PAOLA GUGLIELMELLI (FLORENCE)
PRE-MYELOFIBROSIS & MYELOFIBROSIS
In this presentation, I report the case of a patient with a history of prefibrotic- myelofibrosis
erroneously considered to have ET, progressed to an overt-PMF who underwent allogeneic
stem cell transplantation. A 51-year old woman with a history of thrombocytosis of a few years
duration was referred for evaluation of a possible MPN. Her May 2010 complete blood
chemistry (CBC) results were: hemoglobin (Hb) 15.0 g/dL; hematocrit (Hct) 46%; WBC count
11.8×10/L; platelets 778×10^9/L. In 2014 she referred to a private hematologist and the
following test results were also obtained: JAK2V617 was positive by polymerase chain reaction
(PCR) and the bone marrow biopsy has been interpreted as an essential thrombocythemia
(ET). Initial treatment consisted of low dose of aspirin; however, in 2017 she was evaluated at
our Hematological Center because a greater increase in spleen volume. Her peripheral blood
smear showed mild anisopoikilocytosis and thrombocytosis and bone marrow (BM)
histopathology revealed hypercellularity, increased granulopoiesis and megakaryopoiesis,
highly pleomorphic megakaryocytes displaying atypia, tight clusters of megakaryoctyes, grade
1 fibrosis. A careful re-evaluation of BM biopsy performed in 2014 according to 2016 WHO
criteria showed a morphology compatible with Pre-PMF.
Prefibrotic myelofibrosis (pre-PMF), was formally introduced in the previous 2001 and 2008
World Health Organization (WHO) classifications of tumors and defined as a distinct clinic-pathologic
entity in the recent 2016 revision. The role of bone marrow histology is crucial in
diagnosing pre-PMF In particular, ET differs from pre-PMF in that cellularity is usually
preserved, granulopoiesis and erythropoiesis are in regular ratio and not expanded, and
megakaryocytes, although significantly increased, show no or only mild atypia, with mature
hyperlobulated nuclei. Conversely, the 2016 WHO classification of myeloid neoplasms
dictated distinct criteria for pre-PMF and overt fibrotic PMF (overt PMF). Criteria mainly rely
on bone marrow (BM) morphology (with megakaryocyte proliferation and atypia in both
diseases, and increased age-adjusted cellularity with granulocyte proliferation and often
decreased erythropoiesis in pre-PMF) and fibrosis grade (grade 0-1 indicates pre-PMF and
grade 2-3 overt PMF); accordingly, grade 1 fibrosis is included in the pre-PMF category.
Two years later, the patient repeat biopsy indicated that the patient had progressed to overt
PMF based on marrow histopathology. NGS analysis also revealed the presence of mutation
in ASXL1, U2AF1. She also had progressed anemia, presence of blast cells in peripheral blood
and she referred profound asthenia and worsening of constitutional symptoms. The year
before (July 2018) a deep vein thrombosis in the common femoral vein with a massive acute
pulmonary embolism was documented and an anticoagulant therapy in place of ASA was
initiated.
In the last decade, several prognostic models have been introduced and have enabled
clinicians to determine the most appropriate therapy for patients with myelofibrosis. Beyond
their role in pathogenesis of driver mutations have been associated with a distinct clinical
phenotype and recognized prognostic implications. The genetic landscape of MPN patients
has been successfully dissected within the past years with the advent of new sequencing
technologies. Integrating the genetic information within a clinical setting is already benefitting
patients in terms of disease monitoring and prognostic information of disease progression
Landmark studies recently published demonstrated somatic mutations, additional subclonal
driver and non-driver genes such as ASXL1,SRSF2,EZH2,IDHs and U2AF1 have been identified
as being associated with disease progression. The progressive utilization of molecular