On Myelofibrosis: A Paragon of Heterogeneity

Part I. Imaging in myelofibrosis Bone marrow (BM) biopsies have several limitations, which complicate the reliable evaluation of disease activity in myelofibrosis. We evaluated the potential value of imaging techniques as an alternative method. Chapter 2 describes the results of our systematic literature review. Techniques that have been explored in myelofibrosis include conventional radiography, DXA, thermography, ultrasonography, CT, MRI, scintigraphy, PET, and SPECT. Most studies were explorative, describing general imaging findings. Correlations between imaging findings and histopathological BM characteristics were described, but diagnostic accuracy could be extracted from only seven studies, most of which showed a significant risk of bias. Prognostic implications of imaging results were seldom reported. None of the imaging techniques proved ready for use in clinical practice. However, T1-weighted MRI/Dixon and 18F-FDG-/18F-FLT PET/CT have a potential value for disease monitoring, given their seeming correlation to BM fat content and fibrosis grade, respectively. Chapter 3 describes the results of our diagnostic pilot study, in which we aimed to characterize the BM compartment in myelofibrosis, before and during treatment with ruxolitinib. All four included patients showed a low baseline BM fat content on T1-weighted MRI and Dixon, indicating hypercellularity and/or fibrosis. Furthermore, baseline vertebral BM blood flow (as measured by 15O-water PET/CT) and skeletal 18F-NaF uptake were increased in all patients. During treatment, various degrees of reversal in BM fat content were seen. One patient, who also showed the fastest clinical response, showed normalization of BM perfusion on 15O-water PET/CT and DCE-MRI. Vertebral 18F-NaF uptake did not change in any patient. Comparisons to histopathology were complicated by limitations in the BM biopsies. Part II. A real-life perspective on myelofibrosis in the Netherlands Chapter 4 describes the results of our population-based study, including Dutch myelofibrosis patients diagnosed between 2001-2018. We found a mean standardized incidence rate of 0.49/100,000 person-years. Five-year relative survival increased slightly between 2001-2010 and 2011-2018 (51% to 55%), which was most pronounced in patients aged >65 years at diagnosis (38% to 45%). In the first year after diagnosis, most patients received a wait-and-see policy. Allogeneic SCT was performed in ±10% of patients <65 years. Non-chemotherapeutic systemic treatment was increasingly prescribed in all age groups, which mainly concerned JAK1/2 inhibitor therapy. IPSS risk distribution in the 2014-2018 cohort was comparable to recent literature. Chapter 5 reports on the safety of ruxolitinib treatment in patients with thrombocytopenia, based on a retrospective analysis of a Dutch real-life cohort and a systematic literature search. In our cohort, the incidence of grade ≥3 thrombocytopenia was increased in the 12 patients with baseline thrombocytopenia compared with those with platelet counts >100x109/L (42% versus 15%). This was in line with previous literature. Interestingly, the FDA-advised starting dose was exceeded in 11/12 patients. However, when combining our data with previous literature, the pooled incidence of severe bleeding in patients with baseline thrombocytopenia was not significantly increased compared to data from the COMFORT-1 trial. We conclude that ruxolitinib treatment in patients with a platelet count of 50-100x109/L is safe in daily clinical practice, even at higher starting doses. In Chapter 6, we retrospectively evaluated the outcome of patients treated with allogeneic SCT in three Dutch university centers. The cumulative neutrophil engraftment at 60 days was lower in patients who received NMA conditioning compared with those who received RIC (56% vs 84%). No differences in baseline characteristics could account for this difference. Importantly, no significant differences in TRM were found when comparing RIC and NMA regimens, despite a higher incidence of aGVHD in the RIC group. We conclude that NMA regimens result in high rates of primary graft failure, and should not be used in MF.