Prefibrotic primary myelofibrosis (prefibrotic PMF) is a myeloproliferative neoplasm (MPN) with distinct characteristics comprising histopathological, clinical, and biological parameters. There are currently two distinct subtypes of PMF: early or prefibrotic PMF, the focus of this article, and overt fibrotic PMF.
Brief Diagnostic History
The earliest awareness of prefibrotic PMF came in 1976 when European pathologists recognized that a subtype of chronic myeloproliferative disorder was characterized by megakaryocytic and granulocytic hyperplasia, with atypical megakaryocyte morphology, but without any significant bone marrow fibrosis. Work in the 1990s led to a more mature understanding of histopathologic and clinical differences between various MPNs with thrombocythemia, culminating in the 2001 WHO classification of “chronic idiopathic myelofibrosis (CIMF), prefibrotic stage.” The 2016 World Health Organization (WHO) classification was the first to recognize prefibrotic PMF as a distinct cinicopathological entity, and the 2022 WHO classification (5th edition) and the International Consensus Classification (ICC) continue to recognize early/prefibrotic PMF, without any changes to the diagnostic criteria, as a distinct subtype of PMF that is different from overt PMF.
Making the Diagnosis
In clinical practice, it is critical to correctly distinguish prefibrotic PMF from essential thrombocythemia (ET) especially, but also from overt PMF, besides other myeloid neoplasms. The three major ICC diagnostic criteria for prefibrotic PMF are as follows:
- Bone marrow (BM) biopsy showing megakaryocytic proliferation and atypia, BM fibrosis grade <2, increased age-adjusted BM cellularity, granulocytic proliferation, and (often) decreased erythropoiesis
- JAK2, CALR, or MPL mutation or the presence of another clonal marker or absence of reactive BM reticulin fibrosis
- Diagnostic criteria for BCR-ABL1-positive chronic myeloid leukemia, polycythemia vera (PV), ET, myelodysplastic syndromes, or other myeloid neoplasms are not met
The four minor criteria include the following characteristics: anemia not attributed to a comorbid condition, leukocytosis ≥11 × 109/L, palpable splenomegaly, and a lactate dehydrogenase level above the reference range.
Diagnosis requires confirmation of all three major criteria and at least one minor criterion confirmed in two consecutive determinations.
Importantly, although the fifth edition of the WHO classification includes leukoerythroblastosis as a minor criterion for both prefibrotic and overt PMF, in the authors’ experience, this “feature is typically not seen in prefibrotic PMF.”
Pankit Vachhani, MD, and colleagues recommend performing a BM aspiration and biopsy, reviewing the peripheral blood smear, and strictly adhering to the established diagnostic criteria.
“Hematologists and pathologists should realize the inherent subjectivity in some of the diagnostic criteria and the associated imperfect intra- and interprofessional reproducibility,” the authors wrote.
Risk Stratification for Prefibrotic PMF
Risk stratification and survival outcomes for prefibrotic PMF are worse than ET but better than overt PMF. Rates of progression to overt PMF and blast phase disease are also higher for prefibrotic PMF than ET. Major bleeding episodes may be more common in prefibrotic PMF than ET, with one study finding that major bleeding associated with thrombocytosis might be relatively specific to PMF, and that low-dose aspirin exacerbates these hemorrhagic events. Overall, prefibrotic PMF is associated with worse outcomes for the combined endpoints of thrombosis, bleeding, and progression to overt PMF or acute myeloid leukemia (AML).
Risk stratification tools specifically designed for prefibrotic PMF are lacking. In clinical practice, the existing tools for overt PMF are often extended for prognostication and, therefore, management guidance, although the authors note caution must be exercised when applying these models to clinical decision-making because they are not well validated in prefibrotic PMF.
The use of the International Prognostic Score of Thrombosis (IPSET-T) or revised IPSET-T has been suggested until more dedicated risk tools are available. Recently, a validation study found that the IPSET-T score, and to a somewhat lesser extent (as indicated by the hazard ratios [HRs] of the individual risk categories) the revised IPSET-T, effectively discriminates patients with pre-PMF into low-, intermediate- (HR, 2.81 vs low-risk), and high-risk (HR, 4.14) categories of thrombotic risk. The rates of thrombosis in these categories were generally similar to those reported in patients with ET and approximately two- to threefold higher than expected in a normal population.
Managing Patients With Prefibrotic PMF
Neither the National Comprehensive Cancer Network guidelines nor the European LeukemiaNet 2018 recommendations specifically address the management of patients with prefibrotic PMF. Clinical trials have also not investigated outcomes in prefibrotic PMF specifically. As such, there is no specific management paradigm for those with prefibrotic PMF. Whether MF- or ET-like approaches should be taken continues to be debated, and practices vary. Given the generally indolent course of prefibrotic PMF, the day-to-day concerns in managing the disease lie more in preventing bleeding and thrombotic episodes.
As patients with prefibrotic PMF without prior thrombotic events have a thrombotic risk comparable with those with ET, one method is to adopt the IPSET-T-based approach to aspirin prophylaxis and cytoreduction in prefibrotic PMF patients. This approach translates to use of low-dose acetylsalicylic acid (ASA; 81-100 mg once or twice daily) in those with low-risk disease (aged under 60 years with JAK2 mutation) or worse and cytoreduction in those with intermediate- and especially high-risk disease.
In those patients with a history of thrombotic episodes, both ASA prophylaxis and cytoreduction should be performed—akin to management of PV and ET. On the other hand, in those with a previous major bleeding event or at high bleeding risk (eg, acquired von Willebrand disease secondary to “extreme” thrombocytosis), cytoreduction but not ASA prophylaxis should be performed.
Several studies have compared the baseline characteristics, complications, and outcomes of patients with prefibrotic PMF to those of either ET or overt PMF. Although some of these studies have raised concerns about the reproducibility, interobserver reliability, and utility of the bone marrow histology-based subjective diagnostic criteria in differentiating ET from prefibrotic MF, several other studies have demonstrated that amongst experienced hematopathologists, WHO criteria were applicable, reliable, and reproducible, and there is a notably high proportion of patients with a change in diagnosis when the cases are reviewed by expert hematopathologists.
Hydroxyurea is the most used cytoreductive treatment, not because of well-established efficacy in prefibrotic PMF, but rather due to familiarity with its use across MPN and randomized, controlled trial data in ET. In those with hydroxyurea resistance or intolerance, recombinant interferons can be considered. Anagrelide use is generally discouraged because the drug may increase BM fibrosis. Ruxolitinib may possibly stabilize or improve fibrosis in those with overt PMF; such effects, if any, in prefibrotic PMF patients are unknown. Its use should be considered in those with spleen-related or other symptoms.
High-risk patients with prefibrotic PMF (approximately 12% of all prefibrotic PMF) according to the International Prognostic Scoring System have a median survival of less than 5 years. In such patients, and in those who are similarly risk-stratified by MIPSS70 score, aggressive management approaches, including allogeneic stem cell transplant, should be considered.
Critical Need in Prefibrotic PMF Research
Although algorithms and formulae exist for differentiating ET from prefibrotic PMF, these remain complex, abstract, and largely unvalidated externally. They are capable of confidently allocating only about half of patients with WHO-defined ET or prefibrotic PMF. Ultimately, diagnosis could be improved with expanded expertise in BM assessment and identification of novel biomarkers. The use of artificial intelligence also holds promise in distinguishing between PMF and ET. It should help with efficient and correct diagnosis, and even potentially inform therapy selection, both in routine practice and in clinical trials, as well as prediction of outcomes.
At least two items are critically needed in prefibrotic PMF research. The first is prospectively collected data of confirmed prefibrotic PMF patients in registries as per the current diagnostic criteria. This would help elucidate the true natural course of prefibrotic PMF. The second is a risk-stratification schema based on clinical and molecular factors dedicated to prefibrotic PMF. Current practice is variable (eg, the choice of ET- or overt PMF-based models). Ideally, a dedicated risk-stratification model would help with prognostication and management decisions.
In the future, newer approaches that incorporate therapies that modify the disease course will emerge.
“Identifying those at highest risk for progression to overt PMF and AML would be important,” the authors wrote. “Other patients could then receive treatment primarily based on symptomatology and risk of thrombotic and hemorrhagic events. Until then, we should remain cognizant that prefibrotic PMF has an indolent course with relatively long survival. Therefore, it is important to not over-treat patients.”
Pankit Vachhani is an Assistant Professor of Medicine at the University of Alabama at Birmingham and Associate Scientist of Experimental Therapeutics. Sanam Loghavi, MD, is an Assistant Professor in the Department of Hematopathology at the University of Texas MD Anderson Cancer Center. Prithviraj Bose, MD, is a Professor in the Department of Leukemia at the MD Anderson Cancer Center.
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