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Novel Drug Combinations Achieving Undetectable Minimal Residual Disease in Patients with CLL

TOP - January 2021 Vol 14, No 1

The approaches to the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma are evolving, including the sequencing of therapy and a possibly expanded role for minimal residual disease (MRD) status, said William G. Wierda, MD, PhD, Section Chief, Chronic Lymphocytic Leukemia, M.D. Anderson Cancer Center, Houston, TX, at the National Comprehensive Cancer Network 2020 Virtual Congress: hematologic malignancies.

Eliminating chemoimmunotherapy and replacing it with more effective combinations of small-molecule inhibitors are important goals in the treatment of CLL.

“We’d like to get as high a proportion of patients in as deep a remission as possible, with a fixed duration of treatment, and in that way, lengthen progression-free survival [PFS] and overall survival [OS],” said Dr Wierda. Undetectable MRD correlates with longer PFS and OS.

“We’re refocused on MRD as a treatment end point, particularly now with our combination therapies. We’re now integrating MRD status as a response assessment tool,” Dr Wierda said. “MRD status correlates with clinical outcomes, therefore making it a good early indicator for response and expected outcomes.”

Immune reconstitution is another goal of treatment because patients with CLL do not have normal immune function and are at increased risk for infections and second cancers.

According to Dr Wierda, tests that are essential in the selection of first-line treatment for CLL include fluorescence in situ hybridization to determine the rate of cells with the 17p deletion (del 17p), as well as TP53 and IGHV mutations status. Among treatment-naïve patients with CLL and TP53 abnormalities, the presence of IGHV mutation indicates a better long-term prognosis.

BTK and BCL-2 Inhibitors, CD20 Antibodies

Bruton tyrosine kinase (BTK) inhibitor–based therapy for CLL has proved superior to chemoimmunotherapy in the first-line setting, resulting in prolonged PFS and OS. In the RESONATE-2 study, ibrutinib (Imbruvica) overcame the poor prognosis associated with del 11q and no IGHV mutation, whereas with chemoimmunotherapy, “del 11q and unmutated IGHV were high-risk features, with a shorter PFS,” observed Dr Wierda.

In the ELEVATE-TN study, the PFS was improved with the combination of the BTK inhibitor acalabrutinib (Calquence) and the CD20 antibody obinutuzumab (Gazyva) compared with acalabrutinib monotherapy. This combination was also far superior to the chemoimmunotherapy combination of obinutuzumab and chlorambucil (Leukeran).

The BCL-2 inhibitor venetoclax (Venclexta) is associated with a high rate of undetectable MRD, and combinations that include a BCL-2 inhibitor result in high rates of response and undetectable MRD, Dr Wierda said.

In the CLL14 study presented earlier this year, in treatment-naïve patients with CLL and comorbidities, the combination of venetoclax and obinutuzumab had a significantly superior median PFS versus chlorambucil plus obinutuzumab (not reached vs 35.6 months, respectively) and 3-year PFS of 81.9% versus 49.5%, respectively.

At the end of treatment, 71% of the patients who received venetoclax plus obinutuzumab had undetectable MRD in the blood. At 18 months of follow-up, 47.2% of the patients who received this combination had undetectable MRD compared with only 7.4% of patients who received chlorambucil plus obinutuzumab.

The combination of venetoclax and ibrutinib has shown synergy in the first-line treatment setting, resulting in undetectable MRD in bone marrow in 75% of patients at 24 months. Other studies have confirmed the efficacy of this BCL-2 and BTK inhibition in terms of undetectable MRD in the peripheral blood and bone marrow.

The novel triplet combination of acalabrutinib, venetoclax, and obinutuzumab has also shown clinical promise.

BCL-2 and BTK Inhibition in the Relapsed Setting

Venetoclax consolidation therapy after BTK inhibition is being explored in a clinical trial at Dr Wierda’s institution.

“With BTK inhibitor–based therapy, you don’t see deep remissions. We still have disease we can measure even in patients who have been on ibrutinib or acalabrutinib for more than a year,” he said. In the ongoing trial, 68% of patients receiving venetoclax combination therapy have achieved undetectable MRD in bone marrow at 12 months.

In patients with relapsed CLL in the RESONATE study, ibrutinib treatment was associated with better PFS and OS than treatment with the CD20 antibody ofatumumab (Arzerra). In this setting, however, “we still worry about patients with del 17p,” Dr Wierda said, because their outcomes are worse than those of patients without del 17p.

In the ASCEND trial, acalabrutinib improved outcomes in patients with relapsed or refractory CLL compared with idelalisib (Zydelig) plus rituximab (Rituxan) or with bendamustine (Bendeka) plus rituximab, as reported earlier this year.

In the MURANO study, 60% of patients achieved undetectable MRD with the combination of venetoclax and rituximab in the relapsed setting. “This is unexpectedly high for relapsed treatment,” said Dr Wierda.

Venetoclax has been shown to be active after nonresponse with ibrutinib treatment. In the M14-032 study, patients whose disease progressed after treatment with ibrutinib and who had received a median of 4 previous therapies had an overall response rate of 65% with venetoclax. Of these patients, 42% had undetectable MRD in the peripheral blood at 24 weeks of follow-up. Venetoclax is also active in combination with ibrutinib in the relapsed setting, Dr Wierda said.

The investigational BTK inhibitor LOXO-305 has shown promising results in patients with CLL who have previously received an earlier-generation BTK inhibitor.

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