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.

MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study

Idasanutlin, an MDM2 antagonist, showed clinical activity and rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label, phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily, days 1-5 of each 28-day cycle. The primary endpoint was composite response (hematocrit control and spleen volume reduction >35%) in patients with splenomegaly, and hematocrit control in patients without splenomegaly at week 32. Key secondary endpoints included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n=27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n=13), 9 (69%) attained any spleen volume reduction and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (n=6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥3 nausea and vomiting experienced in 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. Registration: NCT03287245.

Platelet count/spleen volume ratio has a good predictive value for esophageal varices in patients with hepatitis B liver cirrhosis

Background & aims Platelet count/spleen longest diameter ratio (PSDR) is widely used in clinical practice due to its good performance in predicting esophageal varices (EV). We obtained spleen volume (SV) by magnetic resonance examination, the purpose of this study was to evaluate the clinical value of platelet count/spleen volume ratio (PSVR) and spleen volume in predicting EV in patients with hepatitis B cirrhosis. Methods: This study was a diagnostic accuracy experiment and retrospective, 199 patients with hepatitis B cirrhosis who met the criteria were selected as the research subjects. All patients were collected blood samples in the morning on an empty stomach within 2 days, and related indicators were tested. Within 10 days, they received electronic gastroscopy and abdominal magnetic resonance examination. According to the Child-Pugh score, the patients were divided into groups with or without EV and with or without high-risk esophageal varices (HRV), then statistical analysis of the two groups was performed. Results The area under the curve (AUC) of PSVR in predicting EV or HRV in each group (85.5%-92.6%) was higher than PSDR, SV, spleen diameter, and platelet count. The AUC of PSDR in diagnosing HRV was higher than SV, and the AUC of SV in diagnosing EV was higher than PSDR, but the difference was not significant (P>0.05). In Child-Pugh A patients, Multivariate logistic regression analysis showed PSVR could be a predictor of HRV (P<0.05), SV was a reliable predictor of EV (P<0.05). Conclusion PSVR is better than PSDR, spleen diameter, platelet count in predicting EV; in the absence of serological results, SV could be used instead of PSDR. Both can predict EV or HRV of patients with hepatitis B cirrhosis.

A Phase 2 Study to Evaluate the Efficacy and Safety of Selinexor in Patients with Myelofibrosis Refractory or Intolerant to JAK Inhibitors

Background: Selinexor is an oral, small molecule, selective inhibitor of nuclear export (SINE) compound that specifically blocks the karyopherin protein exportin 1 (XPO1, CRM1). In an shRNA library screen, we discovered that the survival of JAK2V167F mutant HEL cells is dependent on XPO1-mediated nuclear-cytoplasmic transport. Selinexor selectively suppressed primary myelofibrosis (MF) cells as compared with normal progenitor cells and induced hematologic responses in an MPN mouse model. Methods: An open label, prospective, investigator-initiated single center study is ongoing in adults with primary or secondary MF with resistance or intolerance to JAK inhibitor (JAKi) therapy with platelets &gt; 30 K/μL and neutrophils &gt; 500/μL. Selinexor was given orally once a week. Spleen volume was assessed by MRI at week 12 and week 24. The study was amended to include additional MRIs every 12 weeks in the year 1 and 24 weeks in the year 2. Primary end point is spleen response, defined as ≥ 35% spleen volume reduction (SVR) by MRI or CT, where applicable) at week 24. Bone marrow was evaluated at baseline and at week 24. The projected sample size of 24 will provide 83% power to reject a response rate of 15% and allow for up to a 25% dropout rate. We provide an interim report after completing 50% enrollment. Results: Between May 2019 and February 2021, 12 patients (pts) were enrolled. JAK2, CALR and MPL mutations were present in 7 (58.3%), 4 (33.3%) and 1 (8.3%) pts respectively. Eight pts (66.6%) had at least one high molecular risk mutation at baseline (Table 1). Median duration of prior JAKi therapy was 22 months (0.5 to 96 months) and 11 out of 12 were refractory to ruxolitinib at study enrollment. Median baseline spleen volume was 1454 cm 3(range 835 to 5792). Selinexor starting dose was 80 mg weekly in the first 6 pts and 60 mg for subsequent pts. At data cutoff, median duration of selinexor therapy was 36 weeks (range 11-114 weeks). One pt was not response evaluable and died due to liver abscess at week 12 (unrelated). One pt discontinued selinexor at week 18 due to grade 3 fatigue and was not evaluable for the primary end point. Of the 11 pts who had week 12 MRI or CT, 6 showed ≥ 10% SVR, 3 showed ≥ 25% SVR and 1 pt had early progression (Figure 1). At week 24, 5/9 (56%) pts had ≥ 25% SVR and 2/9 (22%) had ≥ 35% SVR (Figure 1). In 9 pts who had ≥24 weeks of selinexor, SVR ≥ 25% and ≥ 35% occurred at any point during study treatment in 4 (44%) and 3 (33%) pts, respectively. Two pts were red cell transfusion dependent at baseline; 1 became transfusion independent after 36 weeks of treatment, has not required transfusion for 49 weeks and remains on study treatment to date (114 weeks). Six pts (50%) discontinued selinexor. Reasons for treatment discontinuation are death in 1 pt, progressive disease in 1 pt, alternative treatment in 2 pts, and toxicity in 2 pts. Ten pts required dose reduction due to fatigue (1pt), anemia (1 pt), thrombocytopenia (2 pts), abdominal pain (1pt) and weight loss (5 pts). The most common treatment related adverse event was weight loss (grade 2 in 4 pts and grade 3 in 1 pt). This was manageable with treatment interruption and dose reduction, except in one pt who discontinued selinexor. As yet no changes in reticulin fibrosis MF grade were observed among 9 patients who received at least 24 weeks of treatment. Conclusions: Once weekly, oral selinexor showed single agent activity with sustained spleen responses in pts with JAKi refractory MF. Long-term administration of selinexor was well tolerated over time in MF pts. Correlatives studies including circulating inflammatory cytokine levels and mutant allele burden, as well as clonality studies by X-chromosome inactivation studies in woman, are underway and will be presented. Figure 1 Figure 1. Disclosures Tantravahi: BMS: Research Funding; Novartis: Research Funding; CTI BioPharma: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Patel: Stemline: Research Funding; Genentech: Research Funding; Roche: Research Funding. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. George: Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines: Consultancy. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding.

Indirect Treatment Comparisons of the Effect of Fedratinib Versus Navitoclax Plus Ruxolitinib on Spleen Volume and Symptoms in Patients with Myelofibrosis and Prior Ruxolitinib Treatment

Introduction: Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm that is characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, anemia and splenomegaly. The Janus kinase (JAK) pathway is the critical pathway in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor, was the first US Food and Drug Administration (FDA)-approved therapy for intermediate- and high-risk MF. However, there remains a high unmet need for alternative treatment options for patients who discontinue (41.1%-60.9% of patients discontinue after 3 months and 48.4%-73.0% after 6 months) (Fonseca E, et al. Blood 2013;122. Abstract 2833) or are no longer responding to ruxolitinib therapy (Bose P, Verstovsek S. Leuk Lymphoma 2020;61:1797-1809). The efficacy and safety of fedratinib, a JAK2 inhibitor approved by the FDA in 2019, was investigated post ruxolitinib in the single-arm trial JAKARTA-2 (NCT01523171) (Harrison CN, et al. Lancet Haematol 2017;4:e317-324; Harrison CN, et al. Am J Hematol 2020;95:594-603). New clinical evidence for treating a similar population with navitoclax plus ruxolitinib was presented at the American Society of Hematology Annual Meeting in 2020 (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50). The efficacy of fedratinib relative to navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib has not yet been evaluated. Objective: To explore the comparative efficacy of fedratinib versus navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib for the 2 binary endpoints of ≥ 35% spleen volume reduction (SVR) from baseline to the end of cycle 6 (EOC6; 24 weeks) and ≥ 50% reduction in total symptom score (TSS) from baseline to the EOC6. Methods: Evidence for fedratinib was informed by JAKARTA-2 patient-level data, and evidence for navitoclax plus ruxolitinib was informed by known reported evidence from the REFINE study (NCT03222609) (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50; Harrison CN, et al. J Clin Oncol 2019;37 (suppl 15). Abstract 7057). The suitability of these studies for indirect treatment comparison (ITC) was assessed by considering the comparability of study design, population, intervention, and outcomes. Given the lack of a common comparator in the identified studies, unanchored ITCs were performed for SVR using matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) methods. Univariable and multivariable regression models were used to identify potential prognostic factors to adjust for in the ITCs. Additionally, all reported Dynamic International Prognostic Scoring System (DIPSS)-Plus criteria were considered. Where sample size was too small, response rates (number of responders divided by total number of patients) were compared naively. Results: A subgroup of 58 JAKARTA-2 patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 and intermediate-2 or high-risk disease most closely aligned with the REFINE population was used in the analyses. Baseline mean platelet count was similar between subgroups. Across the analyses performed, results suggested fedratinib consistently increased the odds/risk of a spleen response compared with navitoclax plus ruxolitinib (Table). The MAIC, matching on ECOG PS, suggested that the odds of having an SVR for patients in the fedratinib group was 2.19 times (95% confidence interval [CI], 1.26 to 3.66) that of the navitoclax plus ruxolitinib group, and the risk of having an SVR for patients in the fedratinib group was 17.59% higher (95% CI, −2.14 to 36.97). The results from the MAIC that additionally matched on all possible DIPSS-Plus criteria (age, hemoglobin, and platelet count) were consistent. Results from the 2 methods (MAIC and STC) were also consistent. For TSS reduction, the sample size (N = 20) in REFINE was considered too small to perform a meaningful ITC; however, the absolute response rates for TSS reduction were similar across the 2 groups (29% [16/56] in the fedratinib group and 30% [6/20] in the navitoclax plus ruxolitinib group). Conclusion: In the population of patients with MF previously treated with ruxolitinib, these analyses suggest treatment with fedratinib was associated with a greater proportion of patients achieving a spleen response compared with navitoclax plus ruxolitinib. Limited data were available for comparison of TSS. Figure 1 Figure 1. Disclosures Abraham: Bristol Myers Squibb: Current Employment. Liao: BMS: Consultancy. Chevli: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Smith: Sarah Smith is an employee of BresMed. BresMed received consultancy fees from BMS/Celgene for the reasearch in this abstract. She did not receive direct payment as a result of this work outside of her normal salary payments.: Consultancy.

Longitudinal Analysis of the Effect of Repeated Transarterial Chemoembolization for Liver Cancer on Portal Venous Pressure

ObjectivesInvestigate long-term effects of repeated transarterial chemoembolization (TACE) on portal venous pressure (PVP) using non-invasive surrogate markers of portal hypertension.MethodsRetrospective, Institutional Review Board-approved study. 99 patients [hepatocellular carcinoma (HCC) group (n=57); liver metastasis group (n=42)] who underwent 279TACEs and had longitudinal pre-/post-therapy contrast-enhanced-MRI (n=388) and complete blood work were included. Outcomes of interest were platelet count (PC), spleen volume, ascites and portosystemic collaterals. Variables included TACE type/number, tumor type, microcatheter location, Child-Pugh, baseline tumor burden (tumor number/total/largest size), vessel invasion, alpha-fetoprotein, Eastern Cooperative Oncology Group (ECOG) performance status, and Model for End-Stage Liver Disease (MELD) score. Generalized Estimating Equations assessed the associations between TACE and outcomes. Power analysis determined the sample size was sufficient.ResultsNo significant change in PC over time was observed in either groups, regardless of liver function (P&gt;0.05). Baseline spleen volume was 226 cm3 for metastatic group, and was larger by 204 cm3 for HCC group (P&lt;0.001). Spleen volume increased by 20 cm3 (95%CI: 8-32; P=0.001) for both groups after 1stTACE and by 16cm3/TACE (P=0.099) over the full follow-up (up to 9TACEs). Spleen volume also tended to increase by 23cm3 (95%CI: -1–48; P=0.064) with higher tumor burden. Odds of developing moderate/severe ascites for metastatic patients was decreased by 0.5 (95%CI: 0.3–0.9; P=0.014), regardless of the Child-Pugh, and increased by 1.5 (95%CI: 1.2–1.9; P&lt;0.001) among HCC patients with unstable Child-Pugh, whereas no change was noted with stable Child-Pugh. HCC patients with unstable Child-Pugh demonstrated a significant increase in portosystemic collaterals number over time (P=0.008). PVP-related complications such as variceal bleeding post-TACE were low (0.4%).ConclusionRepeated TACEs did seem to have an impact on PVP. However, the increase in PVP had marginal effects with low portal hypertension-related complications.

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.

Quantitative splenic embolization possible: application of 8Spheres conformal microspheres in partial splenic embolization (PSE)

Background To investigate the safety and efficacy of 8Spheres in partial splenic embolization. To explore the possibility of accurate control of splenic embolic volume by quantifying the number of microspheres used during PSE. Method The data of 179 patients who underwent PSE were collected. The patients were divided into two groups: 300–500 um microsphere group (N = 83) and 500–700 um microsphere group (N = 96). The spleen volume before PSE, infarct volume and infarct rate of the spleen after PSE, changes in peripheral blood cells after PSE, postoperative adverse events and incidence of infection were compared between the two groups. Results 300–500 um group vs 500–700 um group: postoperative spleen volume (cm3): 753.82 ± 325.41 vs 568.65 ± 298.16 (P = 0.008); spleen embolization volume (cm3): 525.93 ± 118.29 vs 630.26 ± 109.71 (P = 0.014); spleen embolization rate: 41.1 ± 12.3% vs 52.4 ± 10.1% (P = 0.021). Leukocytes and platelets were significantly increased after PSE in both groups; leukocyte, 1 month: 4.13 ± 0.91 vs 5.08 ± 1.16 (P = 0.026); 3 months: 4.08 ± 1.25 vs 4.83 ± 0.98 (P = 0.022); platelet, 1 month: 125.6 ± 20.3 vs 138.7 ± 18.4 (P = 0.019); 3 months: 121.8 ± 16.9 vs 134.3 ± 20.1 (P = 0.017). Incidence of abdominal pain after PSE, 72 (86.7%) vs 69 (71.9%), P = 0.027. The incidence of other adverse events and infections after PSE was not statistically different. Conclusion PSE with 8Spheres is safe and effective. The use of 500–700 um microsphere for PSE can make the increase of peripheral blood cells more stable. Each vial of 8Spheres corresponds to a certain volume of splenic embolization, so it is possible to achieve quantitative embolization in PSE.