Current Treatment of Chronic Lymphocytic Leukemia: the Diminishing Role of Chemoimmunotherapy

Abstract

In this review, we examine the literature supporting treatment decision making in the front-line and relapsed/refractory settings for patients with chronic lymphocytic leukemia (CLL). In the front-line setting, novel-agent based approaches, including continuous Bruton Tyrosine Kinase inhibitor (BTKi)-based therapy and time-limited venetoclax with obinutuzumab, have demonstrated survival benefit over chemoimmunotherapy. While novel agent-based front-line approaches are appropriate for most patients, fludarabine, cyclophosphamide, and rituximab (FCR) remains a consideration for a selected population of young patients with IGHV mutated disease given the possibility of a prolonged remission following FCR. As front-line novel-agent based approaches have not been compared directly, decision making regarding which novel-agent based approach to use in the front-line setting is often based on comorbidities and shared decision making. In the relapsed/refractory setting, BTK inhibitors, venetoclax-based therapy, and phosphoinositide 3-kinase (PI3K) inhibitors have demonstrated survival benefit when compared to chemoimmunotherapy regimens. Data to support various treatment sequences is limited, which highlight the need for prospective data to examine the optimal treatment sequence. Finally, we examine novel-novel combination therapies and novel agents in development, including covalent and non-covalent BTK inhibitors, PI3K inhibitors, BCL2 inhibitors, immunotherapies, and cellular therapies. With effective approved options and new agents in development, the role of chemoimmunotherapy in the management of CLL has diminished.

1. Introduction

The therapeutic approach for patients with chronic lymphocytic leukemia (CLL) has dramatically changed since 2014 with the approval of five targeted agents including the Bruton Tyrosine Kinase inhibitors (BTKi) ibrutinib and acalabrutinib, the B cell lymphoma 2 inhibitor (BCL2i) venetoclax, and the phosphoinositide 3-kinase inhibitors (PI3Ki) idelalisib and duvelisib. These drugs, either as monotherapy or in combination with anti-CD20 monoclonal antibodies (anti-CD20 mAb) including rituximab and obinutuzumab, have consistently compared favorably to chemotherapy and/or chemoimmunotherapy. Approved front-line targeted agents include ibrutinib with or without rituximab or obinutuzumab, acalabrutinib with or without obinutuzumab, and venetoclax with obinutuzumab. All five targeted agents are approved in the relapsed and/or refractory setting based on clinical trials in which these drugs demonstrated survival benefit compared to chemoimmunotherapy. While data support the use of agents in their approved settings, limited prospective data regarding optimal sequencing is available. Further, data regarding use of novel agents in a “chemotherapy-free” patient population and data regarding use of chemoimmunotherapy in novel agent treated patients are extremely limited. Here, we review the data supporting use of novel agents in each clinical scenario, highlight the gaps in data regarding the optimal approach to treatment in a chemotherapy-free paradigm, and discuss the diminishing role of chemoimmunotherapy in the modern treatment paradigm.

2. Front Line Treatment of CLL

2.1. Approved Therapeutic Options

Ibrutinib was the first targeted agent to be approved in the front-line setting based on data from RESONATE-2, which demonstrated a progression free survival (PFS) and overall survival (OS) benefit when compared to chlorambucil.¹ This study included patients who were 65 years or older and excluded those with deletion of chromosome 17p (del17p). PFS and OS benefits have been sustained with seven years of follow up (6.5-year PFS estimate 71%; 6.5-year OS estimate 78%), including in high-risk patients with deletion of chromosome 11q (del11q; PFS HR 0.033, 95% CI 0.010-0.107) and those with unmutated IGHV (PFS HR 0.1.09, 95% CI 0.063-0.189).² While patients with del17p were excluded from this study, a subsequent retrospective data set has suggested that PFS and OS are inferior for patients with del17p.³

Ibrutinib with or without anti-CD20 mAb has subsequently been compared to other chemoimmunotherapy regimens. In younger patients (age < 70) who required front line therapy, an OS benefit was observed for Ibrutinib/rituximab when compared to fludarabine, cyclophosphamide, and rituximab (FCR) with a HR for death of 0.17 (95% CI 0.05 – 0.54).⁴ In subset analyses, the benefit was observed in patients with unmutated IGHV (HR 0.28, p<0.0001) while patients no significant difference in PFS was observed for patients with mutated IGHV (HR 0.42, p=0.086).⁵ Thus, front line therapy with FCR remains a consideration for a selected set of patients with mutated IGHV, understanding the notable differences in toxicity profile for these two regimens. Ibrutinib with or without rituximab has demonstrated a PFS benefit when compared to bendamustine/rituximab (BR) in patients over 65 years of age; ibrutinib-based therapy led to higher rates of infection, atrial fibrillation and hypertension than BR.⁶ Notably, ibrutinib as monotherapy versus in combination with rituximab demonstrated no significant difference in PFS. Ibrutinib/obinutuzumab was further compared to chlorambucil/obinutuzumab in patients over 65 years or younger patients with comorbidities who required front-line therapy and is associated with a PFS benefit (30-month PFS HR 0.26, p<0.0001).⁷ Notably, this study did not include an ibrutinib monotherapy arm, so the utility of adding obinutuzumab remains unclear.

Acalabrutinib, a second covalent BTKi, was approved based on the results of the ELEVATE-TN trial, which demonstrated a significant improvement in PFS for acalabrutinib with or without obinutuzumab compared to chlorambucil/obinutuzumab.^8,9 In this study, which included treatment naïve patients 65 years or older or younger with comorbidities, patients treated on acalabrutinib-containing arms experienced relatively low rates of atrial fibrillation (3% with acalabrutinib/obinutuzumab, 4% with acalabrutinib monotherapy) and hypertension (3% for acalabrutinib/obinutuzumab, 2% with acalabrutinib monotherapy) while bleeding was noted in 43% on acalabrutinib/obinutuzumab and 39% on acalabrutinib. While the primary endpoint was PFS between acalabrutinib / obinutuzumab versus chlorambucil/obinutuzumab, post-hoc analyses compared acalabrutinib/obinutuzumab versus acalabrutinib monotherapy. Acalabrutinib / obinutuzumab was associated with a PFS benefit at 24 months and superior overall response rate (ORR; 94% vs. 86%) compared to acalabrutinib monotherapy. Further, PFS curves appear to be widening over time with 48-month PFS of 87% for acalabrutinib/obinutuzumab vs. 78% for acalabrutinib vs. 25% for chlorambucil/obinutuzumab.⁹

The improved outcomes associated with acalabrutinib/obinutuzumab compared to acalabrutinib monotherapy in ELEVATE-TN stands in contrast to the lack of improvement associated with addition of rituximab to ibrutinib.⁶ These data raise question regarding whether the benefit is specific to the anti-CD20 mAb partner or the BTKi used. Notably, ibrutinib has never been compared directly to ibrutinib/obinutuzumab. BTKi with or without anti-CD20 mAb therapy has been studied as a continuous therapy with a treat-to-progression approach. The addition of obinutuzumab to acalabrutinib was associated with higher rates of neutropenia (34% vs. 12%) and infusion related reactions (14% vs. 0%) but similar rates of diarrhea (41% vs. 40%), headache (4% vs. 38%), nausea (23% vs 23%), bleeding (47% vs 42%), hypertension (8% vs 7%), and atrial fibrillation (4% vs 6%) when compared to acalabrutinib alone.⁹ The decision regarding addition of obinutuzumab to acalabrutinib must weigh the risks of added toxicity with the PFS benefit.

In patients with comorbidities and/or impaired renal function, venetoclax/obinutuzumab as a one-year duration therapy has showed a PFS benefit when compared to chlorambucil/obinutuzumab (HR 0.35, 95% CI 0.23-0.53).¹⁰ This 12 month, fixed-duration combination is approved for all patients in the front-line setting. With 40 months of follow up, PFS remains significantly longer for those treated with venetoclax and obinutuzumab with estimated 3-year PFS of 82% versus 50% for chlorambucil/obinutuzumab.¹¹ With extended follow up, the improvement over chlorambucil / obinutuzumab extends to subgroups including those with TP53 aberration and unmutated IGHV. Patients with TP53 aberration do appear to have inferior outcomes when treated with venetoclax / obinutuzumab when compared to those without TP53 aberration.¹²

In aggregate, these studies have demonstrated the superiority of targeted agent-based approaches over chemoimmunotherapy for most patients requiring front-line CLL directed therapy with improved survival and manageable toxicity profile. However, based on long term data from the CLL8 trial, a subset of patients with mutated IGHV who receive FCR experience long-term remissions with a 5-year OS of 86% and few relapses appear to occur after 7 years.¹³ Further, a single center experience demonstrated a PFS of 54% at a median of 12.8 years of follow up. Based on a plateau of the PFS curve for patients with mutated IGHV treated with FCR, there is a a suggestion that select patients have a potential of long term PFS following front-line FCR.¹⁴ Finally, as reviewed earlier, data from E1912 demonstrate no PFS benefit for ibrutinib/rituximab over FCR.⁴ For young, fit patients who can tolerate FCR and have mutated IGHV without TP53 aberration (deletion of chromosome 17p and/or a mutation in the TP53 gene), FCR remains a treatment option in the front-line setting. This decision, of course, must also consider the short- and long-term toxicity associated with FCR, specifically risk of secondary cancers including therapy-related myeloid neoplasm.¹³

For most patients with CLL, front-line treatment with targeted agent-based approaches is preferred. Venetoclax versus BTKi-based approaches have not yet been examined head-to-head in the front-line setting, and sequencing from BTKi to Venetoclax versus Venetoclax to BTKi has not been studied prospectively. Thus, choice of front-line treatment is based on shared decision making, patient comorbidities and patient preference.

2.2. Novel-Novel Combination Strategies

In addition to the single targeted agent approaches outlined above, combinations of targeted agents are also being examined as front-line strategies. Doublet therapy with ibrutinib/venetoclax and triplet combinations including ibrutinib/venetoclax/obinutuzumab, acalabrutinib/venetoclax/obinutuzumab, and zanubrutinib/venetoclax/obinutuzumab have been studied.

Ibrutinib/venetoclax was examined in a phase 2 study that included high-risk patients (defined as presence of TP53 aberration, del11q, unmutated IGHV, or age ≥ 65) as a fixed duration 27-cycle therapy, though patients with persistent minimal residual disease (MRD) in the bone marrow could continue ibrutinib monotherapy until progression. After 18 cycles of ibrutinib/venetoclax, ORR was 100%, and 69% had undetectable MRD (U-MRD) in the bone marrow by flow cytometry, sensitivity 10⁻⁴.¹⁵ PFS and OS at three years were estimated to be 93% and 96%.¹⁶ Sixty percent of patients experienced grade 3 or greater toxicity. The most common adverse events were easy bruising, arthralgias, diarrhea, and grade 3 or 4 neutropenia occurred in 48%. Dose reductions of ibrutinib were required for 44% and venetoclax for 24%.¹⁵

The phase 2 study CAPTIVATE examined ibrutinib/venetoclax and included 2 cohorts, a fixed duration cohort and an MRD-guided cohort. In the fixed duration cohort, patients received 3 cycles of ibrutinib monotherapy followed by 15 cycles of ibrutinib/venetoclax. ORR was 96% with 77% achieving U-MRD in peripheral blood and 60% in bone marrow as measured by flow cytometry, defined as <10⁻⁴. 24-month PFS was 95% and 24-month OS was 98%.¹⁷ A second cohort used an MRD-guided randomization at the conclusion of 15 cycles with MRD positive patients randomized to continuous ibrutinib monotherapy vs. continuous ibrutinib/venetoclax and U-MRD patients randomized to ibrutinib vs. placebo. For those who achieved U-MRD, outcomes were similar for those who received ibrutinib and placebo.¹⁸ Notable grade 3/4 adverse events in this study included neutropenia (33-36%) and hypertension (6-10%); discontinuations were rare (4% discontinued ibrutinib, 2% discontinued venetoclax in the fixed duration cohort).^17,18

In the Phase 3 GLOW study, ibrutinib/venetoclax was compared to Chlorambucil/Obinutuzumab in patients over 65 or younger with comorbidities. Ibrutinib/Venetoclax resulted in a superior PFS (HR 0.216, 95% CI 0.131-0.357), including in patients with comorbidities (HR 0.248) and older age (≥65 years; HR 0.234).¹⁹ In this study, grade 3/4 adverse events included neutropenia in 35%, diarrhea in 10%, and hypertension in 7.5%. Seven grade 5 adverse events occurred in those treated with ibrutinib/venetoclax. Given this toxicity, consideration of the ideal patient population in whom to use novel agent combination therapy must consider not only depth and durability of remission, but also toxicity.

Fixed duration ibrutinib/venetoclax presents an all-oral combination regimen with high ORR and survival rates in studies with relatively short follow up, though adverse events are seen more frequently with combination therapy than monotherapy. Given this, the optimal use of combination ibrutinib/venetoclax requires identification of patients most likely to benefit from and tolerate the combination as opposed to sequential novel-agent monotherapy.

Triplet approaches are also under investigation. Ibrutinib/venetoclax/obinutuzumab has been reported as a 14-cycle fixed-duration regimen with 28% achieving U-MRD (by flow cytometry, <10⁻⁴) and ORR of 84% at the completion of therapy. With this triplet, 66% experienced grade 3 or 4 neutropenia, though only 1 patient experienced febrile neutropenia.²⁰ Acalabrutinib/venetoclax/obinutuzumab has been studied as a 15-cycle combination with those having persistent MRD (by flow cytometry, >10⁻⁴) continuing acalabrutinib/venetoclax through 24 cycles. Preliminary data show that ORR at completion of C8 is 100% with 65% achieving U-MRD in peripheral blood and 50% in bone marrow. Thirty-two percent of this population experienced grade 3 or 4 neutropenia.²¹ The combination of zanubrutinib/venetoclax/obinutuzumab has been studied with an MRD-driven endpoint with treatment duration ranging from 8 to 24 months. ORR with this combination at a median follow up of 14 months was 100% and 77% achieved U-MRD (flow cytometry, <10⁻⁴) and discontinued therapy after a median of 20 months. With a median follow up of 8 months, the rate of grade 3/4 neutropenia was 13%.²² Ongoing studies are examining ibrutinib and obinutuzumab with or without venetoclax (NCT03701282) and acalabrutinib with venetoclax with or without obinutuzumab versus chemoimmunotherapy (NCT03836261).

Novel-novel treatment strategies appear to induce deep responses with time-limited therapy, though toxicity for combination therapy appears to exceed that of single novel agent approaches. Phase 3 studies aimed to address important unanswered questions, including comparison of doublet and triplet combinations, are underway and will help guide the future of front-line therapy for CLL [NCT04608318, NCT05057494].

3. Relapsed/Refractory CLL Treatment

3.1. Approved Therapeutic Options

In the R/R setting, five targeted agents are approved: ibrutinib, acalabrutinib, venetoclax, idelalisib, and duvelisib. Notably, these agents were approved based on studies that included patients treated with prior chemoimmunotherapy with an extremely limited number of patients who had prior targeted agent exposure (n=9 across all studies). Current sequencing strategies have been studied in retrospective real-world data sets, though prospective data regarding sequencing strategies are not yet available.

In the RESONATE study, ibrutinib was compared to ofatumumab in a patient population with a median of 3 prior lines of therapy and had with an ORR of 91% and median OS of 68 months.²³ Acalabrutinib was compared to investigator’s choice of BR or idelalisib/rituximab in a group with a median of 1 prior lines of therapy. The ORR for patients treated with acalabrutinib was 81% and the 1-year PFS was 88%.²⁴ Targeted agent treated patients were not included in either of these studies. In the relapsed/refractory setting, a head-to-head study of acalabrutinib versus ibrutinib in patients with high risk (del11q or del17p) CLL demonstrated a median PFS of 38.4 months for both therapies with a lower incidence of all-grade atrial fibrillation with acalabrutinib vs. ibrutinib (9.4% vs. 16.0%).²⁵ Both BTKis are approved as continuous therapies in the R/R setting.

Venetoclax/Rituximab is approved as a fixed 2-year duration therapy for R/R disease.²⁶ Four-year PFS for this combination is 58% with four-year OS of 85%. Notably, MRD status at the completion of therapy was significantly associated with PFS with those achieving U-MRD subsequently enjoying superior PFS.²⁷ Only 5 patients (2.6%) in this population had previously received a BTKi or PI3Ki. Venetoclax monotherapy has been studied prospectively in patients with prior ibrutinib or idelalisib exposure.^28,29 Following ibrutinib, venetoclax treated patients experience an ORR of 65%, 1-year PFS of 75%, 1-year OS of 91% and median PFS of 24.7 months (95% CI 19.6-NR).²⁸

The PI3K inhibitors idelalisib in combination with rituximab and duvelisib as monotherapy are approved for treatment of CLL and have been studied in populations without prior targeted agent exposure. Patients treated with idelalisib/rituximab had an ORR of 81% and 1 year OS of 92% in a population with a median of 3 prior lines of therapy³⁰ Patients treated with duvelisib had an ORR of 74% and median PFS of 13 months (median of 2 prior lines of therapy).³¹

For a subset of fit patients, allogeneic stem cell transplant can also be considered as the only potentially curative treatment modality. Data regarding the efficacy of transplant following novel agent therapy are limited. However, a retrospective study of allogeneic stem cell transplant in patients previously treated with novel agents suggest that the number of novel agents prior to transplant does not impact outcomes.³² In this cohort, 24-month PFS and OS were estimated to be 63% and 81%, respectively.

3.2. Agents in Development

CLL remains an incurable disease outside of allogeneic hematopoietic stem cell transplantation, and therefore many patients will require multiple therapies throughout their lifetime. For patients with progressive CLL following treatment with targeted agents, particularly patients with progressive disease following both BTKi and BCL2i (i.e., “double refractory”), there remains a need for additional CLL-directed therapies. In this section we highlight some of the many additional agents in development for the treatment of CLL.

3.2.1. BTK Inhibitors

Zanubrutinib is a highly selective, covalent BTKi that has shown excellent clinical activity in CLL as well as a favorable safety profile in both the front-line and relapsed/refractory settings.^33-35 In the initial phase I/II trial of zanubrutinib in CLL which included patients with relapsed/refractory and treatment naïve CLL (23% of patients), the safety profile was favorable, with neutropenia being the most common grade ≥3 AE (n=6 patients, 6.4%).³³ Additionally, efficacy was excellent (treatment naïve ORR 100%, relapsed/refractory 94.6%). Additional studies have shown continued safety and efficacy. Importantly, the phase III SEQUOIA trial included an arm of zanubrutinib monotherapy for the front-line treatment of CLL with del17p.³⁴ The estimated 18 month PFS for patients treated with zanubrutinib was 88.6% (n=109 patients). This is one of the largest dedicated prospective studies examining front-line treatment for CLL patients with del17p, which is currently an area with limited data to guide clinical practice. In a planned interim analysis from the phase III APLINE trial comparing zanubrutinib versus ibrutinib, 415 patients with relapsed/refractory CLL were randomized to treatment with ibrutinib or zanubrutinib. Zanubrutinib produced a significantly higher ORR (78.3% vs 62.5%, p=0.0006), though patients with PR-L were not included as responders in this study. AEs due to zanubrutinib less frequently resulted in drug discontinuation (7.8% discontinuation due to AEs for zanubrutinib vs 13% due to ibrutinib).³⁵ Taken together, these results suggest that zanubrutinib has excellent clinical activity with a favorable safety profile.

Noncovalent BTKis are also in clinical development and are emerging as clinically active agents for patients with progressive CLL following treatment with covalent BTKis as well as other targeted agents. Pirtobrutinib (LOXO-305) is an oral, highly selective, BTK inhibitor with a reversible binding mode.³⁶ In the recently reported results of the Phase I/II trial of pirtobrutinib in relapsed/refractory B cell malignancies, pirtobrutinib demonstrated an excellent safety profile in 170 CLL/SLL patients with only 1% of patients discontinuing therapy due to AEs. Importantly, the drug was efficacious in both patients with BTKC481 acquired binding site mutations (ORR 71%, n=24 efficacy evaluable) and in BTK wildtype patients (ORR 66%, n=65 efficacy evaluable). The study included heavily pre-treated patients, including those treated with ibrutinib, venetoclax and PI3K inhibitors (median prior therapies 3).³⁶ ARQ 531 is another noncovalent BTKi inhibitor in development. In a phase I, dose-escalation study investigating ARQ 531 in relapsed/refractory B cell malignancies, there were 26 patients with CLL/SLL treated (40 patients total), including 22 patients with BTKC481S mutation.³⁷ Eight treated patients had grade 3 or higher treatment emergent adverse events with neutropenia being the most common AE. In the higher dose cohorts, 7 CLL patients had partial responses, indicating preliminary clinical activity.³⁷ The phase I/II study is ongoing (NCT03162536). Longer follow-up and larger, comparative trials are needed to determine the clinical efficacy and long-term safety profile of these agents.

3.2.2. PI3K Inhibitors

Clinical trials exploring the PI3Ki umbralisib, an oral dual PI3K-delta and casein kinase-1-epsilon inhibitor, have also shown promising clinical efficacy as well as an acceptable safety profile. The phase III UNITY trial compared umbralisib in combination with ublituximab, an anti-CD20-mAb (U2 regimen) versus chlorambucil and obinutuzumab.³⁸ This study included both treatment naïve and relapsed/refractory CLL patients and the U2 regimen had significantly longer PFS when compared to chlorambucil in combination with obinutuzumab (median follow-up 36.2 months, HR 0.546, p<0.0001). PFS with U2 was longer for both treatment naïve (median PFS 38.5 months) and relapsed/refractory (median 19.5 months) subgroups.³⁸ Umbralisib monotherapy was also recently shown to be an active regimen following discontinuation of prior treatment with BTKi or PI3Ki for intolerance (median PFS 23.5 months, median follow-up 23 months, n=51 patients.³⁹ In this population of patients with prior intolerance to kinase inhibitors, only 12% of patients discontinued umbralisib due to AEs and 16% required a dose reduction.³⁹

3.2.3. BCL2 Inhibitors

New BCL2is are also in clinical development. Lisaftoclax is a novel BCL2i and results of the first-in-human phase I clinical trial in relapsed/refractory hematologic malignancies were recently reported at ASCO 2021.⁴⁰ The phase I trial included 15 patients with R/R CLL (35 patients total) with no dose limiting toxicities or laboratory or clinical tumor lysis syndrome reported. Limited efficacy data is available at this time.

3.2.4. Cellular Therapies and Immunotherapies

CD19-directed chimeric antigen receptor T-cell (CART) therapy has been studied in patients with CLL and appears to be a clinically active option for heavily pretreated patients. In the phase I TRANSCEND CLL monotherapy trial, lisocabtagene maraleucel, a CD19-directed 4-1BB CAR T cell therapy, was demonstrated to have clinical efficacy in a heavily pre-treated patient population (91% prior ibrutinib, 48% “double refractory”) with an ORR of 68% at day 30 and 50% of patients with a continued response at 18 months (n=22 efficacy evaluable patients). Grade 3 or higher CRS (n=2 patients) and neurotoxicity (n=5 patients) were rare.⁴¹ An ongoing cohort is examining ibrutinib in combination with lisocabtagene maraleucel and has shown a favorable safety profile with low incidences of grade 3 CRS (n=1 of 19 patients) and grade 3 or higher neurologic events (n=3 patients) and appears to have preliminary efficacy (95% OR at 1 month or more).⁴²

Additionally, there are ongoing clinical trials exploring bispecific T-cell engager (BITE) therapy in relapsed/refractory CLL (epcoritamab in NCT04623541; mosentuzumab in NCT02500407).

3.3. Sequencing Novel Agents

One of the most pressing questions in the treatment of CLL is the optimal sequencing of targeted agents. The decision-making regarding treatment sequencing is highly dependent on prior lines of therapy and reasons for discontinuation of prior therapies.

In patients with prior BTKi exposure, next line treatment decision making is largely based on reason for BTKi discontinuation. For those with progression on BTKi, prospective and retrospective data support the use of venetoclax. A phase 2 study of venetoclax monotherapy for patients with prior BTKi exposure demonstrated an ORR of 54% in those who had progress on BTKi and was associated with 1 year OS of 91%.²⁸ In retrospective series including patients with prior BTKi exposure (discontinued for either progression or toxicity), ORR has ranged from 69% to 85% with one-year OS ranging from 75% to 88%.^43-46 Based on these data, the treatment sequence of BTKi to venetoclax is well supported by prospective and retrospective data. Retrospective series examining PI3K inhibitors following BTKi exposure have shown lower ORR (28-46%).^43,44 Second line treatment with venetoclax rather than PI3Ki is better supported by the sum of these data.

Following BTKi discontinuation for toxicity, consideration of an alternate B cell receptor inhibitor is additionally an option. Acalabrutinib, zanubrutinib, and umbralisib had been specifically studied in patients with prior intolerance to ibrutinib. Two studies have examined acalabrutinib in patients with prior ibrutinib intolerance. In a study of 60 patients who had discontinued ibrutinib for persistent grade ¾ adverse events or grade 2 AEs that persisted despite dose modification or interruption, ORR was 73% and 24-month PFS was estimated to be 72%. Seventeen percent of this cohort had discontinued acalabrutinib for AEs with a median follow-up of 35 months.⁴⁷ In 33 patients who discontinued ibrutinib for toxicity, acalabrutinib demonstrated an ORR of 76% and 1-year PFS of 83%. Of the toxicities that led to prior ibrutinib discontinuation, 76% did not recur and 13% recurred with lower grade than had been observed with ibrutinib.⁴⁸ Zanubrutinib was examined in patients with prior ibrutinib or acalabrutinib intolerance. In this population, grade ≥3 adverse events occurred in 14% with dose interruptions occurring in 14% and dose reductions in 5% with no discontinuations for adverse events.⁴⁹ Of note, zanubrutinib is not approved for treatment of CLL. Umbralisib, a PI3Ki not currently approved for treatment of CLL, was studied in 44 patients with BTKi intolerance and was associated with a median PFS of 23.5 months.³⁹ Thus, for some patients who discontinued BTKi for toxicity, consideration of an alternate B cell receptor inhibitor may be appropriate. Of course, this decision should be based on severity of initial toxicity and risk of recurrence with alternate available B cell receptors. For patients who have discontinued BTKis for toxicity, treatment with venetoclax is another data-driven choice as outlined previously. Notably, following BTKi discontinuation for toxicity, patients may experience a prolonged progression free period in which therapy is not required.

After venetoclax-based therapy, decision making for the next line of therapy again depends on the clinical setting. For patients who have completed fixed duration venetoclax-based therapy and subsequent progress, consideration of venetoclax retreatment vs. BTKi based therapy are both supported by limited data.

Regarding venetoclax re-treatment, 32 patients treated with venetoclax/rituximab in the MURANO study have been subsequently retreated with a venetoclax-based regimen with 5 years of follow-up. The ORR for venetoclax re-treatment was 72% (13 of 18 evaluable patients).⁵⁰ A retrospective series of venetoclax treated patients who subsequently received venetoclax re-treatment in a later line of therapy also demonstrated an ORR of 72% (13 of 18 evaluable patients) with 12-month PFS of 69%. Notably, in this study, 60% of patients had BTKi exposure prior to the initial venetoclax-based regimen.⁵¹ Use of BTKi following venetoclax has been examined retrospectively, though no prospective studies have yet examined this sequence. In a series of patients treated with venetoclax with discontinuation for progression or toxicity, predominately in the relapsed/refractory setting (96%), who subsequently required other therapies, 44 BTKi-naïve patients were treated with BTKi. These patients experienced an ORR of 84% with median PFS of 32 months (median follow up of 10.5 months).⁵² A smaller series of 23 patients resistant to venetoclax and subsequently treated with BTKi demonstrated an ORR of 81% with a median PFS of 34 months.⁵³ A retrospective examination of 17 patients treated with PI3Ki following venetoclax suggested that this approach is associated with lower response rates (ORR 47%) and less durable responses with a median PFS of 4 months.⁵²

As discussed previously, targeted agent combination approaches are being examined in the front-line setting. These combinations will present new unanswered questions in the relapsed/refractory setting, as the optimal approach for treatment in the relapsed setting following combination therapy with BTKi and venetoclax will need to be explored.

There are no prospective data examining chemoimmunotherapy-based treatment in the relapsed/refractory setting for patients previously treated with targeted agents. For almost all patients in the current treatment landscape, chemoimmunotherapy does not play a significant role in the R/R setting. For patients requiring 3^rd and subsequent lines of therapy after BTKi and venetoclax-based therapy (in either sequence), clinical trial enrollment should be considered.

4. Conclusion

While CLL remains an incurable B cell malignancy, the therapeutic options available in the modern era allow for long-term disease control for many patients without reliance on chemoimmunotherapy. Herein, we have reviewed the data supporting use of novel agents in the front-line and R/R settings. The optimal sequencing strategy has not been established, though data support several reasonable treatment sequencing strategies. The treatment pathway for patients at the current time is highly dependent on shared decision-making, though future prospective data will help shape treatment approach for patients with CLL with the goal of optimizing long-term disease control.

Table 1.

Front-line studies comparing novel agents to chemoimmunotherapy regimens

Drug	Control Arm	Study Population	Efficacy Outcomes	Selected toxicities with novel agent
Ibrutinib RESONATE-2 study54	Chlorambucil	Age ≥ 65 years Excluded pts with del17p	5-year PFS: ibrutinib 70% vs chlorambucil 12% (HR 0.146) 5-year OS: ibrutinib 83% vs chlorambucil 68% (HR 0.450)	Ibrutinib (grade ≥3 unless specified): Neutropenia (13%) Pneumonia (12%) Hypertension (8%) Anemia (7%) Hyponatremia (6%) Any grade hypertension (26%) Any grade atrial fibrillation (16%) Any major hemorrhage (11%)
Ibrutinib and rituximab E1912 Study4	Fludarabine cyclophosphamide and rituximab (FCR)	Age ≤ 70 years Excluded pts with del17p	3-year PFS: ibrutinib + rituximab 89.4% vs FCR 72.9% (HR 0.35) 3-year OS: ibrutinib + rituximab 98.9% vs FCR 91.5% (HR 0.17)	Ibrutinib + rituximab (grade ≥3 unless specified) Neutropenia (25.6%) Hypertension (18.8%) Infection (9.1%) Anemia (4.8%) Arthralgia (4.8%) Diarrhea (4.3%) Atrial fibrillation (3.2%) Rash (3.1%) Hemorrhage (1.1%) Any grade atrial fibrillation (7.4%)
Ibrutinib Ibrutinib + rituximab ALLIANCE study6	Bendamustine and rituximab	Age ≥ 65	2-year PFS: 87% ibrutinib (HR 0.39 compared to CIT) vs 88% ibrutinib + rituximab (HR 0.39 compared to CIT) vs 74% bendamustine + rituximab; no significant difference between ibrutinib and ibrutinib + rituximab OS: No significant difference between groups at a median follow-up of 38 months	Ibrutinib (grade ≥3) Any hematologic 41% Neutropenia 15% Infection 20% Atrial fibrillation 9% Hypertension 29% Bleeding 2% Ibrutinib + Rituximab (grade ≥3) Any hematologic 39% Neutropenia 21% Infection 20% Atrial fibrillation 6% Hypertension 34% Bleeding 4%
Ibrutinib and Obinutuzumab ILLUMINATE study7	Chlorambucil and Obinutuzumab	Age ≥ 65 years or < 65 years with co-existing conditions	Median PFS: ibrutinib + obinutuzumab not reached vs chlorambucil + obinutuzumab 19 months (HR 0.23, median follow-up 31.3 months) Median overall survival: not reached in either group	Ibrutinib + Obinutuzumab (grade ≥3 unless specified) Neutropenia 37%) Pneumonia 7% Hypertension 4% Atrial fibrillation 5% Hypertension any grade 17% Atrial fibrillation any grade 12%
Acalabrutinib Acalabrutinib and Obinutuzumab ELEVATE-TN Study4,8	Chlorambucil and Obinutuzumab	Age ≥ 65 years old or Age 18-65 years and creatinine clearance 30-69 mL/min or Cumulative Illness Rating Scale for Geriatrics score greater than 6	Median PFS: acalabrutinib + obinutuzumab not reached (HR 0.1 compared with CIT) vs acalabrutinib not reached (HR 0.2 compared with CIT) vs 22.6 months with chlorambucil with obinutuzumab (median follow-up 28.3 months)	Acalabrutinib (grade ≥3 unless specified) Headache any grade 36.9% Neutropenia 9.5% Diarrhea 0.6% Hypertension 3% Upper respiratory tract infection any grade 18.4% Bleeding 2% Atrial fibrillation any grade 4% Acalabrutinib + Obinutuzumab (grade ≥3 unless specified) Headache any grade 39.9% Neutropenia 29.8% Diarrhea 4.5% Upper respiratory tract infection any grade 21.3% Hypertension 2% Bleeding 2% Atrial fibrillation any grade 3%
Venetoclax and Obinutuzumab (VO) CLL-14 Study11	Chlorambucil and Obinutuzumab	Age 18 years or older, and creatinine clearance 30-69 mL/min or Cumulative Illness Rating Scale for Geriatrics score greater than 6	Median PFS VO not reached vs 35.6 months chlorambucil + obinutuzumab (median follow-up 39.6 months)	VO (grade ≥3 unless specified) Neutropenia (53%) Infusion related reaction (9%) Infusion related reaction any grade (36%) Pneumonia (5%) Febrile neutropenia (5%) Diarrhea (4%)
Ibrutinib and venetoclax (I+V) GLOW Study19	Chlorambucil and Obinutuzumab	Age ≥ 65 years old or Age 18-65 years and creatinine clearance <70 mL/min or Cumulative Illness Rating Scale score greater than 6	Median PFS I+V not reached vs chlorambucil + obinutuzumab 21.0 months (HR 0.216, median follow-up 27.7 months)	I+V (grade ≥3) Neutropenia 34.9% Diarrhea 10.4% Hypertension 7.5%
Umbralisib + Ublituximab (U2) UNITY38	Chlorambucil + Obinutuzumab (CO)	Included treatment naïve and relapsed/refractory CLL patients	Median PFS: 31.9 months (U2) vs 17.9 months (CO, HR 0.482, treatment naïve subgroup)	U2 (grade ≥3) Neutropenia (30.6%) Thrombocytopenia (3.4%) Diarrhea (12.1%) Elevated AST/ALT (8.3%) Colitis (3.4%) Pneumonitis (2.9%)

Table 2.

Randomized studies of novel agents in patients with relapsed/refractory CLL

Drug	Control Arm	Study Population	Efficacy Outcomes	Selected Key AEs for Novel Agents
Ibrutinib RESONATE study23	Ofatumumab	Relapsed/refractory CLL Purine analogue ineligible patients: short PFS after chemoimmunotherapy or co-existing illnesses, age ≥70 years or del17p	Median PFS: 44.1 months (ibrutinib) vs 8.1 months (ofatumumab, HR 0.148, median follow-up 65.3 months) Median OS: 67.7 months (ibrutinib) vs 65.1 months (ofatumumab)	Ibrutinib (grade ≥3): Neutropenia (25%) Pneumonia (21%) Thrombocytopenia (10%) Major hemorrhage (10%) Hypertension (9%) Anemia (9%) UTI (7%) Diarrhea (7%) Atrial fibrillation (6%)
Acalabrutinib ASCEND study24	Idelalisib + rituximab or bendmustine + rituximab	Relapsed/refractory CLL Age ≥ 18 years	Estimated PFS: 83% (acalabrutinib) versus 56% (investigator’s choice, median follow-up 16.1 months)	Acalabrutinib (grade ≥3): Neutropenia (16%) Anemia (12%) Pneumonia (5%) Idelalisib + rituximab (grade ≥3): Neutropenia (40%) Diarrhea (24%) Pneumonia (9%) Increased ALT (9%) Thrombocytopenia (8%) Neutropenia (8%) Anemia (75) Pyrexia (7%) Increased AST (5%) Transaminases increased (5%)
Acalabrutinib ELEVATE-RR25	Ibrutinib	Relapsed/refractory CLL Age ≥ 18 years Either del17p or del11q	Median PFS 38.4 months (acalabrutinib) vs 38.4 months (HR 1.0, ibrutinib, median follow-up 40.9 months)	Acalabrutinib (grade ≥3) Neutropenia (19.5%) Anemia (11.7%) Pneumonia (10.5%) Thrombocytopenia (9.8%) Atrial fibrillation (4.5%) Hypertension (4.1%) Fatigue (3.4%) Pyrexia (3.0%) Any grade atrial fibrillation (9.0%) Any grade headache (92.0%) Any grade hypertension (8.6%) Any grade diarrhea (34.6%) Ibrutinib (grade ≥3 unless specified) Neutropenia (22.8%) Anemia (12.9%) Pneumonia (8.7%) Hypertension (8.7%) Thrombocytopenia (6.8%) Diarrhea (4.9%) Atrial fibrillation (3.4%) Any grade atrial fibrillation (15.6%) Any grade hypertension (22.8%) Any grade diarrhea (46.0%)
Idelalisib + Rituximab55	Placebo + Rituximab	Relapsed/refractory CLL Patients unable to receive “cytotoxic agents” (Cumulative Illness Rating Score of 6, Creatinine Clearance <60 mL/minute), severe neutropenia or thrombocytopenia from prior therapies	Median OS 40.6 months (idelalisib + rituximab) versus 34.6 months (rituximab + placebo)	Idelalisib arm (grade ≥3): Neutropenia (41.8%) Diarrhea (9.1%) Colitis (4.5%) Pneumonitis (3.6%) Rash (3.6%) Pneumocystis jirovecii pneumonia (3.6%) Febrile neutropenia (4.5%) ALT increased (9.1%) AST increased (5.5%)
Duvelisib DUO31	Ofatumumab	Relapsed/refractory CLL	Median PFS 13.3 months (duvelisib) vs 9.9 months (oftatumumab, HR 0.52)	Duvelisib (grade ≥3): Neutropenia (30%) Diarrhea (15%) Pneumonia (14%) Anemia (13%) Colitis (12%) Thrombocytopenia (8%)
Umbralisib + Ublituximab (U2) UNITY38	Chlorambucil + Obinutuzumab (CO)	Included treatment naïve and relapsed/refractory CLL patients	Median PFS 19.5 months (U2) vs 12.9 months (CO, relapsed/refractory cohort, HR 0.601)	U2 (grade ≥3, combined cohort) Neutropenia (30.6%) Thrombocytopenia (3.4%) Diarrhea (12.1%) Elevated AST/ALT (8.3%) Colitis (3.4%) Pneumonitis (2.9%)

Key Points.

• Robust data support the efficacy of targeted agents for treatment of CLL in the front line and relapsed/refractory settings

• Chemoimmunotherapy plays an increasingly limited role in the management of CLL as targeted agents have demonstrated superiority in many settings