Comparing the efficacy and safety of first-line treatments for chronic lymphocytic leukemia: a network meta-analysis

BACKGROUND: The chronic lymphocytic leukemia treatment strategies have transitioned from chemotherapy and chemoimmunotherapy to chemotherapy-free regimens. Frequentist network meta-analysis allows for direct and indirect comparisons between different treatments. METHODS: Randomized controlled trials assessing first-line treatments were included. Outcomes were progression-free survival (PFS), overall survival, undetectable minimal residual disease, objective response rate, and adverse events. Studies with comparable characteristics also underwent subgroup analysis, stratifying by age, comorbidities, IGHV status, and cytogenetic abnormalities. RESULTS: A total of 30 eligible trials involved 12 818 patients, and 30 treatments were included. Acalabrutinib demonstrated a PFS advantage over ibrutinib and obinutuzumab-venetoclax in patients aged older than 65 years or with unmutated IGHV. In younger patients with comorbidities, acalabrutinib-obinutuzumab had superior PFS compared with ibrutinib-obinutuzumab, ibrutinib-venetoclax, and obinutuzumab-venetoclax. For older patients with comorbidities, acalabrutinib and acalabrutinib-obinutuzumab outperformed obinutuzumab-venetoclax without statistically difference between them. Minimal residual disease-guided ibrutinib-venetoclax surpassed obinutuzumab-venetoclax in patients without comorbidities. Ibrutinib-obinutuzumab exhibited extended PFS benefits compared with obinutuzumab-venetoclax in patients with mutated IGHV or with del(17p) and/or TP53 mutations. Ibrutinib-venetoclax and ibrutinib-obinutuzumab had lower neutropenia rates than obinutuzumab-venetoclax. Ibrutinib-venetoclax had fewer infections than acalabrutinib and acalabrutinib-obinutuzumab. Acalabrutinib-obinutuzumab caused less diarrhea than ibrutinib-venetoclax but more headaches than ibrutinib-obinutuzumab and obinutuzumab-venetoclax. Obinutuzumab-venetoclax had lower hypertension rates than ibrutinib-obinutuzumab. Ibrutinib-venetoclax had fewer arthralgia than acalabrutinib-obinutuzumab. For any grade secondary primary neoplasms, ibrutinib-venetoclax and obinutuzumab-venetoclax was less than acalabrutinib-obinutuzumab. CONCLUSION: Tailored chemotherapy-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different adverse events spectra.