Current Genetic Models for Prediction of Primary Myelofibrosis

MYELOID TUMORS , , ,

LB Polushkina1, VA Shuvaev1, MS Fominykh1, YuA Krivolapov2, EA Belyakova2, ZP Asaulenko2, EV Motyko1, LS Martynenko1, MP Bakai1, NYu Tsybakova1, SV Voloshin1,3, SS Bessmeltsev1, AV Chechetkin1, IS Martynkevich1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

3 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

For correspondence: Lyubov Borisovna Polushkina, PhD in Biology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; e-mail: polushkina.lb@gmail.com

For citation: Polushkina LB, Shuvaev VA, Fominykh MS, et al. Current Genetic Models for Prediction of Primary Myelofibrosis. Clinical oncohematology. 2019;12(4):391–7 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-391-397

ABSTRACT

Aim. To study the relationship of karyotype, JAK2, CALR, and MPL driver mutations and ASXL1 mutation status with the progression and prediction of primary myelofibrosis (PMF).

Materials & Methods. The trial included 110 PMF patients (38 men and 72 women), median age was 59 years (range 18–82) with median follow-up after diagnosis of 2.6 years (range 0.1–23). The patients were examined for JAK2, CALR, MPL, and ASXL1 mutations. Restriction fragment length polymorphism technique was used for the analysis of V617F substitution in JAK2 and 515 codon mutation in MPL. CALR (exon 9) and ASXL1 (exon 12) mutation tests were performed using Sanger direct sequencing. In 48 (44 %) out of 110 patients bone marrow cell karyotype was determined. Clinical and hematological parameters and median overall survival (OS) of patients were analyzed with regard to detected genetic aberrations and combinations of them.

Results. JAK2, CALR, MPL mutations were detected in 55 (50 %), 28 (25.5 %), and 7 (6.4 %) out of 110 patients, respectively. Triple negative (TN) status was identified in 20 (18.2 %) out of 110 examined patients. ASXL1 mutations were detected in 22 (20 %) out of 110 patients. Out of 48 patients in 32 (66.7 %) normal karyotype, in 3 (6.3 %) favorable karyotype, in 4 (8.3 %) intermediate-prognosis karyotype, and in 9 (18.7 %) unfavorable karyotype were detected. The comparison of clinical and hematological parameters showed a number of significant differences. JAK2-positive patients had a higher hemoglobin level (median 129 g/L; p = 0.021). TN was associated with a high IPSS risk (p = 0.011), low hemoglobin level (median 101 g/L; p = 0.006), continuing drop in platelet count (median 266 × 109/L; p = 0.041), increased lymphocyte count (median 26.9 × 109/L; p = 0.001). The detection of terminating mutations in ASXL1 correlated with palpable enlarged spleen (p = 0.050), reduced platelet count (median 184 × 109/L; p = 0.016), leukocyte count > 25 × 109/L (p = 0.046), and blast count ≥ 1 % (p < 0.001). Univariate regression analysis showed that terminating mutations in ASXL1 (hazard ratio [HR] 2.9; p = 0.018), unfavorable karyotype (HR 8.2; p < 0.001), and TN (ОР 8.1; p < 0.001) had prognostic value for OS. ASXL1 mutation was associated with significantly worse OS in TN patients. Median OS of ASXL1-negative patients without high-risk chromosomal aberrations was significantly longer than in patients with high-risk karyotype and/or ASXL1 mutation.

Conclusion. Several genetic defects in tumor cells are associated with phenotypic manifestations of PMF. Based on the results of cytogenetic analysis and mutation determination of JAK2, CALR, MPL, and ASXL1, patients can be classified in different “genetic” risk groups when PMF is diagnosed.

Keywords: primary myelofibrosis, mutations, karyotype, prediction.

Received: April 8, 2019

Accepted: September 1, 2019

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REFERENCES

  1. Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Первичный миелофиброз: собственный опыт и новое в диагностике и лечении. Онкогематология. 2015;10(2):26–36. doi: 10.17650/1818-8346-2015-10-2-26-36.

    [Abdulkadyrov KM, Shuvaev VA, Martynkevich IS. Primary myelofibrosis: own experience and news from diagnostic and treatment. Oncohematology. 2015;10(2):26–36. doi: 10.17650/1818-8346-2015-10-2-26-36. (In Russ)]

  2. Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Миелопролиферативные новообразования. М.: Литтерра, 2016. 298 с.

    [Abdulkadyrov KM, Shuvaev VA, Martynkevich IS. Mieloproliferativnye novoobrazovaniya. (Myeloproliferative neoplasms.) Moscow: Litterra Publ.; 298 p. (In Russ)]

  3. Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Критерии диагностики и современные методы лечения первичного миелофиброза. Вестник гематологии. 2013;9(3):44–78.

    [Abdulkadyrov KM, Shuvaev VA, Martynkevich Diagnostic criteria and current methods of primary myelofibrosis treatment. Vestnik gematologii. 2013;9(3):44–78. (In Russ)]

  4. Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol. 2005;23(23):8520–30. doi: 10.1200/jco.2004.00.9316.

  5. Levine RL, Pardanani A, Tefferi A, et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7(9):673–83. doi: 10.1038/nrc2210.

  6. Milosevic Feenstra JD, Nivarthi H, Gisslinger H, et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016;127(3):325–32. doi: 10.1182/blood-2015-07-661835.

  7. Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018;93(12):1551–60. doi: 10.1002/ajh.25230.

  8. Tefferi A, Lasho TL, Finke CM, et al. Targeted deep sequencing in primary myelofibrosis. Blood Adv. 2016;1(2):105–11. doi: 10.1182/bloodadvances.2016000208.

  9. Hussein K, Van Dyke DL, Tefferi A. Conventional cytogenetics in myelofibrosis: literature review and discussion. Eur J Haematol. 2009;82(5):329–38. doi: 10.1111/j.1600-0609.2009.01224.x.

  10. Gangat N, Caramazza D, Vaidya R, et al. DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status. J Clin Oncol. 2011;29(4):392–7. doi: 10.1200/jco.2010.32.2446.

  11. Guglielmelli P, Biamonte F, Score J, et al. EZH2 mutational status predicts poor survival in myelofibrosis. Blood. 2011;118(19):5227–34. doi: 10.1182/blood-2011-06-363424.

  12. Tefferi A, Lasho TL, Tischer A, et al. The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR Blood. 2014;124(15):2465–6. doi: 10.1182/blood-2014-07-588426.

  13. Tefferi A, Lasho TL, Finke C, et al. Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia. 2014;28(7):1568–70. doi: 10.1038/leu.2014.83.

  14. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494–500. doi: 10.1038/leu.2014.57.

  15. Argote JA, Dasanu CА. ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival. Curr Med Res Opin. 2016;34(5):757–63. doi: 10.1080/03007995.2016.1276896.

  16. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision of the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.

  17. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol. 2018;36(4):310–8. doi: 10.1200/jco.2017.76.4886.

  18. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ Version 2.0: Mutation and Karyotype Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol. 2018;36(17):1769–70. doi: 10.1200/jco.2018.78.9867.

  19. Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia. 2018;32(7):1631–42. doi: 10.1038/s41375-018-0107-z.