Ruxolitinib Re-Treatment in Patients with Myelofibrosis: Real-World Evidence on Patient Characteristics and Outcomes

Ruxolitinib is an FDA-approved treatment of intermediate- and high-risk myelofibrosis. In the phase 3 COMFORT studies, ruxolitinib reduced spleen volume in patients with myelofibrosis, with a median time to response of 3 months. However, nearly 20% of patients discontinued by month 4 with few treatment options available following discontinuation of ruxolitinib treatment. In this study, 2 independent patient care data sources were queried (Cardinal Health Oncology Provider Extended Network [OPEN] and HealthCore Integrated Research Environment [HIRE®]), and a retrospective review of medical charts was conducted. Patients aged ≥18 years with a diagnosis of myelofibrosis (primary or secondary), use of ruxolitinib for myelofibrosis, and documented physician-directed ruxolitinib interruption were included. Among 26 included patients, pre-interruption median (interquartile range [IQR]) ruxolitinib treatment duration was 123 (57–391, OPEN) and 110 (37–148, HIRE) days. Half the patients interrupted treatment within 3 months, commonly for adverse events (42% and 71%, respectively). After restarting ruxolitinib, median (IQR) re-treatment duration was 196 (54–553) and 166 (108–262) days, respectively. Consistent with previous reports, symptoms and spleen size improved in (OPEN/HIRE) 45%/43% and 40%/33% of evaluable patients, respectively. Further studies investigating the management of dose modifications and interruptions are needed to optimize benefit from ruxolitinib therapy.

Splenomegaly (SPML) in Polycythemia Vera (PV): Its Clinical Significance and Relation to Myelofibrosis and Survival

Introduction: SPML is considered a hallmark of PV, but its frequency, as reported in the literature, ranges from 20% to 75%. It has been assumed, without documentation, that SPML may be accompanied by symptoms and signs and may affect prognosis. Moreover, expensive radiographic tests have become mandatory in some recent phase 2 drug trials in PV (and ET) to carefully document spleen size on trial entry and its change, if any, during therapy. Because systematic studies have not been performed, we studied SPML in patients (pts) with PV at their initial diagnosis (DX) or at first presentation (PRES) at our institution, Weill Cornell Medicine (WCM), and determined its clinical significance. Methods: This single-center retrospective study was approved by the WCM institutional review board. A systematic literature search including PubMed, Embase, and Cochrane School relevant to the specific search questions was unrevealing. We used a research data repository based on an automated query system which had aggregated longitudinal clinical information pertaining to our PV patients for our analysis of spleen size (Abu-Zeinah et al. Leukemia 2021). Standardized PV diagnostic criteria were used for all pts (Silver et al. Blood 2013). As a tertiary referral center within a major metropolitan area, our PV population is composed of those diagnosed at WCM (DX) and those presenting to WCM some time after diagnosis (PRES). Degree of SPML was categorized into 3 subgroups: (1) <1 cm if the spleen was not enlarged, (2) palpable 1-5 cm, or (3) more than 5.0 cm below the left costal margin of the abdomen in the medial clavicular line in the supine or left lateral decubitus position; it was also considered enlarged after splenic ultrasound scan (US) based upon the method and verified formula of Chow KU, et al. Radiology 2016. Spleen size was correlated with age, sex, race, and ELN risk score, and symptoms including pruritus, night sweats, anorexia, abdominal discomfort and pain. Progression to myelofibrosis (MF) with myeloid metaplasia was defined per ELN/IWG-MRT criteria. Spleen measurements after progression to MF were excluded. Peripheral blood smears were routinely examined to view RBC morphology and to exclude leukoerythroblastosis. MF-free survival (MFS) and overall survival (OS) were calculated using the Kaplan-Meier log rank test among the various spleen subgroups. Multivariable survival analysis (MVA) was performed using a Cox proportional hazards model. Results: From our 470 PV dataset, 351 pts had documented spleen size at DX (165) or PRES (186). The median age for all patients was 60 years (yr), for DX 54 yr, for PRES 62 yr. The median DX ages of SPML <1 cm, 1-5 cm, and >5 cm were 56, 50, and 54 yr respectively (p=0.011). The median time between first evaluation for PV and first visit at WCM (PRES) was 2 years (range 0-30). 49% were female and 13% were non-white (Figure 1a). There was no correlation between spleen size and ELN risk scores. The linkage between SPML and symptoms will be reported. Overall survival of the three groups was similar at 12 years (Figure 1b). SPML at presentation, however, was associated with increased risk of MF (1-5cm versus 0: HR 2.56, p=0.026; >=5cm versus 0: HR 5.64, p<0.001), independent of age or disease duration in MVA. Discussion & Conclusion: Patients who had SPML > 5cm at presentation had a worse MFS than those with a lesser degree of SPML or no SPML (1-5 cm or <1 cm). For determining SPML, clinical examination and calculated US length were equally satisfactory. In the absence of clinical SPML, radiographic tests appear unnecessary. However, for SPML > 5cm, and unusual body types, more detailed radiographic studies may still be required. SPML was more common in younger patients, suggesting more aggressive disease and earlier progression to MF. ELN risk category did not correlate with SPML, suggesting an additional reason for its revision. Our PV patients with SPML > 5cm at DX or PRES did not have a decreased OS at 12 years, but did have a reduced MF-free survival. These data support the WHO mandated requirement for marrow biopsy for diagnosis of PV, especially for patients with SPML but also as a baseline requirement to establish the presence of MF less than grade 2. Patients with SPML> 5cm appear to be at high risk of MF progression and must be monitored closely for this event and treated appropriately. Figure 1 Figure 1. Disclosures Silver: Abbvie: Consultancy; PharamEssentia: Consultancy, Speakers Bureau. Scandura: CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees ; MPN-RF (Foundation): Research Funding; Constellation: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Abu-Zeinah: PharmaEssentia: Consultancy.

Imaging Based Spleen Volume Assessments in Myelofibrosis Clinical Trials - Do We Need a Double Read Model?

Myelofibrosis (MF) is a type of chronic blood cancer characterized by bone marrow fibrosis, extramedullary hematopoiesis and splenomegaly. Approximately 89% of patients present palpable splenomegaly with a compromised quality of life and reduced survival. The International Working Group Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) criteria utilize spleen volume (SV) as part of clinical improvement (CI) response in MF trials. These include evaluation of spleen response as a primary/ secondary endpoint - defined as ≥35% SV reduction from baseline. Progressive disease is defined as ≥25% increase in SV from baseline level. Magnetic resonance imaging (MRI) and Computed tomography (CT) provide a non-invasive way to assess change in spleen size both spatially and temporally in a clinical study. While image acquisition with optimized and harmonized protocols is key, a central independent review of images also plays a critical role in correct patient outcome determination. The aim of this study is to determine if a double read model for central independent review is necessary to maintain a high accuracy of SV estimation. To this effect, alignment among independent readers over review criteria was assessed: inter-reader variability (IRV), in addition to assessment of consistency in review approach: intra-reader variability (ARV). Retrospective analysis was implemented on imaging data across 12 multi-center MF trials-MRI/CT images of two time-points (baseline and 1 follow-up) from 142 trial participants for ARV and 85 trial participants for IRV analysis. All images passed image quality checks and were processed for manual segmentation of the spleen by image analysts, followed by an over-read by trained radiologists. The spleen volume was calculated as the sum of spleen cross-sectional area across all slices multiplied by slice interval. For ARV analysis, the images were presented to the same readers in a blinded fashion at least three weeks after the initial review. For IRV analysis, images read by a primary reader were then presented to the secondary reader. The percent discrepancy for ARV and IRV were calculated as the ratio of difference between primary and secondary spleen volumes, divided by the average of the two. The average ARV discrepancy was 0.37±0.55 % (mean±standard deviation) as shown in Fig 1a. Zero subjects had an ARV discrepancy of more than 5%. As shown in Fig 2a, majority of the cases were under an ARV discrepancy of 1%. These results show excellent consistency in approach of readers over time in comparison to 2.8±3.5% reportedby Harris et al (European Journal of Radiology, 2010). For IRV, the average discrepancy was 0.62±0.85 % as shown in Fig 1b. 1.1% of cases had an IRV discrepancy of more than 5%. As shown in Fig 2b, most of the cases were within an ARV discrepancy of 1%. These results show a high level of alignment between readers in their imaging review approach in comparison to 6.4±9.8% reportedby Harris et al (European Journal of Radiology, 2010). The high level of reliability and repeatability seen across radiological reads suggests that a single read model is sufficient to assess imaging volumetrics-based endpoints. It is important to note that a multi-step approach was used to thoroughly train, test and monitor independent readers throughout the study duration. Readers were chosen based on high level of experience with the indication and analysis application. Reader onboarding involved an accurate overview and clear instruction on the review assessments. Multiple MRI/ CT imaging cases were utilized for reader testing and training. Since image quality can be a significant factor influencing the confidence level of a reader, these cases reflected examples of imaging artifacts expected on such trials, such as motion artifacts, low image resolution, ghosting and low contrast to noise ratio. Routine quality checks and variability assessments were done throughout the trial duration, with prompt corrective action taken to prevent inaccuracy of study results. These actions included issuing training points or re-read of cases that contained established error. Further work is necessary on assessing how variables such as spleen size, imaging artifacts and change in imaging modality affect reader variability. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Immune competence and spleen size scale with colony status in the naked mole-rat

Naked mole-rats (NM-R; Heterocephalus glaber) live in multi-generational colonies with a social hierarchy, show low cancer incidence and long life-spans. Here we asked if such extreme physiology might have an immune component. The spleen is the largest lymphoid organ and plays an essential role in response to immunological insults and may participate in combating cancer and slowing ageing. We investigated the anatomy, molecular composition and function of the NM-R spleen using RNA-sequencing and histological analysis in healthy animals. We found that spleen size in healthy NM-Rs varies considerably. We therefore classified NM-Rs according to spleen size as NM-Rs with small spleens or enlarged spleens. Animals with enlarged spleens showed potentially better anti-microbial profiles and were much more likely to have a high rank within the colony. Splenomegaly was associated with infection in sick NM-Rs, but not in NM-Rs with enlarged spleens. In all healthy NM-Rs splenic erythropoiesis, megakaryopoiesis and myelopoiesis were increased, but B lymphopoiesis was reduced and splenic marginal zone showed markedly altered morphology when compared to other rodents. However, in NM-Rs lymphocytes were found in secondary sites such as lymph nodes, gut lymphoid nodules and thymus. Thus, the NM-R spleen is a major site of adult hematopoiesis under normal physiological conditions. Overall, the NM-R immune system seems to rely mainly on innate immune responses with a more restricted adaptive immune response. We propose that the anatomical plasticity of the spleen might be regulated by social interaction and gives immunological advantage to increase the life-span of higher ranked animals.

Sonographic evaluation of spleen size in apparently healthy children in north-west Ethiopia, 2020: time to define splenomegaly

Background Assessment of spleen size is an important part of the clinical skills of medical students and physicians. Many diseases can affect the size of the aforementioned organ, ranging from infective processes to malignant disorders. However, to detect changes, prior knowledge of the actual normal size of these viscera is required in the population being studied. Establishing a customized chart and curve for a specific population of the same sociodemographic characteristics enables a better interpretation of sonographic assessments. Methods A hospital-based cross-sectional study design was conducted among 403 children in primary and referral hospitals of the east and west Gojjam zone. Data were collected using a structured questionnaire, physical examination, and ultrasound. The collected data were entered into Epi Data version 3.1 and exports to SPSS version 24 for analysis. Descriptive data were analyzed using descriptive statistics. A Pearson product-moment correlation was run to determine the relationship between age, anthropometric measurements of children, and ultrasound measurements of the spleen. Reference intervals were established using non-parametric reference limits (2.5th -97.5th ) and (5th – 97th ) percentiles by MedCalc software version 20.0.3. Results Four hundred three children aged from 7 to 15 years were included in this study. The mean sonographic longitudinal (length), anteroposterior(depth) and transverse (width) dimension of the spleen was, (8.24 ± 1.26 cm), (3.98 ± 0.57 cm), and (4.26 ± 0.59 cm) respectively. The mean volume of the spleen was 75.04 ± 23.92 cm3. The height and body surface area of children were best correlated with sonographic dimensions of the spleen. Reference intervals were established using height, age, and body surface area specific for clinically practical dimensions of the spleen. Conclusions According to this study, the children are considered as having enlarged longitudinal dimension of the spleen(splenomegaly) if he or she has a size above 97.5th percentile based on their respective height.

Sustained splenic contraction after daily cocaine administration in rats

The purpose of this study is to examine the effect of repeated cocaine administration on the whole body of rats. Rats (male, 6 weeks old, Sprague Dawley) were injected intraperitoneally with cocaine (50 mg/kg) once a day for 1, 3 or 7 days, and major organs (heart, liver, lung, brain, kidney, spleen) were excised from the sacrificed animals. During autopsy, we found a reduction in spleen size, but not other organs, in cocaine-administered rats as compared to control rats. This reduction became to be noticed at 3 day and easily perceived at 7 day. No marked changes were observed in other organs examined. H&E and EMG staining showed a tendency for a decrease in the number of red blood cells (RBCs) as well as an increase in collagen fibers in the spleens of rats treated repeatedly with cocaine. Transcriptome analysis indicated that repeated cocaine administration depletes RBCs from the spleen. Immunoblot analysis showed that cocaine increases the phosphorylation of myosin light chain (MYL) as well as the levels of transgelin, both of which are involved in the contraction of myofibrils. Collectively, these results show that repeated cocaine administration results in sustained contraction of the spleen, which leads to the release of RBCs from the spleen into circulation.