Ibrutinib and venetoclax in combination for chronic lymphocytic leukemia: synergy in practice

Pathophysiology studies of chronic lymphocytic leukemia (CLL) have identified 2 primary pathways responsible for production, proliferation, survival, and migration of CLL cells, namely B-cell receptor (BCR) pathway signaling and abundance of B-cell lymphoma 2 (BCL-2) family antiapoptotic proteins. These biologic features of CLL were instrumental for identifying and establishing targeted therapies in CLL.

To mitigate BCR pathway signaling, targeting the Bruton tyrosine kinase (BTK) node has proved to be the most successful strategy. Ibrutinib, a small molecule inhibitor, is a first-in-class oral irreversible inhibitor of BTK that binds covalently to cysteine 481 in its kinase domain. This binding prevents the activation of BTK by hindering its autophosphorylation at tyrosine 223 and consequently suppressing the downstream BCR signaling required for B-cell proliferation, migration, and survival.¹ The phase 1 and 2 trials and the RESONATE trial series demonstrated the high efficacy and safety of ibrutinib monotherapy in patients with both treatment-naïve^2-4 and relapsed/refractory (R/R)^4-9 disease. Ibrutinib is continued until disease progression or the emergence of serious adverse effects (AEs). Despite its success, especially in reducing lymph node tumor burdens, the need for continuous treatment, the lower rates of achieving complete remission (CR)^4,8-10 and undetectable minimal residual disease (uMRD) status, the accrual of undesirable toxicity events,^11-15 and the development of drug resistance over time^4,11,16-19 have underscored the necessity for alternative approaches. Ibrutinib toxicity, rather than disease progression, is a predominant reason for discontinuation of the drug. AEs include bleeding, hypertension, cytopenia, and atrial fibrillation.^11-16 Death analysis using VigiBase (the World Health Organization global database of adverse drug reaction) revealed that ibrutinib is associated with severe and sometimes fatal cardiovascular adverse drug reactions, including supraventricular and ventricular arrhythmias, heart failure, conduction disorders, and central nervous system events.^20,21 Limited-time ibrutinib treatment and second-generation of BTK inhibitors, such as acalabrutinib²² and zanubrutinib, along with the new noncovalent BTK inhibitor pirtobrutinib, provide an alternative approach for a favorable safety profile.^23,24 

Among the BCL-2 family of antiapoptotic proteins, the most pronounced member in CLL biology is BCL-2 itself. The BCL-2 inhibitor venetoclax has emerged as a promising monotherapy, demonstrating impressive results, especially in peripheral blood (PB) and bone marrow (BM).^25-27 The potent effect of venetoclax and its rapid reduction of tumor burden have presented challenges, notably tumor lysis syndrome (TLS), which is managed through a carefully administered ramp-up period to reach the full therapeutic dose.^28-30 The risk for TLS and hematologic toxicities have emerged as limiting factors for the use of venetoclax.^31-33 

Despite the advantages and drawbacks of ibrutinib and venetoclax as single agents, the combination of these 2 distinct drugs may enable a potential synergistic approach in the evolving landscape of CLL treatment. This review first describes the rationale for ibrutinib plus venetoclax combination treatment. We then synthesized the clinical trial results obtained thus far (Table 1). We examined various trial designs, the results for genetic subpopulations, the safety of the combination, and the molecular findings at disease progression. Finally, we discussed ongoing trials and novel drug combinations.

The lymph node creates a supportive microenvironment for CLL cells, offering protection against proapoptotic signals. Figure 1 illustrates cell signaling and activity within and outside the lymph nodes. Within proliferation niches, various cell types, including T cells, natural killer cells, leukemia-associated macrophages, endothelial cells, and mesenchymal stem cells, provide essential stimulation, whereas CLL cells suppress antitumor immune responses.^34-36 Not only does BCR stimulation sustain survival signaling, but the interaction with T cells through CD40-CD40L engagement also induces the upregulation of antiapoptotic BCL-2 family proteins such as B-cell lymphoma-extra large (BCL-XL) and myeloid cell leukemia-1  (MCL-1).^36-41 This interconnected relationship was further highlighted in in vitro and ex vivo experiments in which primary samples from patients with CLL demonstrated that Toll-like receptor stimulation and CD40 overexpression collectively diminish the sensitivity to pharmacologic BCL-2 inhibition by venetoclax.^42,43 In CLL cells, BCL-2 protein levels are upregulated because of the loss of microRNA cluster miR-15a/miR-16-1 (miR-15/16). These microRNAs normally act as tumor suppressors by directly targeting BCL-2 messenger RNA for degradation. This dysregulation promotes the survival and accumulation of CLL cells by inhibiting apoptosis.⁴⁴ 

The ibrutinib-venetoclax combination exhibits clinically complementary activity with ibrutinib effectively inducing CLL cells to undergo a compartment shift from the lymph nodes to PB and venetoclax addressing all 3 compartments, namely PB, BM, and lymph nodes. Ibrutinib treatment leads to a reduction in the cell surface levels of CXCR4, which leads to the rapid redistribution of CLL cells from the spleen and lymph nodes to PB circulation, thereby inducing transient lymphocytosis in treated patients.⁴⁵ Although CLL cells that have recently migrated from lymph nodes have higher MCL-1 and BCL-XL expression, the levels change after treatment with ibrutinib.³⁷ Ibrutinib was shown to decrease MCL-1 protein levels and to make CLL cells highly dependent on BCL-2 signaling, thereby reinforcing the efficacy of its combination with venetoclax.^46-48 

Recent studies have shown that tyrosine 223 phosphorylation is not fully critical for maintaining BCR signaling; kinase-deficient or dead BTK mutants still play an integral role in BCR signaling through their scaffolding function.^49-52 The L528W mutation of BTK prevents adenosine triphosphate (ATP) binding, thereby making it kinase-dead; however, it was shown to contribute to ibrutinib, zanubrutinib, and pirtobrutinib resistance in patients with CLL.^53,54 CLL cells lacking BTK catalytic activity are still capable of activating phospholipase C γ2 through alternative signaling such as phosphatidylinositol 3-kinase, hematopoietic cell kinase, and Toll-like receptor 9. ^51,55,56 It has been demonstrated that ibrutinib treatment leads to a reduction in the BTK transcript and protein levels, which would also decrease the intensity of the BTK scaffolding function.⁵⁷ Patients who developed the L528W mutation were responsive to subsequent venetoclax treatment.⁵³ Thus, BTK inhibition by ibrutinib may be complemented by the proapoptotic effect of venetoclax. ⁵⁷ 

Ex vivo drug profiling of primary CLL lymphocytes from patients treated with ibrutinib demonstrated enhanced sensitivity to venetoclax. Furthermore, the levels of MCL-1 and BCL-XL were reduced in these samples. In primary CLL cells from treatment-naïve patients, the combination of ibrutinib and venetoclax showed a synergistic effect on the apoptosis rate.⁴⁸ Incubation of isolated CLL cells with ibrutinib demonstrated increased BCL-2 dependence, revealed through BCL-2 homology-3 (BH3) profiling.⁴⁷ Ibrutinib and venetoclax synergism was confirmed in in vivo studies in the T-cell leukemia/lymphoma 1 (TCL1) mouse model.⁵⁸ Furthermore, ibrutinib and venetoclax selectively act on different CLL subpopulations with distinct proliferative capacities; the proliferating subset of CLL cells displays a more favorable response to ibrutinib, whereas the quiescent subpopulation responds more to venetoclax.⁵⁹ This comprehensive approach, backed by preclinical evidence of synergism and nonoverlapping toxicity profiles, underlies the promising therapeutic potential of the ibrutinib-venetoclax combination in CLL.

Based on preclinical findings, the first investigator-initiated clinical trial in CLL was initiated in 2016 at the MD Anderson Cancer Center for high-risk treatment-naïve (N = 120)^60-62 and previously treated (N = 80) patients,⁶³ (NCT02756897). High risk was defined as the presence of a TP53 aberration, chromosome 11q deletion (del(11q)), unmutated IGHV, or age >65 years. The treatment regimen (Figure 2) started with ibrutinib (420 mg/d) for 3 cycles to achieve debulking, lower MCL-1 protein levels, and enable migration of cells from lymph nodes to the blood and then venetoclax was commenced with a weekly dose escalation up to a target dose of 400 mg daily. The combination therapy spanned 24 cycles with MRD measurements performed (assessed in BM by flow cytometry) at regular intervals. uMRD was defined as <0.01%, low MRD was defined as 0.01% to <1%, and high MRD was defined as ≥1%.⁶⁰ The study applied the concept of MRD-driven treatment duration in which patients with uMRD concluded treatment at 24 cycles, whereas MRD-positive patients continued the combination of ibrutinib and venetoclax for another 12 cycles.

Initially, the combination of ibrutinib and venetoclax was tested in a cohort of patients with R/R CLL. After 12 cycles of the combination, 29 of 60 patients (48%) achieved BM uMRD, and among 24 patients who completed 24 cycles, 16 (67%) achieved uMRD remission. Limited data are published on the long-term results; however, the median progression-free survival (PFS) and overall survival (OS) durations were not reached by month 36 of follow-up.⁶³ 

Subsequently, treatment-naïve patients with high-risk CLL demonstrated a 69% CR rate (n = 55) or CR with incomplete BM recovery (CRi) by cycle 12 and a 69% (n = 55) CR rate by cycle 24. In the BM, the rates of uMRD were 56% at 12 cycles and 66% at 24 cycles. The best response was uMRD in 72% (86/120) of patients. One patient experienced Richter transformation, and another had disease progression within the first 2 years of therapy.⁶¹ Data on the trial’s 5-year follow-up were presented at the 2023 American Society of Hematology Annual Meeting⁶²; at a median of 61.5 months, PFS was 90.1% and OS was 95.6%. In summary, the administration of 24 cycles of fixed-duration ibrutinib and venetoclax demonstrated its efficacy, characterized by a high rate of uMRD and a substantial rate of response retained even after treatment discontinuation.

The international industry-sponsored trial, CAPTIVATE, investigated the combination of venetoclax and ibrutinib in 323 treatment-naïve patients with CLL. Patients were stratified into 2 cohorts, namely fixed duration (N = 159) and MRD-driven duration (N = 164).^64,65 Ibrutinib was administered for 3 cycles, followed by a 5-week ramp-up of venetoclax, after which a full-dose combination regimen of both agents was continued for 12 cycles (Figure 2). After 12 cycles, uMRD status was achieved in the PB in 75% of patients and in the BM in 68% of patients.⁶⁵ 

In the MRD cohort, patients with flow cytometry–confirmed uMRD after 12 cycles of combination therapy were randomized 1:1 to either receive ibrutinib (n = 43) or a placebo (n = 43). Patients without confirmed uMRD continued either ibrutinib (n = 31) or ibrutinib with venetoclax (n = 32). The fixed-duration cohort received the combination for 12 cycles or until disease progression or toxicity if either occurred earlier. The main variables studied in the CAPTIVATE trial were fixed-duration treatment and the impact of MRD on disease-free survival.

For the MRD cohort, in the uMRD subgroup, the 1-year disease-free survival rates were similar between the placebo and the ibrutinib groups (95% vs 100%, respectively; P = .15). This result emphasizes the favorable impact on uMRD status. Continuing treatment may not confer a substantial additional benefit in terms of maintaining disease-free status in patients with uMRD. Patients who remained MRD positive after 12 cycles continued treatment with either ibrutinib alone or a combination of ibrutinib and venetoclax. Both groups had similar 30-month estimated PFS rates (95% vs 97%, respectively). Among patients who achieved a partial remission (PR) as their best response during the initial 12 cycles of combination treatment, nearly half experienced a deepening of their response to CR with continued treatment (8/15 in the ibrutinib group and 10 of 24 in the combination group).⁶⁵ 

For the fixed-duration cohort, with a median follow-up of 27.9 months, the efficacy observed with the combination regimen was remarkable with a 56% rate of CR and 76% and 62% rates of uMRD in the PB and BM, respectively.⁶⁶ 

The significance of achieving uMRD was evident in this cohort. Based on the MRD status after 12 cycles of combination treatment, there was minimal difference in the PFS rates at 24 months (100% for uMRD vs 91% for MRD positive). However, by the 4-year follow-up time, there was a substantial difference in the PFS rates (90% for uMRD vs 66% for MRD positive).⁶⁷ This result serves as a compelling illustration of how a prolonged follow-up period unveils the impact of prognostic factors. By the 5-year follow-up, the PFS and OS rates for the fixed-duration cohort were 70% and 97%, respectively. Overall, 58% achieved CR or CRi as their best response, which in most cases lasted >12 cycles. ⁶⁸ 

The UK CLARITY trial explored a modified approach to the ibrutinib-venetoclax combination by administering ibrutinib as a monotherapy for 2 cycles before introducing the combination in patients with R/R CLL (Figure 2). A unique aspect of the study design was the definition of therapy duration based on the pace of achieving remission and MRD status, which was evaluated using highly sensitive, multiparameter flow cytometry. Patients who achieved uMRD in the PB and BM at 6 months of combination therapy ceased ibrutinib-venetoclax treatment at cycle 12. Those who attained uMRD later (by cycle 12 or 24) ceased combination treatment at cycle 24. Patients with persistent MRD at the final assessment continued ibrutinib therapy.⁶⁹ 

Of 50 patients with CLL who completed the combined treatment, 14 achieved MRD negativity in the PB and BM at the early time point of 6 cycles.⁷⁰ Remarkably, MRD responses showed ongoing improvement beyond the initial 12 cycles with 40% (n = 20) achieving uMRD in the BM at cycle 14 and increasing to 48% (n = 24) by cycle 26. Of the 23 patients who discontinued treatment before 36 months, 17 did so because of achieving uMRD. At the 36-month mark, 18 patients who stopped therapy because of uMRD still had uMRD. Notably, 90% of patients who attained uMRD achieved this status within the initial 24 cycles of combination therapy. Finally, 1 case of progressive disease occurred at month 38.

Patients who achieved uMRD at cycle 24 demonstrated better CLL depletion during the initial 4 cycles than MRD-positive patients; however, from cycles 4 to 8, disease depletion rates were slower across all groups. The 2-log reduction in MRD levels at 2 months of combined ibrutinib-venetoclax therapy emerged as a strong predictor for long-term response in R/R CLL.⁷¹ 

Following the favorable outcomes of the CLARITY trial, the UK CLL group investigated the combination of ibrutinib and venetoclax in 260 patients with untreated CLL in the FLAIR trial. Initially comparing the gold standard of FCR (fludarabine, cyclophosphamide, and rituximab) with the combination of ibrutinib and rituximab,⁷² the trial's design was later adapted to include 2 additional arms, namely ibrutinib monotherapy and the ibrutinib-venetoclax combination. The duration of ibrutinib-venetoclax therapy was determined by flow cytometry assessment of MRD in PB and BM and lasted up to 6 years for patients without a uMRD response.⁷³ The results of the interim analysis of the ibrutinib-venetoclax cohort indicated a high rate of uMRD in the BM (65.4%), which was superior to the absence of a uMRD response among patients who received ibrutinib alone.⁷⁴ After 27 cycles of ibrutinib and venetoclax, 49.9% stopped therapy because of achieving uMRD; the rate increased to 72.9% by 51 months.^73,75 

Ultimately, the ibrutinib-venetoclax arm (N = 260) was compared with the FCR arm (N = 263). MRD-guided venetoclax and ibrutinib therapy demonstrated superiority over FCR in terms of PFS (93.5% vs 64.8% at 4 years) and OS (94.9% vs 87.3% at 3 years).⁷⁵ In addition, there was a difference in the association between IGHV mutational status and PFS at the 3-year follow-up; PFS for patients with unmutated IGHV who received ibrutinib and venetoclax was 98.3% vs 70.9% for patients who received FCR (P < .001). A total of 42 patients had disease progression on FCR therapy in comparison with only 5 patients on ibrutinib-venetoclax therapy.⁷³ 

The European multicenter GLOW trial^76,77 compared the efficacy and safety of 24 cycles of fixed-duration ibrutinib-venetoclax therapy (N = 106) with those of chlorambucil and obinutuzumab (N = 105) in untreated patients who were older than 65 years and/or who had comorbidities. Patients with del(17p) were excluded from this study. MRD was assessed using next-generation sequencing (clonoSEQ) and flow cytometric assays. The ibrutinib-venetoclax combination demonstrated superiority in terms of PFS with the median PFS not reached by 46 months of follow-up, whereas the chlorambucil and obinutuzumab arm had a median PFS of 21.7 months. After 12 cycles of ibrutinib and venetoclax combination therapy, 55% achieved uMRD in PB 3 months after treatment, but the rate decreased to 38% after 24 months.⁷⁶ 

Following the results of the phase 3 GLOW trials, the European Commission granted approval in August 2022 for ibrutinib in combination with venetoclax as an oral fixed-duration regimen for untreated CLL.

The discussed clinical trials can be broadly categorized into 2 subgroups, namely those that employed 12 cycles of fixed-duration treatment and those that employed 24 cycles. Although reducing the number of cycles may seem appealing to minimize potential adverse events, the risk for acquiring drug resistance, and therapy costs, it is essential to weigh these benefits against treatment efficacy. Although most uMRD responses typically manifest within the initial 12 cycles of treatment, distinct dynamics emerge across various studies depending on the duration of treatment. For instance, the MD Anderson^60,62 and FLAIR⁷³ trials have observed an increase in MRD rates between 12 and 24 cycles if treatment is prolonged. In the CAPTIVATE trial, the MRD rates remained stable without a distinct increase in uMRD after 12 cycles of treatment.⁶⁴ Notably, the GLOW trial exhibited a decrease in uMRD rates over time, particularly in the cohort of patients with unmutated IGHV, after 12 months of fixed-duration treatment.⁷⁶ 

The MD Anderson trial amendment allowed for the administration of an additional 12 cycles of venetoclax if MRD persisted at the 24th cycle of combined treatment. Overall, 101 patients completed 24 cycles, and 77 patients achieved BM uMRD, whereas 24 patients remained MRD positive. Ultimately, 18 patients with MRD positivity opted to resume venetoclax, leading to 11 patients who achieved uMRD remission during the third year of the combined therapy.⁷¹ 

The MD Anderson trial for the R/R population demonstrated an increase in uMRD rates in the BM from 48% (29/60 patients) at 12 cycles to 67% (16/24 patients) by cycle 24 of combination treatment.⁶³ Similarly, for the CLARITY trial, there was ongoing improvement in MRD dynamics with 36% achieving BM uMRD and 53% achieving PB uMRD after 12 cycles of combination therapy, and this increased to 44% of patients who achieved uMRD by cycle 24.⁶⁹ 

However, MRD is not the sole criterion used to define the optimal treatment duration. Disease progression while on ibrutinib and venetoclax time-limited treatment predominantly occurred during the off-therapy phase, regardless of the treatment duration.^62,76,78 Therefore, sustained response emerges as one of the primary considerations for determining therapy duration.

Diverse outcomes are noted among distinct CLL subgroups, including those with TP53/del(17p) and IGHV-mutated vs -unmutated CLL. The ibrutinib-venetoclax combination demonstrated promising effectiveness in patients with TP53 abnormalities, although outcomes remain less favorable than those in standard-risk patients with CLL. In the MD Anderson trial, in which all untreated patients exhibited high-risk features, the 5-year PFS was 90.1%, whereas patients with TP53 abnormalities had a numerically lower PFS of 86.1%.⁶² 

The CAPTIVATE trial included 129 patients with at least 1 higher-risk feature (IGHV-unmutated status, n = 119; del[17p] and/or TP53 mutated, n = 29).⁷⁹ Patients with del(17p) displayed a 4-year follow-up PFS of 63% as opposed to 79% among those without TP53 abnormalities⁷⁹; however, at the 54-month mark among those with del(17p)/mutated TP53, there was a decline to 45%.⁷⁸ Patients with CLL with TP53 abnormalities had a lower rate of uMRD in the BM (45%) than patients without del(17p) mutations (72%), suggesting increased resistance to therapy when these mutations are present.

Noteworthy findings emerged during the analysis of MRD and IGHV status. There was a trend among patients with unmutated IGHV toward a higher likelihood of achieving uMRD. In the MD Anderson trial for treatment-naïve patients, patients without an IGHV mutation had a uMRD rate of 60% (n = 38) at 12 cycles and 67% (n = 42) at 24 cycles as opposed to 38% (n = 5) and 54% (n = 7), respectively, among patients with a mutation. Notably, this trial primarily recruited patients with high-risk features, and 86% had unmutated IGHV.

In the CAPTIVATE analysis, among patients with IGHV-unmutated CLL, the rates of uMRD in the PB and BM were 88% and 73%, respectively as opposed to 72% and 60% among those with IGHV-mutated CLL. Patients with IGHV-unmutated CLL had a 36-month PFS of 88%, whereas those with IGHV-mutated CLL had a PFS of 92%.⁷⁹ 

More uMRD cases were observed among patients with IGHV-unmutated CLL in the FLAIR trial. Within the ibrutinib and venetoclax arm, patients with unmutated IGHV achieved uMRD rates of 83% in the PB and 80% in the BM at 24 months. In contrast, patients with mutated IGHV had uMRD rates of 64% in the PB and 56% in the BM.⁷³ 

Similar results were observed in the GLOW trial. Patients with IGHV-unmutated CLL achieved higher uMRD rates earlier (60% at 12 months). However, this rate decreased to 36% at the 24-month follow-up. Patients with IGHV-mutated CLL had a stable uMRD rate of 41% up to the 24-month follow-up. However, in patients with mutated IGHV, the 2-year PFS was 92.3% among those with detectable MRD (n = 14) and 100% among those with uMRD (n = 13), whereas in patients with unmutated IGHV, PFS was 67% with detectable MRD (n = 16) and 89.9% with undetectable MRD (n = 40).⁷⁶ 

Generally, uMRD is considered a favorable prognostic marker, and its status is frequently used as a surrogate end point for PFS.⁷⁹ Despite higher initial rates of uMRD during ibrutinib-venetoclax therapy, the PFS was shorter among patients with unmutated IGHV, highlighting that higher uMRD rates do not necessarily translate into improved PFS for this CLL subgroup. Conversely, this phenomenon may suggest that the MRD status has a minor impact on the survival outcomes among patients with mutated IGHV.

In terms of side effects, the ibrutinib-venetoclax regimen seems to have a combination of the AE profiles of each of the drugs. Ibrutinib is known for its unfavorable cardiovascular events, including hypertension and atrial fibrillation, which often necessitate the withdrawal of BTK inhibitors.¹⁵ Venetoclax can lead to TLS, necessitating close monitoring of laboratory results during venetoclax ramp-up^28,29 and hematologic toxicity, particularly grade 3 to 4 neutropenia.^31,32 The limited treatment duration of the ibrutinib-venetoclax regimen aims to mitigate the occurrence of these adverse events, which tend to increase over prolonged drug exposure. However, despite these efforts, infections and cardiovascular events were still observed across the discussed studies, but no new toxicities were observed with this drug combination.

AEs noted in the fixed-duration ibrutinib-venetoclax trials occurred at varied rates with the most common grade 3 to 4 AEs being neutropenia (10.3%-51%), atrial fibrillation (0.8%-16%), and hypertension (6%-16%).^62,64,73 Drug discontinuations and interruptions because of AEs remained a significant concern in the clinical trials. In the MD Anderson trial for treatment-naïve patients, therapy discontinuation owing to AEs occurred in 8 (10%) patients, and 2 patients discontinued during ibrutinib monotherapy because of pneumonia and a severe skin rash, and 7 patients discontinued during the combination treatment.⁶¹ In the CAPTIVATE trial, within the MRD cohort, dose reductions were necessary for 24 patients (15%) on ibrutinib and for 16 patients (10%) on venetoclax. In addition, 10 patients (6%) discontinued ibrutinib, and 4 patients (4%) discontinued venetoclax.⁶⁵ In the fixed-duration cohort, AEs led to dose reductions for 9 patients (6%) on ibrutinib, 18 patients (11%) on venetoclax, and 6 patients (4%) on both drugs. Of the 33 patients with AEs that led to dose reductions, 88% saw resolution at the time of analysis. Discontinuation because of AEs occurred in 5 patients (3%) on ibrutinib, 1 patient (1%) on venetoclax, and 2 patients (1%) on both drugs.⁶⁶ The CLARITY trial reported 4 discontinuations during ibrutinib monotherapy but none during combination treatment. Ibrutinib treatment was interrupted in 28 of 50 patients (56%) and reduced in 8 patients (16%), whereas venetoclax treatment was interrupted in 23 patients (46%) and reduced in 11 patients (22%). Most treatment modifications were because of toxicity with diarrhea and neutropenia being the most common AEs.⁶⁹ In the FLAIR trial, early discontinuation of treatment was reported in 58 of 252 patients (23.0%), mostly because of toxicity, including 21 cases treated with ibrutinib and 11 treated with venetoclax. Dose modifications, including reductions, delays, and omissions, were reported for 143 patients (55.0%) in the ibrutinib-venetoclax group.⁷³ The GLOW trial that specifically involved patients with older age and/or comorbidities showed a discontinuation rate of 10.4% for the ibrutinib-venetoclax combination with 2 patients (1.9%) discontinuing ibrutinib because of atrial fibrillation while continuing venetoclax. Fifteen deaths were reported with 3 attributed to posttreatment infections and 4 to cardiac events.^76,77 

As an alternative to fixed-duration treatment aimed at reducing AEs, clinical trials and real-world practice have explored the use of low-dose single-agent ibrutinib. A pilot study (NCT02801578) investigated whether lower doses of ibrutinib could maintain biologic activity in patients with CLL. After an initial cycle of 420 mg/d, the dose was systematically and preemptively reduced to 280 mg/d in cycle 2 and then to 140 mg/d in cycle 3. The results showed that the lowest dose of ibrutinib was sufficient to suppress >95% of BTK protein. BTK downstream signaling inhibition was maintained, and biomarkers of ibrutinib response were similar across the cycles. This suggests that after 1 full-dose cycle, ibrutinib can be safely reduced without losing efficacy.⁸⁰ Real-world practice studies reported more frequent dose reductions than clinical trials, ranging from 11% to 31.3%, mostly because of the AEs of ibrutinib.⁸¹ As part of this exploration, the TAILOR clinical trial (NCT05963074) aimed to assess the efficacy and safety of ibrutinib plus venetoclax and ibrutinib monotherapy regimens and incorporated proactive or reactive modifications of ibrutinib dosing in response to adverse events.

Investigating the impact of fixed-duration ibrutinib-venetoclax therapy on immune restoration revealed interesting patterns in various immune cell subsets. The MD Anderson trial found stable immunoglobulin G (IgG) and IgM levels, whereas IgA levels increased during the ibrutinib monotherapy phase. Absolute T-cell and natural killer– cell numbers decreased during combination treatment and remained low at the 12-month follow-up. ⁶¹ Immune cell subsets were evaluated in the CAPTIVATE and GLOW trials, and, despite a decrease in the normal B cells during the first 12 cycles of combined treatment, healthy B cells recovered to normal levels after 16 cycles. Within 6 months, T-cell, monocyte, and dendritic cell counts returned to normal levels and resembled those of a healthy donor.⁸² Over time, infections showed a general decrease, regardless of the randomized treatment, with the lowest frequency observed in patients assigned to the placebo group after cycle 16. Integrating 2 to 3 debulking cycles of ibrutinib before venetoclax has led to a reduction in the TLS risk, thereby allowing patients to avoid hospitalization for venetoclax initiation. Clinical TLS has not been reported, and predominantly laboratory TLS has occurred in the range of 1% to 4% of cases.^{60,64,75,83,84} 

In patients with CLL, mutations in BTK, PLCG2, and BCL-2 have been observed in those with progressive disease during continuous, single-agent BTK or BCL-2 inhibitor treatment.⁸⁵ In the MD Anderson and CAPTIVATE trials, among patients who completed fixed-duration treatment, no evidence of BTK, PLCG2, and BCL-2 mutations was observed at disease progression.^62,85 One patient in the CAPTIVATE trial developed a BCL-2 (A113G) mutation.⁷⁸ Targeted next-generation sequencing panels were employed; however, it was noted that their sensitivity might be insufficient, and ultradeep sequencing techniques, capable of detecting subclonal variants, were suggested.⁸⁶ Nevertheless, clinically, these patients remained responsive to covalent BTK inhibitors (ibrutinib, acalabrutinib), ibrutinib-venetoclax or venetoclax-rituximab, or obinutuzumab combination treatment.^62,78,85 Notably, retreatment with single-agent ibrutinib proved effective, yielding an overall response rate of 85% (21/22 patients), predominantly comprising PR in 81% of cases.⁷⁸ 

The CLL17 trial is an ongoing German CLL Study group phase 3 trial (NCT04608318) that is comparing 3 treatment regimens for previously untreated CLL. Patients receive either continuous ibrutinib, a fixed-duration combination of obinutuzumab and venetoclax, or a fixed-duration combination of venetoclax and ibrutinib. In the latter, ibrutinib is given for 3 cycles, followed by the addition of venetoclax starting at cycle 4, with combination treatment given for 12 cycles. Although the results have not been published yet, the trial builds on previous evidence to optimize treatment combinations and durations for patients with CLL. The SAKK 34/17 trial from the Swiss Group for Clinical Cancer Research is investigating ibrutinib and venetoclax combination with flexible TLS risk–based ibrutinib lead-in duration in R/R CLL (NCT03708003).

The success of ibrutinib-venetoclax treatment has spurred a diverse range of clinical trials that explored venetoclax treatment in combination with new generations of BTK inhibitors. Notably, the REVEAL trial (NCT04523428) is investigating the efficacy of venetoclax retreatment in combination with acalabrutinib following fixed-duration venetoclax therapy. The PreVent-ACaLL trial (NCT03868722) aims to study short-term acalabrutinib and venetoclax for newly diagnosed patients with CLL with a high risk for infection. Similarly, the MAJIC clinical trial explores MRD-driven fixed-duration treatment with acalabrutinib plus venetoclax in comparison with venetoclax plus obinutuzumab in previously untreated CLL. In addition, zanubrutinib and venetoclax are under investigation for treatment-naïve (NCT05650723) and R/R cases (ZANU-VEN trial, NCT05168930). The noncovalent BTK inhibitor pirtobrutinib is also being explored in clinical trials for both treatment-naïve (NCT05677919) and R/R CLL (NCT04965493).

As research ventures into new combinations with BTK inhibitors, investigations into BCL-2 inhibitors are also gaining momentum and expanding the horizon of CLL treatment options. In an ongoing phase 1/2 trial, the novel BCL-2 inhibitor sonrotoclax, in combination with zanubrutinib and obinutuzumab, is being investigated for patients with treatment-naïve CLL with the BCL-2 G101V mutation (NCT04277637).⁸⁷ Sonrotoclax, classified as a BH3 mimetic with >10-fold increase in potency when compared with venetoclax and higher selectivity,⁸⁸ will be further studied in a global phase 3 trial (NCT06073821). Another BCL-2 inhibitor, lisaftoclax,⁸⁹ will be combined with a BTK inhibitor in the NCT06104566 trial. These trials represent a comprehensive effort to advance treatment options in the management of CLL.

The combination of ibrutinib and venetoclax shows promising efficacy beyond CLL. In the recent SYMPATICO trial of 267 patients with R/R mantle cell lymphoma, the combination achieved superior 24-month PFS (57%) and CR rates (54%) when compared with ibrutinib alone (45% and 32%, respectively).^90,91 In addition, in a study of 45 patients with treatment-naïve MYD88-mutated Waldenström macroglobulinemia, the combination demonstrated effectiveness in 19 patients, yielding a 42% very good PR rate. Moreover, this regimen clinically improved hemoglobin levels, hyperviscosity symptoms, and extramedullary disease. However, within this trial, ibrutinib treatment was linked to a higher-than-expected incidence of ventricular arrhythmia, prompting an early discontinuation of the study.⁹² The combination of ibrutinib and venetoclax demonstrated efficacy in patients with activated B-cell-like (ABC) subtype and BCL-2-overexpressing diffuse large B-cell lymphoma with a median PFS of 5.6 months, an overall response rate of 61%, and a CR rate of 21.1%. Although the PFS and CR rates were relatively low when compared with those in CLL cases, they represent a significant improvement over current therapies for R/R diffuse large B-cell lymphoma.⁹³ 

Several mature clinical trials of ibrutinib and venetoclax have demonstrated the feasibility and efficacy of fixed-duration combination therapy, showcasing high rates of PFS and OS, even with long-term follow-up, in high-risk CLL. Despite these advancements, there remains a lack of consensus regarding the optimal treatment duration with many trials using the MRD status as a guide for therapy cessation. However, although achieving uMRD is associated with improved survival outcomes, as observed, it does not necessarily correlate with a better prognosis for high-risk CLL. Testing of the MRD-driven approach indicates that prolonged treatment can lead to increased MRD rates, even during the third year of combination administration. This result underscores the need for a nuanced understanding of the impact of uMRD and the implications of extended treatment duration on CLL outcomes.

A significant number of patients who maintained uMRD status for 4 or 5 years after ibrutinib-venetoclax treatment were observed in the discussed clinical trials. A longer follow-up, as seen for the FCR regimen (median of 19 years),⁹⁴ is crucial for revealing the potential risk for late relapse and for highlighting the possibility of a functional CLL cure.

The authors thank Sunita Patterson, a senior scientific editor in the Research Medical Library, MD Anderson Cancer Center, for providing editorial assistance.

This work was supported by a CLL Global Research Foundation Grant (#00011311), an Alliance Grant, and MD Anderson Cancer Center’s Moon Shots Program.

Contribution: N.T. and V.G. researched the literature, outlined the review, and wrote the review; and N.J. reviewed the manuscript.

Conflict-of-interest disclosure: N.J. reports receiving research funding from Pharmacyclics, AbbVie, Genentech, AstraZeneca, Bristol Myers Squibb (BMS), Pfizer, Antibody Drug Conjugates (ADC) Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, MingSight, Takeda, Medisix, Loxo Oncology, NovalGen, Dialectic Therapeutics, Newave, Novartis, Carna Biosciences, Sana Biotechnology, and KisoJi Biotechnology; and receiving honoraria from Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, BeiGene, Cellectis, Marshall Edwards, Inc Pharma, Ipsen, CareDx, MingSight, Autolus, and NovalGen. V.G. reports receiving research grants from Pharmacyclics, Acerta Pharma, AbbVie, Gilead Sciences, Sunesis Pharmaceuticals, Infinity Pharmaceuticals, Loxo Oncology, and Clear Creek Bio; and receiving honoraria from AbbVie. N.T. declares no competing financial interests.

Correspondence: Varsha Gandhi, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 1950, 1901 East Rd, Houston, TX 77054; email: [email protected].