Thomas Nösslinger

New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients

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.

New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge

PURPOSE The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. PATIENTS AND METHODS Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. RESULTS In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. CONCLUSION In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.

Predictive Role of Interphase Cytogenetics for Survival of Patients With Multiple Myeloma

PURPOSE Recent metaphase cytogenetic studies suggested that specific chromosomal abnormalities are of prognostic significance in patients with multiple myeloma (MM). Because the true incidence of chromosomal abnormalities in MM is much higher than that detected by metaphase analysis, we used interphase fluorescence in situ hybridization (FISH) to determine the prognostic value of specific chromosomal aberrations. PATIENTS AND METHODS Bone marrow plasma cells from 89 previously untreated patients with MM were studied consecutively by FISH to detect the deletions of 13q14, 17p13, and 11q and the presence of t(11;14)(q13;q32). FISH results were analyzed in the context of clinical parameters (response to treatment and survival after conventional-dose chemotherapy), and a multivariate analysis of prognostic factors was performed. RESULTS By FISH, the deletion of 13q14 occurred in 40 patients (44.9%), deletion of 17p13 in 22 (24.7%), and 11q abnormalities in 14 (15.7%; seven with t(11;14)). Deletions of 13q14 and 17p13 were associated with poor response to induction treatment (46.9% v 77.3% in those without deletions, P =.006 and 40.0% v 73.2%, P =.008, respectively) and short median overall survival (OS) time (24.2 v 88.1 months, P =. 008 and 16.2 v 51.3 months, P =.008, respectively). Short median OS time was also observed for patients with 11q abnormalities (13.1 v 41.6 months, P =.02). According to the number of unfavorable cytogenetic features (deletion of 13q14, deletion of 17p13, and aberrations of 11q) that were present in each patient (0 v 1 v 2 or 3), patients with significantly different OS times could be discriminated from one another (102.4 v 29.6 v 13.9 months, P <.001, respectively). CONCLUSION For patients with MM who were treated with conventional-dose chemotherapy, interphase FISH for 13q14, 17p13, and 11q provides prognostically relevant information in addition to that provided by standard prognostic factors. This observation may be considered for risk-adapted stratifications of MM patients in future clinical trials.

Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS)

The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian–German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.

Coalesced Multicentric Analysis of 2,351 Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics of Myelodysplastic Syndromes in the International Prognostic Scoring System

PURPOSE The International Prognostic Scoring System (IPSS) remains the most commonly used system for risk classification in myelodysplastic syndromes (MDSs). The IPSS gives more weight to blast count than to cytogenetics. However, previous publications suggested that cytogenetics are underweighted in the IPSS. Here we investigate the prognostic impact of cytogenetic subgroups compared with that of bone marrow blast count in a large, multicentric, international patient cohort. PATIENTS AND METHODS In total, 2,351 patients with MDS who have records in the German-Austrian and the MD Anderson Cancer Center databases were included and analyzed in univariate and multivariate models regarding overall survival and risk of transformation to acute myeloid leukemia (AML). The data were analyzed separately for patients treated with supportive care without specific therapy, with AML-like chemotherapy, or with other therapy regimens (low-dose chemotherapy, demethylating agents, immune modulating agents, valproic acid, and cyclosporine). RESULTS The prognostic impact of poor-risk cytogenetic findings (as defined by the IPSS classification) on overall survival was as unfavorable as an increased (> 20%) blast count. The hazard ratio (compared with an abnormal karyotype or a bone marrow blast count < 5%) was 3.3 for poor-risk cytogenetics, 4.8 for complex abnormalities harboring chromosomes 5 and/or 7, and 3.1 for a blast count of 21% to 30% (P < .01 for all categories). The predictive power of the IPSS cytogenetic subgroups was unaffected by type of therapy given. CONCLUSION The independent prognostic impact of poor-risk cytogenetics on overall survival is equivalent to the impact of high blast counts. This finding should be considered in the upcoming revision of the IPSS.

Cross-validation of prognostic scores in myelodysplastic syndromes on 386 patients from a single institution confirms importance of cytogenetics

In myelodysplastic syndromes (MDS) different prognostic risk analysis systems based on clinical and morphological data are used for predicting survival. Data on diagnostic and prognostic relevance of karyotype aberrations have prompted the development of scores including cytogenetics. The aim of this study was to assess and compare the explanatory power of different scoring systems and to assess the additional explanatory power of cytogenetics by evaluating the clinical and laboratory data of MDS patients from a single institution. Data of 386 MDS patients was available, with cytogenetic analysis at time of diagnosis in 256. Clinical/morphological scores: Bournemouth, modified Bournemouth and Düsseldorf; and scores including cytogenetics: Lausanne–Bournemouth, Lille and the International Prognostic Scoring System (IPSS), were calculated and their predictive power was compared for both overall survival and preleukaemic duration. Each of the scores had significant correlation on both endpoints. Calculating the prognostic value of different cytogenetic aberrations we found that differentiating between evidence for no aberration, single aberrations excluding chromosomes 7 and 8, aberrations on chromosomes 5, 7 or 8 and complex aberrations was important. These data were incorporated in a ‘prognostic index cytogenetics’ (pi score). Cytogenetic scores significantly improved the prognostic value of the best clinical/morphological score in regard to both overall survival and preleukaemic duration. In conclusion, our data further stress the importance of cytogenetics for predicting prognosis in MDS.

Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study

Myelodysplastic syndromes (MDS) with del(5q) are considered to have a benign course of the disease. In order to address the issue of the propensity of those patients to progress to acute myeloid leukemia (AML), data on 381 untreated patients with MDS and del(5q) characterized by low or intermediate I International Prognostic Scoring System (IPSS) risk score were collected from nine centers and registries. Median survival of the entire group was 74 months. Transfusion-dependent patients had a median survival of 44 months vs 97 months for transfusion-independent patients (P<0.0001). Transfusion need at diagnosis was the most important patient characteristic for survival. Of the 381 patients, 48 (12.6%) progressed to AML. The cumulative progression rate calculated using the Kaplan–Meier method was 4.9% at 2 years and 17.6% at 5 years. Factors associated with the risk of AML transformation were high-risk World Health Organization adapted Prognostic Scoring System (WPSS) score, marrow blast count >5% and red-cell transfusion dependency at diagnosis. In conclusion, patients with MDS and del(5q) are facing a considerable risk of AML transformation. More detailed cytogenetic and molecular studies may help to identify the patients at risk of progression.

Absence of clonal chromosomal relationship between concomitant B-CLL and multiple myeloma – a report on two cases

Abstract. B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) are chronic B-cell malignancies that represent different stages of B-cell maturation. Occasionally, both diseases are present in the same patient, and this raises the question of clonal associations between the two neoplasms. We here report on two patients with concomitant B-CLL and MM. Clonal chromosomal abnormalities in both lymphocytic cells and plasma cells were studied by interphase fluorescence in situ hybridization (FISH) using a panel of 24 chromosome- and region-specific DNA probes. In the first patient, cytogenetics revealed 47, X, t(Y;22)(p11;q10), +12, del14(q21q32). By FISH, +12 was present in lymphoid cells, but not in plasma cells. MM cells were characterized by multiple chromosomal gains (1, 11q23) and losses (5q, 10, 13q14, 15, 17p13, Y), which were all undetectable in lymphoid cells. The second patient, in whom no clonal abnormalities were obtained by conventional cytogenetic analysis, had lymphoid cells with loss of 8q24 by FISH. In contrast, evidence for a gain of 8q24 (consistent with amplification of c-myc) was obtained in 13% of plasma cells. Plasma cells were further characterized by gains of chromosomes 1, 3, 11, 18, and Y. We thus conclude that this comprehensive molecular cytogenetic analysis demonstrates the existence of two clonally distinct B-cell malignancies in both patients.

Both chromosome 13 abnormalities by metaphase cytogenetics and deletion of 13q by interphase FISH only are prognostically relevant in multiple myeloma

Objectives: Deletion of chromosome 13q [del(13q)] has emerged as a major adverse prognostic factor in multiple myeloma (MM). Del(13q) is detected two to three times more frequently by interphase fluorescence in situ hybridization (FISH) than by metaphase cytogenetics (CG). However, it has remained unclear whether or not del(13q) detected by FISH only provides the same prognostic information as its detection by CG.

Monosomal karyotype in MDS: explaining the poor prognosis?

Monosomal karyotype (MK) is associated with an adverse prognosis in patients in acute myeloid leukemia (AML). This study analyzes the prognostic impact of MK in a cohort of primary, untreated patients with myelodysplastic syndromes (MDS). A total of 431 patients were extracted from an international database. To analyze whether MK is an independent prognostic marker in MDS, cytogenetic and clinical data were explored in uni- and multivariate models regarding overall survival (OS) as well as AML-free survival. In all, 204/431 (47.3%) patients with MK were identified. Regarding OS, MK was prognostically significant in patients with ⩽4 abnormalities only. In highly complex karyotypes (⩾5 abnormalities), MK did not separate prognostic subgroups (median OS 4.9 months in MK+ vs 5.6 months in patients without MK, P=0.832). Based on the number of abnormalities, MK-positive karyotypes (MK+) split into different prognostic subgroups (MK+ and 2 abnormalities: OS 13.4 months, MK+ and 3 abnormalities: 8.0 months, MK+ and 4 abnormalities: 7.9 months and MK+ and ⩾5 abnormalities: 4.9 months; P<0.01). In multivariate analyses, MK was not an independent prognostic factor. Our data support the hypothesis that a high number of complex abnormalities, associated with an instable clone, define the subgroup with the worst prognosis in MDS, independent of MK.