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Latest advances in time-limited BTK and BCL2 inhibitor combinations for the frontline treatment of CLL

“So from this year’s ASH I’m really most excited about the AMPLIFY Phase III trial. This is likely going to lead to the registration of an AV doublet in the U.S. – this will be our first BTK/BCL2 doublet here. It’s an all-oral regimen that, at least based on the abstract, seems to be highly effective and well-tolerated.” – Matthew Davids, MD, Dana-Farber Cancer Institute, Boston, MA, at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.

The frontline treatment landscape for CLL

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, with significant advancements in frontline treatment shifting the standard of care away from chemoimmunotherapy (CIT) toward targeted agents.1 Previously, fludarabine, cyclophosphamide, and rituximab (FCR) were preferred for younger, fit patients, and bendamustine-rituximab (BR) was used for older adults, but CIT use has declined due to superior outcomes with targeted therapies.1 Bruton’s tyrosine kinase inhibitors (BTKis), such as ibrutinib and acalabrutinib, are effective treatment options that are approved as monotherapy in the frontline; a seven-year progression-free survival (PFS) of 83% is achieved with frontline ibrutinib.1 However, remissions are usually only partial, so continuous administration is required, which can lead to toxicity and resistance, highlighting the need for time-limited therapy.1 Venetoclax, a BCL2 inhibitor (BCL2i), is an alternative for patients intolerant to BTKis or those requiring time-limited treatment, and in combination with obinutuzumab, remains the only U.S. Food and Drug Administration (FDA)-approved time-limited doublet for frontline CLL.2

The synergistic mechanism of BTK and BCL2 inhibition

The combination of BTK and BCL2 inhibition in CLL leverages distinct yet complementary mechanisms to enhance tumor cell eradication. BTKis disrupt B-cell receptor signaling, impairing CLL cell adhesion, migration, and survival within lymphoid tissues, while venetoclax directly induces apoptosis by antagonizing BCL2. BTKis increase CLL cell dependence on BCL2, making them more vulnerable to venetoclax, while venetoclax eliminates residual CLL cells that persist despite BTK inhibition. Together, these agents target both proliferating and resting CLL subpopulations, overcoming resistance mechanisms and achieving deeper, more durable remissions.3

Combining ibrutinib and venetoclax

The combination of ibrutinib and venetoclax was approved in Europe in August 2022 for previously untreated CLL based on the pivotal Phase III GLOW (NCT03462719) and Phase II CAPTIVATE (NCT02910583) trials. The GLOW trial found that ibrutinib plus venetoclax had superior PFS to chlorambucil-obinutuzumab (PFS hazard ratio [HR]: 0.216; 95 percent confidence interval [CI], 0.131 to 0.357; p<0.001) in elderly or unfit patients with CLL.4


Carsten Niemann, MD, PhD, Copenhagen University Hospital, Copenhagen, Denmark, spoke about the 64-month follow-up from GLOW at ASH 2024, stating, “what we present this year is a focus on the toxicity along with the efficacy, thus we use toxicity-free PFS as an outcome…we see that patients treated with ibrutinib-venetoclax gain more than 20 months toxicity-free PFS as compared to patients treated with chlorambucil-obinutuzumab”.

The Phase II HOVON 158/NEXT STEP trial (NCT04639362) is investigating the efficacy of adding six cycles of ibrutinib and obinutuzumab for patients who do not achieve complete remission (CR) and undetectable measurable residual disease (uMRD) after receiving ibrutinib plus venetoclax. The primary analysis of this trial was presented at ASH 2024.5 Mark-David Levin, MD, Albert Schweitzer Hospital, Dordrecht, The Netherlands, discusses the findings with us.

The AMPLIFY trial

Findings from the interim analysis of the Phase III AMPLIFY trial (NCT03836261) were presented at ASH 2024. This trial is investigating the combination of acalabrutinib plus venetoclax (AV) with and without obinutuzumab (AVO) versus standard CIT in fit, treatment-naïve (TN) CLL, and it is anticipated that it will lead to the FDA approval of this combination.6

The trial includes 867 patients without del(17p) or TP53 mutation, who were randomized 1:1:1 to receive AV, AVO, or the investigator’s choice of FCR/BR. The primary endpoint was blinded independent central review (BICR)-assessed PFS of AV versus FCR/BR, with secondary endpoints including BICR-assessed PFS for AVO versus FCR/BR, uMRD rates, and overall survival (OS).6

At a median follow-up of 41 months, both AV and AVO significantly improved PFS compared with FCR/BR (HR 0.65, p=0.0038; HR 0.42, p<0.0001, respectively). Median PFS was not reached in either experimental arm, compared with 47.6 months in the FCR/BR arm. The estimated 36-month PFS rates were 76.5% (AV), 83.1% (AVO), and 66.5% (FCR/BR). Objective response rates (ORR) were also higher in the AV (92.8%) and AVO (92.7%) arms versus FCR/BR (75.2%; p<0.0001). A trend toward improved OS was observed with AV (HR 0.33, nominal p<0.0001).6

Safety findings showed that neutropenia was the most common grade ≥3 adverse event (AE) (26.8% AV; 35.2% AVO; 32.4% FCR/BR). Rates of tumor lysis syndrome (TLS), atrial fibrillation, and grade ≥3 hypertension were low across all arms. Serious AEs were more frequent in the AVO group (38.4%) compared with AV (24.7%) and FCR/BR (27.4%).6 These findings demonstrate that AV and AVO provide deep and durable responses with manageable toxicity.

Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute, Boston, MA, shared these findings with us at ASH 2024. She adds, “we did notice that the unmutated IGHV patients receiving AVO had a similar three-year PFS to the mutated patients, which is unusual and favorable. So I would consider the addition of the obinutuzumab particularly for the fitter, younger patients with unmutated IGHV or higher-risk disease”.

Other ongoing trials

Several ongoing early-stage investigations are exploring additional BTKi/BCL2i combinations. One such Phase II trial (NCT05536349) is evaluating the non-covalent BTKi pirtobrutinib in combination with venetoclax and obinutuzumab. At ASH 2024, Nitin Jain, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, gave an update on this trial, reporting results at a median follow-up of one year.

The first-in-human Phase I/Ib dose-escalation/expansion BGB-11417-101 trial (NCT04277637) is assessing the safety and recommended Phase II dose of the combination of sonrotoclax with zanubrutinib in TN CLL. Sonrotoclax, a second-generation BCL2i, has enhanced selectivity and potency over venetoclax, and there is evidence that zanubrutinib has superior efficacy and safety compared with ibrutinib, including improved PFS and fewer cardiac AEs, making this an attractive combination for investigation. Data presented at ASH 2024 showed that this combination was safe and well-tolerated, with only one patient discontinuing treatment due to a treatment emergent AE and no cases of TLS. In 108 response-evaluable patients, a 100% overall response rate was observed, and there was a 90% best uMRD rate in patients who received 48 weeks of therapy with a sonrotoclax dose of 320 mg.7 These promising findings have led to the initiation of the Phase III CELESTIAL-TNCLL trial (BGB-11417-301; NCT06073821), which is assessing zanubrutinib with sonrotoclax at a dose of 320 mg. We spoke with Piers Patten, MB ChB, MRCP, FRCPath, PhD, King’s College London, London, UK, at ASH 2024, who told us that “recruitment is now close to completion, or may even be completed, and we will be looking for a readout in the next few years”. 

Clinical implications and National Comprehensive Cancer Network (NCCN) update

The advances in BTKi and BCL2i combinations offer a promising shift toward time-limited regimens for frontline CLL treatment, with the potential for deeper, more durable responses and more manageable toxicity profiles compared with CIT. Although some experts contend that CIT may still have a role in select patient populations, particularly young, fit patients with IGHV-mutated (low-risk) disease1, the landscape is evolving away from CIT and toward targeted agents. Reflecting this evolving landscape, recent updates to the NCCN guidelines have further reinforced the role of BTKi and BCL2i combinations in frontline CLL. The key updates include the addition of venetoclax + acalabrutinib ± obinutuzumab as a Category 1 preferred regimen for patients without del(17p)/TP53 mutation and a Category 2A preferred regimen for those with del(17p)/TP53 mutation. Ibrutinib + venetoclax has been upgraded from a Category 2B to a Category 2A recommendation.8

The potential FDA approval of AV or AVO could further expand treatment options, offering the first BTK/BCL2 combination in the U.S. Ongoing trials continue to investigate other BTKi/BCL2i combinations, with additional data expected later this year. The aim remains to improve outcomes and provide a time-limited, chemotherapy-free option for patients with CLL in the frontline setting.

Written by Hannah Elkheir

Edited by Solyana Johannes

References

  1. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020 Jul;383(5):460-473.
  2. National Cancer Institute. Combination therapy with venetoclax approved for chronic lymphocytic leukemia. Available here. (Last accessed 04/03/2025).
  3. Zhang J, Lu X, Li J, Miao Y. Combining BTK inhibitors with BCL2 inhibitors for treating chronic lymphocytic leukemia and mantle cell lymphoma. Biomark Res. 2022 Apr;10:17.
  4. Johnson & Johnson. European Commission approves IMBRUVICA® (ibrutinib) in a fixed-duration combination regimen for adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Available here. (Last accessed 04/03/2025).
  5. Levin MD, Kersting S, Dubois J, et al. Improved efficacy with response- and MRD-guided ibrutinib-obinutuzumab (IO) intensification after ibrutinib-venetoclax (IV) in first-line chronic lymphocytic leukemia (CLL) patients: Primary analysis of the HOVON 158/Next STEP Phase 2 trial. Blood. 2024 Nov;144(Suppl 1):1013.
  6. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: Interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Blood. 2024 Nov;144(Suppl 1):1009.
  7. Soumerai JD, Cheah CY, Anderson MA, et al. Sonrotoclax and zanubrutinib as frontline treatment for CLL demonstrates high MRD clearance rates with good tolerability: Data from an ongoing Phase 1/1b study BGB-11417-101. Blood. 2024 Nov;144(Suppl 1):1012.
  8. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Available here. (Last accessed 05/03/2025).