Publications by authors named "Axel R Zander"

88 Publications

Comparison of matched sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT.

J Hematol Oncol 2017 06 24;10(1):130. Epub 2017 Jun 24.

Acute Leukemia Working Party Office, Hôpital Saint Antoine, APHP, Paris, France.

Background: Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML.

Methods: The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors (n = 660) versus unrelated donors (n = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate.

Results: HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality.

Conclusions: HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients' outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated.
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http://dx.doi.org/10.1186/s13045-017-0498-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483262PMC
June 2017

β-MSCs: successful fusion of MSCs with β-cells results in a β-cell like phenotype.

Oncotarget 2016 Aug;7(31):48963-48977

Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany.

Bone marrow mesenchymal stromal cells (MSC) have anti-inflammatory, anti-apoptotic and immunosuppressive properties and are a potent source for cell therapy. Cell fusion has been proposed for rapid generation of functional new reprogrammed cells. In this study, we aimed to establish a fusion protocol of bone marrow-derived human MSCs with the rat beta-cell line (INS-1E) as well as human isolated pancreatic islets in order to generate insulin producing beta-MSCs as a cell-based treatment for diabetes.Human eGFP+ puromycin+ MSCs were co-cultured with either stably mCherry-expressing rat INS-1E cells or human dispersed islet cells and treated with phytohemagglutinin (PHA-P) and polyethylene glycol (PEG) to induce fusion. MSCs and fused cells were selected by puromycin treatment.With an improved fusion protocol, 29.8 ± 2.9% of all MSCs were β-MSC heterokaryons based on double positivity for mCherry and eGFP.After fusion and puromycin selection, human NKX6.1 and insulin as well as rat Neurod1, Nkx2.2, MafA, Pdx1 and Ins1 mRNA were highly elevated in fused human MSC/INS-1E cells, compared to the mixed control population. Such induction of beta-cell markers was confirmed in fused human MSC/human dispersed islet cells, which showed elevated NEUROD1, NKX2.2, MAFA, PDX1 and insulin mRNA compared to the mixed control. Fused cells had higher insulin content and improved insulin secretion compared to the mixed control and insulin positive beta-MSCs also expressed nuclear PDX1. We established a protocol for fusion of human MSCs and beta cells, which resulted in a beta cell like phenotype. This could be a novel tool for cell-based therapies of diabetes.
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http://dx.doi.org/10.18632/oncotarget.10214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226484PMC
August 2016

Mesenchymal Stromal/Stem Cells Do Not Ameliorate Experimental Autoimmune Encephalomyelitis and Are Not Detectable in the Central Nervous System of Transplanted Mice.

Stem Cells Dev 2016 08 13;25(15):1134-48. Epub 2016 Jul 13.

1 Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf , Hamburg, Germany .

Mesenchymal stromal/stem cells (MSCs) constitute progenitor cells that can be isolated from different tissues. Based on their immunomodulatory and neuroprotective functions, MSC-based cell-therapy approaches have been suggested to antagonize inflammatory activity and neuronal damage associated with autoimmune disease of the central nervous system (CNS), for example, multiple sclerosis (MS). Intravenous MSC transplantation was reported to ameliorate experimental autoimmune encephalomyelitis (EAE), the murine model of MS, within days after transplantation. However, systemic distribution patterns and fate of MSCs after administration, especially their potential to migrate into inflammatory lesions within the CNS, remain to be elucidated. This question has of recent become particularly important, since therapeutic infusion of MSCs is now being tested in clinical trials with MS-affected patients. Here, we made use of the established EAE mouse model to investigate migration and therapeutic efficacy of murine bone marrow-derived MSCs. Applying a variety of techniques, including magnetic resonance imaging, immunohistochemistry, fluorescence in-situ hybridization, and quantitative polymerase chain reaction we found no evidence for immediate migration of infused MSC into the CNS of treated mice. Moreover, in contrast to other studies, transplanted MSCs did not ameliorate EAE. In conclusion, our data does not provide substantiation for a relevant migration of infused MSCs into the CNS of EAE mice supporting the hypothesis that potential therapeutic efficacy could be based on systemic effects. Evaluation of possible mechanisms underlying the observed discrepancies in MSC treatment outcomes between different EAE models demands further studies.
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http://dx.doi.org/10.1089/scd.2016.0020DOI Listing
August 2016

Prognostic factors for survival of patients with newly diagnosed chronic GVHD according to NIH criteria.

Ann Hematol 2015 Oct 24;94(10):1727-32. Epub 2015 Jul 24.

Department of Stem Cell Transplantation, University Medical Center Hamburg, Martinistr. 52, 20246, Hamburg, Germany,

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.
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http://dx.doi.org/10.1007/s00277-015-2452-6DOI Listing
October 2015

Immunomodulatory effects of the ether phospholipid edelfosine in experimental autoimmune encephalomyelitis.

J Neuroimmunol 2014 Sep 21;274(1-2):111-24. Epub 2014 Jul 21.

Institute for Neuroimmunology and Clinical MS Research (inims), Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany; Neuroimmunology and MS Research (nims), Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. Electronic address:

The 2-lysophosphatidylcholine analog edelfosine induces apoptosis in highly proliferating cells, e.g. activated immune cells. We examined mechanisms of action of edelfosine on immune functions in experimental autoimmune encephalomyelitis, a well-accepted animal model for multiple sclerosis. We observed activated caspase-3 expression in lymphoid organs and the central nervous system; however, edelfosine did not induce global apoptosis. Edelfosine improved the disease course and led to reduced frequencies of CD4(+) T cells infiltrating into the central nervous system. Our data suggest edelfosine as an interesting treatment candidate for multiple sclerosis.
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http://dx.doi.org/10.1016/j.jneuroim.2014.07.007DOI Listing
September 2014

Serum albumin level predicts survival of patients with gastrointestinal acute graft-versus-host disease after allogeneic stem cell transplantation.

Ann Hematol 2014 May 19;93(5):855-61. Epub 2013 Nov 19.

Clinic for stem cell transplantation, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20245, Hamburg, Germany,

In a retrospective single-centre study, we analysed the prognostic impact of factors identifiable at initial diagnosis of acute GVHD (aGVHD). We retrospectively analysed 495 adult patients of whom 308 (62 %) developed acute GVHD (I-IV) and were included in further analysis. Gut aGVHD was diagnosed in 163/308 cases (53 %). Conditioning was myeloablative conditioning (MAC) in 123 (39.9 %) and reduced intensity (RIC) in 185 (60.1 %) patients. Median serum albumin level at diagnosis of aGVHD was 34 g/l, which was used as cut-off for low vs. normal albumin levels. In patients with gut aGVHD, low albumin level at the time of diagnosis of aGVHD was associated with poorer overall survival (OS) which was 52 vs. 67 % at 1 year and 40 vs. 61 % at 3 years, p = 0.015. In patients with only skin aGVHD, 1- and 3-year OS of patients with low vs. normal albumin levels were 72 vs. 72 % and 59 vs. 57 %, respectively, p = 0.69. In multivariate analysis of patients with gut aGVHD, low serum albumin level ≤34 g/l (relative risk (RR) 2.13, p = 0.003), gut aGVHD grades 3-4 (RR 2.70, p = 0.001), RIC (RR 1.84, p = 0.024), matched unrelated donor (RR 1.86, p = 0.18) and mismatched unrelated donor (RR 2.76, p = 0.03) retained negative impact on OS. Subgroup analysis revealed that impact of albumin was restricted to patients with gut aGVHD after RIC. Low serum albumin levels are associated with poorer OS in patients with gut but not skin aGVHD after RIC but not MAC allogeneic stem cell transplantation.
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http://dx.doi.org/10.1007/s00277-013-1957-0DOI Listing
May 2014

Outcome of allogeneic SCT in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.

Ann Hematol 2013 Apr 19;92(4):487-96. Epub 2012 Dec 19.

Department for Stem Cell Transplantation, University Cancer Center Hamburg (UCCH), Martinistr. 52, 20246, Hamburg, Germany.

The introduction of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) led to a dramatic change in the role of allogeneic stem cell transplantation (SCT) with a rapid decline in the number of patients receiving SCT in first chronic phase (CP1). We evaluated 68 consecutive patients in all phases of CML (male/female = 39:29, 27 in CP1), who received SCT from related/unrelated donors (related/unrelated = 23:45) under myeloablative or reduced intensity conditioning (MAC/RIC = 45:23). Forty-eight patients (71 %) received TKIs pre-SCT, 20 patients post-SCT (29 %). Overall survival (OS) of CP1 patients achieved a plateau of 85 % at 10 months. Relapse-free survival (RFS) of CP1 patients was 85 % at 1 and 2 years, and 81 % at 5 years. Multivariate analysis showed adverse OS and RFS for patients transplanted >CP1 (hazard ratio (HR) = 6.61 and 4.62) and those who had grade III-IV aGvHD (HR = 2.45 and 1.82). Patients with advanced CML had estimated OS of 65 and 47 %; and RFS of 41 and 32 % at 1 and 2 years respectively. Therefore, for patients with advanced CML phases, allogeneic SCT provides an acceptable chance of cure. Transplant research should focus on improving conditioning regimens and post-SCT management for this subgroup of CML patients.
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http://dx.doi.org/10.1007/s00277-012-1650-8DOI Listing
April 2013

Impact of high-risk cytogenetics and achievement of molecular remission on long-term freedom from disease after autologous-allogeneic tandem transplantation in patients with multiple myeloma.

Biol Blood Marrow Transplant 2013 Mar 16;19(3):398-404. Epub 2012 Oct 16.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Within a prospective protocol, the incidence and impact of achievement of molecular remission (mCR) and high-risk cytogenetics was investigated in 73 patients with multiple myeloma (MM) after autologous (auto)-allogeneic (allo) tandem stem cell transplantation (SCT). After induction chemotherapy, patients received melphalan 200 mg/m(2) before undergoing auto-SCT, followed 3 months later by melphalan 140 mg/m(2) and fludarabine 180 mg/m(2) before allo-SCT. Sixteen patients had high-risk cytogenetic features, defined by positive FISH for del(17p13) and/or t(4;14). Overall, 66% of the patients achieved CR or near-CR, and 41% achieved mCR, which was sustained negative (at least 4 consecutive samples negative) in 15 patients (21%), with no significant difference in incidence between the patients with high-risk cytogenetics and others (P = .70). After a median follow-up of 6 years, overall 5-year progression-free survival was 29%, with no significant difference between del 17p13/t(4;14)-harboring patients and others (24% versus 30%; P = .70). The 5-year progression-free survival differed substantially according to the achieved remission: 17% for partial remission, 41% for CR, 57% for mCR, and 85% for sustained mCR. These results suggest that auto-allo tandem SCT may overcome the negative prognostic effect of del(17p13) and/or t(4;14) and that achievement of molecular remission resulted in long-term freedom from disease.
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http://dx.doi.org/10.1016/j.bbmt.2012.10.008DOI Listing
March 2013

Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study.

Psychooncology 2013 Jul 4;22(7):1509-16. Epub 2012 Sep 4.

Department and Outpatient Clinic of Medical Psychology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Owing to its neurotoxicity, allogeneic hematopoietic stem cell transplantation (HSCT) carries risks for cognitive impairment. In this multicenter study, we prospectively evaluated cognitive functioning and its medical and demographic correlates in patients undergoing allogeneic HSCT.

Methods: A total of 102 patients were consecutively assessed prior to (T0 ), 100 ± 20 days (T1 ) after, and 12 ± 1 months (T2 ) after HSCT (61% men, 41% acute myeloid leukemia). A comprehensive neuropsychological test battery was applied to evaluate attention, memory, executive function, and fine motor function, summing up into 14 test scores.

Results: Before and after HSCT, patients performed below test norms in up to 50% of the test scores. Patients were mostly impaired on word fluency (24%, T0 ), fine motor function, and verbal delayed recall (19% each, T2 ). Impairment on ≥ 1/5 cognitive domains occurred in 47% (T0 ) and 41% (T2 ) of the patients. Performance (mean z-scores) partially improved over time (i.e., visual span forward, verbal learning, and word fluency). However, from baseline to T2 , 16% of the patients showed reliable decline on ≥ 3/14 test scores (reliable change index method). For the majority of neuropsychological subtests, no associations with conditioning intensity, total body irradiation, graft-versus-host disease, cyclosporine treatment, and length of hospital stay were found. Age and premorbid intelligence level were consistently associated with cognition.

Conclusions: Below average cognitive performance is common in this patient group. In addition, a subgroup shows reliable cognitive decline after allogeneic HSCT. Healthcare professionals should be aware of these treatment-related cognitive side effects.
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http://dx.doi.org/10.1002/pon.3159DOI Listing
July 2013

Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting.

Br J Haematol 2012 Oct 22;159(2):172-81. Epub 2012 Aug 22.

Department of Stem Cell Transplantation, University Cancer Centre Hamburg, Hamburg, Germany.

Thirty myelofibrosis patients (21 males, nine females) with relapse (n = 27) or graft-rejection (n = 3) after dose-reduced allografting underwent a salvage strategy including donor lymphocyte infusions (DLIs) and/or second allogeneic haematopoietic stem cell transplantation (HSCT). Twenty-six patients received a median number of three (range, 1-5) DLIs in a dose-escalated mode starting with a median dose of 1·2 × 10(6) (range, 0·003-8 × 10(6) ) up to median dose of 40 × 10(6) T-cells/kg (range, 10-130 × 10(6) ). 10/26 patients (39%) achieved complete response (CR) to DLIs. Acute (grade II-IV) and chronic graft-versus-host (GvHD) disease occurred in 12% and 36% cases. Thirteen non-responders to DLI and four patients who did not receive DLI due to graft-rejection or acute transformation of the blast phase underwent a second allogeneic HSCT from alternative (n = 15) or the same (n = 2) donor. One patient (6%) experienced primary graft-failure and died. Acute (II-IV) and chronic GvHD were observed in 47% and 46% of patients. Overall responses after second HSCT were seen in 12/15 patients (80%: CR: n = 9, partial response: n = 3). The 1-year cumulative incidence of non-relapse mortality for recipients of a second allograft was 6%, and the cumulative incidence of relapse was 24%. After a median follow-up of 27 months, the 2-year overall survival and progression-free survival for all 30 patients was 70% and 67%, respectively. In conclusion, our two-step strategy, including DLI and second HSCT for non-responding or ineligible patients, is an effective and well-tolerated salvage approach for patients relapsing after reduced-intensity allograft after myelofibrosis.
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http://dx.doi.org/10.1111/bjh.12013DOI Listing
October 2012

Role of interleukin 16 in multiple myeloma.

J Natl Cancer Inst 2012 Jul 28;104(13):1005-20. Epub 2012 Jun 28.

Department of Medicine II, Oncology/Hematology/Stem Cell Transplantation, University Cancer Center Hamburg (Hubertus Wald Tumorzentrum), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.

Background: Multiple myeloma is a malignancy characterized by the expansion of a plasma cell clone that localizes to the human bone marrow. Myeloma cells and bone marrow stromal cells produce soluble factors that promote the survival and progression of multiple myeloma. Interleukin 16 (IL-16) is involved in regulating the migration and proliferation of normal leukocytes. However, the role of IL-16 in human cancers, including multiple myeloma, is unclear.

Methods: We investigated IL-16 expression in cell lines (n = 10) and in the bone marrow of myeloma patients (n = 62) and healthy bone marrow donors (n = 12) by quantitative reverse transcription-polymerase chain reaction, immunoblot analysis, enzyme-linked immunosorbent assay, flow cytometry, and immunohistochemistry. Transfection of two human multiple myeloma cell lines with small interfering RNAs was used to examine the effect of IL-16 gene silencing on apoptosis by flow cytometry, on proliferation by bromodeoxyuridine incorporation, and on colony formation. Protein neutralization assays were performed by treating multiple myeloma cells with a monoclonal antibody against the carboxyl-terminal fragment of IL-16. All statistical tests were two-sided.

Results: IL-16 was strongly overexpressed in the bone marrow of myeloma patients compared with healthy donors. Myeloma cell lines as well as primary tumor cells from myeloma patients constitutively expressed IL-16 and its receptors CD4 and/or CD9 and spontaneously secreted soluble IL-16. Silencing of IL-16 reduced the proliferative activity of myeloma cells by approximately 80% compared with untreated cells (mean relative proliferative activity IL-16 siRNA vs untransfected cells, EJM cells: 20.1%, 95% confidence interval [CI] = 14.3% to 26.0%, P = .03; KMS-12-BM cells: 22.8%, 95% CI = 5.5% to 40.0%, P = .04), and addition of a recombinant carboxyl-terminal IL-16 peptide reversed that effect. A monoclonal antibody directed against IL-16 or its receptors had a comparably strong growth-inhibiting effect on the tumor cells.

Conclusions: IL-16 is an important growth-promoting factor in multiple myeloma and a candidate for novel diagnostic, prognostic, and therapeutic applications for this incurable human malignancy.
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http://dx.doi.org/10.1093/jnci/djs257DOI Listing
July 2012

Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial.

Biol Blood Marrow Transplant 2012 Nov 17;18(11):1716-26. Epub 2012 Jun 17.

Department of Hematology and Oncology, Universitätsklinikum Freiburg, Freiburg, Germany.

Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2012.06.001DOI Listing
November 2012

Mobilized peripheral blood stem cells compared with bone marrow as the stem cell source for unrelated donor allogeneic transplantation with reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission: an analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2012 Sep 20;18(9):1422-9. Epub 2012 Mar 20.

Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Reduced-intensity conditioning allogeneic stem cell transplant (RIC-alloSCT) is being increasingly used for patients with acute myelogenous leukemia (AML) with comorbidities. Few published data are currently available regarding for the use of peripheral blood stem cells (PBSCs) compared to bone marrow (BM) in the RIC-alloSCT using unrelated donors (URDs). This retrospective report compared the outcomes of PBSC versus BM RIC-alloSCT. Between 2000 and 2007, 602 patients with AML in complete remission (CR) underwent RIC-alloSCT from URDs with PBSC (508) or BM (94) grafts. Recipient's age was higher in the PBSC versus BM groups 57 (range, 17-77 years) and 51 (range, 17-76 years), respectively (P < .0001). Leukemia features and disease status at RIC-alloSCT were also comparable between the PBSC versus BM groups. Engraftment was achieved in 97% and 96% with BM versus peripheral blood (PB), respectively. Acute graft-versus-host disease (aGVHD) grade >II was significantly higher in the PBSC group: 27% versus 12% in the BM group (P < .002). Similarly, chronic graft-versus-host disease (cGVHD; at 2 years) was somewhat higher in the PBSC group with 43% ± 3% versus 35% ± 6% in the BM group, respectively (P = .04). The 2-year probabilities of leukemia-free survival (LFS) were 46% ± 3% for the PBSC group in comparison to 43% ± 6% for the BM transplant group (P = NS), whereas relapse incidence was significantly higher in the BM versus the PB transplant group: 46% ± 6% versus 32% ± 3%, respectively (P = .014). Non-relapse mortality (NRM) was significantly higher for the PBSC versus the BM group: 28% ± 2% versus 13% ± 4%, respectively (P = .004). In multivariate analysis, after adjustment for differences between both groups, the PBSC group was associated with a higher incidence of aGVHD (grade II-IV; hazard ratio [HR] = 2.33; P = .06), higher NRM (HR = 2.3; P = .015), and a decreased relapse incidence (HR, 0.61; P = .02) with no statistical difference of LFS between the 2 groups (P = .88). In conclusion, our results indicate significantly higher incidence of aGVHD and NRM and a lower incidence of relapse but not statistically different LFS comparing unrelated PBSC to BM grafts after RIC-alloSCT.
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http://dx.doi.org/10.1016/j.bbmt.2012.02.013DOI Listing
September 2012

Risk models predicting survival after reduced-intensity transplantation for myelofibrosis.

Br J Haematol 2012 Apr 27;157(1):75-85. Epub 2012 Jan 27.

Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

To define a prognostic model for predicting outcome of reduced-intensity allogeneic stem cell transplantation (RIC-ASCT) for myelofibrosis we evaluated 150 homogeneously treated patients and developed a new risk score for overall survival (OS). In a multivariate Cox model for OS, only JAK2 V617F wild-type, age ≥57 years and constitutional symptoms were independently predictive for OS (Hazard Ratio: 2·02; 2·43 and 2·80 respectively). Depending on the presence of one, two or all of these factors, HR of death was 3·08; 4·70 and 16·61 respectively (P < 0·001). This score was compared to the Lille, Cervantes, International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS) and modified European Blood and Marrow Transplantation Group (EBMT) scores. Lille score correlated significantly with OS but discriminated poorly between the intermediate and high-risk groups (5-year OS 56% and 51% respectively). IPSS and DIPSS correlated significantly with OS but differences between intermediate-1 and intermediate-2 groups were not significant (5-year OS 78% vs. 78% and 70%, 60% respectively). Modified EBMT and Cervantes models did not predict OS post-ASCT. In conclusion, a simple model which includes: age, JAK2 V617F-status and constitutional symptoms can clearly separate distinct risk groups and can be used in addition to the Lille model to predict OS after RIC-ASCT for myelofibrosis.
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http://dx.doi.org/10.1111/j.1365-2141.2011.09009.xDOI Listing
April 2012

Drug dosing and monitoring in obese patients undergoing allogenic stem cell transplantation.

Int J Clin Pharm 2011 Dec 29;33(6):918-24. Epub 2011 Sep 29.

Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Background: The effects of physiological changes in patients with obesity on pharmacokinetic parameters and the time course of drug response, especially in the field of haematology/oncology, are poorly understood. For some antimicrobial drugs, dosing considerations exist, while for cytostatic drugs, dose modifications for obese patients are not consistently recommended. Glomerular filtration rate and renal perfusion appear to be similar in obese and normal weight individuals, thus elimination of hydrophilic and extensively renally cleared drugs mainly depends upon creatinine clearance.

Aim Of The Review: To provide information about drug dosing in morbidly obese patients undergoing allogenic haematopoietic stem cell transplantation and to develop dosing recommendations for those patients, based on literature data, pharmacokinetic properties and own experiences.

Method: A review on the literature on drug dosing in obese patients as well as on the pharmacokinetic properties of drugs which are supposed to be used in the field of stem cell transplantation was combined with own data on drug dosing and pharmacokinetic drug monitoring in a morbidly obese patient undergoing matched-unrelated allogenic peripheral blood stem cell transplantation.

Results: For hydrophilic and extensively renally cleared drugs (e.g. piperacillin/sulbactam, cotrimoxazole, fludarabine) standard dosages for adult patients or dosing based on ideal body weight (IBW) (e.g. aciclovir, methotrexate) can be used. For ciclosporin and digitoxin we could show that high initial doses are needed to achieve sufficient plasma concentrations. After steady state distribution was completed, maintenance doses comparable to normal weight patients are sufficient. Likewise, distribution of enoxaparin and phenytoin seems to take longer in obese patients. Dosing recommendations of 25 drugs that can be used in morbidly obese patients undergoing allogenic stem cell transplantation are given.

Conclusions: Pharmacotherapy in morbidly obese patients undergoing allogenic stem cell transplantation is possible, if pharmacokinetic properties of the drugs are considered and close monitoring of plasma concentrations is performed.
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http://dx.doi.org/10.1007/s11096-011-9568-0DOI Listing
December 2011

Mesenchymal stromal cells: main factor or helper in regenerative medicine?

Kidney Int Suppl (2011) 2011 Sep;1(3):74-76

Section of Nephrology, George E. Wahlen VA Medical Center, University of Utah , Salt Lake City, Utah, USA; ; Department of Medicine, University of Utah College of Medicine , Salt Lake City, Utah, USA ; Department of Physiology, University of Utah College of Medicine , Salt Lake City, Utah, USA.

Mesenchymal stromal cells (mSCs) are presently studied for the prophylaxis and therapy of a variety of diseases such as acute graft-versus-host disease after allogeneic stem cell transplantation, cardiac indications, bone degeneration, Crohn's disease, and organ rejection, as well as prevention of acute renal failure in high-risk situations. mSCs appear to function through paracrine mechanisms that exert immunosuppressive, anti-inflammatory, anti-apoptotic, mitogenic, and other organ-protective and repair-stimulating actions. mSCs are either cultured in the presence of fetal calf serum (FCS) or platelet lysate (PL). PL lysate-generated mSCs exhibit faster doubling times, different gene expression profiles, and more potent immunosuppressive activity compared with FSC-generated mSCs. The utility of mSCs in the treatment of chronic inflammatory diseases is being evaluated in prospective studies.
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http://dx.doi.org/10.1038/kisup.2011.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089635PMC
September 2011

High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials.

J Clin Oncol 2011 Aug 18;29(24):3214-23. Epub 2011 Jul 18.

Division of Quantitative Sciences, Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1402, USA.

Purpose: Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets.

Methods: We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status.

Results: Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients.

Conclusion: Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.
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http://dx.doi.org/10.1200/JCO.2010.32.5910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322115PMC
August 2011

Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial.

Haematologica 2011 Sep 9;96(9):1344-50. Epub 2011 Jun 9.

Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.

Background: An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome.

Design And Methods: A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m(2) treosulfan and 5×30 mg/m(2) fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival.

Results: All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III-IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II-IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively.

Conclusions: Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: NCT01062490.
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http://dx.doi.org/10.3324/haematol.2011.043810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166105PMC
September 2011

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma.

Haematologica 2011 Oct 23;96(10):1512-20. Epub 2011 May 23.

Center of Oncology, Department of Medicine II, Oncology/Hematology/Stem Cell Transplantation, University Cancer Center Hamburg (Hubertus Wald Tumorzentrum), Hamburg, Germany.

Background: To date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myeloma-specific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors.

Design And Methods: Potential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA-mediated downregulation of CD229. Antibody-dependent cellular and complement-dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen's immunotherapeutic potential.

Results: Our screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients' bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement- and cell-mediated lysis of myeloma cells.

Conclusions: Our results demonstrate that the immunoreceptor CD229 is specifically over-expressed on myeloma cells including their clonogenic precursors and contributes to their malignant phenotype. Monoclonal antibodies against this protein may represent a promising diagnostic and immunotherapeutic instrument in this disease.
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http://dx.doi.org/10.3324/haematol.2010.036814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186313PMC
October 2011

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

Blood 2011 Jun 5;117(23):6375-82. Epub 2011 Apr 5.

Service d'Hématologie-Greffe de Moelle, Hôpital Saint Louis, Paris, France.

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.
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http://dx.doi.org/10.1182/blood-2011-01-329821DOI Listing
June 2011

Challenges for allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

Acta Haematol 2011 17;126(1):30-9. Epub 2011 Mar 17.

Department for Stem Cell Transplantation, University Cancer Center Hamburg, Hamburg, Germany.

Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (HSCT) scene in CML has changed dramatically. The number of patients receiving HSCT in first chronic phase (CP) has declined rapidly, as allogeneic HSCT in CP is now performed in these patients only in case of failure or intolerance of TKIs. Second, those CML patients who undergo allogeneic HSCT represent a selection of high-risk patients due to more advanced disease with high rates of accelerated or blast phase (being associated with an increased relapse risk), advanced age and relevant co-morbidities. Efforts at meeting these special challenges are being developed: treatment with TKIs aims to improve the pre-transplant remission status before HSCT. Dose-reduced conditioning protocols were introduced to decrease transplant-related mortality in patients with co-morbidities or older age. In the post-transplant period, TKIs may be administered for prophylaxis and for treatment of post-transplant relapse. Still, the outcome of patients in advanced CML phases remains guarded, and requires an improvement in current transplant strategies.
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http://dx.doi.org/10.1159/000323662DOI Listing
August 2011

Radiation rescue: mesenchymal stromal cells protect from lethal irradiation.

PLoS One 2011 Jan 5;6(1):e14486. Epub 2011 Jan 5.

Clinic for Stem Cell Transplantation, Department of Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC) transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals.

Methods And Findings: Mouse mesenchymal stromal cells (mMSCs) were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures) and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i) decreased proinflammatory, ECM formation and adhesion properties and (ii) boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals.

Conclusions: Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis thereby serving as fast and effective first-line treatment to combat radiation-induced hematopoietic failure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014486PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016319PMC
January 2011

Caspofungin plus posaconazole as salvage therapy of invasive fungal infections in immunocompromised patients.

Mycoses 2011 Jan;54 Suppl 1:39-44

Clinic for Stem Cell Transplantation, Center of Oncology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients. Substantial improvements of treatment have been achieved by the introduction of new antifungal agents including azoles (e.g. posaconazole) and echinocandins (e.g. caspofungin). However, mortality associated with treatment-refractory aspergillosis remains high. Preliminary data suggest that the combination of azoles and echinocandins may increase activity against refractory IA. The objective of the present study was to evaluate efficiency and safety of caspofungin plus posaconazole for salvage therapy in immunocompromised patients. In this monocentric, retrospective study, 31 hospitalised haematopoietic stem cell transplant recipients with IA refractory to primary treatment were treated with a combination therapy of caspofungin 50 mg a day and posaconazole 200 mg four times per day. Efficacy was assessed by signs, symptoms and the degree of pulmonary infiltrate regression. A favourable response was seen in the majority of patients (77%). In two patients (6%), clinical improvement, but no decline in pulmonary infiltrates, was observed. Five patients (16%) did not respond to combination therapy with a fatal outcome in four of them. Combination therapy was well tolerated. No patient discontinued treatment due to toxicity. This study indicates that the combination of caspofungin and posaconazole may provide an effective and tolerable therapy of IA in immunocompromised patients refractory to primary treatment.
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http://dx.doi.org/10.1111/j.1439-0507.2010.01985.xDOI Listing
January 2011

Minimal residual disease diagnostics in patients with acute myeloid leukemia in the post-transplant period: comparison of peripheral blood and bone marrow analysis.

Leuk Lymphoma 2010 Oct;51(10):1837-43

Clinic for Stem Cell Transplantation, University Cancer Center Hamburg, Germany.

Considering the high relapse rates of AML after allogeneic hematopoietic stem cell transplant, research aims to improve post-transplant surveillance. To determine the value of peripheral blood (PB) for post-transplant minimal residual disease monitoring, we compared 38 PB and bone marrow (BM) sample pairs in 25 stem cell recipients with NPM1-mutated AML (12 males, 13 females, ages 21-73 years). NPM1A mutation levels and chimerism ratios were determined in non-separated BM/PB. We observed congruent results in 28/38 (74%). In 14/38 sample pairs (37%), BM and PB were negative for the NPM1A mutation. Fourteen sample pairs were positive in BM and PB, albeit at higher mutation levels in the BM in 11 cases (4- to 278-fold). Results were discordant in 10 cases (26%), with weakly positive mutation levels in the BM but negative levels in the PB. Cases with ≥0.2% NPM1A mutation level in BM were always positive in PB. Chimerism was concordant in BM and PB in 21/34 (62%) of sample pairs. In conclusion, MRD monitoring with qPCR for the NPM1 mutation and chimerism from non-separated PB contributes to surveillance in patients with AML in the post-transplant period, but even with highly sensitive qPCR there is a risk of failure to detect the mutation in PB.
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http://dx.doi.org/10.3109/10428194.2010.508822DOI Listing
October 2010

The cytokine/chemokine pattern in the bone marrow environment of multiple myeloma patients.

Exp Hematol 2010 Oct 7;38(10):860-7. Epub 2010 Jul 7.

Department of Internal Medicine II (Oncology/Hematology/Stem Cell Transplantation), University Cancer Center Hamburg (Hubertus Wald Tumorzentrum), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: The interaction of multiple myeloma (MM) with its bone marrow (BM) microenvironment is important for the homing pattern, survival, and proliferation of malignant plasma cells. We aimed at answering the question which cytokines, chemokines, and growth factors are typically found in the BM of untreated MM patients as well as in MM patients after allogeneic stem cell transplantation (alloSCT).

Materials And Methods: We determined the concentrations of 34 cytokines/chemokines in the supernatants of 10 myeloma cell lines, as well as in the plasma derived from BM and peripheral blood samples of 10 newly diagnosed MM patients, 20 MM patients who had received allogeneic stem cell transplantation (alloSCT), and 20 healthy donors.

Results: Besides cytokines/chemokines known to be secreted by myeloma cell lines, such as interleukin-1 receptor antagonist (IL-1RA), IL-8, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1β, and MIP-3α, we also detected significant levels of epidermal growth factor (EGF), hepatocyte growth factor (HGF), IL2R, IL-12p40/p70, IL-22, interferon-γ (IFN-γ)-inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), and regulated on activation normally T-cell expressed and secreted (RANTES) in culture supernatants. The BM environment in MM patients evidenced elevated concentrations of HGF, IL-2R, IL-16, EGF, IL-1RA, IP-10, MCP-1, and monokine induced by IFN-γ. Additionally, in the BM of MM patients post alloSCT, we found selectively elevated concentration of IL-4, IL-6, IL-8, IL-12p40/p70, and eotaxin. Eotaxin levels were particularly high in patients with chronic graft-vs-host disease.

Conclusions: Our study demonstrates characteristic cytokine/chemokine patterns in the BM environment of MM patients before and after alloSCT. Certain factors, such as MIP-1α, MCP-1, HGF, IL-16, IP-10, and eotaxin, might not only be developed into diagnostic instruments and/or predictive biomarkers, but are also potential targets for future myeloma- or graft-vs-host disease-specific therapies.
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http://dx.doi.org/10.1016/j.exphem.2010.06.012DOI Listing
October 2010

Diagnosis of Toxoplasma gondii infection after allogeneic stem cell transplant can be difficult and requires intensive scrutiny.

Leuk Lymphoma 2010 Aug;51(8):1530-5

Interdisciplinary Clinic for Stem Cell Transplantation, University of Hamburg, Germany.

Infectious complications remain a major problem after allogeneic hematopoietic stem cell transplant (HSCT). Specifically Toxoplasma gondii infection is a life-threatening condition in immunocompromised patients. In order to highlight the difficulties in obtaining an early and definitive diagnosis, we report three cases of toxoplasmosis after HSCT for hematologic malignancies: two cases of T. gondii retinochoroiditis, and one case of encephalitis. All patients had unrelated donors and received antithymocyte globulin; none had received trimethoprim/sulfamethoxazole prophylaxis. Toxoplasmosis occurred early post-transplant and diagnosis was obtained by real-time PCR. In one case, the correct diagnosis could only be established by PCR analysis of a retinal biopsy specimen. Rapid diagnosis--by invasive approaches--and an immediate onset of antiparasite treatment are crucial to avoid disseminated and often lethal Toxoplasma infections in the post-transplant period. Post-transplant prevention strategies and treatment to control advanced infection in this setting are discussed.
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http://dx.doi.org/10.3109/10428194.2010.494260DOI Listing
August 2010

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning.

J Clin Oncol 2010 Jul 24;28(20):3344-51. Epub 2010 May 24.

University of Rostock, Rostock, Germany.

Purpose: Treosulfan was introduced recently as a conditioning agent for allogeneic blood stem-cell transplantation. The favorable nonhematologic toxicity profile at 3 x 10 g/m(2) was the basis for dose escalation in this prospective, multicenter trial.

Patients And Methods: Fifty-six patients with various hematologic malignancies who were not eligible for standard conditioning were treated with one of three doses: 10 g/m(2), 12 g/m(2), or 14 g/m(2) of intravenous treosulfan, which was administered on days -6 to -4 combined with fludarabine 30 mg/m(2) on days -6 to -2. Patients in complete remission (CR; 42%) or non-CR (58%) received grafts from matched related (47%) or matched unrelated (51%) donors; one patient had a mismatched related donor (2%).

Results: No engraftment failure occurred. Overall, extramedullary toxicity and the nonrelapse mortality rate at 2 years (20%) were low and did not increase with dose. Cumulative incidence of relapse/progression reached 31%. The overall survival and progression-free survival rates were 64% and 49%, respectively, in the total study population. An inverse dose dependency of relapse incidence was indicated in the subgroup receiving transplantations from matched related donors (P = .0568).

Conclusion: Treosulfan-based conditioning was feasible at all three doses. The 3 x 14 g/m(2) dose was selected for additional studies, because it combines desired characteristics of low toxicity and a low relapse rate.
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http://dx.doi.org/10.1200/JCO.2009.23.3429DOI Listing
July 2010

Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis.

Blood 2010 Nov 20;116(18):3572-81. Epub 2010 May 20.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.

Allogeneic stem cell transplantation (ASCT) after reduced-intensity conditioning has become a reasonable treatment option for patients with advanced myelofibrosis. The role of characteristic molecular genetic abnormalities, such as JAK2V617F on outcome of ASCT, is not yet elucidated. In 139 of 162 myelofibrosis patients with known JAK2V617F mutation status who received ASCT after reduced-intensity conditioning, the impact of JAK2 genotype, JAK2V617F allele burden, and clearance of mutation after ASCT was evaluated. Overall survival was significantly reduced in multivariate analysis in patients harboring JAK2 wild-type (hazard ratio = 2.14, P = .01) compared with JAK2 mutated patients. No significant influence on outcome was noted for the mutated allele burden analyzed either as continuous variable or after dividing into quartiles. Achievement of JAK2V617F negativity after ASCT was significantly associated with a decreased incidence of relapse (hazard ratio = 0.22, P = .04). In a landmark analysis, patients who cleared JAK2 mutation level in peripheral blood 6 months after ASCT had a significant lower risk of relapse (5% vs 35%, P = .03). We conclude that JAK2V617F-mutated status, but not allele frequency, resulted in an improved survival and rapid clearance after allografting reduces the risk of relapse.
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http://dx.doi.org/10.1182/blood-2009-12-260588DOI Listing
November 2010

Limited immune-modulating activity of porcine mesenchymal stromal cells abolishes their protective efficacy in acute kidney injury.

Stem Cells Dev 2010 May;19(5):719-29

Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

We demonstrated previously that administration of mesenchymal stromal cells (MSCs) after renal ischemia/reperfusion injury (IRI) in rats protected renal function and hastened repair through complex paracrine mechanisms. Here we investigated kidney-protective actions of MSCs in a porcine IRI model that may have relevance to human acute kidney injury (AKI). Groups of female pigs with bilateral IRI were infused with autologous or male allogeneic MSCs. No acute or late complications were observed, but unexpectedly, MSC therapy also had no beneficial effects on kidney function and histology. In vitro, we demonstrated substantial functional and phenotypic overlaps between rodent, human, and porcine MSCs, all of which exhibited trilineage differentiation, characteristic antigen profiles, and secretion of renoprotective vascular endothelial growth factor (VEGF)-A and insulin-like growth factor-1 (IGF-1). However, in striking contrast to human MSCs, porcine MSCs failed to inhibit the mixed lymphocyte reaction (MLR) and induced robust production of proinflammatory interleukin-6 (IL-6). In summary, in contrast to rodent models, treatment of porcine IRI with MSCs was not kidney-protective. This, we conclude, is due to the fact that porcine MSCs exert inadequate immune-modulating effects, further demonstrating that successful therapy of IRI with MSCs critically depends on their anti-inflammatory actions. As a consequence, treatment of AKI with MSCs is not informative regarding the investigation of the underlying mechanisms in this large animal model. We expect, however, that the treatment of human IRI of the kidney with immune-modulating MSCs will be as effective as in rodent models.
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http://dx.doi.org/10.1089/scd.2009.0494DOI Listing
May 2010

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells.

Haematologica 2010 May 16;95(5):785-93. Epub 2009 Dec 16.

Department of Medicine II, Oncology/Hematology, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Background: Multiple myeloma is a life-threatening disease and despite the introduction of stem cell transplantation and novel agents such as thalidomide, lenalidomide, and bortezomib most patients will relapse and develop chemoresistant disease. Therefore, alternative therapeutic modes for myeloma are needed and cancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 have been suggested to represent a class of tumor-specific proteins particularly suited for targeted immunotherapies. Surprisingly, the biological role of cancer-testis genes in myeloma remains poorly understood.

Design And Methods: We performed the first investigation of the function of two cancer-testis antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNA interference-based gene silencing model in myeloma cell lines. Functional assays were used to determine changes in proliferation, cell adhesion, chemosensitivity, colony formation, and apoptosis resulting from gene-specific silencing.

Results: We show that the investigated genes are not involved in regulating cell proliferation or adhesion; however, they play an important role in promoting the survival of myeloma cells. Accordingly, knock-down of MAGE-C1/CT7 and MAGE-A3 led to the induction of apoptosis in the malignant plasma cells and, importantly, both genes were also essential for the survival of clonogenic myeloma precursors. Finally, silencing of cancer-testis genes further improved the response of myeloma cells to conventional therapies.

Conclusions: Cancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting the survival of myeloma cells and clonogenic precursors by reducing the rate of spontaneous and chemotherapy-induced apoptosis and might, therefore, represent attractive targets for novel myeloma-specific therapies.
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http://dx.doi.org/10.3324/haematol.2009.014464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864385PMC
May 2010