Chronic lymphocytic leukemia (CLL) research presented at the 2022 ASH Annual Meeting showed that zanubrutinib can outperform ibrutinib, a triplet is effective for high-risk CLL, cell death may predict the depth of treatment response, and a chimeric antigen receptor (CAR) T-cell therapy is likely not an option for CLL patients.

In the phase 3 ALPINE trial, zanubrutinib improved progression-free survival (PFS) and overall response rate (ORR), when compared with ibrutinib, in patients with relapsed or refractory CLL.1 In a phase 2 trial, the combination of acalabrutinib, venetoclax, and obinutuzumab demonstrated activity in patients with previously untreated, high-risk CLL.2

A phase 1 trial showed limited CAR T-cell expansion in patients with relapsed/refractory CLL treated with brexucabtagene autoleucel.3 And a study of ibrutinib-treated patients revealed an association between initial high cell death and the likelihood of achieving deep, long-term remissions.4

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ALPINE Trial: Zanubrutinib Improves PFS

Zanubrutinib improved outcomes when compared with ibrutinb in the phase 3 ALPINE trial ( Identifier: NCT03734016).1 The trial compared the drugs in patients with relapsed/refractory CLL and small lymphocytic lymphoma (SLL).

The trial enrolled 652 patients from 15 countries, with 327 patients receiving zanubrutinib and 325 receiving ibrutinib. Cohorts were matched for disease characteristics, patient age, and demographics. Patients had received a median of 1 prior line of therapy.

The ORR was higher with zanubrutinib than with ibrutinib — 86.2% and 75.7%, respectively (P =.0007). With a median follow up of 29.6 months, zanubrutinib had superior PFS. The median PFS was 35.0 months with ibrutinib and was not reached with zanubrutinib (hazard ratio, 0.65; 95% CI, 0.49-0.86; P =.0024).

“Zanubrutinib improved progression-free survival compared to ibrutinib, and was also safer, particularly with respect to cardiac safety,” said study presenter Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts. “Zanubrutinib would, in my opinion, always be preferred compared to ibrutinib [in patients with CLL/SLL].”

The treatment discontinuation rate was lower with zanubrutinib (26.3%) than with ibrutinib (41.2%). Most discontinuations were caused by adverse events or progressive disease, both of which were higher with ibrutinib.

Trio of Drugs Effective in High-Risk CLL

The combination of acalabrutinib, venetoclax, and obinutuzumab was effective in previously untreated patients with high-risk CLL, according to results from an ongoing phase 2 trial ( Identifier: NCT03580928).2 Researchers evaluated the combination in a previously reported cohort of 37 patients who were not stratified by risk and an additional 31 patients with aberrant TP53.2,4

The complete response (CR) rate was 52% in patients with aberrant TP53, 44% in patients with wild-type TP53, and 48% in the whole cohort. The rate of CR with undetectable bone marrow minimal residual disease (MRD) at cycle 16 was 43% in all patients and 45% in patients with aberrant TP53.

Also at cycle 16, the rate of undetectable MRD in the peripheral blood was 86% overall, 86% in patients with aberrant TP53, and 85% in patients with wild-type TP53. The rate of undetectable MRD in the bone marrow was 86%, 83%, and 89%, respectively.

At a median follow-up of 35 months, 98.5% of patients were still alive, and 92.6% were progression-free. The combination was considered well tolerated.

“Patients with CLL with TP53-aberrant disease continue to present an unmet clinical need,” said study presenter Christine Ryan, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts. “We are excited about the very high rates of remission seen in high-risk patients with CLL in our study, which points to the efficacy of this triplet regimen in a patient population with historically inferior outcomes.”

The triplet is now under investigation in the phase 3 AMPLIFY trial ( Identifier: NCT03836261). The trial is designed to compare acalabrutinib plus venetoclax, acalabrutinib plus venetoclax and obinutuzumab, and standard chemoimmunotherapy in patients with non-high risk CLL.

ZUMA-8: Brexucabtagene Autoleucel in CLL

Treatment with brexucabtagene autoleucel appeared safe but resulted in limited CAR T-cell expansion in a phase 1 trial of patients with relapsed/refractory CLL who had 2 or more previous lines of therapy ( Identifier: NCT03624036).5

A total of 15 patients received brexucabtagene autoleucel in this study. Their median age at baseline was 63 years, 12 patients had received 3 or more prior lines of therapy, and 13 had received bridging therapy between leukapheresis and conditioning therapy.

The median follow-up was 30.3 months. Notable CAR T-cell expansion occurred in 4 patients, including all 3 patients with a low tumor burden.

The ORR was 47%, with 2 patients achieving a CR and 5 achieving a partial response. All 3 patients with low tumor burden had a response, and both CRs occurred in this group. These 3 patients had responses lasting at least 14 months and were still in response at the data cutoff.

No new safety signals were reported. However, all patients experienced grade 3 or higher adverse events, with 33% of patients experiencing serious grade 3 or higher adverse events. There was 1 patient who experienced dose-limiting toxicities.

This study was discontinued due to suboptimal CAR T-cell expansion, and there are “currently no plans” to further study brexucabtagene autoleucel in patients with CLL/SLL with low tumor burden, according to study presenter Matthew S. Davids, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“Studies with other CAR T-cell products may examine whether combination approaches with agents that improve T-cell function enhance CAR T-cell expansion,” he said.

Cell Death Rates Can Predict Remission Depth in CLL

Long-term follow-up of a clinical trial ( Identifier: NCT01752426) to assess CLL/SLL cell kinetics in patients treated with ibrutinib has revealed a correlation between initial cell death rates and the probability of achieving deeper long-term remissions.4

Researchers used deuterated water to track cancer cell death and proliferation in previously untreated patients with CLL/SLL during long-term treatment with ibrutinib monotherapy. Previously published research showed that ibrutinib induces high rates of CLL/SLL cell death and blocks proliferation.6

Long-term follow-up data on 30 patients revealed a 5-year PFS rate of 80.6%, overall survival rate of 90%, and ORR of 97%.

Peripheral blood MRD was assessed in 18 patients after 54-60 treatment cycles. Researchers found that high CLL cell death rates earlier on in treatment were associated with lower peripheral blood MRD levels 5 years after treatment initiation.

The researchers also found higher CLL cell death rates in patients without IGHV mutations. This suggests IGHV-unmutated clones are more dependent on BCR signaling, which results in deeper responses, according to the researchers.

“This study was relatively small and not designed to answer questions that may change clinical practice,” said study presenter Ekaterina Kim, PhD, of The University of Texas MD Anderson Cancer Center in Houston. “However, we believe that this provides a mechanic explanation of clinical observations that patients with IGHV-unmutated CLL seem to have better chances of achieving undetectable MRD status on ibrutinib-based regimens compared with mutated CLL.”

Disclosures: The ALPINE trial was supported by BeiGene. The triplet trial was partly supported by Genentech and Acerta Pharma, LLC. The trial of brexucabtagene autoleucel was supported by Kite, a Gilead company. The cell death trial was partly supported by Pharmacyclics LLC. Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original references for full lists of disclosures.


1. Brown JR, Eichorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): Results from final analysis of ALPINE randomized phase 3 study. Presented at ASH 2022. December 10-13, 2022. Abstract LBA-6.

2. Ryan CE, Lampson BL, Tyekucheva S, et al. Updated results from a multicenter, phase 2 study of acalabrutinib, venetoclax, obinutuzumab (AVO) in a population of previously untreated patients with CLL enriched for high-risk disease. Presented at ASH 2022. December 10-13, 2022. Abstract 344.

3. Davids MS, Kenderian SS, Flinn IW, et al. ZUMA-8: A phase 1 study of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory chronic lymphocytic leukemia. Presented at ASH 2022. December 10-13, 2022. Abstract 3319.

4. Kim E, Sivina M, Vaca A, et al. High cell death rates at start of ibrutinib therapy predict for deeper remissions in patients with chronic lymphocytic leukemia (CLL). Presented at ASH 2022. December 10-13, 2022. Abstract 1801.

5. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: A single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402. doi:10.1016/s1470-2045(21)00455-1 z

6. Burger JA, Li KW, Keating MJ, et al. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib. JCI Insight. 2017;2(2). doi:10.1172/jci.insight.89904