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3037 Spliceosome Mutations Are Common in MPN-Associated Myelofibrosis with RBC-Transfusion-Dependence and Correlate with Response to Pomalidomide

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Hematology Disease Topics & Pathways:
Diseases, Therapies, MPN, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Onima Chowdhury, MD, PhD1*, Jennifer O'Sullivan, MB BCh BAO1*, Nikolas Barkas1*, Gemma Buck, BSc1*, Angela Hamblin, MD, PhD1*, Ayalew Tefferi, MD2, Haifa Al-Ali3*, Giovanni Barosi, MD4, Timothy Devos5, Heinz Gisslinger6*, Qian Jiang, MD7, Jean-Jacques Kiladjian, MD, PhD8, Ruben A. Mesa, MD, FACP9, Francesco Passamonti, MD10*, Vincent Ribrag, MD11, Gary J. Schiller, MD12, Alessandro M. Vannucchi, MD13*, Daobin Zhou, MD, PhD14*, Mary Frances McMullin, MD15, David Reiser16*, Jim Zhong16*, Robert Peter Gale17 and Adam J. Mead, MD, PhD1

1NIHR Biomedical Research Centre and MRC Molecular Haematology Unit, University of Oxford, Oxford, United Kingdom
2Division of Hematology, Mayo Clinic, Rochester, MN
3Universitätsklinikum Halle, Halle (Saale), Germany
4Center for the Study of Myelofibrosis, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
5Department of Hematology, University Hospitals Leuven (UZ Leuven), Leuven, Belgium
6Medical University of Vienna, Vienna, Austria
7Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
8INSERM U1131, Hopital Saint-Louis, Paris, France
9Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX
10Department of Hematology,University of Insubria, Varese, Italy
11DITEP, Gustave Roussy, Université Paris-Saclay, Villejuif, France
12David Geffen School of Medicine at UCLA, Los Angeles, CA
13CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
14Department of Hematology, Peking Union Medical College Hospital, Beijing, China
15Queen's University Belfast, Belfast, United Kingdom
16Celgene Corporation, Summit, NJ
17Haematology Research Center, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom


Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterised by the frequent presence of driver mutations in genes causing activation of JAK2 signalling pathways (JAK2, CALR and MPL). Additional mutations affecting epigenetic regulators and splicing machinery are common. Anaemia with RBC-transfusion-dependence is common in patients with advanced myelofibrosis and represents a major unmet need. The RESUME study assessed the rates of RBC-transfusion independence (TI) after therapy with Pomalidomide (POM) vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. 16% of patients in both the POM and placebo arms became TI.


The genetic landscape of strictly confirmed transfusion dependent MF is not fully characterised. Our aim was to analyse the genetics of transfusion-dependent myelofibrosis patients in the RESUME trial and correlate with clinical characteristics, outcome and therapy response.


DNA samples were available from 207 of 252 patients and analysed by targeted re-sequencing using a Fluidigm Access Array gene panel followed by next generation sequencing. The panel included JAK2, CALR, MPL, TET2, ASXL1, EZH2, DNMT3A, IDH1/2, CBL, IKZF1, U2AF1, CHEK2, TP53, SF3B1, SRSF2, SH2B3, BARD1, DAP3, HRAS, IRF4, KRAS, KIT, Mir662, NFE2, POLG, SCRIB, SETBP1, TCF12 and VPS45.


97% (95-99%) of subjects had a mutation in ≥1 targeted gene. 2 mutations were detected in 41% (34-48%) and ≥3 in 27% (21-33%). 7 had no detectable mutation. Mutations in JAK2V617F, CALR and MPL were identified in 66% (59-72%), 14% (8-19%) and 7% (4-11%) of subjects (Figure 1), with no driver mutation in 27 patients (13%; 9-18%) (triple-negative). 68% (61-74%) had additional non-driver mutations. 42% (35-48%) (N=86) had spliceosome mutations (U2AF1 [21%]; SF3B1 [11%]; SRSF2 [8%]; ZRSR2; [6%]). More spliceosome mutations were detected in men than women (47% [39-55%] vs 27% [15-40%]; p=0.009). Spliceosome mutations were mutually exclusive in 83 subjects and were less common in subjects with prior polycythaemia vera (17% [5-37%]) compared with prior essential thrombocythaemia (39% [22-58%]) and primary MF (46% [38-54%]; p=0.024). Mutations in epigenetic regulators (ASXL1, 28%; TET2, 8%; DNMT3A 5%; EZH2 4%) were detected at similar rates to those previously reported. High molecular risk (HMR) mutations (ASXL1, EZH2, IDH1/2, SRSF2) were detected in 36% [29-43%] of subjects. Only 10 of 105 subjects with an epigenetic regulator gene mutation had ≥1 related mutation. Subjects with JAK2V617F were significantly more likely than subjects with a CALR mutation to have: (1) ≥1 additional mutation (72% [64-79%] vs. 35% [18-54%], p=0.0001); (2) a spliceosome mutation (44% [36-53%] vs. 17% [6-36%], p=0.07), in particular a U2AF1 mutation (24% [17-32%] vs. 0%; p=0.004) and (3) a HMR mutation (38% [30-47%] vs. 21% [8-40%]; p=0.07). Survival at 1.5 years was 62% (55-67%) and was not significantly associated with the presence or number of mutations in this uniformly high-risk cohort. Survival in subjects without an SF3B1 mutation was better than those SF3B1-mutated (80% [56-91%]) vs. 59% [52-65%]; p=0.07). Driver mutation status did not influence the probability of achieving red blood cell (RBC) TI, regardless of therapy. Additional non-driver mutations were more often detected in those failing to achieve RBC-TI than those achieving RBC-TI (70% [63-77%] vs 56% [40-71%], p=0.07). Furthermore, those with additional non-driver mutations were less likely to achieve ≥50% reduction in RBC transfusions (24% [17-32%] vs. 39% [27-51%]; p=0.03). A significant correlation persisted in subjects receiving POM but not in those receiving placebo. There was also a significant correlation between U2AF1 mutations and RBC-TI in POM treated subjects compared with controls; U2AF1-mutated subjects were less likely to achieve RBC-TI (3% [1, 17%]) than U2AF1-unmutated subjects (25% [17, 34%], p=0.008). No other mutations were significantly correlated with response.


We found a high incidence of spliceosome mutations in persons with MPN-associated MF and RBC-transfusion-dependence. Mutation of U2AF1 correlated with response in subjects receiving POM but not in those receiving placebo. Incorporation of mutation profiling into clinical trial design may help to inform subgroups of patients that may benefit from the intervention.

Disclosures: Devos: Novartis: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Gisslinger: Shire: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann-La Roche AG: Other: Provided Pegylated Interferon Alpha 2a; Novartis: Other: Provided Ruxolitinib . Mesa: Incyte Corporation: Research Funding, Travel Support (EHA 2018); Otsuka: Other: Advisory Board; Onconova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Advisory Board, Research Funding; H3 Biosciences: Other: Research Funds (to institutions not investigator); Gilead: Research Funding; Sierra Oncology: Consultancy, Honoraria; Promedior: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Research Funds (to institutions not investigator), Research Funding; Novartis: Consultancy, Other: Advisory Board; CTI Biopharma: Research Funding; Sensei: Other: Advisory Board; Janssen: Other: Travel Support (EHA 2018); NS Pharma: Research Funding; Genentech: Research Funding. Ribrag: argenX: Research Funding; BMS: Consultancy, Honoraria, Other: travel; NanoString Technologies: Consultancy, Honoraria; pharmamar: Other: travel; Infinity: Consultancy, Honoraria; MSD: Honoraria; Amgen: Research Funding; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy. Schiller: Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Vannucchi: Celgene: Membership on an entity's Board of Directors or advisory committees; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Reiser: Celgene: Employment. Zhong: Celgene: Employment. Mead: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy; Cell Therapeutics: Consultancy; Celgene: Research Funding; Elstar: Research Funding; Evotek: Research Funding.

*signifies non-member of ASH