Cytomegalovirus (HCMV) reactivation is found frequently after allogeneic hematopoietic stem cell transplantation (alloSCT) and is associated with an increased treatment-related mortality. Recent ...reports suggest a link between HCMV and a reduced risk of cancer progression in patients with acute leukemia or lymphoma after alloSCT. Here we show that HCMV can inhibit the proliferation of the acute myeloid leukemia cell line Kasumi-1 and the promyeloid leukemia cell line NB4. HCMV induced a significant up-regulation of HLA-class-II-molecules, especially HLA-DR expression and an increase of apoptosis, granzyme B, perforin and IFN-γ secretion in Kasumi-1 cells cocultured with peripheral blood mononuclear cells (PBMCs). Indolamin-2,3-dioxygenase on the other hand led only to a significant dose-dependent effect on IFN-γ secretion without effects on proliferation. The addition of CpG-rich oligonucleotides and ganciclovir reversed those antiproliferative effects. We conclude that HCMV can enhance alloreactivity of PBMCs against Kasumi-1 and NB4 cells in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required.
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 Ag-identical 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.
Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim ...of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis.
We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55 ± 7.5 months.
Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001).
The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation.
A preventive effect of early human cytomegalovirus (HCMV) replication was evaluated in 136 non-Hodgkin lymphoma (NHL) patients with mature B-cell NHLs (n = 94), and mature T- and NK-cell NHLs (n = ...42) after allogeneic stem cell transplantation (alloSCT). Most study-patients (85%) had received at least 2 cycles of chemotherapy and 60% had also received an autograft prior to alloSCT. First detection of CMV-replication by HCMV antigenemia/viremia was found at a median of day +33 after alloSCT. The cumulative incidence of relapse at 5 years after alloSCT was 38% (95% confidence interval 95%CI: 26-49) in 82 patients without compared to 22% (95%CI: 8-37) in 54 patients with HCMV antigenemia/viremia (p = .013). A decreased relapse risk of HCMV replication was confirmed by multivariate analysis for HCMV antigenemia/viremia (Hazard ratio HR: 0.29, 95%CI: 0.11-0.76, p < .014). This report demonstrated a possible improvement of relapse incidence after replicative HCMV infection in patients with NHL after alloSCT.
Cytomegalovirus (HCMV) reactivation occurs frequently after hematopoietic stem cell transplantation and is associated with an increased treatment-related mortality. Induction of apoptosis by HCMV is ...unusual because HCMV utilizes various strategies to prevent apoptosis in infected cells in order to delay cell death and maintain viral replication. Here we show that HCMV can infect the acute leukemia cell lines Kasumi-1 (AML) and SD-1 (BCR-ABL-positive ALL), which inhibited their proliferation and induced apoptosis in almost all cells after 14 days. Although HCMV induced a significant up-regulation of the anti-apoptotic gene cFLIP and the anti-stress gene Gadd45a, and simultaneously down-regulated the pro-apoptotic genes p53, Gadd45gamma in Kasumi-1 and SD-1 cells, we found that these anti-apoptotic mechanisms failed in HCMV-infected acute leukemia cells and apoptosis occurred via a caspase-dependent pathway. We conclude that HCMV can provide anti-leukemic effects in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required.
NOD2 and TLR-4 genes belong to the innate immune system that detects invading pathogens through several pattern-recognition receptors. Here we analyzed 403 patients for NOD2 gene mutations and 307 ...patients for TLR-4 gene mutations (Thr399Ile) with their respective donors and correlated the results with the incidence of acute graft-versus-host disease (aGVHD), severe acute GVHD (saGVHD), the risk for transplant-related mortality (TRM), overall survival (OS) and incidence of infectious complications.
We performed a retrospective single-center study. Genotyping of TLR-4 and NOD2 were evaluated by real-time polymerase chain reaction.
Surprisingly, we found a significant reduced incidence of aGVHD, saGVHD, and intestinal GVHD for patients with NOD2 gene mutations on the donor side with 50%, 0% and 2% compared to patients with the wild-type NOD2 gene with 65%, 17%, and 26%, respectively (P<0.02). However, the incidence of saGVHD increased in patients with NOD2 mutations on the patient and donor (P/D) side with 44% versus 17% compared to patients with the wild-type gene (P<0.03). TLR-4 gene mutations at P/D side had an increased risk for saGVHD with 42% versus 15% of patients with wild-type gene (P<0.04). OS, TRM, and incidence of infectious complications were not influenced by the mutated genes. Multivariate analysis confirmed that NOD2 gene mutations on the donor side had a reduced risk for saGVHD (P<0.001), whereas mutations of the NOD2 gene on P/D side had an increased risk for saGVHD (P<0.01) in our analysis.
These results suggest that NOD2 mutations have influence on the occurrence of acute GVHD after transplantation.
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 well-defined 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 ligand–incompatible 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 ligand–incompatible 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. In conclusion, unmodified allogeneic HSCT from KIR ligand–incompatible donors provides a superior long-term antileukemic efficacy in patients with myeloid malignancies.
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