Nicolaus Kröger

University Medical Center Hamburg - Eppendorf, Hamburg, Hamburg, Germany

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Publications (258)1205.08 Total impact

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    ABSTRACT: Background Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. Methods We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. Results After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). Conclusions The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275 .).
    Full-text · Article · Jan 2016 · New England Journal of Medicine
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    ABSTRACT: The European Society for Blood and Marrow Transplantation Chronic Malignancies Working Party held a preceptorship meeting in Turin, Italy on 25-26 September 2014, to discuss the role of stem cell transplantation (SCT) in the treatment of multiple myeloma and other plasma cell disorders. Scientists and clinicians working in the field gathered to discuss a variety of topics including the results of recent clinical trials, basic research, the concept of minimal residual disease, and immune modulation. As individual presentations revealed, important advances have occurred in our understanding of the pathophysiology of myeloma and the role that SCT, along with other forms of immunotherapy, plays in treating it. Each presentation stimulated discussion and exchange of ideas among the attendants. We decided to summarize and, importantly, to update the meeting proceedings in this review to share stimulating discussions and ideas on potentially novel treatment strategies among clinicians.
    No preview · Article · Jan 2016 · Leukemia & lymphoma
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    ABSTRACT: The only curative therapy for primary myelofibrosis (PMF) is allogeneic stem cell transplantation (ASCT). However, although we know that patients can benefit from ASCT, we do not know the changes of the expression profile of cytokines and matrix modulation factors. In this first systematic analysis, we evaluated the expression profile of 103 factors before and after transplantation in order to identify potential biomarkers. The expression of fibrosis, inflammation and angiogenesis-associated genes were analysed in a total of 42 bone marrow biopsies: PMF patients (n=14) before and after ASCT and, for control purposes, post-ASCT multiple myeloma cases (n=14) and non-neoplastic haematopoiesis (n=10). In post-ASCT PMF cases, decreased expression of tissue inhibitor of metalloproteinases (TIMP) and platelet-derived growth factor alpha (PDGFA) correlated with bone marrow remodelling and haematological remission. Expression of several other matrix factors remained at high levels and now could contribute to post-ASCT remodelling. This is the first systematic analysis of cytokine expression in post-ASCT PMF bone marrow which shows that normalisation of bone marrow microenvironment is paralleled by decreased TIMP and PDGFA expression.
    No preview · Article · Dec 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for Myelodysplastic Syndromes (MDS). Little is known about the prognostic impact of mutations e.g. in TP53 specifically after allo-HSCT. We here describe the prognostic impact of mutations in a panel of 19 genes analyzed by amplicon-based-next-generation-sequencing in a uniformly treated patient cohort. Sixty-two patients with a median age of 61 years suffered MDS with 0-20% bone marrow blasts. IPSS was intermediate-1 (15%) and higher (79%). Conditioning uniformly was performed using a sequential approach in which FLAMSA-chemotherapy was followed by Busulfan-based conditioning. Patients mostly were transplanted from an unrelated donor (77%), 36% of patients received a graft from a mismatched donor. Median number of mutations was 2 (, range 0-6). RUNX1, GATA2, TET2, and CEBPA were the genes most frequently found mutated. TP53, a factor previously reported to confer adverse prognostic impact after allogeneic stem cell transplantation, was mutated in samples from eight patients, one of which showed a silent mutation. With an estimated 5-year-overall/ disease-free-survival of 48±7%/ 41±7%, none of the mutations analyzed showed a prognostic impact in this analysis of the largest uniformly treated cohort thus far. This especially holds true for patients with a mutation in TP53. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · European Journal Of Haematology
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    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N=37,542; 37%) or autologous (N=65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84–0·91 per 10 patients; p<0·0001; HR 0·90;0·85–0·90 per 10years; p<0·001) and autologous HSCT (HR 0·91;0·87–0·96 per 10 patients; p<0·001; HR 0·93;0·87–0·99 per 10years; p=0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R2=18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.
    Full-text · Article · Nov 2015 · EBioMedicine
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    ABSTRACT: Infections due to vancomycin-resistant enterococci (VRE) are of significant importance in high-risk populations, and daptomycin is a bactericidal antibiotic to treat multidrug-resistant VRE in these patients. The emergence of daptomycin non-susceptibility invasive VRE during daptomycin therapy is a major clinical issue. Here the hypothesis was tested that systemic daptomycin therapy also induces the emergence of daptomycin non-susceptible (DNS-) isolates in colonizing VRE populations. 11 vancomycin-resistant Enterococcus faecium strain pairs recovered from rectal swabs were available for analysis. All initial isolates exhibited daptomycin MICs within the wild type MIC distribution of E. faecium (MIC≤4mg/L). In follow-up isolates from five patients a 4-16-fold daptomycin MIC increase was detected. All patients carrying DNS-VRE received daptomycin (14-28 days) at 4mg/kg body weight, while two patients in whom no DNS-VRE emerged were only treated with daptomycin for 1 and 4 days, respectively. Comparative whole genome sequencing identified DNS-VRE-specific single nucleotide polymorphisms (SNP), including mutations in cardiolipin synthase (Cls), and additional SNPs in independent genes potentially relevant for the DNS phenotype. Mutations within cls were also identified in three additional, colonizing DNS-VRE. Of these, at least one strain was transmitted within the hospital. In none of the VRE isolates tested, pre-existing or de novo mutations in the liaFSR operon were detected. This is the first report documenting the emergence of DNS-VRE in colonizing strains during daptomycin treatment, putting the patient at risk for subsequent DNS-VRE infections and priming the spread of DNS-VRE within the hospital environment.
    No preview · Article · Oct 2015 · International journal of medical microbiology: IJMM
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    ABSTRACT: Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.Bone Marrow Transplantation advance online publication, 5 October 2015; doi:10.1038/bmt.2015.223.
    Full-text · Article · Oct 2015 · Bone marrow transplantation
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    ABSTRACT: In contrast to the upfront setting in which the role of high dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a 1(st) remission in patients with multiple myeloma (MM) is well established, the role of high dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN), the American Society of Blood and Marrow Transplantation (ASBMT), and the European Society of Blood and Marrow Transplantation (EBMT) convened a meeting of MM experts to: 1. Summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy; 2. Propose guidelines for the use of salvage HCT in MM; 3. Identify knowledge gaps; 4 Propose a research agenda and 5. Develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: 1. In transplant eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high dose therapy with HCT as part of salvage therapy should be considered standard; 2. High dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; 3. High dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; 4. The role of post salvage HCT maintenance needs to be explored in the context of well designed prospective trials that should include new agents such as monoclonal antibodies, immune-modulating agents and oral proteasome inhibitors; 5. Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post HCT strategies in patients with short (less than 18 months remissions) after primary therapy; 6. Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing to "best non HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform two transplants early in the course of the disease. In regards to allogeneic HCT the expert committee agreed on the following consensus statements: 1. Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high risk features (i.e cytogenetics, extramedullary disease, plasma cell leukemia or high LDH); 2. Allogeneic HCT should be performed in the context of a clinical trial if possible; 3. The role of post allogeneic HCT maintenance therapy needs to be explored in the context of well designed prospective trials; 4. Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.
    Full-text · Article · Oct 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • Nicolaus Kröger
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    ABSTRACT: Primary or post-ET/PV myelofibrosis is one of the Philadelphia-negative myeloproliferative neoplasms with worst survival. Allogeneic stem cell transplantation (ASCT) can cure a substantial number of patients but is still not universally applicable due to toxicity which leads to therapy-related morbidity and mortality. In the more recent years, outcome of ASCT has improved by less toxic conditioning regimens and optimization of relapse prevention strategies. The introduction of novel therapies such as JAK2 inhibitors may also be helpful in preparation of the transplant by reducing spleen size and constitutional symptoms. To reduce the risk of relapse, molecular monitoring and adoptive immunotherapy with donor lymphocytes have been introduced. Despite lacking prospective randomized trials, it is justified to offer ASCT to eligible patients with PMF whose median survival is expected to be less than 5 years. This includes patients with intermediate-2 and high risk according to IPSS or DIPSS, respectively. The benefit/risk ratio should be considered in each patient taking also transplant- and patient-specific factors into account.
    No preview · Article · Aug 2015 · Current Hematologic Malignancy Reports
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    ABSTRACT: Comparison of long-term outcomes in patients with refractory/relapsed grade 1-2 follicular lymphoma (FL) after allogeneic (allo-HCT) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era. Adult patients with relapsed/refractory grade 1-2 FL undergoing 1(st) reduced-intensity allo-HCT or 1(st) autograft during 2000-2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger; more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto- vs. allo-HCT groups for non-relapse mortality (NRM) were 5% vs. 26% (p<0.0001); relapse/progression: 54% vs. 20% (p<0.0001); progression-free survival (PFS): 41% vs. 58% (p<0.001) and overall survival (OS): 74% vs. 66% (p=0.05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months post-HCT (RR=4.4; p<0.0001), and worse PFS (RR=2.9; p<0.0001) beyond 11 months post HCT. In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.41; p<0.0001), but beyond 24 months with inferior OS (RR=2.2; p=0.006). A landmark analysis of patients alive and progression-free at 2-years post-HCT confirmed these observations, showing no difference in further NRM between both groups, but significantly higher risk of relapse/progression (RR=7.3; p<0.0001) and inferior PFS (RR=3.2; p<0.0001) and OS (RR=2.1; p=0.04) following auto-HCT. The 10-year cumulative incidence of second hematological malignancies following allo- and auto-HCT was 0% and 7%, respectively. Auto- and RIC-allo-HCT as 1(st) transplantation approach can provide durable disease control in grade 1-2 FL patients. Continued disease relapse-risk following auto-HCT translates into improved PFS and OS following allo-HCT, in long-term survivors. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • Holger W Auner · Laurent Garderet · Nicolaus Kröger
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    ABSTRACT: High-dose chemotherapy with melphalan followed by autologous haematopoietic cell transplantation (AHCT) is a standard of care in young patients (<65 years) with multiple myeloma. Most myeloma patients, however, are older than 65 years at the time of diagnosis, and the findings of numerous single-centre and registry studies provide evidence that AHCT can be a feasible and effective treatment option in these patients. Nevertheless, AHCT is not generally recommended as standard treatment in the elderly, due to the fact that a benefit of AHCT over conventional-dose therapy has not been demonstrated by prospective randomized trials. Yet, the use of AHCT has increased substantially in older patients in recent years, and an increasing number of reports suggest comparable outcomes for older and younger patients after AHCT. In this review we summarize the results of AHCT for elderly patients with multiple myeloma. © 2015 John Wiley & Sons Ltd.
    No preview · Article · Jul 2015 · British Journal of Haematology
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    ABSTRACT: The results of allogeneic stem cell transplantation (allo-SCT) in chronic myelomonocytic leukaemia (CMML) are usually reported together with other categories of myelodysplastic syndrome. We analysed transplantation outcome in 513 patients with CMML, with a median age of 53 years reported to the European Group for Blood and Marrow Transplantation. Conditioning was standard (n = 249) or reduced-intensity (n = 226). Donors were human leucocyte antigen-related (n = 285) or unrelated (n = 228). Disease status at transplantation was complete remission (CR) in 122 patients, no CR in 344, and unknown in 47. Engraftment was successful in 95%. Grades 2-4 acute graft-versus-host disease (GvHD) occurred in 33% of the patients and chronic GvHD was reported in 24%. The 4-year cumulative incidence of non-relapse mortality was 41% and 32% for relapse, resulting in a 4-year estimated relapse-free and overall survival (OS) of 27% and 33%, respectively. Patients transplanted in CR had lower probability for non-relapse death (P = 0·002) and longer relapse-free and OS (P = 0·001 and P = 0·005, respectively). In multivariate analysis the only significant prognostic factor for survival was the presence of CR at transplantation (P = 0·005). Allo-SCT remains a curative treatment option for patients with CMML and should preferably be performed early after diagnosis or after establishing the best possible remission status. © 2015 John Wiley & Sons Ltd.
    Full-text · Article · Jul 2015 · British Journal of Haematology
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    ABSTRACT: Chronic graft versus host disease (cGvHD) is the most common cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated the impact of NIH classification on outcome of patients at our center. Primary endpoint was overall survival at 5 years. Two hundred one patients with cGVHD according to NIH were included. Platelets <100,000/μl on day of diagnosis of cGvHD (HR 2.97, 95 % CI 1.7-5.3, p < 0.001), female donor (HR 1.78, 95 % CI 1.0-3.2, p = 0.05), and reduced intensity conditioning (HR 1.95, 95 % CI 1.0-3.8, p = 0.05) impacted overall survival. Non-relapse mortality (NRM) was higher for patients with low vs. high platelets: 26 % (95 % CI 14-40) vs. 6 % (95 % CI 2-10), p < 0.001, and tended to be higher for female vs. male donor: 14 % (95 % CI 7-23) vs. 7 % (95 % CI 3-13), p = 0.08. Relapse tended to be higher for recipients of reduced intensity conditioning (RIC) vs. myeloablative conditioning (MAC): 33 % (95 % CI 23-43) vs. 20 % (95 % CI 10-31), p = 0.06. After excluding patients with myeloma and lymphoma, IgG serum levels at diagnosis of cGvHD of 122 patients were correlated with survival. IgG levels above normal were associated with worse 2-year overall survival (OS), p = 0.04, compared to normal or low IgG levels. Platelet count at diagnosis remains the most valid prognostic factor for survival of patients with cGvHD even in the era of NIH grading. High IgG level at diagnosis of cGVHD represents a potential negative prognostic parameter that deserves further investigation.
    Full-text · Article · Jul 2015 · Annals of Hematology
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    ABSTRACT: Most patients with multiple myeloma (MM) will relapse after an initial response and eventually succumb to their disease. This is due to the persistence of chemotherapy-resistant tumor cells in the patients' bone marrow (BM) and immunotherapeutic approaches could contribute to eradicating these remaining cells. We evaluated SLLP1 as a potential immunotherapeutic target for MM. We determined SLLP1 expression in myeloma cell lines and 394 BM samples from myeloma patients (n = 177) and BM samples from healthy donors (n = 11). 896 blood samples and 64 BM samples from myeloma patients (n = 263) and blood from healthy donors (n = 112) were analyzed for anti-SLLP1 antibodies. Seropositive patients were evaluated regarding SLLP1-specific T cells. Most cell lines showed SLLP1 RNA and protein expression while it was absent from normal BM. Of 177 patients 41% evidenced SLLP1 expression at least once during the course of their disease and 44% of newly diagnosed patients were SLLP1-positive. Expression of SLLP1 was associated with adverse cytogenetics and with negative prognostic factors including the patient's age, number of BM-infiltrating plasma cells, serum albumin, β2-microglobulin, creatinine, and hemoglobin. Among patients treated with allogeneic stem cell transplantation those with SLLP1 expression showed a trend towards a reduced overall survival. Spontaneous anti-SLLP humoral immunity was detectable in 9.5% of patients but none of the seropositive patients evidenced SLLP1-specific T cells. However, antigen-specific T cells could readily be induced in vitro after stimulation with SLLP1. SLLP1 represents a promising target for the immunotherapy of MM, in particular for the adoptive transfer of T cell receptor-transduced T cells.
    Preview · Article · Jun 2015 · Journal of Translational Medicine
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    ABSTRACT: Multiple Myeloma (MM) is a plasma cell (PC) malignancy, which despite significant therapeutic advances, is still considered incurable. This is due to the persistence of chemotherapy-resistant minimal residual disease in the patients' bone marrow (BM) after an effective induction therapy. Immunotherapies targeting surface molecules expressed on the bulk of tumor cells and the chemotherapy-resistant, myeloma-propagating cells could play a central role in this clinical setting. We recently described surface molecule CD229 as a potential therapeutic target for MM. In our current study we assessed the expression of CD229 on different PC subtypes and on cells with a myeloma-propagating phenotype in a total of 77 patients with PC dyscrasias independently at two different cancer centers. We found that CD229 was strongly and homogeneously overexpressed on the PC of patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, MM, and PC leukemia. CD229 was particularly overexpressed on those PC showing an abnormal phenotype such as expression of CD56. Most importantly, CD229 was also highly expressed on those cells in the patients' BM displaying the phenotype of chemotherapy-resistant and myeloma-propagating cells. In conclusion, our combined findings suggest that immunotherapies targeting CD229 will not only be effective for the bulk of tumor cells but will also help to eradicate chemotherapy-resistant cells remaining in the patients' BM after induction treatment. Hopefully, the design of CD229-specific monoclonal antibodies or chimeric antigen receptor-transduced T cells will help to achieve prolonged remissions or even cures in MM patients.
    No preview · Article · May 2015 · Human Vaccines & Immunotherapeutics
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    ABSTRACT: Outcomes after umbilical cord blood transplantation(UCBT) for chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL) are unknown. We analyzed outcomes of 68 patients with poor risk CLL/SLL who underwent reduced intensity(RIC) UCBT from 2004-2012. Median age was 57 years and follow-up 36 months; 17 patients had del17p/p53mutation, 19 patients had fludarabine refractory disease, 11 relapsed after ASCT, 8 had diagnosis of Prolymphocytic Leukemia, 4 Richter Syndrome and 8 were transplanted with progressive or refractory disease. The most common RIC used was CYFLUTBI in 82%; 15 patients received ATG. Most of the cord blood (CB) grafts were HLA mismatched and 76% received a double UCBT. Median total nucleated cells(TNC) collected was 4,7x10(7)/Kg. The cumulative incidence(CI) neutrophil and platelet engraftment were 84% and 72% at 60 and 180 days respectively; day-100 GVHD(II-IV) was 43% and 3-year chronic GVHD 32%. CI of relapse, non-relapse mortality(NRM), overall survival(OS) and progression-free survival(PFS) at 3-years were, respectively, 16%, 39%, 54% and 45%. The use of low dose TBI regimens and fludarabine sensitive disease at transplantation were associated with acceptable PFS. In conclusion, use of UCBT-RIC seems to be feasible in poor-risk CLL/SLL and improved outcomes were observed in patients with fludarabine sensitive disease who received low dose TBI regimens. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials. © 2015 S. Karger AG, Basel.
    Full-text · Article · May 2015 · Acta Haematologica
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    ABSTRACT: Allogeneic hematopoietic cell transplantation is a potentially curative treatment in patients with acute myeloid leukemia. Recent advances in the field of hematopoietic cell allografting have resulted in a practice shift, favoring less intense preparative regimens. We present results of a retrospective comparative analysis of two preparative regimens, namely FB2 (IV fludarabine plus IV busulfan 6.4mg/kg±10%) and FB4 (IV fludarabine plus IV busulfan 12.8mg/kg ±10%), in patients with acute myeloid leukemia undergoing hematopoietic cell allografting in second complete remission at EBMT participating centers. Between 2003 and 2010, 128 AML patients in second complete remission were allografted following a preparative regimen of FB2 (n=88) or FB4 (n=40). The median time-to-neutrophil engraftment was similar whether patients received FB2 (16 (5-38) days) or FB4 (16 (9-29) days), p=0.45. A multivariate analysis showed that use of FB4 resulted in improved 2-year leukemia-free (HR=0.44 (95%CI=0.21, 0.94), p=0.03) and overall survival (HR=0.38 (95%CI=0.16, 0.86), p=0.02). Cumulative incidence of non-relapse mortality (2-year) for all patients was 21% (95%CI=14-28%). Our analysis suggests that FB4 improves 2-year leukemia-free and overall survival in AML allografted in second complete remission. A confirmatory randomized controlled trial that compares these two preparative regimens (FB2 vs. FB4) in AML in CR2 is definitely warranted. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Apr 2015 · Leukemia Research
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    ABSTRACT: Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT-signalling is known to be involved in the regulation of CD4(+) T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4(+) T cell responses, we undertook an in-depth analysis of CD4(+) T cell function upon ruxolitinib exposure. We observed a decrease in total CD3(+) cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro-inflammatory T-helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor-α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2-dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4(+) T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib-treated patients. © 2015 John Wiley & Sons Ltd.
    No preview · Article · Mar 2015 · British Journal of Haematology
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    ABSTRACT: Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic and 54% hematological) after alloSCT. The overall probability of failure- and secondary GVHD-free survival (FGFS) was 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, p<0.001). Chronic GVHD prior to DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS improved from 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse independent adverse prognostic factors for FGFS were: initial dose of CD3(+) cells ≥50x10(6)/kg, donor-recipient sex mismatch, and chronic GVHD prior to DLI. FGFS improved from 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation

Publication Stats

5k Citations
1,205.08 Total Impact Points

Institutions

  • 1997-2016
    • University Medical Center Hamburg - Eppendorf
      • Bone Marrow Transplantation Unit
      Hamburg, Hamburg, Germany
  • 2002-2015
    • University of Hamburg
      • • Department of Stem Cell Transplantation
      • • Bone Marrow Transplantation Unit
      Hamburg, Hamburg, Germany
  • 2013
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 2011
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 2010
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 2009
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 2006-2009
    • Universität Heidelberg
      • Department of Hematology / Oncology
      Heidelburg, Baden-Württemberg, Germany
  • 2001
    • Martin Luther University Halle-Wittenberg
      • Clinic for Internal Medicine IV
      Halle-on-the-Saale, Saxony-Anhalt, Germany