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A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Br J Haematol 198(1), 114-130 (2022). doi:10.1111/bjh.18163, Published by Wiley-Blackwell, Oxford [u.a.]

Discontinuations and dose reductions

Quality of life

Second primary malignancies

Exposure and remissions

Subgroup analysis by randomization strata II

AE incidence and severity

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; P = 0.032), 36% and 23% of patients had stringent CR as best response (P = 0.08), and 4-year OS was 79% and 67% (P = 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.

Centers and enrolment

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 Dusseldorf 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.

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; P = 0.032), 36% and 23% of patients had stringent CR as best response (P = 0.08), and 4-year OS was 79% and 67% (P = 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.

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.

The role of bone marrow dysplastic erythroid precursors (EP) in both MDS and AML has been the subject of considerable debate over the past several decades. We have analyzed a large series of adults with MDS and focused on whether any% of EP identified in the bone marrow aspirates of over 1400 patients selected from the Dusseldorf, Germany adult MDS Registry has prognostic relevance. The data was examined for varying% of blasts, the WHO prognostic MDS subtypes and the IPSS-R. We did not identify any adjustment of bone marrow blast percentage by%EP, incuding the 50% rule" developed by the FAB leukemia working group, to have a meaningful impact on outcome, either leukemic risk of progression or overall survival. There was a trend for a%EP

Im Jahr 1997 wurde durch den Zusammenschluss der fuhrenden Leukamie-Studiengruppen in Deutschland das Kompetenznetz Akute und Chronische Leukamien (KNL) gegrundet. Wichtige Resultate sind neue Kooperationsstudien und Forschungsprojekte, die Fortfuhrung und Erweiterung bestehender und die Grundung neuer nationaler Studiengruppen, die Verbesserung der Studieninfrastruktur sowie die Einrichtung von Patientenregistern und Biomaterialbanken. 2003 fuhrte das Konzept des KNL zur Grundung des European LeukemiaNet (ELN). In der Folge wurden in internationaler Kooperation zahlreiche europaische Managementleitlinien erarbeitet und mehrere landerubergreifende Projekte und Studien durchgefuhrt. Ziel des Netzes ist die Heilung der Leukamien durch kooperative Forschung.

Erythropoiesis is arranged in erythroblastic islands (Ery-Is),[1][1] the specialized niche known for more than 50 years[2][2] in which erythroid precursors proliferate and differentiate. However, the significance of erythropoiesis in anemia, the leading symptom of myelodysplastic syndromes (MDS)

Korrektur zu 10.1038/s41375-020-0826-9

In myelodysplastic syndromes (MDS), deletion of the short arm of chromosome 12 (del(12p)) is usually a small abnormality, rarely detected as a single aberration by chromosome banding analysis (CBA) of bone marrow metaphases. Del(12p) has been described in 0.6 to 5% of MDS patients at initial diagnosis and is associated with a good to intermediate prognosis as a sole anomaly according to current scoring systems. Here, we present the results of a systematic del(12p) testing in a German prospective diagnostic study (clinicaltrials.gov: NCT01355913) on 367 MDS patients in whom CD34+ peripheral blood cells were analysed for the presence of del(12p) by sequential fluorescence in situ hybridization (FISH) analyses. A cohort of 2,902 previously published MDS patients diagnosed by CBA served as control. We demonstrate that, using a sensitive FISH technique, 12p deletion occurs significantly more frequently in MDS than previously described (7.6% by CD34+ PB-FISH vs. 1.6% by CBA, P < 0.001) and is often associated with other aberrations (93% by CD34+ PB-FISH vs. 60% by CBA). Additionally, the detection rate can be increased by repeated analyses in a patient over time which is important for the patient´s prognosis to distinguish a sole anomaly from double or complex aberrations. To our knowledge, this is the first study to screen for 12p deletions with a suitable probe for ETV6/TEL in 12p13. Our data suggest that the supplement of a probe for the detection of a 12p deletion to common FISH probe panels helps to avoid missing a del(12p), especially as part of more complex aberrations.

During the last years, more and more treatment modalities are available for MDS patients. Therefore, we were interested if this is reflected in an improvement of the outcome of the patients. We analyzed the survival and rate of leukemic progression of 4147 patients from the Duesseldorf MDS registry diagnosed during the last 30 years and found an improvement of survival in those patients diagnosed after 2002 (30 vs. 23 months, p0.0001). In detail, the improvement of the prognosis was restricted to high-risk MDS patients diagnosed between 2002 and 2014 in comparison to the patient group diagnosed between 1982 and 2001 (19 vs. 13 months, p0.001), whereas the prognosis of low-risk MDS patients did not change significantly. The improvement of survival was still measurable after exclusion of RAEB-t patients and of those, that received an allogeneic stem cell transplantation. In line with this finding, we found a lower AML progression rate in the later diagnosed group. Unfortunately, we could not identify a clear reason for this finding but rather a multifactorial cause should be assumed. As death due to bleeding complications and infections was significantly lower, an improvement of BSC may be one of the underlying causes.

Background Myelodysplastic syndromes (MDS) present with a normo- or hyperplastic bone marrow in most cases. We aimed at a characterization of patients with different types of cellularity. Methods We assessed marrow cellularity both by histology and cytology in 1270 patients and analyzed hematologic, cytogenetic, and prognostic parameters accordingly. Results The concordance of the assessment of cellularity differed dramatically between histology and cytology as only 36.5% were described as hypocellular by both methods (P

MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/μl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/μl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p = n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population.

International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%-20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34(+)) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34(+) peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34(+) blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913). peerReviewed

Based on centrally diagnosed 3528 patients in the Dusseldorf registry, we validated the new proposals for the classification of the MDS by the WHO working group: 256 patients were diagnosed as MDSSLD (7,3%), 978 MDSMLD (27,7%), 227 MDS RS SLD (6,4%); 321 MDS RS MLD (9,1%), 159 MDS del(5q) (4,5%), 481 MDSEB 1 (13,6%), 620 MDSEB 2 (17,6%), and 148 MDS-U (4,2%). 352 patients (16,9% of the non blastic types) changed the category, mainly moving from RCMD to MDS RS MLD, RCUD and RCMD to MDS del(5q). Median survival times of the refined groups differed from more than 60 months in the MDSSLD (RS) groups, 37 months in the MDSMLD (RS) groups, 79 months of the MDS del(5q) group and 21 and 11 months in the MDSEB 1 and 2 groups, respectively. The difference between the groups with regard to the risk of AML evolution was also impressing. No major changes were made with regard to the MDS-U categories. In summary, the proposals of the WHO group for the classification of MDS are thoughtful, taking into account biologic parameters of the diseases, a more precise wording, to some extend pragmatic and feasible.

Introduction The LenaMain study is a prospective, randomized, open label, multicenter phase III trial which included 188 patients 3 months after first-line high dose treatment and autologous stem cell transplantation (NCT number: NCT00891384). Patients were equally randomized to receive either 25 (n = 94, arm A) or 5 mg (n = 94, arm B) lenalidomide maintenance until disease progression following a uniform 6 months of 25 mg lenalidomide consolidation. Final analysis after follow-up of 46.7 months was presented at ASCO 2018 (#8016) demonstrating an extended event-free survival for arm A (11.8 months, p=0.032) and an about 10% increase of grade 3/4 infections per year as main toxicity. Here we report analysis of quality of life (QoL) data as secondary endpoint of the study. Materials & Methods The EORTC Quality of Life Questionnaire C30 (QLQ-C30) was collected at baseline and then monthly at every new cycle. The Global Health Status/Quality of Life (GHS/QoL) scale, the utility score and seven subscales (fatigue, nausea and vomiting, pain, physical functioning, role functioning, disease symptoms, and adverse effects of treatment) were compared between groups using a mixed model for repeated measures. Results Baseline questionnaire compliance was excellent (95.7%) and declined over time (82%, 76%, 71%, 54%, 49% after consolidation and after year 1, 2, 3 and 4 of maintenance, respectively). At baseline, GHS/QoL (67/67) and utility (0.73/0.72) scores for arm A/B were generally high and did not differ between both arms. The median GHS/QoL change between consolidation baseline and maintenance baseline was -1%. GHS/QoL scores appear constant for both treatment arms at most time points in the first 2 years of maintenance. Relevant improvements ≥ 5 points were observed in 30% of patients while improvements ≥ 15 points were observed in 20% of patients. During the same time a similar percentage of patients had relevant ≥ 5 and ≥15 point deteriorations, with a general tendency for a slight increase at the end of year 2. Notably, a greater number of deteriorations was found in the 5 mg lenalidomide arm. Mean GHS/QoL was constant during maintenance with a slight decrease of Utility values remained constant during maintenance (change from baseline 0.003, p=0.9 at year 1; 0.02, p=0.7 at year 2) and the overall pattern in the change over time does not appear to show any clear differences between the two treatment arms. Looking at QLQ-C30 subgroup domains after two years of maintenance, we observed a significantly higher change from baseline for diarrhea in the 25 mg lenalidomide arm, which may be a long-term drug-related effect. Conversely, role functioning was also significantly better in patients treated within the 25 mg lenalidomide arm. Other subgroups did not show significant differences after the second year. Overall GHS/QOL scores were not significantly different in patients with CR vs. ≥ vgPR. Similarly, there was no statistical difference in patients on treatment for 1, 2, 3 or 4 years of maintenance or in patients suffering from grade 3/4 adverse events or not. Thus, neither disease activity, nor duration of treatment nor high-grade toxicity biased our results. Conclusion The LenaMain trial shows that maintenance treatment with 25 mg lenalidomide vs. 5 mg significantly prolongs event-free survival. QoL, as secondary objective, was not different between both treatment arms, even showing a trend for improved QoL in the 25 mg lenalidomide treatment arm. Thus, QoL was not governed by the higher rate of infectious toxicity during high-dose lenalidomide maintenance. Disclosures Boquoi: Amgen: Honoraria, Other: Travel grant; Bristol-Myers Squibb: Honoraria; Janssen: Other: Travel grant; Celgene: Other: Travel grant. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; ArtTempi: Honoraria; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Symbio: Honoraria. Kroeger:Sanofi: Honoraria; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding. Mai:Celgene: Other: travel grant; Janssen: Honoraria, Other: Travel grant; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding; Onyx: Other: travel grant; Mundipharma: Other: travel grant. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Fenk:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Other: Travel grant, Research Funding; Bristol-Meyers Squibb: Honoraria, Other: travel grant; Janssen: Honoraria.

In 2008, the WHO proposed changes in the classification of MDS regarding RCUD and MDS unclassifiable. We validated these proposals by using 2032 patients of the Düsseldorf MDS Registry. 10% of the patients had RCUD and 6% MDS-U. Among patients with RCUD, only 9% had RN and 6% had RT. There was no correlation between dysplastic cell line and type of cytopenia. There was no difference in prognosis between RCMD and MDS-U and between RA, RT, and RN. The separation of RA, RN, and RT is not justified suggesting a consolidation as RCUD. MDS-U should be integrated into RCMD.

The Competence Network "Acute and Chronic Leukemias" was founded in 1997 by the consolidation of the leading leukemia study groups in Germany. Key results are the development of new trials and cooperative studies, the setup of patient registries and biobanking facilities, as well as the improvement of study infrastructure. In 2003, the concept of the competence network contributed to the foundation of the European LeukemiaNet (ELN). Synergy with the ELN resulted in cooperation on a European and international level, standardization of diagnostics and treatment, and recommendations for each leukemia and interdisciplinary specialty. The ultimate goal of the network is the cure of leukemia through cooperative research.

Citation: Alpermann T, Schnittger S, Eder C, Dicker F, Meggendorfer M, Kern W, Schmid C, Aul C, Staib P, Wendtner CM, Schmitz N, Haferlach C, and Haferlach T. Molecular subtypes of NPM1 mutations have different clinical profiles, specific patterns of accompanying molecular mutations and varying outcome in intermediate risk acute myeloid leukemia. Haematologica. 2015; 100:xxx doi:10.3324/haematol.2015.133819

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P

Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high-risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional (n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD–HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide.

We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects

Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Dusseldorf registry who have been followed up for a median time of 21 months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71 years. At the time of analysis, 2877 patients (75.9 %) had deceased. In 1212 cases (42.1 %), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4 %) succumbed directly disease-related (AML (46.6 %), infection (27.0 %), bleeding (9.8 %)), whereas 277 patients (16.6 %) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease.

This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients' characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (P

8016Background: While Len MT after high-dose therapy (HDT) and autologous blood stem cell transplantation (aBSCT) is standard of care in pts with MM, optimal dosage has not been established. Method...

A 25-year-old man, known to have chronic myeloid leukaemia for four years, acutely developed a fever of 39.5 degrees and severe pain in the shoulder and hip joints. There was no evidence of joint disease. Treatment with indomethacin briefly improved the symptoms, but within 72 hours the patient developed a fulminant illness with high fever and clinical as well as biochemical signs of a severe consumption coagulopathy. Herpetiform efflorescences appeared over the head and trunk shortly before death. At autopsy there was histological and immunohistochemical evidence of a varicella infection with hepatitis, oesophageal involvement and severe internal organ bleedings. In immune-compromised patients with atypical prodromal symptoms a varicella infection must be considered so that causal treatment with acyclovir and hyperimmune-globulin can be begun in time.

In a 29-year-old man with primary thrombotic-thrombocytopenic purpura a significantly increased plasma concentration of platelet-specific proteins was demonstrated as an expression of increased intravascular platelet activation and destruction during the acute phase of the disease. There was also abnormally elevated IgG loading of platelets. During administration of fresh plasma alone (total of six litres over one week) the clinical state deteriorated further into coma and failure of spontaneous ventilation. The marked thrombocytopenia and microangiopathic haemolytic anaemia remained unchanged. Only after repeated plasmapheresis was it possible to break through the acute disease process. Remission (restoration of vital functions, normalization of platelet count and haemolysis signs) was achieved after five courses of plasmapheresis with a total exchange volume of 20 litres. At least in this case, the therapeutic success of plasmapheresis argues for an immunological-toxic genesis of thrombotic-thrombocytopenic purpura.

We have generated a large, unique database that includes morphologic, clinical, cytogenetic, and follow-up data from 2124 patients with myelodysplastic syndromes (MDSs) at 4 institutions in Austria and 4 in Germany. Cytogenetic analyses were successfully performed in 2072 (97.6%) patients, revealing clonal abnormalities in 1084 (52.3%) patients. Numeric and structural chromosomal abnormalities were documented for each patient and subdivided further according to the number of additional abnormalities. Thus, 684 different cytogenetic categories were identified. The impact of the karyotype on the natural course of the disease was studied in 1286 patients treated with supportive care only. Median survival was 53.4 months for patients with normal karyotypes (n = 612) and 8.7 months for those with complex anomalies (n = 166). A total of 13 rare abnormalities were identified with good (+1/+1q, t(1q), t(7q), del(9q), del(12p), chromosome 15 anomalies, t(17q), monosomy 21, trisomy 21, and −X), intermediate (del(11q), chromosome 19 anomalies), or poor (t(5q)) prognostic impact, respectively. The prognostic relevance of additional abnormalities varied considerably depending on the chromosomes affected. For all World Health Organization (WHO) and French-American-British (FAB) classification system subtypes, the karyotype provided additional prognostic information. Our analyses offer new insights into the prognostic significance of rare chromosomal abnormalities and specific karyotypic combinations in MDS.

The International Prognostic Scoring System (IPSS) for myelodysplastic syndromes (MDS) identifies bone marrow (BM) blasts, cytogenetics, and the number of cytopenias as major variables with impact on disease outcome. Weighting of these variables defines distinct subgroups using multivariate analysis approaches. Recent studies, including the work of our group, indicate an underestimation of unfavorable cytogenetics in the IPSS. To delineate the prognostic impact of poor-risk karyotypes in relation to blast counts, we studied clinical outcome of cytogenetic and blast count subgroups in a large cohort of 1440 patients with MDS. Using univariate analytic tools, median survival times of 158 patients with poor-risk cytogenetics and 66 patients with blast counts of > 20% were 11.1 months and 9 months, respectively. Median survival times of patients with poor-risk cytogenetics and normal blast counts (n = 60; median survival, 17 months) were not significantly different from those of good-risk karyotypes and highly elevated BM blasts (11%–20%: n = 89; median survival, 22 months; P = .098; > 20%: n = 32; median survival, 13 months; P = .892). Our data indicate an equal prognostic significance of poor-risk cytogenetics compared with highly elevated BM blasts and suggest a higher score for unfavorable karyotypes in future integrative prognostic systems in MDS.

In the criteria of refractory cytopenia with multilineage dysplasia (RCMD) according to the WHO (World Health Organization) classification, the frequency threshold concerning dysplasia of each lineage was defined as 10%. To predict overall survival (OS) and leukemia-free survival (LFS) for patients with refractory anemia (RA) according to the French-American-British (FAB) classification, we investigated prognostic factors based on the morphological features of 100 Japanese and 87 German FAB-RA patients, excluding 5q-syndrome. In the univariate analysis of all patients, pseudo-Pelger-Huet anomaliesor=10% (Pelger+), micromegakaryocytesor=10% (mMgk+), dysgranulopoiesis (dys G)or=10% and dysmegakaryopoiesis (dys Mgk)or=40% were unfavorable prognostic factors for OS and LFS (OS; P0.001, LFS; P0.001). The prognostic effects of the morphological features were similar in both Japanese and German patients. However, dys Mgkor=10% was not correlated with OS and LFS. In the multivariate analysis, mMgk+ and dys Mgkor=40% were adverse prognostic factors for OS for all patients, and dys Gor=10% and dys Mgkor=40% were adverse prognostic factors for LFS for all patients. On the basis of the present analysis, we propose the following modified morphological criteria for RCMD. Modified RCMD should be defined as FAB-RA, excluding 5q-syndrome with dys Gor=10%, dys Mgkor=40% or mMgk+.