-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

112 Frequency and Prognostic Significance of Cytogenetic Abnormalities in 1269 Patients with Therapy-Related Myelodysplastic Syndrome - a Study of the International Working Group (IWG-PM) for Myelodysplastic Syndromes (MDS)Clinically Relevant Abstract

Myelodysplastic Syndromes—Clinical Studies
Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes—Clinical Studies: CMML and MDS Biology and Treatment
Saturday, December 3, 2016: 10:15 AM
Grand Hall C (Manchester Grand Hyatt San Diego)

Andrea Kuendgen, MD1,2*, Heinz Tuechler3*, Meritxell Nomdedeu, MD4*, Detlef Haase, MD5*, Guillermo Garcia-Manero, MD6, Rami S. Komrokji, MD7, Francesc Sole, PhD8, Mikkael A. Sekeres, MD, MS9,10, Matteo Giovanni Della Porta, MD11*, Alan F List, MD12, Mario Cazzola, MD13, Amy E. DeZern, MD, MHS14, Gail J. Roboz15, David P. Steensma, MD16, Arjan A. van de Loosdrecht, MD, PhD17, Richard F. Schlenk, MD18, Xavier Calvo, MD19*, Sabine Blum, MD20*, Arturo Pereira21*, Arturo Pereira21*, Peter Valent, MD22, Dolors Costa21*, Dolors Costa21*, Aristoteles Giagounidis23, Aristoteles Giagounidis23, Luis Benlloch24*, Uwe Platzbecker, MD25, Carmen Pedro, MD26*, Michael Lübbert, MD27, María Teresa Cedena, MD28*, Julie Schanz, MD29*, Sigrid Machherndl-Spandl, MD30, Maria Lopez-Pavia, MD24*, María Díez-Campelo, MD31*, Claudia D. Baldus, MD32, Montserrat Martínez de Sola33*, Reinhard Stauder, MD34*, Brayan Merchan, MD28*, Claudia Mende2*, Maria Teresa Voso, MD35, Maria Teresa Voso, MD35, Itziar Oiartzabal36*, Itziar Oiartzabal36*, Christina Ganster, PhD29*, Francesc Cobo37*, Thomas Schroeder, MD1,38*, Jordi Esteve39, Rainer Haas, MD38*, Benet Nomdedeu40*, Peter Greenberg, MD41, Ulrich Germing42* and Guillermo Sanz, MD43

1Heinrich-Heine-University Duesseldorf, Düsseldorf, Germany
2Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
3Boltzmann Institute for Leukemia Research, Hanusch Hospital, Vienna, Austria
4Fundació Clínic per la Recerca Biomèdica, Spanish MDS Cooperative Group, Barcelona, Spain
5Department of Hematology and Medical Oncology, Universitätsmedizin Göttingen, Göttingen, Germany
6Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
8MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain, Badalona, Spain
9Taussig Cancer Institute / Leukemia Program, Cleveland Clinic, Cleveland, OH
10Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH
11Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
12Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
13Departments of Hematology Oncology & Molecular Medicine, Fondazione IRCCS Policlinico San Matteo & University of Pavia, Pavia, Italy
14Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
15Weill Cornell Medical College, New York, NY
16Dana-Farber Cancer Institute, Boston, MA
17VU University Medical Center, Amsterdam, Netherlands
18University Hospital of Ulm, Ulm, Germany
19Hematological Cytology Laboratory, Hospital del Mar, GRETNHE, IMIM (Hospital del Mar Research Institute), Barcelona, Spain
20Haematology Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
21Hospital Clinic, Spanish MDS Cooperative Group, Barcelona, Spain
22Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
23Clinic for Oncology, Hematology, and Palliative Medicine, Marienhospital Düsseldorf, Düsseldorf, Germany
24Hospital Universitario La Fe, GESMD, Valencia, Spain
25Carl Gustav Carus an der Technischen Universität, Universitätsklinikum, Dresden, Germany
26Hospital del Mar, GESMD, Valencia, Spain
27Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center University of Freiburg, Freiburg, Germany
28GESMD, Valencia, Spain
29Department of Hematology and Medical Oncology, Georg-August-University Göttingen, Göttingen, Germany
301st Medical Department with Hematology, Stem Cell Transplantation, Hemostasis and Medical Oncology, Elisabethinen Hospital, Linz, Austria
31Hospital Universitario de Salamanca, Spanish MDS Cooperative Group, Salamanca, Spain
32Department of Hematology, Oncology and Tumorimmunology, Charité University School of Medicine, Berlin, Germany
33Hospital Parc Tauli, Sabadell, Spain
34Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Innsbruck, Austria
35University Tor Vergata, Rome, Italy
36Hospital Universitario Araba, Spanish MDS Cooperative Group, Vitoria-Gasteiz, Spain
37Hospital Teknon, Barcelona, Spain
38Dept. of Hematology, Oncology and clinical Immunology, Heinrich-Heine University, Duesseldorf, Germany
39Hospital Clinic de Barcelona, Spanish MDS Cooperative Group, Barcelona, Spain
40Spanish Cooperative Group, Barcelona, Spain
41Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA
42Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
43Hospital Universitario La Fe, Spanish MDS Cooperative Group, Valencia, Spain

To develop a prognostic scoring system tailored for therapy-related myelodysplastic syndromes (tMDS), we put together a database containing 1933 patients (pts) with tMDS from Spanish, German, Swiss, Austrian, US, Italian, and Dutch centers diagnosed between 1975-2015. Complete data to calculate the IPSS and IPSS-R were available in 1603 pts. Examining different scoring systems, we found that IPSS and IPSS-R do not risk stratify tMDS as well as they do primary MDS (pMDS), thereby supporting the need for a tMDS-specific score (Kuendgen et al., ASH 2015). The current analysis focuses on cytogenetic information as a potential component of a refined tMDS score, based on this large, unique patient cohort.

Of the 1933 pts, 477 had normal karyotype (KT), 197 had missing cytogenetics, while 467 had a karyotype not readily interpretable. Incomplete karyotype descriptions will be reedited for the final evaluation. Of the remaining 1269 pts the most frequent cytogenetic abnormalities (abn) were: -7, del(5q), +mar, +8, del(7q), -5, del(20q), -17, -18, -Y, del(12p), -20, and +1 with >30 cases each. Frequencies are shown in Table 1. Some abn were observed mostly or solely within complex KTs, such as monosomies, except -7. Others, like del(20q) or –Y, are mainly seen as single or double abn, while del(5q), -7, or del(7q) are seen in complex as well as non-complex KTs.

The cytogenetic profile overlapped with that of pMDS (most frequent abn: del(5q), -7/del(7q), +8, -18/del(18q), del(20q), -5, -Y, -17/del(17p), +21, and inv(3)/t(3q) (Schanz et al, JCO 2011)), with notable differences including overrepresentation of complete monosomies, a higher frequency of -7 or t(11q23), and a more frequent occurrence of cytogenetic subtypes in complex KTs, which was especially evident in del(5q) occurring as a single abn in 16%, compared to 70% within a complex KT.

IPSS-R cytogenetic groups were distributed as follows: Very Good (2%), Good (35%), Int (17%), Poor (15%), Very Poor (32%). Regarding the number of abn (including incomplete KT descriptions) roughly 30% had a normal KT, 20% 1, 10% 2, and 40% ≥3 abn, compared to pMDS: 55% normal KT, 29% 1, 10% 2, and 6% ≥3 abn.

To be evaluable for prognostic information, abn should occur in a minimum of 10 pts. As a single aberration this was the case for -7, +8, del(5q), del(20q), del(7q), -Y, and t(11;varia) (q23;varia). Of particular interest, there was no apparent prognostic difference between -7 and del(7q); del(5q) as a single abn was associated with a relatively good survival, while the prognosis was poor with the first additional abn; t(11q23) occurred primarily as a single abn and was associated with an extremely poor prognosis, and prognosis of pts with ≥4 abn was dismal independent of composition (Table 1).

To develop a more biologically meaningful scoring system containing homogeneous and prognostically stable groups, we will further combine subgroups with different abn leading to the same cytogenetic consequences. For example, deletions, unbalanced translocations, derivative chromosomes, dicentric chromosomes of 17p, and possibly -17 all lead to a loss of genetic material at the short arm of this respective chromosome affecting TP53.

Further information might be derived from analyses of the minimal common deleted regions. For some abn, like del(11q), del(3p), and del(9q), this can be refined to one chromosome band only (table 1).

Conclusion: Development of a robust scoring system for all subtypes of tMDS is challenging using existing variables. This focused analysis on the cytogenetic score component shows that favorable KTs are evident in a substantial proportion of pts, in contrast to historic data describing unfavorable cytogenetics in the majority of pts. Although complex and monosomal KTs are overrepresented, this suggests the existence of distinct tMDS-subtypes, although some of these cases might not be truly therapy-induced despite a history of cytotoxic treatment. The next steps will be to analyze the prognosis of the different groups, develop a tMDS cytogenetic score, and examine minimal deleted regions to identify candidate genes for development of tMDS, as well as to describe the possible influence of different primary diseases and treatments (radio- vs chemotherapy, different drugs) on induction of cytogenetic subtypes. Our detailed analysis of tMDS cytogenetics should reveal important prognostic information and is likely to help understand mechanisms of MDS development.

Disclosures: Komrokji: Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sole: Celgene: Membership on an entity's Board of Directors or advisory committees. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Roboz: Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Steensma: Genoptix: Consultancy; Ariad: Equity Ownership; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Millenium/Takeda: Consultancy. Schlenk: Celgene: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; AROG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Valent: Deciphera Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Amgen: Honoraria. Giagounidis: Celgene Corporation: Consultancy. Giagounidis: Celgene Corporation: Consultancy. Platzbecker: Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Lübbert: Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid.

*signifies non-member of ASH