Publications by authors named "Aristoteles Giagounidis"

127 Publications

Comparison Between 5-Azacytidine Treatment and Allogeneic Stem-Cell Transplantation in Elderly Patients With Advanced MDS According to Donor Availability (VidazaAllo Study).

J Clin Oncol 2021 10 20;39(30):3318-3327. Epub 2021 Jul 20.

Medical Clinic and Policlinic 1, University Hospital "Carl Gustav Carus" Dresden, Dresden, Germany.

Purpose: In contrast to 5-azacytidine (5-aza), allogeneic stem-cell transplantation (HSCT) represents a curative treatment strategy for patients with myelodysplastic syndromes (MDS), but therapy-related mortality (TRM) limits its broader use in elderly patients with MDS. The present prospective multicenter study compared HSCT following 5-aza pretreatment with continuous 5-aza treatment in patients with higher-risk MDS age 55-70 years.

Methods: One hundred ninety patients with a median age of 63 years were enrolled. Patients received 4-6 cycles of 5-aza followed by HLA-compatible HSCT after reduced-intensity conditioning or by continuous 5-aza if no donor was identified.

Results: Twenty-eight patients did not fulfill inclusion criteria (n = 20), died (n = 2) withdrew informed consent (n = 5), or were excluded for an unknown reason (n = 1). 5-aza induction started in 162 patients, but only 108 (67%) were eligible for subsequent allocation to HSCT (n = 81) or continuation of 5-aza (n = 27) because of disease progression (n = 26), death (n = 12), or other reasons (n = 16). Seven percent died during 5-aza before treatment allocation. The cumulative incidence of TRM after HSCT at 1 year was 19%. The event-free survival and overall survival after 5-aza pretreatment and treatment allocation at 3 years were 34% (95% CI, 22 to 47) and 50% (95% CI, 39 to 61) after allograft and 0% and 32% (95% CI, 14 to 52) after continuous 5-aza treatment ( < .0001 and = .12), respectively. Fourteen patients progressing after continuous 5-aza received a salvage allograft from an alternative donor, and 43% were alive at last follow-up.

Conclusion: In older patients with MDS, reduced-intensity conditioning HSCT resulted in a significantly improved event-free survival in comparison with continuous 5-aza therapy. Bridging with 5-aza to HSCT before is associated with a considerable rate of dropouts because of progression, mortality, and adverse events.
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http://dx.doi.org/10.1200/JCO.20.02724DOI Listing
October 2021

Eligibility for clinical trials is unsatisfactory for patients with myelodysplastic syndromes, even at a tertiary referral center.

Leuk Res 2021 09 11;108:106611. Epub 2021 May 11.

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

Participation in clinical trials may allow patients with MDS to gain access to therapies not otherwise available. However, access is limited by strict inclusion and exclusion criteria, reflecting academic or regulatory questions addressed by the respective studies. We performed a simulation in order to estimate the average proportion of MDS patients eligible for participation in a clinical trial. The simulation drew upon 1809 patients in the Düsseldorf MDS Registry whose clinical data allowed eligibility screening for a wide range of clinical trials. This cohort was assumed to be alive and available for study participation. The simulation also posited that all MDS trials (n = 47) conducted in our center between 1987 and 2016 were open for recruitment. In addition, study activities in the year 2016 were analyzed to determine the proportion of patients eligible for at least one of the 9 MDS trials open at that time. On average, each clinical trial was suitable for about 18 % of patients in the simulation cohort. Conversely, 34 % of the patients were eligible for at least one of the 9 clinical studies in 2016. Inclusion/exclusion criteria of studies initiated by the pharmaceutical industry excluded more than twice the fraction of patients compared with investigator initiated trials (potential inclusion of 10 % vs. 21 %, respectively). Karyotype (average exclusion rate 58 %), comorbidities (40 %), and prior therapies (55 %) were the main reasons for exclusion. We suggest that in- and exclusion criteria should be less restrictive, in order to meet the needs of the real-life population of elderly MDS patients.
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http://dx.doi.org/10.1016/j.leukres.2021.106611DOI Listing
September 2021

Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q).

Ann Hematol 2021 Jun 27;100(6):1463-1471. Epub 2021 Apr 27.

Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.
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http://dx.doi.org/10.1007/s00277-021-04492-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116243PMC
June 2021

Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

J Clin Oncol 2021 05 25;39(13):1426-1436. Epub 2021 Mar 25.

Marienhospital Düsseldorf, Düsseldorf, Germany.

Purpose: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia.

Methods: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI).

Results: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 10/L, and absolute neutrophil count was 1.3 × 10/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 16.2 months; = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 10/L.

Conclusion: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.
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http://dx.doi.org/10.1200/JCO.20.02619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099416PMC
May 2021

Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.

Leukemia 2021 09 18;35(9):2517-2525. Epub 2021 Feb 18.

Klinik für Hämatologie und Onkologie - Stammzelltransplantation, Agaplesion Diakonieklinikum Rotenburg, Rotenburg, Germany.

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
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http://dx.doi.org/10.1038/s41375-021-01148-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410595PMC
September 2021

Impact of complete surgical resection on outcome in aggressive non-Hodgkin lymphoma treated with immunochemotherapy.

Cancer Med 2020 11 14;9(22):8386-8396. Epub 2020 Sep 14.

Klinik für Hämatologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.

Background: Surgical resection is considered to be of purely diagnostic value in aggressive lymphoma. Evidence for an impact on outcome is scant and restricted to retrospective observations.

Methods: In the "Positron Emission Tomography-guided Therapy of Aggressive non-Hodgkin Lymphomas" (PETAL) trial, patients with a negative baseline positron emission tomography (PET) scan were documented in a prospective observational substudy. Baseline PET-negative patients with the absence of lymph node enlargement on computed tomography and a negative bone marrow biopsy were considered to have undergone complete lymphoma resection.

Results: Eighty-two of 1,041 patients (7.9%) had a negative baseline PET scan, and 67 were included in this analysis. All were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), plus rituximab for CD20-positive lymphomas. Among 52 patients with diffuse large B-cell lymphoma (DLBCL), 48 had completely resected disease. Their outcome tended to be better than that of 115 baseline PET-positive stage I DLBCL patients treated in the main part of the PETAL trial (2-year progression-free survival 92.7% [95% confidence interval 84.7-100] versus 88.4% [82.5-94.3], P = .056; 2-year overall survival 92.7% [84.7-100] versus 93.7% [89.2-98.2], P = .176), but this was restricted to patients below the age of 60 years (2-year progression-free survival 100% versus 92.2% [84.8-99.6], P = .031; 2-year overall survival 100% versus 95.9% [90.2-100], P = .075). In peripheral T-cell lymphoma, eight of 11 patients had completely resected disease. In contrast to DLBCL, complete resection was not associated with improved outcome compared to the control.

Conclusion: Young patients with early stage DLBCL may benefit from complete lymphoma resection prior to immunochemotherapy.
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http://dx.doi.org/10.1002/cam4.3448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666729PMC
November 2020

Efficacy and Tolerability of High- versus Low-dose Lenalidomide Maintenance Therapy of Multiple Myeloma after Autologous Blood Stem Cell Transplantation.

Clin Cancer Res 2020 11 17;26(22):5879-5886. Epub 2020 Aug 17.

University Hospital Düsseldorf, Düsseldorf, Germany.

Purpose: For multiple myeloma, high-dose chemotherapy and autologous blood stem-cell transplantation (ASCT) followed by lenalidomide maintenance (LenMT) at 10-15 mg/day is considered standard of care. However, dose reductions due to side effects are common and median LenMT doses achieved over time may remain lower. Dose response during LenMT has never been investigated.

Patients And Methods: In a multicenter, randomized, open-label trial, patients with multiple myeloma after ASCT and high-dose lenalidomide consolidation therapy (CT) at 25 mg/day were randomized to receive LenMT at either 25 or 5 mg/day. Primary endpoint was progression-free survival (PFS).

Results: Ninety-four patients (median age, 58 years) were randomized to either arm, with 22% having International Staging System (ISS) stage 3 and 22% being in complete remission (CR). After median follow-up of 46.7 months, median doses of 14.5 and 5 mg/day were achieved in the two arms; 53% of dose reductions occurring during CT. In the high- and the low-dose arm, median PFS was 44.8 and 33.0 months (HR, 0.65; 95% CI, 0.44-0.97; = 0.032), 36% and 23% of patients had stringent CR as best response ( = 0.08), and 4-year OS was 79% and 67% ( = 0.16), respectively. Hematologic toxicity, grade ≥3 neutropenia, and infections were initially more common with LenMT 25 mg, but decreased after dose adjustments. SPM incidence and quality-of-life (QoL) scores in both arms were similar.

Conclusions: LenMT dose correlated with efficacy and toxicity. High rates of dose reductions during CT argue against a high starting dose. However, continuous up- and down-titration for each patient to the current maximum tolerated dose is prudent.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0841DOI Listing
November 2020

Where Does Morphology Fit in Myelodysplastic Syndrome Diagnosis in the Era of Molecular Testing?

Hematol Oncol Clin North Am 2020 04 21;34(2):321-331. Epub 2020 Jan 21.

Klinik für Hämatologie, Onkologie und Palliativmedizin, Marien Hospital Düsseldorf, Rochusstr. 2, Düsseldorf 40479, Germany.

The recognition of cytologic dysplasia in blood and bone marrow remains the cornerstone of myelodysplastic syndromes (MDS) diagnosis because it distinguishes MDS from clonal hematopoiesis of indeterminate potential or clonal cytopenia of undetermined significance. Expert morphologists achieve high concordance in the diagnosis of MDS if appropriate clinical information is provided. Because of the low prevalence of MDS, diagnostic approaches based solely on molecular diagnosis will likely be erroneous.
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http://dx.doi.org/10.1016/j.hoc.2019.11.005DOI Listing
April 2020

Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma: A subgroup analysis of the PETAL trial.

Hematol Oncol 2020 Aug 18;38(3):244-256. Epub 2020 Feb 18.

Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund, Germany.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV ) and SUV thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUV approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm using SUV and 460 cm using SUV . For iPET response, the respective thresholds were 46.9% SUV reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV and SUV , and 29% and 25% for iPET response by ΔSUV and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV and 3.206 (1.524-6.743) for SUV . At iPET, it was 3.910 (1.891-8.087) for ΔSUV and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.
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http://dx.doi.org/10.1002/hon.2697DOI Listing
August 2020

Achievement of red blood cell transfusion independence in red blood cell transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes correlates with serum erythropoietin levels.

Leuk Lymphoma 2020 06 17;61(6):1475-1483. Epub 2020 Feb 17.

Service d'Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France.

In the randomized, phase 3, MDS-005 study (NCT01029262), lenalidomide-induced red blood cell transfusion independence (RBC-TI) in 27% of transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS) ineligible for or refractory to erythropoiesis-stimulating agents. To determine the influence of erythropoietin (EPO) level on response, 155 patients treated with lenalidomide in MDS-005 were categorized into four groups by baseline EPO level. The EPO >500 mU/mL group had higher RBC transfusion burden and the lowest proportion of patients with ring sideroblasts ≥15% versus lower EPO groups. Achievement of RBC-TI ≥8 weeks inversely correlated with EPO level, ranging from 42.5 to 15.5%. EPO level did not affect erythroid hematologic improvement response (36.2-44.4%). This analysis suggests patients with lower EPO levels experience the strongest benefit from lenalidomide. Although meaningful improvements were observed in some patients with EPO level >500 mU/mL, new treatments are needed for this population.
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http://dx.doi.org/10.1080/10428194.2020.1719088DOI Listing
June 2020

[Myelodysplastic syndromes].

Internist (Berl) 2020 Feb;61(2):175-184

Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Rochusstr. 2, 40479, Düsseldorf, Deutschland.

Myelodysplastic syndromes (MDS)-previously called "preleukemias"-are clonal diseases of the pluripotent hematopoietic stem cell. Their hallmark is peripheral cytopenias. Early forms are characterized by dysplasia of mature cells in the peripheral blood or erythropoiesis, granulopoiesis or megakaryocytes in the bone marrow, and later stages tend to accumulate blasts. About 30% transform into acute myeloid leukemia. MDS are diseases of the elderly and are prognostically divided into lower and higher risk diseases. Median survival times vary accordingly between 6 months and 10 years. Chromosomal abnormalities are identified in 50% of patients, and single or multiple gene mutations occur in 80%. They are the driving force leading to abnormalities in differentiation and to the accumulation of blasts in the bone marrow. Therapeutic options include supportive care, erythropoiesis-stimulating agents, demethylating agents, and allogeneic stem cell transplantation.
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http://dx.doi.org/10.1007/s00108-019-00718-7DOI Listing
February 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.

Hannover Medical School, Hannover, 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 Study of the ALK5 Inhibitor Galunisertib in Very Low-, Low-, and Intermediate-Risk Myelodysplastic Syndromes.

Clin Cancer Res 2019 12 3;25(23):6976-6985. Epub 2019 Sep 3.

Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

Purpose: Overactivation of TGF-β signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-β receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies.

Patients And Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off.

Results: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4-40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%).

Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1338DOI Listing
December 2019

Treatment of Combined Autoimmune Neutropenia and Immune Thrombocytopenia with Methotrexate.

Acta Haematol 2020 28;143(1):89-90. Epub 2019 Jun 28.

Clinic for Oncology, Hematology and Palliative Care, Marien Hospital Düsseldorf, Düsseldorf, Germany.

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http://dx.doi.org/10.1159/000500872DOI Listing
April 2020

Clinical Benefit-Risk Profile of Lenalidomide in Patients With Lower-risk Myelodysplastic Syndromes Without del(5q): Results of a Phase III Trial.

Clin Lymphoma Myeloma Leuk 2019 04 21;19(4):213-219.e4. Epub 2018 Dec 21.

MDS Unit, AOU Careggi, University of Florence, Florence, Italy.

Background: In the phase III MDS-005 study of patients with lower-risk, non-del(5q) myelodysplastic syndromes, lenalidomide was associated with a higher rate of ≥ 8 weeks red blood cell transfusion independence (RBC-TI) compared with placebo, but also with a higher risk of hematologic adverse events (AEs).

Patients And Methods: This analysis evaluated the ratio of clinical benefit-risk in patients treated with lenalidomide or placebo, and assessed the effect of lenalidomide dose reductions on response. Clinical benefit was a composite endpoint defined as RBC-TI, transfusion reduction ≥ 4 units packed red blood cells, hemoglobin increase ≥ 1.5 g/dL, or cytogenetic response.

Results: The rate of clinical benefit was higher with lenalidomide than with placebo (31.9% vs. 3.8%). The ratio of response (RBC-TI and clinical benefit) to risk (hematologic AEs) favored lenalidomide over placebo. Patients who underwent ≥ 1 lenalidomide dose reduction had a longer duration of treatment, received a higher cumulative dose, and were more likely to experience clinical benefit versus patients without dose reductions.

Conclusion: Despite the occurrence of hematologic AEs, the overall benefit-risk profile supported lenalidomide treatment. Appropriate management of hematologic AEs by dose reductions may help patients with myelodysplastic syndromes to remain on treatment and achieve clinical benefit.
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http://dx.doi.org/10.1016/j.clml.2018.12.012DOI Listing
April 2019

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Ann Hematol 2019 Apr 4;98(4):897-907. Epub 2019 Jan 4.

Klinik für Hämatologie, Onkologie und Klinische Immunologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.
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http://dx.doi.org/10.1007/s00277-018-3578-0DOI Listing
April 2019

Clonal architecture in patients with myelodysplastic syndromes and double or minor complex abnormalities: Detailed analysis of clonal composition, involved abnormalities, and prognostic significance.

Genes Chromosomes Cancer 2018 11 24;57(11):547-556. Epub 2018 Sep 24.

Department of Hematology and Medical Oncology, University of Göttingen, Göttingen, Germany.

The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution. UC were detected in 23/191 patients (12%). The composition of UC showed great variability. The only recurrent combination of abnormalities was del(5q) and + 8 in 8 of 23 patients (35%). In patients with clonal evolution, the clone size of the primary and secondary clone varied: Patients with -7 and + 8 in the primary clone showed a larger primary and a smaller secondary clone (-7: median 74% vs 10%; +8 73% vs 18%) while patients with del(5q) in the primary clone showed a smaller primary and a larger secondary clone (33% vs 61%). Univariate and multivariate analyses showed no significant differences regarding overall or AML-free survival between the clonal subtypes. Only the subtype 3C (3 abnormalities and clonal evolution) was an independent risk factor for developing AML (Hazard Ratio 5.5 as compared to subtype 2A, P < .05). Finally, our study confirms that the number of abnormalities clearly defines a significant risk factor for overall- as well as AML-free survival. Importantly, in patients with more than one clone, the calculation of the number of abnormalities in the entire sample instead of the number of abnormalities per clone allows a higher prognostic accuracy.
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http://dx.doi.org/10.1002/gcc.22667DOI Listing
November 2018

Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations.

Blood 2018 09 21;132(12):1225-1240. Epub 2018 Jun 21.

Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

, , and are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34 cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators and aberrantly spliced target genes of and mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology.
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http://dx.doi.org/10.1182/blood-2018-04-843771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172604PMC
September 2018

A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS.

Leukemia 2018 12 30;32(12):2648-2658. Epub 2018 Mar 30.

Medizinische Klinik und Poliklinik I, Dresden, Germany.

Erythropoiesis-stimulating agents are first choice for treating anemia in low-risk MDS. This double-blind, placebo-controlled study assessed the efficacy and safety of epoetin-α in IPSS low- or intermediate-1 risk (i.e., low-risk) MDS patients with Hb ≤ 10.0 g/dL, with no or moderate RBC transfusion dependence (≤4 RBC units/8 weeks). Patients were randomized, 2:1, to receive epoetin-α 450 IU/kg/week or placebo for 24 weeks, followed by treatment extension in responders. The primary endpoint was erythroid response (ER) through Week 24. Dose adjustments were driven by weekly Hb-levels and included increases, and dose reductions/discontinuation if Hb > 12 g/dL. An independent Response Review Committee (RRC) blindly reviewed all responses, applying IWG-2006 criteria but also considering dose adjustments, drug interruptions and longer periods of observation.A total of 130 patients were randomized (85 to epoetin-α and 45 to placebo). The ER by IWG-2006 criteria was 31.8% for epoetin-α vs 4.4% for placebo (p < 0.001); after RRC review, the ER was 45.9 vs 4.4% (p < 0.001), respectively. Epoetin-α reduced RBC transfusions and increased the time-to-first-transfusion compared with placebo.Thus, epoetin-α significantly improved anemia outcomes in low-risk MDS. IWG-2006 criteria for ER may require amendments to better apply to clinical studies.
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http://dx.doi.org/10.1038/s41375-018-0118-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286328PMC
December 2018

Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial.

J Clin Oncol 2018 07 11;36(20):2024-2034. Epub 2018 May 11.

Ulrich Dührsen, Stefan Müller, Jan Dürig, Johannes Matschke, Christine Schmitz, Thorsten Pöppel, Andreas Bockisch, and Andreas Hüttmann, Universitätsklinikum Essen; Claudia Ose, Marcus Brinkmann, Karl-Heinz Jöckel, André Scherag, and Jan Rekowski, Universität Duisburg-Essen, Essen; Bernd Hertenstein and Henrike Thomssen, Klinikum Bremen Mitte; Christiane Franzius, Zentrum für moderne Diagnostik, Bremen; Jörg Kotzerke and Frank Kroschinsky, Universitätsklinikum Carl Gustav Carus; Gabriele Prange-Krex, Onkologische Gemeinschaftspraxis, Dresden; Rolf Mesters, Wolfgang E. Berdel, and Matthias Weckesser, Universitätsklinikum Münster, Münster; Dorothea Kofahl-Krause, Frank M. Bengel, and Lilli Geworski, Medizinische Hochschule Hannover, Hannover; Paul La Rosée, Martin Freesmeyer, and André Scherag, Universitätsklinikum Jena, Jena; Andreas Hertel and Heinz-Gert Höffkes, Klinikum Fulda, Fulda; Dirk Behringer, Augusta-Kranken-Anstalt, Bochum; Stefan Wilop and Thomas Krohn, Universitätsklinikum Aachen, Aachen; Jens Holzinger and Martin Griesshammer, Johannes Wesling Klinikum, Minden; Aristoteles Giagounidis, Helios St Johannes Klinik, Duisburg; Aruna Raghavachar, Helios Universitätsklinikum, Wuppertal; Georg Maschmeyer and Ingo Brink, Klinikum Ernst von Bergmann, Potsdam; Helga Bernhard, Klinikum Darmstadt, Darmstadt; Uwe Haberkorn, Universitätsklinikum Heidelberg, Heidelberg; Tobias Gaska, Brüderkrankenhaus St Josef, Paderborn; Lars Kurch, Universitätsklinikum Leipzig, Leipzig; Wolfram Klapper, Universitätsklinikum Schleswig-Holstein, Kiel; Dieter Hoelzer, Onkologikum, Frankfurt/Main, Germany; and Daniëlle M.E. van Assema, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

Purpose Interim positron emission tomography (PET) using the tracer, [F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUV method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.
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http://dx.doi.org/10.1200/JCO.2017.76.8093DOI Listing
July 2018

Concomitant Non-Small Cell Lung Cancer and Hairy Cell Leukemia in a Patient Harboring BRAF-V600E Mutation in Both Tissues: A Case Report.

Case Rep Oncol 2018 Jan-Apr;11(1):109-113. Epub 2018 Feb 14.

Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Düsseldorf, Germany.

The BRAF-V600E mutation has been established as a signature alteration occurring almost universally in hairy cell leukemia. Moreover, it can be detected in a small percentage of patients with non-small cell lung cancer. We report the case of a patient with a metastatic BRAF-V600E-mutated lung adenocarcinoma suffering from concomitant hairy cell leukemia. The identification of an identical BRAF mutation in both malignancies raises physiopathological considerations and might offer unique therapeutic strategies for this group of patients.
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http://dx.doi.org/10.1159/000486640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869534PMC
February 2018

The Effect of Lenalidomide on Health-Related Quality of Life in Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes: Results From the MDS-005 Study.

Clin Lymphoma Myeloma Leuk 2018 02 30;18(2):136-144.e7. Epub 2017 Dec 30.

Service d'Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France.

Background: The phase III MDS-005 study compared lenalidomide versus placebo in red blood cell transfusion-dependent (RBC-TD) patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS), ineligible/refractory to erythropoiesis-stimulating agents. Lenalidomide-treated patients were more likely to achieve transfusion independence (TI) ≥ 8 weeks (26.9% vs. 2.5%; P < .001) and hemoglobin increase ≥ 1.5 g/dL (19.4% vs. 2.5%) versus placebo.

Patients And Methods: Patients were randomized 2:1 to oral lenalidomide 10 mg once daily or placebo once daily (both on 28-day cycles). Patients with creatinine clearance 40 to 60 mL/min were given lenalidomide 5 mg once daily. Health-related quality of life (HRQoL), a predefined secondary end point, was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 questionnaire at baseline, week 12, week 24, every 12 weeks thereafter, and at discontinuation.

Results: At week 24, lenalidomide was associated with benefit versus placebo across all 5 preselected questionnaire scales (fatigue, dyspnea, global quality of life, physical functioning, and emotional functioning). After adjustment for baseline scores, only emotional functioning achieved significance (P = .047). Further improvement versus baseline was observed for patients who continued lenalidomide after week 24. In post hoc analyses, achievement of TI ≥ 8 weeks was associated with significant improvements across all scales (P < .01); an increase in hemoglobin level correlated with significant improvements in all scales at week 24, except emotional functioning (P < .05).

Conclusion: Lenalidomide did not adversely affect HRQoL in RBC-TD patients with lower-risk non-del(5q) MDS and response to lenalidomide was associated with significant improvements in HRQoL.
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http://dx.doi.org/10.1016/j.clml.2017.12.004DOI Listing
February 2018

Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial.

Lancet Haematol 2018 Mar 26;5(3):e117-e126. Epub 2018 Jan 26.

Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital, Düsseldorf, Germany.

Background: Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement-platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4-3·8).

Methods: This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18-90 years, and had platelets of 20 × 10 per L or less with or without a history of bleeding or 50 × 10 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 10 per L or <20 × 10 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 μg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523.

Findings: Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48-2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72-1·47]; p=0·89) were not significantly different between the two groups.

Interpretation: Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns.

Funding: Amgen Inc.
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http://dx.doi.org/10.1016/S2352-3026(18)30016-4DOI Listing
March 2018

Current treatment algorithm for the management of lower-risk MDS.

Hematology Am Soc Hematol Educ Program 2017 12;2017(1):453-459

Department of Hematology, Oncology and Palliative Care, Marien Hospital Düsseldorf, Düsseldorf, Germany.

Lower risk myelodysplastic syndromes (MDS), defined as MDS with a Revised International Prognostic Scoring System score ≤3.5 points, will remain a challenging entity in 2018. Supportive care continues to be the linchpin of treatment, although the options to reduce transfusion needs are broadening. To achieve red blood cell transfusion independence in non-del(5q) patients, erythropoiesis-stimulating agents remain a mainstay of therapy as long as endogenous erythropoietin levels are <500 U/L (and preferably <200 U/L). Experimental strategies for patients ineligible for erythropoiesis-stimulating agents or relapsing after gaining transfusion independence include immunosuppressive agents, transforming growth factor β inhibitors, and lenalidomide. All these alternatives have shown reasonable response rates in selected patient populations with lower risk MDS. Patients with del(5q) disease can derive long-term benefit from lenalidomide, and some patients remain transfusion free for extended periods even after discontinuation of the drug. In rare cases in which thrombocytopenia is the main clinical problem leading to clinically significant bleeding events, thrombopoietin receptor analogues may alleviate bleeding, increase platelet counts, and rarely lead to trilineage responses. It seems prudent to use these drugs only in patients with confirmed bone marrow blast counts <5%. Allogeneic stem cell transplantation is reasonable for patients with high molecular risk of progression and those failing several lines of treatment with signs of progression toward higher-risk MDS.
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http://dx.doi.org/10.1182/asheducation-2017.1.453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142548PMC
December 2017

Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions.

Oncotarget 2017 Sep 5;8(43):73483-73500. Epub 2017 Jul 5.

Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, dysplasia, and a variable clinical course with about 30% risk to transform to secondary acute myeloid leukemia (AML). In the past 15 years, diagnostic evaluations, prognostication, and treatment of MDS have improved substantially. However, with the discovery of molecular markers and advent of novel targeted therapies, new challenges have emerged in the complex field of MDS. For example, MDS-related molecular lesions may be detectable in healthy individuals and increase in prevalence with age. Other patients exhibit persistent cytopenia of unknown etiology without dysplasia. Although these conditions are potential pre-phases of MDS they may also transform into other bone marrow neoplasms. Recently identified molecular, cytogenetic, and flow-based parameters may add in the delineation and prognostication of these conditions. However, no generally accepted integrated classification and no related criteria are as yet available. In an attempt to address this challenge, an international consensus group discussed these issues in a working conference in July 2016. The outcomes of this conference are summarized in the present article which includes criteria and a proposal for the classification of pre-MDS conditions as well as updated minimal diagnostic criteria of MDS. Moreover, we propose diagnostic standards to delineate between ´normal´, pre-MDS, and MDS. These standards and criteria should facilitate diagnostic and prognostic evaluations in clinical studies as well as in clinical practice.
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http://dx.doi.org/10.18632/oncotarget.19008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650276PMC
September 2017

Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study.

Lancet Oncol 2017 10 1;18(10):1338-1347. Epub 2017 Sep 1.

Marien Hospital Düsseldorf, Düsseldorf, Germany.

Background: Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes.

Methods: In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/μL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383.

Findings: Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration.

Interpretation: Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing.

Funding: Acceleron Pharma.
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http://dx.doi.org/10.1016/S1470-2045(17)30615-0DOI Listing
October 2017

Isolated Splenic Metastasis from Non-Small-Cell Lung Cancer: A Case Report and Review of the Literature.

Case Rep Oncol 2017 May-Aug;10(2):638-643. Epub 2017 Jul 11.

Department of Oncology, Hematology and Palliative Care, Marien Hospital Düsseldorf, Düsseldorf, Germany.

Metastases to the spleen are rare but have been reported for different tumor entities, including breast cancer, lung cancer, colorectal cancer, ovarian cancer, and melanoma. As an isolated event, splenic metastasis from non-small-cell lung cancer (NSCLC) is exceedingly rare. Until now, only 28 cases have been reported in the medical literature. We report the case of a 66-year-old woman with NSCLC (adenocarcinoma) who presented with a synchronous, isolated splenic metastasis. Operative removal of both primary tumor and metastasis was not possible due to multiple comorbidities. Therefore, treatment was limited to combined systemic chemotherapy and simultaneous radiation of the primary tumor, which led to partial remission of the disease. Isolated metastasis to the spleen in NSCLC has been reported only 28 times in the medical literature, most often in male patients with right-sided lung tumors, most of which were adenocarcinomas. The majority of patients were asymptomatic with respect to splenic metastasis. About half of the reported cases were isolated metachronous splenic metastases. Splenectomy seems to confer a survival advantage. We review the pertinent medical literature.
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http://dx.doi.org/10.1159/000478002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567076PMC
July 2017
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