Watch-and-Wait Approach Remains the Standard for Patients with Early-Stage CLL


Phase 3 findings from the CLL12 trial support a watch-and-wait approach over systemic treatment with ibrutinib for patients with asymptomatic early-stage chronic lymphocytic leukemia.

Petra Langerbeins, MD

Petra Langerbeins, MD

Final results from the phase 3 CLL12 trial (NCT02863718) showed that ibrutinib (Imbruvica) did not improve survival outcomes for patients with asymptomatic early-stage chronic lymphocytic leukemia (CLL) compared with placebo and that it instead increased their risk of bleeding. According to investigators presenting the data at the 2023 EHA Congress, these findings support the standard watch-and-wait approach in early-stage, even though ibrutinib had been associated with prolonged event-free survival (EFS) in this population.

A total of 648 patients with Binet Stage A disease were screened for eligibility and underwent risk assessment. Patients with low risk (n = 152) were allocated to the watch-and-wait arm and those determined to be at increased risk were randomly assigned to receive 420 mg daily of ibrutinib (n = 182) vs placebo (n = 181). Investigators determined that 133 patients were not eligible for participation.2

The primary end point was EFS, defined as time to symptomatic progression. Secondary end points were CLL treatment, or death, progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS).

“EFS, PFS, and TTNT were significantly longer for patients in the ibrutinib group,” said Petra Langerbeins, MD, of the Division of Haematology, Immunology, Infectiology, Intensive Care, and Oncology at the University of Cologne in Germany. “But ibrutinib did not prolong survival as compared with placebo.”

The overall response rate (ORR) was 72.5% in the ibrutinib group at a median of 69.3 months observation time. Further, EPS, PFS, and TTNT were not reached in the treatment group compared with 14 months (HR, 0.174; 95% CI, 0.122-0.246; P < .001), 51.6 months (HR, 0.276; 95% CI, 0.188-0.407; P < .001), and 68.5 months (HR, 0.244; 95% CI, 0.156-0.380; P < .001), respectively, in the placebo group.1

Regarding safety, 9.9% of patients in the ibrutinib group (n = 170) reported a serious adverse event (AE) vs 14.9% in the placebo group (n = 168) and both groups reported AEs of common toxicity criteria of 99.4% (grades 1 to 5).

Grades 1 to 5 second malignancies were reported in 12.9% of patients in the ibrutinib group vs 21.4% in the placebo arm. Grade 5 second malignancies were reported in 1.2% and 3%, respectively. In the watch and wait group (n = 152), 9.9% of patients reported a grade 1 to 5 second malignancy and 1.3% of patients reported a grade 5 second malignancy.

“Adverse events of clinical interest were documented in 80% of the ibrutinib group, including 4 grade 5 events,” Langerbeins said. “The rate of bleeding was 36.5% and cardiac arrythmias including atrial fibrillation was 22.4% in the ibrutinib group.”

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

“With longer follow-up, we have identified the superiority of ibrutinib over placebo in terms of EFS and symptomatic disease progression. The median EFS was not reached in the ibrutinib group and was 51.6 months in the ibrutinib group,” Langerbeins said. PFS until disease progression or death, not including symptomatic disease progression, was not reached in the ibrutinib group vs 14 months in the placebo group.

Turning to 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 ibrutinib 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 TTNT was not reached in the ibrutinib arm and was 68.5 months in the placebo group. An experimental end point from the start of subsequent treatment showed that patients in the ibrutinib group had a median PFS2 of 16.6 months vs 35.1 months for the placebo group.

The mortality rate was 6.6% in the ibrutinib group, 7.7% in the placebo group, and 3.9% in the watch-and-wait group. “Only 1 case of progressive disease was documented in both the ibrutinib and placebo group,” Langerbeins said. “However, in the ibrutinib group, 2 cases of intracranial bleeding and 2 cases of cardiac decompensation or sudden death were reported in the ibrutinib group and 1 case in the placebo group.” Five deaths in the placebo group were attributed to a second malignancy, including Richter’s transformation.

When comparing the OS with the treatment and placebo groups, OS was not reached for both arms (HR, 0.791; 95% CI, 0.358-1.748; P = .562). Investigators reported that OS 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, ibrutinib 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.


  1. Langerbeins P, Robrecht S, Nieper P, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage chronic lymphocytic leukemia (CLL): final results of the phase 3, double-blind, placebo controlled CLL12 trial. HemaSphere. 2023;7(suppl 3):S200.
  2. Langerbeins P, Zhang C, Robrecht S, et al. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022;139(2):177-187. doi:10.1182/blood.2021010845
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