Publications by authors named "Reinhard Stauder"

84 Publications

The EORTC QLU-C10D was more efficient in detecting clinical known group differences in myelodysplastic syndromes than the EQ-5D-3L.

J Clin Epidemiol 2021 Mar 19. Epub 2021 Mar 19.

Italian Group for Adult Hematologic Diseases (GIMEMA), Data Center & Health Outcomes Research Unit, Rome, Italy.

Background: The aim was to investigate the relative validity of the preference-based measure EORTC QLU-C10D in comparison with the EQ-5D-3L in myelodysplastic syndromes (MDS) patients.

Methods: We used data from an international multicentre, observational cohort study of MDS patients. Baseline EORTC QLU-C10D and EQ-5D-3L scores were used and index scores calculated for Italy, Australia, and the UK. Criterion validity was established by Spearman and intraclass correlations (ICC) and Bland-Altman plots. Construct validity was established by the instruments' ability to discriminate known groups, i.e. groups whose health status is expected to differ.

Results: We analysed data from 619 MDS patients (61.1% male; median age 73.8 years). Correlations between theoretically corresponding domains were largely higher than between unrelated domains. ICCs and Bland-Altman plots indicated moderate to good criterion validity. Ceiling effects were lower for the QLU-C10D (4.7%) than for the EQ-5D-3L (22.6%). The EQ-5D-3L failed to discriminate known-groups in two and the QLU-C10D in one of the comparisons; the QLU-C10D's efficiency in doing so was higher in clinical known-groups. Results were comparable between the countries.

Conclusions: The QLU-C10D may be suitable to generate health utilities for economic research in MDS. Responsiveness and minimal important differences need yet to be established.
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http://dx.doi.org/10.1016/j.jclinepi.2021.03.015DOI Listing
March 2021

Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia.

Int J Mol Sci 2020 Aug 22;21(17). Epub 2020 Aug 22.

Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO), Medical University of Vienna, 1090 Vienna, Austria.

We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in , and that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated but not was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival ( < 0.00001) and time to transformation ( = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including , however, was predictive for inferior survival ( = 0.00059) as well as for increased risk of transformation ( = 0.01429). In conclusion, we show that the composite molecular profile derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML.
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http://dx.doi.org/10.3390/ijms21176057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504428PMC
August 2020

Guideline-based indicators for adult patients with myelodysplastic syndromes.

Blood Adv 2020 08;4(16):4029-4044

Department of Hematology and Central Hematology Laboratory, Inselspital/Bern University Hospital, and.

Myelodysplastic syndromes (MDSs) represent a heterogeneous group of hematological stem cell disorders with an increasing burden on health care systems. Evidence-based MDS guidelines and recommendations (G/Rs) are published but do not necessarily translate into better quality of care if adherence is not maintained in daily clinical practice. Guideline-based indicators (GBIs) are measurable elements for the standardized assessment of quality of care and, thus far, have not been developed for adult MDS patients. To this end, we screened relevant G/Rs published between 1999 and 2018 and aggregated all available information as candidate GBIs into a formalized handbook as the basis for the subsequent consensus rating procedure. An international multidisciplinary expert panel group (EPG) of acknowledged MDS experts (n = 17), health professionals (n = 7), and patient advocates (n = 5) was appointed. The EPG feedback rates for the first and second round were 82% (23 of 28) and 96% (26 of 27), respectively. A final set of 29 GBIs for the 3 domains of diagnosis (n = 14), therapy (n = 8), and provider/infrastructural characteristics (n = 7) achieved the predefined agreement score for selection (>70%). We identified shortcomings in standardization of patient-reported outcomes, toxicity, and geriatric assessments that need to be optimized in the future. Our GBIs represent the first comprehensive consensus on measurable elements addressing best practice performance, outcomes, and structural resources. They can be used as a standardized instrument with the goal of assessing, comparing, and fostering good quality of care within clinical development cycles in the daily care of adult MDS patients.
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http://dx.doi.org/10.1182/bloodadvances.2020002314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448599PMC
August 2020

Adapting care for older cancer patients during the COVID-19 pandemic: Recommendations from the International Society of Geriatric Oncology (SIOG) COVID-19 Working Group.

J Geriatr Oncol 2020 11 16;11(8):1190-1198. Epub 2020 Jul 16.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

The COVID-19 pandemic poses a barrier to equal and evidence-based management of cancer in older adults. The International Society of Geriatric Oncology (SIOG) formed a panel of experts to develop consensus recommendations on the implications of the pandemic on several aspects of cancer care in this age group including geriatric assessment (GA), surgery, radiotherapy, systemic treatment, palliative care and research. Age and cancer diagnosis are significant predictors of adverse outcomes of the COVID-19 infection. In this setting, GA is particularly valuable to drive decision-making. GA may aid estimating physiologic reserve and adaptive capability, assessing risk-benefits of either providing or temporarily withholding treatments, and determining patient preferences to help inform treatment decisions. In a resource-constrained setting, geriatric screening tools may be administered remotely to identify patients requiring comprehensive GA. Tele-health is also crucial to ensure adequate continuity of care and minimize the risk of infection exposure. In general, therapeutic decisions should favor the most effective and least invasive approach with the lowest risk of adverse outcomes. In selected cases, this might require deferring or omitting surgery, radiotherapy or systemic treatments especially where benefits are marginal and alternative safe therapeutic options are available. Ongoing research is necessary to expand knowledge of the management of cancer in older adults. However, the pandemic presents a significant barrier and efforts should be made to ensure equitable access to clinical trials and prospective data collection to elucidate the outcomes of COVID-19 in this population.
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http://dx.doi.org/10.1016/j.jgo.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365054PMC
November 2020

Clinical, Hematologic, Biologic and Molecular Characteristics of Patients with Myeloproliferative Neoplasms and a Chronic Myelomonocytic Leukemia-Like Phenotype.

Cancers (Basel) 2020 Jul 14;12(7). Epub 2020 Jul 14.

Department of Internal Medicine V with Hematology, Oncology and Palliative Care, Hospital Hietzing, 1130 Vienna, Austria.

Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from -mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (-mutated, 28 months; -nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.
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http://dx.doi.org/10.3390/cancers12071891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409251PMC
July 2020

High serum ferritin levels in newly diagnosed patients with myelodysplastic syndromes are associated with greater symptom severity.

Int J Hematol 2020 Aug 25;112(2):141-146. Epub 2020 Jun 25.

Data Center and Health Outcomes Research Unit, Italian Group for Adult Haematologic Diseases (GIMEMA), Rome, Italy.

We examined the association between serum ferritin (SF) levels and patient-reported functional aspects and symptoms, as measured by the EORTC QLQ-C30, in newly diagnosed patients with myelodysplastic syndromes (MDS). Analysis was conducted on 497 MDS patients who were classified in two groups based on the SF value of 1000 ng/mL. Clinically relevant differences of patient-reported functional and symptom scales were evaluated and classified as small, medium and large, based on established thresholds. Multivariable linear regression analysis was performed to account for potential confounding factors. Patients with SF of ≥ 1000 ng/mL reported statistically significant and clinically relevant worse outcomes across various health domains. Dyspnea was the symptom indicating the largest difference and mean scores of patients with higher and lower SF levels were 40 and 24.3, respectively (p = 0.005), indicating a large clinically relevant difference (Δ = 15.7). Further research is needed to better understand the relationship between SF levels and specific health-related quality of life domains.
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http://dx.doi.org/10.1007/s12185-020-02920-yDOI Listing
August 2020

Development of a core outcome set for myelodysplastic syndromes - a Delphi study from the EUMDS Registry Group.

Br J Haematol 2020 11 14;191(3):405-417. Epub 2020 May 14.

Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Innsbruck, Austria.

Treatment options for myelodysplastic syndromes (MDS) vary widely, depending on the natural disease course and patient-related factors. Comparison of treatment effectiveness is challenging as different endpoints have been included in clinical trials and outcome reporting. Our goal was to develop the first MDS core outcome set (MDS-COS) defining a minimum set of outcomes that should be reported in future clinical studies. We performed a comprehensive systematic literature review among MDS studies to extract patient- and/or clinically relevant outcomes. Clinical experts from the European LeukemiaNet MDS (EUMDS) identified 26 potential MDS core outcomes and participated in a three-round Delphi survey. After the first survey (56 experts), 15 outcomes met the inclusion criteria and one additional outcome was included. The second round (38 experts) resulted in six included outcomes. In the third round, a final check on plausibility and practicality of the six included outcomes and their definitions was performed. The final MDS-COS includes: health-related quality of life, treatment-related mortality, overall survival, performance status, safety, and haematological improvement. This newly developed MDS-COS represents the first minimum set of outcomes aiming to enhance comparability across future MDS studies and facilitate a better understanding of treatment effectiveness.
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http://dx.doi.org/10.1111/bjh.16654DOI Listing
November 2020

Geriatric assessment in older patients with a hematologic malignancy: a systematic review.

Haematologica 2020 06 7;105(6):1484-1493. Epub 2020 May 7.

Department of Geriatric Medicine, Diakonessenhuis Utrecht, Utrecht, the Netherlands.

The aim of this systematic review is to give an update of all currently available evidence on the relevance of a geriatric assessment in the treatment of older patients with hematologic malignancies. A systematic search in MEDLINE and EMBASE was performed to find studies in which a geriatric assessment was used to detect impaired geriatric domains or to address the association between geriatric assessment and survival or clinical outcome measures. The literature search included 4,629 reports, of which 54 publications from 44 studies were included. Seventy-three percent of the studies were published in the last 5 years. The median age of the patients was 73 years (range, 58-86) and 71% had a good World Health Organization (WHO) performance status. The median prevalence of geriatric impairments varied between 17% and 68%, even in patients with a good WHO performance status. Polypharmacy, nutritional status and instrumental activities of daily living were most frequently impaired. Whereas several geriatric impairments and frailty (based on a frailty screening tool or summarized geriatric assessment score) were predictive for a shorter overall survival, WHO performance status lost its predictive value in most studies. The association between geriatric impairments and treatment-related toxicity varied, with a trend towards a higher risk of (non-)hematologic toxicity in frail patients. During the follow-up, frailty seemed to be associated with treatment non-completion, especially when patients were malnourished. Patients with a good physical capacity had a shorter stay in hospital and a lower rate of hospitalization. Geriatric assessment, even in patients with a good performance status, can detect impaired geriatric domains and these impairments may be predictive of mortality. Moreover, geriatric impairments suggest a higher risk of treatment-related toxicity, treatment non-completion and use of healthcare services. A geriatric assessment should be considered before starting treatment in older patients with hematologic malignancies.
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http://dx.doi.org/10.3324/haematol.2019.245803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271571PMC
June 2020

Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia-A Retrospective Analysis in 337 Patients.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.

Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, = 236) and with (B, = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% ( < 0.0001), and of high colony growth (≥20/10 peripheral blood mononuclear cells) 31%, 44%, and 80% ( < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.
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http://dx.doi.org/10.3390/ijms21083025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215883PMC
April 2020

Comorbidities cluster with impaired functional capacities and depressive mood and predict adverse outcome in older patients with hematological malignancies.

Leuk Lymphoma 2020 08 13;61(8):1954-1964. Epub 2020 Apr 13.

Department of Internal Medicine V (Haematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria.

This study evaluates prevalence of comorbidities and their association with impairments in older patients with hematological malignancies at initial diagnosis ( = 209). At least one comorbidity was present in 62.2%, 68.5% and 93.8% as defined by CCI (Charlson Comorbidity Index), Cumulative Illness Rating Scale-Geriatric (CIRS-G) and HCT-Comorbidity Index, respectively. Severe comorbidities (CIRS-G Grade 3/4) were present in 57.9%. The mean number of affected organ systems was 3.6 (CIRS-G categories), with diabetes (18.2%), congestive heart failure and prior solid tumors (each 17.7%) detected most frequently. Comorbidities were significantly correlated with reduced functional and objective physical capacities, impaired performance and depressive mood. Both CCI and CIRS-G were found to be prognostic factors for OS ( < 0.05). CCI scoring of comorbidities, diagnosis MDS/AML and a body mass index <23kg/m were independent adverse predictors for OS. This first prospective analysis reveals a prognostic significance of comorbidities. Clustering of comorbidities with impairments suggests common mechanisms.
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http://dx.doi.org/10.1080/10428194.2020.1747063DOI Listing
August 2020

The Prognostic Impact of Comorbidities in Patients with De-Novo Diffuse Large B-Cell Lymphoma Treated with R-CHOP Immunochemotherapy in Curative Intent.

J Clin Med 2020 Apr 2;9(4). Epub 2020 Apr 2.

Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, 6020 Innsbruck, Austria.

Background: Patient-related factors, namely comorbidities, impact the clinical outcome of patients with diffuse large B-cell lymphoma (DLBCL).

Methods: The prevalence and prognostic impact of comorbidities were examined using the validated scores Charlson Comorbidity Index (CCI) and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) in 181 patients with DLBCL at initial diagnosis before treatment with rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP).

Results: Pronounced comorbidities as defined by CCI and HCT-CI scoring of ≥2 were detected in 9.9% and 28.2% of patients, respectively, and occurred more frequently at advanced age ( < 0.001). Higher CCI scoring was associated with lower complete response rate ( = 0.020). Both advanced CCI and HCT-CI were significantly associated with shortened overall survival (3-year OS: CCI ≥2 vs. 0-1, 38.9% vs. 81.3%, < 0.001; HCT-CI ≥2 vs. 0-1, 56.9% vs. 84.9%, < 0.001). Both comorbidity scores remained independent risk factors in the multivariate analysis (HCT-CI ≥2 HR: 2.6, = 0.004; CCI ≥2 HR: 3.6, = 0.001).

Conclusion: This study demonstrates the prognostic relevance of comorbidities classified by CCI and HCT-CI in patients with DLBCL undergoing curative treatment with R-CHOP. A structured evaluation of comorbidities might refine prognostication alongside currently used prognostic parameters, namely age, and should be evaluated in prospective trials.
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http://dx.doi.org/10.3390/jcm9041005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230391PMC
April 2020

Structured assessment of frailty in multiple myeloma as a paradigm of individualized treatment algorithms in cancer patients at advanced age.

Haematologica 2020 05 2;105(5):1183-1188. Epub 2020 Apr 2.

Department of Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.3324/haematol.2019.242958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193478PMC
May 2020

The IPSS-R more accurately captures fatigue severity of newly diagnosed patients with myelodysplastic syndromes compared with the IPSS index.

Leukemia 2020 09 21;34(9):2451-2459. Epub 2020 Feb 21.

Data Center and Health Outcomes Research Unit, Italian Group for Adult Haematologic Diseases (GIMEMA), Rome, Italy.

We aimed to compare fatigue of newly diagnosed patients with myelodysplastic syndromes (MDS) with that of the general population (GP). We also investigated the ability of the IPSS and IPSS-R to capture severity of patient-reported fatigue at diagnostic workup. A sample of 927 newly diagnosed patients with MDS was consecutively enrolled in a large international observational study and all patients completed the FACIT-Fatigue questionnaire at baseline. Fatigue was compared with that of the GP (N = 1075) and a 3-point difference in mean scores was considered as clinically meaningful. Fatigue of MDS patients was on average 4.6 points below the mean of the GP (95% CI, -5.9 to -3.2, p < 0.001), reflecting clinically meaningful worse fatigue. Unlike the IPSS, the IPSS-R identified clearly distinct subgroups with regard to burden of fatigue. Mean scores differences compared with GP ranged from nonclinically relevant for very low risk (Δ = -1.8, 95% CI, -4.0 to 0.5, p = 0.119) to large clinically meaningful differences for very high-risk IPSS-R patients (Δ = -8.2, 95% CI, -10.3 to -6.2, p < 0.001). At diagnostic workup, fatigue of MDS is clinically meaningful worse than that reported by the GP. Compared with the IPSS classification, the IPSS-R provides a better stratification of patients with regard to fatigue severity.
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http://dx.doi.org/10.1038/s41375-020-0746-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509847PMC
September 2020

Malnutrition in Older Patients With Hematological Malignancies at Initial Diagnosis - Association With Impairments in Health Status, Systemic Inflammation and Adverse Outcome.

Hemasphere 2020 Feb 15;4(1):e332. Epub 2020 Jan 15.

Department of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria.

Poor nutritional status is a common problem in cancer patients at advanced age, but the prevalence and impact of malnutrition in hematological malignancies remains underinvestigated. To evaluate nutritional status in older adults over age 70 with newly diagnosed hematological malignancies, we enrolled 147 patients and assessed weight loss, food intake, Mini Nutritional Assessment (MNA), and BMI. We compared nutritional status with demographic data, inflammation markers, and restrictions in multidimensional geriatric assessment. MNA classified 43% of patients being at risk of, and 15% having manifest malnutrition. A moderate/severe decrease in food intake was reported by 24% or 16%, a recent weight loss of 1 to 3 kg or >3 kg by 19% or 31%, and a BMI <23 kg/m by 29%. Lowered serum albumin (<3.5 g/dL) was prevalent in 14% of patients, and in 38% Glasgow Prognostic Score indicated hyperinflammation. Principal component analysis clustered malnutrition with inflammation markers and pronounced impairments, that is, fatigue, depression, comorbidities, reduced functional capacities. Severe decrease in food intake (HR: 3.3 (1.9-5.8), p < 0.001), >3 kg weight loss (HR: 2.3 (1.4-3.9), p = 0.001), impaired MNA (HR: 2.8 (1.3-6.2), p = 0.010), and low serum albumin (HR: 2.1 (1.1-4.0), p = 0.030) were significantly associated with shortened overall survival. Recent weight loss >3 kg (HR: 2.2 (1.1-4.3), p = 0.022), and low BMI (HR: 3.3 (1.8-6.0), p < 0.001) remained independent adverse parameters in multivariate Cox proportional hazard regression analyses. Malnourishment at initial diagnosis is frequent in older patients with hematological malignancies and represents an adverse prognosticator. Clustering of malnutrition with impairments and systemic inflammation suggests an underlying common pathway.
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http://dx.doi.org/10.1097/HS9.0000000000000332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000469PMC
February 2020

Patient-reported outcome measures in studies of myelodysplastic syndromes and acute myeloid leukemia: Literature review and landscape analysis.

Eur J Haematol 2020 May 3;104(5):476-487. Epub 2020 Mar 3.

Celgene, A Bristol-Myers Squibb Company, Boudry, Switzerland.

Objectives: This study aims to describe the use of patient-reported outcome measures (PROMs) in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) studies and the PROMs landscape.

Methods: A comprehensive literature review was performed in Medline/Embase (since 2000) and ClinicalTrials.gov (since 2013) to identify PROMs used in MDS and AML clinical studies. Additionally, PROMs included in approved drug labels since 2000 were reviewed.

Results: Overall, 112 different PROMs were used in 168 published MDS studies and 152 PROMs were used in 172 AML studies. From ClinicalTrials.gov, 16 different PROMs were used in 22 ongoing registered studies in MDS, and 24 were reported in 41 AML studies. The most frequently used PROMs were cancer-specific (eg, EORTC QLQ-C30, FACT-An) or generic (SF-36, EQ-5D) instruments, whereas MDS- and AML-specific instruments (eg, QUALMS and QOL-E in MDS; FACT-Leu and EORTC QLQ-Leu in AML) were used in a minority of studies. Two EMA-approved drugs for MDS included PROMs in their label. EORTC QLQ-C30 is by far the most frequently used cancer-specific PROM in both MDS and AML studies.

Conclusions: This research indicated an underuse of AML/MDS-specific PROMs for these two indications in clinical studies and labeling claims. However, AML/MDS-specific instruments in development might be considered in future studies.
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http://dx.doi.org/10.1111/ejh.13389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217037PMC
May 2020

The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) : A representative and useful real-life data source for further biomedical research.

Wien Klin Wochenschr 2019 Sep 18;131(17-18):410-418. Epub 2019 Jul 18.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.
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http://dx.doi.org/10.1007/s00508-019-1526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748886PMC
September 2019

Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry.

Haematologica 2020 03 5;105(3):640-651. Epub 2019 Jul 5.

Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, USA.

Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at
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http://dx.doi.org/10.3324/haematol.2018.212332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049356PMC
March 2020

Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes.

Haematologica 2020 03 6;105(3):632-639. Epub 2019 Jun 6.

Department of Tumor Immunology - Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands

Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (<1×10): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at
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http://dx.doi.org/10.3324/haematol.2018.212217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049377PMC
March 2020

Classical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytes.

JCI Insight 2019 04 18;4(8). Epub 2019 Apr 18.

Department of Internal Medicine II.

Myelomonocytic cells are critically involved in iron turnover as aged RBC recyclers. Human monocytes are divided in 3 subpopulations of classical, intermediate, and nonclassical cells, differing in inflammatory and migratory phenotype. Their functions in iron homeostasis are, however, unclear. Here, we asked whether the functional diversity of monocyte subsets translates into differences in handling physiological and pathological iron species. By microarray data analysis and flow cytometry we identified a set of iron-related genes and proteins upregulated in classical and, in part, intermediate monocytes. These included the iron exporter ferroportin (FPN1), ferritin, transferrin receptor, putative transporters of non-transferrin-bound iron (NTBI), and receptors for damaged erythrocytes. Consequently, classical monocytes displayed superior scavenging capabilities of potentially toxic NTBI, which were augmented by blocking iron export via hepcidin. The same subset and, to a lesser extent, the intermediate population, efficiently cleared damaged erythrocytes in vitro and mediated erythrophagocytosis in vivo in healthy volunteers and patients having received blood transfusions. To summarize, our data underline the physiologically important function of the classical and intermediate subset in clearing NTBI and damaged RBCs. As such, these cells may play a nonnegligible role in iron homeostasis and limit iron toxicity in iron overload conditions.
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http://dx.doi.org/10.1172/jci.insight.98867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538345PMC
April 2019

Association of anemia with health-related quality of life and survival: a large population-based cohort study.

Haematologica 2019 03 11;104(3):468-476. Epub 2018 Oct 11.

Department of Hematology, University Medical Center Groningen, the Netherlands.

Anemia is highly prevalent, especially in older individuals. In selected populations, anemia has been reported to be associated with impaired survival and health-related quality of life. However, data on this impact in the general population are rare. Furthermore, discussions on the optimal definition of anemia have not been conclusive. We investigated these issues using survival data, scores from a health-related quality of life questionnaire (RAND-36), and hemoglobin concentration from 138670 subjects, aged 18-93 years, participating in the Lifelines cohort. Anemia was defined according to World Health Organization criteria and was further subclassified in participants over 60 years old. Anemia was present in 5510 (4.0%) of all 138670 subjects and 516 (2.8%) in the 18667 individuals older than 60 years. Anemia had no impact on overall survival and limited impact on health-related quality of life in individuals less than 60 years old. In contrast, in individuals over 60 years old anemia significantly impaired overall survival and health-related quality of life. The lower health-related quality of life was mainly observed in subscales representing physical functioning. Although consensus on the subclassification of anemia is lacking, our data suggest that particularly anemia of chronic inflammation was associated with worse overall survival and decreased health-related quality of life. Multivariate models confirmed that anemia was an independent risk factor for decreased health-related quality of life in older individuals. Finally, women with a hemoglobin concentration between 12.0-13.0 g/dL (considered anemia in men, but not in women) experienced a significantly lower health-related quality of life. This large, prospective, population-based study indicates that anemia is associated with worse overall survival and health-related quality of life in older individuals, but not in younger individuals. The findings of this study challenge the definition of anemia in women over 60 years old, and suggest that the optimal definition of anemia, in the perspective of health-related quality of life, in women over 60 years old should be altered to a hemoglobin concentration below 13.0 g/dL (8.0 mmol/L), which is comparable to that in men.
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http://dx.doi.org/10.3324/haematol.2018.195552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395328PMC
March 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

Multidisciplinary care in the hematology clinic: Implementation of geriatric oncology.

J Geriatr Oncol 2019 05 18;10(3):497-503. Epub 2018 Sep 18.

Dept. of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Innsbruck, Austria.

Multidisciplinary care is believed to provide benefits to patients with cancer. Tumor board conferences as well aspalliative care or psycho-oncological services have not only become common in oncology, but also in hematology clinics dedicated to the treatment of hematological cancers. Malignant hematological diseases are highly prevalent among older persons. Demographic changes in many countries worldwide are prompting the integration of geriatric principles, methodology, and expertise into existing procedures and infrastructure of multidisciplinary care in hematology clinics. Achieving this goal requires the close collaboration or even incorporation of multiple new professions in the hematology clinic in order to meet the needs of older patients with hematological malignancies who also have comorbidities and functional impairments. We here review the rationale, current evidence, and practical approaches of integrating geriatric oncology into multidisciplinary care in the hematology clinic.
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http://dx.doi.org/10.1016/j.jgo.2018.09.003DOI Listing
May 2019

Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes: Analysis from the International Working Group for Prognosis of MDS.

Leuk Res 2018 10 6;73:51-57. Epub 2018 Sep 6.

Stanford Cancer Institute, Stanford, CA, United States.

Clinical features of myelodysplastic syndromes (MDS) could be influenced by many factors, such as disease intrinsic factors (e.g., morphologic, cytogenetic, molecular), extrinsic factors (e.g, management, environment), and ethnicity. Several previous studies have suggested such differences between Asian and European/USA countries. In this study, to elucidate potential differences in primary untreated MDS between Japanese (JPN) and Caucasians (CAUC), we analyzed the data from a large international database collected by the International Working Group for Prognosis of MDS (300 and 5838 patients, respectively). JPN MDS were significantly younger with more severe cytopenias, and cytogenetic differences: less del(5q) and more +1/+1q, -1/del(1p), der(1;7), -9/del(9q), del(16q), and del(20q). Although differences in time to acute myeloid leukemia transformation did not occur, a significantly better survival in JPN was demonstrated, even after the adjustment for age and FAB subtypes, especially in lower, but not in higher prognostic risk categories. Certain clinical factors (cytopenias, blast percentage, cytogenetic risk) had different impact on survival and time to transformation to leukemia between the two groups. Although possible confounding events (e.g., environment, diet, and access to care) could not be excluded, our results indicated the existence of clinically relevant ethnic differences regarding survival in MDS between JPN and CAUC patients. The good performance of the IPSS-R in both CAUC and JP patients underlines that its common risk model is adequate for CAUC and JP.
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http://dx.doi.org/10.1016/j.leukres.2018.08.022DOI Listing
October 2018

Early platelet count kinetics has prognostic value in lower-risk myelodysplastic syndromes.

Blood Adv 2018 08;2(16):2079-2089

Department of Tumor Immunology-Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Prognosis of lower-risk (International Prognostic Scoring System [IPSS] low/intermediate-1) myelodysplastic syndrome (MDS) is heterogeneous and relies on steady-state assessment of cytopenias. We analyzed relative drops in neutrophil and platelet counts during the first 6 months of follow-up of lower-risk MDS patients. We performed a landmark analysis of overall survival (OS) of lower-risk MDS patients prospectively included in the European LeukaemiaNet MDS registry having a visit at 6 ± 1 month from inclusion to assess the prognostic relevance of relative drops in neutrophils and platelets, defined as (count at landmark - count at inclusion)/count at inclusion. Of 2102 patients, 807 were eligible for the stringent 6-month landmark analysis. Median age was 73 years. Revised IPSS was very low, low, and intermediate/higher in 26%, 43%, and 31% of patients, respectively. A relative drop in platelets >25% at landmark predicted shorter OS (5-year OS, 21.9% vs 48.6% with platelet drop ≤25%, < 10), regardless of baseline IPSS-revised or absolute platelet counts. Relative neutrophil drop >25% had no significant impact on OS. We built a classifier based on red blood cell transfusion dependence (RBC-TD) and relative platelet drop >25% at landmark. Patients with none (62%), either (27%), or both criteria (11%) had 5-year OS of 53.3%, 32.7%, and 9.0%, respectively ( < 10). This classifier was validated in an independent cohort of 335 patients. Combining relative platelet drop >25% and RBC-TD at 6 months from diagnosis provides an inexpensive and noninvasive way to predict outcome in lower-risk MDS. This study was registered at www.clinicaltrials.gov as #NCT00600860.
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http://dx.doi.org/10.1182/bloodadvances.2018020495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113605PMC
August 2018

Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts.

Haematologica 2018 10 3;103(10):1593-1603. Epub 2018 Aug 3.

Imagine Institute, INSERM U 1163, CNRS 8654, Université Paris Descartes, Sorbonne, Paris Cité, France

Pathological erythropoiesis with consequent anemia is a leading cause of symptomatic morbidity in internal medicine. The etiologies of anemia are complex and include reactive as well as neoplastic conditions. Clonal expansion of erythroid cells in the bone marrow may result in peripheral erythrocytosis and polycythemia but can also result in anemia when clonal cells are dysplastic and have a maturation arrest that leads to apoptosis and hinders migration, a constellation typically seen in the myelodysplastic syndromes. Rarely, clonal expansion of immature erythroid blasts results in a clinical picture resembling erythroid leukemia. Although several mechanisms underlying normal and abnormal erythropoiesis and the pathogenesis of related disorders have been deciphered in recent years, little is known about specific markers and targets through which prognosis and therapy could be improved in anemic or polycythemic patients. In order to discuss new markers, targets and novel therapeutic approaches in erythroid disorders and the related pathologies, a workshop was organized in Vienna in April 2017. The outcomes of this workshop are summarized in this review, which includes a discussion of new diagnostic and prognostic markers, the updated WHO classification, and an overview of new drugs used to stimulate or to interfere with erythropoiesis in various neoplastic and reactive conditions. The use and usefulness of established and novel erythropoiesis-stimulating agents for various indications, including myelodysplastic syndromes and other neoplasms, are also discussed.
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http://dx.doi.org/10.3324/haematol.2018.192518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165792PMC
October 2018

Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study.

Leukemia 2018 06 6;32(6):1380-1392. Epub 2018 Mar 6.

Department of Tumor Immunology - Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

In myelodysplastic syndromes (MDS), health-related quality of life (HRQoL) represents a relevant patient-reported outcome, which is essential in individualized therapy planning. Prospective data on HRQoL in lower-risk MDS remain rare. We assessed HRQOL by EQ-5D questionnaire at initial diagnosis in 1690 consecutive IPSS-Low/Int-1 MDS patients from the European LeukemiaNet Registry. Impairments were compared with age- and sex-matched EuroQol Group norms. A significant proportion of MDS patients reported moderate/severe problems in the dimensions pain/discomfort (49.5%), mobility (41.0%), anxiety/depression (37.9%), and usual activities (36.1%). Limitations in mobility, self-care, usual activities, pain/discomfort, and EQ-VAS were significantly more frequent in the old, in females, and in those with high co-morbidity burden, low haemoglobin levels, or red blood cells transfusion need (p < 0.001). In comparison to age- and sex-matched peers, the proportion of problems in usual activities and anxiety/depression was significantly higher in MDS patients (p < 0.001). MDS-related restrictions in the dimension mobility were most prominent in males, and in older people (p < 0.001); in anxiety/depression in females and in younger people (p < 0.001); and in EQ-VAS in women and in persons older than 75 years (p < 0.05). Patients newly diagnosed with IPSS lower-risk MDS experience a pronounced reduction in HRQoL and a clustering of restrictions in distinct dimensions of HRQoL as compared with reference populations.
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http://dx.doi.org/10.1038/s41375-018-0089-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990524PMC
June 2018

Prognostic impact of a suboptimal number of analyzed metaphases in normal karyotype lower-risk MDS.

Leuk Res 2018 04 31;67:21-26. Epub 2018 Jan 31.

Dep. of Tumor Immunology - Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address:

Conventional karyotype is one of the most relevant prognostic factors in MDS. However, about 50% of patients with MDS have a normal karyotype. Usually, 20-25 normal metaphases (nMP) are considered to be optimal to exclude small abnormal clones which might be associated with poor prognosis. This study evaluated the impact of examining a suboptimal number of metaphases in patients recruited to the EUMDS Registry with low and intermediate-1 risk according to IPSS. Only 179/1049 (17%) of patients with a normal karyotype had a suboptimal number of nMP, defined as less than 20 metaphases analyzed. The outcome (overall survival and progression-free survival) of patients with suboptimal nMP was not inferior to those with higher numbers of analyzed MP both in univariate and multivariate analyses. For patients with an abnormal karyotype, 224/649 (35%) had a suboptimal number of MP assessed, but this did not impact on outcome. For patients with a normal karyotype and suboptimal numbers of analyzable metaphases standard evaluation might be acceptable for general practice, but we recommend additional FISH-analyses or molecular techniques, especially in candidates for intensive interventions.
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http://dx.doi.org/10.1016/j.leukres.2018.01.022DOI Listing
April 2018