Application Value of 68 Ga-FAPI PET/CT in the Evaluation of Myelofibrotic Diseases.

PURPOSE: Fibroblast activation protein is highly expressed in neoplastic lesions and various fibrotic tissues, making it an attractive target for disease evaluation. 68 Ga-labeled fibroblast activation protein inhibitor (FAPI), a new tumor interstitial imaging agent, holds promise for evaluating myelofibrosis. Therefore, this study aimed to use 68 Ga-FAPI PET/CT for the noninvasive visualization and quantification of the extent of myelofibrosis. PATIENTS AND METHODS: This was a prospective clinical study involving 22 patients with myelofibrosis who underwent 68 Ga-FAPI PET/CT. The uptake of 68 Ga-FAPI was measured in their respective bone marrow and spleen, and the obtained imaging findings were compared with laboratory, cytogenetic, and histopathological data. RESULTS: 68 Ga-FAPI uptake in the bone marrow was significantly and positively correlated with the myelofibrosis grade ( r > 0.8, P < 0.001). 68 Ga-FAPI PET/CT showed visually negative results in patients with grades 0-1 myelofibrosis and positive in those with grades 2-3, but the level of involvement varied. 68 Ga-FAPI PET/CT provides a noninvasive means of visualizing the extent of systemic bone marrow involvement and differentiation between the early and advanced stages of fibrosis. CONCLUSIONS: 68 Ga-FAPI PET/CT shows promise as a method for visualizing and quantifying myelofibrosis, providing suitable sites for bone marrow biopsy. The extent of 68 Ga-FAPI uptake by bone marrow increases with the progression of myelofibrosis, thus it is a simple and noninvasive measurement that can be used to evaluate the progression of myelofibrosis. Nevertheless, although 68 Ga-FAPI PET/CT has demonstrated a potential value in prognostic assessment, further confirmation is needed.

Quantitative MRI reveals heterogeneous impacts of treatment on diseased bone marrow in a mouse model of myelofibrosis.

PURPOSE: Analyzing bone marrow in the hematologic cancer myelofibrosis requires endpoint histology in mouse models and bone marrow biopsies in patients. These methods hinder the ability to monitor therapy over time. Preclinical studies typically begin treatment before mice develop myelofibrosis, unlike patients who begin therapy only after onset of disease. Using clinically relevant, quantitative MRI metrics allowed us to evaluate treatment in mice with established myelofibrosis. METHODS: We used chemical shift-encoded fat imaging, DWI, and magnetization transfer sequences to quantify bone marrow fat, cellularity, and macromolecular components in a mouse model of myelofibrosis. We monitored spleen volume, the established imaging marker for treatment, with anatomic MRI. After confirming bone marrow disease by MRI, we randomized mice to treatment with an approved drug (ruxolitinib or fedratinib) or an investigational agent, navitoclax, for 33 days. We measured the effects of therapy over time with bone marrow and spleen MRI. RESULTS: All treatments produced heterogeneous responses with improvements in bone marrow evident in subsets of individual mice in all treatment groups. Reductions in spleen volume commonly occurred without corresponding improvement in bone marrow. MRI revealed patterns associated with effective and ineffective responses to treatment in bone marrow and identified regional variations in efficacy within a bone. CONCLUSIONS: Quantitative MRI revealed modest, heterogeneous improvements in bone marrow disease when treating mice with established myelofibrosis. These results emphasize the value of bone marrow MRI to assess treatment in preclinical models and the potential to advance clinical trials for patients.

Spleen volume and length determined by computed tomography impact outcome after allogeneic stem cell transplantation for myelofibrosis.

Splenomegaly is a hallmark of myelofibrosis (MF), and reports on the impact of spleen size on the outcome of allo-HSCT have been conflicting, possibly due to differences in methods of assessment. We retrospectively analysed the impact of spleen volume and length measured by computed tomography on allo-HSCT outcome in 93 patients, 74% of whom had prior ruxolitinib treatment. Median spleen volume and length were 1.58 dm3 and 20 cm, respectively. We found a strong correlation between spleen volume and length (Pearson's r = 0.95, p < 0.001), Spearman (rho = 0.96, p < 0.001). After a median follow-up of 41.7 months, 5-year overall and disease-free survival were 66% and 59%, respectively. Spleen size did not impact overall survival or non-relapse mortality. Larger spleen volume and length as continuous variables were associated with slower platelet and leucocyte engraftment and a higher risk of disease relapse in univariate and multivariate analyses. Spleen length measured precisely by imaging is a good surrogate for spleen volume. In the era of JAK inhibitors, larger spleen size reflects advanced disease in MF and is associated with an increased risk of relapse but has no impact on non-relapse mortality and overall survival after allo-HSCT.

Characterizing the Bone Marrow Environment in Advanced-Stage Myelofibrosis during Ruxolitinib Treatment Using PET/CT and MRI: A Pilot Study.

Current diagnostic criteria for myelofibrosis are largely based on bone marrow (BM) biopsy results. However, these have several limitations, including sampling errors. Explorative studies have indicated that imaging might form an alternative for the evaluation of disease activity, but the heterogeneity in BM abnormalities complicates the choice for the optimal technique. In our prospective diagnostic pilot study, we aimed to visualize all BM abnormalities in myelofibrosis before and during ruxolitinib treatment using both PET/CT and MRI. A random sample of patients was scheduled for examinations at baseline and after 6 and 18 months of treatment, including clinical and laboratory examinations, BM biopsies, MRI (T1-weighted, Dixon, dynamic contrast-enhanced (DCE)) and PET/CT ([15O]water, [18F]NaF)). At baseline, all patients showed low BM fat content (indicated by T1-weighted MRI and Dixon), increased BM blood flow (as measured by [15O]water PET/CT), and increased osteoblastic activity (reflected by increased skeletal [18F]NaF uptake). One patient died after the baseline evaluation. In the others, BM fat content increased to various degrees during treatment. Normalization of BM blood flow (as reflected by [15O]water PET/CT and DCE-MRI) occurred in one patient, who also showed the fastest clinical response. Vertebral [18F]NaF uptake remained stable in all patients. In evaluable cases, histopathological parameters were not accurately reflected by imaging results. A case of sampling error was suspected. We conclude that imaging results can provide information on functional processes and disease distribution throughout the BM. Differences in early treatment responses were especially reflected by T1-weighted MRI. Limitations in the gold standard hampered the evaluation of diagnostic accuracy.

Repeatability of Quantitative Magnetic Resonance Imaging Biomarkers in the Tibia Bone Marrow of a Murine Myelofibrosis Model.

Quantitative MRI biomarkers are sought to replace painful and invasive sequential bone-marrow biopsies routinely used for myelofibrosis (MF) cancer monitoring and treatment assessment. Repeatability of MRI-based quantitative imaging biomarker (QIB) measurements was investigated for apparent diffusion coefficient (ADC), proton density fat fraction (PDFF), and magnetization transfer ratio (MTR) in a JAK2 V617F hematopoietic transplant model of MF. Repeatability coefficients (RCs) were determined for three defined tibia bone-marrow sections (2-9 mm; 10-12 mm; and 12.5-13.5 mm from the knee joint) across 15 diseased mice from 20-37 test-retest pairs. Scans were performed on consecutive days every two weeks for a period of 10 weeks starting 3-4 weeks after transplant. The mean RC with (95% confidence interval (CI)) for these sections, respectively, were for ADC: 0.037 (0.031, 0.050), 0.087 (0.069, 0.116), and 0.030 (0.022, 0.044) µm2/ms; for PDFF: 1.6 (1.3, 2.0), 15.5 (12.5, 20.2), and 25.5 (12.0, 33.0)%; and for MTR: 0.16 (0.14, 0.19), 0.11 (0.09, 0.15), and 0.09 (0.08, 0.15). Change-trend analysis of these QIBs identified a dynamic section within the mid-tibial bone marrow in which confident changes (exceeding RC) could be observed after a four-week interval between scans across all measured MRI-based QIBs. Our results demonstrate the capability to derive quantitative imaging metrics from mouse tibia bone marrow for monitoring significant longitudinal MF changes.

Improved Repeatability of Mouse Tibia Volume Segmentation in Murine Myelofibrosis Model Using Deep Learning.

A murine model of myelofibrosis in tibia was used in a co-clinical trial to evaluate segmentation methods for application of image-based biomarkers to assess disease status. The dataset (32 mice with 157 3D MRI scans including 49 test-retest pairs scanned on consecutive days) was split into approximately 70% training, 10% validation, and 20% test subsets. Two expert annotators (EA1 and EA2) performed manual segmentations of the mouse tibia (EA1: all data; EA2: test and validation). Attention U-net (A-U-net) model performance was assessed for accuracy with respect to EA1 reference using the average Jaccard index (AJI), volume intersection ratio (AVI), volume error (AVE), and Hausdorff distance (AHD) for four training scenarios: full training, two half-splits, and a single-mouse subsets. The repeatability of computer versus expert segmentations for tibia volume of test-retest pairs was assessed by within-subject coefficient of variance (%wCV). A-U-net models trained on full and half-split training sets achieved similar average accuracy (with respect to EA1 annotations) for test set: AJI = 83-84%, AVI = 89-90%, AVE = 2-3%, and AHD = 0.5 mm-0.7 mm, exceeding EA2 accuracy: AJ = 81%, AVI = 83%, AVE = 14%, and AHD = 0.3 mm. The A-U-net model repeatability wCV [95% CI]: 3 [2, 5]% was notably better than that of expert annotators EA1: 5 [4, 9]% and EA2: 8 [6, 13]%. The developed deep learning model effectively automates murine bone marrow segmentation with accuracy comparable to human annotators and substantially improved repeatability.

The Manifestation of a Patient With Myelofibrosis in 68Ga-DOTA-FAPI-04 PET/CT Mimicking "Super Bone Imaging".

ABSTRACT: Primary myelofibrosis is a chronic inflammatory disease of the bone marrow. It progresses from an early robust inflammatory state to a more advanced fibrotic response, representing the advanced stage of the disease. We report a 50-year-old woman who was diagnosed with primary myelofibrosis. 18F-FDG PET/CT showed mild uptake in diffuse sclerotic lesions in the bone matrix, whereas 68Ga-DOTA-FAPI-04 showed intense uptake at the whole skeleton.

Positron emission tomography - computed tomography as a monitoring response tool in pre-fibrotic myelofibrosis: A case report.

Primary myelofibrosis is a haematopoietic stem cell neoplasm resulting in ineffective haematopoiesis and bone marrow fibrosis. We present a case of a 67-year-old male patient who came to the oncology/haematology department of Dr. Ziauddin Hospital, Karachi, in February 2020 with complaints of weight loss, gastroesophageal reflux and loss of appetite. Examination revealed splenomegaly and initial workup demonstrated bicytopenia on complete blood picture. Bone marrow biopsy was consistent with pre-fibrotic myelofibrosis (Janus kinase 2 (JAK-2) positive). He was categorized as intermediate-2 risk according to Dynamic International Prognostic Scoring System (DIPPS) with score of 3 and was advised to start JAK-1/JAK-2 inhibitors. Prior to therapy, he underwent positron emission tomography-computed tomography (PET/CT) scan which showed increased fluorodeoxyglucose (FDG) uptake in the spleen and bone marrow. Monitoring by the scan after initiating treatment demonstrated decreased FDG uptake in bone marrow and spleen, demonstrating that PET/CT is a non-invasive way to assess and monitor treatment response in pre-fibrotic myelofibrosis.

Assessing Bone Marrow Activity with [18F]FLT PET in Patients with Essential Thrombocythemia and Prefibrotic Myelofibrosis: A Proof of Concept.

Objectives: This study aims to assess the value of FLT-PET as a non-invasive tool to differentiate between patients with ET and Pre-PMF. This study is a pilot study to have a proof of concept only. Methods: This is a prospective, interventional study where a total of 12 patients were included. Each patient underwent FLT PET imaging as well as bone marrow examination (gold standard). In addition, semi-quantitative (SUVmax and SUVmean) measurements of FLT uptake in the liver, spleen, and Lspine, SUVmean, as well as the Total Lesion Glycolysis (TLG) of the Lspine were performed. Results from the two patient cohorts were compared using = Kruskal-Wallis statistical test. A P-value of <.05 is considered to be statistically significant. Results: The differences in FLT SUVmax and SUVmean measurements in the three organs (liver, spleen, and LSpine) between the ET and Pre-PMF patients were not statistically significant (P > .05). In contrast, TLG measurements in the LSpine were statistically different (P = .013), and therefore, compared to gold standard bone marrow results, TLG can separate ET and Pre-PMF patients. Conclusion: This study is a proof of concept about the potential to discriminate between ET and pre-PMF patients in a non-invasive way. TLG of the LSpine in FLT PET images is a potential quantitative parameter to distinguish between ET and pre-PMF patients.

Osteolytic bone lesions in patients with primary myelofibrosis: A systematic review.

Philadelphia negative myeloproliferative neoplasms (MPNs) are classically characterized by excess production of terminal myeloid cells in the peripheral blood. They include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Among this group, primary myelofibrosis is the least common and usually carries the worst prognosis. Bone involvement in primary myelofibrosis has many forms; it affects bone marrow leading to bone marrow fibrosis, it can cause periostitis, in addition to bone and joint pain. A common radiologic finding in primary myelofibrosis is the presence of osteosclerotic lesions. However, the presence of osteolytic lesions in bone imaging was described in few reports. In this review, we searched English literature using the PRISMA guidelines looking for patients with Primary myelofibrosis who had osteolytic bone lesions to assess the impact of such findings on the disease and its effect on prognosis. We found the vast majority of lesions were painful affecting most commonly the vertebral column, pelvis, and ribs, and were detected in patients above 50 years of age with no gender preference, unfortunately they represented advanced disease stages, resulting in inadequate treatment response and poor outcome.

Spleen Stiffness Measurement by Using Shear-Wave Elastography as a Predictor of Progression to Secondary Myelofibrosis.

OBJECTIVE: Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative diseases that can transform to secondary myelofibrosis (SMF). In this study, we evaluated spleen stiffness using shear-wave elastography (SWE) as a predictor of progression to SMF. METHODS: Participants were grouped as healthy volunteers (HVs), PV/ET patients, and SMF patients. Participants' spleen sizes, spleen stiffness values, bone marrow fibrosis degrees, and the other parameters were evaluated. Spleen stiffness values and spleen sizes were compared between groups. RESULTS: Of the 121 participants included in this study, 52 patients were HVs, 52 patients were PV and/or ET patients, and 17 patients were SMF patients. In terms of age and sex, there was no difference between groups. Splenic parenchymal stiffness median values by using SWE were found to be 0.82 m/s in HVs, 1.41 m/s in PV/ET patients, and 2.32 m/s in SMF patients (P < 0.001). In terms of median length of the spleen, the difference between groups was significant (P < 0.001). In addition, we found a significant positive correlation between spleen stiffness and bone marrow fibrosis degree (P < 0.001, r = 0.757). However, in multivariate analysis, there was no strong independent risk factor for spleen stiffness. CONCLUSION: In this study, we showed that measurement of spleen stiffness using SWE can distinguish SMF from PV/ET patients and HVs. Therefore, we believe that SWE may be used as a noninvasive and easily accessible method to check the fibrotic progression of bone marrow in PV and ET patients to monitor the transformation to SMF, and enables to detect fibrosis in early phase.

Volumetric splenomegaly in patients with essential thrombocythemia and prefibrotic/early primary myelofibrosis.

Non-palpable, volumetric splenomegaly at diagnosis was evaluated using computed tomography in patients with essential thrombocythemia (ET) and prefibrotic/early primary myelofibrosis (pre-PMF) based on 2016 World Health Organization guidelines. Each patient's spleen volume was adjusted for their age and body surface area. The degree of splenomegaly was classified as no, borderline volumetric, overt volumetric, or palpable splenomegaly. Seventy-six patients with ET (median age, 62.5 years) and 19 patients with pre-PMF (median age, 65 years) were followed up for a median of 2.4 years (range 0.1-17.6 years) and 4.2 years (range 0.2-19.6 years), respectively. Spleen volume was significantly greater in pre-PMF patients than in ET patients (377.9 ± 92.2 cm3 vs. 224.9 ± 115.2 cm3, P < 0.001). No, borderline volumetric, overt volumetric, and palpable splenomegaly were found in 42 (55.3%), 24 (31.6%), 10 (13.2%), and 0 (0%) patients with ET, respectively, and in 0 (0%), 8 (42.1%), 19 (52.6%), and 1 (5.2%) patient with pre-PMF, respectively (P < 0.001). Volumetric splenomegaly did not affect thrombosis-free survival in patients with ET or those with pre-PMF. This study indicates that all patients with pre-PMF present with splenomegaly, whereas half of the patients with ET have a normal-sized spleen at diagnosis.

Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked.

Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss-of-function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b-B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b-/- ) mice. Although male and female Mpig6b-/- mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b-/- mice developed progressive splenomegaly starting at 8 weeks of age. Micro-computed tomography (µCT) of femurs showed that female Mpig6b-/- mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b-/- mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10-week-old female Mpig6b-/- mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b-/- mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b-/- mice also demonstrated improvement in spleen weight compared to sham-operated Mpig6b-/- mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte-driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Classical Hodgkin lymphoma-like post-transplant lymphoproliferative disease after allogeneic stem cell transplantation for primary myelofibrosis is successfully treated with nivolumab: A case report.

INTRODUCTION: Post-transplant lymphoproliferative disease (PTLD), a lymphoid proliferation observed after the solid organ transplantation or allogeneic stem cell transplant, is an important and mortal complication that can occur during the post-transplant period. Classical Hodgkin lymphoma-like PTLD is the least form of PTLD. We are presenting an adult case of classical Hodgkin lymphoma-like PTLD which was successfully treated with nivolumab. CASE REPORT: A 31-year-old female was diagnosed with primary myelofibrosis and we performed allogeneic stem cell transplantation from her HLA fully matched brother in 2015. Two years after transplant, classical Hodgkin lymphoma-like PTLD was diagnosed. The patient was resistant to six cycles of ABVD chemotherapy and four cycles of brentuximab vedotin. MANAGEMENT AND OUTCOME: After the failure of ABVD and brentuximab vedotin, we started nivolumab therapy at a dose of 3 mg/kg every 2 weeks. After six cycles, we achieved a PET negative complete remission. After 10 cycles of nivolumab, the patient is still followed with a complete remission. Still, there is no evidence of acute or chronic GvHD, and therefore no need for immunosuppressive treatment. No auto-immune complication was observed. It is planned to give nivolumab treatment to the patient until the progression. DISCUSSION: Our case has depicted that the classical Hodgkin lymphoma type PTLD may be resistant to the conventional treatments and anti-CD30 brentuximab vedotine. In such cases, nivolumab may be an effective and worth assessing agent in terms of both activity and safety profile.

A study of 18F-FLT positron emission tomography/computed tomography imaging in cases of prefibrotic/early primary myelofibrosis and essential thrombocythemia.

The objectives of this research project are to study in patients with primary myelofibrosis (PMF) and Essential Thrombocythemia (ET); (1) the uptake patterns of FLT-PET (FLT-PET) and its value in diagnosing, staging, and treatment response monitoring of malignant hematopoiesis, (2) compare imaging findings from FLT-PET with bone marrow biopsy (standard of care), and (3) associate FLT-PET uptake patterns with genetic makeup such as JAK2 (Janus kinase 2), CALR (Calreticulin), MPL (myeloproliferative leukemia protein), Triple negative disease, and allele burden.This trial is registered in ClinicalTrials.gov with number NCT03116542. Protocol version: Mar 2017.

Idiopathic myelofibrosis causing inflammatory central retinal vein occlusion mimicking frosted branch angiitis.

Primary idiopathic myelofibrosis is a clonal disorder arising from the neoplastic transformation of early haematopoietic stem cells leading to abnormal fibrous tissue within bone marrow. We present a 51-year-old man complaining of sudden loss of vision in the right eye along with multiple superficial retinal haemorrhages and perivascular infiltration. Fundus fluorescein angiography and optical coherence tomography confirmed the diagnosis of inflammatory central retinal vein occlusion with macular oedema which mimicked frosted branch angiitis. Laboratory tests and bone marrow biopsy confirmed underlying systemic disease to be Janus kinase 2 mutation positive primary idiopathic myelofibrosis. He received one intravitreal injection of antivascular endothelial growth factor along with dexamethasone for his ocular condition. In view of his systemic disease, he was started on systemic chemotherapy and oral corticosteroid which helped in stabilising the eye condition.

TAFRO Syndrome with an Anterior Mediastinal Mass and Lethal Autoantibody-Mediated Thrombocytopenia: An Autopsy Case Report.

TAFRO syndrome, a rare systemic inflammatory disease, can lead to multiorgan failure without appropriate treatment. Although thrombocytopenia is frequently seen in patients with TAFRO syndrome, little is known about its pathogenesis. Moreover, while recent studies have reported the presence of an anterior mediastinal mass in some patients, the pathological status of this remains unclear. Here, we report a case of fatal bleeding in a patient with TAFRO syndrome accompanied by an anterior mediastinal mass. A 55-year-old female was transferred to our hospital with a 2-week history of fever, epistaxis, and dyspnea. Laboratory tests revealed severe thrombocytopenia, computed tomography (CT) showed pleural effusions, and bone marrow biopsy revealed reticulin myelofibrosis. We suspected TAFRO syndrome, but the CT scan showed an anterior mediastinal mass that required a biopsy to exclude malignancy. She soon developed severe hemorrhagic diathesis and died of intracranial hemorrhage despite intensive treatment. She had multiple autoantibodies against platelets, which caused platelet destruction. An autopsy of the mediastinal mass revealed fibrous thymus tissues with infiltration by plasma cells. Our case suggests that thrombocytopenia could be attributed to antibody-mediated destruction and could be lethal. Hence, immediate treatment is imperative in cases of severe thrombocytopenia, even when accompanied by an anterior mediastinal mass.