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1.  Comparison of Allogeneic Stem Cell Transplantation and Non-Transplant Approaches in Elderly Patients with Advanced Myelodysplastic Syndrome: Optimal Statistical Approaches and a Critical Appraisal of Clinical Results Using Non-Randomized Data 
PLoS ONE  2013;8(10):e74368.
Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non –transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of „comparison“, the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an “average” hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.
PMCID: PMC3792099  PMID: 24116002
3.  Immunotherapy for Multiple Myeloma 
PMCID: PMC3546469  PMID: 23346187
4.  Impact of the NK Cell Receptor LIR-1 (ILT-2/CD85j/LILRB1) on Cytotoxicity against Multiple Myeloma 
The role of different receptors in natural-killer- (NK-) cell-mediated cytotoxicity against multiple myeloma (MM) cells is unknown. We investigated if an enhancement of NK-cell-mediated cytotoxicity against MM could be reached by blocking of the inhibitory leukocyte immunoglobulin-like receptor 1 (LIR-1). Our investigations revealed high levels of LIR-1 expression not only on the NK cell line NK-92, but also on myeloma cells (MOLP-8, RPMI8226) as well as on a lymphoblastoid cell line (LBCL; IM-9). Subsequent cytotoxicity assays were designed to show the isolated effects of LIR-1 blocking on either the effector or the tumor side to rule out receptor-receptor interactions. Although NK-92 was shown to be capable of myeloma cell lysis, inhibition of LIR-1 on NK-92 did not enhance cytotoxicity. Targeting the receptor on MM and LBCL did not also alter NK-92-mediated lysis. We come to the conclusion that LIR-1 alone does not directly influence NK-cell-mediated cytotoxicity against myeloma. To our knowledge, this work provides the first investigation of the inhibitory capability of LIR-1 in NK-92-mediated cytotoxicity against MM and the first functional evaluation of LIR-1 on MM and LBCL.
PMCID: PMC3400434  PMID: 22844324
5.  Replacement of hematopoietic system by allogeneic stem cell transplantation in myelofibrosis patients induces rapid regression of bone marrow fibrosis 
Fibrogenesis & Tissue Repair  2012;5(Suppl 1):S25.
Bone marrow fibrosis is a hallmark of primary and post ET/PV myelofibrosis. To investigated the impact of replacement of the hematopoietic system in myelofibrosis patients by allogeneic stem cell transplantation on bone marrow fibrosis, we studied bone marrow fibrosis on bone marrow samples from 24 patients with myelofibrosis before and after dose-reduced conditioning followed by allogeneic stem cell transplantation from related or unrelated donor. Using the European Consensus on Grading Bone Marrow Fibrosis, before allografting all patients had advanced fibrosis MF-2 (n = 13) or MF-3 (n = 11). After transplantation, a complete (MF-0) or nearly complete (MF-1) regression of bone marrow fibrosis was seen in 59 % at day +100, in 90 % at day +180, and in 100 % at day +360. No correlation between occurrence of acute graft-versus-host disease, and fibrosis regression on day +180 was seen. We conclude that dose-reduced conditioning, followed by allogeneic stem cell transplantation, resulted in a rapid resolution of bone-marrow fibrosis suggesting the bone marrow fibrogenesis is a highly dynamic rather than static process in patients with myelofibrosis.
PMCID: PMC3368753  PMID: 23259545
6.  NCI 1st International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Summary and Recommendations from the Organizing Committee 
The First International Workshop on The Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation was organized and convened to identify, prioritize, and coordinate future research activities related to relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT). Each of the Workshop’s six working committees have published individual reports of ongoing basic, translational and clinical research and recommended areas for future research related to the areas of relapse biology, epidemiology, prevention and treatment. This document summarizes each of the committees’ recommendations and suggests three major initiatives for a coordinated research effort to address the problem of relapse after alloHSCT. The first is the need to establish multi-center correlative and clinical trials networks for basic/translational, epidemiological, and clinical research. Second, there is a need for a network of biorepositories for the collection of samples pre- and post-alloHSCT to aid in laboratory and clinical studies. Third, there should be further refinement, implementation, and study of the proposed Workshop disease-specific response and relapse definitions and the recommendations for monitoring of minimal residual disease. These recommendations, in coordination with ongoing research initiatives and transplant organizations, provide a research framework to rapidly and efficiently address the significant problem of relapse following alloHSCT.
PMCID: PMC3102296  PMID: 21224011
7.  Longitudinal Analysis of Tetanus- and Influenza-Specific IgG Antibodies in Myeloma Patients 
Background. Multiple myeloma (MM) and its therapies may induce a severely compromised humoral immunity. We have performed a longitudinal analysis of IgG-antibody responses against influenza virus (FLU) and tetanus toxoid (TT) as surrogate markers for the B cell-mediated immunity in MM patients. Methods. 1094 serum samples of 190 MM patients and samples from 100 healthy donors were analyzed by ELISA for FLU- and TT-specific antibodies. Results. MM patients evidenced lower levels of FLU- and TT-specific antibodies than healthy controls (P < 0.001). Immunoreactivity decreased with progressing disease and worsening clinical status. Levels of FLU- and TT-specific antibodies increased shortly (0-6 months) after alloSCT (P < 0.001), a time-period during which intravenous immunoglobulin (IVIG) is routinely applied. Thereafter, antibody concentrations declined and remained suppressed for 3 years in the case of FLU-specific and for more than 5 years in the case of TT-specific antibodies. Conclusions. We found that MM is associated with a profound disease- and therapy-related immunosuppression, which is compensated for a few months after alloSCT, most likely by application of IVIG. This and the differences regarding the recovery of anti-FLU and anti-TT antibody titers during the following years need to be taken into account for optimizing IVIG application and immunization after alloSCT.
PMCID: PMC3310258  PMID: 22481961
8.  Minimal Residual Disease Following Allogeneic Hematopoietic Stem Cell Transplantation 
Minimal residual disease (MRD), both before and after transplant, is a clinically important yet relatively poorly defined aspect of allogeneic hematopoietic stem cell transplantation (alloHSCT). The clinical relevance of MRD in the context of alloHSCT has been demonstrated by its association with the development of clinical relapse. However, with the possible exception of chronic myeloid leukemia, the specific techniques, timing, frequency and clinical utility, relative to improvement in patient outcomes, for monitoring MRD in the setting of alloHSCT has yet to be clearly defined. A concise overview of monitoring techniques for detecting MRD, as well as treatment strategies and biologic and clinical research initiatives for MRD suggested by the National Cancer Institute 1st International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation, is covered in this paper.
PMCID: PMC3056549  PMID: 21047560
minimal residual disease; allogeneic; relapse; graft-versus-tumor; DLI
9.  Patients with Multiple Myeloma Develop SOX2-Specific Autoantibodies after Allogeneic Stem Cell Transplantation 
The occurrence of SOX2-specific autoantibodies seems to be associated with an improved prognosis in patients with monoclonal gammopathy of undetermined significance (MGUS). However, it is unclear if SOX2-specific antibodies also develop in established multiple myeloma (MM). Screening 1094 peripheral blood (PB) sera from 196 MM patients and 100 PB sera from healthy donors, we detected SOX2-specific autoantibodies in 7.7% and 2.0% of patients and donors, respectively. We identified SOX2211–230 as an immunodominant antibody-epitope within the full protein sequence. SOX2 antigen was expressed in most healthy tissues and its expression did not correlate with the number of BM-resident plasma cells. Accordingly, anti-SOX2 immunity was not related to SOX2 expression levels or tumor burden in the patients' BM. The only clinical factor predicting the development of anti-SOX2 immunity was application of allogeneic stem cell transplantation (alloSCT). Anti-SOX2 antibodies occurred more frequently in patients who had received alloSCT (n = 74). Moreover, most SOX2-seropositive patients had only developed antibodies after alloSCT. This finding indicates that alloSCT is able to break tolerance towards this commonly expressed antigen. The questions whether SOX2-specific autoantibodies merely represent an epiphenomenon, are related to graft-versus-host effects or participate in the immune control of myeloma needs to be answered in prospective studies.
PMCID: PMC3227434  PMID: 22190969
10.  Molecular Diagnostics, Targeted Therapy, and the Indication for Allogeneic Stem Cell Transplantation in Acute Lymphoblastic Leukemia 
Advances in Hematology  2011;2011:154745.
In recent years, the panel of known molecular mutations in acute lymphoblastic leukemia (ALL) has been continuously increased. In Philadelphia-positive ALL, deletions of the IKZF1 gene were identified as prognostically adverse factors. These improved insights in the molecular background and the clinical heterogeneity of distinct cytogenetic subgroups may allow most differentiated therapeutic decisions, for example, with respect to the indication to allogeneic HSCT within genetically defined ALL subtypes. Quantitative real-time PCR allows highly sensitive monitoring of the minimal residual disease (MRD) load, either based on reciprocal gene fusions or immune gene rearrangements. Molecular diagnostics provided the basis for targeted therapy concepts, for example, combining the tyrosine kinase inhibitor imatinib with chemotherapy in patients with Philadelphia-positive ALL. Screening for BCR-ABL1 mutations in Philadelphia-positive ALL allows to identify patients who may benefit from second-generation tyrosine kinase inhibitors or from novel compounds targeting the T315I mutation. Considering the central role of the molecular techniques for the management of patients with ALL, efforts should be made to facilitate and harmonize immunophenotyping, cytogenetics, and molecular mutation screening. Furthermore, the potential of high-throughput sequencing should be evaluated for diagnosis and follow-up of patients with B-lineage ALL.
PMCID: PMC3216286  PMID: 22110503
12.  First-Line Matched Related Donor Hematopoietic Stem Cell Transplantation Compared to Immunosuppressive Therapy in Acquired Severe Aplastic Anemia 
PLoS ONE  2011;6(4):e18572.
Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials.
A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival.
26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
PMCID: PMC3081818  PMID: 21541024
Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease free survival after allogeneic hematopoietic cell transplantation. In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA non-identical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft versus host disease prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day transplant related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5 year overall survival rates were 37%, 30%, and 40% respectively. Disease-free survival rates were 33%, 27% and 22% respectively. Disease-free survival for patients receiving reduced intensity transplants was comparable, 39% for HLA identical sibling donors and 17% for unrelated donors at three years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival in about one-third of patients.
PMCID: PMC2908949  PMID: 19879949
Myelofibrosis; allogeneic transplantation
14.  High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation for Metastatic Rhabdomyosarcoma—A Systematic Review 
PLoS ONE  2011;6(2):e17127.
Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy.
Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations.
A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years) were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws.
HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials.
PMCID: PMC3044147  PMID: 21373200
15.  The Role of Allogeneic Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma Patients 
Advances in Hematology  2010;2011:974658.
Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15–20% of patients remain refractory to chemoradiotherapy, and 20–40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies.
PMCID: PMC2964008  PMID: 20981158
16.  Red blood cell transfusion-dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de novo myelodysplastic syndromes (MDS) 
The prognosis of patients with de novo myelodysplastic syndromes (MDS), who are red blood cell transfusion-dependent (TD) and receive supportive care is inferior to that of patients not requiring transfusions. It is unknown, whether TD also affects outcome after allogeneic transplantation. We therefore analyzed in 172 de novo MDS patients, median age 51 years, the impact of TD on outcome after high-dose conditioning and allogeneic peripheral blood stem cell transplantation (PBSCT). With a median follow-up of 37 months the probability of 3-year overall survival (OS) did not differ significantly between patients who were or were not TD before PBSCT (p=0.1). However, transfusion burden, as reflected by ferritin levels, correlated with a higher probability of severe acute graft versus host disease (p=0.03) and a higher comorbidity index (p=0.01), and OS was inferior among patients with ferritin levels >1000µg/l before PBSCT (p=0.03). In multivariate analysis only marrow myeloblast count (p=0.01) and comorbidity index (p=0.001) had a significant impact on OS. Thus, these data did not identify TD as an independent negative prognostic factor for outcome after allogeneic PBSCT. However, iron overload, presumably transfusion-related, may contribute to inferior transplant success by adding to the overall comorbidities. Whether clinical intervention in the form of iron chelation would improve results of allogeneic PBSCT in TD patients with MDS remains to be determined.
PMCID: PMC2759308  PMID: 18940675
MDS; transplantation; transfusion; WPSS
17.  Detection of Virulence-Associated Genes Not Useful for Discriminating between Invasive and Commensal Staphylococcus epidermidis Strains from a Bone Marrow Transplant Unit 
Journal of Clinical Microbiology  2004;42(12):5614-5619.
Because of their biofilm-forming capacity, invasive Staphylococcus epidermidis isolates, which cause the majority of nosocomial catheter-related bloodstream infections (BSIs), are thought to be selected at the time of catheter insertion from a population of less virulent commensal strains. This fact allows the prediction that invasive and contaminating strains can be differentiated via detection of virulence-associated genes. However, the hospital environment may pave the way for catheter-related infections by promoting a shift in the commensal bacterial population toward strains with enhanced virulence. The distribution of virulence-associated genes (icaADBC, aap, atlE, bhp, fbe, embp, mecA, IS256, and IS257), polysaccharide intercellular adhesin synthesis, and biofilm formation were investigated in S. epidermidis strains from independent episodes of catheter-related BSIs in individuals who have received bone marrow transplantation (BMT). The results were compared with those obtained for commensal S. epidermidis isolates from hospitalized patients after BMT and from healthy individuals, respectively. The clonal relationships of the strains were investigated by pulsed-field gel electrophoresis. icaADBC, mecA, and IS256 were significantly more prevalent in BSI isolates than in commensal isolates from healthy individuals. However, the prevalence of any of the genes in clonally independent, endogenous commensal strains from BMT patients did not differ from that in invasive BSI strains. icaADBC and methicillin resistance, factors important for the establishment of catheter-related infections, already ensure survival of the organisms in their physiological habitat in the hospital environment, resulting in a higher probability of contamination of indwelling medical devices with virulent S. epidermidis strains. The dynamics of S. epidermidis populations reveal that detection of icaADBC and mecA is not suitable for discriminating invasive from contaminating S. epidermidis strains.
PMCID: PMC535265  PMID: 15583290

Results 1-17 (17)