Evaluation of paroxysmal nocturnal hemoglobinuria clone presence in low risk myelodysplastics syndrome patients

Abstract

Aim: Myelodysplastic syndrome (MDS) is a clonal stem cell disease of bone marrow characterized by dysplasia of hematopoietic precursor cells in bone marrow. Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening, clonal, non-malignant hematopoietic stem cell disease of the bone marrow. This study was planned to evaluate both PNH clone level and frequency in patients with low-risk MDS. Methods: The normal distribution of the data was evaluated by Kolmogorov-Smirnov test. Normal distribution of numerical variables was expressed as mean ± standard deviation, and categorical variables were expressed as number and percentage. 

Differences of numerical variables according to the presence of PNH were evaluated by Student T test and Mann Whitney U test. Myelodysplastic syndrome patients followed up in Mersin University Medical Faculty Hematology Department between 2010-2019 were included in the study. Results: The study consisted of 13 patients with PNH clones and 176 total 189 MDS patients without PNH clones.  The rate of patients with PNH clone was 7%. The mean age of the patients was 64.5 ± 13 years, female rate was 51.8%, and the rate of hypocellularity of bone marrow was higher (61.5% vs 16.5%; p = 0.001). Decreased hematocrit levels increased lactic dehydrogenase ratio, increased revised international prognostic score were identified as possible risk factors associated with mortality compared to those without PNH clones. Conclusion: In the presence of a hypocellular bone marrow in some of the low-risk MDS patients, PNH clone analysis is recommended for patients who go with refractory anemia without blast increase, and PNH clone analysis if cytopenia is accompanied by high LDH.

Düşük riskli miyelodisplastik sendrom hastalarında proksismal noktürnal hemoglobinüri klon varlığının değerlendirilmesi

Abstract

Amaç: Miyelodisplastik sendrom (MDS) kemik iliğinde hematopoetik öncül hücrelerin displazisi sonucu sitopenilerle karakterize kemik iliğinin klonal kök hücre hastalığıdır. Kemik iliğinde eritrositik, megakaryositik ve granülositik serilerin her üçü de etkilenebilir. Paroksismal nokturnal hemoglobinüri (PNH) hayatı tehdit edici, kemik iliğinin klonal, malign olmayan hematopoetik kök hücre hastalığıdır. Düşük riskli MDS tanısına sahip hastalarda hem PNH klon düzeyi ve sıklığını değerlendirmek üzere bu çalışma planlanmıştır. Yöntem: Çalışma retrospektif gözlemsel çalışma olarak planalndı. Verilerin normal dağılımı Kolmogorov-Smirnov testi ile değerlendirildi. Sayısal değişkenlerden normal dağılım sergileyenler ortalama±standart sapma olarak, kategorik değişkenler sayı ve yüzde olarak belirtildi. PNH varlığına göre sayısal değişkenlerin farklılığı Studen T testi ve Mann Whitney U ile değerlendirildi. Mortalite ile ilişkili bulgular univariable Cox regression analiz ile değerlendirildi. 2010-2019 yılları arasında Mersin Üniversitesi Tıp Fakültesi Hematoloji BD’da takipli myelodisplastik sendrom hastaları çalışmaya alındı. Bulgular: Araştırma PNH klonu olan 13 hasta ve PNH klonu olmayan 176 toplam 189 MDS hastasından oluştu. PNH klonuna sahip hasta oranı %7 olarak saptandı. Hastaların ortalama yaşı 64.5±13 yıl, kadın oranı %51.8, PNH klonu olanlarda olmayanlara kıyasla kemik iliğinin hiposellülerite oranı yüksek (%61.5 vs %16.5; p=0.001) saptandı. PNH klonu olanlarda olmayanlara kıyasla azalan hematokrit düzeyi, artan laktik dehidrogenaz oranı, artan revize edilmiş uluslararası prognositik skoru mortalite ile ilişki gösteren olası risk faktörleri olarak belirlenmiştir. Sonuç: Düşük riskli MDS hastalarının bir kısmında görülen hiposellüler bir kemik iliği varlığında, blast artışı olmayan refrakter anemi ile giden hastalara PNH klon analizi yapılması, sitopeni tablosuna yüksek LDH eşlik etmesi halinde PNH klon analizi önerilmektedir. 

Keywords

• Myelodisplastik sendrom,paroksismal nokturnal hemoglobinüri,klonalite

References

1. Referans 1: Gilliland G D and Dunbar E C: Myelodysplastic syndromes. In:Blood. Principles and Practice of Hemathology. Ed:Handin I R et al, second edition, Lippincott Williams & Wilkins, Philadelphia, 2003; pp355-377.
2. Referans 2: Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood 2008, 112(1):45-52.
3. Referans 3: Parker E J, Fishlock L K et al: ‘Low risk’ myelodyaplastic syndrome is associated withexcessive apoptosis and an increased ratio of pro-versus anti-apoptotic bcl-2-related proteins. Br J Haematol 1998; 103:1075-1082.
4. Referans 4: Schnatter AR, Glass DC, Tang G, Irons RD, Rushton L. Myelodysplastic syndrome andn benzene exposure among petroleum workers: an international pooled analysis. Journal of the National Cancer Institute 2012;104(22):1724- 37.
5. Referans 5: Sekeres MA, Schoonen WM, Kantarjian H, List A, Fryzek J, Paquette R, et al. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. Journal of the National Cancer Institute 2008,100(21):1542-51.
6. Referans 6: Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Risitano AM, Schubert J, Norkolf D, Simpson N, Hillmen P. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. British Journal of Haematology 2010; 149: 446-450.
7. Referans 7: Santarone S, Bacigalupo A, Risitano AM, Tagliaferri E, Bartolomeo ED, Iori AP, Rambaldi A, AngelucciE, Spagnoli A, Papineschi F, Tamiazzo S, Nicola MD, Bartolomeo PD. Hematopoetic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midillo Osseo (GITMO). Hematologica 2010; 95(6); 983-988.
8. Referans 8: Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal hemoglobinuria. British Journal of Haematology 2007; 137; 181-192.

9. Referans 9: Röth A, Hock C, Konik A, Christoph S, Dührsen U. Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. Int J Hematol 2011; 93 (6); 704-14.
10. Referans 10: Bellido M, Velden VHC, Leebeek FWG, Boekhorst PAW. Thrombotic complications without evidence of hemolysis in paroxysmal nocturnal hemoglobinuria: is eculizumab indicated?. Annals Hematol 2012; 91: 1969-1970.
11. Referans 11: Borowitz MJ, Craig FE, Digiuseppe JA, Illingworth AJ,Rosse W, Sutherland DR, Wittwer CT, Richards SJ. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010;78:211–30.
12. Referans 12: Hillmen P. Paroxysmal Nocturnal haemoglobinuria. In: Hoffbrand AV, Catovsky D, Tuddenham EGD, Green AR, eds. Postgraduate Haematology. 6th ed. Singapore: Wiley-Blackwell; 2011.p.176- 185
13. Referans 13: Brodsky RA, Mukhina GL, Li S, Nelson KL, ChiurazziPL, Buckley JT, Borowitz MJ. Improved detection andcharacterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol 2000;114:459–66.
14. Referans 14: D. Robert Sutherland, Nancy Kuek, Jeff Davidson, David Barth, Hong Chang, Erik Yeo, Sylvia Bamford, Ian Chin-Yee, and Michael Keeney.Diagnosing PNH with FLAER and Multiparameter Flow Cytometry, Cytometry Part B (Clinical Cytometry) 72B:167–177 2007
15. Referans 15: Goldberg SL, Chen E, Corral M, et al. Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol 2010; 28:2847.
16. Referans 16: Foucar K, Langdon RM 2nd, Armitage JO, et al. Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases. Cancer 1985; 56:553.
17. Referans 17: Wang H, Chuhjo T, Yasue S, et al. Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. Blood 2002; 100:3897.
18. Referans 18: Dunn DE, Tanawattanacharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999; 131:401.
19. Referans 19: Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer 2007; 109:1536.
20. Referans 20: Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer 2011; 105:1684.
21. Referans 21: Shetty V, Hussaini S, Broady-Robinson L, et al. Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: apoptotic cells recovered from high-density fraction of bone marrow aspirates. Blood 2000; 96:1388.
22. Referans 22: Pu JJ, Hu R, Mukhina GL, et al. The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells. Haematologica 2012; 97:1225.
23. Referans 23: Schrezenmeier H, Muus P, Socié G, et al. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica 2014; 99:922.
24. Referans 24: Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol 2000; 114:459.
25. Referans 25: Fletcher M, Sutherland DR, Whitby L, et al. Standardizing Leucocyte PNH clone detection: An international study. Cytometry B Clin Cytom 2014.
26. Referans 26: Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454.
27. Referans 27: Sperr WR, Wimazal F, Kundi M, et al. Comorbidity as prognostic variable in MDS: comparative evaluation of the HCT-CI and CCI in a core dataset of 419 patients of the Austrian MDS Study Group. Ann Oncol 2010; 21:114.
28. Referans 28: Breccia M, Federico V, Latagliata R, et al. Evaluation of comorbidities at diagnosis predicts outcome in myelodysplastic syndrome patients. Leuk Res 2011; 35:159.
29. Referans 29: Sloand EM, Wu CO, Greenberg P, et al. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 2008; 26:2505.
30. Referans 30: Della Porta MG, Malcovati L, Strupp C, et al. Risk stratification based on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome. Haematologica 2011; 96:441.