High-risk single-refractory and double-refractory chronic lymphocytic leukemia: feasibility and impact of alloHCT

This study aimed to compare the prognosis of patients with chronic lymphocytic leukemia (CLL) harboring TP53 abnormalities or a complex karyotype who are refractory to a covalent Bruton kinase inhibitors (cBTKi) or B-cell lymphoma 2 inhibitors (BCL2i; single-refractory high-risk [SRHR] genetics) with that of patients refractory to both cBTKi and BCL2i (double-refractory [DR]), and to investigate the outcome of allogeneic hematopoietic cell transplantation (alloHCT) in these settings. Overall, 47 patients were included. Of these, 40 patients entered the study in SRHR status, and 7 patients in DR status. Because 17 patients evolved from having SRHR to DR status over time, the total DR population comprised 24 patients. In the SRHR cohort, 78% had cBTKi-refractory and 22% had BCL2i-refractory disease, and TP53 abnormalities were in present in 90% of the patients with SRHR. Median event-free survival (defined as progression on next line, or death) of the SRHR cohort was 22 months; and median overall survival (OS) of the SRHR and DR cohorts was 51 and 21 months, respectively. A total of 22 patients underwent alloHCT; their nonrelapse mortality, relapse incidence, progression-free survival, and OS at 2 years was 19%, 19%, 62%, and 67%, respectively. Although long-term progression-free survivors were observed after transplantation, exploratory comparisons of patients who received a transplant and those who did not did not show a significant OS benefit in favor of alloHCT. In conclusion, the outlook of patients with high-risk single-refractory CLL is dismal but better than in patients with DR disease. In both settings, alloHCT is feasible and may overcome clinical and biological disease refractoriness; however, its exact benefit and timing remain to be determined.