Introduction
Myeloproliferative neoplasms are hemopathies with primary damage to the stem cell. In the case of polycythemia vera, there is a proliferation of all myeloid lineages in the bone marrow. The proliferation of only the megakaryocytic line is characteristic of essential thrombocythemia. The most interesting histological picture represents primary myelofibrosis with the proliferation of myeloid lines, the deformation of megakaryocytes with the formation of clusters with a terrible image, and collagenous fibrosis of various degrees [1]. The second important moment is the formation of foci of extramedullary hematopoiesis, with the most frequent involvement of the spleen and liver. Less commonly, the lungs, kidneys, central nervous system, and even peripheral lymph nodes are affected. The etiology is not known, which is why the inclusion of the word “idiopathic” in the name of this pathology is logical. It is assumed that causative factors may be chemicals, radiation, etc. Most cases are diagnosed in people over the age of 60 who are in the overtly fibrotic stage. For a long time, it was thought that primary myelofibrosis was a disease of the elderly. In recent years, there has been an increase in the number of articles published about primary myelofibrosis in young people, which is most diagnosed in the prefibrotic phase. The studies, observations, and analyses of these patients are few, which is why this neoplasm is of major interest to hematologists.
The aim of the manuscript was to identify and evaluate the clinical and hematological features of primary myelofibrosis in young patients in the prefibrotic stage.
Material and methods
The clinical aspects and the changes in the complete blood count of the disease were studied in 42 patients with NHL and primary myelofibrosis, aged between 18 and 40 years. The diagnosis was confirmed histologically and molecularly according to WHO criteria. The research was approved by the Research Ethics Committee of Nicolae Testemitanu State University of Medicine and Pharmacy (Protocol No. 1 of February 25, 2021).
The standard descriptive statistics kit was used for data analysis through Microsoft Excel and IBM SPSS Statistics 26.0. The use of the standard descriptive statistics kit facilitated the calculation of mean, median, and p value.
Results
Out of the 42 patients participating in the study, 9 (21.4%) were men and 33 (78.6%) were women. We divided the patients into two groups based on their ages: 18-29 and 30-40. There were 11 (26.2%) patients in the first group and 32 (73.8%) in the second.
The major interest represents the changes in the complete blood count. Starting with hemoglobin levels (Table 1), hemolytic anemia was found in both groups at 7.1%. In most cases (48.4%), the level of hemoglobin was perfectly normal. In 4 (36.4%) cases in the first group, there was anemia, and in 8 (25.8%) in the second group, according to WHO criteria for primary myelofibrosis. The elevated hemoglobin level in 6 (19.3%) patients aged 30 to 40 years, on the other hand, was quite surprising.
Table 1. Distribution of patients according to hemoglobin levels. | ||||
| Laboratory patterns | Number of patients / rates within the age category | Age | Total | |
18-29 years | 30-40 years | |||
| Hemolytic anemia | Number of patients | 1 | 2 | 3 |
% | 9.1% | 6.5% | 7.1% | |
| Normal range of hemoglobin | Number of patients | 5 | 15 | 20 |
% | 45.6% | 48.4% | 47.6% | |
| Low value of hemoglobin | Number of patients | 4 | 8 | 12 |
% | 36.4% | 25.8% | 28.6% | |
| Elevated level of hemoglobin (>160 g/l for men, >140 g/l for women) | Number of patients | 1 | 6 | 7 |
% | 9.1% | 19.3% | 16.7% | |
| Total | Number of patients | 11 | 31 | 42 |
% | 100% | 100% | 100% | |
The second parameter analyzed is leucocyte count (Table 2). Leucopenia was detected in 1 (9.1%) case in the first group and in 3 (9.7%) cases in the second group. The most interesting difference between these two groups is the normal range of white blood cells in patients younger than 30 years: 6 (54.5%) in the first group and 10 (32.3%) in the second group. Leukocytosis in the second age group was revealed in 18 (58.0%) cases and proved to be more common than in the first age group (36.4%, p < 0.05).
Table 2. Distribution of patients according to leukocyte count. | ||||
| Laboratory patterns | Number of patients / rates within the age category | Age | Total | |
18-29 years | 30-40 years | |||
| Leukopenia (< 4x109/l) | Number of patients | 1 | 3 | 4 |
% | 9.1% | 9.7% | 9.5% | |
| Normal range (4-9x109/l) | Number of patients | 6 | 10 | 16 |
% | 54.5% | 32.3% | 38.1% | |
| Leukocytosis (>11x109/l) | Number of patients | 4 | 18 | 22 |
% | 36.4% | 58.0% | 52.4% | |
| Total | Number of patients | 11 | 31 | 42 |
% | 100% | 100% | 100% | |
The most important and interesting parameter of peripheral blood is platelets (Table 3). Patients with myeloproliferative neoplasms are more often diagnosed with thrombotic complications, especially those with primary myelofibrosis. Most patients are diagnosed with primary myelofibrosis due to elevated levels of platelets. 30 patients (71.4%) had thrombocytosis. Thrombocytopenia was found in 1 (9.1%) case from the first group and in 2 (6.5%) cases from the second group. Platelets were within the normal range in 36.4% of patients younger than 30 years old and 16.1% of patients older than 30 years old (p < 0.05).
Table 3. Distribution of patients according to thrombocyte count. | ||||
| Laboratory patterns | Number of patients / rates within the age category | Age | Total | |
18-29 years | 30-40 years | |||
| Low level of platelets (<150x109/l) | Number of patients | 1 | 2 | 3 |
% | 9.1% | 6.5% | 7.1% | |
Normal range of platelets (150-400x109/l) | Number of patients | 4 | 5 | 9 |
% | 36.4% | 16.1% | 21.4% | |
High level of platelets (>400x109/l) | Number of patients | 6 | 24 | 30 |
% | 54.5% | 77.4% | 71.4% | |
| Total | Number of patients | 11 | 31 | 42 |
% | 100% | 100% | 100% | |
The spleen is the primary organ involved in extramedullary hematopoiesis, and splenomegaly is always observed in the overt fibrotic stage. According to this analysis, 4 (36.4%) and 9 (29.0%) of patients, respectively, in the prefibrotic stage have severe splenomegaly (Table 4). But in 2 (18.2 %) of the first group and in 3 (9.7 %) of the second, the normal size of the spleen was found (p < 0.05).
Table 4. Distribution of patients according to the spleen sizes. | ||||
| Number of patients / rates within the age category | Age | Total | |
18-29 years | 30-40 years | |||
| Normal size | Number of patients | 2 | 3 | 5 |
% | 18.2% | 9.7% | 11.9% | |
| Moderate splenomegaly | Number of patients | 4 | 17 | 21 |
% | 36.4% | 54.9% | 50.0% | |
| Severe splenomegaly | Number of patients | 4 | 9 | 13 |
% | 36.4% | 29.0% | 31.0% | |
| Splenectomy | Number of patients | 1 | 2 | 3 |
% | 9.1% | 6.5% | 7.1% | |
| Total | Number of patients | 11 | 31 | 42 |
% | 100% | 100% | 100% | |
The last parameter that was analyzed was the size of the liver (Table 5). In most cases, in 8 (72.7%) patients from the first group and in 14 (45.1%) from the second, the size of the liver was in the normal range. But for the patients in the second group, moderate hepatomegaly occurred in 11 (35.5%) cases and severe hepatomegaly in 6 (19.4%) cases.
Table 5. Distribution of patients according to the liver sizes | ||||
Number of patients / rates within the age category | Age | Total | ||
18-29 years | 30-40 years | |||
| Normal size | Number of patients | 8 | 14 | 22 |
% | 72.7% | 45.1% | 52.4% | |
| Moderate hepatomegaly | Number of patients | 1 | 11 | 12 |
% | 9.1% | 35.5% | 28.6% | |
| Severe hepatomegaly | Number of patients | 2 | 6 | 8 |
% | 18.2% | 19.4% | 19.0% | |
| Total | Number of patients | 11 | 31 | 42 |
% | 100% | 100% | 100% | |
Discussion
The incidence of primary myelofibrosis is low. In the USA, primary myelofibrosis is detected in 0.5–1.5 cases per 100,000 [2], in Great Britain – 0.75, but in the Republic of Moldova, according to Ion Corcimaru's data from 2007, it is 0.2 per 100,000 [3]. Analyzing literature data, due to the diagnosis, a tendency towards an increase in the incidence and prevalence of 40–50% in the initial stage of primary myelofibrosis is observed. The pathology is seen in children only very rarely, being congenital and occurring in conjunction with other malformations. The peak incidence of primary myelofibrosis is between 50 and 70 years of age.
The clinical manifestations of primary myelofibrosis are variable and unusual. The diagnosis can be established early on by performing some prophylactic control analyses until long-term manifestations appear over time.
The weakness is a clinical manifestation that is detected most often in patients with primary myelofibrosis, even in those without anemia, which must attract maximum attention from internists. The second key pathogenic moment in fatigue is the development of anemia with the onset of the anemic syndrome. Most patients complain of constitutional symptoms, such as general weakness, weight loss, profuse night sweats, and fever, which interfere with their daily activities. These complaints can be explained by the already-mentioned imbalance in cytokine homeostasis [4]. These manifestations are associated not only with a negative impact on the patients’ quality of life but also with an unfavorable prognosis [5].
Extramedullary hematopoiesis affects the spleen most often and rarely the liver, manifesting clinically through discomfort and pain under the costal arch caused by the increase in size. Splenomegaly is the result not only of myeloid hematopoiesis but also of the sequestration of myeloid cells. In some cases, there are pronounced pains in the left flank, along with fever and the clinical picture of acute abdomen caused by a splenic infarction. Hepatomegaly occurs in 40-70%. The involvement of the liver in the tumor process results in its dysfunction, manifesting itself through coagulopathy and thrombosis of the portal, splenic, and mesenteric veins [6, 7].
Often, anemia [8, 9, 10] and thrombocytopenia are the first paraclinical manifestations of myelofibrosis. Decreased hemoglobin and low platelet count are prognostic scores [10-14] and leukopenia often portends a poor prognosis [15, 16, 17]. Another special feature of primary myelofibrosis is the clinical-paraclinical variety. It can be manifested by cytopenia (cytopenic phenotype) and by bone marrow hypercellularity and pancytosis (proliferative phenotype) [18, 19]. However, the cytopenic phenotype is characterized by a reserved prognosis.
An interesting paper was published in 2022 on the prognostic impact of cytopenia in primary myelofibrosis. Two groups of patients in the prefibrotic and overt fibrotic phases were evaluated. In both cohorts, cytopenia resulted in progressive and unfavorable evolution. The most important indices were thrombocytopenia and anemia. The published results further extend the characterization of cytopenic features in PMF with a new understanding of the differences between the prefibrotic and overt fibrotic stages [20]. Primary myelofibrosis is characterized by anemia, which is detected in 50% of cases. Anemia is caused by both ineffective erythropoiesis in the bone marrow due to bone and extramedullary fibrosis and erythrocyte sequestration in the spleen.
It was mentioned above that thrombocytopenia is an unfavorable prognostic factor in primary myelofibrosis, and thrombocytosis is part of the proliferative phenotype.
The most common manifestations of primary myelofibrosis were described in the introduction of this article, but they are more characteristic of the overt fibrotic stage. Therefore, the hematologist knows how to manage these complications or minimize the intensification of constitutional symptoms. Young patients with primary myelofibrosis or other myeloproliferative neoplasms are understudied, resulting in unresolved treatment management. The changes in the complete blood count (thrombocytosis and leukocytosis) that are characteristic of the proliferative type are described in this study. Leukocytosis is one of the minor criteria for confirmation of myelofibrosis, but an elevated level of platelets is less common. It is very important for effective management because all patients with primary myelofibrosis are predisposed to thrombotic complications. Timely preventive measures can provide a better quality of life. Organomegaly was detected in most cases, which corresponds to the clinical features, but in the prefibrotic stage, it is smaller. So, the elevated level of platelets and leucocytes can be explained by hyperproliferation in the bone marrow and extramedullary hematopoiesis. Nevertheless, no correlations were found between the cellularity of peripheral blood and the sizes of the spleen or liver.
Conclusions
The classical clinical and hematological characteristics of primary myelofibrosis do not specify low- and intermediate-risk patients’ management in the prefibrotic stage, as compared with the other chronic myeloproliferative BCR-ABL-negative neoplasms.
The proliferation type of primary myelofibrosis is characteristic for young patients in the prefibrotic stage.
According to our results, the main manifestations in the prefibrotic stage are detected in a complete blood count and comprise anemia, leukopenia, leukocytosis, and thrombocytosis.
Authors’ contribution
NSB studied the bibliographic reference sources, summarized, and systematized the data of published research, studies, and clinical recommendations, collected the data, and structured and drafted the article. The manuscript was conceptualized by VM, MR, LJ, LM, AD, CD, and EC, who also summarized and systematized data from published research and studies and revised the draft of the article. All authors read and approved the final version of the article.
Competing interests
None declared
Authors’ ORCID IDs
Nina Sghibneva-Bobeico, https://orcid.org/0000-0001-7980-5183
Vasile Musteață, https://orcid.org/0000-0002-9471-7170
Maria Robu, https://orcid.org/0000-0002-3228-7566
Larisa Musteata, https://orcid.org/0000-0001-7162-6391
Cristina Dudnic, https://orcid.org/0000-0002-1904-1596
References
Greenfield G, McMullin MF & Mills K. Molecular pathogenesis of the myeloproliferative neoplasms. J. Hematol. Oncol., 2021; 14:103. doi: 10.3324/haematol.2014.113845
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011 May 12;117(19):5019-32. doi: 10.1182/blood-2011-01-293050.
Corcimaru I. Mielofibroza idiopatică (p. 190-193). In Hematologie. Editors: Serghienco-Ciobanu L., Ed. Centrul Editoreal-Poligrafic Medicina, Chișinau, Moldova; 2007.
Hasselbalch, HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood, 2012; 119 (14): p. 3219-25.doi: 10.1182/blood-2011-11-394775.
Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int. J. Gen. Med., 2014 Jan 29; 7: 89-101.doi: 10.2147/IJGM.S51800.
Prentice CR. Acquired coagulation disorders. Clin Haematol. 1985 Jun;14(2):413-42. PMID: 3899441.
Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin. Proc., 2003; 78 (10): 1223-1233.doi: 10.4065/78.10.1223.
Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E. et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood, J. Am. Soc. Hematol., 2009; 113: 2895-901. doi: 10.1182/blood-2008-07-170449.
Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A. et al. A dynamic prognostic model top redict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood, J. Am. Soc. Hematol., 2010; 115: 1703–8. doi: 10.1182/blood-2009-09-245837.
Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S. 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., 2010; 29: 392-7. doi: 10.1200/JCO.2010.32.2446.
Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M. et al. MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J. Clin. Oncol., 2017; 36: 310-8. doi: 10.1200/JCO.2017.76.4886.
Patnaik MM, Caramazza D, Gangat N, Hanson CA, Pardanani A, Tefferi A. Age and platelet count are IPSS‐independent prognostic factors in young patients with primary myelofibrosis and complement IPSS in predicting very long or very short survival. Eur. J. Haematol., 2010; 84: 105-8. doi: 10.1111/j.1600-0609.2009.01373.x.
Tam CS, Kantarjian H, Cortes J, Lynn A, Pierce S, Zhou L, Keating MJ, Thomas DA, Verstovsek S. Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol. 2009 Nov 20;27(33):5587-93. doi: 10.1200/JCO.2009.22.8833.
Tefferi A, Pardanani A, Gangat N, Begna KH, Hanson CA, Van Dyke DL, Caramazza D, Vannucchi AM, Morra E, Cazzola M, Pereira A, Cervantes F, Passamonti F. Leukemia risk models in primary myelofibrosis: an International Working Group study. Leukemia. 2012 Jun;26(6):1439-41. doi: 10.1038/leu.2011.374.
Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I. et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996; 88: 1013-8. PMID: 8704209.
Dingli D., Schwager S. M., Mesa R. A., Li C. Y. & Tefferi A. Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system. Cancer, 2006; 106 (3): 623-630. doi: 10.1002/cncr.21644.
Elliott M. A, Verstovsek S, Dingli D, Schwager SM, Mesa RA, Li CY, Tefferi A. Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis. Leukemia research, 2007; 31 (11); 1503-1509. doi: 10.1016/j.leukres.2006.12.025.
Vainchenker W, Constantinescu SN, Plo I. Recent advances in understanding myelofibrosis and essential thrombocythemia. F1000Res. 2016 Apr 19;5:F1000 Faculty Rev-700. doi: 10.12688/f1000research.8081.1.
Marcellino BK, Verstovsek S, Mascarenhas J. The Myelodepletive Phenotype in Myelofibrosis: Clinical Relevance and Therapeutic Implication. Clinical lymphoma, myeloma & leukemia, 2020; 20 (7): 415-421. doi: 10.1016/j.clml.2020.01.008.
Coltro G, Mannelli F, Loscocco GG, Mannarelli C, Rotunno G, Maccari C, Pancani F, Atanasio A, Vannucchi AM, Guglielmelli P. Differential prognostic impact of cytopenic phenotype in prefibrotic vs overt primary myelofibrosis. Blood Cancer Journal, 2022; 12 (8); 116. doi: 10.1038/s41408-022-00713-6.