PRIMARY MYELOFIBROSIS: UPDATE ON PATHOGENESIS, DIAGNOSIS AND MANAGEMENT

Abstract

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) characterized by anemia, teardropshaped red cells in blood, leukoerythroblastosis, bone marrow fibrosis, osteosclerosis and extramedullary hematopoiesis. Approximately 50% of PMF patients harbor JAK2V617F mutation and MPL mutations are present in a further 10%. Bone marrow examination reveals a hypercellular bone marrow with atypical megakaryocytes and slight marrow fibrosis in cellular phase of PMF. Diagnosis requires the exclusion of other MPN. Most patients are diagnosed in the fibrotic phase of PMF, when fibrosis is typically extensive with reticulin fibers and often subsequently accompanied by collagen fibrosis. Overall median survival is approximately 5 years. Death is mainly due to leukemic transformation, accounting for 20% of PMF patients. Others succumb to consequences of cytopenias such as infection or bleeding or to comorbid conditions including cardiovascular events. A number of prognostic scoring systems have been developed for PMF (eg. IPSS, DIPPS, DIPSS Plus). Analysis of a total of 879 patients included in a European and Mayo Clinic cohort showed that ASXL1, SRSF2 and EZH2 mutations independently predicted shortened survival. Leukemia-free survival (LFS) was negatively affected by IDH1/2, SRSF2, and ASXL1 mutations. Profiling for ASXL1, EZH2, SRSF2 and IDH mutations may identify PMF patients at risk for leukemic transformation or death. Currently, these molecular markers are mainly of research interest. Allogeneic hematopoietic stem cell transplantation (AHSCT) is the only curative treatment modality in PMF, yet it is associated with high treatment-related mortality. All other treatment modalities are palliative and show differences in efficacy and toxicity. There are few randomized trials comparing these modalities. Thus, it is not possible to make strong recommendations for selecting one treatment over another. This review aims to highlight the pathogenesis, diagnosis and current management in PMF

Keywords

• JAK2V617F mutation
• MPL mutations
• Myeloproliferative neoplasms
• Primary myelofibrosis

PRİMER MİYELOFİBROZİS: PATOGENEZ, TEŞHİS VE TEDAVİDE GÜNCEL BİLGİLER

Abstract

Primer miyelofibrozis (PMF), anemi, periferik kan yaymasında ‘tear drop’ şeklinde eritrositler, lökoeritroblastozis, kemik iliği fibrozisi, osteosklerozis ve ekstramedüller hematopoez ile karakterize miyeloproliferatif neoplazilerden (MPN) biridir. JAK2V617F mutasyonu PMF olgularının yaklaşık %50’sinde ve MPL mutasyonları %10’unda görülmektedir. PMF’in hücresel fazında kemik iliği biyopsisi atipik megakaryositler ve belirgin olmayan kemik iliği fibrozisi ile birlikte hiperselüler kemik iliğini ortaya çıkarır. PMF tanısı için diğer MPN’lerin dışlanması gerekmektedir. Birçok hasta PMF’in fibrotik fazında tanı alır. Bu fazdaki hastalarda fibrozis, tipik olarak yoğun retikülin lif artışı şeklinde ortaya çıkmakla beraber sonrasında sıklıkla kollagen fibrozisi gözlenir. Ortalama yaşam süresi yaklaşık 5 yıldır. PMF’in yaklaşık %20’sinde ortaya çıkan lösemik transformasyon, ölümün başlıca nedenidir. Diğer ölüm nedenleri arasında kardiyovasküler hastalıklar gibi komorbid hastalıklar yanında sitopeniye bağlı ortaya çıkan enfeksiyonlar ve kanama vardır. PMF için birkaç prognostik skorlama sistemi geliştirilmiştir (örneğin IPSS, DIPSS, DIPSS Plus). PMF’deki somatik mutasyonların prognostik önemi araştırılmıştır. ASXL1, SRSF2 ve EZH2 mutasyonlarının kısa yaşam süresi ile ilişkili bağımsız faktörler olduğu ve IDH1, IDH2, SRSF2 ve ASXL1 mutasyonlarının lösemi ilişkisiz sağkalımı (LFS) kısalttığı bildirilmiştir. Sonuç olarak PMF’de ASXL1, EZH2, SRSF2 ve IDH mutasyonlarının lösemik transformasyon veya ölüm riskini belirlemede yararlı olabileceği söylenebilir. Günümüzde bu moleküler belirteçler yoğun araştırma konusudur. PMF’de tek küratif tedavi yöntemi allogeneik hematopoetik kök hücre nakli (AHKHN) olmasına rağmen tedavi ile ilişkili mortalite oranı yüksektir. AHKHN dışındaki diğer tedavi şekilleri palyatif olup farklı etkinlik ve toksisiteye sahiptir. PMF’de tedavi yöntemlerini karşılaştıran az sayıda çalışma olduğundan, aralarından seçim yapılarak önerilmesi mümkün değildir. Bu derlemenin amacı, PMF tanılı olgularda patogenez, tanı yöntemleri ve güncel tedaviyi özetlemektir.

Keywords

• JAK2V617F mutasyonu
• Miyeloproliferatif neoplaziler
• MPL mutasyonları
• Primer miyelofibrozis

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