In 2014, the U.S. Food and Drug Administration approved the targeted therapy ibrutinib as a first-line treatment for patients with chronic lymphocytic leukemia (CLL) with TP53 aberration. In 2016, the approval was extended to all CLL, irrespective of genetic features. Ibrutinib was the first of what is now a handful of targeted drugs that partially act in a TP53-independent manner, circumventing refractoriness to chemotherapy conferred by TP53 disruption. Targeted therapies are thus associated with enhanced CLL outcomes relative to chemoimmunotherapy, especially in high-risk disease categories.
Petra Langerbeins, MD, of the University Hospital Cologne in Germany, and colleagues report that since the relative effectiveness of targeted therapies varies across risk groups, patients treated with targeted therapies may require new prognostic tools. They published their analysis of the CLL International Prognostic Index (CLL-IPI) and its relevance to patients treated with targeted therapy in Blood.
The CLL-IPI combines multiple genetic, biochemical, and clinical parameters in a prognostic model to identify four subgroups with significantly different five-year survival rates ranging from 23.3% to 93.2%. IGHV mutational status, for example, is a reliable tool for predicting the time to first treatment in patients with treatment-naïve CLL. The serum parameter beta-2 microglobulin (B2M) correlates with disease burden and outcomes.
The investigators pooled data from 10 clinical phase II and III trials to evaluate the prognostic value of CLL-IPI in 991 patients with CLL receiving first-line therapy with targeted drugs and 1,256 patients treated with chemoimmunotherapy. Patients in the targeted therapy population received treatment with at least one dose of venetoclax (n=653), ibrutinib (n=68), ibrutinib plus venetoclax (n=261), or idelalisib (n=9). Patients in the chemoimmunotherapy group received treatment with at least one dose of fludarabine and cyclophosphamide plus rituximab (n=466), bendamustine plus rituximab (n=77), chlorambucil plus rituximab (n=263), or chlorambucil plus obinutuzumab (n=450). The median patient age was 64 years in the targeted treatment group and 68 years in the chemoimmunotherapy treatment group.
The unmutated IGHV status in the two groups was similar (59.3% in the targeted therapy group and 63.5% in the chemoimmunotherapy group). CLL-IPI risk groups in the targeted treatment group and the chemotherapy group were also similar: 13.4% and 13% low risk, 31.1% and 32.4% intermediate risk, 48.7% and 46.5% high risk, and 6.8% and 8.1% very high risk, respectively. The authors noted the short median observation time of the study, which was 40.5 months.
Analysis of the data set of patients treated with chemoimmunotherapy validated the applicability of CLL-IPI to those patients. The median progression-free survival (PFS) was not reached in the patients treated with targeted drugs. The researchers found that PFS rates varied by CLL-IPI risk groups for patients treated with targeted drugs. Those patients’ estimated 36-month PFS rates were 96.5% in the low-, 87.6% in the intermediate-, 82.4% in the high-, and 78.7% in the very high-risk CLL-IPI groups. Of patients treated with targeted drugs, 6% in the low-risk group, 19.5% in the intermediate-risk group, 25.9% in the high-risk group, and 32.8% in the very high-risk group had a documented PFS event.
When the researchers performed a matched-pair analysis, they found PFS differences in targeted therapies versus chemoimmunotherapy across all CLL-IPI risk groups. In the case of overall survival, the CLL-IPI demonstrated differences in all groups other than the low-risk group. CLL-IPI thus maintained its prognostic value in predicting PFS outcomes with targeted drugs but had a diminished ability to predict survival in those patients. The investigators found certain factors continued to offer valuable risk information for patients treated with targeted drugs; these factors included B2M, IGHV status, TP53 status, age, and Binet stage. The authors suggest that future studies focus on individual agents, especially BTK inhibitor monotherapy, which was not included in their analysis.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Langerbeins P, Giza A, Robrecht S, et al. Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies. Blood. 2024;143(25):2588-2598.
