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

The aims of this study were to compare the prognosis of patients with CLL harboring TP53 abnormalities or a complex karyotype who are refractory to a cBTKi or BCL2i (single-refractory high-risk genetics; SRHR) 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. As 17 patients evolved from SRHR to DR over time, the total DR population comprised 24 patients. In the SRHR cohort, 78% were cBTKi-refractory and 22% BCL2i-refractory, and TP53 abnormalities were in present in 90% of the SRHR patients. 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 single- and double-refractory cohorts was 51 and 21 months, respectively. A total of 22 patients underwent alloHCT; their non-relapse 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 transplanted and non-transplanted patients 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 double-refractory disease. In both settings, alloHCT is feasible and may overcome clinical and biological disease refractoriness. However, its exact benefit and timing remains to be determined.