Characterizing the bone marrow environment in advanced-stage myelofibrosis. A PET/MRI study.

In myelofibrosis, it is not yet completely understood how the pathologic
alterations in the bone marrow environment evolve. After long-term treatment
with ruxolitinib - the present standard therapy for patients with
advanced-stage myelofibrosis -, regression of marrow fibrosis has been
demonstrated in several patients. The currently used diagnostic tool - the bone
marrow biopsy - is however not sensitive enough to detect early and functional
changes. In this study we aim to gain more insight into the bone marrow
microenvironment in advanced-stage myelofibrosis and changes herein during
ruxolitinib treatment, by using well-known imaging techniques. More
specifically, we will evaluate osteoblastic activity and bone marrow perfusion
and - diffusion characteristics using 15O-water-PET, 18F-Fluoride-PET and
MRI-DCE and -DWIBS. Furthermore, bone marrow biopsies will be performed in
order to assess histopathological response.

Primary objectives
To characterize the bone marrow microenvironment in advanced stage
myelofibrosis (MF) before and during treatment with ruxolitinib, regarding
osteoblastic activity, marrow fibrosis and - osteosclerosis and perfusion- and
diffusion characteristics.
To this end it will be explored:
1. In which manner the balance between fatty red marrow and fibrotic tissue (as
assessed with MRI T1- and STIR and histopathological examination) is disturbed,
and how it is restored during treatment.
2. a. What the degree of osteoblastic activity (as assessed by
18F-Fluoride-PET) is in advanced stage marrow fibrosis and - osteosclerosis (as
assessed by MRI T1, -STIR and histopathological examination)
b. Whether a decrease in osteoblastic activity (as assessed by
18F-Fluoride-PET) during treatment precedes visible regression of marrow
fibrosis and - osteosclerosis (as assessed by MRI T1, -STIR and
histopathological examination)
3. a. What the degree of diffusion restriction (as assessed by MRI-DWIBS) is in
advanced stage myelofibrosis and whether this correlates directly to the
presence of marrow fibrosis and/or hypercellularity (as assessed by MRI T1, -
STIR and histopathological examination).
b. Whether a decrease in diffusion restriction (as assessed by MRI-DWIBS)
precedes visible regression of marrow fibrosis and/or hypercellularity during
treatment (as assessed by MRI T1, - STIR and histopathological examination).
4. a. What the degrees of vascular perfusion and permeability (as assessed by
15O-water-PET/CT and MRI-DCE) are in advanced stage myelofibrosis and whether
this correlates directly to the presence of hypervascularization and dilatation
of sinusoids (as assessed by histopathological examination).
b. Whether a decrease in perfusion and permeability (as assessed by
15O-water-PET/CT and MRI-DCE) precedes visible regression of marrow
hypervascularization and dilatation of sinusoids (as assessed by
histopathological examination).

Secondary objectives
1. To explore which of the imaging techniques (MRI (-T1, -STIR-, -DCE and -
DWIBS) and PET/CT (15O-water-and 18F-Fluoride)) has the greatest value in the
diagnosis of myelofibrosis and in response monitoring during ruxolitinib
treatment.
2. To explore the degree of sampling error of the bone marrow biopsy in
myelofibrosis

Explorative diagnostic pilot study.

For this study, patients will undergo extra diagnostic procedures. Per
scheduled appointment at the outpatient clinic, the extra time will amount to
150-180 minutes (510 minutes per patient for the entire study). The extra
diagnostic procedures are:
- 9x venapunction (during PET/CT, study protocol page 38)
- 9x intravenous injection (during PET/CT and MRI, protocol pages 33 and 38)
- 2x bone marrow biopsy including - aspirate
- 3x PET/CT (18F-Fluoride, 15O-Water), 8,35-8,85mSv each (dependent on the
amount of movement)
- 3x MRI (-T1, -STIR, -DIXON, -DCE, -DWIBS)

The risks of participation are deemed negligible:
- The extra invasive procedures (venapunctions, bone marrow biopsies) carry a
very low risk of complications (pain, bleeding) and the complications are well
treatable (analgesics, compression).
- The radiation used in the imaging studies is not considered a relevant risk,
given the short life expectancy of this group of patients.
- The risk of contrast-allergy is very small, this complication is also well
treatable.
- The risk of contrast-nephropathy is small because a screening procedure will
be used to determine the need for extra preventive measures in individual
patients.
- Incidental findings can be done with the imaging studies, which we will
discuss with the participants before study entry.

We believe that conduction of this study is justified because it can lead to
better medical care in the future. Momentarily there is little knowledge about
the way that pathological changes evolve in the bone marrow of myelofibrosis
patients and how they change during therapy. Until now this has been monitored
using bone marrow biopsies: an invasive method with proven sampling errors that
only provides static information on the bone marrow. It is important that we
gain more insight into the dynamic processes that take place. In the future,
this can give rise to more reliable - preferably non-invasive - diagnostic
techniques. Also, it might then be possible to demonstrate the influence of a
certain treatment on the natural disease course in an earlier stage, which can
be of importance in determining duration of treatment (with new and/or often
expensive drugs).