wang: Data curation; formal analysis; resources; and writing—original draft. Jian‐Qing Mi: Conceptualization; data curation; formal analysis; funding acquisition; methodology; supervision; writing—original draft; and writing—review and editing.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ACKNOWLEDGMENTS
Funding was provided by Shanghai Hematology Clinical Specialty Capacity Enhancement Project (SHDC22024314). Written informed consent was obtained from all participants.
Zhang J, Luo J, Shen X, et al. Timing matters: impact of covalent BTK inhibitor dose modifications on outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia—A 7‐year real‐world study. Cancer. 2026;e70578. doi: 10.1002/cncr.70578
The clinical trial registration is MR‐31‐26‐020829. The trial has been approved by the institutional review board of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available in the Supporting Information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available in the Supporting Information.