A decade of ibrutinib for CLL with and without TP53 aberration: final report on an investigator-sponsored phase 2 study

Key Points

• •At 10-years of follow-up, single-agent ibrutinib maintained efficacy in CLL; median PFS was 7.2 years; median OS was not reached.
• •After a median of 5 years on ibrutinib, 13 (15.5%) of 84 patients had uMRD that was durable, even after drug discontinuation.

Visual Abstract

Abstract

Bruton tyrosine kinase inhibitors improve outcomes for patients with chronic lymphocytic leukemia (CLL). Long-term data with continuous therapy are limited. With a median follow-up of 10.0 years, we report final results on 84 patients with TP53 aberrations (deletion of chromosomal arm 17p or TP53 mutation) or ≥65 years of age treated with 420 mg of single-agent ibrutinib daily until progression or unacceptable toxicity. A total of 52 (61.9%) patients were previously untreated; 56 (66.7%) had unmutated immunoglobulin heavy-chain variable region; and 53 (63.1%) had TP53 aberrations, including 34 treatment naïve patients. As of 31July 2024, 9 (10.7%) patients continued ibrutinib, 39 (46.4%) discontinued ibrutinib for progressive disease, 31 (36.9%) for adverse events, and 5 (5.9%) withdrew consent. The median progression-free survival (PFS) was 7.2 years; median overall survival (OS) was not reached. In patients with and without TP53 aberrations, median PFS was 5.6 years and not reached, and 10-year OS was 51.3% and 75.3%, respectively. The estimated 10-year PFS and OS for patients with TP53-aberrant CLL treated in first line was 38.6% and 65.7%, respectively. Minimal residual disease (MRD) was quantified by peripheral blood flow cytometry annually. Undetectable MRD (uMRD; at 10⁻⁴) was achieved in 13 (15.5%) patients after a median of 5 years. Twelve patients maintained uMRD, the longest observation ongoing at 8.0 years. Seventeen (42.5%) patients with best response of high MRD (>10⁻²) remained progression-free for >5 years. These results highlight durable benefits and deepening responses with ibrutinib, including in high-risk CLL. Whether patients maintaining uMRD for years can safely discontinue therapy should be assessed prospectively. This trial was registered at www.clinicaltrials.gov as NCT01500733.

The first-in-class covalent Bruton tyrosine kinase inhibitor ibrutinib has transformed chronic lymphocytic leukemia (CLL) therapy over the last 15 years. Itsara and colleagues report 10-year follow-up of the treatment of CLL with ibrutinib in 84 patients, demonstrating a median progression-free survival of 9 years in frontline CLL and 4.1 years in relapsed CLL. Survival outcomes in patients with TP53 mutations were improved compared to those in historic controls but still shorter than those in patients without TP53 aberrations. This study underscores the remarkable durability and depth of response achieved with ibrutinib in CLL.

Introduction

Bruton tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). BTK is an essential component of the B-cell receptor (BCR) signaling pathway that drives CLL cell proliferation and disease progression.^1,2 Ibrutinib, the first-in-class covalent BTKi approved by the US Food and Drug Administration, effectively inhibits BCR signaling and turns off tumor proliferation,^3,4 demonstrating high overall response rates, a favorable safety profile, and improved progression-free survival (PFS) and overall survival (OS) over previous standard-of-care regimens.^{5, 6, 7, 8, 9, 10} Subsequently, comparative trials, conducted in an open-label fashion, randomized patients with relapsed/refractory (R/R) CLL, in a 1:1 ratio, to oral ibrutinib or an alternative covalent BTKi.^11,12 Acalabrutinib, 100 mg twice daily, was compared with ibrutinib 420 mg once daily in 533 patients with previously treated CLL with del(17p) (deletion of chromosomal arm 17p) or del(11q).¹¹ Patients were stratified by del(17p) (yes vs no), Eastern Cooperative Oncology Group performance status score (2 vs ≤1), and number of previous therapies (1-3 vs ≥4). Acalabrutinib was found to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms.¹¹ Overall, acalabrutinib was better tolerated than ibrutinib, with significantly less all grade atrial fibrillation and less hypertension.^11,13 In the ALPINE trial, 652 patients who had received at least 1 previous course of therapy were randomly assigned, in a 1:1 ratio, to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily, in an open-label fashion.¹² Zanubrutinib achieved longer PFS than ibrutinib, with a hazard ratio of 0.68 for progression or death, and was associated with fewer cardiac events.^12,14 Although randomization in the ALPINE study was stratified according to age, geographic region, refractory status, and TP53 aberration, in the ibrutinib arm, there was a trend toward an overrepresentation of patients who had ≥3 previous treatments.¹² All 3 covalent BTKis are orally administered and were studied as continuous treatment until disease progression or the occurrence of unacceptable toxicity. Ibrutinib, which entered clinical testing in 2009,¹⁵ commands the longest follow-up, providing invaluable insights into the efficacy and safety of indefinite therapy with a BTKi.

TP53 aberrations, including TP53 mutations and del(17p), present significant treatment challenges and confer inferior survival with chemoimmunotherapy (CIT) regimens.^{16, 17, 18} In contrast, the efficacy of BTKis is less affected by TP53 aberrations. In a randomized study of first-line therapy comparing ibrutinib with or without rituximab with bendamustine with rituximab, the ibrutinib arms provided superior PFS compared with CIT, an effect that was even greater for patients with TP53 aberrations than those without.¹⁹ Nevertheless, TP53 aberrations do confer adverse prognosis for patients treated with ibrutinib, especially in R/R disease.^12,20,21 For first-line treatment of TP53-aberrant CLL, we previously reported 6-year PFS of 61% and OS of 79% with single-agent ibrutinib.²² In comparison, treatment-naïve patients with del(17p) treated with fludarabine, cyclophosphamide, and rituximab had median PFS of 11.2 months and median OS of 33.1 months.²³

There is growing focus on time-limited therapies. The combination of the B-cell lymphoma 2 antagonist, venetoclax, plus the anti-CD20 monoclonal antibody, obinutuzumab achieved deep remissions with undetectable minimal residual disease (uMRD) in most patients.²⁴ The median PFS for this 1-year fixed-duration regimen was 76.2 months, albeit shorter for patients with del(17p), unmutated immunoglobulin heavy-chain variable region (uIGHV), and any lymph node of ≥5 cm in longest diameter.²⁴ Several studies have reported high response rates and favorable PFS data using time-limited combinations of a BTKi with venetoclax with our without the addition of an anti-CD20 antibody.^{25, 26, 27, 28} In current practice, many patients receive continuous BTKi therapy due to ease of treatment initiation, minimal monitoring, and optional anti-CD20 antibody coadministration. Here, we report on long-term efficacy, safety, and depth of response with single-agent ibrutinib in a cohort of patients, with over half carrying TP53 aberrations.

Methods

Study design and patients

Study design, procedures, and eligibility criteria have been described previously.^20,29 Briefly, patients with CLL (including patients with small lymphocytic lymphoma) gave written informed consent to participate in this investigator-sponsored phase 2 study of ibrutinib conducted in accordance with the Declaration of Helsinki under oversight by the National Heart, Lung, and Blood Institute of National Institutes of Health institutional review boards. This trial was registered at www.ClinicalTrials.gov (identifier: NCT01500733). Eligibility criteria included patients with active CLL requiring therapy, and at least one of the following: evidence of a TP53 aberration (presence of del(17p) by fluorescence in situ hybridization, or a TP53 mutation), or age ≥65 years. Patients who were treatment-naïve and had R/R disease were eligible and treated with single-agent oral ibrutinib, 420 mg once daily, in 28-day cycles. Treatment continued until disease progression or the development of intolerable side effects. Eighty-six patients enrolled between January 2012 and January 2014; however, 2 patients did not meet enrollment criteria and were removed from the study.^20,29 Here, we focus on 84 patients who met all criteria and were eligible for response assessments.

Study end points and assessments

Detailed safety data for this study have been published previously.^20,29 Starting in 2019, the study was amended to capture only new adverse events (AE) that were serious, or grade ≥3, and unexpected problems. Long-term end points included OS, PFS, safety, and MRD status. For the first 5 years, response assessments were conducted annually using computed tomography scans and bone marrow biopsies. Thereafter, response assessments were performed every 3 to 6 months by clinical examination, and radiologic scans were only performed when clinically indicated. Response assessments were based on guidelines by the International Workshop on CLL (iwCLL).³⁰ MRD was assessed annually following European Research Initiative in CLL guidelines.³¹ During the COVID-19 pandemic, many patients missed time points during study years 7, 8, and 9. uMRD was defined as <1 CLL cell per 10 000 leukocytes (10⁻⁴), low MRD from ≥10⁻⁴ to <10⁻², and high MRD at ≥10⁻². The limit of detection of neoplastic cells was 2 × 10⁻⁵.

Statistical analysis

An intention-to-treat analysis was used for safety and survival. A Simon minimax 2-stage design tested the null hypothesis that the overall response rate was ≤15%, vs the alternative hypothesis that it was ≥40% with a type I error of 0.05%, and 90% power. Descriptive statistics were used to summarize population characteristics, and the Kaplan-Meier method was used to assess study end points, including OS (defined as the time from study enrollment to death) and PFS (defined as the time from study enrollment to progression or death). Log-rank tests were conducted to compare the outcomes of patient subgroups, and Fisher exact test was used to evaluate response rates with 95% confidence intervals. The Wilcoxon signed-rank test assessed changes in MRD status over time. Statistical analyses were conducted using R version 4.4.1.

Results

Patient disposition and off-study reasons

All patients were enrolled by January 2014. As of 31 July 2024, 9 of 84 (10.7%) patients remained on ibrutinib (supplemental Figure 1, available of the Blood website). At enrollment, median age was 67 years (range, 34-85), 52 patients (61.9%) were previously untreated, 56 (66.7%) had uIGHV, and 50 (59.5%) met criteria for enrollment in the TP53 cohort, 46 with del(17p) >10%, and 4 with TP53 mutations and no evidence of del(17p). Three patients enrolled based on age of ≥65 years had del(17p) in <10% of cells among a total of 53 patients with a TP53 aberration. As previously reported, 42 (79.2%) of 53 patients had ≥2 TP53 aberrations; in 9 (17.0%) patients only a single TP53 aberration was identified, and for 3 patients no sequencing data were available.³² Baseline characteristics are summarized in supplemental Table 1. Thirty-nine (46.4%) patients discontinued ibrutinib due to progressive disease, including 3 patients with Richter transformation (3.6%) and 3 patients with plasmacytoid or T-cell lymphoma, which were considered possible disease progression in the form of transformation. Thirty-one patients (36.9%) discontinued ibrutinib due to AE, at a median time on ibrutinib of 6.2 years (interquartile range, 3.0-9.14). Five (6%) patients withdrew consent based on personal preferences (Table 1). Overall, the safety profile with long-term therapy was consistent with earlier reports.^20,33 Treatment was discontinued due to cardiac AE in 11 (13.1%) patients, including 4 with atrial fibrillation. Additional AE leading to study discontinuation included second primary, nonhematologic malignancies in 7 (8.3%) patients, infections in 4 (4.8%), dementia in 3 (3.6%), and other causes (including pleural effusion, arthralgia, colitis, and pneumonitis) in 6 (7.1%) patients (Figure 1; Table 1). Of 5 patients who withdrew consent, 4 switched to commercial ibrutinib, and 1 patient with partial response chose to participate in a chimeric antigen receptor T-cell trial. Five deaths (8.3%) occurred on treatment: 4 were due to infections and 1 was a sudden, unexplained death. All deaths on treatment occurred in the first 2 years.

Table 1.

Reasons for ibrutinib discontinuation

	All patients (N = 84)
Any reason, n (%)	75 (89.2)
Progressive disease, n (%)	39 (46.4)
CLL	33 (39.2)
RT, DLBCL∗	2 (2.4)
Plasmacytoid B-cell malignancy	2 (2.4)
RT, cHL	1 (1.2)
T-cell lymphoma, NOS	1 (1.2)
AE, n (%)	31 (36.9)
Cardiac	11 (13.1)
Atrial fibrillation	4 (4.8)
NSVT	3 (3.6)
Palpitations	1 (1.2)
Syncope	1 (1.2)
Hypertension	1 (1.2)
Sudden death∗	1 (1.2)
Second primary malignancy†	7 (8.3)
Infection∗	4 (4.8)
Dementia	3 (3.6)
Pleural effusion	2 (2.4)
Other (arthralgia, colitis, pneumonitis)	4 (4.8)
Withdrawal of consent, n (%)	5 (6.0)
Switch to commercial ibrutinib	4 (4.8)
Switch to CAR T-cell study	1 (1.2)

CAR, chimeric antigen receptor; cHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; NOS, not otherwise specified; NSVT, nonsustained ventricular tachycardia; RT, Richter transformation.

^∗On-study deaths occurred in the first 2 years on study: 1 due to transformation to DLBCL and sepsis; 1 sudden death; 3 fatal infections (details have been reported previously²⁰).

^†Myelodysplastic syndrome in 2 patients previously treated with CIT; 1 each: lung cancer, ovarian cancer, gastric cancer, urothelial cancer, and recurrent renal cell carcinoma.

Figure 1.

Cumulative incidence of ibrutinib discontinuations for AE and elective withdrawals. Of 84 patients enrolled, 31 (36.9%) discontinued ibrutinib due to AE, and 5 (6%) withdrew consent. Afib, atrial fibrillation; HTN, hypertension; NSVT, nonsustained ventricular tachycardia.

Disease progression and survival

At median follow-up of 10.0 years, the median PFS for the entire cohort was 7.2 years and the estimated 10-year PFS was 37.5% (Figure 2A). Median OS was not reached (NR). The estimated 5-year and 10-year OS rates were 79.1% and 59.6%, respectively (Figure 2B). Median PFS for 52 patients with previously untreated CLL was 9.0 years, compared with 4.1 years for 32 patients with R/R disease (P = .018). Median OS was NR in previously untreated CLL vs 8.5 years in the R/R cohort (P = .0033; Figure 3A; Table 2). Compared with those with mutated IGHV (mIGHV; n = 28), patients with uIGHV (n = 56) had a shorter median PFS of 6.7 years vs NR (P = .047), and shorter median OS of 9.8 years vs NR (P = .038; Figure 3B). The estimated 10-year OS for mIGHV was 77.0% (Table 2). Patients with TP53 aberrations (n = 53) had a significantly shorter median PFS of 5.6 years vs NR in those without (n = 31; P = .004; Figure 3C). For both groups, median OS was NR, and 10-year OS was 51.3% vs 75.3% (Figure 3C).

Figure 2.

PFS and OS. Kaplan-Meier estimates of PFS (A) and OS (B) with median follow-up of 10.0 years. mOS, median OS; mPFS, median PFS.

Figure 3.

PFS and OS in subgroups of patients stratified by disease factors. Kaplan-Meier estimates for PFS and OS in patients stratified by treatment status, RR or TN (A); by IGHV status, mutated or unmutated (B); and with (present) or without (absent) TP53 aberrations, del(17p) and/or TP53 mutation (C). P values are based on Kaplan-Meier estimates. M, mutated; RR, relapsed/refractory; TN, treatment-naïve; U, unmutated.

Table 2.

PFS and OS stratified by disease factors

	n	mPFS, y	P value	mOS, y	5-y OS, %	10-y OS, %	P value
All evaluable patients	84	7.2		NR	79.1	59.6
Treatment-naïve	52	9.0	.018	NR	90.2	70.8	.0033
With R/R disease	32	4.1		8.5	61.5	41.6
mIGHV	28	NR	.047	NR	89.3	77.0	.038
unIGHV	56	6.7		9.8	73.7	49.5
No TP53 aberration	31	NR	.0035	NR	89.3	75.3	.04
With TP53 aberration	53	5.6		NR	73.2	51.3
TP53 aberration
Treatment naïve	34	6.8	.002	NR	85.3	65.7	.0015
R/R	19	3.2		5.3	50.5	25.3
TP53 aberration
mIGHV	17	6.8	.189	NR	82.4	68.8	.126
uIGHV	36	5.0		9.6	68.8	42.0

The 34 previously untreated patients with TP53 aberrations had a median PFS of 6.8 years, whereas median OS was NR (supplemental Figure 2). Compared with patients with R/R disease harboring TP53 aberrations, previously untreated patients in this category had a longer PFS and OS (Table 2). The estimated 10-year OS rate in patients with TP53 aberrations was 65.7% for previously untreated patients and 25.3% for patients with R/R disease. Although there was a trend for inferior PFS and OS in previously untreated patients with TP53 aberrations and uIGHV, statistical significance was NR (P = .094 and P = .21; see supplemental Figure 2).

MRD

MRD was assessed annually by peripheral blood flow cytometry. After 1 year on drug, 74 patients were evaluable for MRD and, except for 1 patient, all had CLL counts of ≥1% of leukocytes (high MRD; Figure 4A). At best response, 13 patients (15.5%) achieved uMRD at 10⁻⁴ (CLL cells <0.01% of leukocytes; Figure 4B). The median time to uMRD was 5 years (range, 2-10). Patients across a spectrum of disease factors achieved uMRD, including those with R/R disease, advanced Rai stage, presence of TP53 aberrations, and uIGHV (Table 3). During the first 5 years on ibrutinib, best response, by iwCLL criteria, for patients achieving uMRD was a complete response in 8 (61.5%) and partial response in 5 (38.5%). To limit radiation exposure, and minimize invasive procedures, annual restaging computed tomography scans and bone marrow examinations were discontinued beyond 5 years. At median follow-up of 11.0 years, 12 (92.3%) patients with uMRD continue progression-free for a median of 3.0 years (range, 1-8; Figure 4C). Six patients continue on study, and 6 patients discontinued ibrutinib while in uMRD, 3 for toxicity, 1 to initiate treatment for a second primary malignancy, and 2 patients were taken off study due to dementia resulting in inability to travel. Three patients who discontinued ibrutinib remained in uMRD for ≥1 year without CLL-directed therapy. One patient achieved uMRD at 3 years and discontinued ibrutinib in year 5 for toxicity. Subsequent testing confirmed uMRD at 6 months, 1 year, and 4 years after treatment discontinuation and, at 5.3 years off drug, revealed low MRD at 1.5 × 10⁻⁴ without evidence of clinical progression (Figure 4C). The only patient who progressed while on ibrutinib after having achieved uMRD at 24 months, had del(17p), and was treated in second-line after CIT. The patient presented with low MRD at 36 months, met iwCLL criteria for progression based on increasing lymphadenopathy at 60 months, and had rapidly raising leukemic disease with multiple PLCG2 mutations over the next 12 months. At that time, ibrutinib was stopped, and venetoclax ramp-up started the following day.

Figure 4.

MRD assessments. (A) Number of patients achieving different levels of MRD assessed yearly using flow cytometry as number of CLL cells per leukocyte in peripheral blood. Missing data in years 7 through 9 is due to missed appointments during the COVID-19 pandemic. (B) MRD kinetics in 13 patients achieving uMRD at best response. The dashed horizontal line at 0.01% indicates the threshold for uMRD (10⁻⁴). For patients with no immunophenotypic evidence of CLL by flow cytometry, data points for graphing are set at 0.002%, the detection limit of the assay. (C) MRD trajectory over time in individual patients achieving uMRD (n = 13) through the last follow-up. The arrows indicate patients who continue to be followed. (D) Three-year landmark PFS estimates stratified by MRD status at 3 years after treatment initiation: high MRD (purple), low MRD (orange). Kaplan-Meier curves show no statistically significant difference in PFS among groups (P = .6, log-rank test).

Table 3.

Proportion of patients achieving different levels of MRD at best response

	n	uMRD, n = 13	Low MRD, n = 21	High MRD after ≥5 y on ibrutinib,∗ n = 17
Female	36	7 (19.4)	11 (30.6)	5 (13.9)
Male	48	6 (12.5)	10 (20.8)	12 (25)
Previously untreated	52	8 (15.4)	13 (25.0)	16 (30.8)
R/R disease	32	5 (15.6)	8 (25.0)	1 (3.1)
Rai stage I/II	26	7 (26.9)	10 (38.5)	4 (15.4)
Rai stage III/IV	58	6 (10.3)	11 (19)	13 (22.4)
No TP53 aberration	31	7 (22.6)	11 (35.5)	5 (16.1)
With TP53 aberration	53	6 (11.3)	10 (18.9)	12 (22.6)
uIGHV	56	11 (19.6)	14 (25.0)	7 (12.5)
mIGHV	28	2 (7.1)	7 (25.0)	10 (35.7)

Data are presented as n (%).

^∗Patients on ibrutinib for at least 5 years with best response of high MRD.

Best response of low MRD was seen in 21 of 84 (25.0%) patients (supplemental Figure 3A). Median time to reaching low MRD was 4 years. Eight patients discontinued ibrutinib for toxicity or electively withdrew. Twelve (57.1%) patients lost low MRD status on continuous therapy, progressed, and eventually switched therapy. Median time from reaching low MRD to clinical progression was 4 years (range, 1.1-6.4). In 40 (59.5%) patients, best response was high MRD. All but 1 patient in the high MRD group were treated with first-line ibrutinib, and over half had mIGHV. In contrast, most patients reaching uMRD or low MRD had uIGHV (Table 3). Seventeen (42.5%) of these patients continued on study for at least 5 years without clinical progression, and 5 did so for >10 years (supplemental Figure 3B). To assess the prognostic relevance of depth of MRD, a landmark analysis was performed at 3 years after ibrutinib initiation (Figure 4D). At this time point, 1 patient had achieved uMRD, 15 patients had achieved low MRD, and 48 patients had high MRD (10⁻²). PFS was not significantly different among the groups (P = .6)

Discussion

With more than a decade of follow-up, our data demonstrate durable and deepening responses in patients with CLL receiving single-agent ibrutinib. By design, our cohort encompassed a broad clinical spectrum of CLL cases, including both patients with previously untreated disease and those with R/R disease, enriched for high-risk genetics, including TP53 aberrations. For all patients, median PFS was 7.2 years, and median OS was NR. Inferior PFS and OS were associated with a history of previous treatment, the presence of TP53 aberrations, and uIGHV status. The first 2 factors consistently correlated with inferior outcomes for patients with CLL treated with a BTKi.^{21,34, 35, 36, 37, 38} In contrast, in multiple studies, uIGHV was not identified as an adverse prognostic factor with continuous BTKi therapy.^34,35,39 At >10 years of follow-up, patients with uIGHV had a median PFS of 6.7 years (vs NR) and median OS of 9.0 years (vs NR). Most patients in our study had TP53 aberrations and uIGHV, and interaction between the 2 could increase the prognostic importance of uIGHV in univariate analyses. However, the prognostic relevance of uIGHV has also been reported in a pooled analysis of patients with R/R disease treated with acalabrutinib, and uIGHV was independent of TP53 status in multivariate analysis.³⁶ A not statistically significant trend for inferior PFS with uIGHV vs mIGHV, is also starting to emerge in updates of other studies.^40,41 Similar to existing evidence,^21,35,36,42 patients with R/R disease experienced significantly shorter median PFS (4.1 vs 9.0 years) and 10-year OS than previously untreated patients. Most of the patients with R/R CLL had been treated with CIT. Because chemotherapy is now being replaced by targeted agents in all lines of therapy, outcomes of these patients are expected to improve.⁴³

We did not identify any new safety concerns over existing reports.^20,35,39,44 The most common reason for discontinuation of ibrutinib was progressive disease in 46.9%; AE in 36.9% of patients were the next leading cause. Rates of study discontinuation for these 2 reasons were comparable and quite stable over time. Cardiac AE were the most common. The increase in treatment discontinuations for cardiac AE at later times on study (as shown in Figure 1) coincided with changing approaches to patients with cardiac concerns. Considering updates to the ibrutinib prescribing information, we adopted a low threshold for additional testing and precautionary discontinuation of ibrutinib. Treatment discontinuations for infections were limited to the first years on study, consistent with a reduced overall incidence of infections on continuous BTKi therapy.⁴⁵ Other studies identified AE as a more common reason for ibrutinib discontinuation than progressive disease.^19,41,46 Two reasons may explain the lower discontinuation rate in our study. First, most patients in our trial had TP53-aberrant CLL, which increased the incidence of progressive disease but also enhanced drug adherence in patients having an understanding of the high-risk nature of their disease. Second, the study opened in January 2012, when alternative treatment options were relatively limited.

uMRD has emerged as an important prognostic marker in CLL.^24,26,47,48 In studies using single-agent BTKis, MRD testing is often not done, because deep remissions are not expected. We prospectively included annual MRD testing and found that 15.5% of all patients enrolled achieved a best response of uMRD after a median of 5 years on drug. Of 19 (42.1%) patients completing at least 10 years on study, 8 patients had uMRD. On continuous treatment, uMRD was sustained in all but 1 patient. Patients who discontinued ibrutinib due to ≥1 AE maintained uMRD, off drug, for up to 4 years. Our study was not designed to discontinue therapy based on MRD status. Our MRD assessments were based on peripheral blood flow cytometry with a detection limit of 2 × 10⁻⁵. Arguably, inclusion of bone marrow examinations and/or a higher sensitivity assay could increase confidence in using uMRD as an end point to discontinue treatment.^26,49,50 Nevertheless, durable remissions in patients who discontinued single-agent BTKi due to toxicity suggest that a subset of patients with deep responses could stop therapy without the risk of immediate relapse; a premise that would need to be tested prospectively. There was also a sizable group of patients who continued to benefit from ibrutinib for at least 5 years while their CLL counts consistently stayed >1% of leukocytes (high MRD). In fact, even after 10 years on ibrutinib, CLL cells still constituted >10% of leukocytes in several patients. Consistent with these observations, a 3-year landmark analysis showed no significant difference in PFS between patients with high vs low MRD. In patients with uMRD and low MRD at best response, rising MRD counts predated clinical disease progression often by several years. Although MRD monitoring could be used to time changes in treatment, there appears to be no clinical urgency to do so. Similar observations and considerations have been made when assessing patients for BTK or PLCG2 mutations, which often also predate clinical progression.⁵¹

Compared with historical experiences with CIT, first-line BTKis have clearly improved PFS and OS in patients with TP53 aberrations.^{19,22,23,52, 53, 54, 55} Superiority of BTKis was confirmed in the few randomized studies that assigned patients with TP53 aberrations to chemotherapy.^19,52 The durability of response to BTKis in this difficult-to-treat population is appreciated. At 10 years, 65.7% of previously untreated patients with TP53 aberrations were estimated to be alive, and 38.6% were estimated to be progression-free. Yet, BTKis are not able to completely overcome the adverse impact of this high-risk genetic marker. In particular, the combination of TP53 aberrations and R/R disease portends inferior PFS and OS with ibrutinib.^20,21,56 Notably, the presence of single vs multiple TP53 aberrations also matters. We previously reported on 51 patients from our study assessed by fluorescence in situ hybridization and TP53 sequencing.³² A single hit, usually in the form of del(17p) without a concurrent TP53 mutation was identified in 9 patients, most of whom had mIGHV and were treatment naïve. PFS, OS, and time to progression were all significantly shorter in patients with multihit compared with those with a single hit to TP53.³² Although ibrutinib is increasingly replaced by second-generation agents such as acalabrutinib and zanubrutinib, which are better tolerated,^12,13 outcomes with these agents still remain inferior in patients with TP53 aberrations compared with those without.^{14,21,36,38,52}

How can outcomes for TP53-aberrant CLL be improved further? Zanubrutinib increased the 3-year PFS rate over ibrutinib in patients with R/R CLL. However, in both arms, patients with TP53 aberrations had shorter PFS than patients without: 59.2% vs 65.4% for zanubrutinib and 38.5% vs 54.4% for ibrutinib.¹⁴ In the ELEVATE TN study, 4-year PFS with single-agent acalabrutinib for patients with or without TP53 aberrations was comparable at 76% and 78%, respectively.⁵² For comparison, the 4-year PFS with first-line ibrutinib with or without an anti-CD20 antibody was 79% in 89 patients with TP53 aberrations treated across several studies.⁵³ Thus, it remains unclear how much the choice of a particular BTKi can contribute to improving outcomes for patients with TP53 aberrations. Combining BTKis with additional agents has also generated mixed results. Notably, in patients with TP53 aberrations, the addition of anti-CD20 antibodies to a BTKi failed to improve outcomes.^52,57 Many recent studies have investigated the combination of venetoclax and a BTKi with or without the addition of an anti-CD20 antibody. The 3-year PFS rates for patients with or without TP53 aberrations treated with fixed-duration venetoclax and ibrutinib on the CAPTIVATE study were 81% and 91%, respectively.⁵⁸ In the SEQUOIA arm D study, the 2-year PFS for patients with or without TP53-aberrant disease treated with zanubrutinib and venetoclax were 89% and 94%, respectively. Although duration of venetoclax was limited to 24 cycles, most patients remained on zanubrutinib.⁵⁹ Large randomized studies testing combinations of a BTKi with venetoclax, including the GLOW and AMPLIFY trials, excluded patients with del(17p) and/or TP53 mutations.^{25, 26, 27} Triple combinations in first line for TP53-aberrant CLL were also investigated. In the CLL2 GIVE trial, 3-year PFS with obinutuzumab, venetoclax, and ibrutinib was 79.9%.⁶⁰ Even with this triple combination, PFS for patients with del(17p) and TP53 mutations was significantly worse than for patients with a sole TP53 mutation.⁶⁰ Davids et al reported on outcomes of acalabrutinib, venetoclax, and obinutuzumab given for up to 24 cycles. Four-year PFS in patients with and without TP53 aberrations was 70% and 96%, respectively.⁶¹ In summary, covalent BTKis remain in need of a combination partner capable of improving PFS in patients with TP53 aberrations.

High rates of durable remissions with uMRD can be achieved with time-limited combination targeted therapy. So, what may be the role and value of BTKi monotherapy? For one, patients with TP53-aberrant CLL may benefit from sustained inhibition of BCR signaling to limit further clonal evolution.^1,62 In settings in which convenience, reduced monitoring, and less frequent health care visits are advantageous, BTKis may be favored. For frail patients, patients with cytopenias, and patients burdened by polypharmacy, starting BTKi monotherapy can be easier and safer than immediately embarking on combination therapy. An alternative to the choice between single-agent, indefinite treatment with a BTKi and up-front combination therapy is the initiation of a BTKi followed by, a time-limited, consolidation with ≥1 additional agents.⁶³ Notably, fixed-duration therapy, may lower the risk of acquiring pathway mutations associated with continuous single-agent therapy.⁶⁴ Options to deepen responses in patients on continuous BTKi therapy are increasing, and the sustained benefit with single-agent provides ample time to consider next steps. Our data highlight durable and deepening responses with ibrutinib, including as first-line treatment in patients with TP53-aberrant CLL. The experience can help set expectations about long-term outcomes and identify patients who could benefit from consolidation. Although increasingly replaced by second-generation covalent BTKis, ibrutinib, as the first-in-class, set the example for what can be achieved with continuous therapy.

Conflict-of-interest disclosure: A.W. received research support from Pharmacyclics LLC (an AbbVie company), Acerta Pharma (a member of the AstraZeneca group), Merck, Nurix, and Genmab. C.S. received research funding from Genmab. I.E.A. received research support from BeOne and Lilly and received consulting fees from AstraZeneca, BeOne, and Lilly. A.I. is a current employee of Amgen. M.Z.H.F. is a current employee of Merck Sharpe & Dohme LLC, a subsidiary of Merck and Co, Inc, Rahway, NJ. The remaining authors declare no competing financial interests.

The current affiliation for A.I. is Amgen, Thousand Oaks, CA.

The current affiliation for M.Z.H.F. is Merck Sharpe & Dohme LLC, a subsidiary of Merck and Co, Inc, Rahway, NJ.