Publications by authors named "Hildegard Greinix"

169 Publications

Vinorelbine as substitute for vincristine in patients with diffuse large B cell lymphoma and vincristine-induced neuropathy.

Support Care Cancer 2021 Feb 24. Epub 2021 Feb 24.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology.

Methods: In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables.

Results: Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes.

Conclusion: Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.
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http://dx.doi.org/10.1007/s00520-021-06059-2DOI Listing
February 2021

Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies.

Front Immunol 2020 2;11:613954. Epub 2021 Feb 2.

Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
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http://dx.doi.org/10.3389/fimmu.2020.613954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884746PMC
February 2021

Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients.

NPJ Vaccines 2020 Jul 24;5(1):67. Epub 2020 Jul 24.

Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

The aim of this prospective study was to characterize the humoral immune response to TBE vaccination after hematopoietic stem cell transplantation (HSCT). Nineteen adult patients 11-13 months after HSCT and 15 age-matched immunocompetent adults received up to three TBE vaccinations. Antibodies against TBE virus were measured by neutralization test (NT). As primary endpoint, the antibody response (NT titer of ≥10 and at least a twofold increase from baseline 4 weeks after second vaccination) was compared between patients and controls using Fisher exact test. Prior vaccination, 15 (79%) HSCT patients still had detectable neutralizing antibodies. At primary endpoint, the antibody response was significantly lower in patients than in controls (35% versus 93%; p < 0.001). The CD4+ cell count was a predictor for an antibody response in patients (p = 0.019). Interestingly, the majority of HSCT patients still had detectable antibodies prior vaccination. Following vaccination, antibody response in HSCT patients was associated with the CD4+ cell count.
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http://dx.doi.org/10.1038/s41541-020-00215-1DOI Listing
July 2020

T Cell Phenotyping in Individuals Hospitalized with COVID-19.

J Immunol 2021 Feb 8. Epub 2021 Feb 8.

Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become pandemic. Cytokine release syndrome occurring in a minority of SARS-CoV-2 infections is associated with severe disease and high mortality. We profiled the composition, activation, and proliferation of T cells in 20 patients with severe or critical COVID-19 and 40 matched healthy controls by flow cytometry. Unsupervised hierarchical cluster analysis based on 18 T cell subsets resulted in separation of healthy controls and COVID-19 patients. Compared to healthy controls, patients suffering from severe and critical COVID-19 had increased frequencies of activated and proliferating CD38Ki67 CD4 and CD8 T cells, suggesting active antiviral T cell defense. Frequencies of CD38Ki67 Th1 and CD4 cells correlated negatively with plasma IL-6. Thus, our data suggest that patients suffering from COVID-19 have a distinct T cell composition that is potentially modulated by IL-6.
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http://dx.doi.org/10.4049/jimmunol.2001034DOI Listing
February 2021

Potential Novel Biomarkers in Chronic Graft-Versus-Host Disease.

Front Immunol 2020 23;11:602547. Epub 2020 Dec 23.

Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.

Prognostic, diagnostic or predictive biomarkers are urgently needed for assessment of chronic graft-versus-host disease (cGvHD), a major risk for patients undergoing allogeneic hematopoietic stem cell transplantation. The main goal of this review generated within the COST Action EUROGRAFT "Integrated European Network on Chronic Graft Versus Host Disease" was to identify potential novel biomarkers for cGvHD besides the widely accepted molecular and cellular biomarkers. Thus, the focus was on cellular biomarkers, alloantibodies, glycomics, endothelial derived particles, extracellular vesicles, microbiome, epigenetic and neurologic changes in cGvHD patients. Both host-reactive antibodies in general, and particularly alloantibodies have been associated with cGvHD and require further consideration. Glycans attached to IgG modulate its activity and represent a promising predictive and/or stratification biomarker for cGVHD. Furthermore, epigenetic changes such as microRNAs and DNA methylation represent potential biomarkers for monitoring cGvHD patients and novel targets for developing new treatment approaches. Finally, the microbiome likely affects the pathophysiology of cGvHD; bacterial strains as well as microbial metabolites could display potential biomarkers for dysbiosis and risk for the development of cGvHD. In summary, although there are no validated biomarkers currently available for clinical use to better inform on the diagnosis, prognosis or prediction of outcome for cGvHD, many novel sources of potential markers have shown promise and warrant further investigation using well characterized, multi-center patient cohorts.
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http://dx.doi.org/10.3389/fimmu.2020.602547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786047PMC
December 2020

Adverse event reporting for cellular therapy products: Current status and future directions.

Transfusion 2020 Dec 16;60(12):2815-2827. Epub 2020 Oct 16.

Center for Cellular Therapies, AABB, Bethesda, Maryland, USA.

Adverse event (AE) and adverse reaction (AR) reporting are key components of patient safety and surveillance systems. Review and analysis of this data yields opportunities for process improvement, product information and interventions, and can lead to improved patient outcomes and donor safety overall. AE and AR reporting for cellular therapy products is fragmented and not well characterized in a central reference. This review article, authored by experts from various organizations, serves to summarize the current state of reporting and offers opportunities for streamlining and coordination, as well as key reference for professionals in this field.
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http://dx.doi.org/10.1111/trf.16062DOI Listing
December 2020

Erratum: Author Correction: Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients.

NPJ Vaccines 2020 31;5:79. Epub 2020 Aug 31.

Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

[This corrects the article DOI: 10.1038/s41541-020-00215-1.].
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http://dx.doi.org/10.1038/s41541-020-00230-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459277PMC
August 2020

Cytomegalovirus Infection Downregulates Vitamin-D Receptor in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Transplantation 2020 Sep 2. Epub 2020 Sep 2.

Department of Internal Medicine I, Medical University of Vienna, Austria.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with hematological diseases but associated with high mortality and morbidity. Cytomegalovirus (CMV) infection is common in HSCT patients and modulates vitamin D metabolism in vitro. We aimed at validating CMV-associated vitamin D metabolism in vivo in HSCT.

Methods: Patients treated for significant CMV viremia after HSCT were evaluated for CMV load before, during and after antiviral treatment. RNA was isolated from whole blood samples to test for regulation of key components of the vitamin D receptor (VDR) pathway during different phases of CMV viremia.

Results: CMV viremia developed a mean time of 102 (±34) days post HSCT. Maximum levels of CMV-DNA reached a mean of 5668 (±7257) copies/ml. VDR expression was downregulated to a mean of 64.3% (±42.5%) relative to the VDR expression pre-CMV viremia (p=0.035) and lagged in recovery following antiviral treatment. TLR2 mRNA was upregulated to 225.4% during CMV-viremia relative to the expression pre-CMV viremia (p=0.012), but not TLR6/7/8 and the TLR-adaptor protein MyD88. Levels of 25-OH vitamin D were reduced in all viremic patients (48.0 ± 4.8 vs. 25.1 ± 3.7 ng/ml) and were even lower after periods of CMV viremia compared to the control group (48.3 ± 3.5 vs. 17.8 ± 1.8 ng/ml; p=0.008).

Conclusion: CMV viremia is associated with significant dysregulation of vitamin D metabolism in HSCT patients.
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http://dx.doi.org/10.1097/TP.0000000000003448DOI Listing
September 2020

The Global State of Hematopoietic Cell Transplantation for Multiple Myeloma: An Analysis of the Worldwide Network of Blood and Marrow Transplantation Database and the Global Burden of Disease Study.

Biol Blood Marrow Transplant 2020 12 23;26(12):2372-2377. Epub 2020 Aug 23.

Div. of Hematology and Oncology, University of Leipzig, Leipzig, Germany.

Multiple myeloma (MM) is a plasma cell neoplasm characterized by destructive bony lesions, anemia, and renal impairment. Access to effective therapy is limited globally. We report the rates and utilization of hematopoietic cell transplantation (HCT) globally from 2006-2015 to better characterize access to HCT for patients with MM. This was an analysis of a retrospective survey of Worldwide Network of Blood and Marrow Transplant sites, conducted annually between 2006-2015. Incidence estimates were from the Global Burden of Disease study. Outcome measures included total number of autologous and allogeneic HCTs by world regions, and percentage of newly diagnosed MM patients who underwent HCT, calculated by the number of transplants per region in calendar year/gross annual incidence of MM per region. From 2006 to 2015, the number of autologous HCT performed worldwide for MM increased by 107%. Utilization of autologous HCT was highest in Northern America and European regions, increasing from 13% to 24% in Northern America, and an increase from 15% to 22% in Europe. In contrast, the utilization of autologous HCT was lower in the Africa/Mediterranean region, with utilization only changing from 1.8% in 2006 to 4% in 2015. The number of first allogeneic HCT performed globally for MM declined after a peak in 2012 by -3% since 2006. Autologous HCT utilization for MM has increased worldwide in high-income regions but remains poorly utilized in Africa and the East Mediterranean. More work is needed to improve access to HCT for MM patients, especially in low to middle income countries. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767639PMC
December 2020

Association of Country-Specific Socioeconomic Factors With Survival of Patients Who Experience Severe Classic Acute Graft-vs.-Host Disease After Allogeneic Hematopoietic Cell Transplantation. An Analysis From the Transplant Complications Working Party of the EBMT.

Front Immunol 2020 23;11:1537. Epub 2020 Jul 23.

Department of Haematology, Oncology and Internal Medicine, Medical Uniwersity of Warsaw, Warsaw, Poland.

Acute graft-vs.-host disease (aGvHD) is one of the most frequent causes of transplant-related mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). Its treatment is complex and costly. The aim of this study was to retrospectively analyze the impact of country-specific socioeconomic factors on outcome of patients who experience severe aGvHD. Adults with hematological malignancies receiving alloHCT from either HLA-matched siblings ( = 1,328) or unrelated donors ( = 2,824) developing grade 3 or 4 aGvHD were included. In univariate analysis, the probability of TRM at 2 years was increased for countries with lower current Health Care Expenditure (HCE, = 0.04), lower HCE as % of Gross Domestic Product per capita ( = 0.003) and lower values of the Human Development Index ( = 0.02). In a multivariate model, the risk of TRM was most strongly predicted by current HCE (HR = 0.76, = 0.006). HCE >median was also associated with reduced risk of the overall mortality (HR 0.73, = 0.0006) and reduced risk of treatment failure (either relapse or TRM; HR 0.77, = 0.004). We conclude that country-specific socioeconomic factors, in particular current HCE, are strongly associated with survival of patients who experience severe aGvHD.
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http://dx.doi.org/10.3389/fimmu.2020.01537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390847PMC
July 2020

Post-transplant multimorbidity index and quality of life in patients with chronic graft-versus-host disease-results from a joint evaluation of a prospective German multicenter validation trial and a cohort from the National Institutes of Health.

Bone Marrow Transplant 2021 Jan 31;56(1):243-256. Epub 2020 Jul 31.

Outcomes Research Branch, National Institutes of Health, Bethesda, MD, USA.

Comorbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT) impairs quality of life (QoL), physical functioning, and survival. We developed a new standardized measure to capture comorbidity after transplantation, the Post-transplant Multimorbidity Index (PTMI) in a cohort of 50 long term survivors. We subsequently evaluated the content validity and impact on survival and QoL within a multicenter trial, including 208 patients (pts) after alloHSCT, who were prospectively evaluated applying the FACT-BMT, the Human Activity Profile (HAP), the SF-36 v.2, PTMI and the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). The most prevalent comorbidities were compensated arterial hypertension (28.4%), ambulatory infections (25.5%), iron overload (23%), mild renal function impairment (20%), and osteoporosis (13%). Applying the PTMI 13% of patients had no comorbidity, while 37.1% had 1-3 comorbidities, 27.4% had 4-6 comorbidities, and 13.5% had > 6 comorbidities. Chronic graft-versus-host disease (cGvHD) was significantly associated with the PTMI, while age and prior acute GvHD were not. In contrast, the HCT-CI was not associated with the presence of cGvHD. cGvHD was significantly associated with depression (r = 0.16), neurological disease (r = 0.21), osteoporosis (r = 0.18) and nonmelanoma skin cancer (r = 0.26). The PTMI demonstrated strong measurement properties and compared to the HCT-CI captured a wider range of comorbidities associated with cGvHD.
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http://dx.doi.org/10.1038/s41409-020-01017-8DOI Listing
January 2021

Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients.

NPJ Vaccines 2020 24;5:67. Epub 2020 Jul 24.

Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

The aim of this prospective study was to characterize the humoral immune response to TBE vaccination after hematopoietic stem cell transplantation (HSCT). Nineteen adult patients 11-13 months after HSCT and 15 age-matched immunocompetent adults received up to three TBE vaccinations. Antibodies against TBE virus were measured by neutralization test (NT). As primary endpoint, the antibody response (NT titer of ≥10 and at least a twofold increase from baseline 4 weeks after second vaccination) was compared between patients and controls using Fisher exact test. Prior vaccination, 15 (79%) HSCT patients still had detectable neutralizing antibodies. At primary endpoint, the antibody response was significantly lower in patients than in controls (35% versus 93%;  < 0.001). The CD4+ cell count was a predictor for an antibody response in patients ( = 0.019). Interestingly, the majority of HSCT patients still had detectable antibodies prior vaccination. Following vaccination, antibody response in HSCT patients was associated with the CD4+ cell count.
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http://dx.doi.org/10.1038/s41541-020-00215-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381595PMC
July 2020

Real-World Issues and Potential Solutions in Hematopoietic Cell Transplantation during the COVID-19 Pandemic: Perspectives from the Worldwide Network for Blood and Marrow Transplantation and Center for International Blood and Marrow Transplant Research Health Services and International Studies Committee.

Biol Blood Marrow Transplant 2020 12 24;26(12):2181-2189. Epub 2020 Jul 24.

Department of Adult Hematology and Stem Cell Transplant, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

The current COVID-19 pandemic, caused by SARS-CoV-2, has impacted many facets of hematopoietic cell transplantation (HCT) in both developed and developing countries. Realizing the challenges as a result of this pandemic affecting the daily practice of the HCT centers and the recognition of the variability in practice worldwide, the Worldwide Network for Blood and Marrow Transplantation (WBMT) and the Center for International Blood and Marrow Transplant Research's (CIBMTR) Health Services and International Studies Committee have jointly produced an expert opinion statement as a general guide to deal with certain aspects of HCT, including diagnostics for SARS-CoV-2 in HCT recipient, pre- and post-HCT management, donor issues, medical tourism, and facilities management. During these crucial times, which may last for months or years, the HCT community must reorganize to proceed with transplantation activity in those patients who urgently require it, albeit with extreme caution. This shared knowledge may be of value to the HCT community in the absence of high-quality evidence-based medicine. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380217PMC
December 2020

The Role of Immunohistochemical Overexpression of p53 as Adverse Prognostic Factor in Primary Testicular Diffuse Large B Cell Lymphoma.

Pathol Oncol Res 2020 Oct 29;26(4):2831-2833. Epub 2020 Jun 29.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 38D, A-8036, Graz, Austria.

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http://dx.doi.org/10.1007/s12253-020-00864-6DOI Listing
October 2020

Does Offline Beat Inline Treatment: Investigation into Extracorporeal Photopheresis.

Transfus Med Hemother 2020 Jun 27;47(3):198-204. Epub 2020 Mar 27.

Blood Group Serology and Transfusion Medicine, Medical University Graz, Graz, Austria.

Background: Extracorporeal photopheresis is a therapy based on the induction of apoptosis to cells harvested from peripheral blood, followed by direct retransfusion. Currently, there are two approaches: inline procedures, where cell harvesting, 8-methoxypsoralen (8-MOP) incubation, and UV irradiation is performed with a single device, and offline procedures, with collection in one device, followed by 8-MOP incubation/UV irradiation using a second device.

Study Design And Methods: In a prospective crossover study, we compared an inline (Cellex, Therakos) with an established offline procedure (Optia, Terumo, and MacoGenic G2, Macopharma) in 6 patients, focusing on cell composition and apoptosis induction after 24 h. In total, 32 photopheresis treatments per device were performed.

Results: We observed an overall 2-fold higher number of apoptotic "target" cells for each patient with offline treatment. All yields were stratified per patient. Yields were compared as ratio offline/inline for CD3+ (2.5-fold), CD4+ (2-fold), CD8+ (2.8-fold), CD56+ (2.8-fold), CD19+ (1.8-fold), CD15+ (0.5-fold), and CD14+ (2.2-fold) cells. Apoptosis induction was measured after 24 h with Annexin V/7-AAD for early and late apoptosis rates of CD3+ (CD4+, CD8+) and CD56+ cells. CD3+ cells of the inline treatment had an average of 88% (26% early, 62% late) of apoptotic cells compared to 75% (34% early, 41% late) in the offline treatment. Procedure duration ranged from 80 to 100 min inline, with a maximum of 1,500 mL processed blood, and 125-140 min offline, with at least 3,000 mL processed blood, depending on blood flow. Average hematocrit levels of the products were 2.7% inline versus 1.7% offline.

Conclusions: The offline procedure, as established in our department, provides more apoptotic cells for treatment. The increased number of mononuclear cells collected outweighs a slightly reduced apoptosis rate after 24 h in comparison to the inline procedure. Besides this, the final decision for one or the other procedure has to take into account additional aspects, such as peripheral white blood cell count, hematocrit, and weight of the patient, required before apheresis, extracorporeal volume, and, last but not least, overall costs. The final criterion, however, has to be the reported clinical efficacy of the system applied.
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http://dx.doi.org/10.1159/000506750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315144PMC
June 2020

Response to "COVID-19 in persons with haematological cancers".

Leukemia 2020 08 11;34(8):2265-2270. Epub 2020 Jun 11.

Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1038/s41375-020-0914-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289538PMC
August 2020

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT - A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party.

Front Immunol 2020 15;11:586. Epub 2020 Apr 15.

Department of Hematology and Oncology, Medical University of Warsaw, Warsaw, Poland.

Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 μg/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, < 0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.
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http://dx.doi.org/10.3389/fimmu.2020.00586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174614PMC
April 2020

Psychometric properties of the Activities Scale for Kids-performance after allogeneic hematopoietic stem cell transplantation in adolescents and children : Results of a prospective study on behalf of the German-Austrian-Swiss GVHD Consortium.

Wien Klin Wochenschr 2021 Jan 3;133(1-2):41-51. Epub 2020 Apr 3.

St. Anna Children's Hospital, SCT-Outpatient & Aftercare Clinic, Medical University Vienna and Children's Cancer Research Institute, Kinderspitalgasse 15, 1090, Vienna, Austria.

Background: The psychometric properties of an instrument, the Activity Scale for Kids-performance (ASKp), were assessed which was proposed to capture physical functioning after allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, this multicenter observational prospective study investigated the influence of clinical correlates focusing on chronic graft-versus-host disease (cGVHD).

Methods: Patient-reported ASKp, clinician-reported Karnofsky/Lansky status (KPS/PSS), patient characteristics and cGVHD details were assessed of 55 patients with a median age of 12 years at baseline after day +100 post-HSCT and every 3 months during the next 18 months. The psychometric properties were evaluated and ASKp and KPS/PSS status was compared using ANOVAS and multiple regression models.

Results: The German version of the ASKp showed good psychometric properties except for ceiling effects. Discrimination ability of the ASKp was good regarding the need for devices but failed to predict cGVHD patients. Both the ASKp and the KPS/PSS were associated with patients after adoptive cell therapy being in need for devices, suffering from overlap cGVHD and from steroid side effects but not with patients' age and gender. In contrast to the KPS/PSS the ASKp only showed significant differences after merging moderate and severe cGHVD patients when comparing them to No-cGVHD (F = 4.050; p = 0.049), being outperformed by the KPS/PSS (F = 20.082; p < 0.001).

Conclusion: The ASKp showed no clear advantages compared to KPS/PSS even though economical and patients' effort was higher. Further application range may be limited through ceiling effects. Both should be taken into consideration. Therefore, the results may not support the usage of ASKp after HSCT and rather suggest KPS/PSS, both patient and clinician reported.
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http://dx.doi.org/10.1007/s00508-020-01641-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840624PMC
January 2021

Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma.

Hematol Oncol 2020 Aug 7;38(3):277-283. Epub 2020 Mar 7.

Division of Hematology, Department of Internal Medicine, Medical University of Graz (MUG), Austria.

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.
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http://dx.doi.org/10.1002/hon.2727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496545PMC
August 2020

Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation.

Lancet Haematol 2020 Feb;7(2):e157-e167

Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Poland.

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.
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http://dx.doi.org/10.1016/S2352-3026(19)30256-XDOI Listing
February 2020

Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel.

Bone Marrow Transplant 2020 06 22;55(6):1093-1102. Epub 2020 Jan 22.

University Hospital Eppendorf, Hamburg, Germany.

This collaborative initiative aimed to provide recommendations on the use of polyclonal antithymocyte globulin (ATG) or anti-T lymphocyte globulin (ATLG) for the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). A comprehensive review of articles released up to October, 2018 was performed as a source of scientific evidence. Fourteen clinically relevant key questions to the domains indication, administration, and post-transplant management were developed and recommendations were produced using the Delphi technique involving a Panel of 14 experts. ATG/ATLG was strongly recommended as part of myeloablative conditioning regimen prior to matched or mismatched unrelated bone marrow or peripheral blood allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD. ATG/ATLG was also recommended prior to HLA-identical sibling peripheral HSCT with good but lesser bulk of evidence. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG was deemed appropriate to reduce the incidence of acute and chronic GvHD, but a higher risk of relapse should be taken into account. Recommendations regarding dose, application, and premedication were also provided as well as post-transplant infectious prophylaxis and vaccination. Overall, these recommendations can be used for a proper and safe application of polyclonal ATG/ATLG to prevent GvHD after allogeneic HSCT.
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http://dx.doi.org/10.1038/s41409-020-0792-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269907PMC
June 2020

Pre-transplantation Risks and Transplant-Techniques in Haematopoietic Stem Cell Transplantation for Acute Leukaemia.

EClinicalMedicine 2019 Oct 9;15:33-41. Epub 2019 Aug 9.

Department of Biomedical Data Sciences, Section Medical Statistics, Leiden University Medical Centre, Leiden, the Netherlands.

Background: The role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres.

Methods: This Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1-75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome.

Findings: Treatment groups differed significantly from baseline population (p < 0.001), and within groups regarding patient-, disease-, donor-, and centre-related pre-transplantation risk factors (p < 0.001); choice of technique did depend on pre-transplantation risk factors and centre (p < 0.001). Probability of overall survival at 5 years decreased systematically and significantly with increasing pre-transplantation risk score (score 2 vs 0/1 HR: 1·2, 95% c.i. [1·1-1·.3], p = 0.002; score 3 vs 0/1 HR: 1·5, 95% c.i. [1·3-1·7], p < 0.001; score 4/5/6 vs 0/1 HR: 1·9, 95% c.i. [1·6-2·2], p < 0.001) with no significant differences between treatment groups (likelihood ratio test on interaction: p = 0.40). Overall survival was significantly associated with selection steps and completeness of information (p < 0.001).

Interpretation: Patients' pre-transplantation risk factors determine survival, independent of transplant techniques. Transplant techniques should be regarded as centre policy, not stratification factor in benchmarking. Selection criteria and completeness of data bias outcome. Outcomes may be improved more effectively through better identifying pre-transplantation factors as opposed to refinement of transplant techniques.

Funding: The study was funded by EBMT.
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http://dx.doi.org/10.1016/j.eclinm.2019.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833359PMC
October 2019

Association of uric acid levels before start of conditioning with mortality after allogeneic hematopoietic stem cell transplantation - a prospective, non-interventional study of the EBMT Transplant Complication Working Party.

Haematologica 2020 Jul 10;105(7):1977-1983. Epub 2019 Oct 10.

Medical University of Warsaw, Warsaw, Poland.

Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation (alloSCT) derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft--host disease (GvHD). In a clinical pilot trial, peri-transplant uric acid depletion reduced acute GvHD incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with alloSCT outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling alloSCT from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 alloSCT recipients. There were no significant differences in terms of baseline comorbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from the remaining in terms of acute GvHD grades II-IV incidence (Hazard ratio [HR] 1.5, 95% Confidence interval [CI]: 1.0-2.4, =0.08). However, they had significantly shorter overall survival (HR 2.8, 95% CI: 1.7-4.7, <0.0001) and progression free survival (HR 1.6, 95% CI: 1.1-2.4, =0.025). Non-relapse mortality was significantly increased in alloSCT recipients with high uric acid levels (HR 2.7, 95% CI: 1.4-5.0, =0.003). Finally, the incidence of relapse after alloSCT was increased in patients with higher uric acid levels (HR 1.6, 95% CI: 1.0-2.5, =0.04). We conclude that high uric acid levels before the start of conditioning correlate with increased mortality after alloSCT.
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http://dx.doi.org/10.3324/haematol.2019.228668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327652PMC
July 2020

The role of germline mutation profiling in the selection of related donors for haematopoietic stem cell transplantation.

Bone Marrow Transplant 2020 07 25;55(7):1502-1505. Epub 2019 Sep 25.

Division of Haematology, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1038/s41409-019-0691-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334040PMC
July 2020

The -Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro.

Int J Mol Sci 2019 Sep 24;20(19). Epub 2019 Sep 24.

Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria.

In tumor cells of more than 20 different cancer types, the -axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the -axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of expression and lymphoma infiltration rate as well as a reduction of expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the -axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.
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http://dx.doi.org/10.3390/ijms20194740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801866PMC
September 2019

National Institutes of Health-Defined Chronic Graft-vs.-Host Disease in Pediatric Hematopoietic Stem Cell Transplantation Patients Correlates With Parameters of Long-Term Immune Reconstitution.

Front Immunol 2019 27;10:1879. Epub 2019 Aug 27.

Children's Cancer Research Institute, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.

Recent data revealed the importance of immune reconstitution (IR) for the evaluation of possible biomarkers in National Institutes of Health (NIH)-defined chronic graft-vs.-host disease (cGVHD) and its clinical aspects. In this large pediatric study ( = 146), we have analyzed whether cellular and humoral parameters of IR in the long-term follow-up (FU) with a special emphasis on B-cell reconstitution correlate with NIH-defined cGVHD criteria. HYPOTHESIS: we were especially interested in whether meaningful cGVHD biomarkers could be defined in a large pediatric cohort. We here demonstrate for the first time in a highly homogenous pediatric patient cohort that both cGVHD ( = 38) and its activity were associated with the perturbation of the B-cell compartment, including low frequencies of CD19CD27 memory B-cells and increased frequencies of circulating CD19CD21 B-cells, a well-known hyperactivated B-cell subset frequently found elevated in chronic infection and autoimmunity. Notably, resolution of cGVHD correlated with expansion of CD19CD27 memory B-cells and normalization of CD19CD21 B-cell frequencies. Moreover, we found that the severity of cGVHD had an impact on parameters of IR and that severe cGVHD was associated with increased CD19CD21 B-cell frequencies. When comparing the clinical characteristics of the active and non-active cGVHD patients (in detail at time of analyses), we found a correlation between activity and a higher overall severity of cGVHD, which means that in the active cGVHD patient group were more patients with a higher disease burden of cGVHD-despite similar risk profiles for cGVHD. Our data also provide solid evidence that the time point of analysis regarding both hematopoietic stem cell transplantation (HSCT) FU and cGVHD disease activity may be of critical importance for the detailed investigation of pediatric cohorts. Finally, we have proven that the differences in risk factors and patterns of IR, with cGVHD as its main confounding factor, between malignant and non-malignant diseases, are important to be considered in future studies aiming at identification of novel biomarkers for cGVHD.
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http://dx.doi.org/10.3389/fimmu.2019.01879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718560PMC
October 2020

Worldwide Network for Blood and Marrow Transplantation (WBMT) perspective: the role of biosimilars in hematopoietic cell transplant: current opportunities and challenges in low- and lower-middle income countries.

Bone Marrow Transplant 2020 04 4;55(4):698-707. Epub 2019 Sep 4.

Hematology Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Health care costs attributed to biologics have increased exponentially in the recent years, thus biosimilars offer a possible solution to limit costs while maintaining safety and efficacy. Reducing expenditure is vital to health care especially in developing countries where affordability and access to health care is a major challenge. We discuss the opportunities and the challenges of biosimilars in the field of hematopoietic cell transplantation (HCT) in low- and lower-middle income countries. Developing countries can potentially invest in the forecasted costs reduction by utilizing biosimilars. This can be used to decrease the costs of procedures such as HCT, which is a rapidly growing field in many developing regions. The introduction of biosimilars in the developing regions faces many challenges which include, but are not limited to: legal and regulatory issues, lack of research infrastructure, and the presence of educational barriers. Thus, collaborative efforts are needed to ensure an effective and safe introduction of biosimilars into low- and lower-middle income countries.
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http://dx.doi.org/10.1038/s41409-019-0658-2DOI Listing
April 2020