First-Line Therapy for Chronic Lymphocytic Leukemia: Bruton Tyrosine Kinase or BCL2 or Both?

A revolution in the care of untreated CLL

The firstline treatment of chronic lymphocytic leukemia (CLL) has evolved significantly in the last 5 years with the introduction of oral novel targeted therapies ibrutinib and acalabrutinib targeting Bruton’s tyrosine kinase (BTK) and venetoclax targeting BCL2.^1,2 This has resulted in a paradigm shift away from the reliance on chemoimmunotherapy (CIT) for CLL,^3,4 supported by recent randomized studies demonstrating the superiority of individual novel agents over CIT for different patient populations.^5–10

Clinicians now have access to several non-chemotherapy oral targeted therapy options for treatment of patients with previously untreated CLL across genetic disease risk categories. The regimen of fludarabine, cyclophosphamide, and rituximab (FCR) may still offer fit patients with mutated IGHV the chance for durable long term remissions^11–13 but at the expense of increased incidence of therapy-related myelodysplastic syndrome and acute myeloid leukemia.¹⁴ Other commonly used CIT regimens include bendamustine and rituximab (BR)⁴ and chlorambucil and obinutuzumab¹⁵; the use of these regimens has declined as well in the current targeted therapy era.

Ibrutinib, acalabrutinib, and venetoclax have not been yet compared head-to-head in randomized clinical trials, though planned studies are underway. Each therapy has their advantages and drawbacks when it comes to treatment response, toxicities, and logistics of treatment administration. Questions remain regarding the optimal sequence of individual novel agents. Several ongoing studies are currently investigating combination of novel therapies, either as doublet or triplet combinations. This review will summarize the pivotal firstline clinical trials, compare the features that differentiate the novel agents, and discuss results from trials combining BTK and BCL2 inhibitors.

Bruton’s tyrosine kinase inhibitors

Ibrutinib

BTK is a crucial downstream component of the B-cell receptor (BCR) signaling pathway which is crucial for the survival and proliferation of CLL cells.¹⁶ Ibrutinib is a first-in-class irreversible BTK inhibitor that binds cysteine 481 of the kinase domain and led to high overall response rates (ORR) as a single agent in relapsed/refractory CLL.¹⁷ The pivotal RESONATE-2 study, a phase 3 open-label, international trial comparing single-agent ibrutinib to chlorambucil, was the first randomized study to investigate ibrutinib in the firstline setting.⁵ Patients aged 65 years or older without deletion 17p were randomized to receive ibrutinib until disease progression or intolerance or 12 cycles of chlorambucil. The study demonstrated a significant improvement in both progression free survival (PFS) and overall survival (OS) for ibrutinib over chlorambucil. The ORR was 86% with ibrutinib, though the large majority of responses (77%) were partial responses (PR).⁵ After a median follow-up of 5 years, patients treated with ibrutinib continue to demonstrate encouraging outcomes, with a 5-year PFS of 70%, 5-year OS of 83%, and cumulative complete response (CR) rate improving to 30%. Diarrhea, fatigue, and arthralgias were common, and adverse events of special interest included hypertension (26%), atrial fibrillation (16%), and major hemorrhage (11%).¹⁸

Additional phase 3 studies confirmed the superiority of continuous ibrutinib therapy over CIT in untreated CLL. The Alliance A041202 study randomized patients aged 65 years or older to ibrutinib alone, ibrutinib with 6 cycles of rituximab, or 6 cycles of BR. PFS was significantly longer for the ibrutinib-containing arms and was 87–88% at 2 years compared to 74% for BR. There was no difference in PFS between ibrutinib and ibrutinib-rituximab (Ibr-R). OS was similar between the 3 arms. Hematologic toxicities were more common with BR.⁶ The iLLUMINATE study randomized patients older than 65 or younger than 65 with coexisting conditions to ibrutinib and 6 cycles of obinutuzumab or 6 cycles of chlorambucil and obinutuzumab (Chl-G). PFS was significantly longer for the ibrutinib-obinutuzumab (Ibr-G) arm (79% at 30 months).⁹ Lastly, the ECOG E1912 study randomized patients younger than 70 years without deletion 17p to Ibr-R or 6 cycles of FCR.^8,19 PFS was significantly longer with Ibr-R compared to FCR with a hazard ratio (HR) of 0.35 (95% CI 0.22–0.56) and 3-year PFS of 89% versus 71%, respectively (p < 0.0001). Notably, in a subgroup analysis, the PFS improvement was restricted to IGHV unmutated patients. OS was also significantly longer with Ibr-R and 3-year OS was 99% versus 93% (p = 0.009). The FCR arm experienced higher rates of neutropenia, neutropenic fevers, and infectious complications.

Ibrutinib-based therapy has consistently demonstrated encouraging outcomes in high-risk subgroups of CLL patients, such as those with unmutated IGHV, deletion 17p, or mutated TP53. In a report from NIH, 34 previously untreated patients with TP53 aberration were treated with ibrutinib and the 5-year PFS was 70%.²⁰ In a report from MDACC, 27 previously untreated with CLL and TP53 aberration received ibrutinib (12/27 patients also concomitantly received rituximab) and 5-year PFS was 66%.²¹ In a pooled analysis from 4 ibrutinib-based clinical trials, 89 previously untreated patients with TP53 aberration received ibrutinib (49% received concomitant anti-CD20 monoclonal antibody) and 4-year PFS was 79%.²²

Anti-CD20 therapy with rituximab or obinutuzumab did not demonstrate additive benefit when combined with ibrutinib, suggesting that administering ibrutinib as a single agent is sufficient for most patients.^6,23 Pre-clinical studies found that ibrutinib inhibited antibody-dependent cellular cytotoxicity induced by rituximab and obinutuzumab, potentially because of off-target binding of interleukin-2-inducible T cell kinase (ITK).^24–26 Moreover, off-target kinase inhibition likely drives the unique toxicities associated with ibrutinib therapy, including atrial fibrillation,²⁷ hypertension,²⁸ and bleeding.²⁹ A significant proportion of real-world patients treated with ibrutinib discontinue therapy due to intolerance.³⁰ With long-term follow up ibrutinib demonstrates excellent PFS in untreated CLL patients of all ages but with notable cardiovascular toxicities, low rates of CR and undetectable MRD (uMRD), and the need for indefinite therapy.

Acalabrutinib

Acalabrutinib is a second generation selective covalent BTK inhibitor designed to have fewer off-target effects on other kinases such as ITK, epidermal growth factor receptor, and Tec compared to ibrutinib.^31,32 Acalabrutinib monotherapy demonstrated high response rates in relapsed CLL.³³ The ELEVATE-TN study was a phase 3 open-label clinical trial that randomized untreated patients older than 65 years or younger patients with low creatinine clearance or significant comorbidities to acalabrutinib, acalabrutinib with 6 cycles of obinutuzumab, or 6 cycles of chlorambucil and obinutuzumab.¹⁰ PFS was significantly longer for both acalabrutinib-obinutuzumab (Acal-G) and acalabrutinib monotherapy arms versus Chl-G with 2-year PFS equaling 93%, 87%, and 47%, respectively. The HR for PFS between Acal-G and acalabrutinib was 0.49 (95% CI 0.26–0.95) in a post-hoc analysis. The ORR was 94% for Acal-G (80% PR) and 86% for acalabrutinib (84% PR). Atrial fibrillation, grade 3 or higher bleeding, and hypertension occurred in 3–4%, 2%, and 5–7% of acalabrutinib-treated patients. Notably, 37–40% of acalabrutinib-treated patients experienced headache, a signal not as prevalent on ibrutinib studies.

Overall, acalabrutinib therapy appears to result in similar efficacy outcomes to ibrutinib, with lower rates of cardiovascular toxicity.³⁴ The question of benefit of addition of anti-CD20 monoclonal antibody to acalabrutinib remains unanswered at this time with preclinical studies reporting that acalabrutinib may not affect ADCC as much as ibrutinib.^26,35 In the ELEVATE-TN trial, there was a small PFS improvement with the addition of obinutuzumab to acalabrutinib (2-year PFS 93% vs. 87% for acalabrutinib monotherapy) with more neutropenia (grade 3–4 neutropenia, 30% vs. 10%) and infusion reactions in the obinutuzumab arm. Longer follow-up of this trial is important to see if the PFS difference will improve over time.

Zanubrutinib

Zanubrutinib is a next generation BTK inhibitor with higher selectivity for BTK that demonstrated significantly lower rates of atrial fibrillation and bleeding but higher rates of neutropenia compared to ibrutinib in the phase 3 ASPEN study for Waldenström macroglobulinemia.³⁶ In patients with CLL, zanubrutinib monotherapy led to a 2-year PFS rate of 95% for treatment naïve CLL patients³⁷ and 18-month PFS rate of 91% for treatment naïve CLL patients with deletion 17p.³⁸ Randomized registration studies are ongoing for zanubrutinib in CLL.

Venetoclax

BCL2 is an antiapoptotic protein located on the outer mitochondrial membrane whose overexpression is critical for the survival of CLL cells. Venetoclax is a selective BH3-mimetic inhibitor of BCL2 that demonstrated high overall response rates when administered as monotherapy to patients with previously treated CLL in a phase 1 study.³⁹ The CLL14 study was a phase 3 study that randomized untreated patients with coexisting conditions to 6 cycles of obinutuzumab with either 12 cycles of venetoclax or 12 cycles of chlorambucil. PFS was significantly longer on the venetoclax-obinutuzumab (Ven-G) arm and was 88% at 2 years⁷ and 74% at 4 years.⁴⁰ The ORR was 85% (CR 50%), and 57% and 76% of patients achieved uMRD in the bone marrow (BM) and peripheral blood (PB), respectively, 3 months after completion of venetoclax. Patients who achieved uMRD experienced significantly longer PFS and OS than those with detectable MRD. Notably, 3-year PFS for patients with deletion 17p or TP53 mutation who received Ven-G was 60%.⁴¹ A total of 68% of these patients achieved uMRD at end of treatment implying these patients may not enjoy long term remissions after stopping therapy even after deep initial responses.

Neutropenia (58%), infusion reactions (45%), diarrhea (28%), and thrombocytopenia (23%) were common on the venetoclax arm. Because of cases of tumor lysis syndrome (TLS), venetoclax administration now includes a weekly dose ramp-up, starting at 20mg daily to a target dose of 400mg daily over 5 weeks. Prior to venetoclax initiation, patients should be categorized into different TLS risk groups based on absolute lymphocyte count and lymph node size.⁴²

Venetoclax and obinutuzumab is a time-limited therapy for about 1-year duration that leads to high rates of CR and uMRD but its administration involves both the need for anti-CD20 antibody infusions and monitoring for TLS. Furthermore, patients with TP53 alterations appear to have less durable long-term remissions. The role of extended or continuous venetoclax therapy in these highest-risk patients or those with persistent MRD remains undetermined at this time. The aforementioned randomized studies are summarized in Table 1.

Table 1.

Summary of randomized clinical trials investigating novel agents in untreated CLL

Trial	Population	Comparator arm (N)	Experimental arm (N)	ORR (CR), %	Best uMRD*	PFS	PFS (TP53 altered) †	OS
RESONATE-2 5,18	≥ 65 without del 17p	Chl (133)	Ibr (136)	86 (4)	N/A	5y 70%	5y 56%	5y 83%
A041202 6	≥ 65	BR (183)	Ibr (182) Ibr-R (182)	93 (7) 94 (12)	1% 4%	2y 87% 2y 88%	2y 75% 2y 73%	2y 90% 2y 94%
iLLUMINATE 9	≥ 65 or < 65 and CIRS > 6 or CKD	Chl-G (116)	Ibr-G (113)	88 (19)	35%	30m 79%	N/A	30m 86%
E1912 8,19	< 70 without del 17p	FCR (175)	Ibr-R (354)	96 (17)	8%	3y 89%	N/A	3y 99%
ELEVATE-TN 10	≥ 65 or < 65 and CIRS > 6 or CKD	Chl-G (177)	Acal (179) Acal-G (179)	86 (13) 94 (1)	7%‡ 56%‡	2y 87% 2y 93%	N/A 2y 88/95%¥	2y 95% 2y 95%
CLL14 7,41	CIRS > 6 and/or CKD	Chl-G (216)	Ven-G (216)	85 (50)	76%	4y 74%40	3y 60%	3y 88%

^*MRD cutoff of < 10⁻⁴ in bone marrow and/or peripheral blood

^†Including TP53 mutation and deletion 17p

^‡Only assessed in patients with CR/CRi

^¥2 year PFS was 88% for patients with deletion 17p and 95% for patients with mutated TP53

ORR, overall response rate; PFS, progression free survival; OS, overall survival; del, deletion; BR, bendamustine-rituximab; CIRS, cumulative illness rating scale; CKD, chronic kidney disease; G, obinutuzumab; FCR, fludarabine-cyclophosphamide-rituximab

Comparing novel agents

Ibrutinib, acalabrutinib, and venetoclax have not been compared directly in the firstline setting in randomized studies. These agents are also all approved for use in the relapsed or refractory setting based on their respective phase 3 clinical trials,^43–45 and the optimal sequencing of these drugs is unknown. Multiple studies have demonstrated the efficacy of venetoclax with high ORR (65%–79%) and durable PFS when used as the next line of therapy after BTK inhibitor failure.^46,47 The converse strategy of BTK inhibitor therapy after venetoclax failure is also quite effective (ORR 84%–91%).^48,49 Treatment with acalabrutinib monotherapy after ibrutinib discontinuation due to intolerance led to an ORR of 76%, 2-year PFS of 75%, and recurrence of ibrutinib-related adverse events in only 28% of patients.⁵⁰ Current data suggests that any novel therapy not used in the firstline setting can be considered in the relapsed setting. Agent-specific pros and cons discussed above are summarized in Table 2 to assist readers in choosing the optimal firstline therapy.

Table 2.

Summary of pros and cons of ibrutinib, acalabrutinib, and venetoclax in the firstline setting

	Ibrutinib	Acalabrutinib	Venetoclax
Pro	• Longest follow-up • Durable remissions in TP53-altered disease • Only agent compared to FCR	• Fewer off-target toxicities • Can add obinutuzumab for possible PFS benefit	• Time-limited therapy • Higher rates of CR and uMRD • No cardiovascular toxicities or bleeding risk
Con	• Indefinite therapy • Low rates of CR and uMRD • Cardiovascular toxicities and bleeding	• Shorter follow-up • Twice-daily dosing • Indefinite therapy • Low rates of CR and uMRD	• TLS monitoring • Must be coupled with IV obinutuzumab • Shorter remissions in TP53-altered disease • 50% G3–4 neutropenia

FCR, fludarabine/cyclophosphamide/rituximab; PFS, progression free survival; CR, complete response; MRD, minimal residual disease; TLS, tumor lysis syndrome; IV, intravenous

Combination novel therapy

Rationale

Combination novel therapy could circumvent some of the disadvantages of single-agent approaches, particularly given the largely nonoverlapping toxicities of BTK inhibitors and venetoclax. Pre-clinical models have demonstrated that BTK inhibitors mobilize CLL cells from nodal compartments but led to a lower degree of apoptosis on their own; they did increase dependence of mitochondria on BCL2 in CLL cells, priming them for efficient cell death with the addition of venetoclax.^51,52 Clinically venetoclax can clear residual disease from the PB and BM compartments often left by BTK inhibitor monotherapy. This potential synergy has led to multiple clinical trials combining BTK inhibitors with venetoclax for patients with CLL.

MRD as an endpoint

Though achieving uMRD is rare with BTK inhibitor monotherapy and does not appear to be essential for durable remissions with indefinite BTK inhibitor therapy, the CLL14⁴¹ and MURANO trials⁵³ clearly demonstrated the importance of uMRD as an endpoint predictive of PFS after time-limited venetoclax therapy. There was a subset of patients treated with Ven-G from CLL14 who achieved uMRD and had no clonal growth in the subsequent follow up period, suggesting very durable remissions.⁴⁰ In the MURANO trial in relapsed CLL, the median time from uMRD at end of treatment to detectable MRD was 19 months, and median time from detectable MRD to clinical progression was an additional 25 months,⁵⁴ meaning that patients enjoyed a long treatment-free interval before needing to consider next line of therapy. Thus, MRD is an important endpoint to consider for the following trials to be discussed.

Studies combining novel agents

Jain et al. combined ibrutinib and venetoclax in a phase 2 study of patients with high-risk CLL harboring deletion 17p, deletion 11q, TP53 mutation or unmutated IGHV.⁵⁵ Patients 65 year or older were eligible irrespective of high-risk features, but this constituted a minority (8%) of the patients. Patients were initiated on ibrutinib monotherapy for 3 months followed by the combination of ibrutinib and venetoclax for an additional 24 months. Grade 3–4 neutropenia occurred in 48% of patients; 24% of patients received granulocyte colony-stimulating factor, and 44% and 24% of patients had their ibrutinib or venetoclax dose reduced, respectively. Any grade bruising (60%), arthralgias (48%), and diarrhea (41%) were also common. Extended follow-up has revealed deepening of responses by MRD evaluation over time, with 56% and 66% of all 80 patients on an intent-to-treat analysis achieving uMRD in the BM after 12 and 24 months of ibrutinib-venetoclax, respectively.⁵⁶ Overall, 75% of the patients achieved BM uMRD as a best response. Among the patients who were MRD positive after cycle 12, 50% achieved BM uMRD after an additional 12 cycles of therapy. PFS and OS at 2 years were 96% and 98%, respectively.

The phase 2 international CAPTIVATE study treated patients younger than 70 with untreated CLL with a 3-month lead-in of ibrutinib monotherapy followed by 12 months of ibrutinib and venetoclax.⁵⁷ A total of 164 patients were treated. The best uMRD rate after end of combination therapy was 75% in PB and 68% in BM. Patients with confirmed uMRD in both PB and BM after the end of combination therapy for at least 3 months in a row (58%) were randomized to continue ibrutinib alone or placebo. In this group, subsequent 1-year disease free survival was similar between the ibrutinib and placebo arms (100% versus 95%). Patients who did not have stringent confirmed uMRD were instead randomized to continue ibrutinib or ibrutinib and venetoclax, with additional combination therapy increasing uMRD rates over time. Across all randomized arms, the 30-month PFS was >95%, and common grade 3–4 adverse events included neutropenia (36%) and hypertension (10%).

Other fixed-duration combination studies in the firstline setting investigated triplet therapy with the addition of obinutuzumab. Rogers et al. presented on the administration of obinutuzumab, ibrutinib, and venetoclax to 25 patients with treatment-naïve CLL.^58,59 A total of 56% patients by intent-to-treat analysis achieved uMRD in both PB and BM at the end of 14 cycles of combination therapy. PFS and OS at 3 years were 95%, and grade 3–4 neutropenia (56%), thrombocytopenia (40%), and hypertension (48%) were notable adverse events. The CLL2-GIVe study administered obinutuzumab, ibrutinib, and venetoclax to 41 previously untreated patients with TP53 alteration.⁶⁰ After cycle 15, uMRD in PB and BM was noted in 80% and 68% of patients, respectively. Davids et al. presented on the triplet of acalabrutinib, venetoclax, and obinutuzumab in a population with 39% TP53 alteration, achieving an uMRD rate of 84% in PB and 78% in BM, with grade 3–4 neutropenia (34%), thrombocytopenia (23%), and low grade headache, fatigue, bruising, and nausea being common adverse events.⁶¹ Lastly, Soumerai et al. presented on the triplet of zanubrutinib, obinutuzumab, and venetoclax, achieving a uMRD rate of 92% in PB and 89% in BM in evaluable patients as a best response. Grade 3–4 neutropenia developed in 15% of patients.⁶²

The phase 2 time-limited clinical trials mentioned above led to impressive rates of uMRD and the ability to stop all therapy including the BTK inhibitor. The best time-limited regimen for firstline CLL remains to be determined. The PFS rates from the two studies of ibrutinib-venetoclax^56,57 compare favorably to Ven-G at 2.5–3 years; however, longer follow-up is needed to assess if a BTK inhibitor is a better partner of venetoclax as opposed to obinutuzumab. The CLL17 trial will help further assess this very question in a randomized phase 3 trial. The data with triplet combinations (BTK inhibitor + venetoclax + obinutuzumab) also report high rates of uMRD; however, the follow-up of these trials remain short. With the data available so far, the additive effect obinutuzumab to the doublet oral therapy of BTK inhibitor + venetoclax remains unclear. Ongoing randomized studies will help clarify this question. The aforementioned studies are summarized in Table 3. Ongoing firstline phase 3 randomized studies comparing combination novel therapy with single novel therapy and/or CIT are summarized in Table 4.

Table 3.

Notable firstline phase 2 studies combining Bruton’s tyrosine kinase inhibitors and venetoclax

Identifier and author	Regimen, N	TP53 alteration*, %	Best uMRD†, %	Min duration BTKi, mo	Min duration venetoclax, mo	Grade 3–4 neutropenia, %
NCT02756897 Jain55,56	Ven-Ibr (80)	18/14‡	75 (BM)	27	24	48
CAPTIVATE NCT02910583 Wierda57	Ven-Ibr (164)	20	75 (PB), 68 (BM)	15	12	36
NCT02427451 Rogers58,59	Ven-Ibr-G (25)	12	56 (both)	13	12	56
CLL2-GIVe NCT02758665 Huber60	Ven-Ibr-G (41)	100	81 (PB)	15	11.25	44
NCT03580928 Davids61	Ven-Acal-G (44)	39	84 (PB), 78 (BM)	15	12	34
NCT03824483 Soumerai62	Ven-Zan-G (39)	15	87 (PB), 80 (BM)	8	6	15

^*Including TP53 mutation and deletion 17p

^†MRD cutoff of < 10⁻⁴ in bone marrow and/or peripheral blood. All uMRD rates presented are by intent-to-treat

^‡Del 17p 18%, TP53-mutated 14%

uMRD, undetectable MRD; min, minimum; BTKi, Bruton’s tyrosine kinase inhibitor; mo, months; ven, venetoclax; ibr, ibrutinib; BM, bone marrow; PB, peripheral blood; G, obinutuzumab; both, both bone marrow and peripheral blood; acal, acalabrutinib; zan, zanubrutinib

Table 4.

Active firstline phase 3 studies featuring combination novel therapy

Trial	Identifier	Estimated enrollment	Combination arm	Single novel agent arm	CIT arm
UK FLAIR	ISRCTN01844152	1576	Ven-Ibr	Ibr, Ibr-R	FCR
GAIA/CLL13	NCT02950051	920	Ven-Ibr-G	Ven-G, Ven-R	FCR/BR
ACE-CL-311	NCT03836261	780	Ven-Acal +/− G	-	FCR
CLLGLOW	NCT03462719	211	Ven-Ibr	-	Chl-G
EA9161	NCT03701282	1000	Ven-Ibr-G	Ibr-G	-
AO41702	NCT03737981	454	Ven-Ibr-G	Ibr-G	-
CLL17	NCT04608318	897	Ven-Ibr	Ibr, Ven-G	-

CIT, chemoimmunotherapy; ven, venetoclax; Ibr, ibrutinib; G, obinutuzumab; R, rituximab; FCR, fludarabine-cyclophosphamide-rituximab; BR, bendamustine-rituximab, Acal, acalabrutinib; Chl, chlorambucil

Discussion

The approvals of ibrutinib, venetoclax, and acalabrutinib in the last 5 years have revolutionized the management of treatment naïve CLL patients. Targeting BTK or BCL2 in the firstline setting have led to improved survival outcomes over CIT in several randomized trials. Cross-trial comparisons are difficult and fraught with confounding biases, though there is some suggestion of worse outcomes in TP53-altered disease with time-limited venetoclax-obinutuzumab therapy. Nonetheless, without head-to-head comparisons no novel agent is clearly the best choice in the firstline setting with regards to PFS and OS. Clinicians must take into account other factors such as toxicity profile, frailty, medical comorbidities, duration of therapy, and logistics of administration when counseling patients and engaging in shared decision making. For a patient who is reluctant to come in for frequent visits and intravenous infusions or with deletion 17p or a TP53 mutation, treatment with a BTK inhibitor is the preferred approach. For a patient with cardiovascular comorbidities such as atrial fibrillation or for patients on long-term anticoagulation, therapy with venetoclax with obinutuzumab is preferred.

Ongoing and planned studies investigating combination novel time-limited therapy are eagerly anticipated as such a strategy could result in deeper remissions, and longer time off therapy. Whether this approach would be superior to the current standard practice of sequential novel therapy with regards to OS remains to be seen. Regardless of how novel agents will be utilized together in the future, the advent of these drugs has clearly already changed lives of CLL patients for the better, and their outcomes can only improve from here.

Key points.

• Oral novel targeted therapies have supplanted chemoimmunotherapy for firstline treatment of CLL for most patients

• Both BTK and BCL2 inhibitors have their unique advantages and drawbacks as therapy choice in the firstline setting

• Ongoing clinical trials exploring combination targeted strategies and randomized trials comparing novel therapies will help further define the ideal firstline therapy for CLL

Synopsis.

Novel therapies have largely replaced chemoimmunotherapy as optimal firstline treatment of chronic lymphocytic leukemia (CLL). Approved novel therapies for CLL in the firstline setting include Bruton’s tyrosine kinase inhibitors ibrutinib and acalabrutinib, and the BCL2 inhibitor venetoclax. These novel agents each have their own unique attributes and have not been compared head-to-head in randomized trials. This review will summarize the pivotal trials that led to the approval of novel agents and compare the features of each agent to guide treatment decisions in treatment-naïve CLL. Ongoing studies investigating combinations of novel agents in the firstline setting will also be discussed.