Long-Term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Chronic Lymphocytic Leukemia (CLL): 10-Year Follow-up of the Gcllsg CLL3X Trial

PURPOSE of this analysis was to provide 10-year follow-up of the GCLLSG CLL3X trial which aimed at evaluating reduced-intensity conditioning (RIC) HSCT in patients with poor-risk CLL.

DESIGN: The CLL3X trial included 100 patients (median age 53 (27-65) years), of whom 90 patients were allografted with blood stem cells from related (40%) or unrelated donors (60%) using fludarabine-alkylator-based RIC regimens. 24% had refractory CLL at HSCT, and 37% had a TP53 deletion and/or mutation. The 6-year follow-up of the trial including the observation that genetic risk factors such as TP53 lesions and SF3B1 and NOTCH1 mutations had no prognostic impact has been previously reported (Blood 2013;119:4851). Survival and relapse information was requested for all patients who underwent HSCT within the CLL3X trial in 9 German centres (the Canadian centre was unavailable for follow-up) and were alive at the 6-year follow-up.

RESULTS: Follow-up information was received for 33/44 patients (75%) alive at the 6-year follow-up. Of these, 2 patients had experienced non-relapse mortality (NRM; 1 chronic GVHD, 1 secondary cancer) and another 2 had CLL recurrence 9.3 and 9.7 years post HSCT, respectively. With a median follow-up of survivors of 9.3 (0.6-15.5) years, 10-year NRM, relapse incidence (REL) event-free survival (EFS), and overall survival (OS) of all 90 patients allografted was 26%, 57%, 32%, and 51%, respectively. Absence of minimal residual disease (MRD) at the 12-month landmark post HSCT was highly predictive for an increased relapse risk (10-year REL 25% vs 80% if MRD was present at the 12-month landmark, p <0.0001), in particular if MRD eradication occurred only after immunosuppression withdrawal, suggesting of effective graft-versus-leukemia activity (GVL; 10-year REL 12%). In the 33 patients who were event-free at the 6-year landmark, NRM, REL, EFS, and OS 4 years after the 6-year landmark was 4%, 24%, 74%, and 93% (median follow-up after 6-year landmark 4.1 (0.1-8.5) years) without any effect of TP53 lesions on relapse risk. Notably, no relapse event occurred beyond 10 years post HSCT. Only one out of 33 patients included in the 6-year landmark analysis died from CLL, 4 relapsed patients are currently responding to pathway inhibitors, and the remaining patient with CLL recurrence still does not need treatment.

CONCLUSIONS: Long-term observation of patients allografted in the CLL3X trial confirms that RIC HSCT can provide GVL-mediated sustained disease control in a sizable proportion of patients with poor-risk CLL independent of the TP53 status. Patients who are in MRD-negative remission one year after HSCT have a 75% probability of remaining disease-free at least for 10 years. However, late relapses do occur but may benefit from strategies involving innovative pathway inhibitors.