Efficacy of minimal residual disease driven immune-intervention after allogeneic hematopoietic stem cell transplantation for high-risk chronic lymphocytic leukemia: results of a prospective multicenter trial

Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing chronic lymphocytic leukemia (CLL). Minimal residual disease (MRD) assessment at 12 months (M12) post-HSCT is predictive of relapse. This phase II study aimed to achieve M12 MRD negativity (MRDneg) using an MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed in case of failure by donor lymphocytes infusions. Patients had high-risk CLL according to the 2006 European Society for Blood and Marrow Transplantation consensus, in complete or partial response with lymphadenopathy <5 cm and comorbidity score ≤2. Donors were HLA-matched sibling or matched unrelated (10/10). Fortytwo enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12- MRDneg status was achieved in 27 of 42 patients (64%) versus 6 of 42 (14.2%) before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95% Confidence Interval [CI]: 70.8-94.4), 9.5% (95% CI: 3.7-23.4) and 29.6% (95% CI: 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95% CI: 23-53) and 23% (95% CI: 10-36) including two cases post Md-PII. Fifteen patients converted to MRDneg either after cyclosporine A withdrawal (n=12) or after cGvHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (Hazard ratio [HR] 0.14 [range, 0.04-0.53], P=0.004) and improvement of both progression free (HR 0.18 [range, 0.06-0.6], P<0.005) and overall (HR 0.18 [range, 0.03-0.98], P=0.047) survival. These data highlight the value of MRD-driven immune-intervention to induce prompt MRD clearance in the therapy of CLL (clinicaltrials gov. Identifier: NCT01849939).