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2195 A Molecular-Based Response Prediction Model to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome and Severe Thrombocytopenia

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster II
Hematology Disease Topics & Pathways:
Adult, Diseases, Therapies, MDS, Myeloid Malignancies, Clinically relevant
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Anne Sophie Kubasch1,2,3*, Aristoteles Giagounidis1,3,4, Georgia Metzgeroth5*, Anna Jonasova, MD, PhD6*, Regina Herbst, MD7*, Jose Miguel Torregrosa Diaz8*, Benoit De Renzis, MD9*, Katharina S. Götze1,3,10,11, Marie-Luise Huetter-Kroenke, MD12*, Marie-Pierre Gourin13*, Bohrane Slama, MD14*, Sophie Dimicoli-Salazar, MD15*, Pascale Cony-Makhoul, MD16*, Kamel Laribi, MD17*, Sophie Park, MD, PhD18*, Katja Jersemann19*, Dorothea Schipp20*, Klaus H. Metzeler, MD21, Oliver Tiebel, MD22*, Katja Sockel, MD1,23*, Silke Gloaguen, Msc1,3*, Anna Mies24*, Fatiha Chermat25*, Christian Thiede, MD24, Rosa Sapena26*, Richard F. Schlenk27,28, Pierre Fenaux, MD, PhD3,29,30, Uwe Platzbecker, MD1,3,31 and Lionel Ades, MD, PhD3,25,30

1German MDS Study Group (D-MDS), Leipzig, Germany
2Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital Leipzig, Leipzig, Germany
3The European Myelodysplastic Syndromes Cooperative Group (EMSCO), Leipzig, Germany
4Department of Oncology, Hematology and Palliative Care, Marienhospital Düsseldorf, Düsseldorf, Germany
5Department of Hematology and Oncology, University Medical Centre,, Mannheim, Germany
6Charles University General Hospital 1st Department of Medicine, Prague, Czech Republic
7Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
8Department of Hematology and Oncology, CHU de Poitiers, Poitiers, FRA
9Service d'Hématologie Clinique Adulte, Clermont Ferrand, FRA
10Department of Medicine III, Technical University of Munich, Munich, Germany
11German Cancer Consortium (DKTK), German Cancer Center (DKFZ), Heidelberg, Germany
12Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
13CHU Limoges, Limoges, FRA
14Oncologie Médicale-Hématologie Clinique, Centre Hospitalier Departemental, Avignon, France
15University Hospital Bordeaux, Pessac, France
16Service d'Hématologie, Centre Hospitalier Annecy-Genevois, Pringy, France
17Centre Hospitalier Du Mans, Le Mans, France
18Department of Hematology, CHU Grenoble, Grenoble Cedex 9, France
19GWT-TUD GmbH, Dresden, Germany
20DS-Statistics, Rosenthal-Bielatal, Germany
21Laboratory for Leukemia Diagnostics, Department of Hematology and Oncology, University Hospital, LMU Munich, Munich, Germany
22Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technical University Dresden, Dresden, Germany
23Dept. of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
24Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
25Service d'Hématologie Séniors, Hôpital Saint-Louis, Paris, France
26Groupe Francophone des Myélodysplasies, Paris, France
27Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
28German Cancer Research Center, NCT-clinical trials office, Heidelberg, Germany
29Hôpital Saint-Louis, Paris, France
30Groupe Francophone des Myélodysplasies (GFM), Paris, France
31Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany

*UP, LA contributed equally


A significant proportion of lower risk (LR)-MDS patients present with thrombocytopenia, being associated with shortened survival and higher risk of progression to acute myeloid leukemia (AML). Treatment options for patients with LR-MDS and severe thrombocytopenia remain limited apart from transfusion support. Romiplostim (ROM), a thrombopoietin receptor agonist (TPO-RA) has shown safety and efficacy dependent on endogenous TPO levels as well as platelet transfusion history in a poorly defined subset of LR-MDS patients (Giagounidis et al. Cancer 2014, Sekeres et al. BJH 2014).


The multicenter phase 2 EUROPE trial investigated potential biomarkers of response (e.g. TPO levels, molecular markers) to single agent ROM in LR-MDS patients with severe thrombocytopenia. Patients were eligible if platelet counts were ≤30 G/L or ≤50 G/L in case of bleeding history. The primary efficacy endpoint was the rate of hematologic improvement of platelets (HI-P, according to IWG 2006 criteria) lasting for at least 8 weeks after 16 weeks of ROM (750µg SC qw) treatment. At the time of screening, patients were assigned into 3 different cohorts based on their previous platelet transfusion events (PTE) as well as centrally assessed TPO serum levels (A: TPO<500 ng/l, PTE<6 units/past year; B: TPO<500 ng/l, PTE≥6 units or TPO≥500 ng/l, PTE<6 units, C: TPO≥ 500 ng/l, PTE≥6 units). Bone marrows analysis were centrally reviewed.


From 2015 to 2019, a total of 79 patients were included at 29 trial sites in Germany, France and the Czech Republic. Patients median age was 74 years (range 42-93), median baseline platelet count was 25.5 G/L (range 3-50 G/L) and they were stratified into cohort A (n=51) or B+C (n=28), respectively. The primary endpoint was met with 34 out of 79 (43%) patients responding (HI-P), with response being markedly higher in cohort A (49%, n=25) vs. cohort B and C (32%, n=9) (p=0.145). Ten (13%) and eight (10%) patients had additional neutrophil (HI-N) and erythroid (HI-E) responses, respectively. During treatment, six patients had transient increases in peripheral blasts to more than 10% and one patient progressed to AML after one month of ROM. Although a higher number of responders was observed in group A, neither TPO level at screening (p=0.21), nor number of pretreatment PTE (p=0.12) were significantly associated with response to ROM treatment. Thus, our findings do not confirm that baseline TPO levels and number of pretreatment PTE alone allow reliable prediction of response to ROM.

With the aim to identify new molecular patterns correlating with response, we performed a targeted NGS analysis for somatic variants in 54 candidate genes in 75 patients at baseline and in 44 patients after 16 weeks of ROM. Responders (R) more frequently exhibited mutations like SRSF2 (R=39%, NR=17%), RUNX1 (R=24%, NR=14%) and TET2 (R=30%, NR=29%), whereas non-responders (NR) exhibited mutations like DNMT3A (R=12%, NR=21%), U2AF1(R=9%, NR=14%) or ASXL1 (R=6%, NR 17%) more frequent. The percentages of patients with a response to ROM were similar regardless of total number of baseline somatic mutations. Comparing responders vs. non-responders, we found no significant changes of variant allelic burden of variants detected pre- and post-ROM (Fig. 1).

We identified the presence of a SRSF2 mutation as a significant predictor of response to ROM treatment (p=0.031, logistic regression). Mutated SRSF2 was significantly more frequent in responders (39%) compared to non-responders (17%) (p=0.036, Fisher’s exact test) (Fig. 2A,B). We used logistic regression with stepwise backward selection to assess the influence of the presence of ASXL1, DNMT3A, RUNX1, TET2 and SRSF2 mutations on response. Our final regression model excludes the non-significant ASXL1, DNMT3A, RUNX1 and TET2 mutations and includes the significant SRSF2 mutation, resulting in an overall accuracy of 64.0% for a correct ROM response prediction in this patient cohort.


This prospective study did not confirm a significant association between response to ROM, pretreatment PTE burden and endogenous TPO levels. Instead, patients with a mutated SRSF2 displayed a significantly higher response to ROM treatment. This may allow personalized treatment approaches in patients with LR-MDS and severe thrombocytopenia. In this study, extended treatment with ROM did not lead to a significant increase in AML cases.

Disclosures: Kubasch: Shire: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Giagounidis: AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Götze: Celgene: Research Funding. Cony-Makhoul: Novartis: Consultancy; Pfizer: Consultancy; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; BMS: Speakers Bureau. Laribi: takeda: Research Funding; novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding. Park: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Metzeler: Astellas: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria. Thiede: AgenDix GmbH: Other: Co-owner and CEO. Schlenk: PharmaMar: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Roche: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fenaux: BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Platzbecker: Bergenbio: Research Funding; Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding. Ades: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Research Funding; Celgene/BMS: Research Funding; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding.

OffLabel Disclosure: Romiplostim is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). Limitations of Use: Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.

*signifies non-member of ASH