Nicolaus Kröger

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

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Publications (234)1050.21 Total impact

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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.
    Journal of Translational Medicine 06/2015; 13:197. DOI:10.1186/s12967-015-0562-5 · 3.99 Impact Factor
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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.
    Human Vaccines & Immunotherapeutics 05/2015; DOI:10.1080/21645515.2015.1046658 · 3.64 Impact Factor
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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.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2015; DOI:10.1016/j.bbmt.2015.04.026 · 3.35 Impact Factor
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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.
    Acta Haematologica 05/2015; 134(3):146-154. DOI:10.1159/000380757 · 0.99 Impact Factor
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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.
    Leukemia Research 04/2015; DOI:10.1016/j.leukres.2015.04.009 · 2.69 Impact Factor
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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.
    British Journal of Haematology 03/2015; 169(6). DOI:10.1111/bjh.13373 · 4.96 Impact Factor
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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.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2015; 21(7). DOI:10.1016/j.bbmt.2015.03.012 · 3.35 Impact Factor
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    ABSTRACT: Analysis of haematopoietic chimaerism after allogeneic stem cell transplantation (SCT) represents a crucial method to evaluate donor-cell engraftment. Whereas sensitivity of classical approaches for chimaerism monitoring is limited to ≥1%, quantitative-PCR (qPCR-) based techniques readily detect one patient cell in >1,000 donor cells thus facilitating application of chimaerism assessment as a surrogate for minimal residual disease. However, due to methodological specificities, qPCR combines its high sensitivity with limited resolution power in the state of mixed chimaerism (e.g., >10% patient cells). Our aim was to overcome this limitation by employing a further development of qPCR, namely digital PCR (dPCR) for chimaerism analysis. For proof-of-principle, we established more than 10 dPCR assays detecting Indel polymorphisms or Y-chromosome sequences and tested them on artificial cell mixtures and patient samples. Employing artificial cell mixtures we found that dPCR allows exact quantification of chimaerism over several orders of magnitude. dPCR results proved to be highly reproducible (deviation <5%), particularly in the "difficult" range of mixed chimaerism. Excellent performance of the new assays was confirmed by analysis of multiple retrospective blood samples from patients after allo-SCT, in comparison with established qPCR (14 patients) and STR-PCR (4 patients) techniques. Finally, dPCR is easy to perform, needs only small amounts of DNA for chimaerism assessment (65 ng corresponds to a sensitivity of app. 0.03%) and does not require the use of standard curves and replicate analysis. In conclusion, digital PCR represents a very promising method for routine chimaerism monitoring. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    Experimental hematology 03/2015; 43(6). DOI:10.1016/j.exphem.2015.02.006 · 2.81 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (ASCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on the net advantage over conventional therapies is lacking. Using an ad hoc statistical analysis, we determined outcomes in 438 patients younger than 65 years at diagnosis who received ASCT (n=190) or conventional therapies (n=248). Among patients with low risk by Dynamic International Prognostic Scoring System (DIPSS) prognostic model the relative risk of dying after receiving ASCT versus those treated with non-transplant modalities was 5.6 (95% CI: 1.7-19; P=0.0051); for intermediate-1 risk it was 1.6 (95% CI: 0.79-3.2; P=0.19), for intermediate-2, 0.55 (95% CI: 0.36-0.83; P=0.005), and for high risk 0.37 (95% CI: 0.21-0.66; P=0.0007). Thus, patients with intermediate-2 or high risk PMF clearly benefit from ASCT. Patients at low risk should receive non-transplant therapy, while individual counseling is indicated for patients at intermediate-1 risk. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(21). DOI:10.1182/blood-2014-10-608315 · 10.43 Impact Factor
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    ABSTRACT: Persistent complete donor chimerism is an important clinical indicator for remissions of hematological malignancies after HLA-matched allogeneic stem cell transplantation (SCT). However, the mechanisms mediating the persistence of complete donor chimerism are poorly understood. The frequent coincidence of complete donor chimerism with graft-versus-leukemia effects and graft-versus-host disease suggests that immune responses against minor histocompatibility antigens (mHags) are playing an important role in suppressing the host hematopoiesis after allogeneic SCT. Here, we investigated a possible relationship between donor immune responses against the hematopoiesis-restricted mHag HA-1 and the long-term kinetics of host hematopoietic chimerism in a cohort of 10 patients after allogeneic HLA-matched, HA-1 mismatched SCT. Functional HA-1 specific CTLs (HA-1 CTLs) were detectable in 6/10 patients lysing host-type hematopoietic cells in vitro. Presence of HA-1 CTLs in the peripheral blood coincided with low host hematopoiesis levels quantified by highly sensitive mHag specific PCR. Additionally, co-incubation of host type CD34+ cells with HA-1 CTLs isolated after allogeneic SCT prevented progenitor and cobblestone area forming cell growth in vitro and human hematopoietic engraftment in immunodeficient mice. Conversely, absence or loss of HA-1 CTLs mostly coincided with high host hematopoiesis levels and/or relapse. In summary, in this first study, presence of HA-1 CTLs paralleled low host hematopoiesis levels. This coincidence might be supported by the capacity of HA-1 CTLs isolated after allogeneic SCT to specifically eliminate host type hematopoietic stem/progenitor cells. Additional studies involving multiple mismatched mHags in more patients are required to confirm this novel characteristic of mHag CTLs as factor for the persistence of complete donor chimerism and leukemia remission after allogeneic SCT.
    PLoS ONE 03/2015; 10(3):e0119595. DOI:10.1371/journal.pone.0119595 · 3.53 Impact Factor
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    ABSTRACT: Primary Myelofibrosis is a Myeloproliferative Neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, extramedullary hematopoiesis, and transformation to Acute Myeloid Leukemia. To date the stem cell that incurs the spatial and temporal chain of events during disease development has not been identified. Here we report a CD133+ stem cell population that drives Primary Myelofibrosis pathogenesis. Patient-derived circulating CD133+ but not CD34+CD133- cells, with variable burden for JAK2V617F mutation, had multipotent cloning capacity in vitro. CD133+ cells engrafted for up to 10 months in immunocompromised mice and differentiated into JAK2-V617F+ myeloid but not lymphoid progenitors. We observed the persistence of human, atypical JAK2-V617F+ megakaryocytes, the initiation of prefibrotic state, bone marrow/splenic fibrosis and transition to Acute Myeloid Leukemia. Leukemic cells arose from a subset of CD133+ cells harboring EZH2D265H but lacking secondary JAK2V617F mutation, consistent with the hypothesis that deregulation of EZH2 activity drives clonal growth and increases the risk of Acute Myeloid Leukemia. This is the first characterization of a patient-derived stem cell population that drives disease resembling both chronic and acute phases of PMF in mice. These results reveal the importance of the CD133 antigen in deciphering the neoplastic clone in Primary Myelofibrosis and introduce a new therapeutic target for Myeloproliferative Neoplasms. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 02/2015; 100(6). DOI:10.3324/haematol.2014.118463 · 5.87 Impact Factor
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    ABSTRACT: Myelofibrosis is a rare clonal hematopoietic stem cell disorder characterized by chronic myeloproliferation, atypical megakaryocytic hyperplasia, and potential leukemic transformation. We report a case of leukemic transformation detected by F-FDG PET/CT. A 56-year-old woman with myelofibrosis and newly diagnosed space-occupying lesion of the chest wall underwent whole-body PET/CT for further evaluation. F-FDG PET demonstrated marked tracer uptake within that lesion. Histopathological evaluation revealed myeloid sarcoma evidencing leukemic transformation. F-FDG PET/CT is a valuable tool-enabling sensitive detection of leukemic transformation in myelofibrosis, particularly in case of extramedullary organ involvement.
    Clinical Nuclear Medicine 02/2015; 40(6). DOI:10.1097/RLU.0000000000000728 · 2.86 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S68-S69. DOI:10.1016/j.bbmt.2014.11.072 · 3.35 Impact Factor
  • Thorsten Derlin, Guntram Büsche, Nicolaus Kröger
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    ABSTRACT: Myelofibrosis is a rare hematopoietic stem cell neoplasm leading to marked bone marrow fibrosis and ineffective hematopoiesis. We report a case highlighting the potential role of ¹⁸F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for therapy monitoring. A 62-year-old man with myelofibrosis underwent FDG-PET/CT for evaluation of the extent of disease before and after allogeneic stem cell transplantation (SCT). PET after SCT demonstrated complete normalization of initially increased bone marrow tracer uptake, consistent with bone marrow biopsy showing complete remission. ¹⁸F-FDG-PET/CT may become a valuable diagnostic tool in myelofibrosis, enabling both sensitive initial staging and therapy monitoring.
    Nuclear medicine review. Central & Eastern Europe: journal of Bulgarian, Czech, Macedonian, Polish, Romanian, Russian, Slovak, Yugoslav societies of nuclear medicine and Ukrainian Society of Radiology 01/2015; 18(1):35-6. DOI:10.5603/NMR.2015.0008
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    ABSTRACT: Myelofibrosis is a haematopoietic stem cell neoplasm characterized by bone marrow inflammation, reactive marrow fibrosis and extramedullary haematopoiesis. The aim of this study was to determine if (18)F-FDG PET/CT can be used to noninvasively visualize and quantify the extent and activity of bone marrow involvement. In 30 patients, the biodistribution of (18)F-FDG was analysed by measuring the standardized uptake value in the bone marrow compartment and spleen. Imaging findings were compared with laboratory, cytogenetic and histopathological data. Retention of (18)F-FDG was observed in bone marrow and spleen. Bone marrow involvement varied, ranging from mildly increased uptake in the central skeleton to extensive uptake in most parts of the skeleton. The extent of bone marrow involvement decreased over time from initial diagnosis (r s = -0.43, p = 0.019). Metabolic activity of the bone marrow decreased as the histopathological grade of fibrosis increased (r s = -0.37, p = 0.04). There was a significant positive correlation between the metabolic activity of the bone marrow and that of the spleen (p = 0.04). (18)F-FDG PET/CT is as a promising technique for the quantitation of bone marrow inflammation in myelofibrosis. Our data indicate that the intensity of bone marrow (18)F-FDG uptake decreases as bone marrow fibrosis increases. Further evaluation in prospective studies is required to determine the potential clinical impact and prognostic significance of PET.
    European journal of nuclear medicine and molecular imaging 01/2015; 42(5). DOI:10.1007/s00259-014-2983-4 · 5.22 Impact Factor
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    ABSTRACT: The aim of this study was to determine the impact of the 5-group-revised International Prognostic Scoring System-cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse-free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14) and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group-cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5-group classification. In conclusion, the revised International Prognostic Scoring System-cytogenetic classification allows separating patients with myelodysplastic syndromes into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value in the prediction of patient outcome compared to prediction-models with only traditional risk factors or the 3-group International Prognostic Scoring System-cytogenetic classification. Copyright © 2014, Ferrata Storti Foundation.
    Haematologica 12/2014; 100(3). DOI:10.3324/haematol.2014.116715 · 5.87 Impact Factor
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    ABSTRACT: - Copyright © 2014, Ferrata Storti Foundation.
    Haematologica 12/2014; 100(4). DOI:10.3324/haematol.2014.120345 · 5.87 Impact Factor
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    ABSTRACT: To expand the current knowledge about Azacitidine (Aza) and donor lymphocyte infusions (DLI) as salvage therapy for relapse after allo-HSCT and to identify predictors for response and survival we retrospectively analysed data of 154 patients with acute myeloid leukemia (AML, n=124), myelodysplastic (MDS, n=28) or myeloproliferative syndrome (n=2). All patients received a median number of 4 courses of Aza (range: 4-14) and DLI were administered to 105 patients (68%, median number of DLI = 2, range: 1-7). Complete and partial remission (CR, PR) rates were 27% and 6% resulting in an overall response rate of 33%. Multivariate analysis identified molecular-only relapse (hazard ratio [HR]: 9.4; 95%CI, 2.0 to 43.5, p=0.004) and diagnosis of MDS (HR: 4.1; 95%CI, 1.4 to 12.2, p=0.011) as predictors for CR. Overall survival (OS) at 2 years was 29% ±4%. Molecular-only relapse (HR: 0.14; 95%CI, 0.03 to 0.59, p=0.007), diagnosis of MDS (HR: 0.33; 95%CI, 0.16 to 0.67, p=0.002) and bone marrow blasts < 13% (HR: 0.54; 95%CI, 0.32 to 0.91, p=0.021) were associated with better OS. Accordingly, 2-year OS rate was higher in MDS patients (66% ±10%; p=0.001) and correlated with disease burden in AML patients. In summary, Aza and DLI is an effective and well-tolerated treatment option for patients with relapse after allo-HSCT, in particular those with MDS or AML and low disease burden. The latter finding emphasizes the importance of stringent disease monitoring and early intervention. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2014; 21(4). DOI:10.1016/j.bbmt.2014.12.016 · 3.35 Impact Factor
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    ABSTRACT: This study aimed to determine the impact of tyrosine-kinase inhibitors given pre- and post-allogeneic stem cell transplantation on long term outcome of patients allografted for Philadelphia chromosome-positive acute lymphoblastic leukemia. This retrospective analysis from the Acute Leukemia Working Party of EBMT included 473 de novo Philadelphia chromosome-positive acute lymphoblastic leukemia patients in first complete remission who underwent an allogeneic stem cell transplantation using an human leucocyte antigen-identical sibling or human leucocyte antigen-matched unrelated donor between 2000 and 2010. Three hundred ninety patients received tyrosine-kinase inhibitors before transplant, 329 at induction and 274 at consolidation. The Kaplan-Meier estimates of leukemia-free survival, overall survival, cumulative incidences of relapse incidence, and non-relapse mortality at 5 years were 38%, 46%, 36% and 26%, respectively. In multivariate analysis, tyrosine-kinase inhibitors given before allogeneic stem cell transplantation was associated with a better overall survival (HR=0.68; P=.04) and was associated with lower relapse incidence (HR=0.5; P=.01). In the post-transplant period, multivariate analysis identified prophylactic tyrosine-kinase inhibitors administration to be a significant factor for improved leukemia-free survival (HR=0.44; P=.002) and overall survival (HR=0.42; P=.004), and a lower relapse incidence (HR=0.40; P=.01). In conclusion, over the past decade, tyrosine-kinase inhibitors administration before allogeneic stem cell transplantation has significantly improved the long term allogeneic stem cell transplantation outcome of adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Prospective studies will be of great interest to further confirm the potential benefit of the prophylactic use of tyrosine-kinase inhibitors in the post-transplant setting. Copyright © 2014, Ferrata Storti Foundation.
    Haematologica 12/2014; 100(3). DOI:10.3324/haematol.2014.116954 · 5.87 Impact Factor
  • ASH Annual Meeting 2014; 12/2014

Publication Stats

4k Citations
1,050.21 Total Impact Points


  • 1997–2015
    • University Medical Center Hamburg - Eppendorf
      • Bone Marrow Transplantation Unit
      Hamburg, Hamburg, Germany
  • 2002–2014
    • University of Hamburg
      • • Department of Stem Cell Transplantation
      • • Bone Marrow Transplantation Unit
      Hamburg, Hamburg, Germany
  • 2013
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 2011
    • Klinikum Augsburg
      Augsberg, Bavaria, Germany
  • 2010
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 2009
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 2007
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 2005
    • University of Greifswald
      Griefswald, Mecklenburg-Vorpommern, Germany