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.

This article originally appeared on Hematology Advisor