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Abstract: In patients with myelodysplastic syndrome (MDS), higher revised International Prognostic Scoring System (IPSS-R) scores at transplant are associated with worse transplant outcome and, thus, lowering IPSS-R scores by therapeutic intervention before transplantation may seem beneficial. However, there is no evidence, to date, to support this approach. In a retrospective analysis, a total of 1482 patients with MDS with sufficient data to calculate IPSS-R score at diagnosis and at time of transplantation were selected from the European Society for Blood and Marrow Transplantation transplant registry and analyzed for transplant outcome in a multivariable Cox model including IPSS-R score at diagnosis, treatment intervention, change in IPSS-R score before transplant, and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R score change in untreated patients and moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after hypomethylating agents (HMAs) or other therapies showed no beneficial effect. However, when IPSS-R score progressed after chemotherapy, HMAs, or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R score downstaging or reduction of BM blasts after chemotherapy and no benefit for HMAs or other treatments and thus question the role of prior therapy in patients with MDS scheduled for transplantation. The model-based survival estimates should help inform decision-making for both doctors and patients., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Primary Epstein-Barr virus (EBV) infections may cause infectious mononucleosis (IM), whereas EBV reactivations in solid organ and hematopoietic stem cell transplant recipients are associated with posttransplantation lymphoproliferative disorders (PTLDs). It is still unclear why only a minority of primary EBV-infected individuals develop IM, and why only some patients progress to EBV+PTLD after transplantation. We now investigated whether nonclassic human leukocyte antigen E (HLA-E)-restricted immune responses have a significant impact on the development of EBV diseases in the individual host. On the basis of a large study cohort of 1404 patients and controls as well as on functional natural killer (NK) and CD8+ T-cell analyses, we could demonstrate that the highly expressed HLA-E∗0103/0103 genotype is protective against IM, due to the induction of potent EBV BZLF1-specific HLA-E-restricted CD8+ T-cell responses, which efficiently prevent the in vitro viral dissemination. Furthermore, we provide evidence that the risk of symptomatic EBV reactivations in immunocompetent individuals as well as in immunocompromised transplant recipients depends on variations in the inhibitory NKG2A/LMP-1/HLA-E axis. We show that EBV strains encoding for the specific LMP-1 peptide variants GGDPHLPTL or GGDPPLPTL, presented by HLA-E, elicit strong inhibitory NKG2A+ NK and CD8+ T-cell responses. The presence of EBV strains encoding for both peptides was highly associated with symptomatic EBV reactivations. The further progression to EBV+PTLD was highly associated with the presence of both peptide-encoding EBV strains and the expression of HLA-E∗0103/0103 in the host. Thus, HLA-E-restricted immune responses and the NKG2A/LMP-1/HLA-E axis are novel predictive markers for EBV+PTLD in transplant recipients and should be considered for future EBV vaccine design., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity., (© 2022 by The American Society of Hematology.)

Background & Aims: The burden of hepatitis E virus (HEV) infection among patients with haematological malignancy has only been scarcely reported. Therefore, we aimed to describe this burden in patients with haematological malignancies, including those receiving allogeneic haematopoietic stem cell transplantation., Methods: We conducted a retrospective, multicentre cohort study across 11 European centres and collected clinical characteristics of 50 patients with haematological malignancy and RNA-positive, clinically overt hepatitis E between April 2014 and March 2017. The primary endpoint was HEV-associated mortality; the secondary endpoint was HEV-associated liver-related morbidity., Results: The most frequent underlying haematological malignancies were aggressive non-Hodgkin lymphoma (NHL) (34%), indolent NHL (iNHL) (24%), and acute leukaemia (36%). Twenty-one (42%) patients had received allogeneic haematopoietic stem cell transplantation (alloHSCT). Death with ongoing hepatitis E occurred in 8 (16%) patients, including 1 patient with iNHL and 1 patient >100 days after alloHSCT in complete remission, and was associated with male sex (p = 0.040), cirrhosis (p = 0.006) and alloHSCT (p = 0.056). Blood-borne transmission of hepatitis E was demonstrated in 5 (10%) patients, and associated with liver-related mortality in 2 patients. Hepatitis E progressed to chronic hepatitis in 17 (34%) patients overall, and in 10 (47.6%) and 6 (50%) alloHSCT and iNHL patients, respectively. Hepatitis E was associated with acute or acute-on-chronic liver failure in 4 (8%) patients with 75% mortality. Ribavirin was administered to 24 (48%) patients, with an HEV clearance rate of 79.2%. Ribavirin treatment was associated with lower mortality (p = 0.037) and by trend with lower rates of chronicity (p = 0.407) when initiated <24 and <12 weeks after diagnosis of hepatitis E, respectively. Immunosuppressive treatment reductions were associated with mortality in 2 patients (28.6%)., Conclusion: Hepatitis E is associated with mortality and liver-related morbidity in patients with haematological malignancy. Blood-borne transmission contributes to the burden. Ribavirin should be initiated early, whereas reduction of immunosuppressive treatment requires caution., Lay Summary: Little is known about the burden of hepatitis E among patients with haematological malignancy. We conducted a retrospective European cohort study among 50 patients with haematological malignancy, including haematopoietic stem cell transplant recipients, with clinically significant HEV infection and found that hepatitis E is associated with hepatic and extrahepatic mortality, including among patients with indolent disease or among stem cell transplant recipients in complete remission. Hepatitis E virus infection evolved to chronic hepatitis in 5 (45.5%) patients exposed to a rituximab-containing regimen and 10 (47.6%) stem cell transplant recipients. Reducing immunosuppressive therapy because of hepatitis E was associated with mortality, while early ribavirin treatment was safe and effective., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: The paucity of population-based research indicates that the application of intensive chemotherapy (ICT) among elderly acute myeloid leukemia (AML) patients, as well as their accrual to randomized controlled trials (RCTs) remains low for several decades. Therefore, a contemporary, comprehensive apprehension on patient-, disease-, and treatment-specific characteristics of elderly AML patients at the population level can inform treatment choices and facilitate increased patient accrual in upcoming RCTs., Objectives: In this population-based study, we investigated patient- and disease-specific characteristics in elderly AML patients, and their association with treatment and survival., Methods: We retrospectively obtained data on all over 65-year-old AML patients diagnosed between 2010-2013 in the referral area of two university hospitals in the Netherlands. Multivariable analyses were performed to assess factors associated with treatment choice and overall survival., Results: Of all 356 patients, 77% received non-intensive therapy (NIT), and 15% and 8% received ICT within and outside a RCT, respectively. Cytogenetic (74%) and molecular (93%) analyses were not performed in most NIT recipients. Age and comorbidity were independently associated with NIT, whereas only comorbidity was associated with decreased trial participation. The adjusted risk of mortality among ICT recipients was not influenced by trial participation status., Conclusion: The application of ICT and accrual to RCTs remains staggeringly low in an elderly AML population. Since survival of ICT-treated patients was not affected by trial participation status, exclusion criteria might be relaxed in upcoming RCTs. Furthermore, appropriate management strategies can be accomplished by comprehensive comorbidity assessment and augmented genetic prognostication., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although double umbilical cord blood transplantation (dUCBT) in adult patients may be associated with less graft failure compared with single UCBT, hematopoietic recovery generally originates from a single cord blood unit (CBU). CBU predominance is still incompletely understood. We recently showed that blood CD4 + T-cell numbers rapidly increase after dUCBT, and early CD4 + T-cell chimerism predicts for graft predominance. Given the frequent HLA class II allele mismatches between CBUs in dUCBT, we hypothesized that alloreactive HLA class II-specific CD4 + T cells from the "winning" CBU may contribute to rejection of the "loser" CBU. We evaluated whether CD4 + T cells originating from the predominant (PD)-CBU would recognize HLA class II allele mismatches, expressed by the nonengrafting (NE)-CBU. Alloreactive effector CD4 + T cells toward 1 or more mismatched HLA class II alleles of the NE-CBU were detected in 11 of 11 patients, with reactivity toward 29 of 33 (88%) tested mismatches, and the strongest reactivity toward DR and DQ alleles early after dUCBT. Mismatched HLA class II allele-specific CD4 + T cells recognized primary leukemic cells when the mismatched HLA class II allele was shared between NE-CBU and patient. Our results suggest that cytotoxicity exerted by CD4 + T cells from the PD-CBU drives the rapid rejection of the NE-CBU, whose alloreactive effect might also contribute to graft-versus-leukemia., (© 2016 by The American Society of Hematology.)

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice., (© 2016 by The American Society of Hematology.)

Postremission therapy in patients with acute myeloid leukemia (AML) may consist of continuing chemotherapy or transplantation using either autologous or allogeneic stem cells. Patients with favorable subtypes of AML generally receive chemotherapeutic consolidation, although recent studies have also suggested favorable outcome after hematopoietic stem cell transplantation (HSCT). Although allogeneic HSCT (alloHSCT) is considered the preferred type of postremission therapy in poor- and very-poor-risk AML, the place of alloHSCT in intermediate-risk AML is being debated, and autologous HSCT is considered a valuable alternative that may be preferred in patients without minimal residual disease after induction chemotherapy. Here, we review postremission transplantation strategies using either autologous or allogeneic stem cells. Recent developments in the field of alternative donors, including cord blood and haploidentical donors, are highlighted, and we discuss reduced-intensity alloHSCT in older AML recipients who represent the predominant category of patients with AML who have a high risk of relapse in first remission., (© 2016 by The American Society of Hematology.)

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 α gene (CEBPα). 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 ± 5% in NPM1(mut)/FLT3(wt), 75 ± 3% in NPM1(wt)/FLT3(wt), 66 ± 3% in NPM1(mut)/FLT3-ITD, and 54 ± 7% in NPM1(wt)/FLT3-ITD (P = .003). Analysis of CEBPα among patients with NPM1(wt)/FLT3(wt) revealed excellent results both in patients with CEBPα(mut) and with a triple negative genotype (2-year OS: 100%/77 ± 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 ± 3%/79 ± 4% without any, 77 ± 2%/73 ± 3% with one, and 53 ± 4%/50 ± 4 with ≥2 risk factors (P = .003/.002)., (© 2015 by The American Society of Hematology.)

We analyzed 661 adult patients who underwent single-unit (n = 226) or double-unit (n = 435) unrelated cord blood transplantation (UCBT) following a reduced-intensity conditioning (RIC) consisting of low-dose total body irradiation (TBI), cyclophosphamide, and fludarabine (Cy/Flu/TBI200). Eighty-two patients received rabbit antithymocyte globulin (ATG) as part of the conditioning regimen (ATG group), whereas 579 did not (non-ATG group). Median age at UCBT was 54 years, and diagnoses were acute leukemias (51%), myelodysplastic syndrome/myeloproliferative neoplasm (19%), and lymphoproliferative diseases (30%). Forty-four percent of patients were transplanted with advanced disease. All patients received ≥4 antigens HLA-matched UCBT. Median number of collected total nucleated cells was 4.4 × 10(7)/kg. In the ATG group, on 64 evaluable patients, ATG was discontinued 1 (n = 27), 2 (n = 20), or > 2 days before the graft infusion (n = 17). In multivariate analyses, the use of ATG was associated with decreased incidence of acute graft-versus-host disease (hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.17-0.55; P < .0001), higher incidence of nonrelapse mortality (HR, 1.68; 95% CI, 1.16-2.43; P = .0009), and decreased overall survival (HR, 1.69; 95% CI, 1.19-2.415; P = .003). Collectively, our results suggest that the use of ATG could be detrimental, especially if given too close to graft infusion in adults undergoing UCBT following Cy/Flu/TBI200 regimen., (© 2015 by The American Society of Hematology.)

The success of a Toxoplasma gondii surveillance program in European pig production systems depends partly on the quality of the test to detect infection in the population. The test accuracy of a recently developed serological bead-based assay (BBA) was investigated earlier using sera from experimentally infected animals. In this study, the accuracy of the BBA was determined by the use of sera from animals from two field subpopulations. As no T. gondii infection information of these animals was available, test accuracy was determined through a Bayesian approach allowing for conditional dependency between BBA and an ELISA test. The priors for prevalence were based on available information from literature, whereas for specificity vague non-informative priors were used. Priors for sensitivity were based either on available information or specified as non-informative. Posterior estimates for BBA sensitivity and specificity were (mode) 0.855 (Bayesian 95% credibility interval (bCI) 0.702-0.960) and 0.913 (bCI 0.893-0.931), respectively. Comparing the results of BBA and ELISA, sensitivity was higher for the BBA while specificity was higher for ELISA. Alternative priors for the sensitivity affected posterior estimates for sensitivity of both BBA and ELISA, but not for specificity. Because the difference in prevalence between the two subpopulations is small, and the number of infected animals is small as well, the precision of the posterior estimates for sensitivity may be less accurate in comparison to the estimates for specificity. The estimated value for specificity of BBA is at least optimally defined for testing pigs from conventional and organic Dutch farms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Patients with acute myeloid leukemia (AML) and abnormalities of chromosome 17p (abnl(17p)) are at high-risk of treatment failure. Poor outcomes have been reported with conventional chemotherapy. To accurately define the outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with abnl(17p) AML, we analyzed the results of patients with this abnormality who received an allogeneic HSCT between January 2000 and December 2010 in 1 of 4 well-defined cohorts (Fred Hutchinson Cancer Research Center, Haemato Oncology Foundation for Adults in the Netherlands, Study Alliance Leukemia, German Cooperative Transplant Study Group). Data of 201 patients with a median age of 54 years were evaluable. At the time of analysis, 30 patients were alive with a median follow-up of 30 months. The 3-year probability of overall survival (OS) was 15% (95% confidence interval [CI], 10-20). The cumulative incidence of relapse at 3 years was 49% (95% CI, 42-56). Notably, almost 70% of all relapses occurred within the first 6 months after HSCT. Patients who were transplanted in first complete remission (CR1) had superior OS compared with those with advanced disease (22% vs 9%, P < .001). Our findings confirm the high-risk of treatment failure in abnl(17p) AML even after allogeneic HSCT in CR1. Although allogeneic HSCT remains a valid option in CR1, alternative treatment strategies are needed for the remaining patients.

The clinical value of allogeneic hematopoietic stem cell transplantation (alloHSCT) and autologous hematopoietic stem cell transplantation (autoHSCT) in the subtype of acute myeloid leukemia (AML) with double mutant CEBPA (CEBPAdm) has remained unsettled. Among 2983 patients analyzed for CEBPA mutational status (age 18-60 years) treated on 4 published Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group (HOVON/SAKK) and 3 German-Austrian AML Study Group (AMLSG) protocols (2 published, 1 registered, clinicaltrials.gov NCT00151255), 124 had AML with CEBPAdm and achieved first complete remission (CR1). Evaluation of the clinical impact of alloHSCT and autoHSCT vs chemotherapy was performed by addressing time dependency in the statistical analyses. Thirty-two patients proceeded to alloHSCT from a matched related (MRD, n = 29) or a matched unrelated donor (MUD, n = 3), 20 to autoHSCT in CR1 and 72 received chemotherapy. Relapse-free survival was significantly superior in patients receiving an alloHSCT or autoHSCT in CR1 as compared with chemotherapy (P < .001), whereas overall survival was not different (P < .12). Forty-five patients relapsed. Of 42 patients treated with reinduction therapy, 35 achieved a second CR (83%) and most patients (n = 33) received an alloHSCT MRD, n = 11; MUD, n = 19; haplo-identical donor, n = 3). Survival of relapsed patients measured from date of relapse was 46% after 3 years. Adult AML patients with CEBPAdm benefit from alloHSCT and autoHSCT; relapsed patients still have a favorable outcome after reinduction followed by alloHSCT.

Hepatitis E virus (HEV) is increasingly acknowledged as a cause of hepatitis in healthy individuals as well as immunocompromised patients. Little is known of HEV infection in recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we set out to study the incidence and sequelae of HEV as a cause of hepatitis in a recent cohort of 328 alloHSCT recipients. HEV RNA was tested in episodes of liver enzyme abnormalities. In addition, HEV RNA and HEV serology were assessed pre- and post-alloHSCT. We found 8 cases (2.4%) of HEV infection, of which 5 had developed chronic HEV infection. Seroprevalence pre-alloHSCT was 13%. Four patients died with HEV viremia, with signs of ongoing hepatitis, having a median time of infection of 4.1 months. The 4 surviving patients cleared HEV after a median period of 6.3 months. One patient was diagnosed with HEV reactivation after a preceding infection prior to alloHSCT. Although the incidence of developing acute HEV post-alloHSCT is relatively low, the probability of developing chronic hepatitis in severely immunocompromised patients is high. Therefore, alloHSCT recipients should be screened pretransplantation by HEV serology and RNA. Furthermore, a differential diagnosis including hepatitis E is mandatory in all alloHSCT patients with severe liver enzyme abnormalities.

Patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have a poor prognosis with conventional chemotherapy. In the present study, we retrospectively analyzed the outcome of patients with BPDCN who underwent allogeneic stem cell transplantation (allo-SCT) or autologous stem cell transplantation (auto-SCT). A total of 39 patients (allo-SCT, n = 34; auto-SCT, n = 5) were identified in the European Group for Blood and Marrow Transplantation registry. The 34 allo-SCT patients had a median age of 41 years (range, 10-70) and received transplantations from sibling (n = 11) or unrelated donors (n = 23) between 2003 and 2009. MAC was used in 74% of patients. Nineteen allo-SCT patients (56%) received transplantations in first complete remission. The 3-year cumulative incidence of relapse, disease-free survival, and overall survival was 32%, 33%, and 41%, respectively. By univariate comparison, being in first remission at allo-SCT favorably influenced survival, whereas age, donor source, and chronic GVHD had no significant impact. We conclude that high-dose therapy followed by allo-SCT from related or unrelated donors can provide durable remission even in elderly patients with BPDCN. However, it remains to be shown if graft-versus-malignancy effects can contribute significantly to BPDCN control after allo-SCT.

To prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy. Two hundred sixty patients having received an autologous-SCT fulfilled the criteria to be included, 138 patients without an HLA-identical sibling donor and 122 patients with a donor. After a median follow-up of 77 months, complete remission, progression-free survival (PFS), and overall survival were not significantly different between the 2 groups. PFS at 6 years was 28% for patients with a donor versus 22% for patients without a donor (P = .19) and overall survival at 6 years from high-dose melphalan was 55%, irrespective of having a donor (P = .68). Cumulative incidence of nonrelapse mortality at 6 years after autologous-SCT was 16% in the donor group versus 3% in the no-donor group (P < .001). However, PFS was significantly prolonged in the 99 patients who actually proceeded to allo-SCT compared with the 115 patients who continued maintenance or received a second high-dose melphalan, but the difference did not translate into a prolonged survival benefit. These results do not support a general application of allo-SCT in all myeloma patients as part of first-line therapy.

Because information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.

We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P = .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. This trial is registered at www.trialregister.nl as #NTR230 and #NTR291.

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

Objective: The adoptive transfer of regulatory T cells (Treg) in murine models has been shown to ameliorate graft-versus-host disease while it may preserve the graft-versus-leukemia effect. However, the impact of Treg on infectious immunity after bone marrow transplantation (BMT) is still unclear. Immunocompetence against opportunistic viral infections depends on the kinetics of T cell recovery after BMT through two distinctive processes, i.e. lymphopenia-induced proliferation (LIP) of mature T cells and generation of T cells through thymopoiesis., Methods: In this study, we set out to assess the effects of adoptively transferred Treg on T cell regeneration in a homeostatic peripheral T cell expansion model and a thymopoiesis-dependent BMT model, and on murine cytomegalovirus (mCMV) clearance and mortality following mCMV challenge., Results: Using lymphopenic Rag-2(-/-)γc(-/-) mice that received a limited number of congenic T cells, we demonstrate that adoptively transferred Treg abrogate LIP of T cells. mCMV challenge resulted in a rapid increase of viral load and death in mice that received Treg, but not in controls. In contrast, following syngeneic T cell-depleted BMT in Rag-2(-/-)γc(-/-) mice, adoptively transferred Treg did not delay T cell reconstitution nor suppressed thymic output and had no effect on viral clearance and survival following mCMV-challenge., Conclusion: The effect of Treg on T cell-mediated immunocompetence against mCMV early after BMT depends on the relative contribution of peripheral expansion and thymopoiesis to T cell regeneration., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant recipients despite the introduction of posttransplantation viral monitoring and preemptive antiviral therapy. We evaluated the use of HLA class I tetramers in monitoring CMV-specific T-cell recovery to predict patients at risk for CMV-related complications. This prospective multicenter clinical trial obtained nearly 1400 tetramer/allele results in more than 800 biweekly blood samples from 83 patients monitored for 1 year after transplantation. Major HLA types were included (A*0101, A*0201, B*0702, B*0801, B*3501). iTAg MHC Tetramers (Beckman Coulter) were used to enumerate CMV-specific CD8(+) T cells by flow cytometry using a single-platform absolute counting method. Assay variability was 8% or less and results were available within 3 hours. Delayed recovery of CMV-specific T cells (< 7 cells/μL in all blood samples during the first 65 days after transplantation) was found to be a significant risk factor for CMV-related complications; these patients were more likely to develop recurrent or persistent CMV infection (relative risk 2.6, CI 1.2-5.8, P = .01) than patients showing rapid recovery, which was associated with protection from CMV-related complications (P = .004). CMV tetramer-based immune monitoring, in conjunction with virologic monitoring, can be an important new tool to assess risk of CMV-related complications and to guide preemptive therapeutic choices.

While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio [HR], 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (+/- 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P = .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is nowadays most frequently applied in patients with acute myeloid leukemia (AML). It combines chemoradiotherapy with immunotherapy, also known as the graft-versus-leukemia (GVL) effect. While it effectively reduces the relapse rate in patients, transplanted in remission, non-relapse mortality (NRM) may counterbalance that beneficial effect. As a result, alloSCT is generally associated with a modest gain in overall survival. Therefore, alloSCT may especially be applied in patients with a relatively high risk of relapse and a relatively low risk of NRM. Here, we discuss how recent findings that have identified and validated specific prognostic factors may affect our decision making for which category of AML-patients alloSCT may especially be indicated.

Inadequate rodent control is considered to play a role in Toxoplasma gondii infection of pigs. This issue was addressed in the current study by combining a 4-month rodent control campaign and a 7-month longitudinal analysis of T. gondii seroprevalence in slaughter pigs. Three organic pig farms with known rodent infestation were included in the study. On these farms, presence of T. gondii in trapped rodents was evaluated by real-time PCR. All rodent species and shrews investigated had T. gondii DNA in brain or heart tissue. Prevalence was 10.3% in Rattus norvegicus, 6.5% in Mus musculus, 14.3% in Apodemus sylvaticus and 13.6% in Crocidura russula. Initial T. gondii seroprevalence in the slaughter pigs ranged between 8% and 17% and dropped on the three farms during the rodent control campaign to 0-10%, respectively. After 4 months of rodent control, T. gondii infection was absent from pigs from two of the three farms investigated and appeared again in one of those two farms after the rodent control campaign had stopped. This study emphasizes the role of rodents and shrews in the transmission of T. gondii to pigs and the importance of rodent control towards production of T. gondii-free pig meat.

The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m(2)) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m(2)). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.

The Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON-SAKK) collaborative study group evaluated outcome of patients (pts) with acute myeloid leukemia (AML) in first remission (CR1) entered in 3 consecutive studies according to a donor versus no-donor comparison. Between 1987 and 2004, 2287 pts were entered in these studies of whom 1032 pts (45%) without FAB M3 or t(15;17) were in CR1 after 2 cycles of chemotherapy, received consolidation treatment, and were younger than 55 years of age and therefore eligible for allogeneic hematopoietic stem cell transplantation (allo-SCT). An HLA-identical sibling donor was available for 326 pts (32%), whereas 599 pts (58%) lacked such a donor, and information was not available in 107 pts. Compliance with allo-SCT was 82% (268 of 326). Cumulative incidences of relapse were, respectively, 32% versus 59% for pts with versus those without a donor (P < .001). Despite more treatment-related mortality (TRM) in the donor group (21% versus 4%, P < .001), disease-free survival (DFS) appeared significantly better in the donor group (48% +/- 3% versus 37% +/- 2% in the no-donor group, P < .001). Following risk-group analysis, DFS was significantly better for pts with a donor and an intermediate- (P = .01) or poor-risk profile (P = .003) and also better in pts younger than 40 years of age (P < .001). We evaluated our results and those of the previous MRC, BGMT, and EORTC studies in a meta-analysis, which revealed a significant benefit of 12% in overall survival (OS) by donor availability for all patients with AML in CR1 without a favorable cytogenetic profile.

Treatment related mortality (TRM) has restricted the application of allogeneic hematopoietic stem cell transplantation (allo-SCT) as a treatment modality for patients with a variety of malignant and non-malignant hematological disorders. TRM is mainly caused by severe opportunistic infections, due to an impaired immune reconstitution. The extreme slow recovery of newly developed, donor stem cell derived naive T-cells is currently considered to be the most important determinant of the impaired immune competence after allo-SCT. Therefore, enhancing naive T-cell recovery following allo-SCT by improving thymopoiesis has recently gained new interest. Possible strategies to improve thymopoiesis may include approaches to protect the nursing stromal compartment and approaches to directly stimulate the differentiation and proliferation of T-cell progenitors intra-thymically. Among the latter is interleukin-7 (IL-7), which has appeared promising in preclinical experimental settings and is expected to enter early clinical studies soon. Keratinocyte growth factor (KGF) is an epithelial growth factor that may protect the thymic epithelium and thereby may preserve it's support of thymopoiesis. KGF has been evaluated clinically in the setting of autologous stem cell transplantation and studies in the setting of allo-SCT are awaited in the near future.

The graft-versus-myeloma (GVM) effect of donor lymphocyte infusions (DLIs) is well established. We now report the outcome of DLI in 54 patients with relapsed myeloma following allogeneic transplantation. Twenty-eight patients (52%) responded, 19 patients (35%) with a partial response and 9 patients (17%) with a complete response. Progression-free and overall survival were 19 and 23 months, respectively. We found that acute and chronic graft-versus-host disease (GVHD) observed in 57% and 47% of patients, respectively, following DLI were the strongest predictors for response. This suggests that targets for GVHD and GVM are identical. In a subgroup analysis, deletion of chromosome 13, as determined by double-color fluorescence in situ hybridization (FISH), had no impact on outcome, indicating that these patients are candidates for early allogeneic transplantation followed by DLI, in case of insufficient response.

Interleukin-7 (IL-7) has been shown to enhance thymic output of newly developed T cells following bone marrow transplantation (BMT) in mice. In addition, IL-7 may affect peripheral expansion of T cells. In order to study the relative contribution of thymopoiesis versus peripheral T-cell expansion in the setting of compromised thymopoiesis, we have applied IL-7 in an experimental stem cell transplantation model using T cell-deficient RAG-1(-/-) mice. C57BL/6 RAG-1(-/-) mice received transplants of syngeneic T-cell-depleted (TCD) bone marrow (Ly5.1) with or without supplemented T cells (Ly5.2). IL-7 was administered until day 63 after BMT. Peripheral blood T- and B-cell recovery was quantified by flow cytometry and thymopoiesis was studied by quantification of T-cell receptor rearrangement excision circles (TRECs). In mice receiving a T-cell-replete BMT, IL-7 selectively expanded mature CD45.2+ T cells without affecting the recovery of new bone marrow-derived CD45.1+ T cells. In contrast, IL-7 significantly enhanced the recovery of bone marrow-derived T cells after TCD BMT. Quantification of TRECs in mice receiving a TCD BMT revealed that enhanced T-cell recovery following IL-7 treatment resulted from a strong expansion of newly developed naive T cells. These results suggest that peripheral expansion of recent thymic emigrants or mature T cells may be a preferential mechanism by which IL-7 enhances T-cell recovery after BMT.

Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes are considered pivotal to prevent lymphoproliferative disease (LPD) in allogeneic stem cell transplantation (SCT) recipients. We evaluated the recovery of EBV-specific CD8+ T cells after partially T-cell-depleted SCT and studied the interaction between EBV-specific CD8+ T cells, EBV reactivation, and EBV-LPD. EBV-specific CD8+ T cells were enumerated using 12 class I HLA tetramers presenting peptides derived from 7 EBV proteins. Blood samples were taken at regular intervals after SCT in 61 patients, and EBV DNA levels were assessed by real-time polymerase chain reaction. Forty-five patients showed EBV reactivation, including 25 with high-level reactivation (ie, more than 1000 genome equivalents [geq] per milliliter). Nine of these 25 patients progressed to EBV-LPD. CD8+ T cells specific for latent or lytic EBV epitopes repopulated the peripheral blood at largely similar rates. In most patients, EBV-specific CD8+ T-cell counts had returned to normal levels within 6 months after SCT. Concurrently, the incidence of EBV reactivations clearly decreased. Patients with insufficient EBV-specific CD8+ T-cell recovery were at high risk for EBV reactivation in the first 6 months after SCT. Failure to detect EBV-specific CD8+ T cells in patients with high-level reactivation was associated with the subsequent development of EBV-LPD (P =.048). Consequently, the earlier defined positive predictive value of approximately 40%, based on high-level EBV reactivation only, increased to 100% in patients without detectable EBV-specific CD8+ T cells. Thus, impaired recovery of EBV-specific CD8+ T cells in patients with high-level EBV reactivation may identify a subgroup at very high risk for EBV-LPD and supports that EBV-specific CD8+ T cells protect SCT recipients from progressive EBV reactivation and EBV-LPD.

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m(2) administered intravenously in 2 doses of 70 mg/m(2) (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P =.002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P =.28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 months versus 47 months; P =.41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.

In this multicenter retrospective study, the outcomes of 234 patients with myelodysplastic syndrome (MDS) who underwent transplantation between 1995 and 1999 from HLA-identical siblings were analyzed according to the hematopoietic stem cell source used, that is, bone marrow (BM, n = 132) or granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells (PBPCs, n = 102). There were 69 cases of refractory anemia (RA), 86 RA with excess blasts (RAEB), 75 RAEB in transformation (RAEB-t), and 4 unclassified MDS at diagnosis. The International Prognostic Scoring System was intermediate-2 or high in 104 of the 158 available scores. Multivariate analyses focused on transplantation-related mortality (TRM), 2-year treatment failure incidence, and survival. Use of PBPCs reduced the median duration of neutropenia and thrombocytopenia by 4 and 12 days, respectively. The incidence of acute GVHD was similar whatever the graft type used. Chronic GVHD was more likely to have occurred with PBPCs (odds ratio [OR], 1.62; 95% confidence interval [CI], 0.87-3.02). Two-year TRM was significantly reduced with PBPCs (relative risk [RR], 0.33; 95% CI, 0.15-0.73; P <.007), except for patients who had either RA or high-risk cytogenetics. The 2-year treatment failure incidence was significantly decreased with PBPCs, from 38% to 13% (RR, 0.22; 95% CI, 0.10-0.48; P <.001). Estimate of the 2-year event-free survival was 50% with PBPCs versus 39% with BM. In multivariate analysis, the outcome was significantly improved with PBPCs (RR, 0.27; 95% CI, 0.13-0.52; P <.001), except for patients with either RA or high-risk cytogenetics. In conclusion, PBPCs might be preferred for allogeneic transplantation in MDS patients at high risk for relapse on the basis of morphologic criteria because the use of this hematopoietic stem cell was associated with lower treatment failure incidence and improved survival.

Recipients of a partially T-cell-depleted (TCD) allogeneic stem cell transplantation (allo-SCT) developing reactivation of Epstein-Barr virus (EBV) with quantified viral DNA levels exceeding 1000 genome equivalents/milliliter (geq/mL) are at high risk for EBV-lymphoproliferative disease (EBV-LPD). We studied whether preemptive therapy with rituximab prevents EBV-LPD, LPD-mortality, and abrogates viral reactivation in high-risk patients. We monitored 49 recipients of a TCD allo-SCT weekly for EBV reactivation by quantitative real-time polymerase chain reaction (PCR). Preemptive therapy by a single infusion of rituximab was given to patients with viral reactivation more than or equal to 1000 geq/mL. Results were compared with an historical control group of patients retrospectively monitored for EBV reactivation at similar intervals. There were 17 prospectively monitored patients who showed EBV reactivation more than or equal to 1000 geq/mL and 15 received preemptive therapy. Median time to preemptive therapy was 113 days (range, 41-202 days) after SCT. There were 14 patients who showed complete response (CR) as characterized by prevention of EBV-LPD and complete clearance of EBV-DNA from plasma, which was achieved after a median number of 8 days (range, 1-46 days). One patient progressed to EBV-LPD despite preemptive therapy, but obtained CR after 2 infusions of rituximab and donor lymphocyte infusion. There were 2 patients who had already developed EBV-LPD prior to preemptive rituximab, but obtained CR following 2 rituximab infusions. Comparison of this prospectively followed series to our historical cohort with the same high-risk profile showed a reduction of EBV-LPD incidence (18% +/- 9% versus 49% +/- 11%, respectively) and a complete abrogation of LPD-mortality (0% versus 26% +/- 10%, respectively) (P =.04) at 6 months from EBV-DNA more than or equal to 1000 geq/mL. Frequent quantitative monitoring of EBV reactivation and preemptive therapy by rituximab improves outcome in patients at high risk of EBV-LPD. (Blood. 2002;99:4364-4369)