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A fixed-duration, three-drug regimen for chronic lymphocytic leukemia (CLL) achieved deep and durable remissions lasting for up to 7 years, according to updated results from a prospective study.

Median progression-free survival (PFS) exceeded 80 months with IVO, comprising obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta), among patients with untreated or relapsed/refractory CLL. Almost 60% of patients with untreated disease had undetectable minimal residual disease (uMRD) status, as did 44% of the relapsed/refractory cohort. Overall response rate (ORR) at the end of treatment was 88% in patients with previously treated CLL, and 84% and 96% for two untreated cohorts.

Interestingly, uMRD status had no association with PFS, reported Kerry Rogers, MD, of the Ohio State University in Columbus, at the European Hematology Association (EHA) meeting in Madrid.

"Additional studies are needed to determine the relative benefit of either three- versus two-drug regimens, particularly the inclusion of an anti-CD20 monoclonal antibody, as well as mechanisms of resistance and sensitivity, and, of course, the optimal sequence of treatments over the lifespan of patients with CLL," she said.

A smaller study reported at EHA showed that 90% of patients with untreated CLL had uMRD4 status (<10^-4) in both bone marrow and peripheral blood after seven cycles of pirtobrutinib (Jaypirca), venetoclax, and obinutuzumab (PVO). Responses continued to deepen over time, with 85% to 90% of patients achieving uMRD6 (<10^-6) after 13 cycles of therapy, reported Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Long-Term Follow-Up

Rogers reported an update on the IVO regimen, which had previously demonstrated durable remissions in CLL at 4 years. Several triplet regimens have shown the ability to achieve durable remissions, she noted. However, more precise information about duration of disease control and factors predictive of uMRD status and PFS is needed.

The IVO evaluation involved 75 patients with relapsed/refractory (n=25) or untreated (n=50) CLL. Treatment consisted of 14 cycles of 28 days each, beginning with obinutuzumab in the first cycle, then adding ibrutinib in cycle 2, and venetoclax in cycle 3. Primary endpoints were PFS and rates of uMRD in peripheral blood or bone marrow.

At the end of treatment, 88% of relapsed/refractory patients had achieved partial response or better, and two different cohorts of untreated patients had an ORR of 84% and 96%. The uMRD rates were 44% for the relapsed/refractory group and 58% for the two untreated cohorts combined.

The median PFS was 81.8 months for the relapsed/refractory patients and 88.5 months for the first cohort of untreated patients. Median PFS had yet to be reached in the second untreated cohort, but Rogers reported that the group had an estimated 48-month PFS rate of 91%. Median overall survival (OS) had yet to be reached in any of the cohorts, but 60-month estimates were 95% for the relapsed/refractory group and 90.9% for the first untreated group.

Analyses of factors associated with PFS identified a number of prior treatments and increased beta-2 microglobulin as univariate predictors of worse PFS. Only increased beta-2 microglobulin remained significant in a multivariable analysis. Factors that adversely affected uMRD were increased beta-2 microglobulin and lactate dehydrogenase (LDH). Only LDH remained significant in the multivariable analysis.

An evaluation of PFS by uMRD status showed no significant association.

Impressive Results in Smaller Study

Jain reported findings from a study of PVO in patients with previously untreated CLL. In a previous study of the ibrutinib-venetoclax doublet, uMRD4 rates were 33% at 6 months and 52% at 12 months, he said. Pirtobrutinib currently has FDA approval for relapsed/refractory CLL, following treatment with a Bruton's tyrosine kinase inhibitor and a BCL2 inhibitor.

The primary objective was uMRD4 with the PVO regimen, and the primary endpoint was uMRD4 after cycle 7. Using a historical rate of 40% at 6 months with the venetoclax-ibrutinib doublet, investigators had a 60% target for the PVO regimen.

The trial included 40 patients who had a median follow-up of 11.7 months. One patient stopped treatment after cycle 3 because of a newly diagnosed head and neck cancer.

The results showed a shift in risk category after the first cycle of therapy, which included only pirtobrutinib and obinutuzumab. At the start of treatment, 38 (95%) patients were classified as medium or high risk. At the start of cycle 2, 10 patients were classified as medium or high risk (only two as high risk).

The trial met the primary endpoint, achieving uMRD4 rates of 92% and 90% in peripheral blood and bone marrow, respectively, after the seventh cycle of therapy. After cycle 13 (n=20), uMRD6 rates in peripheral blood and bone marrow were 90% and 85%. Only one of the 20 patients did not achieve at least uMRD4 (in bone marrow).

With respect to adverse events (AEs), grade 3/4 neutropenia and thrombocytopenia occurred in 60% and 18% of patients, respectively, and 55% required growth factor support. Neutropenia was the most common reason for dose reduction of pirtobrutinib and venetoclax.

"With a median follow-up of 11.7 months, no patient has progressed or died in the study," said Jain. "The trial is currently enrolling a 40-patient expansion cohort, which we hope to report at a subsequent meeting."

The three-drug regimen competition in CLL has become crowded. In addition to the IVO and PVO regimens, at least two other triplet regimens have produced encouraging results.

Just 2 months ago, a published study showed that 42 of 45 patients with relapsed/refractory CLL achieved uMRD status in peripheral blood with acalabrutinib (Calquence), obinutuzumab, and venetoclax. The estimated 3-year OS rate was 93.8%.

In addition, the combination of zanubrutinib (Brukinsa), obinutuzumab, and venetoclax led to a uMRD rate (blood and bone marrow) of 89% (33 of 37) among patients with untreated CLL.