In this analysis (data cut-off on May 31, 2022), a total of 960 patients diagnosed with essential thrombocythemia (n = 495) and myelofibrosis (n = 465) were reported by 31 centers (Fig. 1).

Participating centers and number of total patients (black bar), ET patients (white bar) and MF patients (grey bar) reported per center

Patients received their diagnosis after publication of the 2016 WHO-classification of MPN. As anticipated, patients' gender distribution for ET (55.4% female vs. 44.6% male) was predominately female, whereas that for MF (50.5% female vs. 49.5% male) was balanced. The majority of MPN patients investigated here were of older age in both the ET- (63.4% > 65 years) and MF- (76.4% > 65 years) groups, respectively (Table 1).

Overall, the patient population was older than in previously published multicenter trials for ET or MF. As demanded by inclusion criteria, all patients in the primary analysis had been diagnosed after publication of the WHO 2016 re-classification of myeloproliferative neoplasms (Arber et al. 2016).

Molecular diagnostics regarding detection of driver mutations was available in 97.6% of ET and 94.6% of MF patients (Fig. 2). JAK2V617F was detected in 74.1% (n = 337) ET and 76.9% (n = 320) of MF patients. In contrast, MPL-mutations were found in 6.4% (n = 29) and 7.0% (n = 29) and CALR-mutations in 22.2% (n = 101) and 18.7% (n = 78) patients with ET and MF, respectively. These findings show comparable rates of JAK2, CALR and MPL-mutations as recently published in a large dataset of 2035 MPN patients (Grinfeld et al. 2018), including patients with PV and MPN-U. Compared to molecular analyses of large ET and MF cohorts (Zoi and Cross 2017), this population shows a bias towards patients with JAK2 mutations.

Molecular diagnostics and analysis of driver mutations in 495 patients classified as ET and 465 patients classified as MF. A Percentage of patients, who received molecular diagnostics at diagnosis. B Rate of driver mutations detected at diagnosis

Only 58.6% (n = 290) of patients diagnosed as ET had a bone marrow (BM)-biopsy performed as part of the examination at the time of initial diagnosis. (Fig. 3). In contrast, patients classified as MF had received BM histology in 91.8% of the cases (n = 427). Within the ET cohort, 85.2% (n = 247/290) showed myelofibrosis grade 0 or 1. Only 4/290 cases had a documented fibrosis grade of 2 or 3 that would not be compatible with the clinical diagnosis of ET. Of note, in 13.4% of patients (n = 39/290) the fibrosis grade was not available or documented in the histopathology report. In contrast, patients within the MF cohort were diagnosed with fibrosis grade 0 or 1 in 56.9% (n = 243/427) and with grade 2 or 3 in 36.8% (n = 157/427) of cases. Myelofibrosis grading was not available in 6.3% (n = 27/427) of patients classified as MF. Together, these findings show that across both cohorts 68.3% (n = 490) of patients receiving a bone marrow biopsy with available fibrosis grading had fibrosis grade 0 or 1. Thus, the majority of patients within the MF cohort fulfil histologic criteria of pre-fibrotic myelofibrosis according to the 2016 WHO classification.

Bone marrow histology of 495 patients with ET and 465 patients with MF. A Bone marrow assessment at time of diagnosis. B Fibrosis grading at time of diagnosis, percentage of subgroup as indicated in A

Assessment of clinical characteristics focused specifically on parameters with relevance for diagnostic classification (ET versus MF) according to the WHO 2016 classification: spleen size assessment by palpation and ultrasound, lactate dehydrogenase levels (LDH), circulating blasts in the peripheral blood, white blood cell count (WBC) and hemoglobin levels (HGB) (Table 2).

Among the pre-selected ET patient cohort, 22.8% (n = 113) showed splenomegaly (> 11 cm diameter), and 1% (n = 5) by palpation; 80.4% (n = 398) had elevated LDH (above upper normal limit), 3.6% (n = 18) had circulating blasts, 27.1% (n = 134) elevated leukocyte values (> 11Gpt/l), 12.5% (n = 62) mild anemia (Hb ≥ 10 g/dl and < 12 g/dl) and 2% (n = 10) severe anemia (Hb < 10 g/dl). Without having had histological BM evaluation, the majority of patients who were categorized as ET showed at least one minor criterion indicative of pre-fibrotic MF. On the other hand, splenomegaly was more frequently identified in patients who were classified as MF: 58.5%; (n = 272) with > 11 cm diameters assessed by imaging and 22.4% (n = 61) by palpation. Moreover, patients classified as MF showed elevated peripheral blasts ≥ 1% (13.8%; n = 64), leukocytosis (42.4%; n = 197) or anemia (36.2%, n = 168; 14%, n = 65 with severe anemia Hb < 10 g/dl).

In summary, > 80% of the selected patient cohort classified as ET showed at least one diagnostic minor criterion for MF according to WHO 2016. More than 50% of patients classified as MF had findings consistent with pre-fibrotic disease. These findings indicate that the majority of patients from both ET and MF cohorts in this chart review, show criteria indicative for pre-fibrotic disease stage of myelofibrosis. However, clinical diagnosis of patients classified as ET could not be histologically confirmed due to lack of BM histology at diagnosis in 41.4% of patients.

MPN patients frequently report on disease-related symptoms that have negative impact on social interactions, productivity, physical activity, and quality of life (Harrison et al. 2017; Mesa et al. 2016). Symptom burden does not necessarily correlate with disease subtype, thromboembolic risk, or risk of disease progression. In this chart review analysis, classical constitutional symptoms such as fever, weight loss, night sweats general MPN-associated symptoms such as fatigue, abdominal pain, restricted physical mobility, cough, pruritus, skeletal pain, loss of appetite, and other symptoms were assessed as reported at initial diagnosis.

At time of diagnosis, the classical constitutional symptoms fever, night sweats and weight loss were reported in 0.7, 13.0 and 11.6% of patients in the ET cohort and 1.7, 18.0 and 25.5% of patients in the MF cohort, respectively (Fig. 4). Besides constitutional symptoms, fatigue was the most prominent symptom documented for both ET (41.3%) and MF (59.0%), followed by abdominal pain (ET 11.6%; MF 16.3%), skeletal pain (ET 17.4%; MF 8.4%), pruritus (ET 8.7%; MF 10.0%), restriction of motion (ET 9.4%; MF 2.9%), decreased appetite (ET 5.8%; MF 5.0%), and cough (ET 0.0%; MF 2.1%).

Percent of patients reporting on specific MPN-associated symptoms at time of diagnosis (multiple answers possible)

Overall, the reported symptom burden appeared to be more prominent in MF than in ET patients, except for skeletal pain. Of note, the symptom burden documented in the patients’ charts appeared less when compared to symptoms published previously in either clinical trials (Harrison et al. 2012; Verstovsek et al. 2010) or patient-reported questionnaires (Harrison et al. 2017; Mesa et al. 2016). These findings are consistent with differences reported between physician- and patient-reported symptoms in one of our recent reports (Jentsch-Ullrich et al. 2016).

35.3% (n = 164) of patients had their MF risk classification scored at the time of diagnosis. Most frequently used scoring systems included static scoring systems such as IPSS (37.8%, n = 62) which is validated at the timepoint of diagnosis and dynamic scoring systems such as DIPSS (24.4%, n = 40), DIPSS-plus (16.5%, n = 27) for primary myelofibrosis (PMF) and MYSEC-PM (11.6%, n = 19) for secondary myelofibrosis (SMF). Interestingly, molecular scores were used in less than 8% of cases. Overall, 25% of MF patients presented as low-risk, 42.1% as intermediate-1 risk, 21.3% as intermediate-2 risk and 11.6% as high-risk at the timepoint of diagnosis. To assess whether structured risk assessment was more frequently performed at later timepoints, the questionnaire asked for prognostic scoring in the further course of the disease. Unexpectedly, a prognosis score assessment was only performed in 12.9% (n = 60) of MF patients at later time points. Here, dynamic and molecular/genetic scoring systems were more frequently used compared to the scores used at primary diagnosis: 30% (n = 18) DIPSS-plus, 3.3% (n = 2) MIPSS70, 21.7% (n = 13) MIPSS70plus 2.0 and 30% (n = 18) MYSEC-PM. Of note, IPSS was still used in 10% of patients, although not formally validated for dynamic assessment. A higher proportion of MF patients (50%, n = 30) were categorized as int-2 or high risk. These numbers may indicate selection of a high-risk subgroup with early clonal progression or secondary myelofibrosis.

Thromboembolic (TE) complications are a clinical challenge in patients with ET but also pre-fibrotic myelofibrosis. Therefore, we aimed to assess for cardiovascular risk, use of anticoagulants and disease-specific therapeutic strategies (Fig. 5).

Prevalence of cardiovascular risk factors and anticoagulation. A Prevalence of general comorbidities at time of diagnosis. B Prevalence of cardiovascular risk factors prevalent at time of diagnosis, percentage indicated as percent of patients with comorbidities (as indicated in A). C Anticoagulation (incl. platelet inhibitors, heparins, DOACs, OACs) initiated at time of diagnosis, percentage based on number of patients, who received a pharmacological therapy at time of diagnosis (403 ET and 352 MF)

70.5% (n = 349/495) ET patients and 79.1% (n = 368/465) MF patients reported on comorbidities at diagnosis. 76.5% (n = 267/349) of ET patients and 74.2% (n = 273/368) of MF patients had cardiovascular comorbidities defined as cardiovascular disease (CVD), arterial hypertension (AH), heart failure (HF) or peripheral artery disease (PAD). Anticoagulation including platelet inhibitors (ASA or P2Y inhibitors), heparins, direct oral anticoagulants (DOACs) and oral anticoagulants (OACs) as part of the initial therapy following diagnosis was documented for 56.8% (n = 229/403) of ET and 38.1% (n = 134/352) MF patients. Watchful waiting was the primary treatment choice for 21.4% of ET (n = 106) and 22.2% of MF (n = 103) patients. 2.4% (n = 12) of ET and 8.4% (n = 39) of MF patients were transfusion dependent, respectively (Fig. 6). After diagnosis, 84.7% (n = 233) of ET patients received hydroxycarbamide (HC) for pharmacologic cytoreduction. 56.8% (n = 229) were treated with anticoagulants.

Pharmacologic therapy in 495 patients with ET and 465 patients with MF. A Treatment initiated at time of diagnosis (multiple answers possible), B Reason for initiation of pharmacotherapy (multiple answers possible). C Pharmacological cytoreduction chosen at time of diagnosis, percentage of patients as indicated in B

Similar to this, 38.1% (n = 134) of MF patients received anticoagulant treatment, and 53.1% (n = 155) received HC medication after diagnosis. At diagnosis, 62.4% (n = 290) of MF patients had platelet counts that were high (> 450 Gpt/l). JAK inhibitors were administered to 40.4% (n = 118) of the patients receiving symptom-focused therapy. For both ET and MF (> 40% of patients), cytoreduction and TE risk-reduction were the primary justifications for starting medication. In 19.3 and 18.5% of the cases, respectively, splenomegaly and symptom management were further justifications for MF treatment. Taken together, pharmacologic therapy was focused on cytoreduction which is consistent with the high numbers of ET and pre-MF cases in this cohort. Anticoagulants were used less frequently in patients classified as MF despite the high number of patients presenting as pre-fibrotic MF.