As reported in the Journal of Clinical Oncology, Ahn et al developed a four-factor model that identified risk groups for poorer outcomes among patients treated with ibrutinib for chronic lymphocytic leukemia.
Study Details
Patients treated with ibrutinib in phase II and III trials constituted the discovery data set (n = 720) and were divided into training (n = 541) and internal validation (n = 179) cohorts. An external validation cohort included 84 patients enrolled in a National Institutes of Health (NIH) phase II trial. Multivariate analysis and machine-learning algorithms identified factors for a prognostic model that was validated in the internal and external cohorts.
Key Findings
Four factors independently associated with inferior progression-free survival and overall survival were identified:
- TP53 aberration
- Prior treatment
- β-2 microglobulin ≥ 5 mg/L
- Lactate dehydrogenase > 250 U/L.
Each of the four factors contributed one point to a prognostic model that stratified patients into three risk groups: 0 to 1 point = low risk; 2 points = intermediate risk; and 3 to 4 points = high risk.
In the training, internal validation, and external validation cohorts, hazard ratios (HR) for 3-year progression-free survival for intermediate- and high-risk vs low-risk groups were 1.8 and 4.3, 2.0 and 4.5, and 1.8 and 7.3, respectively. The hazard ratios for 3-year overall survival were 2.7 and 6.2, 1.8 and 2.5, and 2.6 and 10.0, respectively. Differences for intermediate and high risk vs low risk did not always achieve statistical significance.
Among all 804 patients, 3-year progression-free survival rates were 47% for the high-risk (HR vs low-risk = 4.7, P < .0001), 74% for the intermediate-risk (HR vs low-risk = 1.9, P = .0010), and 87% for the low-risk group, respectively.
Among all 804 patients, 3-year overall survival rates were 63% for the high-risk (HR vs low-risk = 5.3, P < .0001), 83% for the intermediate-risk (HR vs low-risk = 2.5, P = .0002), and 93% for the low-risk group, respectively. The model remained significant when assessed in treatment-naive and relapsed/refractory patient cohorts.
In the NIH cohort, patients were assessed for BTK and PLCG2 mutations on a cross-sectional basis and at progression. The cumulative incidence of mutations was 50%, 40%, and 17% for the high-, intermediate-, and low-risk groups, respectively. In the NIH cohort, Richter’s transformation occurred in 17% of patients in the high-risk group and in no patients in the low-risk group.
The investigators concluded, “Patients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials.”
Inhye E. Ahn, MD, of the Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported the National Institutes of Health; Pharmacyclics LLC, an AbbVie Company; an American Society of Hematology Scholar Award; and Acerta LLC, a member of the AstraZeneca Group. For full disclosures of the study authors, visit ascopubs.org.
