Clonal relapse dynamics in acute myeloid leukemia following allogeneic hematopoietic cell transplantation.

Patients with acute myeloid leukemia (AML) who experience relapse following allogeneic hematopoietic cell transplantation (alloHCT) face unfavorable outcomes regardless of the chosen relapse treatment. Early detection of relapse at the molecular level by measurable residual disease (MRD) assessment enables timely intervention, which may prevent hematological recurrence of the disease. It remains unclear whether molecular MRD assessment can detect MRD before impending relapse and, if so, how long in advance.

The graft-versus-leukemia effect of prophylactic donor lymphocyte infusions after allogeneic stem cell transplantation is equally effective in relapse prevention but safer compared to spontaneous graft-versus-host disease.

Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL.

Spectral flow cytometry cluster analysis of therapeutic donor lymphocyte infusions identifies T cell subsets associated with outcome in patients with AML relapse.

Identification of immune phenotypes linked to durable graft-versus-leukemia (GVL) response following donor lymphocyte infusions (DLI) is of high clinical relevance. In this prospective observational study of 13 AML relapse patients receiving therapeutic DLI, we longitudinally investigated changes in differentiation stages and exhaustion markers of T cell subsets using cluster analysis of 30-color spectral flow cytometry during 24 months follow-up. DLI cell products and patient samples after DLI were analyzed and correlated to the clinical outcome.

Navigating preemptive and therapeutic donor lymphocyte infusions in advanced myeloid malignancies by high-sensitivity chimerism analysis.

Preemptive and therapeutic donor lymphocyte infusions (preDLI and tDLI) are widely used in relapsing and relapsed hematopoietic malignancies after allogeneic stem cell transplantation (alloSCT) to enhance the graft-versus-malignancy effect. However, in advanced myeloid malignancies, long-term survival after preDLI and tDLI remains low, reflecting our inability to master the double-edged sword of alloreactivity, balancing anti-neoplastic activity versus graft-versus-host disease (GvHD). We previously evaluated a quantitative PCR-based high-sensitivity chimerism (hs-chimerism) based on insertion/deletion polymorphisms instead of short tandem repeats, where increasing host chimerism in peripheral blood predicts relapse more than a month before clinical diagnosis, and declining host chimerism signals anti-host alloreactivity.

Increased Late Noncardiac Nonrelapse Mortality in Patients with Atrial Fibrillation Diagnosed During Their Hospital Stay for Allogeneic Stem Cell Transplantation.

Atrial fibrillation (AF) is the most common arrhythmia in adults but its impact on allogeneic stem cell transplantation (SCT) is not well characterized. We studied AF manifestation during the hospital stay for allogeneic SCT, referred to as AF in hospital (AFiH), and analyzed the incidence of, risk factors for, and clinical impact of AFiH on intensive care unit (ICU)-/hospital-/ and overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS). This retrospective matched cohort study comprised 553 consecutive SCT recipients at Hannover Medical School between January 2013 and October 2019.

Adaptive NK cells undergo a dynamic modulation in response to human cytomegalovirus and recruit T cells in in vitro migration assays.

Human cytomegalovirus (HCMV) reactivation remains a relevant complication after hematopoietic stem cell transplantation (HSCT) despite the great progress made in prophylaxis and treatment. Adaptive Natural Killer (NK) cells undergo a persistent reconfiguration in response to HCMV reactivation however, the exact role of adaptive NK cells in HCMV surveillance is currently unknown. We studied the relationship between HCMV reactivation and adaptive NK cells in 70 patients monitored weekly until day +100 after HSCT.

Cytomegalovirus-specific CD8+ T-cells are associated with a reduced incidence of early relapse after allogeneic stem cell transplantation.

Leukemia relapse is the main cause for mortality after allogeneic stem cell transplantation (allo-SCT). Donor-derived allo-immune responses eliminate the residual host hematopoiesis and protect against relapse. Cytomegalovirus (CMV) reactivation (CMV-R) after allo-SCT may trigger anti-leukemic effects.

Improved short- and long-term outcome of allogeneic stem cell recipients admitted to the intensive care unit: a retrospective longitudinal analysis of 942 patients.

Purpose: Intensive care unit (ICU) admission of allogeneic hematopoietic stem cell transplant (HSCT) recipients is associated with relatively poor outcome. Since longitudinal data on this topic remains scarce, we analyzed reasons for ICU admission as well as short- and long-term outcome of critically ill HSCT recipients.

Methods: A total of 942 consecutive adult patients were transplanted at Hannover Medical School from 2000 to 2013.

Diagnostic value of highly-sensitive chimerism analysis after allogeneic stem cell transplantation.

Conventional analysis of host chimerism (HC) frequently fails to detect relapse before its clinical manifestation in patients with hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Quantitative PCR (qPCR)-based highly-sensitive chimerism analysis extends the detection limit of conventional (short tandem repeats-based) chimerism analysis from 1 to 0.01% host cells in whole blood.

Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation.

CMV reactivation is a major complication after allogeneic stem cell transplantation (SCT). Immune reconstitution of CMV-specific CTLs (CMV-CTLs) is essential for virus control. During CMV-CTL monitoring using mutated HLA/CMV tetramers selectively detecting high-avidity T cells, we observed coappearance of CMV-CTLs with low (CMV tet CTLs) and high tetramer binding (CMV tet CTLs) in 53/115 CMV IgG patients stem cell transplanted from CMV IgG donors.

Possible Impact of Cytomegalovirus-Specific CD8 T Cells on Immune Reconstitution and Conversion to Complete Donor Chimerism after Allogeneic Stem Cell Transplantation.

Complete donor chimerism is strongly associated with complete remission after allogeneic stem cell transplantation (allo-SCT) in patients with hematologic malignancies. Donor-derived allo-immune responses eliminate the residual host hematopoiesis and thereby mediate the conversion to complete donor chimerism. Recently, cytomegalovirus (CMV) reactivation was described to enhance overall T cell reconstitution, to increase graft-versus-host disease incidence, and to reduce the leukemia relapse risk.

Sequential anti-cytomegalovirus response monitoring may allow prediction of cytomegalovirus reactivation after allogeneic stem cell transplantation.

Background: Reconstitution of cytomegalovirus-specific CD3(+)CD8(+) T cells (CMV-CTLs) after allogeneic hematopoietic stem cell transplantation (HSCT) is necessary to bring cytomegalovirus (CMV) reactivation under control. However, the parameters determining protective CMV-CTL reconstitution remain unclear to date.

Design And Methods: In a prospective tri-center study, CMV-CTL reconstitution was analyzed in the peripheral blood from 278 patients during the year following HSCT using 7 commercially available tetrameric HLA-CMV epitope complexes.

Improving safety of preemptive therapy with oral valganciclovir for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Valganciclovir (VGC), an oral prodrug of ganciclovir (GCV), has been shown to clear cytomegalovirus (CMV) viremia in preemptive treatment of patients after allogeneic hematopoietic stem cell transplantation (alloHSCT), apparently without significant toxicity. Since VGC obviates hospitalization, it is increasingly being adopted, although not approved, in alloHSCT. When we retrospectively evaluated preemptive treatment with VGC versus GCV, foscarnet or cidofovir, in all 312 consecutive CMV viremias of 169 patients allotransplanted at our institution between 1996 and 2006, we found VGC more efficacious (79%) than non-VGC therapies (69%).

Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome.

The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG).

High lethality of human adenovirus disease in adult allogeneic stem cell transplant recipients with high adenoviral blood load.

Background: Human adenoviruses (HAdV) can cause disseminated disease as a severe complication after haematopoietic stem cell transplantation (SCT) and may originate from the reactivation of latent infections. However, data about the clinical relevance of HAdV DNAaemia and disease in adults are scarce.

Objectives: To retrospectively analyse the outcome of adult allogeneic SCT recipients with high HAdV loads in peripheral blood.

Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation.

Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34(+) cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells.

Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML.

Angiogenesis plays an important role in the growth and viability of hematologic malignancies. Emerging data suggest a crucial involvement of the endothelial-specific Tie2 receptor and its antagonistic ligand Angiopoietin-2 (Ang-2) in this process. The purpose of this study was to elucidate whether the soluble domain of the Tie2 receptor (sTie2)predicts outcome in patients with acute myeloid leukemia(AML) undergoing allogeneic hematopoietic stem cell transplantation(HSCT).

Prolonged isolated red blood cell transfusion requirement after allogeneic blood stem cell transplantation: identification of patients at risk.

Background: Delayed donor red blood cell chimerism (DRCC), pure red blood cell aplasia (PRCA), and autoimmune hemolytic anemia (AIHA) are poorly documented complications after hematopoietic cell transplantation (HCT). The clinical variable "prolonged isolated red blood cell transfusion requirement" (PRTR) was evaluated as a trigger for an extended diagnostic workup.

Study Design And Methods: PRTR was defined as the need for red blood cell (RBC) transfusions beyond Day 60 after HCT.

Diagnostic value of procalcitonin serum levels in comparison with C-reactive protein in allogeneic stem cell transplantation.

Background And Objectives: Infections represent the major complications following allogeneic stem cell transplantation (SCT). A promising marker for a more specific and early detection of bacterial or fungal infections is procalcitonin (PCT).

Design And Methods: Maximum values (m) and increase (Delta) of PCT and C-reactive protein (CRP) were prospectively analyzed during 214 clinical events in a cohort of 61 patients undergoing allogeneic SCT.