Thiele, Jürgen

ABSTRACT This study aimed to distinguish between essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre‐PMF) using routine blood tests, with a focus on white blood cell (WBC) and platelet (PLT) levels. We evaluated the predicted probability of a pre‐PMF diagnosis based on the interaction between WBC and PLT levels using data from a logistic regression model involving 891 patients with ET and 180 patients with pre‐PMF. Patients were divided into four groups based on whether their WBC and PLT values were below or above the respective thresholds of 8.85 × 10 9 /L and 793 × 10 9 /L. The results showed that patients with low levels of both WBCs and PLTs had the lowest predicted probability of pre‐PMF (6%), indicating a profile more typical of ET. When either WBC or PLT levels were elevated, the probability increased to approximately 18%–19%, indicating a potential shift toward pre‐PMF features. Notably, patients with elevated levels of both WBCs and PLTs had the highest probability of a pre‐PMF diagnosis (26%), which was more than four times higher than that of the low–low group. The association between combined WBC/PLT levels and a pre‐PMF diagnosis remained significant ( p < 0.001), even when adjusting for serum lactate dehydrogenase (LDH) and splenomegaly. These findings suggest that elevated WBC and PLT levels together can serve as a practical and accessible diagnostic tool for supporting the differential diagnosis of ET or pre‐PMF in cases of uncertainty, and for deferring bone marrow biopsy in cases of early disease presenting with isolated thrombocytosis.

AbstractA group of international experts, including hematopathologists, oncologists, and geneticists were recently summoned (September 2021, Chicago, IL, USA) to update the 2016/17 World Health Organization classification system for hematopoietic tumors. After careful deliberation, the group introduced the new International Consensus Classification (ICC) for Myeloid Neoplasms and Acute Leukemias. This current in‐depth review focuses on the ICC‐2022 category of JAK2 mutation‐prevalent myeloproliferative neoplasms (MPNs): essential thrombocythemia, polycythemia vera, primary myelofibrosis, and MPN, unclassifiable. The ICC MPN subcommittee chose to preserve the primary role of bone marrow morphology in disease classification and diagnostics, while also acknowledging the complementary role of genetic markers for establishing clonality, facilitating MPN subtype designation, and disease prognostication.

Abstract The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Abstract Introduction Patients with masked polycythemia vera (mPV) present with hemoglobin (HB) values borderline inferior to those required by the World Health Organization (WHO) diagnostic criteria (HB >16.5g% and >18.5 g% in female and male respectively) but are suspected to have PV for presenting clinico-hematological features. The diagnostic HB values required by the WHO guidelines have been considered surrogate of increased red cell mass (RCM). However, in both males and females HB values are not always equal to an absolute erythrocytosis and conversely a HB concentration below the required cut off level could be associated with an increased red cell mass. We believe that bone marrow (BM) morphology may play an important role in differentiating PV from other MPN entities and reactive changes. In this study we investigated JAK2V617/Exon12-positive patients showing BM features characteristic for PV and classified as mPV or overt PV according to their hemoglobin levels and evaluated their respective outcomes including thrombosis, progression to myelofibrosis (MF), acute leukemia (AL) and overall survival with the purpose to support the diagnosis of PV also in patients presenting with lower HB levels than required by WHO criteria. Materials and Methods A clinicopathological database of patients who were diagnosed and treated for PV was created by clinicians and hematopathologists from seven international centers of excellence for MPNs. Eligibility criteria for entry included the presence of JAK2V617F (or Exon12) mutation, EPO measurement, no evidence of subnormal ferritin levels and the availability of representative, treatment-naive BM biopsies (hematoxylin-eosin staining and silver impregnation after Gomori or Gordon-Sweet). All BM biopsies were centrally re-reviewed by one of the authors (J.T.) who was completely blinded to outcome data. In both mPV and overt PV patients, phlebotomy and cytoreductive therapy were used with the same frequency (p=0.101). Results and Discussion Among 397 mutated patients, with PV BM morphology as defined by WHO, 257 (65%) met the full WHO-2008 criteria. The remaining 140 patients (35%) were classified as mPV for levels of HB at diagnosis, ranging from 16.5 to 18.5 g/dL in men and from 15.0 to 16.5 g/dL in women, and frequent presence of subnormal EPO levels (65%). At baseline, mPV patients were more males, had more previous arterial thrombosis and presented more frequently with platelet counts exceeding the required level of WHO-defined ET (450 x 109/L), often mimicking clinically this entity at onset. After a median follow-up of 3.8 (0-29.8) and 4.5 (0-21.1) years in mPV and overt PV, respectively, time to the first thrombotic event was superimposable in the two groups while time to progression to MF and AL was significantly different .These combined events were recorded in 10% of mPV and 5.8% of overt PV, corresponding to an annual rate of 1.60 % pts/year in mPV and 0.97 % pts/year in overt PV, respectively (p=0.010). In addition, an inferior overall survival was documented in mPV patients in comparison with overt PV (p=0.011). The annual rate of death in mPV was almost twice that of overt PV, mainly due to an excess of hematological transformation (overt MF and AL). Multivariable analysis identified age older than 65 years (hazard ratio (HR) 6.63, P<.0001), WBC >10 x109/L (HR 2.99, P=.005) and diagnosis of mPV (HR 2.38, P=.036) as independent risk factors for survival in these patients. These results show that in JAK2 mutated patients with borderline HB levels, BM features may be a valid support to confirm the suspicion of PV diagnosis. Of interest, recent data demonstrated that all patients with increased RCM also had BM morphology typical of PV. It is tempting to speculate that the clinico-hematologic phenotype of mPV may represent an early stage of a JAK2 mutated MPN, presenting as a variant of PV, with a more rapid progression to MF and AL. The recognition of these early PV patients has an important clinical impact since, in spite of not meeting the full WHO criteria, mPV share the same vascular risk as overt PV. In conclusion, these data suggest that mPV is not necessarily only an early form of classical PV but a distinct entity with disease outcomes akin to primary myelofibrosis. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Current risk stratification in Polycythemia Vera (PV), is designed to estimate the likelihood of thrombotic complications. In ECLAP large prospective study of 1638 PV cases diagnosed by Polycythemia Vera Study Group (PVSG) criteria, risk factors were age over 65 years and prior thrombotic events. After the JAK2V617F discovery, diagnosis has undergone substantial revision by the World Health Organization (WHO). Consequently, current risk factors determination should be described in patients diagnosed by the most recent recommendations and requires a large sample size with reliable and sufficiently long clinical course documentation. Accordingly, the current study includes 1545 patients with strictly WHO-defined PV diagnosed and followed-up in seven centers from Italy, Austria and the United States, belonging to the International Working Group for Myeloproliferative Neoplasm (MPN) Research and Treatment (IWG-MRT). Objective and design 1) Describe the rate of thrombosis in this population; 2) Report the sites and frequency of recurrences after a first arterial or venous event; 3) Identify separately risk factors for arterial versus venous thrombosis and develop practically useful prognostic models. Results 1. Presenting features The characteristics of the cohort recruited reflected well the heterogeneity of epidemiologic and clinical features that are found in the routine clinical practice of PV. Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) and 114 (7.4%) patients, respectively. The frequencies of arterial and venous thrombosis were lower than those recorded in the ECLAP4 (27% and 11% respectively) but comparable to those reported in the recent Cyto-PV2 (arterial 17%, venous 12%) studies. The discrepancy might be partly related to earlier diagnosis in the post-ECLAP JAK2mutation era. 2. Thrombotic events after diagnosis Median follow-up was 6.9 years and treatment included aspirin (84%) and cytoreductive agents (73%), in addition to phlebotomy. Post-diagnosis total major thrombosis rate was 2.62% pt/yr, lower than reported in the ECLAP trial (4.4% pt/yr) but comparable to the Cyto-PV study (2.7% pt/yr) where management of cardiovascular risk factors was more intensive than in ECLAP. Arterial or venous thrombosis occurred in 184 (12%, rate: 1.59 % pts/yr) and 137 (9%, rate: 1.05 % pts/yr) patients, respectively. In addition, prior arterial events were associated in 75% of cases with subsequent arterial events and in the remaining 25% with venous thrombosis including splanchnic vein events. Moreover, patients with prior venous events had recurrences in venous district in 61% of cases and in the arterial district in 39%. 3. Risk factors for arterial versus venous thrombosis and prognostic models In multivariable analysis, arterial thrombosis was predicted by previous arterial event (HR 1.7, 95% CI 1.2-2.4), and hypertension (HR 1.6, 95% CI 1.2-2.2) while predictors of venous events were previous venous thrombosis (HR 2.6, 95% CI 1.5-4.4), and age ≥ 65 years (HR 1.7, 95% CI 1.2-2.5). We used the above-mentioned risk factors in order to develop prognostic models allowing to identify patients at different probability to develop arterial or venous thrombosis. For arterial thrombosis, the absence of previous arterial thrombosis and hypertension defined lower-risk (rate 1.27 % pts/yr) while the presence of one or both identified higher-risk patients (rate 2.04 % pts/yr). Previous venous event and/or age ≥ 65 years identified patients at higher risk of venous (rate 1.62 % pts/yr) thrombosis and, if absent, patients at lower risk (rate 0.78 % pts/yr). Conclusion The overall rate of thrombosis was half than in ECLAP and should be considered in future clinical trials. Of note, patients with a prior venous thrombosis had a more frequent subsequent recurrence in the venous district but a proportion of them (40%) had also arterial events; conversely, recurrences after previous arterial event were also registered in the leg and non-leg veins in 30 % of cases, indicating that in PV, venous and arterial thrombosis may share some common pathogenetic mechanisms. These findings may have practical implications and suggests antiplatelet therapy and anticoagulant therapy as the favorite choice to prevent arterial and venous thrombosis, respectively, but also suggests studies of antithrombotic drug combination. Disclosures No relevant conflicts of interest to declare.

In myeloproliferative neoplasms (MPNs), controversy persists regarding the usefulness and reproducibility of bone marrow (BM) features. Disagreements concerning the WHO classification are mainly focused on the discrimination between essential thrombocythemia (ET) and prefibrotic/early primary myelofibrosis (prePMF) and prodromal polycythemia vera (PV). Criticism mostly refers to lack of standardization of distinctive BM features precluding correct morphological pattern recognition. The distinction between WHO‐defined ET and prePMF is not trivial because outcome is significantly worse in prePMF. Morphology was generally considered to be non‐specific for the diagnosis of PV. Recent studies have revealed under‐diagnosis of morphologically and biologically consistent PV. Am. J. Hematol. 91:430–433, 2016. © 2015 Wiley Periodicals, Inc.

Most studies in polycythemia vera (PV) include patients with both remote and most recent diagnostic periods and are therefore vulnerable to inaccurate interpretation of time‐dependent data. We addressed the particular issue by analyzing presenting characteristics and outcome data among 1,545 patients with WHO‐defined PV stratified by a diagnosis period of before or after 2005, which coincides with the first description of JAK2V617F as the molecular marker of PV. Patients diagnosed after 2005 displayed lower hemoglobin values (P < 0.0001) and older age (P = 0.007) at diagnosis; we suggest ease of diagnosis offered by a molecular marker enabled earlier diagnosis and broader application across older age groups that is further enhanced by recent trends in increased attention and health monitoring for the elderly. Post‐2005 diagnosed patients were also more or less likely to receive aspirin and cytoreductive therapy, respectively, and, despite their older age distribution, displayed significantly lower risk of thrombosis in high risk disease. Regardless of the contributing factors to the latter phenomenon, our observations underscore the need to reassess current demographics and frequencies of thrombosis in clinical trial designs including thrombosis prevention in PV. Am. J. Hematol. 90:434–437, 2015. © 2015 Wiley Periodicals, Inc.

In patients not meeting the required hematocrit (HCT) or hemoglobin (Hb) thresholds according to BCSH and the WHO diagnostic criteria, the diagnosis of masked polycythemia vera (mPV) has been proposed. A comparison of HCT or Hb values with the expression of JAK2V617F, JAK2 exon 12, and CALR mutations in strictly WHO‐defined 257 overt PV and 140 mPV (59 mPV according to BCSH) and 397 patients with essential thrombocythemia (ET) was performed. Hb and HCT thresholds of mPV patients were significantly higher than JAK2V617F ET (P < 0.0001). The best cut‐off for Hb to discriminate JAK2‐mutated ET from PV was 16.5 g/dL for males and 16.0 g/dL for females. For HCT, this was 49% in males and 48% in females. The proportion of patients correctly classified as ET or PV when regarding Hb or HCT levels was 95% in males and 93% in females and 94% in both males and females, respectively. Am. J. Hematol. 89:588–590, 2014. © 2014 Wiley Periodicals, Inc.

Polycythemia vera (PV) is currently diagnosed by the World Health Organization (WHO) criteria regarding hemoglobin (HB) levels and JAK2V617F and related mutations or by the British Committee for Standards in Haematology (BCSH) guidelines predominantly based on hematocrit (HCT) values (>52% in men and >48% in women) in JAK2 mutated patients. We examined clinical features at diagnosis and outcome in 397 mutated PV patients showing a bone marrow (BM) morphology conforming with the WHO descriptions but including also cases with a HB level <18.5 g/dL in males (range 16.0–18.4) and <16.5 g/dL in females (range 15.0–16.4). These patients were regarded as masked PV (mPV) comprising 140 (35%) cases of our cohort. A comparison with the BCSH criteria based on HCT levels revealed a decrease of mPV patients to 59 (15%). In both classification systems, mPV patients were more males, presented more frequently with higher platelet counts, and increased BM reticulin fibrosis. A worsening of overall survival was documented in mPV patients in comparison with overt PV following the WHO (P = 0.011) as well as the BCSH (P = 0.0019) criteria. Risk factors for inferior survival in mPV were age >65 years and white blood cell count >15 × 109/L. Without these risk factors mPV patients had the same survival as overt PV suggesting that a fraction of patients with HB lower than that required for WHO diagnosis should still be considered as overt PV. This study has established the existence of mPV by two different classification systems based on either HB or HCT threshold values. Am. J. Hematol. 89:199–202, 2014. © 2013 Wiley Periodicals, Inc.

We examined the baseline features and clinical outcomes of 140 patients presenting with JAK2V617F positivity and a bone marrow morphology conforming with WHO criteria of polycythemia vera (PV), but a hemoglobin level of <18.5 g/dL in males (range 16.0–18.4) and <16.5 g/dL in females (range 15.0–16.4). This cohort operationally referred to as masked PV (mPV) was compared with 257 patients with overt PV and displayed male predominance, a more frequent history of arterial thrombosis and thrombocytosis. Incidence of thrombosis was similar between the two groups but mPV displayed significantly higher rates of progression to myelofibrosis and acute leukemia and inferior survival. In multivariable analysis mPV diagnosis was an independent predictor of poor survival along with age >65 years and leukocyte count >10 × 109/L. Our data suggest that mPV is a heterogeneous myeloproliferative neoplasia and not necessarily an early/ pre‐polycythemic form of classical PV that at onset in a small fraction of patients clinically may mimic essential thrombocythemia. On the other hand, the majority mPV may have a longer prodrome of undiagnosed PV or a disease biology akin to primary myelofibrosis‐post PV myelofibrosis that could explain the worsening of outcome in comparison to overt/classical manifestations. Am. J. Hematol. 89:52–54, 2014. © 2013 Wiley Periodicals, Inc.