Study of Patients with Polycythemia Vera in JAK2V617F and Mutated and Unmutated Status along with their Anxiety and Worried Thoughts: A Single-center Experience from Eastern India

INTRODUCTION

A Philadelphia-negative myeloproliferative neoplasm (MPN) with pan-myelosis is referred to as Polycythemia vera (PV). It differs from other MPNs in terms of elevated hematocrit/red cell mass and subnormal erythropoietin (EPO) level. Polycythemia vera is linked to point mutations in Janus 2 tyrosine kinase (JAK-2) that result in a gain of function and increased JAK-2 activity.^1,2 Usually, JAK-2V617F mutation has been observed in 90–95% cases of PV and 50–60% cases of primary myelofibrosis as well as Essential Thrombocythemia.^3,4 JAK-2V617F mutation status and allele burden are also known to affect the clinical phenotype of PV patients.⁵ The clinical behavior of JAK-2V617F mutation status among PV patients in an Eastern Indian population was examined in this study. The anxiety associated with PV, which is usually present, was also assessed in this study. The investigation aims to examine prevalent anxiety symptoms in PV patients.

MATERIALS AND METHODS

A retrospective study was executed on 50 patients who suffered from PV between July 2018 and August 2023. In 2016, the World Health Organization (WHO) issued updated guidelines for PV diagnosis. The criteria consist of three major and one minor criterion. A diagnosis is established when all three major criteria or two major criteria along with one minor criterion are satisfied.⁵

RESULTS

A retrospective analysis of 50 individuals who visited Hematology OPD between July 2018 and February 2023 who were diagnosed with PV based on WHO criteria was conducted. Patient characteristics of JAK-2V617F mutated and unmutated were examined. 52 years was the median age of presentation. The ratio of male to female patients was 5:1. Of the 50 patients, 34 (68%) had a mutation in JAK2V617F, while 16 (32%) did not. No significant association with respect to gender was revealed through statistical comparison between JAK2V617F mutated and unmutated, incidence of thrombosis (18.75 vs 11.76%; p = 0.396), bleeding manifestations (6.25 vs 8.82%; p = 0.617), pruritus (18.75 vs 8.82%; p = 0.285), transformation to myelofibrosis (0 vs 2.94; p = 0.680), as well as high-risk disease (56.25 vs 32.3%; p = 0.097). Nevertheless, a significant statistical difference among JAK-2V617F mutated as well as unmutated PV patients have been observed, with median age (61 vs 44.5 years; p = 0.002), median Hb (20.7 vs 17.5 gm/dL; p = 0.001), median total leukocyte count (TLC) (15,700 vs 8100 µL; p = 0.001), median platelet count at the time of presentation (3,20,000 vs 1,90,000 µL; p = 0.044), and low serum EPO level (p = 0.00) (Table 1).

Distribution of patients with anxiety levels at diagnosis of PV as depicted in (Fig. 1) shows that the majority of study patients showed a moderate level of anxiety and few were severely anxious considering the phlebotomy procedure and associated risks of deep venous thrombosis besides long-term risks for progression toward myelofibrosis using the generalized anxiety disorder (GAD-7 questionnaire.

However at six months, after initiation of therapy and on assessment of anxiety scores it was found that the majority of patients showed mild and minimal levels of anxiety compared to moderate and severe anxiety levels at baseline (Fig. 2).

At one year, when anxiety levels were again assessed in the study patients, it was found that none of the patients were severely anxious about their disease entity and few were moderately anxious. Almost all were mild and minimally anxious, and they were actively involved with their daily livelihoods (Fig. 3).

DISCUSSION

The presence of mutated JAK2V617F is an essential diagnostic criterion required in diagnosing Philadelphia-negative MPNs. Published literature has shown that the JAK2V617F allele burden positively correlates with systemic symptoms as well as the risk of disease progression.^6,7 In this study, we assessed whether the absence or presence of mutated JAK2V617F is correlated with the phenotype of disease in PV patients. We observed that there was no significant difference with respect to gender, risk of thrombosis, bleeding manifestations, pruritus, high-risk disease, and disease progression. However, the median age at diagnosis was higher in JAK2 mutated patients, and median Hb, TLC, as well as platelet count at presentation, were higher in JAK2 positive patients. Also, JAK2-positive PV patients had lower serum EPO levels. Vannucchi et al.^{7, 8,9} suggested that the presence of JAK2V617F mutation was significantly related to thrombosis. According to Passamonti et al.,¹⁰ no significant correlation had been exhibited with the risk of thrombosis among Italian PV patients.

At the beginning of diagnosis, it was found that most patients were anxious related to subsequent complications like the risk of thrombosis and the remote chance of transformation to myelofibrosis. Another important implication is bone marrow procedure which incites needful stress and anxiety among patients with all hematological diseases. However, at 6 months, most patients gradually get accustomed as their symptoms and hematocrit level come down with needful therapy and routine phlebotomy is seldom required. At one year none of the patients were seriously anxious and most returned to their routine activities of daily living; however, a query for a definite disease-modifying agent is always there from patients with PV.

The study by Gibek et al. emphasized the significance of identifying somatic disorders, depression, anxiety, and other associated symptoms in patients receiving interferon-alpha treatment who have MPNs as well as those receiving alternative therapies. None of our study patients received interferon alpha that has unique side effects. The study included all categories of MPN patients but our study was only concerned with patients with PV only.^10,11

The therapeutic landscape of patients with PV is with a lot of unmet needs. The concurrent administration of low aspirin dose (81 mg/day) and phlebotomy to attain a target hematocrit below 45% is commonly employed in clinical practice.¹² This combination is suitable to be employed in conjunction with cytoreductive therapy for individuals in high-risk groups and is the first-line treatment choice for individuals having low risk.¹³ The application of ruxolitinib is presently restricted to PV patients who exhibit resistance to hydroxyurea or demonstrate intolerance to it.¹⁴

The limitation of our study was the lack of usage of Interferon alfa in our patients with PV. It was also not possible to use ruxoltinib in some resistant patients because of its fancy cost issues; however, one waits for MDM2 inhibitors and HDAC inhibitors that are required in certain pilot studies, and more research should be done before they form part of patient care.¹⁵

CONCLUSION

The study evaluated the influence of the JAK2V617F mutation state over the phenotype of PV in relation to clinical as well as other laboratory characteristics. Despite the absence of variation in the majority of clinical characteristics between mutated and unmutated groups, the age of diagnosis as well as other laboratory parameters, such as TLC, Hb, platelet counts, and serum EPO levels, exhibited a statistically significant difference. Thrombosis was more prevalent in patients with JAK2V617F mutation. With the passage of time gradually the stress and anxiety decline among patients with PV and can lead to a near normal life.

ORCID

Shuvra Neel Baul https://orcid.org/0000-0002-9911-4985

REFERENCES

1. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434(7037):1144–1148. DOI: 10.1038/nature03546.

2. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352(17):1779–1790. DOI: 10.1056/NEJMoa051113.

3. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7(4):387–397. DOI: 10.1016/j.ccr.2005.03.023.

4. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365(9464):1054–1061. DOI: 10.1016/S0140-6736(05)71142-9.

5. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391–2405. DOI: 10.1182/blood-2016-03-643544.

6. Spitzer RL, Kroenke K, Williams JB, et al. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006;166(10):1092–1097. DOI: 10.1001/archinte.166.10.1092.

7. Moliterno AR, Kaizer H, Reeves BN. JAK2 V617F allele burden in polycythemia vera: Burden of proof. Blood 2023;141(16):1934–1942. DOI: 10.1182/blood.2022017697.

8. Vannucchi AM, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: Effects on phenotype, prognosis and change with treatment. Ther Adv Hematol 2011;2(1):21–32. DOI: 10.1177/2040620710394474.

9. Vannucchi AM. JAK2 mutation and thrombosis in the myeloproliferative neoplasms. Curr Hematol Malig Rep 2010;5:22–28. DOI: 10.1007/s11899-009-0038-x.

10. Passamonti F, Rumi E, Pietra D, et al. A prospective study of 338 patients with polycythemia vera: The impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 2010;24:1574–1579. DOI: 10.1038/leu.2010.148.

11. Gibek K, Sacha T, Cyranka K. Comparison of depressive, anxiety, and somatic symptoms in patients with essential thrombocythemia, polycythemia vera, and myelofibrosis treated with interferon alpha. Acta Haematol Polonica 2022;54:18–30. DOI: 10.5603/AHP.a2022.0058.

12. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114–124. DOI: 10.1056/NEJMoa035572.

13. Barbui T, Carobbio A, Ghirardi A, et al. No correlation of intensity of phlebotomy regimen with risk of thrombosis in polycythemia vera: Evidence from European Collaboration on low-dose aspirin in polycythemia vera and cytoreductive therapy in polycythemia vera clinical trials. Haematologica 2017;102:e219–e221. DOI: 10.3324/haematol.2017.165126.

14. McMullin MF, Harrison CN, Ali S, et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. Br J Haematol 2019;184:176–191. DOI: 10.1111/bjh.15648.

15. Arya Y, Syal A, Gupta M, et al. Advances in the treatment of polycythemia vera: Trends in disease management. Cureus 2021;13(3):e14193. DOI: 10.7759/cureus.14193.