Publications by authors named "Mats Remberger"

139 Publications

Cytokine levels following allogeneic hematopoietic cell transplantation: a match-pair analysis of home care versus hospital care.

Int J Hematol 2021 Feb 5. Epub 2021 Feb 5.

Translational Cell Therapy Research Group (TCR), Department of Pediatrics, CLINTEC, Karolinska Institutet, Kliniskt Forskningscentrum, KFC, NOVUM Plan 6, Hälsovägen 7-9, 141 57, Huddinge, Sweden.

Following allogeneic hematopoietic cell transplantation (HCT), patients living near the hospital were treated at home instead of in isolation in the hospital. We analyzed cytokines using Luminex assays for the first 3 weeks after HCT and compared patients treated at home (n = 42) with matched patients isolated in the hospital (n = 37). In the multivariate analysis, patients treated at home had decreased GM-CSF, IFN-γ (p < 0.01), IL-13, IL-5 (p < 0.05), and IL-2 (p < 0.07). Bloodstream infections, anti-thymocyte globulin, G-CSF treatment, immunosuppression, reduced-intensity conditioning (RIC), related vs. unrelated donors, and graft source affected various cytokine levels. When patients with RIC were analyzed separately, home care patients had reduced G-CSF (p = 0.04) and increased vascular endothelial growth factor (VEGF, p = 0.001) at 3 weeks compared with hospital care patients. Patients with low GM-CSF (p < 0.036) and low IFNγ (p = 0.07) had improved survival. Acute GVHD grades III-IV was seen in 7% and 16% of home care and hospital care patients, respectively. One-year transplantation-related mortality was 7% and 16% and survival at 5 years was 69% and 57% in the two groups, respectively. To conclude, patients treated in the hospital showed varying increased levels of GM-CSF, IFN-γ, IL-13, G-CSF, IL-5, and IL-2 and decreased VEGF, which may contribute to acute GVHD.
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http://dx.doi.org/10.1007/s12185-021-03087-wDOI Listing
February 2021

Real-world study of direct medical and indirect costs and time spent in healthcare in patients with chronic graft versus host disease.

Eur J Health Econ 2021 Feb 4;22(1):169-180. Epub 2020 Dec 4.

Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

Chronic graft versus host disease (cGVHD) is a debilitating and costly complication following haemopoietic stem cell transplantation (HSCT). This study describes the economic burden associated with cGVHD. Direct costs associated with specialised healthcare utilisation (inpatient admissions and outpatient visits), as well as indirect costs associated with sickness absence-associated productivity loss were estimated in patients who underwent allogeneic HSCT in Sweden between 2006 and 2015, linking population-based health and economic registers. To capture the period of chronic GVHD, patients were included who survived > 182 days post-HSCT (start of follow-up), and cGVHD was classified based on patient treatment records to correct for any diagnosis underreporting. Patients were classified as 'non-cGVHD' if they received no immunosuppressive treatment, 'mild cGVHD' if they received only systemic corticosteroid treatment or immunosuppressive treatment, or 'moderate-severe cGVHD' if they received extracorporeal photopheresis (ECP) only, corticosteroid treatment and immunosuppressive treatment, or systemic corticosteroid treatment and ECP treatments. Patients with moderate-severe cGVHD spent more time in healthcare, had higher healthcare resource costs and higher sickness absence-related productivity loss compared to patients with non- or mild cGVHD. The cumulative total costs during the first 3 years of follow-up were EUR 14,887,599, EUR 20,544,056, and EUR 47,811,835 for non-, mild, and moderate-severe groups, respectively. The long-term costs incurred with cGVHD following HSCT continue to be very high and significantly impacted by cGVHD severity. This study adds real-world health resource and economic insight relevant for policy-makers and healthcare providers when considering the clinical challenge of balancing immunosuppression to reduce cGVHD.
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http://dx.doi.org/10.1007/s10198-020-01249-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822787PMC
February 2021

Mesothelin Expression in Patients with High-Grade Serous Ovarian Cancer Does Not Predict Clinical Outcome But Correlates with CD11c Expression in Tumor.

Adv Ther 2020 12 14;37(12):5023-5031. Epub 2020 Oct 14.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Introduction: Mesothelin (MSLN) is overexpressed in several tumors including ovarian cancer and is the target of current trials. There is limited and conflicting data on MSLN prognostic impact in ovarian cancer.

Methods: We performed a retrospective study on patients with high-grade serous ovarian cancer, analyzing MSLN expression by immunohistochemistry and examining the correlation of its expression to overall and progression-free survival. Correlations of expression of MSLN, CD8, and macrophage markers in different tumor compartments were also investigated.

Results: Positive MSLN expression was detected in 55.1% of primary tumors and 51.5% of the metastases. MSLN expression was not correlated with survival. We observed a significant positive correlation (r = 0.34, p = 0.01) between MSLN expression in the metastatic site and CD11c expression in total tumor area and perivascular area in the primary tumor.

Conclusion: Our results show that MSLN expression does not correlate with clinical outcome. The impact of the correlation between MSLN and CD11c cells on immunotherapy outcome should be further explored.
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http://dx.doi.org/10.1007/s12325-020-01520-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595982PMC
December 2020

Oral mucositis after tacrolimus/sirolimus or cyclosporine/methotrexate as graft-versus-host disease prophylaxis.

Oral Dis 2020 Oct 4. Epub 2020 Oct 4.

Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.

Objectives: To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft-versus-host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following haematopoietic stem cell transplantation.

Subjects And Methods: The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68 to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak and duration of oral mucositis from the day -3 to day 24 post-transplant.

Results: Eighty-seven patients developed oral mucositis in the first 24 days post-transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post-transplant, no significant difference compared with the Tac/Sir group was found.

Conclusions: The introduction of tacrolimus/sirolimus as a graft-versus-host disease prophylaxis in haematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate.
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http://dx.doi.org/10.1111/odi.13663DOI Listing
October 2020

High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis.

Leuk Lymphoma 2020 12 25;61(13):3198-3208. Epub 2020 Jul 25.

Department of Medicine, Division of Medical Oncology and Hematology, University of Toronto, Toronto, ON, Canada.

We explore risk factors and impacts of post-transplant EBV-Reactivation (EBV-R) and PTLD in 270 patients that underwent RIC alloHCT using ATG-PTCy and cyclosporine for GVHD prophylaxis. Twenty-five (12%) patients had probable ( = 7) or proven ( = 18) PTLD. Patients were managed with reduction of immunosuppression and 22 with weekly rituximab (375 mg/m IV). ORR was 84%; 8 (32%) recipients died, and one-year OS and NRM of patients with PTLD was 59.7% and 37%, respectively. One hundred seventy-two (63.7%) recipients had EBV-R. One-year OS and RFS of patients with EBV-R were 68.2% and 60.6%, and of EBV-Negative patients were 62.1% and 50.1%, respectively. High incidence but low mortality of EBV-R and PTLD was documented. EBV-R induced a protective effect on RFS in multivariable analysis (HR 0.91,  = .011). Therefore, EBV-R may have a protective effect on RFS in this setting. Further research is necessary to evaluate the interplay of EBV-R, immune reconstitution, and post-transplant outcomes.
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http://dx.doi.org/10.1080/10428194.2020.1797010DOI Listing
December 2020

Histopathological Grading of Oral Mucosal Chronic Graft-versus-Host Disease: Large Cohort Analysis.

Biol Blood Marrow Transplant 2020 10 10;26(10):1971-1979. Epub 2020 Jul 10.

Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden.. Electronic address:

Graft-versus-host disease (GVHD) can manifest as acute or chronic complications in patients after hematopoietic cell transplantation (HCT). Oral chronic GVHD (cGVHD) occurs in approximately 70% of HCT recipients and includes lichenoid-like mucosal reactions, restricted mouth opening, and salivary gland dysfunction. However, the underlying histopathological presentation remains to be validated in large cohorts. We characterized the histopathological features of oral mucosal cGVHD and devised a scoring model in a large patient cohort (n = 112). Oral mucosal biopsy sections (n = 303) with and without oral cGVHD were identified from archived and current HCT recipients with additional healthy controls. Histological screening was performed on hematoxylin and eosin-stained and periodic acid-Schiff-stained sections. A points-based grading tool (0 to 19, grade 0 to IV) was established based on intraepithelial lymphocytes and band-like inflammatory infiltrate, atrophic epithelium with basal cell liquefaction degeneration, including apoptosis, as well as separation of epithelium and pseudo-rete ridges. Validation involved 62 biopsy specimens, including post-HCT (n = 47) and healthy (n = 15) specimens. Remaining biopsy specimens (n = 199) were blindly graded by 3 observers. Histological severity was correlated with clinical diagnostic and distinctive features, demonstrating a spectrum of individual patient severity, including frequent signs of subclinical GVHD in healthy mucosa. However, oral cGVHD presented with significantly higher (P < .001) scores compared with HCT controls, with moderate to high positive likelihood ratios for inflammatory infiltrate, exocytosis, and basal membrane alterations. The grade II-IV biopsy specimens demonstrated a histopathological diagnosis of active mucosal lichenoid-like cGVHD, highlighting the importance of correlating clinical presentation with the dynamic histopathological processes for improved patient stratification. In addition, this tool could be used for assessing treatments, pathological processes, and immune cellular content to provide further insight into this debilitating disease.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.031DOI Listing
October 2020

Multicenter evaluation of parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

Am J Transplant 2020 08 6;20(8):2198-2205. Epub 2020 Mar 6.

Department of Radiology, Michigan Medicine, Ann Arbor, Michigan.

Parametric response mapping (PRM) is a novel computed tomography (CT) technology that has shown potential for assessment of bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). The primary aim of this study was to evaluate whether variations in image acquisition under real-world conditions affect the PRM measurements of clinically diagnosed BOS. CT scans were obtained retrospectively from 72 HCT recipients with BOS and graft-versus-host disease from Fred Hutchinson Cancer Research Center, Karolinska Institute, and the University of Michigan. Whole lung volumetric scans were performed at inspiration and expiration using site-specific acquisition and reconstruction protocols. PRM and pulmonary function measurements were assessed. Patients with moderately severe BOS at diagnosis (median forced expiratory volume at 1 second [FEV1] 53.5% predicted) had similar characteristics between sites. Variations in site-specific CT acquisition protocols had a negligible effect on the PRM-derived small airways disease (SAD), that is, BOS measurements. PRM-derived SAD was found to correlate with FEV1% predicted and FEV1/ forced vital capacity (R = -0.236, P = .046; and R = -0.689, P < .0001, respectively), which suggests that elevated levels in the PRM measurements are primarily affected by BOS airflow obstruction and not CT scan acquisition parameters. Based on these results, PRM may be applied broadly for post-HCT diagnosis and monitoring of BOS.
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http://dx.doi.org/10.1111/ajt.15814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395854PMC
August 2020

Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan-Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation.

Clin Transl Sci 2020 03 6;13(2):293-300. Epub 2019 Nov 6.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan (Bu) and cyclophosphamide before allogeneic HSCT during 1990-2015. Patients' supportive care was changed in order to reduce the regimen-related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of Bu was initiated in 2000, and the use of liver supportive drugs, such as ursodeoxycholic acid and N-acetyl-L-cysteine, were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995-1999 (16.2%) compared with 2.3% during 2010-2015. Overall survival for patients with SOS was 62%, 46%, and 27% at 100 days, 1 year, and 5 years after HSCT, respectively, compared with 92%, 77%, and 66% for those who did not develop SOS (P < 0.001). In conclusion, the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and, hence, improve the clinical outcome.
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http://dx.doi.org/10.1111/cts.12709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070785PMC
March 2020

Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation.

Vox Sang 2019 Oct 11;114(7):769-777. Epub 2019 Aug 11.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Background And Objectives: Mucositis is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is caused by a combination of conditioning-induced mucosal damage and severe neutropenia. The symptoms include oral and abdominal pain, inability to swallow food and fluids, and severe diarrhoea. Severe mucositis is associated with increased risk of Graft-versus-Host disease and infection. Granulocyte transfusions (GCX) could be a treatment option, and our objective was to study its feasibility and potential benefits.

Material And Methods: This retrospective, single-centre study included 30 patients receiving GCX because of severe oral mucositis after HSCT during 2005-2017. Clinical outcome, response to GCX, change in opiate administration and adverse events were studied.

Results: Twenty-seven patients received GCX from donors pre-treated with steroids and G-CSF, and three from donors pre-treated with steroids only. Overall response was 83% (24/29 evaluable patients). Fifteen patients reached a complete response. In 14 of 24 responders, a reduction of the administration of opiate pain relief was seen. In eight patients this reduction was ≥50% of the dose. Adverse events (AEs) were reported in 14 cases, and were mild to moderate, and well manageable with symptomatic treatment. No life-threatening or fatal AEs were recorded.

Conclusions: These results indicate that GCX could be a safe and effective treatment for oral mucositis after HSCT with the potential to reduce the necessity of opiate analgesic treatment in this disorder. No severe AEs were seen in this study, but the risk for severe pulmonary AEs after GCX needs to be considered.
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http://dx.doi.org/10.1111/vox.12835DOI Listing
October 2019

Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting.

Biol Blood Marrow Transplant 2019 09 6;25(9):1770-1778. Epub 2019 Jun 6.

Division of Hematology, Department of Medicine, Karolinska Institute, Stockholm, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Secondary AML (s-AML), including AML with an antecedent hematologic disorder (AHD-AML) and therapy-related AML (t-AML), constitutes a large proportion of patients with AML and is considered to confer a dismal prognosis. The role of allogeneic hematopoietic cell transplantation (HCT) in patients with s-AML and the extent to which HCT is performed in these patients has been little studied to date. We used the population-based Swedish AML Registry comprising 3337 intensively treated adult patients over a 17-year period to study the role of HCT within the group of patients with s-AML as well as compared with patients with de novo AML. HCT was performed in 576 patients (22%) with de novo AML, in 74 patients (17%) with AHD-AML, and in 57 patients (20%) with t-AML. At 5 years after diagnosis, there were no survivors among patients with previous myeloproliferative neoplasms who did not undergo HCT, and corresponding survival for patients with antecedent myelodysplastic syndromes and t-AML was and 2% and 4%, respectively. HCT was compared with chemotherapy consolidation in s-AML using 3 models: (1) a 200-day landmark analysis, in which HCT was favorable compared with conventional consolidation (P = .04, log-rank test); (2) a multivariable Cox regression with HCT as a time-dependent variable, in which the hazard ratio for mortality was 0.73 (95% confidence interval, 0.64 to 0.83) for HCT and favored HCT in all subgroups; and (3) a propensity score matching analysis, in which the 5-year overall survival (OS) and relapse-free survival in patients with s-AML in first complete remission (CR1) was 48% and 43%, respectively, for patients undergoing HCT versus 20% and 21%, respectively, for those receiving chemotherapy consolidation (P = .01 and .02, respectively, log-rank test). Our observational data suggest that HCT improves survival and offers the only realistic curative treatment option in patients with s-AML.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.038DOI Listing
September 2019

Long-Term Follow-Up of a Pilot Study Using Placenta-Derived Decidua Stromal Cells for Severe Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2019 10 4;25(10):1965-1969. Epub 2019 Jun 4.

Translational Cell Therapy Research, Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institute, Huddinge, Sweden.

There is a need for effective therapy with few side effects for severe acute graft-versus-host disease (GVHD). The placenta protects the fetus from the mother's haploidentical immune system during pregnancy. We found that maternal stromal cells from the fetal membrane, so-called decidua stromal cells (DSCs), are more immunosuppressive than other sources of stromal cells. We prospectively treated 21 patients (median age, 49 years; range, 1.6 to 72 years) for grade II-IV acute GVHD. All 21 patients had biopsy-proven gastrointestinal GVHD. The majority of patients were either steroid-refractory or had progressive GVHD, 11 patients after >7 days or with progression after 3 days, and 10 were refractory to steroids after >3 days. We used an improved protocol in which DSCs were thawed and infused in a buffer with 5% human albumin. DSCs were given at a median dose of 1.2 (range, 0.9 to 2.9) × 10 cells/kg body weight with a median of 2 (range, 1 to 6) doses, given 1 week apart. The median viability of thawed DSCs was 93% (range, 69% to 100%), and the median cell passage number was 4 (range, 2 to 4). Complete resolution of GVHD was seen in 11 patients, with a partial response in the other 10. The cumulative incidence of chronic GVHD was 52%. GVHD was mild in 6 patients, moderate in 4 patients, and severe in 1 patient based on National Institutes of Health chronic GVHD severity scoring. Nine patients died, including 3 from relapse and 1 each from acute GVHD and septicemia, Zygomycetes infection, liver insufficiency, cerebral hemorrhage, multiple organ failure, and chronic GVHD with obstructive bronchiolitis. Four-year transplantation-related mortality was 28.6%, and overall survival was 57%. Survival was similar (P = .33) to that for all 293 patients who underwent allogeneic hematopoietic cell transplantation during the same period (2012 to 2015), with 66% overall survival. DSC infusion is a novel therapy for acute GVHD grade II-IV, and a randomized trial is currently underway (ClinicalTrials.gov NCT02172937).
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http://dx.doi.org/10.1016/j.bbmt.2019.05.034DOI Listing
October 2019

Higher response rates in patients with severe chronic skin graft-versus-host disease treated with extracorporeal photopheresis.

Cent Eur J Immunol 2019 15;44(1):84-91. Epub 2019 Apr 15.

Department of Clinical Immunology and Transfusion Medicine, Karolinska University Laboratory, Stockholm, Sweden.

Introduction: Different forms of graft-versus-host disease (GVHD) remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The prognosis for steroid-refractory chronic GVHD (cGVHD) remains poor. Our aim was to evaluate extracorporeal photopheresis (ECP) treatment in cGVHD patients with different organ involvement to detect subgroups of patients with the best response.

Material And Methods: Thirty-four patients who underwent HSCT and developed moderate (n = 7) or severe (n = 27) steroid-refractory or steroid-dependent cGVHD treated with ECP were included in the analysis. A matched cGVHD control patient group untreated with ECP was collected for comparison.

Results: Compared to the control group and the stable/progressive disease (SD/PD) patients, individuals with complete/partial remission have higher overall survival and lower transplant-related mortality. Furthermore, patients with complete and partial remission (CR/PR) had significantly higher levels of albumin and platelets after ECP treatment compared to patients with stable or progressive cGVHD (SD/PD). Corticosteroid treatment and other immunosuppressive agents could successfully be tapered in the CR/PR group compared to the SD/PD patients. In this study patients with skin cGVHD are those with the highest rate of CR/PR after ECP treatment.

Conclusions: Our results suggest that ECP treatment is safe and effective for patients with predominantly skin, oral and liver cGVHD.
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http://dx.doi.org/10.5114/ceji.2018.75831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526584PMC
April 2019

The importance of graft cell composition in outcome after allogeneic stem cell transplantation in patients with malignant disease.

Clin Transplant 2019 06 7;33(6):e13537. Epub 2019 May 7.

Department of Clinical Research Center, Karolinska Institute, Stockholm, Sweden.

Background: Graft-versus-host disease (GVHD) and relapse remain majobstacles ftreatment success in allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, we evaluated the immune cell profile of the graft to outcome after HSCT.

Study Design And Method: Flow cytometry data of graft cell subsets [CD34 , CD3 , CD19 , CD4 , CD8 , CD3-CD56 CD16 , CD4 CD127 CD25 ] from G-CSF primed peripheral blood stem cell (PBSC) donors was collected retrospectively from 299 patients with hematological malignancies undergoing HSCT between 2006 and 2013. The association to overall survival, transplant-related mortality (TRM), GVHD and probability of relapse was analyzed. Patients outcome from HLA-identical sibling (Sib) (n = 97) and unrelated donors (URD) (n = 202) were analyzed separately as all URD patients received anti-thymocyte globulin (ATG).

Results: Five-year overall survival was similar in the two cohorts (68% (Sib) vs 65% (URD)). The relapse incidence was significantly lower in the Sib cohort (24% vs 35%, P = 0.04). Multivariate analysis in the URD group revealed an association between a higher CD8 dose and less relapse (HR, 0.94; 95%CI, 0.90-0.98; P = 0.006) as well as an association between higher CD34 dose and both higher TRM (HR, 1.09; 95%CI, 1.02-1.20; P = 0.02) and relapse (HR, 1.09; 95%CI, 1.01-1.17; P = 0.025). The Sib analysis showed an association between a higher graft CD19 dose and more severe acute GVHD (HR, 1,09; 95%CI, 1.03-1.15; P = 0.003) and TRM (HR, 1.09; 95%CI, 1.01-1.17; P = 0.036). In addition, a higher CD4 graft content was associated to an increased risk for chronic GVHD (HR, 1.02; 95%CI 1.00-1.04; P = 0.06).

Conclusion: These data indicate an importance of PBSC dongraft composition in patients with a hematological malignancy.
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http://dx.doi.org/10.1111/ctr.13537DOI Listing
June 2019

Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 06 30;25(6):1260-1268. Epub 2019 Jan 30.

Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden.

Lymphocyte reconstitution is pivotal for successful long-term outcome after allogeneic hematopoietic stem cell transplantation (HSCT), and conditioning regimen and post-transplantation immunosuppression are risk factors for prolonged immunodeficiency. Nevertheless, the effects of different immunosuppressive protocols on lymphocyte output and replicative capacity have not been investigated. Here we assessed T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and T cell telomere length (TL) as proxy markers for immune reconstitution in patients in a prospective randomized trial comparing graft-versus-host disease (GVHD) prophylaxis after transplantation (cyclosporine/methotrexate versus tacrolimus/sirolimus; n = 200). Results showed that medians of TREC, KREC, and TL were not significantly different between the prophylaxis groups at any assessment time point during follow-up (24 months), but the kinetics of TREC, KREC, and TL were significantly influenced by other transplantation-related factors. Older recipient age, the use of antithymocyte globulin before graft infusion, and use of peripheral blood stem cell grafts were associated with lower TREC levels, whereas acute GVHD transiently affected KREC levels. Patients with lymphocyte excision circle levels above the median at ≤6 months post-transplantation had reduced transplantation-related mortality and superior 5-year overall survival (P < .05). We noticed significant T cell telomere shortening in the patient population as a whole during follow-up. Our results suggest that lymphocyte reconstitution after transplantation is not altered by different immunosuppressive protocols. This study has been registered at ClinicalTrials.gov (identifier: NCT00993343).
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http://dx.doi.org/10.1016/j.bbmt.2019.01.029DOI Listing
June 2019

The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Inherited Diseases Is Influenced by HLA Match, Year of Transplantation, and Immunized Female Donor.

Transplantation 2019 06;103(6):1247-1252

Translational Cell Therapy Research, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

Background: For many inborn errors of metabolism (IEM), allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure.

Methods: We report the outcome in 160 patients with inherited diseases, who were treated with HSCT in 3 decades. Median age was 3 years (range 0.1-63). Grafts were from matched related donors (MRDs, 56), matched unrelated donors (MUDs, 66), or HLA-mismatched donors (38).

Results: Graft failure (GF) occurred in 26 patients (16%), severe acute graft-versus-host disease (GVHD) in 9 (6%), and chronic GVHD in 23 (12%). Ten-year survival was 64% before the year 2000 and 86% after that (P = 0.01). Ten-year survival for MRD grafts was 90%, as opposed to 79% for MUD grafts and 56% for HLA-mismatched grafts (P = 0.03). In multivariate analysis, GF was associated with having an HLA-mismatched donor (P < 0.05) or MUD (P = 0.015) and with reduced-intensity conditioning (P < 0.01). Death was associated with year of transplant (P = 0.015), having an HLA-mismatched donor (P < 0.001), and being a male recipient from an immune female donor (P = 0.05).

Conclusions: The outcome after HSCT for IEM depends on HLA match, year and immune female donor.
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http://dx.doi.org/10.1097/TP.0000000000002481DOI Listing
June 2019

Continuous Immune Cell Differentiation Inferred From Single-Cell Measurements Following Allogeneic Stem Cell Transplantation.

Front Mol Biosci 2018 12;5:81. Epub 2018 Sep 12.

Unit of Clinical Pediatrics, Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

The process of immune system regeneration after allogeneic stem cell transplantation is slow, complex, and insufficiently understood. An entire immune system with all of its cell populations must regenerate from infused donor hematopoietic stem cells over the course of weeks and months post-transplantation. Both innate and adaptive arms of the immune system differ in their capacity and speed to reconstitiute in the recipient, which contributes to inadequacy in global immunity during the delayed reconstitution period. Systems-level analyses of immune systems in human patients have been made possible by high-throughput and high-dimensional, state-of-the-art, single-cell methodologies such as mass cytometry. Mass cytometry has revolutionized our ability to comprehensively profile all immune cell populations simultaneously in blood or tissue samples, providing signatures of differentially regulated cells in a range of clinical conditions. Such kind of systems immunology analyses promise not only for more accurate descriptions of variation between patients but also within individual patients over time, inter-dependencies between cell populations and the inference of developmental trajectories for specific cell populations. Here, we took advantage of a recently performed longitudinal mass cytometry analysis in 26 patients with hematological malignancies followed during the first 12 months following allogeneic stem cell transplantation. We present a proof-of-principle analysis to understand the evolution of individual immune cell populations. By applying non-linear dimensionality reduction and feauture extraction algorithms, we infer trajectories for individual immune cell populations, and map continuous marker expression changes occuring during immune cell regeneration that add novel information about this developmental process.
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http://dx.doi.org/10.3389/fmolb.2018.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143687PMC
September 2018

The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation.

Sci Rep 2018 05 29;8(1):8293. Epub 2018 May 29.

ECM, KFC, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity. NAC does not interfere with the busulphan myeloablative effect. We investigated the effect of NAC concomitant treatment during busulphan conditioning on the liver enzymes as well as the clinical outcome. Prophylactic NAC treatment was given to 54 patients upon the start of busulphan conditioning. These patients were compared with 54 historical matched controls who did not receive NAC treatment. In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were significantly (P < 0.05) decreased after conditioning compared to their start values. Within the NAC-group, liver enzymes were normalized in those patients (30%) who had significantly high start values. No significant decrease in enzyme levels was observed in the control group. Furthermore, NAC affected neither Bu kinetics nor clinical outcome (sinusoidal obstruction syndrome incidence, graft-versus-host disease and/or graft failure).

In Conclusion: NAC is a potential prophylactic treatment for hepatotoxicity during busulphan conditioning. NAC therapy did not alter busulphan kinetics or affect clinical outcome.
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http://dx.doi.org/10.1038/s41598-018-26033-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974141PMC
May 2018

Reduced intensity conditioning increases risk of severe cGVHD: identification of risk factors for cGVHD in a multicenter setting.

Med Oncol 2018 Apr 25;35(6):79. Epub 2018 Apr 25.

Division of Hematology, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Aim is to identify risk factors for the development of cGVHD in a multicenter setting. Patients transplanted between 2000 and 2006 were analyzed (n = 820). Donors were HLA-identical siblings (57%), matched unrelated donors (30%), and HLA-A, B or DR antigen mismatched (13%). Reduced intensity conditioning (RIC) was given to 65% of patients. Overall incidence of cGVHD was 46% for patients surviving more than 100 days after HSCT (n = 747). Older patient age [HR 1.15, p < 0.001], prior acute GVHD [1.30, p = 0.024], and RIC [1.36, p = 0.028] increased overall cGVHD. In addition, RIC [4.85, p < 0.001], prior aGVHD [2.14, p = 0.001] and female donor to male recipient [1.80, p = 0.008] increased the risk of severe cGVHD. ATG had a protective effect for both overall [0.41, p < 0.001] and severe cGVHD [0.20, p < 0.001]. Relapse-free survival (RFS) was impaired in patients with severe cGVHD. RIC, prior aGVHD, and female-to-male donation increase the risk of severe cGVHD. ATG reduces the risk of all grades of cGVHD without hampering RFS. GVHD prophylaxis may be tailored according to the risk profile of patients.
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http://dx.doi.org/10.1007/s12032-018-1127-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918523PMC
April 2018

Cytomegalovirus-Specific CD8+ T-Cells With Different T-Cell Receptor Affinities Segregate T-Cell Phenotypes and Correlate With Chronic Graft-Versus-Host Disease in Patients Post-Hematopoietic Stem Cell Transplantation.

Front Immunol 2018 10;9:760. Epub 2018 Apr 10.

Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden.

Virus-specific T-cell responses are crucial to control cytomegalovirus (CMV) infections/reactivation in immunocompromised individuals. Adoptive cellular therapy with CMV-specific T-cells has become a viable treatment option. High-affinity anti-viral cellular immune responses are associated with improved long-term immune protection against CMV infection. To date, the characterization of high-affinity T-cell responses against CMV has not been achieved in blood from patients after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, the purpose of this study was to describe and analyze the phenotype and clinical impact of different CMV-specific CD8+ cytotoxic T-lymphocytes (CMV-CTL) classes based on their T-cell receptor (TCR) affinity. T-cells isolated from 23 patients during the first year following HSCT were tested for the expression of memory markers, programmed cell death 1 (PD-1), as well as TCR affinity, using three different HLA-A*02:01 CMV-Pp65 tetramers (wild-type, a245v and q226a mutants). High-affinity CMV-CTL defined by q226a tetramer binding, exhibited a higher frequency in CD8+ T-cells in the first month post-HSCT and exhibited an effector memory phenotype associated with strong PD-1 expression as compared to the medium- and low-affinity CMV-CTLs. High-affinity CMV-CTL was found at higher proportion in patients with chronic graft-versus-host disease ( < 0.001). This study provides a first insight into the detailed TCR affinities of CMV-CTL. This may be useful in order to improve current immunotherapy protocols using isolation of viral-specific T-cell populations based on their TCR affinity.
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http://dx.doi.org/10.3389/fimmu.2018.00760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903031PMC
June 2019

Placenta-Derived Decidua Stromal Cells for Treatment of Severe Acute Graft-Versus-Host Disease.

Stem Cells Transl Med 2018 04 13;7(4):325-331. Epub 2018 Mar 13.

Translational Cell Therapy Research (TCR), Department of Laboratory Medicine.

Severe acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). The placenta protects the fetus from the mother's immune system. We evaluated placenta-derived decidua stromal cells (DSCs), which differ from bone marrow mesenchymal stromal cells (BM-MSCs), as a treatment for severe acute GVHD. DSCs were obtained from term placentas. The DSCs were given to 38 patients with severe acute GVHD; 25 were steroid refractory (SR). DSCs were thawed and infused in buffer supplemented with either 10% AB plasma (group 1, n = 17), or 5% albumin (group 2, n = 21). The viability of cells was higher when thawed in albumin rather than AB plasma (p < .001). Group 1 received a higher cell dose (p < .001), cells of lower passage number (p < .001), and fewer infusions (p = .002) than group 2. The GVHD response (no/partial/complete) was 7/5/5 in group 1 and 0/10/11 in group 2 (p = .01). One-year survival in the two groups was 47% (95% confidence interval [CI] 23-68) and 76% (95% CI 51-89), respectively (p = .016). For the SR patients, 1-year survival was 73% (95% CI 37-90) in SR group 2 (n = 11), which was better than 31% (95% CI 11-54) in SR group 1 (n = 13; p = .02), 20% (95% CI 5-42) in BM-MSC treated (n = 15; p = .0015), and 3% (95% CI 0-14) in historic controls (n = 32; p < .001). DSCs are a promising new treatment for severe acute GVHD. Prospective randomized trials are needed for evaluation of efficacy. (Clinical trial NCT-02172937.) Stem Cells Translational Medicine 2018;7:325-332.
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http://dx.doi.org/10.1002/sctm.17-0167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866941PMC
April 2018

Placenta-Derived Decidua Stromal Cells for Hemorrhagic Cystitis after Stem Cell Transplantation.

Acta Haematol 2018;139(2):106-114. Epub 2018 Feb 7.

Division of Translational Cell Therapy Research (TCR), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Background/aims: Hemorrhagic cystitis (HC) is a serious complication after hematopoietic stem cell transplantation (HSCT). Stromal cells have been tested as therapy for HC. Decidua stromal cells (DSCs) protect the fetus from the mother's immune system.

Methods: Eleven patients with HC of grades 3-4 were treated with DSCs after HSCT. The median age was 33 years (range 8-50), and the median dose of DSCs was 1.5 × 106/kg (range 0.7-2.5). The patients were given 1 dose (1-4).

Results: In 5 patients, HC disappeared within 5 days after DSC infusion. Patients who received DSCs within 3 days after the start of HC had a duration of HC of 5 days and a shorter duration of pain than patients who were given DSCs later (p = 0.02). Three patients received DSCs prepared in albumin instead of AB-plasma and tended to have a shorter duration of pain (p = 0.07). There was no infusion toxicity. Adverse events were those often seen after HSCT. Nine of the 11 patients (82%) were alive 1 year after HSCT.

Conclusions: Based on this pilot study, we started a randomized, placebo-controlled double-blind study using 2 doses of 1 × 106 DSCs/kg suspended in albumin for treatment of early HC.
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http://dx.doi.org/10.1159/000485735DOI Listing
March 2019

Norovirus causing severe gastrointestinal disease following allogeneic hematopoietic stem cell transplantation: A retrospective analysis.

Transpl Infect Dis 2018 Apr 26;20(2):e12847. Epub 2018 Feb 26.

Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Background: Norovirus (NV) can cause chronic and severe gastroenteritis with possible lethal outcome in immunocompromised patients. The knowledge of NV infections in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is limited. The aim of this study was to clarify the clinical importance of NV in a large cohort of HSCT recipients.

Methods: All patients undergoing HSCT and diagnosed with NV at Karolinska University Hospital from 2006-2012 were included in the study (63 patients). Clinical data were collected from medical records, and statistics were performed using the logistic regression method.

Results: The majority of patients (70%) had short-term symptoms (≤14 days). However, 54% of all patients required admission or prolonged hospitalization owing to the infection. In 16% of the patients the symptoms were chronic (>30 days), and in all but one of these patients the clinical picture also was severe, with malnutrition requiring long-term TPN, or serious dehydration. Severe combined immune deficiency (SCID) diagnosis was associated with chronic symptoms of NV infection (OR 30.3, CI 2.5-368).

Conclusion: NV is an important pathogen in the HSCT setting, although the infection seems to be mild in most patients. Increased knowledge is needed to further identify risk factors for a severe course of NV infection in HSCT patients.
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http://dx.doi.org/10.1111/tid.12847DOI Listing
April 2018

Mucosal-Associated Invariant T Cells Display a Poor Reconstitution and Altered Phenotype after Allogeneic Hematopoietic Stem Cell Transplantation.

Front Immunol 2017 21;8:1861. Epub 2017 Dec 21.

Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells which are important in the defense against certain bacteria and yeast. The reconstitution of MAIT cells after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We investigated MAIT cell phenotype and function in 17 patients devoid of relapse and severe graft-versus-host disease (GvHD) in paired samples collected 1-2, 3-6, 12, and 24 months after transplantation. Data were compared to 17 healthy controls (HC), as well as 22 patients with acute GvHD grade 2-3. The frequency of MAIT cells within CD3 cells was approximately 10-fold lower than in HC and did not increase over the 2 years following HSCT. MAIT cells in HSCT patients displayed an elevated expression of CD69 and intracellular granzyme B and were predominantly composed of CD4/CD8 double-negative cells. The expression of PD-1 on MAIT cells was low and did not change during the observational time, whereas the CD3CD161TCRVα7.2 cells (non-MAIT T cells) displayed a high expression early after HSCT that decreased to normal levels at 24 months. MAIT cells collected 2-6 months post-HSCT showed an impaired IFN-γ and perforin response after bacterial stimulation, but the response was restored at 24 months. Patients with acute GvHD had similar proportions of MAIT cells as patients with grade 0-1, but consisted mainly of CD8 cells. Finally, MAIT cells were more sensitive to cyclosporine A and sirolimus than non-MAIT T cells. To conclude, MAIT cell reconstitution following HSCT is deficient compared to non-MAIT T cells and GvHD grade ≥2 is not correlated with MAIT cell frequency. MAIT cell functionality was impaired early after HSCT, but restored at 24 months post-HSCT. MAIT cells have an increased sensibility to common immunosuppressive drugs, which maybe could explain their hampered reconstitution after HSCT.
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http://dx.doi.org/10.3389/fimmu.2017.01861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742569PMC
December 2017

Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition.

Biol Blood Marrow Transplant 2018 03 29;24(3):467-477. Epub 2017 Nov 29.

Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden; Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden; Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Huddinge, Sweden. Electronic address:

Acute graft-versus-host disease (aGVHD) is 1 of the main major complications of post-hematopoietic stem cell transplantation (HSCT). Identifying patients at risk of severe aGVHD may lead to earlier intervention and treatment, resulting in increased survival and a better quality of life. We aimed to identify biomarkers in donor grafts and patient plasma around the time of transplantation that might be predictive of aGVHD development. We build on our previously published methods by using multiplex assays and multicolor flow cytometry. We identified 5 easily assessable cellular markers in donor grafts that combined could potentially be used to calculate risk for severe aGVHD development. Most noteworthy are the T cell subsets expressing IL-7 receptor-α (CD127) and PD-1. Additionally, we identified a potential role for elevated tumor necrosis factor-α levels in both graft and patient before HSCT in development of aGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.026DOI Listing
March 2018

Long-term outcome in patients treated at home during the pancytopenic phase after allogeneic haematopoietic stem cell transplantation.

Int J Hematol 2018 Apr 15;107(4):478-485. Epub 2017 Nov 15.

Department of LABMED, Translational Cell Therapy Research Group (TCR), Karolinska Institutet, Kliniskt Forskningscentrum (KFC), NOVUM Plan 6, Hälsovägen 7-9, 141 57, Huddinge, Sweden.

Patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) were given the option to be treated at home during the pancytopenic phase. Daily visits by a nurse and phone calls from a physician from the unit were part of the protocol. During almost two decades, 252 patients with haematological malignancies and non-malignant disorders were included. Median age was 47 (range 0-72) years. Myeloablative conditioning was given to 102 patients and reduced intensity to 150. Donors were matched unrelated (n = 160), HLA-identical siblings (n = 71), or HLA-mismatched (n = 21). Cumulative incidence of acute graft-versus-host disease (GVHD) was 35% and that of chronic GVHD was 46%. Non-relapse mortality was 14% 10 years after HSCT. In patients with haematological malignancies (n = 229), the 10-year probability of relapse was 34%. No patients died at home. Overall survival was 59% and relapse-free survival was 50% after 10 years. We conclude that patients treated at home after HSCT have an encouraging long-term outcome.
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http://dx.doi.org/10.1007/s12185-017-2363-5DOI Listing
April 2018

Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation.

Cell Rep 2017 Aug;20(9):2238-2250

Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden; Unit of Infectious Diseases, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Neonatology, Karolinska University Hospital, 17176 Stockholm, Sweden. Electronic address:

Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.
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http://dx.doi.org/10.1016/j.celrep.2017.08.021DOI Listing
August 2017

Toxicological effects of fludarabine and treosulfan conditioning before allogeneic stem-cell transplantation.

Int J Hematol 2017 Oct 28;106(4):471-475. Epub 2017 Aug 28.

Center for Allogeneic Stem Cell Transplantation Unit, Karolinska University Hospital, SE-141 86, Stockholm, Sweden.

We studied early potential treosulfan-related toxicity in 118 patients treated with treosulfan-based conditioning before allogeneic hematopoietic stem-cell transplantation. Most patients (n = 93) had a hematological malignancy. In 80 cases, a HLA-A, -B and -DR matched unrelated donor was used, while 33 patients had a HLA-identical sibling donor, and five received an HLA-A, -B or -DR allele mismatched, unrelated donor. Levels of AST, ALT, and bilirubin were significantly increased 1 week after HSCT compared to before HSCT. However, only a few patients had transaminase levels >2 to 3 × the upper normal level. All patients became neutropenic; 61% were already so at the time of graft infusion. Nearly all patients engrafted, except for three who died very early. Non-relapse mortality was 7.5% at 100 days and 11.9% at 1 year after HSCT. Veno-occlusive disease of the liver occurred in one patient and hemorrhagic cystitis in two patients. This study shows that early regimen-related toxicity after HSCT was low despite similar marrow toxicities compared to myeloablative regimens.
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http://dx.doi.org/10.1007/s12185-017-2320-3DOI Listing
October 2017

Safety and Side Effects of Using Placenta-Derived Decidual Stromal Cells for Graft-versus-Host Disease and Hemorrhagic Cystitis.

Front Immunol 2017 11;8:795. Epub 2017 Jul 11.

Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.

Mesenchymal stromal cells (MSCs) are increasingly used in regenerate medicine. Placenta-derived decidual stromal cells (DSCs) are a novel therapy for acute graft-versus-host-disease (GVHD) and hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT). DSCs are more immunosuppressive than MSCs. We assessed adverse events and safety using DSCs among 44 treated patients and 40 controls. The median dose of infused cells was 1.5 (range 0.9-2.9) × 10 DSCs/kg. The patients were given 2 (1-5) doses, with a total of 82 infusions. Monitoring ended 3 months after the last DSC infusion. Three patients had transient reactions during DSC infusion. Laboratory values, hemorrhages, and transfusions were similar in the two groups. The frequency of leukemic relapse (2/2, DSC/controls) and invasive fungal infections (6/6) were the same in the two groups. Causes of death were those seen in HSCT patients: infections (5/3), respiratory failure (1/1), circulatory failure (3/1), thromboembolism (1/0), multiorgan failure (0/1), and GVHD and others (2/7). One-year survival for the DSC patients with GVHD was 67%, which was significantly better than achieved previously at our center. One-year survival was 90% in the DSC-treated HC group. DSC infusions appear safe. Randomized studies are required to prove efficacy.
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http://dx.doi.org/10.3389/fimmu.2017.00795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504152PMC
July 2017

Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft-versus-Host Disease.

Front Immunol 2017 19;8:717. Epub 2017 Jun 19.

Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.

Chronic graft-versus-host disease (cGVHD) is a debilitating complication arising in around half of all patients treated with an allogeneic hematopoietic stem cell transplantation. Even though treatment of severe cGVHD has improved during recent years, it remains one of the main causes of morbidity and mortality in affected patients. Biomarkers in blood that could aid in the diagnosis and classification of cGVHD severity are needed for the development of novel treatment strategies that can alleviate symptoms and reduce the need for painful and sometimes complicated tissue biopsies. Methods that comprehensively profile complex biological systems such as the immune system can reveal unanticipated markers when used with the appropriate methods of data analysis. Here, we used mass cytometry, flow cytometry, enzyme-linked immunosorbent assay, and multiplex assays to systematically profile immune cell populations in 68 patients with varying grades of cGVHD. We identified multiple subpopulations across T, B, and NK-cell lineages that distinguished patients with cGVHD from those without cGVHD and which were associated in varying ways with severity of cGVHD. Specifically, initial flow cytometry demonstrated that patients with more severe cGVHD had lower mucosal-associated T cell frequencies, with a concomitant higher level of CD38 expression on T cells. Mass cytometry could identify unique subpopulations specific for cGVHD severity albeit with some seemingly conflicting results. For instance, patients with severe cGVHD had an increased frequency of activated B cells compared to patients with moderate cGVHD while activated B cells were found at a reduced frequency in patients with mild cGVHD compared to patients without cGVHD. Moreover, results indicate it may be possible to validate mass cytometry results with clinically viable, smaller flow cytometry panels. Finally, no differences in levels of blood soluble markers could be identified, with the exception for the semi-soluble combined marker B-cell activating factor/B cell ratio, which was increased in patients with mild cGVHD compared to patients without cGVHD. These findings suggest that interdependencies between such perturbed subpopulations of cells play a role in cGVHD pathogenesis and can serve as future diagnostic and therapeutic targets.
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http://dx.doi.org/10.3389/fimmu.2017.00717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474470PMC
June 2017