One-Two Combo Packs a Punch in High-Risk CLL

A one-two combination of ibrutinib (Imbruvica) followed by add-on venetoclax (Venclexta) produced impressive responses for the vast majority of high-risk chronic lymphocytic leukemia (CLL) patients with previously untreated disease, a phase II study indicated.

In the investigator-initiated trial of 80 such patients, 88% achieved either a complete remission (CR) or CR with incomplete count recovery after 12 cycles of the combination, and 61% had undetectable minimal residual disease (MRD), reported Nitin Jain, MD, of MD Anderson Cancer Center in Houston, and colleagues.

Importantly, and as was hoped, the use of upfront ibrutinib greatly attenuated the risk of patients developing tumor lysis syndrome on venetoclax, they wrote in the New England Journal of Medicine.

Only three patients developed laboratory evidence of tumor lysis syndrome and no patient developed symptomatic evidence of the syndrome, which can occur when large amounts of tumor cells are killed off during treatment, causing electrolyte and metabolic disturbances that can lead to multi-system organ failure and death.

“These efficacy results are substantially better than what has been reported with ibrutinib or venetoclax monotherapy for patients with CLL,” Jain and colleagues observed. “Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents.”

In the recent approval of venetoclax plus obinutuzumab (Gazyva) for first-line CLL, 57% of patients achieved MRD negativity in bone marrow after 3 months of therapy (CR data are still unavailable).

The current study confirmed that initial treatment with ibrutinib not only reduces tumor bulk, but the risk of tumor lysis syndrome associated with venetoclax too, said Adrian Wiestner, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, commenting on the findings in an accompanying editorial.

Wiestner noted that if physicians extrapolate from earlier venetoclax studies, patients who achieve undetectable MRD in bone marrow will likely enjoy a long period of progression-free survival even after treatment is discontinued. “Similarly, on the basis of experience with single-agent ibrutinib in first-line therapy, patients with detectable MRD who continue ibrutinib can be expected to do well,” he added.

Important questions that remain, said Wiestner, include whether or not this regimen can ever be safely discontinued in those who achieve remission but with detectable MRD, and whether some high-risk subgroups will need additional therapy.

“Preclinical studies provide a strong rationale for combining ibrutinib and venetoclax, and it is hoped that the combination can prevent the emergence of drug resistance,” Wiestner wrote, but added that the mechanisms of resistance to the combination, as well as whether or not a different BTK inhibitor might preserve activity following such resistance, remain to be answered.

Patients in the study were required to have at least one-high risk genetic feature of CLL (chromosome 17p or 11q deletions, mutated TP53, unmutated IgVH), or be at least age 65, regardless of genetic features. Median age of the whole population was 65 years, but 30% of the group were 70 or older. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, was given daily at a dose of 420 mg for the first three 28-day cycles followed by the addition of the potent BCL2 inhibitor venetoclax at the start of cycle four, which was given in weekly dose escalations to a target dose of 400 mg per day.

The combination was given for a total of 24 cycles, at which point patients who tested positive for MRD in bone marrow could continue with ibrutinib alone until disease progression or unacceptable toxicity. All patients received antiviral prophylaxis with valacyclovir or acyclovir.

The authors noted that after the first three ibrutinib monotherapy cycles, mostly partial responses were observed. However, once exposed to venetoclax, responses improved with increasing numbers of patients achieving either a CR, CR with incomplete count recovery, or remission with undetectable MRD.

For example, after 6 cycles of the combination, 73% had achieved either a CR or CR with incomplete count recovery, while 40% were in remission with undetectable MRD. After 18 cycles of the combination, 96% of patients were in CR or CR with incomplete count recovery, while 69% were in remission with undetectable MRD. After six cycles in patients ages 65 and older, 74% achieved a CR or CR with incomplete count recovery, while 44% had undetectable MRD. After 12 cycles these rates increased to 94% and 76%, respectively.

Good responses were documented in all high-risk subgroups independent of mutation status. At 1 year, 98% of the cohort were free of disease progression and 99% were alive.

Grade 3/4 adverse events (AEs) occurred in 60% of patients, with bruising, arthralgia, and diarrhea being the most common non-hematologic AEs. Some 48% of patients also developed grade 3/4 neutropenia; two patients developed thrombocytopenia during the combination phase of the study.