Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Chronic myeloproliferative neoplasms

Pegylated interferon Alfa-2a and hydroxyurea in polycythemia vera and essential thrombocythemia: differential cellular and molecular responses

Leukemia volume 32, pages 1830–1833 (2018)Cite this article

Subjects

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPNs) with high risk of thromboembolism and tendency to transform to myelofibrosis and acute leukemia. Pegylated interferon-α (PegINFa) is an effective treatment and unlike hydroxyurea (HU), it is reported to improve cytogenetic abnormalities, decrease JAK2V617F and CALR allelic burdens and achieve molecular remission [1,2,3]. We reported a return to polyclonal hematopoiesis in some females after PegINFa therapy [3], and unlike HU, PegINFa promoted proliferation and differentiation of PV and ET hematopoietic stem cells in vivo [4]. Cytokines, such as TNFα and interleukins are found to be elevated in MPN [5, 6] and are implicated as drivers of clonal expansion of JAK2V617F bearing cells [7]. Genome wide association studies have shown IL28 SNP and treatment with PegINFa were associated with sustained virologic response in hepatitis C [8] and suggested favorable hematological response in 20 PV/ET patients [9].

Given these observations, we analyzed the effect of PegINFa and HU treatment on molecular response, clonal hematopoiesis (females), TNFα transcript levels, and IL28B haplotype as correlated with PegINFa response. We included 82 patients diagnosed with high-risk PV (n = 45) and ET (n = 37) (per WHO 2008) treated from 2008 to March 2017. Mutational analysis for JAK2V617F and cMPL was performed by quantitative allele-specific-PCR [10], and CALR mutations by semi-quantitative fragment analysis [11]. In females, SNPs of 5 X-chromosome genes (G6PD, MPP1, FHL1, BTK and IDS) were genotyped and in heterozygotes transcriptional allelic frequencies of granulocytes were determined by quantitative allele-specific PCR. TaqMan Gene Expression Assays were used to determine TNFα and cytokine mRNAs and plasma levels of cytokines were measured. Relative TNFα expressions and JAK2V617F allelic burden were compared using paired t-test in GraphPad Prism (La Jolla, CA). As many of these patients participated in the MPD-RC trials the hematologic and clinical responses of these patients will be reported by the MPD-RC group.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065–72.

    Article  PubMed  CAS  Google Scholar 

  2. Quintas-Cardama A, Kantarjian H, Manshouri T, Luthra R, Estrov Z, Pierce S, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27:5418–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Liu E, Jelinek J, Pastore YD, Guan Y, Prchal JF, Prchal JT. Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. Blood. 2003;101:3294–301.

    Article  PubMed  CAS  Google Scholar 

  4. King KY, Matatall KA, Shen CC, Goodell MA, Swierczek SI, Prchal JT. Comparative long-term effects of interferon alpha and hydroxyurea on human hematopoietic progenitor cells. Exp Hematol. 2015;43:912–8 e2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Pourcelot E, Trocme C, Mondet J, Bailly S, Toussaint B, Mossuz P. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp Hematol. 2014;42:360–8.

    Article  PubMed  CAS  Google Scholar 

  6. Vaidya R, Gangat N, Jimma T, Finke CM, Lasho TL, Pardanani A, et al. Plasma cytokines in polycythemia vera: phenotypic correlates, prognostic relevance, and comparison with myelofibrosis. Am J Hematol. 2012;87:1003–5.

    Article  PubMed  CAS  Google Scholar 

  7. Fleischman AG, Aichberger KJ, Luty SB, Bumm TG, Petersen CL, Doratotaj S, et al. TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood. 2011;118:6392–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Hayes CN, Imamura M, Aikata H, Chayama K. Genetics of IL28B and HCV--response to infection and treatment. Nat Rev Gastroenterol Hepatol. 2012;9:406–17.

    Article  PubMed  CAS  Google Scholar 

  9. Lindgren M, Pettersson H, Westin J, Lindh M, Johansson P, Andreasson B. Influence of interferon-α treatment outcome in polycythemia vera and essential thrombocythemia by genetic polymorphism in IL28B. J Hematol Malig. 2012;2:18–25.

    Google Scholar 

  10. Nussenzveig RH, Swierczek SI, Jelinek J, Gaikwad A, Liu E, Verstovsek S, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007;35:32–8.

    Article  PubMed  CAS  Google Scholar 

  11. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90.

    Article  PubMed  CAS  Google Scholar 

  12. Moliterno AR, Williams DM, Rogers O, Isaacs MA, Spivak JL. Phenotypic variability within the JAK2 V617F-positive MPD: roles of progenitor cell and neutrophil allele burdens. Exp Hematol. 2008;36:1480–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Bruchova H, Yoon D, Agarwal AM, Swierczek S, Prchal JT. Erythropoiesis in polycythemia vera is hyper-proliferative and has accelerated maturation. Blood Cells Mol Dis. 2009;43:81–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Gaikwad A, Nussenzveig R, Liu E, Gottshalk S, Chang K, Prchal JT. In vitro expansion of erythroid progenitors from polycythemia vera patients leads to decrease in JAK2 V617F allele. Exp Hematol. 2007;35:587–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Chen Y, Zou Z, Wu Z, Zhao Z, Luo X, Xie C, et al. TNF-alpha-induced programmed cell death in the pathogenesis of acquired aplastic anemia. Expert Rev Hematol. 2015;8:515–26.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr. Bruce Beutler for advice to use TNFα inhibitor, adalimumab.

Author contributions

JP conceived and designed this study; TT collected and analyzed the data and drafted the manuscript; SS conceived TNFα studies and with SJK and JS performed the molecular analyses; KK isolated CD34+ cells from the marrows, MS and NH analyzed cytokines, KH and SL secured IRB compliance. All authors approved the manuscript.

Author information

Authors and Affiliations

  1. Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT, USA

    Tsewang Tashi, Sabina Swierczek, Soo Jin Kim, Jihyun Song, Kim Hickman, Scott Litton & Josef T. Prchal

  2. Department of Pathology, ARUP Institute of Research and Development, University of Utah School of Medicine, Salt Lake City, UT, USA

    Mohamed E. Salama, Nahla Heikal & Josef T. Prchal

  3. Department of Pediatric Infectious Diseases and Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA

    Katherine Y. King

Authors
  1. Tsewang Tashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabina Swierczek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soo Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohamed E. Salama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jihyun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nahla Heikal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katherine Y. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kim Hickman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Scott Litton
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Josef T. Prchal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Josef T. Prchal.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

These authors contributed equally: Tsewang Tashi, Sabina Swierczek, Soo Jin Kim.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tashi, T., Swierczek, S., Kim, S.J. et al. Pegylated interferon Alfa-2a and hydroxyurea in polycythemia vera and essential thrombocythemia: differential cellular and molecular responses. Leukemia 32, 1830–1833 (2018). https://doi.org/10.1038/s41375-018-0080-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0080-6

This article is cited by

Search

Advanced search

Quick links