No abstract

The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Agidentical unrelated (n ‫؍‬ 148) or sibling (n ‫؍‬ 118) donors. A total of 63% of patients (n ‫؍‬ 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio ‫؍‬ 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients.

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD).Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] ‫؍‬ 1.21, P ‫؍‬ .47, and HR ‫؍‬ 0.68, P ‫؍‬ .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR ‫؍‬ 0.84, P ‫؍‬ .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity. (Blood. 2011; 117(23):6375-6382) IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used worldwide as a curative therapy for malignant and nonmalignant hematologic disorders. Chronic graft-versushost disease (cGVHD) is the leading cause of nontransplantation mortality and morbidity after allogeneic HSCT. 1-3 cGVHD is a multiorgan disease resembling autoimmune disorders, such as scleroderma or systemic lupus. 4,5 Its incidence and prevalence are rising because of transplantation practices known to be associated with increased risk of cGVHD. 4,6 Indeed, older patients now undergo HSCT, and more transplantations are being performed from unrelated donors and/or with peripheral blood stem cells instead of bone marrow. Furthermore, the reduced-intensity conditioning (RIC) regimens developed during recent years have also led to higher numbers of transplantations performed worldwide. 7,8 However, although the acute GVHD (aGVHD) rate appears lower after RIC, the incidence of cGVHD seems to be unaffected. 9 Altogether, cGVHD thus remains the most challenging complication after allogeneic HSCT. 10 The main risk factor for developing cGVHD is the previous occurrence of aGVHD. 11 Thus, transplantation physicians have focused on decreasing the rate of aGVHD to lower nonrelapse mortality (NRM) associated with both aGVHD and cGVHD. However, although calcineurin inhibitors (cyclosporine or tacrolimus) in association with methotrexate have proven to decrease the aGVHD rate in randomized studies and although new regimens, such as the association of rapamycin with tacrolimus, seem to l...

It remains controversial whether alloreactive donor-derived natural killer (NK) cells display graft-versus-leukemia reactions after unmodified allogeneic hematopoietic stem cell transplantation (HSCT). The present study evaluated the role of inhibitory killer immunoglobulin-like receptor (KIR) ligand incompatibility using a welldefined and uniform setting of unmodified allogeneic HSCT in 374 patients with myeloid leukemias. The most striking finding was a significant heterogeneity in the 5-year estimates of hematologic leukemic relapse after human leukocyte antigen (HLA)-identical (n ‫؍‬ 237; 22%), HLA class I-disparate (n ‫؍‬ 89; 18%), and KIR ligandincompatible transplantations (n ‫؍‬ 48; 5%) (P < .04). Multivariate analysis confirmed that the relative relapse risk (RR) was influenced by HLA class I disparity alone (RR 0.49), but was lowest after HLA class I-disparate, KIR ligand-incompatible transplantations (RR 0.24) (P < .008). The primary graft failure rates, however, increased from 0.4% after HLA class I-identical to 2.3% after HLA class I-disparate, and to 6.3% after KIR ligandincompatible transplantations, respectively (P < .02). Unlike some other reports, no beneficial effect of KIR ligand incompatibility on other major endpoints of allogeneic HSCT (transplantation-related mortality, and overall and event-free survival) was detectable in the present study.

These results suggest that NOD2 mutations have influence on the occurrence of acute GVHD after transplantation.