Donors were HLA-matched sibling or matched unrelated (10/10). (64%) 6 of 42 (14.2%) before HSCT. With a median follow-up of 36 months (range, 19-53), 3-12 months 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 2-12 months limited and considerable chronic graft host disease (cGVHD) is usually 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], mutations were considered high-risk patients with reduced overall survival (OS). Better understanding of the molecular and genetic aspects of CLL brought Mouse monoclonal to PRAK novel and highly active strategies such as targeting kinases downstream of the Bcell receptor (BCR) pathway.1-3 These therapies have profondly modified the CLL therapeutic scenery, thanks to improved efficacy and better tolerability. However, the disease is still incurable and allogeneic hematopoietic AZD 7545 stem cell transplantation (HSCT) remains a valid option in selected high-risk patients.4,5 Prospective studies have shown that allogeneic HSCT can offer long progression free survival (PFS) and even a cure in 35% to 45% of high-risk patients. Reduced intensity conditioning (RIC) HSCT can be proposed AZD 7545 to older patients and patients with comorbidities who represent the bulk of the CLL populace. However disease recurrence, recorded in 22% to 46% patients, is usually still a major issue.6-9 Pre-transplantation refractoriness and bulky disease is associated with higher risk of post-transplantation progression.9,10 The level of post-transplantation minimal residual disease (MRD) is widely associated with the risk of further progression. In several studies, a negative MRD (MRDneg) status at 6 to 12 months translated into a progression incidence below 10%.11-14 Moreover, the MRDneg status may be reached by post-transplantation immunomodulation such as cyclosporine A (CsA) tapering or donor lymphocyte infusion (DLI).15 These data led us to conduct a prospective study evaluating an approach of RIC HSCT followed by a preemptive MRD-driven immune-intervention with the aim to achieve a MRDneg status at 12 months post-transplantation. Methods Study AZD 7545 design The ICLL03 RICAC-PMM (Reduced Intensity Conditioning Allogeneic Transplantation for CLL with Preemptive MDR Management), a joint FILO (French Innovative Leukemia Business) and SFGM-TC (Socit Francophone de Greffe de Moelle et de Thrapie Cellulaire) multicenter phase II trial evaluated the efficacy and safety of a preemptive immune-intervention based on MRD assessment in high-risk CLL. Eligible patients were 18 to 70 years old, with CLL (Matutes score 4 or 5 5) or lymphocytic lymphoma, and high-risk features according to the 2006 European Society for Blood and Marrow Transplantation (EBMT) consensus16 (observe (pneumonia associated with limited cGvHD (n=1) and early cytomegalovirus contamination (n=1) in a patient who received alemtuzumab in the last weeks AZD 7545 prior to transplantation. The three remaining deaths were related to disease progression with Richter transformation. Moreover three patients presented severe complications, namely two polyradiculopathy and one EpsteinCBarr virusinduced lymphoproliferative disease. With a median follow-up of survivors of 36 months (range, 19-53) the 3-year OS, PFS, and NRM were 86.9% (95% CI: 70.8-94.4), 62.9% (95% CI: 45.8-75.9) and 9.5% (95% CI: 3.7-23.4) respectively. Ten patients had progression occurring after a median of 12 months (range, 1-34). The 3-year cumulative incidence of relapse was 29.6% (95% CI: 17.3-47.7) (Figure 1). Salvage therapy was delivered in patients who relapsed after donor engraftment; eight patients received ibrutinib; six of them are still in remission at the last follow-up (32 to 52 months) while two had a transient response followed by progression with Richter transformation. (Table 2). Minimal residual disease (MRD) status at 12 months and MRD kinetics after hematopoietic stem cell transplantation At M12, 27 patients achieved MRDneg status, including 23 patients with an undetectable MRD (MRD limit of detection), seven patients remained.