Frontline CLL Treatment: What's the Right Approach?


The treatment paradigm for chronic lymphocytic leukemia has expanded beyond continuous treatment with BTK inhibitors with the addition of the time-limited regimen of venetoclax plus obinutuzumab.

Jennifer R. Brown, MD, PhD

Jennifer R. Brown, MD, PhD

The treatment paradigm for chronic lymphocytic leukemia (CLL) has expanded beyond continuous treatment with BTK inhibitors with the addition of the time-limited regimen of venetoclax (Venclexta) plus obinutuzumab (Gazyva), according to Jennifer R. Brown, MD, PhD.

Several experimental combinations are also under exploration, she added, which may serve to further improve progression-free survival (PFS) for some patient subsets.1

“Continuous therapy is appealing for older patients who want to minimize clinic visits. Ibrutinib [Imbruvica] has significant toxicities, especially in older patients, but the second-generation covalent BTK inhibitors are demonstrating improved safety profiles,” noted Brown. “Some data suggest that continuous therapy with BTK inhibitors may be preferred over time-limited venetoclax/obinutuzumab for those with p53-abberant disease, but time-limited therapy is appealing for younger patients, those with high out-of-pocket costs, and maybe for those with IGHV-mutated disease, as they might achieve particularly durable remissions.”

The question of whether a novel combination comprised of a BTK inhibitor and a BCL-2 inhibitor or the addition of an anti-CD20 agent to a BTK inhibitor and a BCL-2 inhibitor will improve PFS vs venetoclax/obinutuzumab remains unanswered, according to Brown.

In a presentation delivered during the 25th Annual International Congress on Hematologic Malignancies, Brown, director of the CLL Center at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, further discussed key developments in the frontline treatment of patients with CLL.

Benefit of Ibrutinib

Ibrutinib is the BTK inhibitor for which the longest follow-up data are available. Five-year follow-up data from the phase 2 RESONATE-2 trial (NCT01722487) comparing frontline ibrutinib with chlorambucil in patients with CLL/small lymphocytic lymphoma (SLL) showed that the PFS and overall survival (OS) benefits achieved with the BTK inhibitor were sustained.2

At 5 years, the PFS estimates in the investigative and control arms were 70% vs 12% (hazard ratio [HR], 0.146; 95% CI, 0.098-0.218), respectively; the estimated 5-year OS rates were 83% vs 68%, respectively (HR, 0.450; 95% CI, 0.266-0.761). “However, 41% of patients discontinued the drug primarily due to adverse effects [AEs],” noted Brown.

In another phase 3 trial (NCT01886872), investigators compared ibrutinib with regimens like rituximab (Rituxan)/bendamustine and ibrutinib/rituximab in treatment-naïve patients with CLL. The estimated 24-month PFS rates were comparable in the ibrutinib and ibrutinib/rituximab arms, at 87% (95% CI, 81%-92%) and 88% (95% CI, 81%-92%), respectively.3

“There was no benefit from adding rituximab and they were both significantly better than BR in terms of PFS,” noted Brown. “Although this was primarily driven by outcomes in the higher-risk IGHV-unmutated population.”

Similarly, in the phase 3 ECOG-E1912 trial (NCT02048813), patients with untreated CLL/SLL were randomized between ibrutinib/rituximab and fludarabine phosphate, cyclophosphamide, and rituximab (FCR) and the former regimen proved to result in a significant PFS improvement over the latter regimen. The 3-year PFS rates in the IGHV-unmutated patients in the investigative and control arms were 89% vs 65% (HR, 0.28; 95% CI, 0.17-0.48; P <.0001), respectively.4 No statistically significant difference in PFS was observed in the patients with IGHV-mutated disease (P = .086).

“We do know that the lower-risk, younger, fit population can experience prolonged PFS with FCR, as shown in long-term follow-up data from investigators at The University of Texas MD Anderson Cancer Center, German randomized trials, and an Italian retrospective study,” said Brown. “Fifty-five percent of patients with IGHV-mutated disease were still in remission at 12 years after therapy.”

In an effort to build on the benefit achieved with FCR, investigators decided to evaluate the addition of ibrutinib to the regimen in younger, treatment-naïve patients with CLL as part of a single-arm, multicenter, phase 2 trial (NCT02251548).5 The best response of undetectable minimal residual disease (MRD) in the bone marrow was achieved in 84% of patients, including all risk groups. 

“The regimen was well tolerated,” noted Brown. “Similar data have been obtained with ibrutinib with FCR and obinutuzumab. All [regimens] are highly effective for young, fit patients with IGHV-mutated disease based on MRD achievement, which is better than FCR alone, although we’re waiting for longer-term PFS data.”

Improved Safety With Second-Generation BTK Inhibitors?

Although ibrutinib has demonstrated survival benefit in this patient population, it is not without toxicity. To improve on these benefits, next-generation BTK inhibitors such as acalabrutinib (Calquence) and zanubrutinib (Brukinsa) have since entered the treatment landscape. “[These agents are] significantly more specific than ibrutinib,” noted Brown. “Zanubrutinib is intermediate and acalabrutinib is the most specific of the 3 covalent BTK inhibitors.”

Mature results from the phase 2 ACE-CL-001 trial (NCT02029443) showed that the 48-month event-free survival (EFS) rate with acalabrutinib in the treatment-naïve cohort of patients with CLL was 90% (95% CI, 82%-94%).6 “Importantly, EFS here includes discontinuation of drug for an AE,” noted Brown. “In fact, only 6% of patients discontinued for an AE and most remained on drug, which is important for the longest-term remissions with continuous BTK inhibition.”

In the phase 3 ELEVATE-TN trial (NCT02475681), investigators examined acalabrutinib vs acalabrutinib/obinutuzumab vs obinutuzumab/chlorambucil in older patients with treatment-naïve CLL. At a median follow-up of 28.3 months, the cohorts who received the BTK inhibitor alone or in combination with obinutuzumab experienced a significant improvement in PFS per independent review committee assessment over the cohort that received obinutuzumab/chlorambucil, with HRs of 0.20 (P <.0001), 0.10 (P <.0001), and 0.49, respectively.7

High-level results from the phase 3 ELEVATE-RR trial (NCT02477696), which is comparing acalabrutinib with ibrutinib in patients with previously treated, high-risk CLL, showed that the second-generation BTK inhibitor met the primary end point of noninferior PFS vs ibrutinib.8 Moreover, acalabrutinib was found to have a statistically significant lower incidence of atrial fibrillation vs ibrutinib. “We’ve yet to see the data and look forward to learning more later this year,” said Brown.

Zanubrutinib is also under exploration in clinical trials in both the frontline and relapsed/refractory settings. Data from arm C of the phase 3 SEQUOIA trial (BGB-3111-3304; NCT03336333) showed that the best overall response rate (ORR) with zanubrutinib in patients with CLL and 17p deletions was 94.5% (95% CI, 88.4%-98.0%).9 The 18-month PFS rate with the newer-generation BTK inhibitor in this subset was 90.6% (95% CI, 83.3%-94.9%).

Zanubrutinib was compared head-to-head with ibrutinib in the phase 3 ASPEN trial (NCT03053440) in patients with Waldenström macroglobulinemia.10 At a median follow-up of 19.4 months, results indicated that the rate of atrial fibrillation was much lower with zanubrutinib vs ibrutinib, at 2% vs 15%, respectively. “Trends for improvement in hypertension, edema, and contusion [with zanubrutinib] was also observed,” noted Brown. “There is more neutropenia seen with zanubrutinib but it’s generally readily manageable with growth factors.”

These agents are also under exploration in a head-to-head trial that is being performed in patients with relapsed CLL, added Brown.

Time-Limited Therapy

Data from the phase 3 CLL14 trial (NCT02242942) showed that the combination of venetoclax and obinutuzumab reduced the risk of disease progression or death by 67% vs obinutuzumab/chlorambucil in patients with treatment-naïve CLL and coexisting medical conditions (HR, 0.33; 95% CI, 0.25-0.45; P <.0001).11 The data led to the May 2019 FDA approval of the doublet for use in this population. The 4-year PFS rates in the investigative and control arms were 74.0% vs 35.4%, respectively.

At the conclusion of therapy, the rate of undetectable MRD in the peripheral blood with the combination was 74%, while it was 57% in the bone marrow. At 18 months of follow-up, the undetectable MRD rate with venetoclax/obinutuzumab was 47% in the peripheral blood.

“A number of studies have demonstrated that patients with CLL and high-risk features had higher MRD growth rates, not surprisingly and not dissimilar from what we saw in the chemoimmunotherapy era, where patients who achieved undetectable MRD with, for example, unmutated IGHV experienced recurrence more commonly and more rapidly than patients with mutated IGHV, who we saw have very prolonged remissions,” Brown explained.

Additional data from the trial indicated that patients with mutated IGHV had a better PFS following 1 year of treatment with venetoclax/obinutuzumab vs those who were unmutated.12 “It does not mean that this is not necessarily a good therapy for patients who have unmutated IGHV,” noted Brown. “If they achieve a long remission off therapy, that’s nonetheless, a substantial benefit.”

Novel Combinations Under Exploration

In a phase 2 trial (NCT02756897), investigators evaluated the combination of ibrutinib and venetoclax in previously untreated, high-risk, older patients with CLL. After receiving treatment for up to 24 months, the rate of undetectable MRD in the bone marrow was 69% after 18 cycles of treatment.13

The combination was also examined in the phase 2 CAPTIVATE trial (NCT02910583) in patients with previously untreated CLL/SLL. Here, patients received 3 months of ibrutinib lead-in and then received 12 months of ibrutinib/venetoclax.14 At the end of treatment, patients with confirmed undetectable MRD were randomized to either continue ibrutinib or stop therapy; those with confirmed MRD were randomized to continue ibrutinib/venetoclax or continue single-agent ibrutinib. The primary end point of the trial was 1-year disease-free survival (DFS) rate in those with confirmed undetectable MRD randomized to ibrutinib vs placebo.

In patients with confirmed undetectable MRD, the 30-month PFS rate with ibrutinib (n = 43) was 100% vs 95.3% (n = 43) with placebo. In those with unconfirmed, undetectable MRD, the 30-month PFS rate with ibrutinib/venetoclax (n = 32) was 96.7% vs 95.2% with ibrutinib (n = 31). The 1-year DFS rate in patients with confirmed undetectable MRD was 100% with ibrutinib vs 95.3% with placebo (P = .1475).

A novel triplet regimen comprised of obinutuzumab, ibrutinib, and venetoclax was evaluated in patients with treatment-naïve (n = 25) or relapsed/refractory (n = 25) CLL as part of a phase 2 trial (NCT02427451).15 Fifty-six percent of patients who were treatment naïve had undetectable MRD vs 44% of those with relapsed/refractory disease. “Obviously, this was better than a 2-drug regimen,” noted Brown. 

Three-year follow-up data indicated that the PFS rates at 36 months with the triplet were 95% in both subsets. At 36 months, the OS rate in those who were treatment naïve was 95% vs 100% in those who had relapsed/refractory disease. “In the treatment-naïve cohort, that’s perhaps not as notable, but in the relapsed/refractory cohort, that is rather notable in terms of durability,” said Brown.

In another phase 2 trial (NCT03580928), investigators examined another triplet regimen comprised of acalabrutinib, venetoclax, and obinutuzumab as frontline treatment in 37 patients with CLL.16 At cycle 16, the rate of undetectable MRD in the bone marrow was 75.0%, while it was 87.5% in the blood. “This is very high,” said Brown. “Follow-up is not yet long enough to comment on PFS.”

In the phase 2 BOVen trial (NCT03824483), the combination of zanubrutinib, obinutuzumab, and venetoclax is under evaluation in patients with untreated CLL.17 “This is actually MRD-guided therapy. Interestingly, most patients did achieve undetectable MRD rapidly, and in fact, have stopped therapy after a median of 10 months,” concluded Brown. “The duration of time that they were treated is shorter than most of the other studies. It will be interesting to see how that affects PFS down the line.”


  1. Brown, JR. First-line therapy in CLL: what is best? Presented at: 25th Annual International Congress on Hematologic Malignancies; February 25-28, 2021; virtual. Accessed March 3, 2021.
  2. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x
  3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi:10.1056/NEJMoa1812836
  4. Shanafelt TD, Wang V, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. Blood. 2019;134(suppl 1):33. doi:10.1182/blood-2019-126824
  5. Davids MS, Brander DM, Kim HT, et al. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Hameatol. 2019;6(8):e419-e428. doi:10.1016/S2352-3026(19)30104-8
  6. Byrd JC, Woyach JA, Furman RR, et al. Acalabrutinib in treatment-naïve chronic lymphocytic leukemia: mature results from phase 2 study demonstrating durable remissions and long-term tolerability. Presented at: 2020 European Hematology Association Annual Congress; June 11-20, 2020; Virtual. Abstract S163.
  7. Calquence significantly prolonged the time patients lived without disease progression or death in previously untreated chronic lymphocytic leukemia. News release. AstraZeneca. December 7, 2019. Accessed March 3, 2021.
  8. Calquence met primary efficacy endpoint in head-to-head trial against ibrutinib in chronic lymphocytic leukemia. News release. AstraZeneca. January 25, 2021. Accessed March 3, 2021.
  9. Brown JR, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of the SEQUOIA (BGB-3111-304) trial. Blood. 2020;136(suppl 1):11-12. doi:10.1182/blood-2020-134280
  10. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. doi:10.1182/blood.2020006844
  11. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized phase 3 CLL14 trial. Presented at: 2020 European Hematology Association Annual Congress; June 11-20, 2020; Virtual. Abstract S155.
  12. Al-Sawaf O, Zhang C, Robrecht S, et al. Clonal dynamics after venetoclax–obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial. Blood. 2020;136(suppl 1):22-23. doi:10.1182/blood-2020-136977
  13. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574
  14. Wierda WG, Tam CS, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2020;136(suppl 1):16-17. doi:10.1182/blood-2020-134446
  15. Rogers KA, Huang Y, Rupper AS, et al. Three-year follow-up from a phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia. Blood. 2020;136(suppl 1):9-10. doi:10.1182/blood-2020-137655
  16. Davids MS, Lampson BL, Tyekucheva S, et al. Updated safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab (AVO) for frontline treatment of chronic lymphocytic leukemia (CLL). Blood. 2020;136(suppl 1):20-21. doi:10.1182/blood-2020-139864
  17. Soumerai JD, Mato AR, Carter J, et al. MRD-driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax (BOVen) in previously untreated chronic lymphocytic leukemia. Presented at: 2020 ASH Annual Meeting & Exposition; December 5, 2020. Accessed March 3, 2021.

This article was originally published on OncLive as, "Brown Breaks Down How to Choose the Optimal Frontline Approach for CLL."

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