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Chronic myeloproliferative neoplasms

Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide

Leukemia volume 35, pages 1197–1202 (2021)Cite this article

Subjects

Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal disorder characterized by decreased blood cell concentrations, bone marrow fibrosis and a risk of transformation to acute myeloid leukemia (AML). Persons who become RBC-transfusion-dependent have a poor prognosis with limited therapeutic options to reverse their anemia [1]. Most persons with MPN-associated myelofibrosis have driver mutations in JAK2, CALR, or MPL resulting in aberrant JAK/STAT signaling [2]. Non-driver mutations are common in spliceosome components, epigenetic regulators, and notably in ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157, which are associated with adverse outcomes and are termed high-risk molecular mutations [3, 4].

RESUME was a randomized, double-blind, parallel group, controlled trial, assessing rates of RBC-transfusion-independence in subjects with MPN-associated myelofibrosis and RBC-transfusion-dependence receiving pomalidomide or placebo [5]. Although response rates were similar, the study identified some differences between responders in the pomalidomide and placebo cohorts, including some subjects with a sustained response to pomalidomide not observed in the placebo cohort. We reasoned the mutational landscape of subjects in the RESUME study might correlate with these pomalidomide responses.

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Fig. 1: The mutational landscape of transfusion dependent myelofibrosis.
Fig. 2: Impact of mutational status on transfusion responses.

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Acknowledgements

Supported in part by a National Institute for Health Research (NIHR) academic clinical lectureship (OC), the John Fell Fund, a Medical Research Council Senior Clinical Fellowship (AJM, MR/l006340/1), a Cancer Research UK (CRUK) Senior Cancer Research Fellowship. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. Supported in part by an unrestricted educational grant from Celgene Corp.

RESUME trialist

John Catalano18, William Stevenson19, Günther Gastl20, Werner Linkesch21, Jan Van Droogenbroeck22, Philippe Mineur23, Vikas Gupta24, Andrew Turner25, Thomas Nevill26, Jianyong Li27, Zhixiang Shen28, Ting Liu29, Dominique Bordessoule30, Shanti Natarajan-Amé31, Christian Recher32, Jean Loup Demory33, Richard Schlenk34, Martin Griesshammer35, Mario Cazzola36, Giuseppe Saglio37, Giorgina Specchia38, Alessandro Rambaldi39, Fabrizio Pane40, Sonja Zweegman41, Peter te Boekhorst42, Reinier Raymakers43, Kudrat Abdulkadyrov44, Manana Sokolova45, Galina Salogub46, Andrey Zaritskiy47, Francisco Cervantes48, Juan Carlos Hernández Boluda49, Emilio Ojeda50, Daniel Tesfa51, Lars Nilsson52, Mark Drummond53, John Reilly54, Claire Harrison55, Dragana Milojkovic56, Candido Rivera57, Emmanuel Besa58, H. Joachim Deeg59, John Mascarenhas60, Josef Prchal61, Ramon Tiu62, Moshe Talpaz63, Jen Chin Wang64, Raajit Rampal65, Damiano Rondelli66, Kelly McCaul67, Randall Brown68, Norio Komatsu69, Kazuma Ohyashiki70, Kiyoshi Ando71, Hiroshi Kawabata72, Katsuto Takenaka73, Tomoko Hata74, James Vardiman75

Author information

Authors and Affiliations

  1. NIHR Biomedical Research Centre and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Onima Chowdhury, Jennifer O’Sullivan, Nikolaos Barkas, Guanlin Wang, Gemma Buck, Angela Hamblin & Adam J. Mead

  2. Mayo Clinic, Rochester, MN, USA

    Ayalew Tefferi

  3. University Hospital Halle, Halle, Germany

    Haifa K. Al-Ali

  4. Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

    Giovanni Barosi

  5. Department of Hematology, University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), Leuven, Belgium

    Timothy Devos

  6. Medizinische Universität Wien, Vienna, Austria

    Heinz Gisslinger

  7. Peking University, People’s Hospital, Beijing, China

    Qian Jiang

  8. Hôpital Saint-Louis, Paris, France

    Jean-Jacques Kiladjian

  9. Mays Cancer Center at UT Health San Antonio MD Anderson, San Antonio, TX, USA

    Ruben Mesa

  10. University of Insubria, Varese, Italy

    Francesco Passamonti

  11. Cancer Campus, 11 Gustave Roussy, Villejuif, France

    Vincent Ribrag

  12. Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Gary Schiller

  13. Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Alessandro M. Vannucchi

  14. Peking Union Medical College Hospital, Beijing, China

    Daobin Zhou

  15. Queens University Belfast, Belfast, UK

    Mary Frances McMullin

  16. Bristol-Myers Squibb, New Brunswick, NJ, USA

    Jianhua Zhong

  17. Haematology Research Centre, Imperial College London, London, UK

    Robert Peter Gale

  18. Oncology Day Unit, Frankston Hospital, Frankston, VIC, Australia

    John Catalano

  19. Royal North Shore Hospital, St Leonards, NSW, Australia

    William Stevenson

  20. Medizinische Universität Innsbruck, Innsbruck, Austria

    Günther Gastl

  21. Medizinische Universität Graz, Graz, Austria

    Werner Linkesch

  22. Academisch Ziekenhuis Brugge, Brugge, Belgium

    Jan Van Droogenbroeck

  23. Grand Hôpital de Charleroi, Charleroi, Belgium

    Philippe Mineur

  24. Princess Margaret Hospital, Toronto, Canada

    Vikas Gupta

  25. Department of Medical Oncology, Cross Cancer Institute, Toronto, ON, Canada

    Andrew Turner

  26. Vancouver General Hospital, Toronto, ON, Canada

    Thomas Nevill

  27. Jiangsu Province Hospital, Nanjing, China

    Jianyong Li

  28. Shanghai Ruijin Hospital, Shanghai, China

    Zhixiang Shen

  29. West China Hospital, Sichuan University, Chengdu, China

    Ting Liu

  30. Centre Hospitalier Universitaire Limoges, Limoges, France

    Dominique Bordessoule

  31. Centre Hospitalier Universitaire de Strasbourg - Hôpital Civil, Strasbourg, France

    Shanti Natarajan-Amé

  32. Hôpital Purpan, Toulouse, Service Hématologie, Toulouse, France

    Christian Recher

  33. Groupe Hospitalier de I’Institue Catholique de Lille-Hôpital Saint-Vincent de Paul (Belfort), Lille, France

    Jean Loup Demory

  34. Universitätsklinik Ulm, Ulm, Germany

    Richard Schlenk

  35. Johannes-Wesling-Klinikum Minden, Minden, Germany

    Martin Griesshammer

  36. Fondazione IRCCS Policlinico S. Matteo, Pavia PV, Italy

    Mario Cazzola

  37. Azienda Ospedaliero-Univesitaria ‘San Luigi Gonzaga’, Bergamo, Italy

    Giuseppe Saglio

  38. Azienda Ospedaliera Policlinico di Bari, Bergamo, Italy

    Giorgina Specchia

  39. Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

    Alessandro Rambaldi

  40. Azienda Ospedaliera Universitaria ‘Federico II’, Naples, Italy

    Fabrizio Pane

  41. VU University Medical Centre, Amsterdam, the Netherlands

    Sonja Zweegman

  42. Erasmus Medisch Centrum, Rotterdam, the Netherlands

    Peter te Boekhorst

  43. Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands

    Reinier Raymakers

  44. FGU Russian Scientific Research Institute of Hematology and Transfusiology, Saint Petersburg, Russia

    Kudrat Abdulkadyrov

  45. Hematology Scientific Center, Moscow, Russia

    Manana Sokolova

  46. SaintPetersburg I.P. Pavlov State Medical University, Saint Petersburg, Russia

    Galina Salogub

  47. FSI ‘V.A. Almazov Federal Centre of Heart, Blood and Endocrinology of Rosmedtechnologies’, Saint Petersburg, Russia

    Andrey Zaritskiy

  48. Hospital Clinic I Provincial de Barcelona, Barcelona, Spain

    Francisco Cervantes

  49. Hospital Clinico Universitario de Valencia, Valencia, Spain

    Juan Carlos Hernández Boluda

  50. Hospital Puerta de Hierro Majadahonda, Majadahonda, Spain

    Emilio Ojeda

  51. Karolinska University Hospital Huddinge, Solna, Sweden

    Daniel Tesfa

  52. Skånes Universitetssjukhus i Lund, Lund, Sweden

    Lars Nilsson

  53. Beatson Oncology Centre, Glasgow, UK

    Mark Drummond

  54. Royal Hallamshire Hospital, Sheffield, UK

    John Reilly

  55. Guy’s Hospital, London, UK

    Claire Harrison

  56. London Hammersmith Hospital, London, UK

    Dragana Milojkovic

  57. Mayo Clinic, Jacksonville, FL, USA

    Candido Rivera

  58. Jefferson Medical College, Philadelphia, PA, USA

    Emmanuel Besa

  59. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    H. Joachim Deeg

  60. Mount Sinai Hospital, The Donald H Ruttenberg Cancer Treatment Center, New York, NY, USA

    John Mascarenhas

  61. University of Utah Health Sciences Center, Salt Lake City, USA

    Josef Prchal

  62. The Cleveland Clinic Foundation, Cleveland, OH, USA

    Ramon Tiu

  63. University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    Moshe Talpaz

  64. Brookdale Hospital Medical Center, New York, NY, USA

    Jen Chin Wang

  65. Memorial Sloan- Kettering Cancer Center, New York, NY, USA

    Raajit Rampal

  66. University of Illinois at Chicago, Chicago, IL, USA

    Damiano Rondelli

  67. Avera Hematology and Transplant, Sioux Falls, SD, USA

    Kelly McCaul

  68. University of Florida Shands Cancer Center, Gainesville, FL, USA

    Randall Brown

  69. Juntendo University Hospital, Bunkyo, Japan

    Norio Komatsu

  70. Tokyo Medical University Hospital, Shinjuku, Japan

    Kazuma Ohyashiki

  71. Tokai University Hospital, Shibuya, Japan

    Kiyoshi Ando

  72. Kyoto University Hospital, Kyoto, Japan

    Hiroshi Kawabata

  73. Kyushu University Hospital, Fukuoka, Japan

    Katsuto Takenaka

  74. Nagasaki University Hospital, Nagasaki, Japan

    Tomoko Hata

  75. University of Chicago, Chicago, Japan

    James Vardiman

Authors
  1. Onima Chowdhury
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  2. Jennifer O’Sullivan
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  3. Nikolaos Barkas
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  4. Guanlin Wang
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  5. Gemma Buck
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  6. Angela Hamblin
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  7. Ayalew Tefferi
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  8. Haifa K. Al-Ali
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  9. Giovanni Barosi
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  10. Timothy Devos
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  11. Heinz Gisslinger
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  12. Qian Jiang
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  13. Jean-Jacques Kiladjian
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  14. Ruben Mesa
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  15. Francesco Passamonti
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  16. Vincent Ribrag
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  17. Gary Schiller
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  18. Alessandro M. Vannucchi
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  19. Daobin Zhou
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  20. Mary Frances McMullin
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  21. Jianhua Zhong
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  22. Robert Peter Gale
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  23. Adam J. Mead
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Consortia

for the RESUME trialists

  • John Catalano
  • , William Stevenson
  • , Günther Gastl
  • , Werner Linkesch
  • , Jan Van Droogenbroeck
  • , Philippe Mineur
  • , Vikas Gupta
  • , Andrew Turner
  • , Thomas Nevill
  • , Jianyong Li
  • , Zhixiang Shen
  • , Ting Liu
  • , Dominique Bordessoule
  • , Shanti Natarajan-Amé
  • , Christian Recher
  • , Jean Loup Demory
  • , Richard Schlenk
  • , Martin Griesshammer
  • , Mario Cazzola
  • , Giuseppe Saglio
  • , Giorgina Specchia
  • , Alessandro Rambaldi
  • , Fabrizio Pane
  • , Sonja Zweegman
  • , Peter te Boekhorst
  • , Reinier Raymakers
  • , Kudrat Abdulkadyrov
  • , Manana Sokolova
  • , Galina Salogub
  • , Andrey Zaritskiy
  • , Francisco Cervantes
  • , Juan Carlos Hernández Boluda
  • , Emilio Ojeda
  • , Daniel Tesfa
  • , Lars Nilsson
  • , Mark Drummond
  • , John Reilly
  • , Claire Harrison
  • , Dragana Milojkovic
  • , Candido Rivera
  • , Emmanuel Besa
  • , H. Joachim Deeg
  • , John Mascarenhas
  • , Josef Prchal
  • , Ramon Tiu
  • , Moshe Talpaz
  • , Jen Chin Wang
  • , Raajit Rampal
  • , Damiano Rondelli
  • , Kelly McCaul
  • , Randall Brown
  • , Norio Komatsu
  • , Kazuma Ohyashiki
  • , Kiyoshi Ando
  • , Hiroshi Kawabata
  • , Katsuto Takenaka
  • , Tomoko Hata
  •  & James Vardiman

Contributions

OC designed and analyzed experiments and prepared the typescript; JO performed the statistical analysis and contributed to preparing the typescript. NB and GW performed bioinformatic analysis; GB designed the sequencing panels, processed samples, and performed experiments; AH contributed to the design of the panels and advised on data analyses; AT, HKA, GB, TD, HG, QJ, J-JK, RM, FP, VR, GS, AMV, DZ, MFM, and JZ contributed samples. RPG supervised the project and helped prepare the typescript. AJM conceived and supervised the project, designed experiments and helped prepare the typescript. All authors read and approved the typescript.

Corresponding author

Correspondence to Adam J. Mead.

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Conflict of interest

GS has participated in speakers bureau and received research funding from Celgene. MFM has participated in advisory boards and speakers bureaus for Celgene and Novartis. AJM has participated in advisory boards and speakers bureaus for Celgene and Novartis.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Members of the RESUME trialists are listed below Acknowledgements.

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Chowdhury, O., O’Sullivan, J., Barkas, N. et al. Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide. Leukemia 35, 1197–1202 (2021). https://doi.org/10.1038/s41375-020-0979-6

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