Standard Approach for Inactive, Early CLL Remains a Wait-and-Watch Strategy

A watch-and-wait approach remains the standard of care for patients with early-stage chronic lymphocytic leukemia (CLL) with inactive disease, according to findings from a recent phase 3 trial.

In particular, the final analysis of the phase 3 CLL12 trial was presented by Dr. Petra Langerbeins at the 2023 EHA Congress.

Findings from a previous analysis demonstrated that Imbruvica (ibrutinib) improved event-free survival in patients with early-stage disease.

Patients with Binet stage A disease (meaning no anemia, no thrombocytopenia and fewer than three areas of lymphoid tissue enlargement) were screened for eligibility for the trial and underwent risk assessment. Patients with low risk (152 patients) were assigned to the watch-and-wait arm, and those determined to be at increased risk were assigned to receive Imbruvica (182 patients) versus placebo (181 patients).

The primary focus of this trial was event-free survival, defined as time to symptomatic progression, CLL treatment or death. Other areas of interest included progression-free survival (the time during and after treatment when a patient with cancer lives without disease worsening), time to next treatment (the time from initiating one treatment to the initiation of another line of therapy) and overall survival (the time when a patient with cancer is alive).

“(Event-free survival), (progression-free survival) and (time to next treatment) were significantly longer for patients in the (Imbruvica) group,” said Langerbeins, of the division of hematology, immunology, infectiology, intensive care and oncology at the University of Cologne in Germany. “But (Imbruvica) did not prolong survival as compared with placebo.”

The overall response rate (the percentage of patients with a partial or complete response to treatment) was 72.5% in the Imbruvica group at a median of 69.3 months of observation time. Further, event-free survival, progression-free survival and time to next treatment were not reached (meaning that more than half of patients in a trial were still alive or did not meet a certain outcome) in the treatment group compared with 14 months, 51.6 months and 68.5 months, respectively, in the placebo group.

Regarding safety, 9.9% of patients in the Imbruvica group (170 patients) reported a serious side effect versus 14.9% in the placebo group (168 patients).

Mild to life-threatening second malignancies were reported in 12.9% of patients in the Imbruvica group versus 21.4% in the placebo arm. Second malignancies that caused death were reported in 1.2% and 3%, respectively. In the watch-and-wait group (152 patients), 9.9% of patients reported a mild to life-threatening second malignancy and 1.3% of patients reported a second malignancy that led to death.

The median number of treatment cycles was 39 in the Imbruvica group and 27.5 in the placebo group. The main reason for early treatment discontinuation was side effects in the Imbruvica group (72.4%) compared with progressive disease (48.5%) in the placebo group.

Regarding subsequent therapies administered, 9.9% of the watch-and-wait group received subsequent treatment, with the majority receiving targeted therapies (86.7%) or chemoimmunotherapy (13.3%). In the Imbruvica group, 15.9% received subsequent treatment. Patients received targeted therapies or chemoimmunotherapy equally (48.3%) or anti-CD20 monoclonal antibody (3.4%). In the placebo group, 43.6% received subsequent treatment. Patients received chemoimmunotherapy (53.2%), targeted therapies (45.6%) or anti-CD20 monoclonal antibody (1.3%).

The mortality rate was 6.6% in the Imbruvica group, 7.7% in the placebo group and 3.9% in the watch-and-wait group.

When comparing the overall survival between the treatment and placebo groups, overall survival was not reached for both arms. Investigators reported that overall survival from diagnosis was not reached and revealed no significant differences in the median when comparing treatment, placebo and watch-and-wait groups.

“The CLL12 study demonstrates that in patients with early stage CLL, (Imbruvica) is associated with relevant cardiovascular toxicity and increased susceptibility to bleeding,” Langerbeins said. “The median survival is fantastic for untreated patients with risk features and is estimated to be more than 20 years,” Langerbeins concluded.

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