Publications by authors named "Armin Gerbitz"

47 Publications

Prognostic impact of the adverse molecular-genetic profile on long-term outcomes following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia.

Bone Marrow Transplant 2021 Mar 25. Epub 2021 Mar 25.

Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HCT) has not been fully elucidated. Accordingly, we have profiled somatic mutations at diagnosis using next-generation sequencing (NGS) in 178 AML patients who received allogeneic HCT. NGS revealed 598 somatic mutations in 165/178 patients (92.7%). Frequently mutated genes include DNMT3A, TET2, NPM1, RUNX1, IDH2, and FLT3. Commonly detected cytogenetic profiles include normal karyotype, trisomy 8, monosomal karyotype (MK), deletion 5, complex karyotype (CK), and monosomy 7. In univariate analyses, TP53 mutation, MK, CK, and monosomy 7 were associated with decreased overall survival (OS), relapse-free survival (RFS), and a higher relapse incidence (RI). We defined adverse molecular-genetic profile as harboring at least one of the molecular/genetic abnormalities of TP53 mutation, MK, CK, monosomy 7, and deletion 5. The patients harboring adverse molecular-genetic profile (n = 30) showed a lower 2-year OS (24.9% vs. 57.9%; p = 0.003), RFS (23.7% vs. 57.9%; p = 0.002), and higher RI (47.2% and 17.2%; p = 0.001) after HCT when compared to patients without those lesions. Multivariate analysis confirmed adverse molecular-genetic profile as an independent prognostic factor, associated with decreased OS (HR 2.19), RFS (HR 2.23), and higher RI (HR 2.94).
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http://dx.doi.org/10.1038/s41409-021-01255-4DOI Listing
March 2021

Moderate-severe grade of chronic graft versus host disease and younger age (less than 45 years old) are risk factors for avascular necrosis in adult patients undergoing allogeneic hematopoietic cell transplantation.

Ann Hematol 2021 May 12;100(5):1311-1319. Epub 2021 Mar 12.

Hans Messner Allogeneic Blood and Marrow Transplant Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 700 University Ave., Toronto, Ontario, M5G 1Z5, Canada.

Avascular necrosis (AVN) is a debilitating complication of allogeneic hematopoietic cell transplantation (HCT). A retrospective review of 845 patients who underwent HCT was conducted. Cumulative incidence of AVN was 6.3% at 4 years. The following risk factors were significantly associated with AVN risk on univariate analysis: age < 45 (p=0.004), moderate to severe chronic GvHD (p<0.001), reduced intensity conditioning (p=0.02), and a diagnosis of acute leukemia (p=0.045). Multivariate analysis confirmed two risk factors: younger age (<45 years), 9.0% vs 4.4% (p=0.011, hazard ratio (HR) 2.134), and moderate-severe chronic GvHD, 15.4% vs 2.1% (p<0.001, HR 4.950). A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to moderate-severe GvHD or those with age <45. Total score was calculated, thus dividing patient into three groups: low (score 0, n=349, 41.3%), intermediate (score 1, n=379, 44.9%), and high risk (score 2; n=116, 13.7%). This risk score could stratify the patients according to AVN risk (p<0.001). The risk of AVN was 1.5% in the low risk, 6.2% in the intermediate risk, and 20.8% in the high risk groups. Moderate-severe chronic GvHD and younger age (<45 years) are key risk factors for AVN following allogeneic HCT.
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http://dx.doi.org/10.1007/s00277-021-04480-5DOI Listing
May 2021

Comparison of the Prognostic Ability of the HCT-CI, the Modified EBMT, and the EBMT-ADT Pre-transplant Risk Scores for Acute Leukemia.

Clin Lymphoma Myeloma Leuk 2021 Feb 3. Epub 2021 Feb 3.

Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Electronic address:

Background: Allogeneic hematopoietic cell transplantation (HCT) outcomes may be predicted by published risk scores; however, the ideal system has not been identified for acute leukemias.

Patients And Methods: We retrospectively examined the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), modified European Group for Blood and Marrow Transplantation (mEBMT), EBMT-Alternating Decision Tree (ADT), and others on 231 patients with acute leukemia.

Results: Acute myeloid leukemia was diagnosed in 200 patients, and acute lymphocytic leukemia was diagnosed in 31 patients. For HCT-CI, patients were grouped as 0 to 1, 2 to 3, and > 3. For mEBMT, patients were grouped as 0 to 2, 3, and > 3. For EBMT-ADT, the 100-day mortality was calculated and grouped as ≤ 4.1%, 4.1% to 11.5%, and > 11.5%. Higher HCI-CI demonstrated inferior overall survival (P = .04; c-statistic, 0.57), whereas mEBMT and EBMT-ADT did not stratify well. A new weighted score was developed that assigned 1 point for age ≥ 60 years, acute lymphocytic leukemia diagnosis, mismatch unrelated or haploidentical donor, cardiovascular comorbidity, and pre-transplant diabetes, whereas arrhythmia received 2 points. The new weighted score assigned 0 points to 88 (38%), 1 to 2 points to 121 (52%) and ≥ 3 points to 22 (10%) patients, and demonstrated improved prognostic capability compared with the other scores (P = .0001; c-statistic, 0.61).

Conclusions: The HCT-CI stratifies patients with leukemia for overall survival but is inferior to our single-center score, which is influenced by cardiac comorbidity and arrhythmia. Differences in pre-transplant risk scores may be related to different transplant practices.
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http://dx.doi.org/10.1016/j.clml.2021.01.022DOI Listing
February 2021

Refined hepatic grading system in chronic graft-versus-host disease improves prognostic risk stratification of long-term outcomes.

Eur J Haematol 2021 Apr 25;106(4):508-519. Epub 2021 Jan 25.

Department of Medical Oncology and Hematology, Hans Messner Allogeneic Stem Cell Transplant Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Objectives: Hepatic grading systems for categorizing severity in chronic graft-versus-host disease (cGvHD) were determined arbitrarily, leading us to initiate the present study to provide objective evidence for the determination of optimal cutoff values and devise a hepatic grading system to predict prognosis.

Methods: Of 842 patients who received allogeneic hematopoietic stem transplant (HCT), 336 patients diagnosed with cGvHD were evaluated for overall survival (OS) and non-relapse mortality (NRM) after cGVHD development. Multiple statistical parameters were evaluated to define optimal cutoff values of liver profile, including negative predictive value (NPV), positive predictive value (PPV), accuracy, and p-values as measures of risk stratification power.

Results: We found that alkaline phosphatase (ALP) ≥ 146 IU/L (NPV: 83.4%; PPV: 32.8%; accuracy: 52.7%) and bilirubin ≥ 14 µmol/L (NPV: 81.8%; PPV: 39.4%; accuracy 68.1%) significantly correlated with OS. We developed a refined hepatic cGvHD grading score (RHS), stratifying patients into a low-RHS group with RHS score 0, OS at 3 years (n = 162) to 80.5%, compared to high-RHS group with score 1-2 (n = 172) 62.7%. Regarding NRM, score 0 segregated NRM at 3 years to 11.9%, compared with score 1-2 19.6%, P = .1.

Conclusions: Refined hepatic score is promising for stratifying patients with cGVHD and liver involvement according to long-term outcomes.
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http://dx.doi.org/10.1111/ejh.13576DOI Listing
April 2021

Post-transplantation cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation from HLA-identical sibling donors: A retrospective analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Cancer 2021 Jan 29;127(2):209-218. Epub 2020 Oct 29.

Hematology Department, Hôpital Saint Antoine, Service d'Hématologie et Thérapie Cellulaire, Paris, France.

Background: Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Addition of antithymocyte globulin (ATG) or post-transplantation cyclophosphamide (PTCY) to standard immunosuppressive agents reduces GVHD in different donor settings.

Methods: We compared the outcomes of adults with acute myeloid leukemia undergoing allo-HSCT from HLA-identical sibling donors after the use of PTCY (n = 197) or ATG (n = 1913).

Results: Patients in the PTCY group were younger than those in the ATG group (median age, 47 vs 54 years; P < .01). Peripheral blood was the most frequently used stem cell source, being significantly more frequent in the ATG group than in the PTCY group (95% vs 70% P < .01). The conditioning regimen was more frequently myeloablative in the PTCY group than in the ATG group (59% vs 48%; P < .01). Time to neutrophil engraftment was shorter in the ATG group than in the PTCY group (17 vs 20 days; P < .01). No differences were observed according to the other transplantation outcomes, except for chronic GVHD of all grades and extensive chronic GVHD at 2 years, which were significantly lower in the ATG group compared with the PTCY group (P < .02).

Conclusion: PTCY is feasible in an HLA-identical sibling setting, and despite similar outcomes, ATG may be associated with lower incidence of chronic GVHD.
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http://dx.doi.org/10.1002/cncr.33255DOI Listing
January 2021

Outcomes of adult patients with acute myeloid leukemia and unsuccessful cytogenetic analysis undergoing allogeneic hematopoietic stem cell transplantation.

Hematol Oncol Stem Cell Ther 2020 Oct 8. Epub 2020 Oct 8.

Hans Messner Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective/background: Unsuccessful cytogenetic (US) analysis at baseline has been reported to be a poor prognostic feature in patients with acute myeloid leukemia (AML). We conducted this study to examine the prognostic impact of UC/inconclusive cytogenetic analysis on outcomes in patients with AML undergoing allogeneic hematopoietic stem cell transplantation (Allo HSCT).

Methods: We retrospectively analyzed all adults undergoing Allo HSCT for AML from January 2011 to August 2019. Patients with any documented cytogenetic abnormalities were excluded. Baseline characteristics and transplant outcomes were compared between patients with normal cytogenetics and those with UC.

Results: Overall, 243 AML patients (median age, 55 years; 55.1% female) were included. UC were reported in 79 patients, whereas 164 patients had a normal karyotype. The two groups were similar to each other in terms of baseline demographics, treatment received, and transplant related variables. There was no difference between patients with UC and normal cytogenetics in terms of relapse-free survival (66 months vs. 42 months, p = .53) or overall survival (OS; 77 months vs. 76 months, p = .72). Survival parameters remained similar even in subgroup analysis based on NPM1 and FLT3 mutation status. Significant predictors of OS after Allo HSCT in AML patients with UC were increased age at time of Allo HSCT (hazard ratio [HR] = -1.049; 95% confidence interval [CI], 1.005-1.095), favorable (NPM1/FLT3) mutation profile (HR = 0.11; 95% CI, 0.01-0.84), neutrophil engraftment < 17 days, and absence of chronic graft-versus-host disease (HR = 3.27; 95% CI, 1.20-8.60).

Conclusion: Outcomes after Allo HSCT are comparable between AML patients with UC analysis and patients with normal cytogenetics even after stratification based on molecular risk factors. Allogeneic Allo HSCT may mitigate the poor prognosis of UC analysis in patients with AML.
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http://dx.doi.org/10.1016/j.hemonc.2020.09.001DOI Listing
October 2020

Prolactin, a potential biomarker for chronic GVHD activity.

Eur J Haematol 2021 Feb 26;106(2):158-164. Epub 2020 Oct 26.

Section of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Introduction: The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long-term post-alloHCT survivors.

Methods: Three-hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels.

Results: Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty-five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6-13.1); P < .001) in the multivariate analysis. In conclusion, patients with hyperprolactinemia were 6.4 times more likely to have active cGVHD in comparison with those patients with normal levels of PRL (P < .001).

Conclusion: Prolactin may serve as a biomarker for cGVHD activity. Further studies are required to confirm these findings, and to explore if hyperprolactinemia has an impact on cGVHD severity and prognosis.
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http://dx.doi.org/10.1111/ejh.13531DOI Listing
February 2021

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

Pilot prospective study of Frailty and Functionality in routine clinical assessment in allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Jan 30;56(1):60-69. Epub 2020 Jun 30.

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

A Frailty and Functionality evaluation for alloHCT was implemented using existing resources. We describe the implementation of this evaluation across all ages and at first consultation, and correlate results with posttransplant outcomes in 168 patients. The evaluation consists of: Clinical Frailty Scale (CFS), Instrumental Activities of Daily Living (IADL), grip strength (GS), timed up and go test (TUGT), self-rated health question (SRH), Single question of Falls, albumin and C-Reactive Protein (CRP) levels. Median time to perform the evaluation was 5-6 min. Median age was 58 years (range: 19-77) and median follow-up was 5.3 months. TUGT > 10 s (HR 2.92; p = 0.003), raised CRP (HR 4.40; p < 0.001), and hypoalbuminemia (HR 2.10; p = 0.043) were significant risk factors for worse overal survival (OS). CFS ≥ 3 (HR 3.11; p = 0.009), TUGT > 10 s (HR 3.47; p = 0.003), GS (HR 2.56; p = 0.029), SRH ( 10 s and raised CRP were significant predictors for worse OS and NRM. SRH (
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http://dx.doi.org/10.1038/s41409-020-0979-1DOI Listing
January 2021

Clinical prevalence and outcome of cardiovascular events in the first 100 days postallogeneic hematopoietic stem cell transplant.

Eur J Haematol 2021 Jan 13;106(1):32-39. Epub 2020 Oct 13.

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Introduction: Recent advances in allogeneic hematopoietic stem cell transplant (HSCT) have allowed us to offer HSCT to older, advanced disease patients with more co-morbidities. Cardiovascular toxicity post-transplant is a major concern due to the increased risk of mortality. Few studies have examined the prevalence of CV events including CAD (MI, angina, PCI, CABG, CHF, arrhythmias), HTN, stroke/TIA, and death in the first 100 days post-transplant.

Patients: We assessed the impact of pretransplant MUGA results in predicting postallogeneic HSCT CV events and overall survival in the first 100 days, and whether or not transient anthracycline-induced cardiomyopathy or cumulative anthracycline dose affected overall survival. This retrospective, cohort study included 665 patients with a median age of 52 years who underwent HSCT from 2009 to 2015.

Results: The most frequent CV event in the first 100 days post-HSCT was arrhythmia seen in 2.9% of patients followed up by CHF (12.3%), MI (9%), and angina (8%). Two patients had PCI, and both survived the first 100 days. Cardiovascular risk factors predict for a poor MUGA scan but not survival. Higher dose anthracycline pretransplant predicted for a poor outcome.

Conclusion: A history of CV disease, MI, or CAD was the most important predictive of CV events, P-value = .00002. 88.6% survived the first 100 days. Patients with an EF < 50% had a significant likelihood of having a CV event compared to patients with an EF > 60% (OR = 5.3, 95% CI [1.6-18.1], P = .0219). Cumulative anthracycline dose did not have a significant impact on overall survival.
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http://dx.doi.org/10.1111/ejh.13482DOI Listing
January 2021

Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia.

Biol Blood Marrow Transplant 2020 08 16;26(8):1511-1519. Epub 2020 May 16.

Hans Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Hematology Department, Institut Català d'Oncologia-Hospitalet, IDIBELL, Barcelona, Spain.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.021DOI Listing
August 2020

Phase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell Transplantation.

Antimicrob Agents Chemother 2020 03 24;64(4). Epub 2020 Mar 24.

USA Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).
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http://dx.doi.org/10.1128/AAC.02467-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179282PMC
March 2020

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Age >69 Years with Acute Myelogenous Leukemia: On Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 10 7;25(10):1975-1983. Epub 2019 Jun 7.

European Society for Blood and Marrow Transplantation, Paris study office/CEREST-TC, Paris, France; Hematology Division and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Reduced-intensity conditioning (RIC) allows for the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older patients with acute myelogenous leukemia (AML). We compared outcomes between 713 patients age ≥70 years and 16,161 patients age 50 to 69 years who underwent HSCT between 2004 and 2014. A higher proportion of the older patients were male and had secondary AML, active disease, a peripheral blood stem cell graft, a matched unrelated donor, an RIC regimen, and a lower Karnofsky Performance Status (KPS) score (P< .001). In multivariate analysis, the incidences of acute and chronic graft-versus-host disease and relapse were similar in the 2 age groups. Nonrelapse mortality at 2 years was 34% (95% confidence interval [CI], 31% to 38%) in patients age ≥70 years and 24% (95% CI, 25% to 32%) in those age 50 to 69 years (P< .001). Survival at 2 years in the 2 groups was 38% (95% CI, 34% to 42%) and 50% (95% CI, 49% to 50%), respectively (P< .001). In patients with active disease, the corresponding percentages were 35% (95% CI, 29% to 41%) in those age ≥70 years and 33% (95% CI, 31% to 34%) in those age <70 years (P = .36). In patients age ≥70 years, a KPS score of ≥80% was associated with improved survival (hazard ratio, 1.53; 95% CI, 1.14 to 2.06; P = .003). In summary, patients age ≥70 years had worse outcomes, except for those with active AML.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.037DOI Listing
October 2019

Changes in Immunosuppressive Treatment of Chronic Graft-versus-Host Disease: Comparison of 2 Surveys within Allogeneic Hematopoietic Stem Cell Transplant Centers in Germany, Austria, and Switzerland.

Biol Blood Marrow Transplant 2019 07 13;25(7):1450-1455. Epub 2019 Mar 13.

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

Chronic graft-versus-host disease (cGVHD) remains the leading cause of late morbidity and mortality. Despite the growing number of treatment options in cGVHD, evidence remains sparse. The German-Austrian-Swiss GVHD Consortium performed a survey on clinical practice in treatment of cGVHD among transplant centers in Germany, Austria, and Switzerland in 2009 and 2018 and compared the results. The survey performed in 2009 contained 20 questions on first-line treatment and related issues and 4 questions on second-line scenarios followed by a survey on all systemic and topic treatment options known and applied, with 31 of 36 transplant centers (86%) responding. The survey in 2018 repeated 7 questions on first-line treatment and 3 questions on second-line scenarios followed by an updated survey on all current systemic treatment options known and applied, with 29 of 66 centers (43%) responding. In summary, the results show a large overlap of first-line treatment practice between centers and the 2 surveys because of a lack of new data that changes practice, except significant heterogeneity of treatment of cGVHD progressive onset type, which can be explained by the lack of trials focusing on this high-risk entity. In contrast, treatment options applied to second-line therapy vary considerably, with new agents like ibrutinib and ruxolitinib entering clinical practice. Moreover, treatment of bronchiolitis obliterans syndrome demonstrates heterogeneity in applied therapeutic options and sequence because of a lack of controlled data and different conclusions from already existing evidence. In summary, the survey results demonstrate an increasing number of treatment options applied to cGVHD accompanied by a significant heterogeneity in second-line treatment and underline the urgent need for clinical trials and registry analyses on rare entities with high mortality like progressive onset type and lung involvement of cGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2019.03.003DOI Listing
July 2019

Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 04 15;25(4):e128-e140. Epub 2019 Jan 15.

Department of Internal Medicine IV, Hematology and Oncology, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.016DOI Listing
April 2019

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation.

J Clin Oncol 2019 02 7;37(5):375-385. Epub 2018 Nov 7.

1 Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT).

Methods: We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS).

Results: A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434).

Conclusion: Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.
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http://dx.doi.org/10.1200/JCO.2018.79.2184DOI Listing
February 2019

Clinical-grade generation of peptide-stimulated CMV/EBV-specific T cells from G-CSF mobilized stem cell grafts.

J Transl Med 2018 05 9;16(1):124. Epub 2018 May 9.

Department of Hematology, Oncology and Tumorimmunology, Charité Berlin, Berlin, Germany.

Background: A major complication after allogeneic hematopoietic stem cell transplantation (aSCT) is the reactivation of herpesviruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Both viruses cause significant mortality and compromise quality of life after aSCT. Preventive transfer of virus-specific T cells can suppress reactivation by re-establishing functional antiviral immune responses in immunocompromised hosts.

Methods: We have developed a good manufacturing practice protocol to generate CMV/EBV-peptide-stimulated T cells from leukapheresis products of G-CSF mobilized and non-mobilized donors. Our procedure selectively expands virus-specific CD8+ und CD4+ T cells over 9 days using a generic pool of 34 CMV and EBV peptides that represent well-defined dominant T-cell epitopes with various HLA restrictions. For HLA class I, this set of peptides covers at least 80% of the European population.

Results: CMV/EBV-specific T cells were successfully expanded from leukapheresis material of both G-CSF mobilized and non-mobilized donors. The protocol allows administration shortly after stem cell transplantation (d30+), storage over liquid nitrogen for iterated applications, and protection of the stem cell donor by avoiding a second leukapheresis.

Conclusion: Our protocol allows for rapid and cost-efficient production of T cells for early transfusion after aSCT as a preventive approach. It is currently evaluated in a phase I/IIa clinical trial.
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http://dx.doi.org/10.1186/s12967-018-1498-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941463PMC
May 2018

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling.

J Immunol 2015 Oct 31;195(7):3139-48. Epub 2015 Aug 31.

Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany;

Recently, a novel subset of TCRαβ(+) CD4(-) CD8(-) double-negative (DN) T cells was described to suppress immune responses in both mice and humans. Moreover, in murine models, infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4(+) and CD8(+) T cell responses. After hematopoietic stem cell transplantation and other lymphopenic conditions, IL-7 plays an important role in the reconstitution, survival, and homeostasis of the T cell compartment. Because IL-7 was shown to interfere with T cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells toward allogeneic CD4(+) effector T cells. Of interest, our studies revealed that IL-7 activates the Akt/mechanistic target of rapamycin (mTOR) pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR reversed the IL-7 effect, thereby restoring the functionality of DN T cells, whereas inhibition of other central T cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors that may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T cell functionality in graft-versus-host disease.
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http://dx.doi.org/10.4049/jimmunol.1501389DOI Listing
October 2015

Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma.

Sci Transl Med 2015 Apr;7(282):282ra47

Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.

Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as Burkitt's lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. We show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D-treated M2 macrophages is cathelicidin-dependent. Finally, vitamin D treatment of 25-hydroxyvitamin D (25D)-deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor activity of TAMs and improves the efficacy of ADCC.
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http://dx.doi.org/10.1126/scitranslmed.aaa3230DOI Listing
April 2015

Macrophages and dendritic cells as actors in the immune reaction of classical Hodgkin lymphoma.

PLoS One 2014 3;9(12):e114345. Epub 2014 Dec 3.

Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.

Background: The inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (MΦ) and dendritic cells (DC).

Methods: MΦ and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, MΦ stimulated with GM-CSF (MΦGM-CSF, pro-inflammatory MΦ-1-model) or M-CSF (MΦM-CSF, immunomodulatory MΦ-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or MΦ polarization were investigated by flow cytometry. Furthermore, the impact of DC or MΦ on cHL cell proliferation was analyzed by BrdU/CFSE assay.

Results: In cHL tissues mature myeloid (m)DC and MΦ predominated. High numbers of CD83+ mDC and low numbers of CD163+ MΦ were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory MΦ phenotype were promoted by SN derived from cHL cell lines. TNFα neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory MΦ inhibited the proliferation of cHL cells.

Conclusion: Adopting an immunomodulatory phenotype is a potential mechanism for how MΦ promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255018PMC
December 2015

Targeting high-grade B cell lymphoma with CD19-specific T cells.

Int J Cancer 2014 Sep 20;135(5):1153-64. Epub 2014 Feb 20.

Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.

Adoptive T cell therapy is an important additional treatment option for malignant diseases resistant to chemotherapy. Using a murine high-grade B cell lymphoma model, we have addressed the question whether the B cell differentiation antigen CD19 can act as rejection antigen. CD19(-/-) mice inoculated with CD19(+) B cell lymphoma cells showed higher survival rates than WT mice and were protected against additional tumor challenge. T cell depletion prior to tumor transfer completely abolished the protective response. By heterotypic vaccination of CD19(-/-) mice against murine CD19, survival after tumor challenge was significantly increased. To define protective epitopes within the CD19 molecule, T cells collected from mice that had survived the tumor transfer were analyzed for IFNγ secretion in response to CD19-derived peptides. The majority of mice exhibited a CD4(+) T cell response to CD19 peptide 27, which was the most dominant epitope after CD19 vaccination. A peptide 27-specific CD4(+) T cell line protected CD19(-/-) mice against challenge with CD19(+) lymphoma and also cured a significant proportion of WT mice from recurrent disease in a model of minimal residual disease after chemotherapy. In conclusion, our data highlight CD19-specific CD4(+) T cells for adoptive T cell therapy of B cell lymphomas.
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http://dx.doi.org/10.1002/ijc.28760DOI Listing
September 2014

Advances in cellular therapy: 7th international symposium on the clinical use of cellular products, March 14 and 15, 2013, Erlangen, Germany.

Cancer Immunol Immunother 2014 Feb 5;63(2):185-93. Epub 2013 Nov 5.

Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.

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http://dx.doi.org/10.1007/s00262-013-1498-3DOI Listing
February 2014

Targeting c-MYC with T-cells.

PLoS One 2013 10;8(10):e77375. Epub 2013 Oct 10.

Department of Immunology, Charité Berlin, Berlin, Germany.

Over-expression of the proto-oncogene c-MYC is frequently observed in a variety of tumors and is a hallmark of Burkitt´s lymphoma. The fact that many tumors are oncogene-addicted to c-MYC, renders c-MYC a powerful target for anti-tumor therapy. Using a xenogenic vaccination strategy by immunizing C57BL/6 mice with human c-MYC protein or non-homologous peptides, we show that the human c-MYC protein, despite its high homology between mouse and man, contains several immunogenic epitopes presented in the context of murine H2(b) haplotype. We identified an MHC class II-restricted CD4⁺ T-cell epitope and therein an MHC class I-restricted CD8⁺ T-cell epitope (SSPQGSPEPL) that, after prime/boost immunization, protected up to 25% of mice against a lethal lymphoma challenge. Lymphoma-rejecting animals contained MHC multimer-binding CD8⁺ cell within the peripheral blood and displayed in vivo cytolytic activity with specificity for SSPQGSPEPL. Taken together these data suggest that oncogenic c-MYC can be targeted with specific T-cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795085PMC
June 2014

Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers.

Biol Blood Marrow Transplant 2013 May 29;19(5):767-76. Epub 2013 Jan 29.

Department of Hematology and Clinical Oncology, University of Regensburg, Germany.

To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience.
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http://dx.doi.org/10.1016/j.bbmt.2013.01.018DOI Listing
May 2013

Humanized c-Myc mouse.

PLoS One 2012 31;7(7):e42021. Epub 2012 Jul 31.

Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, Munich, Germany.

Background: A given tumor is usually dependent on the oncogene that is activated in the respective tumor entity. This phenomenon called oncogene addiction provides the rationale for attempts to target oncogene products in a therapeutic manner, be it by small molecules, by small interfering RNAs (siRNA) or by antigen-specific T cells. As the proto-oncogene product is required also for the function of normal cells, this raises the question whether there is a therapeutic window between the adverse effects of specific inhibitors or T cells to normal tissue that may limit their application, and their beneficial tumor-specific therapeutic action. To address this crucial question, suitable mouse strains need to be developed, that enable expression of the human proto-oncogene not only in tumor but also in normal cells. The aim of this work is to provide such a mouse strain for the human proto-oncogene product c-MYC.

Principal Findings: We generated C57BL/6-derived embryonic stem cells that are transgenic for a humanized c-Myc gene and established a mouse strain (hc-Myc) that expresses human c-MYC instead of the murine ortholog. These transgenic animals harbor the humanized c-Myc gene integrated into the endogenous murine c-Myc locus. Despite the lack of the endogenous murine c-Myc gene, homozygous mice show a normal phenotype indicating that human c-MYC can replace its murine ortholog.

Conclusions: The newly established hc-Myc mouse strain provides a model system to study in detail the adverse effects of therapies that target the human c-MYC protein. To mimic the clinical situation, hc-Myc mice may be cross-bred to mice that develop tumors due to overexpression of human c-MYC. With these double transgenic mice it will be possible to study simultaneously the therapeutic efficiency and adverse side effects of MYC-specific therapies in the same mouse.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409231PMC
January 2013

Stromal interferon-γ signaling and cross-presentation are required to eliminate antigen-loss variants of B cell lymphomas in mice.

PLoS One 2012 30;7(3):e34552. Epub 2012 Mar 30.

Department of Immunology, Charité Berlin, Berlin, Germany.

To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60-70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80-100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316708PMC
July 2012

Advances in cellular therapy: 6th International Symposium on the clinical use of cellular products, March 24 and 25, 2011, Erlangen, Germany.

Cancer Immunol Immunother 2012 Mar 27;61(3):433-43. Epub 2011 Dec 27.

Department of Medicine 5, Hematology and Oncology, University Hospital of Erlangen, Erlangen, Germany.

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http://dx.doi.org/10.1007/s00262-011-1190-4DOI Listing
March 2012

Migration of bone marrow-derived cells and improved perfusion after treatment with erythropoietin in a murine model of myocardial infarction.

J Cell Mol Med 2012 Jan;16(1):152-9

Medical Department I, Klinikum der Universität München, Munich, Germany.

Erythropoietin (EPO) was shown to have protective effects after myocardial infarction (MI) by neovascularization and antiapoptotic mechanisms. Beside direct receptor-dependent mechanisms, mobilization and homing of bone marrow-derived cells (BMCs) may play a pivotal role in this regard. In this study, we intended to track different subpopulations of BMCs and to assess serially myocardial perfusion changes in EPO-treated mice after MI. To allow tracking of BMCs, we used a chimeric mouse model. Therefore, mice (C57BL/6J) were sublethally irradiated, and bone marrow (BM) from green fluorescent protein transgenic mice was transplanted. Ten weeks later coronary artery ligation was performed to induce MI. EPO was injected for 3 days with a total dose of 5000 IU/kg. Subpopulations (CD31, c-kit, CXCR-4 and Sca-1) of EGFP(+) cells were studied in peripheral blood, bone marrow and hearts by flow cytometry. Myocardial perfusion was serially investigated in vivo by pinhole single-photon emission computed tomography (SPECT) at days 6 and 30 after MI. EPO-treated animals revealed an enhanced mobilization of BMCs into peripheral blood. The numbers of these cells in BM remained unchanged. Homing of all BMCs subpopulations to the ischaemic myocardium was significantly increased in EPO-treated mice. Among the investigated subpopulations, EPO predominantly affected migration of CXCR-4(+) (4.3-fold increase). Repetitively SPECT analyses revealed a reduction of perfusion defects after EPO treatment over time. Our study shows that EPO treatment after MI enhances the migration capacity of BMCs into ischaemic tissue, which may attribute to an improved perfusion and reduced size of infarction, respectively.
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http://dx.doi.org/10.1111/j.1582-4934.2011.01286.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823101PMC
January 2012

Intrathecal application of donor lymphocytes in leukemic meningeosis after allogeneic stem cell transplantation.

Ann Hematol 2011 Aug 12;90(8):911-6. Epub 2011 Feb 12.

Campus Benjamin Franklin, Department of Hematology and Oncology, Charité, University Hospital Berlin, Berlin, Germany.

Extramedullary relapses after allogeneic stem cell transplantation, especially within the central nervous system (CNS), are not only difficult to treat but also associated with poor outcome. Although the graft-versus-leukemia (GvL) effect is nowadays accepted and well documented, it remains controversial whether one can make use of GvL effects in immunological-restricted areas ("sanctuary sites") like the central nervous system. Here, we present data of three hematological patients suffering from isolated CNS relapse of CML or AML after allogeneic stem cell transplantation. Patients received in addition to chemotherapy intrathecal infusions of donor lymphocytes by CD14 depletion of peripheral blood mononuclear cells from the correspondent allogeneic donor. Referring to an observation period of maximum 17 months no immediate or delayed side effects could be detected.
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http://dx.doi.org/10.1007/s00277-011-1171-xDOI Listing
August 2011