Publications by authors named "William Krüger"

55 Publications

Implementation of Palliative Care in Clinical Practice in German Units for Allogeneic Stem Cell Transplantation: A Nationwide Survey.

Am J Hosp Palliat Care 2021 Jan 12:1049909120986963. Epub 2021 Jan 12.

Clinic for Internal Medicine C - Haematology, Oncology, Stem Cell transplantation and Palliative Care, Greifswald, Germany.

Allogeneic stem cell transplantation (alloSCT) is a curative therapy for otherwise fatal diseases, however it is associated with a considerable morbidity and mortality. In consequence, it can be assumed that a considerable percentage of patients would benefit from high-quality palliative care (PC) during their course of disease. To assess the standard of PC in German transplant centers, a questionnaire was sent out to all German centers recognized from the EBMT membership list and the annually ZKRD report (n = 52). The response rate was not as high as expected with n = 27 (51,9%), even after reminding by phone calls or by e-mails. In brief, palliative care after allogeneic stem cell transplantation shows a wide variation in Germany. This is true for structures, processes and measures. A national standard for SCT-patients has not been established so far and there are no pre-conditions concerning palliative care after alloSCT for a certification by the EBMT according the JACIE standards. There is a considerable need for a crosslinking of alloSCT with PC. Clear standards should be established by the scientific societies concerning personnel, structure and processes.
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http://dx.doi.org/10.1177/1049909120986963DOI Listing
January 2021

Haematopoietic stem cell transplantation in adult soft-tissue sarcoma: an analysis from the European Society for Blood and Marrow Transplantation.

ESMO Open 2020 10;5(5):e000860

Internal Medicine and Medical Therapy, Università degli Studi di Pavia, Pavia, Lombardia, Italy.

Background: The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups.

Methods: The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016.

Results: Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact.

Conclusions: Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.
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http://dx.doi.org/10.1136/esmoopen-2020-000860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590345PMC
October 2020

Targeting IL-11 in the treatment of BK virus-associated haemorrhagic cystitis-A promising new approach.

J Cell Mol Med 2020 08 25;24(16):9097-9100. Epub 2020 Jun 25.

Department of Hematology/Oncology, University Medical Center Greifswald, Greifswald, Germany.

The BK polyomavirus (BKPyV) has pathogenic relevance especially in immunocompromised patients. No causal therapy has been established yet. Therefore, new therapeutic targets need to be identified in experimental studies. A 3D organotypic cell culture model with primary urothelial cells and fibroblasts was used as infection model. The detection of virus replication was performed with quantitative polymerase chain reaction (qPCR), and immunohistochemistry (IHC) was also used for analysis. Interleukin levels were measured by enzyme-linked immunosorbent assay (ELISA). Interestingly, the signal transducer and activator of transcription 3 (STAT3) pathway seems to be activated during infection with BKPyV, for example phosphorylated STAT3 is significantly (P < 0.0001) elevated on day 6 following infection. Therefore, we performed ELISAs for involved interleukins in STAT3 pathway. Interleukin 11 (IL-11) was significantly (P = 0.026) elevated at day 9. Subsequently, 3D cultures were treated with IL-11 neutralizing antibody. At day 9 following infection, the median virus replication rate is 4.4 × 10 copies/ml. The difference to replication rate without treatment was significantly lower at day 6 (P < 0.0001) and at day 9 (P < 0.0001), respectively. STAT3 pathways seem to be involved during BKPyV infection and need further investigation in experimental studies. A very promising target for treatment might be IL-11.
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http://dx.doi.org/10.1111/jcmm.15546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417724PMC
August 2020

Novel 3D organotypic urothelial cell culture model for identification of new therapeutic approaches in urological infections.

J Clin Virol 2020 03 21;124:104283. Epub 2020 Jan 21.

University Medicine Greifswald, Department of Haematology and Oncology, Greifswald, Germany.

Purpose: 3D organotypic cell cultures offer the possibility to study cell growth in a more in vivo like situation. To our knowledge no 3D culture of primary urothelial cells has been established yet. BK Polyomavirus (BKPyV), replicating in urothelial cells, may cause haemorrhagic cystitis in immunocompromised patients.

Primary Endpoints Of This Study: Establishment of a 3D organotypic cell culture of primary urothelial cells and fibroblasts; use of this model as infection model for archetype BKPyV; description of first parts of viral life cycle with identification of therapeutic targets.

Methods: This is an experimental study. Primary urothelial cells were purchased from CellnTec, Bern, Switzerland; fibroblasts were isolated from the ureter of patients with no urothelial malignancy in their medical history. As main methods we used quantitative real-time PCR and immunohistochemistry. Outcomes were analysed using SPSS 23.0.

Results: We were able to develop a 3D organotypic culture for primary urothelium. An infection with archetype BKPyV was established in this model with virus replication rates up to 6.41 × 108 copies/ml on day 9 following Infection. Interestingly, proliferation rate of the urothelial cells is significantly (p = 0.049 at day 6 following infection) elevated while cells are losing differentiation under infection. Phosphorylated STAT3 is also significantly elevated (p < 0.0001) during infection.

Conclusions: The established of urothelial 3D cultures is a new method to study several urothelial diseases. The archetype BKPyV infection model is novel and the first method to study archetype viral life cycle. The STAT3 pathway might be an interesting target for the development of a causal therapy.
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http://dx.doi.org/10.1016/j.jcv.2020.104283DOI Listing
March 2020

Does rehabilitation pose a risk to patients suffering from haemato-oncological diseases? Results of a monocentric, retrospective analysis in Germany.

Eur J Cancer Care (Engl) 2020 Mar 6;29(2):e13201. Epub 2019 Dec 6.

Klinik und Poliklinik für Hautkrankheiten, Universität Greifswald, Greifswald, Germany.

Objective: Patients suffering from haemato-oncological diseases tend to have a weakened immune system after the end of their therapy. To avoid infections, patients are advised to limit contact with other people. This poses the question whether a stay at a rehabilitation facility can be recommended.

Methods: We report about 134 rehabilitation stays of patients. Premature discontinuation of the rehabilitation stay was selected as the criterion for a serious complication during the rehabilitation, and the underlying reasons were analysed.

Results: Compared to the discontinuation rates of patients suffering from solid tumours (2.4%), the percentage of haemato-oncological patients ending prematurely their rehabilitation stay (8.2%) is significantly increased. This rises to 17.1% for patients who have undergone an allogeneic stem cell transplantation. The analysis of the discontinuation reasons revealed that they were not directly connected to the rehabilitation. Apart from the already known risk factors for premature termination of the rehabilitation stay, we have identified the period (days) between the last therapy and the beginning of the rehabilitation stay as a risk factor.

Conclusions: We show for the first time that a rehabilitation stay does not pose additional risks for patients suffering from haemato-oncological diseases.
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http://dx.doi.org/10.1111/ecc.13201DOI Listing
March 2020

Ibrutinib as a salvage therapy after allogeneic HCT for chronic lymphocytic leukemia.

Bone Marrow Transplant 2020 05 7;55(5):884-890. Epub 2019 Nov 7.

Department of Hematology, University Hospital Dresden, Dresden, Germany.

The purpose of our study is to provide information on safety and efficacy of ibrutinib as salvage treatment after allo-HSCT for CLL. A total of 56 patients were included, 36 (64%) males; median age at transplantation was 48 years (range: 35-64) and the median number of treatment lines prior to transplantation was 3 (1-10). The median time between allo-HSCT and Ibrutinib was 30 months (range: 1-140). Overall, 40 (71%) patients responded to Ibrutinib; 23 (41%) PR, and 17 (30%) CR. At time of ibrutinib initiation, ten patients had active chronic GVHD that resolved under Ibrutinib, whilst a single patient developed limited de novo chronic GVHD on Ibrutinib. Fourteen patients discontinued ibrutinib, four because of toxicity and ten because of disease progression. Overall, 14 patients progressed (median PFS = 24 months) among them 10 died. Two-year OS and PFS probabilities were 72% (95% CI: 52-84) and 50% (95% CI: 32-66), respectively. Patients with late relapse after allo-HSCT (≥24 months) had a better PFS after ibrutinib. Our study shows that ibrutinib can be safely administered for CLL relapse after allo-HSCT, with comparable efficacy to non-transplanted patients with high-risk disease.
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http://dx.doi.org/10.1038/s41409-019-0742-7DOI Listing
May 2020

Ruxolitinib for Therapy of Graft-versus-Host Disease.

Biomed Res Int 2019 6;2019:8163780. Epub 2019 Mar 6.

University Medicine Greifswald, Internal Medicine C, Hematology and Oncology, Stem Cell Transplantation and Palliative Care, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany.

Objective: Steroid-resistant graft-versus-host disease (GvHD) is a major challenge after allogeneic stem cell transplantation and associated with significant morbidity and mortality. There is no therapeutic standard defined beyond calcineurin inhibitors (CNI) and steroids. Furthermore, some patients may have contraindications against CNI or high-dose steroids. Efficacy of ruxolitinib against GvHD has been described recently.

Methods: Ruxolitinib was used for treatment of acute or chronic GvHD in eight patients. The patients either needed intensification of therapy or had contraindications against use of CNI or high-dose steroids.

Results: Supplementation of therapy in acute GvHD with severe diarrhea with ruxolitinib was unsuccessful. All these patients died from acute GvHD. Introduction of ruxolitinib into therapy and relapse prophylaxis in other patients was successful in 4/4 cases (CR=3, PR=1). Indications for ruxolitinib were contraindications against CNI due to aHUS in two cases and the need for steroid sparing in two other cases. None of these patients suffered from diarrhea at the initiation of ruxolitinib.

Conclusion: Ruxolitinib was effective for therapy of acute and chronic GvHD in higher lines in patients without severe diarrhea. Ruxolitinib could replace successfully CNI and high-dose steroids. Further investigations are necessary to define the position of ruxolitinib in GvHD-therapy.
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http://dx.doi.org/10.1155/2019/8163780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431395PMC
July 2019

Shaping of CD56 Natural Killer Cells in Patients With Steroid-Refractory/Resistant Acute Graft-vs.-Host Disease via Extracorporeal Photopheresis.

Front Immunol 2019 20;10:547. Epub 2019 Mar 20.

Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany.

CD56 natural killer (NK) cells play an important role in the pathogenesis of graft-vs. -host disease (GVHD) and immune defense in the early period after allogeneic hematopoietic stem cell transplantation. Extracorporeal photopheresis (ECP) as an immunomodulating therapy has been widely used for GVHD treatment. However, the mechanism of action of ECP still remains to be elucidated, particularly the influence of ECP on NK cells. Thirty-four patients with steroid-refractory/resistant acute GVHD (aGVHD) ≥ °II and moderate to severe chronic GVHD (cGVHD) received ECP therapy. Patient samples obtained during intensive and long-term treatment were analyzed. Immunomonitoring with respect to cell phenotype and function was performed on rested peripheral blood mononuclear cells (PBMCs) using multiparametric flow cytometry. NK activity in terms of cytokine release was analyzed by intracellular cytokine staining after co-culture with K562 cells. Moreover, the proliferative capacity of NK cells, CD4, and CD8 T cells was determined by carboxyfluorescein succinimidyl ester (CFSE) staining. Clinically, 75% of aGVHD and 78% of cGVHD patients responded to ECP therapy. Moreover, our data show that aGVHD, cGVHD patients and healthy donors (HDs) present distinct NK patterns: aGVHD patients have a higher frequency of CD56 NK subsets with stronger NKG2D and CD62L expression, while CD56CD16 NK cells with higher expression of CD57 and CD11b stand out as a signature population for cGVHD. ECP therapy could significantly decrease CD56CD16 NK cells with shifting the quality from a cytotoxic to a regulatory pattern and additionally mature CD56 NK cells via upregulation of CD57 in complete responding aGVHD patients. Moreover, ECP could keep the anti-viral and anti-leukemic effects intact via maintaining specialized anti-viral/leukemic CD57NKG2CCD56 NK cells as well as remaining the quality and quantity of cytokine release by NK cells. The proliferative capacity of effector cells remained constant over ECP therapy. In conclusion, ECP represents an attractive option to treat GVHD without compromising anti-viral/leukemic effects. Shaping of CD56 NK cell compartment by downregulating the cytotoxic subset while upregulating the regulatory subset contributes to the mechanisms of ECP therapy in aGVHD.
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http://dx.doi.org/10.3389/fimmu.2019.00547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436423PMC
September 2020

Is BK Virus-Associated Cystitis a Generalized Epithelial Disease?

Acta Haematol 2019 3;141(2):65-67. Epub 2019 Jan 3.

Department of Haematology/Oncology, University Medicine Greifswald, Greifswald, Germany.

BK polyomavirus-associated haemorrhagic cystitis (BKHC) is a complication after allogeneic stem cell transplantation, which can occur in 5-60% of the cases. BK viruria alone can also occur in up to 100%. BKHC can lead to severe morbidity in stem cell-transplanted patients, but data about this disease is limited. Consequently, we conducted a prospective unicentric non-interventional trial on BKHC as well as BK viruria after first adult allogeneic stem cell transplantation with a follow-up time of 1 year after inpatient treatment. Between November 2013 and December 2015, we were able to include 40 adult patients with a mean age of 52.8 years. Twenty-seven (67.5%) of these patients were male and 13 (32.5%) were female. Acute myeloid leukaemia was the most frequent underlying disease (n = 15; 37.5%). Only 1 patient developed BKHC during inpatient treatment (n = 1; 2.5%), but BK viruria was frequent (n = 11; 27.5%) during inpatient treatment as well as in the follow-up time (n = 14; 35%). Interestingly, BK viruria was significantly associated with mucositis (p = 0.038) and number of transfused platelet concentrates (p = 0.001). This unexpected association will be discussed and needs further investigation.
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http://dx.doi.org/10.1159/000494748DOI Listing
September 2019

Modulation of B Cells and Homing Marker on NK Cells Through Extracorporeal Photopheresis in Patients With Steroid-Refractory/Resistant Graft-Vs.-Host Disease Without Hampering Anti-viral/Anti-leukemic Effects.

Front Immunol 2018 8;9:2207. Epub 2018 Oct 8.

Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany.

Graft-vs.-host disease (GvHD), a severe complication of allogeneic hematopoietic stem cell transplantation, significantly affects the post-transplant morbidity and mortality. Systemic steroids remain the gold standard for the initial management of GvHD. However, up to 60% of patients will not sufficiently respond to steroids. Extracorporeal photopheresis (ECP), a cell-based immunotherapy, has shown good clinical results in such steroid-refractory/resistant GvHD patients. Given its immunomodulatory, but not global immunosuppressive and steroid-sparing capacity, ECP constitutes an attractive option. In the case of GvHD, the balance of immune cells is destroyed: effector cells are not any longer efficiently controlled by regulatory cells. ECP therapy may restore this balance. However, the precise mechanism and the impact of ECP on anti-viral/anti-leukemic function remain unclear. In this study, 839 ECP treatments were performed on patients with acute GvHD (aGvHD) and chronic GvHD (cGvHD). A comprehensive analysis of effector and regulatory cells in patients under ECP therapy included multi-parametric flow cytometry and tetramer staining, Luminex-based cytokine, interferon-γ enzyme-linked immunospot, and chromium-51 release assays. Gene profiling of myeloid-derived suppressor cells (MDSCs) was performed by microarray analysis. Immunologically, modulations of effector and regulatory cells as well as proinflammatory cytokines were observed under ECP treatment: (1) GvHD-relevant cell subsets like CD62L NK cells and newly defined CD19CD20 B cells were modulated, but (2) quantity and quality of anti-viral/anti-leukemic effector cells were preserved. (3) The development of MDSCs was promoted and switched from an inactivated subset (CD33CD11b) to an activated subset (CD33CD11b). (4) The frequency of Foxp3CD4 regulatory T cells (Tregs) and CD24CD38 regulatory B cells was considerably increased in aGvHD patients, and Foxp3CD8 Tregs in cGvHD patients. (5) Proinflammatory cytokines like IL-1β, IL-6, IL-8, and TNF-α were significantly reduced. In summary, ECP constitutes an effective immunomodulatory therapy for patients with steroid-refractory/resistant GvHD without impairment of anti-viral/leukemia effects.
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http://dx.doi.org/10.3389/fimmu.2018.02207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186805PMC
September 2019

Comparison of intravenous or intravesical cidofovir in the treatment of BK polyomavirus-associated hemorrhagic cystitis following adult allogeneic stem cell transplantation-A systematic review.

Transpl Infect Dis 2018 Aug 21;20(4):e12914. Epub 2018 Jun 21.

Department of Haematology/Oncology, University Medicine Greifswald, Greifswald, Germany.

Introduction: BK polyomavirus can lead to hemorrhagic cystitis (BKPyV-HC) in allogeneic stem cell transplantation and therefore to increased morbidity. No causal therapy has been established yet. Cidofovir (CDV) is a nucleotide analog of cytosine that is active against various DNA viruses and it has been described for therapy of BKPyV-HC using 2 admission routes: intravenous and intravesical.

Methods: We performed a systematic review regarding the comparison of intravenous or intravesical cidofovir in the treatment of BKPyV-HC following adult allogeneic stem cell transplantation. Since there is a lack of randomized controlled trials, we considered all kinds of studies for this review. Due to heterogeneity of the data, we were not able to perform a meta-analysis, so the results are shown descriptively.

Results: The literature search for primary studies yielded 232 results. Finally, 9 studies where considered which included a total of 189 adult patients with BKPyV-HC after allogeneic stem cell transplantation. We could only identify retrospective studies for this review. A total of 172 patients received intravenous CDV, 17 patients received intravesical CDV, and 2 patients received CDV in both admission routes. In 68.0% of the cases, a complete response for intravenous CDV was documented and in 88.2% for intravesical CDV. Interestingly, no kidney toxicity was mentioned in intravesical CDV. 9.3% of the intravenously treated patients had renal failure.

Conclusion: There is only weak evidence for the use of CDV. The intravesical admission route should be further investigated because of a good toxicity profile.
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http://dx.doi.org/10.1111/tid.12914DOI Listing
August 2018

Efficacy and safety of keratinocyte growth factor (palifermin) for prevention of oral mucositis in TBI-based allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplant 2018 09 15;53(9):1188-1192. Epub 2018 Mar 15.

Department of Haematology and Medical Oncology, Clinic of Internal Medicine II, University Hospital Jena, Jena, Germany.

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http://dx.doi.org/10.1038/s41409-018-0135-3DOI Listing
September 2018

Recovery from hypogonadism and male health in adult allogeneic stem cell transplantation.

Eur J Haematol 2018 Jun 6;100(6):584-591. Epub 2018 Apr 6.

Department of Haemaotology/Oncology, University Medicine Greifswald, Greifswald, Germany.

Objective: There is a substantial lack of data about men`s health in adult allogeneic stem cell transplantation.

Methods: We conducted prospective unicentric non-interventional clinical study on men's health with a follow-up time of 1 year.

Results: Between 11/2013 and 12/2015, we were able to include 27 patients. AML was the most frequent underlying disease (25.9%), and we mainly used intermediate intense conditioning protocols (77.8%). Erectile dysfunction, loss of libido, and loss of efficiency were the most frequent symptoms of hypogonadism. At inclusion of the study, hypogonadism was already frequent. Primary hypogonadism was found in eight cases (29.6%) and secondary hypogonadism in one case (3.7%). We did not observe hypogonadism 6 months after inpatient treatment anymore, but there might still be the impairment of fertility because of still rising FSH levels at the end of the observation period. There were no significant associations of hypogonadism with myeloablative conditioning or kind of donor. Interestingly, there is a significant association with nicotine abuse (P = .049).

Conclusions: On the whole, male hypogonadism was found in one-third of the patients who underwent allogeneic stem cell transplantation.
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http://dx.doi.org/10.1111/ejh.13052DOI Listing
June 2018

No indication of increased infection rates using low-dose alemtuzumab instead of anti-thymocyte globulin as graft-versus-host disease prophylaxis before allogeneic stem cell transplantation.

Transpl Infect Dis 2018 Feb 27;20(1). Epub 2017 Dec 27.

Department of Haematology, Oncology, Transplantation, University Medical Centre, Ernst-Moritz-Arndt University, Greifswald, Germany.

Background: Alemtuzumab as part of the conditioning protocol is effective in reducing graft-versus-host disease (GvHD), but may be associated with increased infection rates, especially when using high doses (ie, 100 mg).

Methods: We performed a retrospective, single-center, case-control study analyzing the rates of neutropenic fever, cytomegalovirus (CMV) reactivation, Epstein-Barr virus (EBV) reactivation, clinical manifest toxoplasmosis, and clinical manifest human herpesvirus-6 (HHV6) infection using low-dose alemtuzumab in comparison with anti-thymocyte globulin (ATG) as GvHD prophylaxis before allogeneic stem cell transplantation. Forty-four patients transplanted from unrelated donors between 2001 and 2012 were matched by age, diagnosis, and conditioning regimen and treated either with alemtuzumab 10 mg at day -2 (respectively, 20 mg in case of mismatch transplantation) or ATG. ATG Fresenius (10 mg/kg for 3 days) or Thymoglobulin (2 mg/kg for 3 days) were used.

Results: Rates of CMV reactivation, EBV reactivation, and clinical manifest HHV6 infection or toxoplasmosis did not differ significantly between both groups until 2 years after transplantation. No case of post-transplant lymphoproliferative disorder was observed. Also, rates of neutropenic fever during inpatient treatment after transplantation did not differ significantly in both groups.

Conclusion: We saw no indication of increased infections rates when using low-dose alemtuzumab as GvHD prophylaxis before allogeneic stem cell transplantation in this retrospective analysis.
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http://dx.doi.org/10.1111/tid.12822DOI Listing
February 2018

Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

Ann Hematol 2018 Feb 18;97(2):335-342. Epub 2017 Nov 18.

Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, University of Duesseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.

In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n = 35) or molecular relapse (n = 1) of acute myeloid leukemia (AML, n = 29) or myelodysplastic syndrome (MDS, n = 7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2 DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10 months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (± 6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure.
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http://dx.doi.org/10.1007/s00277-017-3185-5DOI Listing
February 2018

No Relapse of Calcineurin Inhibitor-Associated Thrombotic Microangiopathy after Discontinuation of Eculizumab.

Acta Haematol 2017 15;138(4):194-197. Epub 2017 Nov 15.

Department of Internal Medicine C (Haematology and Oncology, Stem Cell Transplantation, Palliative Care), University Hospital Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany.

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http://dx.doi.org/10.1159/000481724DOI Listing
July 2018

Urological complications associated with adult allogeneic stem cell transplantation.

Am J Hematol 2018 01 10;93(1):E3-E4. Epub 2017 Nov 10.

Department of Hematology/Oncology, University Medicine Greifswald, Greifswald, Germany.

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http://dx.doi.org/10.1002/ajh.24920DOI Listing
January 2018

Baseline Characteristics Predicting Very Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Patients With High Cytogenetic Risk Chronic Lymphocytic Leukemia - A Retrospective Analysis From the Chronic Malignancies Working Party of the EBMT.

Clin Lymphoma Myeloma Leuk 2017 10 17;17(10):667-675.e2. Epub 2017 Jun 17.

DKMS Clinical Trials Unit, Dresden, Germany; Medizinische Klinik und Poliklinik I, University Hospital of the Technical University Dresden, Dresden, Germany.

Background: Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase- and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population.

Patients And Methods: Risk factors for 2-year NRM and 8-year PFS were identified in patients < 50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90.4 months) by Cox regression modeling, and predicted probabilities of NRM and PFS of 2 reference patients with favorable or unfavorable characteristics were plotted.

Results: Predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.1-2.5) and partially human leukocyte antigen (HLA)-mismatched unrelated donor (HR, 2.8; 95% CI, 1.5-5.2). The latter variable also predicted a higher risk of 2-year NRM (HR, 4.0; 95% CI, 1.4-11.6) compared with HLA-matched sibling donors. Predicted 2-year NRM and 8-year PFS of a high cytogenetic risk (del(17p) and/or del(11q)) patient in remission with a matched related donor were 12% (95% CI, 3%-22%) and 54% (95% CI, 38%-69%), and for an unresponsive patient with a female partially HLA-matched unrelated donor 37% (95% CI, 12%-62%) and 38% (95% CI, 13%-63%).

Conclusion: Low predicted NRM and high 8-year PFS in favorable transplant high cytogenetic risk patients compares favorably with outcomes with KI or BCL2i. Taking into account the amount of uncertainty for predicting survival after alloHCT and after sequential administration of KI and BCL2i, alloHCT remains a valid option for younger patients with high cytogenetic risk chronic lymphocytic leukemia with a well-HLA-matched donor.
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http://dx.doi.org/10.1016/j.clml.2017.06.007DOI Listing
October 2017

Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

Acta Haematol 2017 8;138(1):3-9. Epub 2017 Jun 8.

Institute of Virology, Saarland University Medical Center, Saarland University, Homburg/Saar, Germany.

Background: The association of polyomaviruses BK and JC with other opportunistic infections and graft-versus-host disease (GvHD) in allogeneic stem cell transplantation is controversially discussed.

Methods: We conducted a retrospective study of 64 adult patients who received their first allogeneic stem cell transplantation between March 2010 and December 2014; the follow-up time was 2 years.

Results: Acute leukemia was the most frequent underlying disease (45.3%), and conditioning included myeloablative (67.2%) and nonmyeloablative protocols (32.8%). All patients received 10 mg of alemtuzumab on day -2 (20 mg in case of mismatch) as GvHD prophylaxis. Twenty-seven patients (41.5%) developed cytomegalovirus (CMV) reactivation. BKPyV-associated hemorrhagic cystitis was diagnosed in 10 patients (15.6%). Other opportunistic infections caused by viruses or protozoa occurred rarely (<10%). There was no association of BKPyV or JCPyV with CMV reactivation, Epstein-Barr virus reactivation, human herpes virus 6, or parvovirus B19 infection requiring treatment. There was a significant correlation of BKPyV-associated hemorrhagic cystitis with toxoplasmosis (p = 0.013). Additionally, there was a significant link of simultaneous BKPyV and JCPyV viruria with toxoplasmosis (p = 0.047). BKPyV and JCPyV were not associated with GvHD, relapse, or death.

Conclusion: We found no association of BKPyV or JCPyV with viral infections or GvHD. Only the correlation of both polyomaviruses with toxoplasmosis was significant. This is a novel and interesting finding.
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http://dx.doi.org/10.1159/000468972DOI Listing
September 2017

Clinical course and end-of-life care in patients who have died after allogeneic stem cell transplantation.

J Cancer Res Clin Oncol 2017 Oct 27;143(10):2067-2076. Epub 2017 May 27.

Department of Internal Medicine C-Haematology, and Oncology, Stem Cell Transplantation, Palliative Care, University Hospital Greifswald, Ernst-Moritz-Arndt University, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany.

Purpose: Allogeneic stem cell transplantation may cure approximately 50% of patients, however, a significant part of the other half might benefit from a high-quality palliative care medicine at the end of life. Somatic, psychic and spiritual needs of these patients may differ from those of patients suffering from incurable solid tumours and are not comprehensively evaluated so far.

Methods: To address this question, data from charts of 123 patients who have died after allogeneic stem cell transplantation were extracted. In detail, the time line of the clinical course, the symptoms, the administered drugs and other applied procedures were analysed.

Results: Approximately one half of the patients, who have died after stem cell transplantation, did not live more than 5 months. Two-thirds of patients died within 14 months after SCT. 28.5% of the patients could not be discharged after transplantation. However, a significant proportion had a low ECOG-score (0-1) prior to death, indicating a high degree of mobility. Major symptoms were weakness, fatigue and need for aid at daily activities. Severe pain, dyspnoea and obstipation, as known from patients suffering from advanced solid tumours, were rare. In consequence, use of opioids seemed to be less frequent than in patients with solid tumours. Measures of intensive care and i.v.-drug administration were applied to a significant proportion of patients.

Conclusion: The present investigation indicates that the somatic, psychic and spiritual end-of-life-care after allogeneic stem cell transplantation could be optimised. A significant problem for the transplantation team seems to be the realisation of necessity to switch the curative concept into a palliative ambition. Requirements are a subsequent prospectively conducted investigation and an intensification of cooperation between transplant and palliative care teams.
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http://dx.doi.org/10.1007/s00432-017-2446-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101727PMC
October 2017

Nationwide survey of BK polyomavirus associated hemorrhagic cystitis in adult allogeneic stem cell transplantation among haematologists and urologists.

Ann Hematol 2017 May 3;96(5):797-803. Epub 2017 Feb 3.

Department of Haematology/Oncology, University Medicine Greifswald, Greifswald, Germany.

There are no epidemiological data on BK virus associated hemorrhagic cystitis (BKHC) in adult allogeneic stem cell transplantation in Germany available and associations with clinical conditions like GvHD are controversially discussed. Therefore, we conducted a nationwide survey among haematologists and urologists about this disease. We developed two questionnaires, one for haematologists (26 items) and one for urologists (20 items) concerning BKHC in adult allogeneic stem cell transplantation with epidemiological data and clinical implications. The survey was sent out at least three times to EBMT registered centres performing at least five transplantations a year, leading to 39 centres. The recruiting time was between January and June 2016. Total response rates were 76.9% among haematologists and 74.4% among urologists. BKHC seems to appear less frequent in this survey than it is described in the literature. Six deaths in the last 5 years due to this disease have been reported. Interestingly, haematologists as well as urologists mostly think that local therapy is most effective while 50.0% stated that there is no real effective oral or intravenous medication. Associations with other clinical conditions mentioned were heterogeneous, e.g. transplantation type, CMV reactivation, acute GvHD, nephropathy and worse clinical outcome. There was a significant discrepancy between haematologists and urologist concerning the association with acute GvHD (p = 0.004). We need prospective, multicentric clinical studies to evaluate local therapy and for developing a risk stratification model since this disease can be severe with morbidity and rarely mortality. In our opinion, this should be an interdisciplinary approach.
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http://dx.doi.org/10.1007/s00277-017-2935-8DOI Listing
May 2017

Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016.

Ann Hematol 2016 Sep 24;95(9):1435-55. Epub 2016 Jun 24.

Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany.

Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria.
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http://dx.doi.org/10.1007/s00277-016-2711-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972852PMC
September 2016

Urological Complications and BK Virus-Associated Diseases Under Allogenic Stem Cell Transplantation.

Urol Int 2016 24;97(4):434-439. Epub 2016 Mar 24.

Department of Urology, University Medicine Greifswald, Greifswald, Germany.

Every year 50,000 patients receive a stem cell transplantation worldwide, but there is lack of data pertaining to urological complications.

Methods: We performed a retrospective analysis of all adult patients undergoing their first allogenic stem cell transplantation from January 2011 to June 2013 in our institution. Statistical tests performed were Pearson's correlation, chi-square testing and logistic regression using SPSS 22.0.

Results: We identified 39 patients (22 males, 17 females). Twenty four patients (61.5%) had a urological complication. Most frequent urologic complications were bacterial urinary tract infection (n = 13; 33.3%), acute renal failure (n = 6; 15.4%) and BK virus-associated haemorrhagic cystitis (n = 5; 12.8%). BK viruria was detected in 12 patients (30.8%). We observed an association of creatinine increase (about 20 µmol/l at time of onset of BK viruria) with BK viruria (Pearson's correlation 0.64; p = 0.01), and BK viruria is significantly linked to acute renal failure (Pearson's correlation 0.35; p = 0.029). In univariate regression, BK viruria is significantly linked to urological complication (p = 0.025).

Conclusions: We suggest that BK virus infection during stem cell transplantation can lead to BK virus associated nephropathy, which is so far only known from patients after kidney transplantation.
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http://dx.doi.org/10.1159/000445124DOI Listing
April 2018

Reduced platelet transfusions and earlier platelet engraftment using alemtuzumab-based conditioning regimen in allogeneic stem cell transplantation.

J Cancer Res Clin Oncol 2016 May 16;142(5):1091-7. Epub 2016 Jan 16.

Department of Hematology, Oncology, Transplantation, University Medical Center, Ernst-Moritz-Arndt University, Greifswald, Germany.

Purpose: In patients undergoing allogeneic stem cell transplantation, conditioning regimens containing alemtuzumab instead of anti-thymocyte globulin (ATG) may result in an earlier platelet engraftment and a reduced number of platelet transfusions.

Methods: We performed a retrospective, single-center, case-control study analyzing time to engraftment and transfusion needs using alemtuzumab in comparison with ATG as part of conditioning protocol.

Results: Median values for time to platelet engraftment, number of transfused platelet concentrates and number of transfused red cell concentrates were 12 versus 19.5 days (p < 0.001), 2 versus 14 (p < 0.001) and 6 versus 14.5 (p = 0.003) in the alemtuzumab and ATG group. Time to leukocyte engraftment did not differ with median 15 days in both groups. Patients in the ATG group showed a significant higher decrease in platelet count during conditioning (68 vs. 29 %, p = 0.001), leading to significant lower median platelet counts at the day of stem cell infusion (38 vs. 95.5 Gpt/l, p = 0.008), and higher values for median C-reactive protein after first antibody infusion (69.0 vs. 43.6 mg/l, p = 0.001) compared with alemtuzumab group. Test for significance was done by using Wilcoxon rank-sum test. Subgroup analysis considering the type of ATG used (Thymoglobulin vs. ATG Fresenius) revealed that differences between alemtuzumab and ATG group were more due to effects of ATG Fresenius than Thymoglobulin.

Conclusions: The use of alemtuzumab in comparison with ATG as part of the conditioning regimen may be an approach to reduce the number of transfused platelet and red cell concentrates after allogeneic stem cell transplantation.
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http://dx.doi.org/10.1007/s00432-016-2114-7DOI Listing
May 2016

Treatment of High-Risk T-NHL with Stem Cell Transplantation: A Single Center Experience.

Indian J Hematol Blood Transfus 2015 Mar 11;31(1):14-20. Epub 2014 May 11.

Department of Internal Medicine C (Haematology and Oncology, Marrow Transplantation), Ernst-Moritz-Arndt-University Greifswald, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.

Prognosis of peripheral and other advanced T cell lymphomas is poor. 20 patients with a median age of 46.4 (range 20.5-64.1) years were treated with autoSCT (n = 6) or alloSCT (n = 14) from 1996 to 2013. All patients were at high risk either due to the IPI-score or to the fact that SCT was part of a salvage therapy. Conditioning prior to alloSCT was myeloablative in seven cases (50 %). The patients were pretreated with 8.5 (median, range 2-38) cycles of chemotherapy. Ten patients are alive in CR after a median follow-up of 1.3 years (range 0.1-13.3). OS was 53 % after one and 40 % after 10 years. Best survival was reached after related alloSCT (80 % at 10 years) compared to other modalities. GvHD did not influence survival. AlloSCT from related donors can cure patients from T-cell lymphomas. Unrelated alloSCT or high-dose therapy and autoSCT are an option for patients without a familiar donor.
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http://dx.doi.org/10.1007/s12288-014-0398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275534PMC
March 2015

Allogeneic stem cell transplantation in patients above 55: suggestion for a further stratification of the HCT-CI.

J Cancer Res Clin Oncol 2014 Nov 26;140(11):1981-8. Epub 2014 Jun 26.

Department of Internal Medicine C - Haematology and Oncology, Marrow Transplantation, and Palliative Care, Ernst-Moritz-Arndt-University Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Germany.

Introduction: Allogeneic stem cell transplantation (alloSCT) has become available for elderly patients or for patients with comorbidities by introduction of reduced-intense conditioning. Comorbidity-related prognosis after alloSCT can be estimated by the hematopoietic cell transplantation comorbidity index (HCT-CI).

Material And Methods: The charts from 85 patients who have undergone 90 alloSCTs between 1999 and 2011 were analysed. Most patients received a dose-reduced conditioning and a graft from an unrelated donor. Patients were stratified for age, HCT-CI, cGvHD versus no cGvHD, and a modified HCT-CI with a further split high-risk score.

Results: Age over 60 years did not affect the outcome. Manifestation of cGvHD improved the prognosis significantly. An additional stratification of the high-risk group of the HCT-CI revealed that even a fraction of these patients can have considerable benefit from an alloSCT. Furthermore, this high-risk collective could be clearly discriminated into two groups with different outcomes.

Conclusions: The investigation confirms that age is no absolute risk factor for alloSCT and demonstrates the heterogeneity of the high-risk group of the HCT-CI. A comprehensive investigation of an additional stratification is suggested. Furthermore, the authors encourage early withdrawal of immunosuppression, even in elderly patients and patients with comorbidities to permit graft-versus-leukaemia/lymphoma, since cGvHD is associated with a significantly better prognosis.
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http://dx.doi.org/10.1007/s00432-014-1748-6DOI Listing
November 2014

Allogeneic stem cell transplantation for mantle cell lymphoma--final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO).

Ann Hematol 2014 Sep 30;93(9):1587-97. Epub 2014 Apr 30.

Department of Internal Medicine C-Haematology and Oncology, Stem Cell Transplantation, Ernst-Moritz-Arndt-University, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany,

This study was conducted in order to evaluate allogeneic stem cell transplantation (alloSCT) as consolidation for patients with mantle cell lymphoma (MCL). Patients with MCL were included into two prospective trials OSHO #060 (refractory/relapsed) and #074 (de novo). Induction was rituximab and chemotherapy. Responding patients proceeded to alloSCT. Minimal residual disease was monitored by quantitative RT-PCR detecting either t(11;14) or clonospecific CDR-III regions. In case of circulating lymphoma cells, immunomodulation (cyclosporine A withdrawal, rituximab, donor lymphocyte infusion) was initiated. Thirty-three of 39 patients underwent alloSCT after myeloablative (n = 7) or toxicity-reduced (n = 26) conditioning. Leukocytes engrafted at day +16 (median, range 0-101) and platelets at day +14 (0-142). Acute graft-versus-host disease stages I-II occurred in 42 % and stages III-IV in 15 %. Five patients have relapsed after SCT. The overall mortality after SCT was 24 % (n = 8). Median follow-up after SCT was 2.8 years (range 0.0-10.9). Five-year progression-free survival was 67 %, and overall survival 73 % after SCT. The results were comparable for primary MCL and refractory/relapsed disease as well as for related vs. unrelated SCT. Younger patients had a significantly better outcome than the elderly. AlloSCT is a feasible and promising consolidation therapy for relapsed and refractory disease and an attractive option for young patients with de novo MCL of high risk.
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http://dx.doi.org/10.1007/s00277-014-2087-zDOI Listing
September 2014

Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

Ann Hematol 2014 Jan 12;93(1):13-32. Epub 2013 Sep 12.

Interdisziplinäres Zentrum für Palliativmedizin, Agaplesion Markus Krankenhaus, Wilhelm Epstein-Straße 4, 60431, Frankfurt, Germany,

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
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http://dx.doi.org/10.1007/s00277-013-1867-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889633PMC
January 2014

Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation-a matched pair analysis.

Ann Hematol 2013 Jul 5;92(7):945-52. Epub 2013 Mar 5.

Department of Internal Medicine C (Haematology and Oncology, Marrow Transplantation), Ernst-Moritz-Arndt-University Greifswald, Ferdinand-Sauerbruch-Str, 17475, Greifswald, Germany.

Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA-identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10 mg; HLA mismatch, 20 mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant-related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p = 0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM-SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted.
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http://dx.doi.org/10.1007/s00277-013-1714-4DOI Listing
July 2013

Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation.

Exp Hematol Oncol 2012 Oct 16;1(1):32. Epub 2012 Oct 16.

Internal Medicine C (Hematology and Oncology, Palliative Care, Transplant Centre), University Hospital Greifswald, Ernst-Moritz-Arndt-University, Greifswald, Germany.

Therapy of indolent lymphomas with involvement of the central nervous system (CNS) has not been standardized so far. A 42-year old male patient presented with neurological signs because of leukemic splenic marginal zone lymphoma (SMZL) manifested in bone marrow, lymph nodes and CNS. Due to the aggressiveness of the disease and the young age of the patient, an intensive immunochemotherapy followed by high-dose therapy with busulfan, thiotepa and fludarabine and subsequent unrelated allogeneic stem cell transplantation (alloSCT) was performed. The haemopoietic stem cells engrafted in time and the patient is doing well (ECOG 0) without evidence for active lymphoma three years after transplantation. Highly sensitive tests by specific quantitative real-time polymerase chain reaction for presence of lymphoma cells in blood and bone marrow indicated also a molecular remission. The reported case shows the feasibility of high-dose therapy and allogeneic stem cell transplantation in high-risk patients with CNS-involvement of indolent non-Hodgkin's lymphoma. In addition, the case supports the hypothesis that the graft-versus lymphoma effect after alloSCT is also active within the CNS.
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http://dx.doi.org/10.1186/2162-3619-1-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515347PMC
October 2012