Both preemptive therapy and universal prophylaxis are used to prevent cytomegalovirus (CMV) disease after transplantation. Randomized trials comparing both strategies are sparse. Renal transplant recipients at risk for CMV (D+/R−, D+/R+, D−/R+) were randomized to 3-month prophylaxis with valacyclovir (2 g q.i.d., n = 34) or preemptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days, n = 36) for significant CMV DNAemia (≥2000 copies/mL by quantitative PCR in whole blood) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. The 12-month incidence of CMV DNAemia was higher in the preemptive group (92% vs. 59%, p < 0.001) while the incidence of CMV disease was not different (6% vs. 9%, p = 0.567). The onset of CMV DNAemia was delayed in the valacyclovir group (37 ± 22 vs. 187 ± 110 days, p < 0.001). Significantly higher rate of biopsy-proven acute rejection during 12 months was observed in the preemptive group (36% vs. 15%, p = 0.034). The average CMV-associated costs per patient were $5525 and $2629 in preemptive therapy and valacyclovir, respectively (p < 0.001). However, assuming the cost of $60 per PCR test, there was no difference in overall costs. In conclusion, preemptive valganciclovir therapy and valacyclovir prophylaxis are equally effective in the prevention of CMV disease after renal transplantation.

Life-threatening graft-versus-host disease (GVHD) limits the use of HLA-C-mismatched unrelated donors in transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient's only option for cure. We examined the role for HLA-C expression levels to identify permissible HLA-C mismatches. The median fluorescence intensity, a proxy of HLA-C expression, was assigned to each HLA-C allotype in 1975 patients and their HLA-C-mismatched unrelated transplant donors. The association of outcome with the level of expression of patients' and donors' HLA-C allotypes was evaluated in multivariable models. Increasing expression level of the patient's mismatched HLA-C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. Increasing expression level among HLA-C mismatches with residue 116 or residue 77/80 mismatching was associated with increased nonrelapse mortality. The immunogenicity of HLA-C mismatches in unrelated donor transplantation is influenced by the expression level of the patient's mismatched HLA-C allotype. HLA-C expression levels provide new information on mismatches that should be avoided and extend understanding of HLA-C-mediated immune responses in human disease

A catalog of common, intermediate and well‐documented (CIWD) HLA‐A, ‐B, ‐C, ‐DRB1, ‐DRB3, ‐DRB4, ‐DRB5, ‐DQB1 and ‐DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two‐field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well‐documented (≥5 occurrences) or not‐CIWD. Overall 26% of alleles in IPD‐IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two‐field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well‐documented alleles. Full‐field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.

The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (Po0.001).In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (Po0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of o6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR ¼ 1.1), whereas there was a suggestion for higher relapse risk in patients given X6 mg/kg ATG (HR ¼ 1.4, P ¼ 0.08). In summary, these data suggest that a certain amount of in vivo T-cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC. INTRODUCTIONThe use of PBSC instead of BM in patients receiving grafts from HLA-matched donors after myeloablative conditioning has been associated with faster hematological recovery, lower relapse risk in patients with advanced disease (due to higher immune-mediated graft-versus-tumor (GVT) effects), but also higher incidence extensive chronic GVHD. 1-4 These observations prompted several groups of investigators to study in vivo T-cell depletion of the graft with antithymocyte globulin (ATG) or alemtuzumab as a way to reduce severe GVHD in patients given PBSC after highdose myeloablative conditioning regimen. [5][6][7] These studies demonstrated that the use of ATG or alemtuzumab was successful at preventing severe GVHD without apparently increasing the relapse incidence (RI). [5][6][7] In contrast to patients given grafts after myeloablative conditioning who benefit from both the high-dose chemo/radiotherapy given as part of the conditioning regimen and the GVT effect for tumor eradication,

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.

Key Points• In AML with normal cytogenetics, age, response to induction, and FLT3-ITD allow for an estimate of outcome after allogeneic HSCT in CR1.• Neither variation of classical transplant techniques nor development of chronic GVHD outweighs the negative impact of FLT3-ITD.To analyze the influence of distinct combinations of molecular aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for cytogenetically normal acute myeloid leukemia (CN-AML), a retrospective registry analysis was performed on 702 adults undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1 mut ) and FLT3 internal tandem duplications (FLT3-ITD). Double-negative patients were evaluated for mutations of the CCAAT/enhancer binding protein a gene (CEBPa). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. Two-year OS from HSCT was 81 6 5% in NPM1 wt revealed excellent results both in patients with CEBPa mut and with a triple negative genotype (2-year OS: 100%/77 6 3%). In a Cox-model of predefined variables, age, FLT3-ITD and >1 course of chemotherapy to reach CR were risk factors associated with inferior outcome, regardless of NPM1 mutational status, variations of transplant protocols, or development of graft-versus-host disease. In a prognostic risk classification, 2-year OS/LFS rates were 88 6 3%/79 6 4% without any, 77 6 2%/73 6 3% with one, and 53 6 4%/50 6 4 with ‡2 risk factors (P 5

BACKGROUND: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are 2 widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT). METHODS: The current survey compared transplantation outcomes for a cohort of 394 acute myeloid leukemia (AML) patients given bone marrow or peripheral blood stem cells from human leukocyte antigen-identical siblings after FB (n 5 218) or FM (n 5 176). Patients given manipulated grafts and those given Tcell-depleting agents (anti-thymocyte globulins or alemtuzumab) were not included. RESULTS: At the time of transplantation, 266 patients (68%) were experiencing their first complete remission (CR), 69 (18%) were experiencing a later CR, and 59 (15%) had advanced disease. The incidences of acute and chronic graft-versus-host disease were similar in the 2 groups of patients. The 2-year relapse incidence (RI), nonrelapse mortality (NRM) rate, leukemia-free survival (LFS) rate, and overall survival (OS) rate were 31% 6 3%, 18% 6 3%, 51% 6 4%, and 54% 6 4%, respectively, for FB patients and 20% 6 3% (P 5.007), 20% 6 3% (P 5.4), 60% 6 4% (P 5.08), and 62% 6 4% (P 5.2), respectively, for FM patients. Among FB patients given intravenous busulfan (n 5 81), the 2-year RI, NRM, LFS, and OS rates were 26% 6 5% (P 5.43 vs FM patients), 25% 6 6% (P 5.18), 49% 6 7% (P 5.07), and 54% 6 7% (P 5.13), respectively. In multivariate analyses, FM was associated with a lower RI (hazard ratio [HR], 0.5; P 5.01) and a trend toward higher NRM (HR, 1.6; P 5.1) with similar LFS (HR, 0.8; P 5.2) and OS (HR, 0.9; P 5.6). CONCLUSIONS: These results suggest that although FM provides better AML control than FB as an RIC regimen for allo-SCT, the 2 regimens provide similar survival. Multicenter randomized studies are needed to confirm these findings. Cancer 2015;121:1048-55.

Valacyclovir and oral ganciclovir are equally effective in the prevention of CMV disease after renal transplantation. Both regimens are cost-effective. Valacyclovir is associated with a significantly reduced risk of acute rejection compared with both ganciclovir prophylaxis and deferred therapy.