Mounting Data for Small Molecule Therapies in CLL Push Chemoimmunotherapy Further From the Frontline


The growing use of minimal residual disease as a prognostic marker of progression-free survival and overall survival suggests that it might aid in clinical decision-making.

William Wierda, MD, PhD

The evidence for the efficacy of combinations with small molecule inhibitors, including BTK (Bruton tyrosine kinase) and BCL-2, over standard chemoimmunotherapy regimens in the first-line setting continues to mount in the chronic lymphocytic leukemia (CLL) space, thereby moving chemoimmunotherapy further away from initial treatment. Deep and durable responses have been observed with some of these agents, prompting clinicians to stop therapy after 1 or 2 years; however, it remains unclear which patients can safely stop. The growing use of minimal residual disease (MRD) as a prognostic marker of progression-free survival (PFS) and overall survival (OS) suggests that it might aid in clinical decision-making.

“Ideally, we'd like to get as many patients in as deep a remission as possible with a fixed duration of treatment, improving and lengthening progression-free survival and overall survival,” William Wierda, MD, PhD, said during his presentation at the NCCN 2020 Virtual Congress: Hematologic Malignancies conference.1

Wierda, professor of medicine, Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, made the case for eliminating chemoimmunotherapy altogether and replacing it with more effective combinations of small molecule inhibitors.

For BTK inhibitors, RESONATE-2 (NCT01722487), ECOG E1912 (NCT02048813), and ELEVATE-TN (NCT02475681), have been positive, but Wierda did emphasize that only the RESONATE-2 trial and the ECOG E1912 trial showed improvement in OS.

In RESONATE-2, older patients with CLL were randomized to receive either ibrutinib (Imbruvica) or chlorambucil in the frontline setting.2 Patients who received ibrutinib had superior PFS compared with the control group (not reached vs 15 months, respectively). Patients in the treatment arm also demonstrated an 88% reduction in the risk of progression or death (HR, 0.121; 95% CI, 0.074-0.198; P < .0001).

Further, this benefit in PFS was observed across all subgroups. Regardless of del(11q) status, Wierda noted that patients who received ibrutinib did well (5-year PFS rate: 79% with del(11q) vs 67% without; HR, 0.719; 95% CI, 0.315-1.642). In contrast, patients with the del(11q) mutation were at higher risk of progression if they received chemoimmunotherapy. Similar observations in PFS were reported in patients with IGHV-mutated versus unmutated status, with patients who received ibrutinib demonstrating significantly better PFS (5-year PFS rate with ibrutinib: 81% IGHV-mutated vs 67% unmutated IGHV; HR, 0.632; 95% CI, 0.262-1.525).

ECOG E1912 evaluated ibrutinib/rituximab (Rituxan) versus FCR (fludarabine, cyclophosphamide, and rituximab). PFS favored the ibrutinib arm over the FCR arm (HR, 0.352; 95% CI, 0.223-0.558; P < .0001), as did OS (HR, 0.168; 95% CI, 0.053-0.538; P = .0003) in the intention-to-treat population.3

ELEVATE-TN was a frontline, 3-arm randomized trial that evaluated acalabrutinib (Calquence) monotherapy versus acalabrutinib plus obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil.4 There was clear evidence of improved PFS in those patients who received acalabrutinib-based therapy. Estimated PFS rates at 24 months was 93% with acalabrutinib plus obinutuzumab (95% CI, 87%-96%), 87% with acalabrutinib monotherapy (95% CI, 81%-92%), and 47% with obinutuzumab plus chlorambucil (95% CI, 39%-55%).

“Although there was a trend toward improved PFS in this setting, I think it’s important that we obtain further follow-up,” Wierda said. “Acalabrutinib, like ibrutinib, is continuous and [requires] indefinite treatment. I think there’s some controversy around whether or not obinutuzumab adds to the benefits that we see with acalabrutinib in the frontline.”

BCL-2 Inhibition

Moving onto the BCL-2 inhibitors ), Wierda focused on CLL14 (NCT02242942), a randomized trial evaluating venetoclax (Venclexta) plus obinutuzumab versus chlorambucil plus obinutuzumab in patients with previously untreated CLL and coexisting conditions.5 Patients with a cumulative illness rating scale score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard chlorambucil or venetoclax in combination with obinutuzumab for the first 6 cycles.

This trial showed an improvement in median PFS for patients who received venetoclax-based therapy versus chlorambucil-based therapy (not reached vs 35.6 months, respectively). In the trial, investigators observed a 3-year PFS rate of 81.9% in the venetoclax arm versus 49.5% in the chlorambucil arm (HR, 0.31; 95% CI, 0.22-0.44; P < .0001).

Wierda also touched on the potential benefit of combining these small molecules in CLL.

Combination trials involving both of these small molecules have been encouraging, Wierda said. Because deep remissions have not been observed in patients treated with BTK inhibitors, with disease still measured in patients who have been taking BTK inhibitors for more than a year, a trial at MD Anderson is evaluating the addition of venetoclax to ibrutinib in patients with high-risk CLL or small lymphocytic lymphoma (SLL) who continue to demonstrate measurable disease (NCT03128879).6

The rate of conversion to MRD negative in this trial showed among 22 patients who completed 12 months of treatment with the combination, 68% achieved an undetectable MRD status in the bone marrow. “We’re excited about these findings and we have expanded the trial,” Wierda said.

Wierda noted that these 2 agents are clinically complementary, with venetoclax effective at clearing blood and bone marrow of disease, whereas ibrutinib is effective at shrinking lymph nodes. In vitro data also show the synergistic nature between the 2, he added.

Findings from the CAPTIVATE trial (NCT02910583) also support the use of the combination of ibrutinib and venetoclax with high rates of undetectable MRD achieved in peripheral blood and bone marrow.7 The trial assessed MRD-guided discontinuation and fixed-duration therapy in patients with treatment-naïve CLL or SLL. In bone marrow, 72% of patients had undetectable MRD at the end of 12 months of combination therapy. Wierda noted that this was a higher rate than previously reported for FCR for 6 cycles.


As evidence for the growing use of MRD as a biomarker to guide treatment decision-making, Wierda highlighted an ongoing trial at MD Anderson comparing acalabrutinib plus venetoclax with or without obinutuzumab. MRD was the primary end point (NCT04169737).8

After the first year of treatment, patients were re-evaluated. If they still had measurable disease, they were able to receive 6 cycles of obinutuzumab in addition to the acalabrutinib plus venetoclax regardless of whether or not they received obinutuzumab initially.

The MURANO trial (NCT02005471) looked at patients in the relapsed setting who received venetoclax plus rituximab versus bendamustine plus rituximab.9 The MRD negativity rate was maintained over time for the venetoclax plus rituximab combination versus the control. “Investigators reported a high rate of 60% for undetectable MRD status for patients who were treated with venetoclax. This was unexpectedly high for the relapse setting,” Wierda said.

A post-treatment follow-up of MURANO concluded that undetectable MRD rates were durable and predicted longer PFS, establishing the effect of peripheral blood MRD on the benefit of fixed-duration therapy using venetoclax.10 Further, the low conversion rates to detectable MRD and sustained PFS demonstrate the feasibility of the regimen.

“We’re seeing a lot of progress, but a lot of work still has to be done,” Wierda said. “We're now integrating MRD status as a response assessment tool, and correlating that with progression-free survival and overall survival with our targeted therapies,” he concluded.


1. Wierda W. Updates in the management of chronic lymphocytic leukemia/small lymphocytic lymphoma: sequencing therapy and the role of MRD testing. Presented at: NCCN 2020 Virtual Congress: Hematologic Malignancies; October 9-10, 2020.

2. Barr P, Roback T, Owen CJ, et al. Updated efficacy and safety from the phase 3 resonate-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128 (22):234. doi:10.1182/blood.V128.22.234.234

3. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase iii study of ibrutinib (pci-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (fcr) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (cll): a trial of the ecog-acrin cancer research group (E1912). Blood. 2018;132 (suppl 1):LBA-4. doi:10.1182/blood-2018-120779

4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

5. Fischer K, Al-Sawaf O, Fink A-M, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. J Clin Oncol. 2019;37(suppl 15):7502. doi:10.1200/JCO.2019.37.15_suppl.7502

6. Thompson PA, Keating MJ, Jain N, et al. Venetoclax added to ibrutinib in high-risk cll achieves a high rate of undetectable minimal residual disease. Blood. 2019;134(suppl 1):358. doi:10.1182/blood-2019-129230

7. Siddiqi T, Tam CS, Allan JN, et al. First-line ibrutinib (ibr) + venetoclax (ven) for patients (pts) with chronic lymphocytic leukemia (cll)/small lymphocytic lymphoma (sll): efficacy and safety results from captivate mrd cohort. Presented at: 25th European Hematology Association Congress (EHA25 Virtual); June 11-21, 2020. Accessed October 10, 2020.

8. Acalabrutinib and venetoclax with or without early obinutuzumab for the treatment of high risk, recurrent, or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Identifier: NCT04169737. Accessed October 10, 2020.

9. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107-1120. doi:10.1056/NEJMoa1713976

10. Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019;37(4):269-277. doi: 10.1200/JCO.18.01580

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