Publications by authors named "Martina Crysandt"

23 Publications

  • Page 1 of 1

Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma: Final Results of the PAPAGEMO Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Feb;7(2):255-262

University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required.

Objective: To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone.

Design, Setting, And Participants: This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020.

Interventions: Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B).

Main Outcomes And Measures: The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates.

Results: A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological.

Conclusions And Relevance: This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma).

Trial Registration: German Clinical Trials Identifier: DRKS00003139.
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http://dx.doi.org/10.1001/jamaoncol.2020.6564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758834PMC
February 2021

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.

Cell Stem Cell 2021 Apr 9;28(4):637-652.e8. Epub 2020 Dec 9.

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands; Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Oncode Institute, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands. Electronic address:

Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
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http://dx.doi.org/10.1016/j.stem.2020.11.004DOI Listing
April 2021

Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

Ann Hematol 2021 Apr 16;100(4):959-968. Epub 2020 Nov 16.

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

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1-19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRD, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
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http://dx.doi.org/10.1007/s00277-020-04321-xDOI Listing
April 2021

Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study.

J Clin Oncol 2020 10 24;38(30):3555-3564. Epub 2020 Aug 24.

Vivantes Clinic Berlin-Spandau, Berlin-Spandau, Germany.

Purpose: Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity.

Patients And Methods: Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis.

Results: Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients.

Conclusion: Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.
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http://dx.doi.org/10.1200/JCO.20.00714DOI Listing
October 2020

Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia.

Leukemia 2020 10 20;34(10):2635-2647. Epub 2020 Jul 20.

Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany.

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34 cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.
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http://dx.doi.org/10.1038/s41375-020-0977-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515845PMC
October 2020

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With -Internal Tandem Duplication Mutation (SORMAIN).

J Clin Oncol 2020 09 16;38(26):2993-3002. Epub 2020 Jul 16.

Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Gießen and Marburg, Campus Marburg, Marburg, Germany.

Purpose: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the like tyrosine kinase 3 gene (ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT.

Patients And Methods: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first.

Results: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib.

Conclusion: Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for ITD-positive AML.
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http://dx.doi.org/10.1200/JCO.19.03345DOI Listing
September 2020

Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial.

J Clin Oncol 2020 01 3;38(3):257-270. Epub 2019 Dec 3.

University Hospital of Ulm, Ulm, Germany.

Purpose: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML).

Patients And Methods: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety.

Results: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided = .06). For valproate, no effect was observed (17.8% with valproate 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided = .44). Median overall survival was 8.2 months with ATRA 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms.

Conclusion: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
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http://dx.doi.org/10.1200/JCO.19.01053DOI Listing
January 2020

Phase II clinical trial of pazopanib in patients with acute myeloid leukemia (AML), relapsed or refractory or at initial diagnosis without an intensive treatment option (PazoAML).

Ann Hematol 2019 Jun 21;98(6):1393-1401. Epub 2019 Mar 21.

Department of Medicine A, University Hospital Muenster, Muenster, Germany.

We evaluated pazopanib (800 mg orally QD) in patients not eligible for intensive treatment with relapsed/refractory AML or at initial diagnosis. Patients receiving pazopanib for > 14 days were analyzed for safety, tolerability, and efficacy. Co-primary endpoints were cumulative response rate and reduction of bone marrow microvessel density. Twenty patients (median age 76 years, range 52-86) were treated. Fifteen had relapsed/refractory and five had newly diagnosed AML. Median ECOG performance status was 1 (range 1-3). Four patients had adverse, 15 intermediate, and 1 patient favorable cytogenetic/molecular risk (ELN 2010 criteria). The safety profile of pazopanib was as reported. The most common adverse events of any grade were gastrointestinal. Two patients achieved PR (blast reduction > 50%), 14 stable disease (SD), and 4 progressive disease. Median PFS was 65 days (95% CI 29-105). After the end of the study, 1 CRi and 1 CRp occurred on demethylating agents, and 1 CR upon alloSCT. In these patients, SD and improved general condition on pazopanib allowed therapy escalation. Median OS for the overall study population was 191 days (95% CI 87-435) and 1-year survival was 35%. There was no significant change in microvessel density. Clinical trial information: NCT01361334.
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http://dx.doi.org/10.1007/s00277-019-03651-9DOI Listing
June 2019

Characterization of acute myeloid leukemia with del(9q) - Impact of the genes in the minimally deleted region.

Leuk Res 2019 01 17;76:15-23. Epub 2018 Nov 17.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen University, Aachen, Germany. Electronic address:

Acute myeloid leukemia is an aggressive disease that arises from clonal expansion of malignant hematopoietic precursor cells of the bone marrow. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of acute myeloid leukemia patients. Our deletion analysis in a cohort of 31 del(9q) acute myeloid leukemia patients further supports the importance of a minimally deleted region composed of seven genes potentially involved in leukemogenesis: GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2. Importantly, among them HNRNPK, encoding heterogeneous nuclear ribonucleoprotein K is proposed to function in leukemogenesis. We show that expression of HNRNPK and the other genes of the minimally deleted region is significantly reduced in patients with del(9q) compared with normal karyotype acute myeloid leukemia. Also, two mRNAs interacting with heterogeneous nuclear ribonucleoprotein K, namely CDKN1A and CEBPA are significantly downregulated. While the deletion size is not correlated with outcome, associated genetic aberrations are important. Patients with an additional t(8;21) show a good prognosis. RUNX1-RUNX1T1, which emerges from the t(8;21) leads to transcriptional down-regulation of CEBPA. Acute myeloid leukemia patients with mutations in CEBPA have a good prognosis as well. Interestingly, in del(9q) patients with CEBPA mutation mRNA levels of HNRNPK and the other genes located in the minimally deleted region is restored to normal karyotype level. Our data indicate that a link between CEBPA and the genes of the minimally deleted region, among them HNRNPK contributes to leukemogenesis in acute myeloid leukemia with del(9q).
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http://dx.doi.org/10.1016/j.leukres.2018.11.007DOI Listing
January 2019

Bosutinib: A Potent Second-Generation Tyrosine Kinase Inhibitor.

Recent Results Cancer Res 2018;212:87-108

Department of Oncology, Hematology, Immunoncology and Rheumatology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

Bosutinib is one of the five tyrosine kinase inhibitors which are currently approved for the treatment of chronic myeloid leukemia. By its dual inhibition of Src and ABL kinase and also targeting further kinases, it creates a unique target portfolio which also explains its unique side effect profile. The approval of bosutinib in 2013 made the drug available for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. As initially the first-line clinical trial comparing bosutinib with imatinib in CML patients in chronic phase did not reach its primary endpoint and therefore the product was not licensed for first-line therapy, a second first-line trial, the so-called BFORE study, was performed and just recently the promising results have been published predicting a quick expansion of the existing label. In comparison with the other approved TKIs, bosutinib harbors a distinct side effect profile with only very few cardiovascular and thromboembolic events and minimal long-term safety issues with most adverse events happening during the first months of treatment. On the other hand, gastrointestinal side effects are very common (e.g., diarrhea rates in more than 80% of the patients) with bosutinib surprising some of the investigators during the early clinical trials evaluating bosutinib. Until then, several approaches have been used to face this problem resulting in extensive supportive efforts (such as early loperamid treatment) as well as new trials testing alternative dosing strategies with early dose adjustment schedules. This article reports preclinical and clinical data available for bosutinib both in hematologic diseases such as CML or ALL and solid tumours as well as other diseases and envisions future perspectives including additional patient groups in which bosutinib might be of clinical benefit.
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http://dx.doi.org/10.1007/978-3-319-91439-8_4DOI Listing
May 2019

Germ line predisposition to myeloid malignancies appearing in adulthood.

Expert Rev Hematol 2018 08 23;11(8):625-636. Epub 2018 Jul 23.

a Medical Faculty, Dept. of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation , University Hospital RWTH Aachen , Aachen , Germany.

Introduction: Germ line predisposition to myeloid neoplasms has been incorporated in the WHO 2016 classification of myeloid neoplasms and acute leukemia. The new category of disease is named hereditary myeloid disorder (HMD). Although most myeloid neoplasms are sporadic, germ line mutations and familial predisposition can contribute to development of chronic myeloid diseases and acute myeloid leukemia. This finding and upcoming frequent use of genome wide detection of molecular aberrations will lead to a higher detection rate of a genetic predisposition and influence treatment decisions. Hereditary predisposition is responsible for 5-10% of myeloid malignancies. Management of affected patients begins by the awareness of treating physicians of the problem and a precise work up of the patient and family members. Areas covered: This review focuses on current knowledge about germ line predisposition for myeloid neoplasms including diagnostic, prognostic, and therapeutic aspects in adult patients. Essential information for clinical routine is provided. Expert commentary: Compared to a patient without predisposition, adaptation of treatment strategy for patients with an HMD is often necessary, especially to avoid higher risk of relapse or higher toxicity during chemotherapy or transplantation. Mistakes in choice of a related donor can be omitted. Relatives at risk of developing a HMD need specific surveillance.
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http://dx.doi.org/10.1080/17474086.2018.1494566DOI Listing
August 2018

Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis.

Eur J Haematol 2018 Sep 4;101(3):305-317. Epub 2018 Jul 4.

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

Introduction: Ruxolitinib is the first approved drug for treatment of myelofibrosis, but its impact of outcome after allogeneic stem cell transplantation (ASCT) is unknown.

Patients And Methods: We reported on 159 myelofibrosis patients (pts) with a median age of 59 years (r: 28-74) who received reduced intensity ASCT between 2000 and 2015 in eight German centers from related (n = 23), matched (n = 86) or mismatched (n = 50) unrelated donors. Forty-six (29%) patients received ruxolitinib at any time point prior to ASCT. The median daily dose of ruxolitinib was 30 mg (range 10-40 mg) and the median duration of treatment was 4.9 months (range 0.4-39.1 months).

Results: Primary graft failure was seen in 2 pts (4%) in the ruxolitinib and 3 (2%) in the non-ruxolitinib group. Engraftment and incidence of acute GVHD grade II to IV and III/IV did not differ between groups (37% vs 39% and 19% vs 28%, respectively), nor did the non-relapse mortality at 2 years (23% vs 23%). A trend for lower risk of relapse was seen in the ruxolitinib group (9% vs 17%, P = .2), resulting in a similar 2 year DFS and OS (68% vs 60% and 73% vs 70%, respectively). No difference in any outcome variable could be seen between ruxolitinib responders and those who failed or lost response to ruxolitinib.

Conclusions: These results suggest that ruxolitinib pretreatment in myelofibrosis patient does not negatively influence outcome after allogeneic stem cell transplantation.
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http://dx.doi.org/10.1111/ejh.13099DOI Listing
September 2018

Presence of TERT Promoter Mutations is a Secondary Event and Associates with Elongated Telomere Length in Myxoid Liposarcomas.

Int J Mol Sci 2018 Feb 18;19(2). Epub 2018 Feb 18.

Department of Hematology, Oncology, Haemostaseology and Stem Cell Transplantation, RWTH Aachen University Medical Faculty, 52074 Aachen, Germany.

The occurrence of promoter mutations has been well described in soft tissue sarcomas (STS). However, the biological role of these mutations as well as their impact on telomere length in STS is still unclear. We analyzed 116 patient samples diagnosed with 22 distinct histological subtypes of bone and STS for the occurrence of promoter mutations by Sanger sequencing. We observed promoter mutations at an overall frequency of 9.5% distributed over 7 different sarcoma subtypes. Except for one chondrosarcoma case harboring a C250T mutation, all other mutations were detected at location C228T. By far the far highest frequency of promoter mutations was found in myxoid liposarcoma (MLS) (4 out of 9 cases studied, i.e., 44%). Assessment of telomere length from tumor biopsies revealed that promoter-mutated MLSs had significantly fewer shortened telomeres in comparison to wildtype MLSs. Based on the frequency of promoter mutations and the elongated telomere length in mutated compared to wildtype MLS, we hypothesize that occurrence of promoter mutations has a pivotal role in the disease progression as a secondary genetic event at a time when tumor cells face the need for telomere elongation to allow further proliferation.
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http://dx.doi.org/10.3390/ijms19020608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855830PMC
February 2018

Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia.

Ann Hematol 2017 Sep 3;96(9):1457-1461. Epub 2017 Jul 3.

Department of Hematology, Oncology, Haemostaseology and Stem Cell Transplantation, RWTH Aachen University Medical Faculty, Aachen, Germany.

Telomere shortening represents an established mechanism connecting aging and cancer development. We sequentially analyzed telomere length (TL) of 49 acute myeloid leukemia (AML) patients at diagnosis (n = 24), once they achieved complete cytological remission (CCR) and/or during refractory disease or relapse and after 1-year follow-up, with all patients having at least two sequential samples. TL was analyzed by monochrome multiplex quantitative polymerase chain reaction. We have observed substantially shortened TL in the cells of patients at diagnosis compared to age-adjusted controls. In patients reaching CCR after chemotherapy, telomere shortening was less pronounced than in persistence or relapse but still significantly shortened compared to controls. We estimate patients harboring approximately 20 years of premature telomere loss compared to healthy aged-matched subjects at the time of AML onset. Our data indicate a pre-existing telomere deficit in non-clonal hematopoiesis of AML patients providing a link between age and AML development.
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http://dx.doi.org/10.1007/s00277-017-3049-zDOI Listing
September 2017

A three-gene expression-based risk score can refine the European LeukemiaNet AML classification.

J Hematol Oncol 2016 09 1;9(1):78. Epub 2016 Sep 1.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Background: Risk stratification based on cytogenetics of acute myeloid leukemia (AML) remains imprecise. The introduction of novel genetic and epigenetic markers has helped to close this gap and increased the specificity of risk stratification, although most studies have been conducted in specific AML subpopulations. In order to overcome this limitation, we used a genome-wide approach in multiple AML populations to develop a robust prediction model for AML survival.

Methods: We conducted a genome-wide expression analysis of two data sets from AML patients enrolled into the AMLCG-1999 trial and from the Tumor Cancer Genome Atlas (TCGA) to develop a prognostic score to refine current risk classification and performed a validation on two data sets of the National Taiwan University Hospital (NTUH) and an independent AMLCG cohort.

Results: In our training set, using a stringent multi-step approach, we identified a small three-gene prognostic scoring system, named Tri-AML score (TriAS) which highly correlated with overall survival (OS). Multivariate analysis revealed TriAS to be an independent prognostic factor in all tested training and additional validation sets, even including age, current cytogenetic-based risk stratification, and three other recently developed expression-based scoring models for AML.

Conclusions: The Tri-AML score allows robust and clinically practical risk stratification for the outcome of AML patients. TriAS substantially refined current ELN risk stratification assigning 44.5 % of the patients into a different risk category.
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http://dx.doi.org/10.1186/s13045-016-0308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009640PMC
September 2016

Salvage High-Dose Chemotherapy for Relapsed Pure Seminoma in the Last 10 Years: Results From the European Society for Blood and Marrow Transplantation Series 2002-2012.

Clin Genitourin Cancer 2017 02 27;15(1):163-167. Epub 2016 Jun 27.

Istituti Ospitalieri di Cremona, Cremona, Italy.

Background: The optimal management of advanced seminoma that relapses after chemotherapy remains unknown. We retrospectively analyzed outcomes with the use of high-dose chemotherapy (HDCT).

Patients And Methods: Eligibility included adult male patients with pure seminomatous histology and treatment with salvage HDCT. Data of patients who received HDCT from 13 European Society for Blood and Marrow Transplantation (EBMT) centers were used. Multivariable Cox analyses evaluated the association of prespecified factors (line of treatment, prior radiotherapy, and chemosensitivity according to standard definition), with progression-free (PFS) and overall survival (OS). The prognostic ability of the model was assessed through the concordance statistic.

Results: From December 2002 to December 2012, 46 cases were identified. Median age was 38 years (interquartile range, 35-46 years). HDCT was provided as second-line therapy (n = 14, 30.4%) and in third-line or beyond third-line therapy (n = 20, 43.5%; 12 had missing information). Sixteen patients (34.8%) received paraortic and/or iliac radiotherapy, and 10 (21.7%) had disease that was cisplatin refractory or absolutely refractory. Median follow-up was 22 months (interquartile range, 8-56). On multivariable Cox analysis, refractory disease was a significantly negative prognostic factor for both PFS (hazard ratio, 6.04; 95% confidence interval, 1.86-19.64) and OS (hazard ratio, 3.93; 95% confidence interval, 1.07-14.45), while prior radiotherapy trended to significance for both. The c index was 0.74 and 0.66 for PFS and OS, respectively. The small numbers and the lack of any comparison with conventional-dose chemotherapy are major study limitations.

Conclusion: Despite our small sample size, this retrospective analysis suggested that HDCT may represent a valuable therapeutic option for patients with a pure seminoma after standard-dose chemotherapy failure. Our observation requires validation through a prospective study.
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http://dx.doi.org/10.1016/j.clgc.2016.06.013DOI Listing
February 2017

A high BMI is a risk factor in younger patients with de novo acute myelogenous leukemia.

Eur J Haematol 2016 Jul 17;97(1):17-24. Epub 2015 Sep 17.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Overweight and obese patients have an increased risk to develop several malignancies and, additionally, body mass index (BMI) impacts on outcome in several solid tumors. However, little is known for AML. We analyzed a cohort of 3526 patients with AML treated in three prospective multicenter trials within the German Study Alliance Leukemia. In multivariate analyses, we identified BMI as an independent risk factor for both DFS (HR 1.014, P = 0.0217) and OS (HR 1.015, P < 0.0036). Interestingly, overweight and obesity seemed to be a risk factor predominantly in patients with de novo AML younger than 65 yr with intermediate risk and adverse cytogenetics. Overweight with a BMI ≥25 kg/m² best discriminated the worse outcome and led to an absolute reduction in long-term survival of 5-7% in the group of all younger patients (3-yr OS 39.9% vs. 47.3%; 10-yr OS 28.7% vs. 33.8%, P = 0.0002). Additionally, response to induction therapy was significantly reduced in these patients (76.9% vs. 82.8%, P < 0.0001). Thus, in younger patients with de novo AML, overweight and obesity are risk factors for impaired response to induction therapy, DFS and OS. This effect is, in part but not fully, explained by dose reduction such as dose-capping at a body surface area of 2 m².
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http://dx.doi.org/10.1111/ejh.12675DOI Listing
July 2016

Activated fibronectin-secretory phenotype of mesenchymal stromal cells in pre-fibrotic myeloproliferative neoplasms.

J Hematol Oncol 2014 Dec 14;7:92. Epub 2014 Dec 14.

Department of Oncology, Hematology and Stem cell transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, Aachen, 52074, Germany.

We characterized bone marrow stromal cells (BMSC) from patients with pre-fibrotic myeloproliferative neoplasms (MPN). MPN-BMSC showed decreased capacity to stimulate the proliferation of colony-forming units of normal hematopoietic stem and progenitor cells and displayed increased matrix remodelling (in particular fibronectin deposition) compared to control BMSC. This finding was confirmed in pre-fibrotic MPN bone marrow biopsies in a tissue microarray (n = 34), which stained positive for fibronectin in the absence of reticulin as a standard myelofibrosis marker. Fibronectin expression correlated significantly with reduced haemoglobin levels in MPN-patients (p = 0.007; R2 = 0.42). Our data show significant cell-intrinsic alterations in MPN-MSC and suggest that Fibronectin expression might be applicable as a biomarker for the identification of early myelofibrotic transformation in reticulin-negative MPN.
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http://dx.doi.org/10.1186/s13045-014-0092-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271470PMC
December 2014

Antineoplastic chemotherapy in cancer patients with methicillin-resistant Staphylococcus aureus (MRSA).

Onkologie 2010 19;33(11):598-603. Epub 2010 Oct 19.

Medizinische Klinik IV, Universitätsklinikum, RWTH Aachen, Germany.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen causing serious morbidity and mortality in immunosuppressed patients. Antineoplastic chemotherapy causes immunosuppression, and thus there is concern whether such patients should proceed to therapy without delay or dose reduction. There are presently no guidelines with appropriate provisions for antineoplastic chemotherapy in cancer patients with MRSA colonization or infection.

Patients And Methods: We retrospectively analyzed the clinical outcome of all 27 patients with known MRSA infection or colonization undergoing antineoplastic chemotherapy for solid or hematological malignancies in our institution.

Results: In our patients, MRSA was detected at multiple sites. 11 patients were found to be colonized with MRSA, whereas 16 patients had colonization and/or infection. MRSA sepsis occurred in 12 cases. Interestingly, at the time of MRSA sepsis, neutrophil counts were less than 500/μl in 42% of our patients. However, fatal complications due to MRSA occurred in only 2 patients. Among patients with MRSA sepsis, the mortality rate was 14%.

Conclusions: Our results with a limited number of patients support the contention that antineoplastic chemotherapy may well be administered to patients with MRSA and should not necessarily lead to dose reduction or treatment delay, especially in cases with curative intent.
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http://dx.doi.org/10.1159/000321141DOI Listing
March 2011

Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy.

J Cancer Res Clin Oncol 2009 Oct 28;135(10):1429-35. Epub 2009 Apr 28.

Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.

Purpose: The renin-angiotensin system plays a crucial role in maintaining vascular homeostasis. Stimulation of angiotensin II type 1 receptors (AT1R) acts proangiogenically by increasing levels of vascular endothelial growth factor (VEGF). Consequently, cell culture experiments and animal studies have shown antiproliferative effects of AT1R blockers (ARB) and angiotensin I converting enzyme inhibitors (ACEI) in several malignancies. Until now, very limited clinical data for this antiangiogenic effect exists for combinations with antineoplastic chemotherapy.

Methods: A total of 287 patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy were retrospectively analysed regarding long-term medication with ACEI and ARB as well as histological type, stage, performance status, gender, age, dose-intensity of chemotherapy and survival.

Results: Patients receiving either ACEI or ARB had a 3.1 months longer median survival than non-recipients (11.7 vs. 8.6 months, HR 0.56, P = 0.03). This survival advantage could not be attributed to other established risk-factors or dose intensity of chemotherapy.

Conclusions: Addition of ACEI or ARB to platinum-based first-line chemotherapy may contribute to prolonged survival in patients with advanced lung cancer.
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http://dx.doi.org/10.1007/s00432-009-0587-3DOI Listing
October 2009

Correlation of C-reactive protein with survival and radiographic response to first-line platinum-based chemotherapy in advanced non-small cell lung cancer.

Onkologie 2008 Dec 14;31(12):665-70. Epub 2008 Nov 14.

Medizinische Klinik IV, Universitatsklinikum Aachen, RWTH Aachen, Germany.

Objective: This study was conducted to assess the prognostic role of regular measurements of C-reactive protein (CRP) in patients with advanced-stage non-small cell lung cancer (NSCLC) during platinum-based first-line therapy.

Methods: A total of 210 patients were retrospectively analyzed regarding CRP values, infections, histological type, stage, performance status, gender, age, body mass index and survival. Additionally, in 88 of these patients, changes of CRP values were correlated with response to chemotherapy by radiographic imaging.

Results: Elevation of CRP prior to the first cycle was an adverse prognostic factor for overall survival. Comparing CRP values before and after 2 cycles correlated with response and identified patient groups with a remarkable difference of overall survival (18.8 vs. 7.5 months). Normalization of CRP was associated with a low risk for progression, whereas patients with an increase of CRP values of more than 25% showed a progressive disease in most cases. Besides performance status, no correlation of CRP with other clinical data was found.

Conclusions: Measurement of CRP before initiation and during a platinum-based chemotherapy can provide prognostic information for the individual patient with advanced NSCLC and is able to support or even replace assessment of response by radiographic imaging in defined situations.
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http://dx.doi.org/10.1159/000165054DOI Listing
December 2008

Intraperitoneal application of rituximab in refractory mantle cell lymphoma with massive ascites resulting in local and systemic response.

Eur J Haematol 2007 Dec 27;79(6):546-9. Epub 2007 Sep 27.

Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, Aachen, Germany.

In the past decade, rituximab in combination with polychemotherapy has become the standard approach in most patients with advanced CD20-positive B-cell lymphoma. In mantle cell lymphoma (MCL), follicular lymphoma and diffuse large B-cell lymphoma, rituximab has been used as monotherapy and in combination with various chemotherapy regimens in different treatment situations. Routinely, rituximab is given intravenously, but other routes of administration have also been described. Here, we report a 64-yr-old woman who was previously treated with three different chemotherapy regimens for stage IV MCL. No sustained clinical and radiological response could be achieved. The patient's general status declined and she developed massive ascites as the dominant clinical problem. Local, intraperitoneal administration of rituximab was initiated as an experimental treatment approach. After 11 doses of rituximab, the general status of the patient improved significantly, ascites resolved completely and computed tomography (CT) scans demonstrated a partial remission of intra-abdominal lymph nodes and splenomegaly. Furthermore, we observed a regression of mediastinal lymph nodes, pleural effusion and centrocytes in peripheral blood as well as improvement of anaemia. The response to the experimental treatment has maintained for more than 6 months. In summary, we observed a sustained local and systemic response to intraperitoneal administration of rituximab in a patient with heavily pretreated advanced MCL.
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http://dx.doi.org/10.1111/j.1600-0609.2007.00955.xDOI Listing
December 2007