Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) are important complications after allogeneic hematopoietic stem cell transplantation (HSCT) with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV replication. Data on CMV replication as a cause of GVHD, in contrast, are controversial. We analyzed the reciprocal association of CMV replication with acute GVHD (aGVHD) in 515 patients treated with allogeneic HSCT between 1993 and 2008. Cumulative incidences at day 100 were 17% for CMV replication, 68% for aGVHD grade I-IV, and 48% for GVHD grade II-IV. Multivariate time-dependent analyses revealed that the presence of GVHD increased the risk of CMV replication in a dose-dependent manner: hazard ratio (HR) for CMV replication for patients with aGVHD grade I was 1.35 (95% confidence interval [CI] 0.82-2.21); HR for patients with aGVHD grade II-IV was 1.61 (95% CI 1.11-2.36, P-value for trend = .01). During phases of CMV replication, patients were at increased risk of developing aGVHD (HR 2.18, 95% CI 1.30-3.65, P < .01). These data confirm that GVHD and its therapy can induce CMV replication. They further demonstrate the reciprocal novel finding that patients are at significantly increased risk of developing aGVHD during CMV replication.

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

The first hematopoietic stem cell transplantation (HSCT), the replacement of the hematopoietic system, by hematopoietic stem cells from the patient (autologous HSCT) or from another person (allogeneic HSCT), was performed almost 45 years ago. Today autologous HSCT is used to bridge hematopoietic failure after high dose chemotherapy for the treatment of selected hematopoietic and non-hematopoietic tumours. Allogeneic HSCT is used to treat congenital or acquired marrow failure, and, more commonly, to exploit the graft versus tumour effect of allogeneic cells against high risk hematologic malignancies. In 2010, 30,000 patients were treated with HSCT (12,000 allogeneic and 18,000 autologous HSCT) in Europe. Substantial progress has been made in the field of allogeneic HSCT in the last decade. First the article describes advances in patient and donor selection, the current concepts of choosing the optimal stem cell source and the most appropriate preparative regimen. Furthermore, recent advances in supportive care are described. We describe how these innovations have allowed indications for allogeneic HSCT to be expanded. Finally, prospects for future developments will be outlined.

Rapid recovery of lymphocytes after T-cell depleted hematopoietic SCT (HSCT) protects from relapse of myeloid malignancies. Whether lymphocyte reconstitution has a similar role after non-manipulated transplantation is controversial. We assessed numbers of CD4 and CD8 T-cells, natural killer (NK) cells and B-cells, before and 1, 3, 6, 12 and 24 months after T-cell replete transplantation in 345 patients. Lymphocyte subset counts up to 6 months post transplant had no effect on relapse. Elevated number of NK cells 12 months post transplant protected from relapse. As a novel finding, early recovery of NK cells was associated with significant protection from TRM already at the 3 and 6 months time points (P ¼ 0.03, P ¼ 0.02). In Cox multivariable models, patients with NK cells above 150/lL were significantly protected from TRM (hazard ratio (HR) 0.45, 95% confidence interval (95% CI) 0.21-0.95, P ¼ 0.03), an effect comparable in magnitude with that of carrying 4200 CD4 T-cells/lL (HR 0.37, 95% CI 0.19-0.74, P ¼ 0.005). CD8 T-cell and B-cell recovery did not affect the rates of relapse or TRM. Early reconstitution of NK cells and CD4 T-cells in patients undergoing T-cell replete HSCT independently protected from TRM. Only a weak protection from disease relapse was noted for patients with high numbers of NK cells, and this occurred only late after transplantation.

BackgroundParamyxoviruses include respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (MPV), which may cause significant respiratory tract infectious disease (RTID) and mortality after allogeneic hematopoietic cell transplantation (HCT). However, clinical data regarding frequency and outcome are scarce.MethodsWe identified all paramyxovirus RTIDs in allogeneic HCT recipients diagnosed by multiplex polymerase chain reaction between 2010 and 2014. Baseline characteristics of patients, treatment, and outcome of each episode were analyzed; ie, moderate, severe, and very severe immunodeficiency (verySID) according to HCT ≤6 months, T- or B-cell depletion ≤3 months, graft-versus-host disease, neutropenia, lymphopenia, or hypo-gammaglobulinemia.ResultsOne hundred three RTID episodes in 66 patients were identified (PIV 47% [48 of 103], RSV 32% [33 of 103], MPV 21% [22 of 103]). Episodes occurred in 85% (87 of 103) at >100 days post-HCT. Lower RTID accounted for 36% (37 of 103). Thirty-nine percent (40 of 103) of RTID episodes required hospitalization and more frequently affected patients with lower RTID. Six percent progressed from upper to lower RTID. Overall mortality was 6% and did not differ between paramyxoviruses. Sixty-one percent (63 of 103) of episodes occurred in patients with SID, and 20.2% (19 of 63) of episodes occurred in patients with verySID. Oral ribavirin plus intravenous immunoglobulin was administered in 38% (39 of 103) of RTIDs, preferably for RSV or MPV (P ≤ .001) and for SID patients (P = .001). Patients with verySID frequently progressed to lower RTID (P = .075), required intensive care unit transfer, and showed higher mortality.ConclusionParamyxovirus RTID remains a major concern in allogeneic HCT patients fulfilling SID and verySID, emphasizing that efficacious and safe antiviral treatments are urgently needed.