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To validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches. HLA-DQB1 mismatched cases showed a trend toward higher mortality, mostly due to HLA-DQB1 antigen disparities. HLA incompatibilities at >1 locus showed additive detrimental effects. HLA mismatching had no significant effect on relapse incidence and primary graft failure. Graft source had no impact on survival end points, neither in univariate nor in multivariate analysis. Higher patient age, advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor adversely influenced outcomes in multivariate analysis. Our study confirms the association of HLA-A, -B, -C, and -DRB1 incompatibilities with adverse outcome in hematopoietic stem cell transplantation (HSCT). The relevance of HLA-DQB1 disparities in single mismatched transplantations remains unclear. Similar hazard ratios for allele and antigen mismatches (possibly with an exception for HLA-DQB1) highlight the importance of allele level typing and matching in HSCT. The number of incompatibilities and their type significantly impact survival.

Leukemia-associated antigens such as proteinase-3 (PR3) and Wilms´ tumor protein-1 (WT-1) are potential targets of T-cell responses, which can be monitored by T-cell assays within vaccination trials and after allogeneic stem cell transplantation (SCT). In chronic myeloid leukemia (CML) an aberrant cytokine profile of antigen-specific T-cells with predominant TNF-a secretion has previously been described. The aim of this study was to investigate whether these TNF-α+/IFN-γ-CD8+T-cells can also be observed in AML patients after SCT. Eight HLA-A2+AML patients at different time points after SCT were evaluated for HLA-A2-restricted CD8+T-cell responses against PR3, WT-1 and influenza-A using pentamer staining and different cytokine-based T-cell assays. Antigen-specific T-cell immune responses against influenza-A and PR3 were observed in 4/8 patients, WT-1-specific T-cells could be detected in in 3/8 patients. Interestingly, four different cytokine secretion profiles of antigen-specific T-cells were detected:1IFN-γ+/TNF-α+,2IFN-γ+/TNF-α-,3TNF-α+/ IFN-γ-and4IFN-γ-/TNF-α-. TNF-α+/ IFN-γ-CD8+T-cells are an interesting biological phenomenon which can obviously be observed also in AML patients. This finding has important implications for both T-cell biology and monitoring within immunotherapy trials. The functional characterization of these TNF-α+/ IFN-γ-CD8+T-cells needs further investigations.

Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.

The role of allogeneic stem cell transplantation in chronic myeloid leukemia is being reevaluated. Whereas drug treatment has been shown to be superior in first-line treatment, data on allogeneic hematopoietic stem cell transplantation (allo SCT) as second-line therapy after imatinib failure are scarce. Using an interim safety analysis of the randomized German CML Study IV designed to optimize imatinib therapy by combination, dose escalation, and transplantation, we here report on 84 patients who underwent consecutive transplantation according to predefined criteria (low European Group for Blood and Marrow Transplantation [EBMT] score, imatinib failure, and advanced disease). Three-year survival after transplantation of 56 patients in chronic phase was 91% (median follow-up: 30 months). Transplantation-related mortality was 8%. In a matched pair comparison of patients who received a transplant and those who did not, survival was not different. Three-year survival after transplantation of 28 patients in advanced phase was 59%. Eighty-eight percent of patients who received a transplant achieved complete molecular remissions. We conclude that allo SCT could become the preferred second-line option after imatinib failure for suitable patients with a donor. The study is registered at the National Institutes of Health, http://clinicaltrials.gov: NCT00055874.

Clinical trials have indicated that immunoablation followed by autologous hematopoietic stem cell transplantation (ASCT) has the potential to induce clinical remission in patients with refractory systemic lupus erythematosus (SLE), but the mechanisms have remained unclear. We now report the results of a single-center prospective study of long-term immune reconstitution after ASCT in 7 patients with SLE. The clinical remissions observed in these patients are accompanied by the depletion of autoreactive immunologic memory, reflected by the disappearance of pathogenic anti–double-stranded DNA (dsDNA) antibodies and protective antibodies in serum and a fundamental resetting of the adaptive immune system. The latter comprises recurrence of CD31+CD45RA+CD4+ T cells (recent thymic emigrants) with a doubling in absolute numbers compared with age-matched healthy controls at the 3-year follow-up (P = .016), the regeneration of thymic-derived FoxP3+ regulatory T cells, and normalization of peripheral T-cell receptor (TCR) repertoire usage. Likewise, responders exhibited normalization of the previously disturbed B-cell homeostasis with numeric recovery of the naive B-cell compartment within 1 year after ASCT. These data are the first to demonstrate that both depletion of the autoreactive immunologic memory and a profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE. This trial was registered at www.clinicaltrials.gov as #NCT00742300.

Recent studies in mice and humans have emphasized an important contribution of host-reactive minor histocompatibility antigen (mH)-specific lymphokine-secreting donor T-helper cells (Th) for the induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). By using limiting dilution (LD) and clonal specificity analyses, we investigated in 14 patients with and without acute GVHD after non-T-depleted HLA-iden-tical sibling BMT whether posttransplant host-reactive mH-specific interleukin-2 (IL-2)-secreting Th are involved in the development of clinically significant acute GVHD and the establishment of tolerance. At different time intervals posttransplant (I, days 0 through 45; II, days 45 through 90; III, days 90 through 180), host-specific IL-2-secreting Th-precursors (Th-p) were quantitatively assessed in six patients during clinically apparent grade H-III acute GVHD. Frequencies of responding Th-p ranged from 1/13,000 to 1/174,000. The presence of host-specific Th-p was significantly correlated with the development of grade II-III acute GVHD (P= .0003 by Fisher’s exact test). The de-tectability of host-specific Th-p preceded the clinical onset of grade ll-lll acute GVHD. Host-specific Th-p were no longer detectable after the clinical resolution of grade ll-lll acute GVHD. No subsequent chronic GVHD was observed in these patients. However, prolonged occurrence of host-specific Th-p was accompanied by clinically persisting acute GVHD and the onset of secondary chronic GVHD. In patients with no acute GVHD (grade 0) (n = 7) and grade I (n = 1) acute GVHD, host-specific Th-p were not detectable at all. We conclude that host-reactive Th are critically involved in the development and maintenance of acute GVHD and may contribute to the establishment of tolerance after genotyp-ically HLA-identical sibling BMT.

The contribution of hepatitis C virus (HCV) infection to liver disease after bone marrow transplantation (BMT) was retrospectively evaluated in 61 patients treated with BMT. HCV genome, as well as antibodies to HCV, was analyzed in sera collected before and serially after BMT. Six patients had been infected with HCV before BMT and three patients acquired the infection during or shortly after BMT. All patients infected before BMT died within 10 weeks after transplantation. Five of these six patients (83%) died of veno-occlusive disease (VOD), compared with nine of 52 patients (17%) not infected with HCV (P <.005). Risk factors for VOD other than HCV were not more prevalent in these patients compared with uninfected patients. Parallel to the development of VOD, replication of HCV increased, as demonstrated by rising concentrations of viral RNA in serum. HCV infection acquired during or after BMT caused only mild acute hepatitis C, which progressed to chronic hepatitis C in one patient surviving 10 years after BMT. These data suggest that patients with liver disease caused by HCV infection are at high risk of developing lethal VOD after BMT.

CD52 is a phosphatidylinositolglycan (PIG)-anchored glycoprotein (PIG-AP) expressed on normal T and B lymphocytes, monocytes, and the majority of B-cell non-Hodgkin lymphomas. We observed the emergence of CD52 T cells in 3 patients after intravenous treatment with the humanized anti-CD52 monoclonal antibody Campath-1H for refractory B-cell lymphoma and could identify the underlaying mechanism. In addition to the absence of CD52, the PIG-AP CD48 and CD59 were not detectable on the CD52-T cells in 2 patients. PIG-AP-deficient T-cell clones from both patients were established. Analysis of the mRNA of the PIG-A gene showed an abnormal size in the T-cell clones from 1 of these patients, suggesting that a mutation in the PIG-A gene was the cause of the expression defect of PIG-AP. An escape from an immune attack directed against PIG-AP+hematopoiesis has been hypothesized as the cause of the occurrence of PIG-AP-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia. Our results support the hypothesis that an attack against the PIG-AP CD52 might lead to the expansion of a PIG-anchor-deficient cell population with the phenotypic and molecular characteristics of PNH cells.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult muhicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with >25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65y) with only 9% adolescents (15 to 20y), but 28% elderly patients (50 to 65y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2(24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2for 5 days, an increase of IdM to high-dose, 1,500 mg/m2(HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (>2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P= .04), and the overall survival rates from 0% to 49% and 51% (P= .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P= .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or >50,000/μL, LFS 71% versus 29% (P= .003) and hemoglobin value > or <8 g/dL, LFS 67% versus 27% (P= .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (>50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

Immunophenotyping disclosed CD10 negativity in 70 of 2408 cases of B-lineage acute lymphoblastic leukemia (ALL), although other criteria followed classification of pre-B ALL (eg, cytoplasmic immunoglobulin positivity). These blasts showed high myeloid antigen expression (60% CD65 positivity) and reacted with antibody 7.1 in 95% of the cases. MLL-AF4fusion transcripts or an 11q23/MLLrearrangement or both were evident in 46 of 56 samples (82%). Although 83% of the patients achieved complete remission, the remission duration remained remarkably low: 141 days for MLLrearrangement-positive and 245 days for MLLrearrangement-negative CD10-pre-B ALL. Thus, the overall survival probability 3 years after diagnosis was 0.34 ± 0.20 SE in MLL-rearrangement-negative versus 0.12 ± 0.06 SE in MLLrearrangement-positive CD10-pre-B ALL. Our data identify CD10-cytoplasmic immunoglobulin-positive pre-B ALL as a rare (2.2%) but distinct immuno-subtype of adult ALL that is characterized by a high MLLrearrangement rate and a worse outcome.

Beelen: Medac: Consultancy, Other: Travel Support. Scheid:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Lenz:Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Research Funding; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria. Hiddemann:Bayer: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stelljes:MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding.

This corrects the article DOI: 10.1038/nm.4484

Introduction:Communicating about the risk of mortality after allogeneic hematopoietic stem cell transplantation (HCT) is a challenging task for physicians. This is especially true for elderly patients with aggressive hematologic malignancies. Mortality after HCT may be split in three major parts, death after relapse, therapy-related mortality (including late complications of previous treatments of the hematologic malignancies) and background or general population mortality from causes unrelated to the treatment or disease. In the framework of the competing endpoints, relapse and non-relapse mortality, background mortality mainly determines the magnitude of non-relapse mortality. To estimate the size of the background mortality, the risk of an age-, sex-, country- and calendar year matched population can be used as approximation. This can be done with methods from relative survival analysis. By nature, background mortality increases among elderly patients. In order to study the size of background and excess mortality we analyzed mortality in a population of adult transplant recipients with myelodysplastic syndromes (MDS) because this indication is characterized by a high median age already at diagnosis and large numbers of transplanted patients.

Background:myelofibrosis is a rare hematological malignancy which can be cured by hematopoietic stem cell transplant (HSCT) and many studies are showing that 3 to 5-year survival after HSCT is between 45 to 70% in relative standard condition (chronic phase disease, HLA matched donor). Relapse and transplant-related mortality are more frequent the first 2 years post HSCT. To optimize the long-term management of these patients, we raised the question of long-term outcome in patients surviving in remission at least 2 years after HSCT. Furthermore, that's a recurrent question from the patient to know if his life expectancy can reach the general population one many years after transplant.

No relevant conflicts of interest to declare.

Meyer: Stanford University: Patents & Royalties. Marks:Pfizer: Honoraria. Lübbert:Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding. Scheid:Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work. Kobbe:Celgene: Honoraria, Other: travel support, Research Funding; Jansen: Honoraria, Other: travel support. Negrin:Stanford University: Patents & Royalties. Brune:Meda Pharma: Consultancy. Mielke:JAZZ Pharma: Speakers Bureau; Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Gilead: Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau. Kuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Peschel:MophoSys: Honoraria. von Bubnoff:BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding.

Pezzutto: Cellgene, Novartis, Roche, Gilead: Membership on an entity's Board of Directors or advisory committees.

Dreger: Novartis: Consultancy; Gilead: Speakers Bureau; Gilead: Consultancy; Novartis: Speakers Bureau; Janssen: Consultancy; Roche: Consultancy. Montoto:Roche: Honoraria; Gilead: Research Funding. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

Hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) is a rare syndrome of potentially fatal, uncontrolled hyperinflammation. Allogeneic stem cell transplantation (alloSCT) is indicated in familial, recurrent or progressive HLH. Additional recommendations include central nervous system involvement and unknown triggering factor. While data for alloSCT outcome are available for the pediatric setting, information for adults is very limited.

DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) mutations is one of the most frequent somatic mutations in acute myeloid leukemia (AML). Although DNMT3Amutations have been studied extensively, influence of mutations on AML prognosis and their role on the pathogenesis of AML remains not completely clear. Little is known about the significance of mutations burden in the time of diagnosis on the clinical and prognostic features of AML. Recently discovered persistence of DNMT3Amutations in complete remission after standard therapy indicates the presence of mutation in early pre-leukemic stem cells. In this aspect, it would be essential to analyze the existence of DNMT3A-positive cells after allogeneic stem cell transplantation (alloSCT).

McLornan: Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

No relevant conflicts of interest to declare.