Reduction In Spleen Volume Research Articles

Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24

Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis, splenomegaly and cytopenias resulting from aberrant megakaryopoiesis and proinflammatory cytokine expression. These processes are heavily regulated by bromodomain and extraterminal domain (BET) protein-mediated gene expression (eg NF-κB target genes, MYC and BCL-2) and lead to myeloproliferation and cytopenias. The current standard of care for patients (pts) with MF is the Janus kinase inhibitor (JAKi) ruxolitinib (RUX); however, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction (TSS) from BL (TSS50) with RUX monotherapy are limited. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). In the ongoing Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. Here, we present results from Arm 3 of MANIFEST (in which JAKi-naïve pts with MF receive PELA in combination with RUX). Aims: The primary endpoint of MANIFEST Arm 3 is SVR35 after 24 weeks (wks) of treatment. Secondary endpoints include TSS50, duration of splenic response, pharmacokinetics and safety. Exploratory endpoints include transfusion independence and changes from BL in BM fibrosis. In this abstract we will discuss results from the September 2021 data cut; longer-term data from the July 2022 data cut will be presented. Methods: Spleen volume was assessed by computed tomography or magnetic resonance imaging every 12 wks; TSS per Myelofibrosis Symptom Assessment Form v4.0; and BM fibrosis by biopsies at Wk 24 and Wk 48. Duration of splenic response and safety data are also evaluated. Data presented are from the September 2021 data cut; a more mature data set will be presented at the conference. Results: Eighty-four pts received ≥1 dose of PELA and RUX. Median age was 68 years (range 37-85); 24%, 61% and 16% had Dynamic International Prognostic Scoring System intermediate-1, intermediate-2 or high risk, respectively. Pts who did not reach Wk 24 were counted as nonresponders. At Wk 24 and Wk 48, 68% (57/84) and 60% (47/79) of pts, respectively, achieved SVR35. SVR35 at any time was achieved by 80% pts (67/84), and 87% (58/67) pts with SVR35 maintained response at the time of data cutoff. Median spleen volume change was -50% (range -84.4% to 27.9%) at Wk 24. Median time to SVR35 response was 12 wks (first on-treatment assessment of splenic response); durable spleen volume reductions were observed as depicted in mean spleen volume change over time in Figure 1. TSS50 was achieved by 56% (46/82) pts at Wk 24 and 43% (34/79) at Wk 48. TSS50 at any time was achieved by 81% pts (68/84). The median change in TSS was −59% (range −100% to 225%) at Wk 24. Mean TSS change over time is shown in Figure 2, indicating sustained reduction in symptom burden. Median follow up for Arm 3 was 21.8 (range 21.2-22.5) months; median treatment duration was not reached as of data cutoff. BM fibrosis improved by ≥1 grade in 28% (16/57) of evaluable pts at Wk 24 as assessed by central pathology review; 56% maintained the improvement at the next available assessment (Wk 48 or beyond) or longer; and 40% achieved ≥1 grade improvement at any time (best response). The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (Grade ≥3: 12%) of pts. Anemia was reported in 42% (Grade ≥3: 34%). Serious adverse events reported in ≥2 pts were respiratory tract infections (6 pts), pyrexia (3 pts) and anemia, multiorgan failure, fall and pelvic fracture (2 pts each). TEAEs that led to PELA discontinuation occurred in 7 pts (8%). Updated data with longer follow-up, including durability of splenic response and safety data from a more mature data set, will be available for presentation at the conference. Conclusions: The combination of PELA and RUX in JAKi-naïve pts with MF showed durable improvements in spleen volume, total symptom score and BM fibrosis, and was generally well tolerated. The randomized, double-blind, active-controlled Phase 3 MANIFEST-2 study is open for enrollment and evaluating the safety and efficacy of PELA in combination with RUX in JAKi treatment-naïve pts with MF (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1, Open-Label, Dose-Escalation Study of Selinexor Plus Ruxolitinib in Patients with Treatment-Naïve Myelofibrosis

Background: Myelofibrosis (MF) is commonly associated with acquired somatic gene mutations in JAK2, CALR, or MPL. Spleen volume reduction and improvement in symptom burden of MF are attained in 40% of patients treated with the common front-line therapy ruxolitinib (RUX), a JAK1/2 inhibitor. Selinexor (SEL) is an oral Selective Inhibitor of Nuclear Export (SINE) compound that inhibits exportin-1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins (e.g., TP53, IkB, p21), reduction in oncoprotein mRNAs (c-Myc, Bcl-2, Bcl-6, cyclin D) and selective apoptosis of cancer cells. Selinexor has received FDA approval for use in patients with multiple myeloma and diffuse large B-cell lymphoma. Preclinical studies demonstrated activity with the combination of SEL plus RUX. In patients with disease refractory to a JAK inhibitor (JAKi), SEL monotherapy had notable clinical activity and a generally manageable safety profile (NCT03627403). Methods: The ongoing multicenter, open-label, Phase 1/2 study (NCT04562389) is evaluating the safety and efficacy of SEL plus RUX in treatment-naïve MF patients. Two dose levels of SEL were evaluated, 40mg and 60mg orally once-weekly (QW) plus RUX twice daily (BID) as per label in 28-day cycles. For nausea prophylaxis, all patients received a 5-HT3 antagonist prior to each dose SEL and then as needed. Primary objectives include safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and preliminary efficacy. Secondary objectives include spleen, symptom, and anemia response, and overall survival. Results: As of July 2022, 19 patients have received at least one dose of oral 40mg (n=4) or 60mg (n=15) weekly SEL with RUX twice daily as per standard of care. Median age was 64 years old (range 44-77). Nine patients had primary MF, 7 had post-ET MF, and 3 had post-PV MF. At baseline, two patients had packed red blood cell (PRBC) transfusion-dependent anemia. DIPSS risk category was int-1 (n=6), int-2 (n=9), and high risk (n=4). Of patients evaluable for spleen response, 11/14 achieved spleen volume reduction of ≥35% (SVR35) at week 12 (79%, 95% CI: 49% to 95%) and 6/7 achieved SVR35 at week 24 (86%, 95% CI: 42% to 100%). Eighty-six percent (12/14) (95% CI: 57% to 98%) of patients achieved SVR35 at any time on study. Thirteen patients with available data and who received at least 12 weeks of treatment were evaluated for symptom response; 9/13 (69%, 95% CI: 39% to 91%) had a total symptom score ≥50% reduction by week 12. Eleven out of 17 PRBC transfusion-independent patients (65%) who received at least 8 weeks of therapy maintained stable hemoglobin (Hgb; ± 2g/dL) or improved Hgb levels (>2g/dL increase) at the last follow up. The most common treatment-emergent adverse events (TEAEs) were nausea (11/19, 58%), anemia (8/19, 42%) and vomiting (8/19, 42%). The most common Grade 3 TEAEs were thrombocytopenia and anemia, with only two Grade 4 TEAEs (thrombocytopenia). Conclusions: In this preliminary analysis, the combination of SEL and RUX shows promising clinical activity to date in patients with treatment-naïve myelofibrosis. The combination has been reasonably well-tolerated and with a manageable side effect profile to date.

Clinical Benefit Associated with Biomarker Changes Indicative of Disease Modification in Patients with Myelofibrosis Treated with the BET Inhibitor Pelabresib As Monotherapy or in Combination with Ruxolitinib

Bromodomain and extraterminal domain (BET) proteins play a key role in the regulation of neoplastic myeloproliferation and proinflammatory cytokine production in myelofibrosis (MF). Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). In the ongoing Phase 2 MANIFEST study (NCT02158858) (Kremyanskaya M, et al. Blood 2021;138:141) PELA is being evaluated as monotherapy in ruxolitinib (RUX)-intolerant, ineligible or refractory patients (pts) with MF (Arm 1) and in combination with RUX as an 'add-on' in pts with MF with suboptimal response to RUX (Arm 2) or in JAK inhibitor (JAKi)-naïve pts with MF (Arm 3). Assessment of ≥35% spleen volume reduction (SVR35) and ≥50% total symptom score reduction (TSS50) are standard clinical trial endpoints to evaluate disease response in MF. However, SVR35 and TSS50 do not fully reflect underlying disease improvement, and additional approaches are needed to understand what constitutes disease modification in MF (Pemmaraju N, et al. Cancer 2022;128:2420-2432) and to provide better insight into the mechanisms of novel drugs in development, such as PELA. Here we report results in pts enrolled in MANIFEST from exploratory analyses of treatment-induced changes at Week 24 in a range of biomarkers that are suggestive of disease modification (≥1 grade improvements in bone marrow fibrosis [BMF], reduction of Janus Kinase 2 V617F [JAK2V617F] variant allele frequency [VAF] in blood, improvements in hemoglobin and increased distance of CD61+ megakaryocytic [MK] cells in bone marrow ['declustering']) with respect to the clinical outcomes of SVR35 and TSS50. We previously demonstrated (Mascarenhas J, et al. HemaSphere 2022;6:99-100) that the increase in distance in MK cells correlated with SVR35 responses. Table 1 shows a summary of SVR35 and TSS50 response rates and changes in biomarkers associated with potential disease modification observed in the MANIFEST study in each study arm. Of note, with PELA monotherapy, 30% (7/23) of pts in a RUX-resistant/intolerant population (Arm 1) showed ≥1 grade improvement in BMF. Additional changes indicating biologic effect of PELA included declustering of MK cells (increase in distance of ≥15%) observed in 46% (5/11) of pts. Similar or better results were observed in pts treated with PELA/RUX combination. Changes in these markers of potential disease modification were associated with SVR35 and TSS50 endpoint responses. In evaluable pts with available data, splenic responses at Week 24 across the three arms were associated with ≥1 grade reduced BMF (in 18/43 pts, 42%), increased MK distance (in 20/26 pts, 77%, median change +34%) and JAK2V617F VAF reductions (in 41/50 pts, 82%, median change -13%). Of TSS50 responders at Week 24 with available data, 36% (16/44) showed ≥1 grade improvements in BMF; 71% (20/28) had an increase in MK distance (median change +22.3%); and 64% achieved reductions in JAK2V617F VAF (30/47, median change -8%). In JAKi-naïve pts (Arm 3), 68% (57/84) achieved SVR35 at Week 24; among these patients with available data, 38% (12/32) improved BMF ≥1 grade; 74% (14/19, median change +19.7%) increased MK distance; and 83% (34/41, median change -18%) reduced JAK2V617F VAF (any level of improvement). TSS50 was observed in 56% (46/82) of JAKi-naïve pts; among these patients with available data, improvements in ≥1 grade BMF, MK distance and JAK2V617F VAF (any level of improvement) were observed in 46% (11/24), 75% (12/16, median change +24%) and 78% (18/23, median change -14.3%) of pts, respectively. In nonresponders, changes in biomarkers were consistently smaller. Our data indicate differences in the association of individual markers of potential disease modification with SVR35 and TSS50. While reduction in JAK2V617F VAF and increase in MK distance appear to be associated with SVR35, a high incidence of BMF improvements were also observed in Arm 3 TSS50 responders. Extended multivariable, longitudinal, biomarker analyses for association with time-to-event endpoints (eg duration of splenic response) will be presented with a new data cutoff with the objective to investigate potential disease-modifying activity of PELA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Study of Ruxolitinib in Combination with Abemaciclib for Patients with Primary or Post-Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

Introduction and preclinical rationale: Patients with primary and secondary myelofibrosis (MF) have a reduced life expectancy compared to age-matched controls. The prognosis of individual patients is defined by clinical, cytogenetic, and molecular disease characteristics. Several oral Janus Kinase (JAK)-1/2 inhibitors such as ruxolitinib are approved by the US FDA for the treatment of patients with intermediate or high-risk MF based on improvements in symptom burden and spleen volume reduction compared to physician choice of best available therapy. However, these inhibitors often have a limited duration of response, and survival in patients after ruxolitinib discontinuation is poor (median survival of 13 months). Novel mechanism-based therapies for patients with suboptimal response or progression on ruxolitinib are thus needed. Preclinical studies have demonstrated that JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A. Notably, CDC25A expression has been shown to be upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been demonstrated to play a role in MPN pathogenesis and to drive myeloproliferation. Preclinical studies testing the combination of the CDK4/6 inhibitor ribociclib and ruxolitinib demonstrated reduction in spleen and liver size when compared to ruxolitinib alone in murine models, suggesting synergism (Rampal et al., Clinical Cancer Research 2021). Methods: Based on these promising preclinical data, we hypothesize that combining ruxolitinib with a CDK4/6 inhibitor could have synergistic effects in patients with primary or secondary MF who have an inadequate response to ruxolitinib monotherapy. In this multicenter, phase I dose-escalation trial we evaluate the safety of combination therapy with ruxolitinib and the CDK4/6 inhibitor abemaciclib. Patients with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to ruxolitinib are eligible for enrollment. An inadequate response will be defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms [presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS (Emanuel at al. JCO 2012). (Table 1). This study follows a conventional "3+3” dose-escalation design, in which patients on a stable dose of ruxolitinib (10mg or 15mg BID) with sufficient baseline platelet and absolute neutrophil count will be treated with increasing doses of abemaciclib. The pre-study dose of ruxolitinib will be maintained to determine the maximum tolerated dose of the combination of ruxolitinib and abemaciclib (Figure 1). The primary endpoint of this study is to determine the safety and tolerability, and to identify the recommended phase II dose of abemaciclib in MF patients on a stable, standard dose of ruxolitinib. Secondary endpoints include overall response rate (defined as a composite of complete remission [CR], partial remission [PR], and clinical improvement [CI; defined as anemia, spleen or symptom response]), rates of CR, PR, and CI as well as progression-free survival (PFS), overall survival (OS), and duration of response (DOR) as defined in accordance with the modified 2013 consensus definitions proposed by the International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN). As part of this clinical trial several correlative studies are planned to identify biomarkers predictive of response to ruxolitinib and abemaciclib as well as mechanisms of resistance (e.g., MAP kinase pathway activation). These include evaluation of changes in variant allele fraction of driver mutations, gene expression profile, cell cycle, clonal architecture, cytokine profile, and bone marrow fibrosis, aiming to inform patient selection as well as other alternative combination therapies for future clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Combination of Navitoclax and Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Mediates Responses Suggestive of Disease Modification

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, high symptom burden, bone marrow fibrosis (BMF), and poor prognosis. The Janus kinase inhibitor (JAKi) ruxolitinib is the current standard of care for patients with MF. It improves splenomegaly and disease symptoms with limited impact on disease biology, highlighting an unmet medical need in MF. Driver mutations of JAK2, CALR, and MPL are key to the pathogenesis of MF. Reduction in variant allele frequency (VAF) of driver mutations and reversal of BMF are suggestive of disease modification (Pemmaraju, Cancer, 2022). Additionally, mutations in ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1 p.Q157 are classified as high molecular risk (HMR) mutations associated with a worse prognosis (Arber et al., Blood, 2016). We previously demonstrated evidence of disease modification independent of HMR mutations by adding navitoclax to ruxolitinib in patients with suboptimal responses to ruxolitinib monotherapy (Pemmaraju, Lancet Oncology, 2022). Herein, we investigated whether the type of MF and risk (e.g., age, Dynamic International Prognostic Scoring System [DIPSS], and HMR) correlated with clinical outcomes and responses suggestive of disease modification (e.g., VAF reduction and improvement in BMF) among JAKi treatment-naïve patients with MF treated with the combination of navitoclax and ruxolitinib. Methods: Cohort-3 of the phase-2 multicenter REFINE study (NCT03222609) enrolled JAKi treatment-naïve patients with MF. Enrolled patients had primary or secondary MF with splenomegaly (DIPSS ≥ Intermediate-1) and did not receive prior JAK-2 therapy or bromodomain and extra terminal motif (BET) inhibitors. Patients initiated navitoclax at 100 mg QD or 200 mg QD if baseline platelet count was ≤ 150 × 109/L or > 150 × 109/L, respectively. Ruxolitinib was given BID with starting dose based on baseline platelet count per local label. The primary endpoint was spleen volume reduction of ≥ 35% (SVR35) from baseline at week 24, assessed by MRI conducted by central review. Key secondary and exploratory endpoints evaluated in this analysis were a reduction in BMF obtained from BM biopsies by local evaluation and a reduction in VAF for the driver gene mutations (JAK2V617, CALR, or MPL), respectively. Driver gene VAF and HMR mutations were determined in whole blood with the 50-gene Focus Myeloid next-generation sequencing panel (Interspace Pharma Solutions, Morrisville, NC, USA). Results: As of Feb 07, 2022, all enrolled patients (N = 32) treated with navitoclax and ruxolitinib were evaluable for biomarker analysis. The median duration of follow-up was 6.1 months (range, 1.9 – 18.6); median age was 69 years (range, 44 – 83), and median spleen volume was 1889.08 cm3 (range, 645.6 – 7339.6). At baseline, 22 (69%) patients had JAK2, 6 (19%) had CALR, and 3 (9%) had MPL mutations. One (3%) patient was triple negative. Nineteen (59%) patients had HMR mutations. SVR35 at week 24 was observed in all subgroups known to confer poor prognosis, including age (≥75 years, 50% [n = 4/8]), high DIPSS score (Intermediate-2, 63% [n = 12/19]; high, 33% [n = 1/3]), and HMR mutations (47% [n = 9/19]; Figure). BMF grade improvement was evaluable in 26/32 (81%) patients, of which 9/26 (35%) achieved ≥ 1-grade improvement at any time during treatment with a median time-to-improvement of 12.3 weeks (range, 12.1 – 24.1). Complete resolution of BMF was observed in 2/9 (22%) patients. The baseline BMF grades of these patients were 2 and 3. BMF ≥ 1-grade improvement was achieved by 7/13 (54%) patients with HMR mutations and 2/13 (15%) without HMR mutations. Reduction in driver gene JAK2V617 mutation VAF > 20% from baseline at week 12 or 24 was observed in 14/28 (50%) patients, and 5/14 (36%) patients achieved > 50% VAF reduction from baseline. There were no differences in > 20% VAF reductions from baseline to week 12 or 24 between those with or without HMR mutations (7/15 [47%] versus 7/13 [54%], respectively). Conclusions: Among JAKi treatment-naïve patients with MF, the combination of navitoclax and ruxolitinib reduced splenomegaly in several high-risk groups known to confer poor prognosis. Reductions in BMF and VAF were independent of HMR mutations. The reduction in BMF and VAF for the driver mutation JAK2V617 is encouraging and suggestive of evidence of disease modification with the combination of navitoclax and ruxolitinib. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

JAK2V617F Molecular Response to Ruxolitinib in Patients with PV and ET Is Associated with Lower Risk of Progression to Secondary Myelofibrosis

Introduction. Ruxolitinib (RUX) is approved for patients (pts) with Polycythemia Vera (PV) who are refractory or intolerant to hydroxycarbamide, based on composite endpoint of spleen volume reduction and Hct control (RESPONSE-1 trial) and Hct control (RESPONSE-2). Conversely, studies in pts with Essential Thrombocythemia (ET) were inconclusive, and the drug is not approved in that indication. Aim. The aim of current study was to analyze changes of JAK2V617F variant allele fraction (VAF) in PV and ET pts who were long-term treated with RUX, and the clinical correlates and outcome of molecular responses. Patients and Methods. The study included 65 PV and 12 ET pts; the latter had been enrolled in phase-2 studies and were still on RUX owing to continuing clinical benefits. Median time from diagnosis to RUX was 5.9y (0.6-24y), age 58y (25-87y), 50.6% were male, history of thrombosis in 21 pts (27%). A JAK2V617F mutation was found in 75 pts (97.4%), JAK2ex12 and MPLW515L in 1 pt each. At circa-annual intervals, JAK2V617F VAF was measured in granulocytes by digital PCR or highly sensitive (threshold <0.01%) RTQ-PCR. MPLW515L was measured by digital PCR. IWG-MRT criteria were used for clinical and molecular response assignment. The latter included partial (PMR: a >50% VAF reduction) and complete (CMR; JAK2V617F undetectable) molecular response, confirmed at >1y. We also considered a deep molecular response (DMR) as a confirmed VAF<2%. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier estimate of survival and log-rank test were used as appropriate. Results. Median FU on RUX was 8.8y (1.3-14.1). The median RUX dose was 20 mg die (5-50mg). RUX was discontinued in 23 pts for AE (n=7, 9.1%), disease progression (n= 12, 15.6%), refractoriness/loss of response (n=3, 3.8%) or pt decision (n=1, 1.3%), after a median of 5.0y (0.8-13y). While on RUX, there were 3 thrombosis and 4 bleedings. Progression to secondary MF (sMF) occurred in 24 pts (31.1%) after a median of 6.0y (2-11.5); of these, 22 (92%) were PV, accounting for 34% of all PV compared to 16.6% of ET. Three pts (3.9%) transformed to AML after 9.2y (1.3-13.7y) and died, and 2 pts (2.6%) died after evolution to sMF while on RUX. A IWG-MRT response was reached in 92% for Hct, 59% for platelet count, 73% for leukocyte count, 77% for spleen volume (<50% palpatory). The median JAK2V617F VAF was 47% (21-98%) and 68% (15-99%) at diagnosis and RUX start, respectively. The overall mean VAF decrease was 64.6%+27.5%. A PMR was observed in 33 pts (44.2%), after a median time of 3.3y (1-7.6y), 51% and 50% of PV and ET; the baseline JAK2V617F VAF was 61.3±27.7% for PV and 32.3±10.4% for ET. A CMR (confirmed) was declared in 5 JAK2V617F mutated pts (6.5%; median baseline VAF 44.7±36.8%) of which 3 were PV, and in the MPLW515L mutated ET pt (baseline VAF 33%). A DMR was confirmed in 9 pts (11.7%; median baseline VAF 30.5±16.0), of which 6 were PV. Median time to CMR and DMR was 4.6y (1.1-7.6y) and 5.0y (2.1-12.1y), respectively. Mean duration of CM + DMR was 8y (7-12y). There was no correlation between any category of molecular response and response of Hct, platelets and spleen length, while normalization of leukocytes occurred more frequently in pts with PMR (93.8% vs 62.5%, P=0.02). Of the pts who progressed to sMF, 21 of 24 pts (87.5%) had not attained an at least PMR (P<0.0001). The HR of sMF evolution was 19.9 (95%CI, 2.4-166.7) for those who did not obtain any molecular response and 3.56 (95%CI, 0.37-34.6) for those who obtained PMR, using CMR+DMR as reference (P<0.0001) (Figure 1). By ROC analysis, a cutoff level of <60% JAK2V617F VAF at baseline (involving 35 pts, 45.5% of the entire population) was associated with a significantly greater likelihood to obtain CMR+DMR (37.1% vs 2.4%; P<0.0001) as well as PMR (60% vs 38.2%, P=0.01). All 3 pts who transformed to AML had not obtained any molecular response. Discussion. In this study, 18% of PV and ET pts receiving RUX developed sustained JAK2V617F complete plus deep molecular response (JAK2V617<2%) over long term treatment, that were associated with lower risk of progression to secondary MF; also pts attaining a PMR had reduced probability to develop sMF compared to those who did not show any changes in JAK2V617 VAF, overall reinforcing that attainment of molecular response may be a surrogate of disease modification. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RF32 | PSUN58 BIO89-100 Treatment Ameliorates a Subclinical Increase in Spleen Volume in Non-cirrhotic NASH in Correlation With Change in Liver Fat, HOMA-IR and Inflammatory Markers in a Phase 1b/2a, Placebo-Controlled, Double-Blind Proof of Concept Study

Abstract Background and Aims Portal venous pressure may begin to rise due to steatosis-induced changes in sinusoidal homeostasis in early stages of NASH and may contribute to progression of fibrosis and portal hypertension1. FGF21 is an endogenous hormone regulating carbohydrate, lipid and energy metabolism. FGF21 analogs improve liver and metabolic abnormalities in NASH. In a phase 1b/2a POC study in subjects with NASH, BIO89-100, a glycoPEGylated FGF21 analog, led to significant reductions in hepatic fat fraction (HFF) and liver volume (LV) by MRI-PDFF, with concurrent metabolic benefits and a favorable safety and tolerability profile. This post-hoc analysis assessed the effect of BIO89-100 on spleen volume (SV). Methods The trial enrolled 81 subjects with liver fat ≥10% by MRI-PDFF and biopsy-confirmed NASH or phenotypic NASH. Subjects were treated for 12 weeks in 6 cohorts (3, 9, 18 or 27mg QW; 18 or 36mg Q2W) or placebo. Key endpoints were safety, tolerability, pharmacokinetics, change in HFF by MRI-PDFF and liver and metabolic markers, and have been previously reported. SV was assessed by MRI at baseline, Day 50 and Day 92 in 16 BIO89-100-treated (pooled; 8 on 27 mg QW, 8 on 36 mg Q2W) and 18 placebo subjects. Results Median baseline (BL) characteristics for BIO89-100 subjects (N=16) and placebo subjects (N=18) were: age 47.6 vs 56.5 years, BMI 36.6 vs 33.5 kg/m2, ALT 53 vs. 29 IU/L, VCTE 8 vs 7.1 kPa, liver fat by MRI-PDFF 19.3% vs 19.7%; 56.3% vs 38.9% of subjects were male, and 25% vs 61% had T2DM. Median SV at BL was within normal limits: 232.6 (range 137.6 - 504.4) cm3 vs 170.9 (range 107.6–366.9) cm3. At BL, there were correlations between SV and LV (r=0.58), HOMA-IR (r=0.39), Adipo-IR (r=0.43), BMI (r=0.38) and VCTE score (r=0.40), and negative correlations between SV and HDL cholesterol (r=-0.48), adiponectin (r=-0.35) and platelet count (PC; r=-0.37). On day 92, reduced SV was observed in BIO89-100-treated subjects [percent change LS mean -11.8 vs -0.8 (p=0.002)]. Percent reduction in SV correlated with % reduction in HFF by MRI-PDFF (r=0.55), % reduction in liver fat volume (r=0.55), reduction in HOMA-IR (r=0.55) and % change in CK-18 (r=0.74); and absolute reduction in SV correlated with absolute change in ALT (r=0.48) and negatively correlated with PC (r=-0.75). Conclusion These preliminary data suggest that in non-cirrhotic NASH, a subclinical increase in SV, within the normal range, is associated with a worsening metabolic profile, increased liver stiffness and decreased PC. Normalization of liver fat and LV may be associated with decreased intrahepatic resistance and improved portal flow (PF), thus decreasing SV, and possibly improving insulin sensitivity. The role of SV measurement as a non-invasive tool for assessment of PF and the clinical significance of subclinical changes in SV Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:18 p.m. - 1:23 p.m.

Multiparametric MRI to quantify disease and treatment response in mice with myeloproliferative neoplasms.

Histopathology, the standard method to assess BM in hematologic malignancies such as myeloproliferative neoplasms (MPNs), suffers from notable limitations in both research and clinical settings. BM biopsies in patients fail to detect disease heterogeneity, may yield a nondiagnostic sample, and cannot be repeated frequently in clinical oncology. Endpoint histopathology precludes monitoring disease progression and response to therapy in the same mouse over time, missing likely variations among mice. To overcome these shortcomings, we used MRI to measure changes in cellularity, macromolecular constituents, and fat versus hematopoietic cells in BM using diffusion-weighted imaging (DWI), magnetization transfer, and chemical shift-encoded fat imaging. Combining metrics from these imaging parameters revealed dynamic alterations in BM following myeloablative radiation and transplantation. In a mouse MPLW515L BM transplant model of MPN, MRI detected effects of a JAK2 inhibitor, ruxolitinib, within 5 days of initiating treatment and identified differing kinetics of treatment responses in subregions of the tibia. Histopathology validated the MRI results for BM composition and heterogeneity. Anatomic MRI scans also showed reductions in spleen volume during treatment. These findings establish an innovative, clinically translatable MRI approach to quantify spatial and temporal changes in BM in MPN.

MPN-141 Retrospective Comparison of Patient Outcomes on Pacritinib Versus Ruxolitinib in Patients With Myelofibrosis and Thrombocytopenia.

Pacritinib (PAC) is a JAK2/IRAK1 inhibitor for patients with myelofibrosis (MF) and thrombocytopenia. Unlike the JAK1/2 inhibitor ruxolitinib (RUX), which is used at lower doses in patients with thrombocytopenia, PAC has been studied at full dose regardless of platelet count. This analysis focused on PERSIST-2 patients with platelet counts ≤100 × 109/L who were randomized to PAC 200mg BID and patients who received RUX on best available therapy (BAT) prior to week 24. Endpoints included percent of patients with 35% spleen volume reduction (SVR), 50% modified total symptom score (mTSS) reduction (based on early satiety, abdominal discomfort, night sweats, itching, bone pain, and rib pain), and improvement in disease symptoms measured by Patient Global Impression of Change (PGIC). Safety analyses were based on all treated patients; efficacy analyses were based on the intention-to-treat population randomized at least 22 weeks prior to study end. The Fisher Exact test was used to describe differences in response. Logistic and Cox regression was used to adjust for differences in baseline characteristics. Safety analysis included 106 patients on PAC and 44 on RUX; efficacy analysis included 74 on PAC and 32 on RUX (median total daily dose 10 mg). Baseline characteristics were similar between groups, including median platelet count (55 vs 61 × 109/L) and percent receiving RBC transfusion (46% vs 43%). Patients treated with PAC vs RUX achieved higher rates of SVR (22% vs 3%, p=0.02) and numerically higher rates of mTSS response (35% vs 19%; p=0.11) and "much" or "very much" improved symptoms (35% vs 16%, p=0.06) at week 24. Among RUX patients with an available PGIC measure at week 24, 50% reported either no improvement or worsening symptoms, while 76% of PAC patients reported improvement. The adjusted hazard ratio on PAC vs RUX was 0.46 [95% CI: 0.15-1.43]. Bleeding occurred at similar rates (43% vs 41%) on PAC vs RUX. Fatal AEs occurred in 8% on PAC compared to 11% on RUX. PAC yielded higher response rates and a similar safety profile to lower-dose RUX in patients with MF who have moderate or severe thrombocytopenia. This study was supported by CTI BioPharma.

MPN-375 BET Inhibitor Pelabresib (CPI-0610) Combined With Ruxolitinib in Patients With Myelofibrosis - JAK Inhibitor-Naïe or With Suboptimal Response to Ruxolitinib - Preliminary Data From the MANIFEST Study.

Myelofibrosis is characterized by splenomegaly, symptoms, cytopenias, and bone marrow (BM) fibrosis. Pelabresib is an investigational, oral, small-molecule BET inhibitor designed to selectively inhibit the BD1 and BD2 bromodomains of BET proteins. Evaluation of pelabresib combined with ruxolitinib in patients with myelofibrosis. In Arm 3 of the Phase 2 MANIFEST study (NCT02158858), JAKi-naïve myelofibrosis patients are treated with pelabresib combined with ruxolitinib. In Arm 2, myelofibrosis patients with suboptimal response to ruxolitinib are treated with pelabresib as 'add-on' to ruxolitinib (Arm 2A: transfusion-dependent [TD]; Arm 2B: non-TD). The primary endpoints are ≥35% spleen volume reduction (SVR35) at Week 24 for Arms 3 and 2B and TD to transfusion independence (TI) in Arm 2A. The key secondary endpoint is ≥50% total symptom score reduction (TSS50) at Week 24; in Arm 2A, SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated. As of September 2021, at Week 24 in Arm 3 (N=84), 68% (57/84) of patients achieved SVR35 (median change: -50%), and 56% (46/82) of patients achieved TSS50 (median change: -59%). At Week 24 in Arm 2 (N=86), 20% (16/81; 17% in Arm 2A and 26% in Arm 2B) of patients achieved SVR35 (median change: -18%), and 37% (30/81) of patients achieved TSS50 (median change: -47%). In Arm 2A, the TD to TI rate was 16% (6/38). At Week 24, BM fibrosis improvement ≥ 1 grade was achieved in 28% (16/57) and 26% (12/47) of patients in Arms 3 and 2, respectively. Hematologic treatment-emergent adverse events (TEAEs) included thrombocytopenia, in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) of patients, and anemia, in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) of patients in Arms 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely resulted in discontinuation. In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxolitinib in JAKi treatment-naïve patients with myelofibrosis (NCT04603495).

Increased spleen volume provoked by temperate head-out-of-water immersion.

This study tested the hypotheses that 1) spleen volume increases during head-out-of-water immersion (HOWI) and returns to pre-HOWI values postdiuresis, and 2) the magnitude of apnea-induced spleen contraction increases when preapnea spleen volume is elevated. Spleen volume was measured before and after a set of five apneas in 12 healthy adults (28 ± 5 yr, 3 females) before, during (at 30 and 150 min), and 20 min after temperate temperature (36 ± 1°C) HOWI. At each time point, spleen length, width, and thickness were measured via ultrasound, and spleen volume was calculated using the Pilström equation. Compared with pre-HOWI (276 ± 88 mL), spleen volume was elevated at 30 (353 ± 94 mL, P < 0.01) and 150 (322 ± 87 mL, P < 0.01) min of HOWI but returned to pre-HOWI volume at post-HOWI (281 ± 90 mL, P = 0.58). Spleen volume decreased from pre- to postapnea bouts at each time point (P < 0.01). The magnitude of reduction in spleen volume from pre- to postapneas was elevated at 30 min of HOWI (-69 ± 24 mL) compared with pre-HOWI (-52 ± 20 mL, P = 0.04) but did not differ from pre-HOWI at 150 min of HOWI (-54 ± 16 mL, P = 0.99) and post-HOWI (-50 ± 18 mL, P = 0.87). Thus, spleen volume is increased throughout 180 min of HOWI, and whereas apnea-induced spleen contraction is augmented after 30 min of HOWI, the magnitude of spleen contraction is unaffected by HOWI thereafter.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

P1041: IMPACT OF FEDRATINIB ON SPLEEN VOLUME AND MYELOFIBROSIS SYMPTOMS IN PATIENTS WITH SUBSTANTIAL SPLENOMEGALY: POST HOC ANALYSES FROM THE JAKARTA AND JAKARTA2 TRIALS

Background: In myelofibrosis (MF), splenomegaly is a marker of disease progression, and larger spleen size (SS) is correlated with poorer survival and debilitating symptoms. Fedratinib (FEDR) is an oral, selective Janus kinase 2 (JAK2) inhibitor approved as first-line (1L) treatment (Tx) of patients (pts) with MF and in pts previously treated with ruxolitinib (RUX). In the phase 3, placebo-controlled JAKARTA trial (NCT01437787) and the phase 2, single-arm JAKARTA2 trial (NCT01523171), pts experienced substantial improvements in spleen volume and MF symptoms after receiving 6 FEDR Tx cycles. Given the prognostic impact of splenomegaly, these analyses explore whether these clinical benefits were influenced by pre-Tx SS. Aims: Investigate the efficacy of FEDR 400 mg/d in JAKARTA and JAKARTA2, in pt subgroups defined by baseline (BL) SS. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS >5 cm from the left costal margin by palpation, platelets ≥50×109/L, and ECOG PS ≤2. These post hoc analyses included pts from both studies who were allocated to receive FEDR 400 mg/d (the approved dosage) in continuous 28-d Tx cycles. Pt subgroups were divided according to BL median SS (mSS) in each trial. Changes from BL in spleen volume and Myelofibrosis Symptom Assessment Form (MFSAF) total symptom score (TSS) were measured at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Eligible pts must have had spleen volume and/or TSS data at BL and EOC6. Results: Overall, 96 pts in JAKARTA and 97 pts in JAKARTA2 received FEDR 400 mg/d; mSS (range) at BL was 16 (5–40) cm and 18 (5–36) cm, respectively. In the JAKARTA <mSS and ≥mSS cohorts, median BL spleen volume was 1771 (316–3396) mL and 3329 (983–6430) mL, respectively, and median TSS was 13.0 (0.0–54.9) and 17.2 (0.4–57.0). In JAKARTA2, median BL spleen volume was 1937 (737–4305) mL and 4002 (1821–7815) mL for pts with <mSS and ≥mSS, respectively; BL TSS was 17.2 (0.7–48.0) and 23.6 (1.0–44.0). Overall, 75 (78%) pts in JAKARTA and 51 (53%) pts in JAKARTA2 had spleen volume data available at BL and EOC6; the <mSS and ≥mSS cohorts, comprised 37 and 38 pts, respectively, in JAKARTA, and 31 and 20 pts in JAKARTA2. Median spleen volume reduction (SVR) from BL was similar between the <mSS and ≥mSS cohorts in each trial, and 97% of pts with ≥mSS in both trials achieved some degree of SVR. In JAKARTA, median SVR at EOC6 was −38% (95% CI, −43 to −31) in the <mSS and −40% (95% CI, −40 to −28) in the ≥mSS cohort; in JAKARTA2, median SVR was −37 (95% CI, −43 to −30) in the <mSS and −38.5% (95% CI, −49 to −14) in the ≥mSS cohort. TSS data were available at BL and EOC6 for 71 (74%) pts in JAKARTA and 51 (53%) pts in JAKARTA2. Changes from BL in TSS at EOC6 were similar in the JAKARTA <mSS and ≥mSS cohorts, with median TSS reductions of −49% and −51%, respectively. Median TSS changes at EOC6 in JAKARTA2 were greater for pts with larger spleens, −36% and −49% in the <mSS and ≥mSS cohorts, respectively. Image:Summary/Conclusion: Pts who completed 6 Tx cycles with FEDR 400 mg/d, whether used as 1L MF Tx or after RUX Tx, experienced substantial improvements in spleen volume and MF symptom severity regardless of the extent of splenomegaly at BL.

P1061: INDIRECT TREATMENT COMPARISONS OF FEDRATINIB VERSUS NAVITOCLAX PLUS RUXOLITINIB: EFFECT ON SPLEEN VOLUME AND SYMPTOMS IN RUXOLITINIB-EXPOSED MYELOFIBROSIS PATIENTS

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm 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 (RUX), a JAK1/2 inhibitor, was the first therapy for intermediate- and high-risk MF approved in the United States; however, a high unmet need remains for alternative treatment options for patients who discontinue or are no longer responding to RUX. The efficacy and safety of fedratinib (FEDR), a JAK2 inhibitor approved by the US Food and Drug Administration in 2019, was investigated post RUX in the single-arm JAKARTA2 trial (NCT01523171). Clinical data from a similar population treated with navitoclax plus RUX (NAV+RUX) have been reported. The efficacy of FEDR relative to NAV+RUX in patients with MF previously treated with RUX has not been evaluated. Aims: To explore the comparative efficacy of FEDR versus NAV+RUX in patients with MF previously treated with RUX for the 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 FEDR was informed by JAKARTA2 patient-level data, and evidence for NAV+RUX was informed by known reported evidence from the REFINE study (NCT03222609). 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. MAICs used effective sample size (ESS) of the FEDR cohort as an indicator of the amount of overlap. Univariable and multivariable regression models were used to identify potential prognostic factors to adjust for in the ITCs. Additionally, all Dynamic International Prognostic Scoring System (DIPSS)-Plus criteria reported were considered. Results: A subgroup of 58 JAKARTA2 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 (N=34) was used in the analyses. Baseline mean platelet count was similar between subgroups. Across all analyses, results suggested FEDR consistently increased the odds/risk of a spleen response compared with NAV+RUX. The MAIC, matching on ECOG PS score, suggested that the odds of having an SVR for patients in the FEDR group was 2.19 times that of the NAV+RUX group (95% confidence interval [CI], 1.26 to 3.66), and the risk of having an SVR for patients in the FEDR group was 17.6% higher (95% CI, −2.1 to 37.0) (Figure). 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 FEDR group and 30% [6/20] in the NAV+RUX group). Image:Summary/Conclusion: In patients with MF previously treated with RUX, these analyses suggest treatment with FEDR was associated with a greater proportion of patients achieving a spleen response compared with NAV+RUX. Limited data were available for comparison of TSS.

P1069: RETROSPECTIVE COMPARISON OF PATIENT OUTCOMES ON PACRITINIB VERSUS RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS AND THROMBOCYTOPENIA

Background: Pacritinib is a JAK2/IRAK1 inhibitor for patients with myelofibrosis and thrombocytopenia. Unlike the JAK1/2 inhibitor ruxolitinib, which is used at lower doses in patients with thrombocytopenia, pacritinib has been studied at full dose regardless of platelet count. Aims: We retrospectively analyzed the phase 3 PERSIST-2 study, comparing pacritinib with ruxolitinib, with a focus on disease symptomatology. Methods: PERSIST-2 enrolled patients with platelet counts ≤100 x 109/L and randomized them 1:1:1 to pacritinib 200 mg twice daily (BID), pacritinib 400 mg once daily (QD), or best available therapy (BAT). This analysis focused on the 200-mg BID dose and patients who received ruxolitinib prior to week 24. Endpoints included the percentage of patients with ≥35% spleen volume reduction (SVR), ≥50% modified total symptom score (mTSS) reduction, and improvement in disease symptoms measured by Patient Global Impression of Change (PGIC). Safety analyses were based on all treated patients; efficacy analyses were based on the intention-to-treat population randomized at least 22 weeks prior to study end. The Fisher Exact test was used to describe differences in response. Logistic regression was used to adjust for differences in baseline characteristics. Results: Safety analysis included 106 patients on pacritinib and 44 on ruxolitinib; efficacy analysis included 74 on pacritinib and 32 on ruxolitinib (median daily dose of 10 mg). Baseline characteristics were similar between the groups, including median platelet count (55 vs 61 x 109/L) and percentage receiving RBC transfusion (46% vs 43%). The following differences in baseline characteristics were accounted for in multivariable modeling: percentage of patients with grade 3 fibrosis (58% vs 36%), primary myelofibrosis (77% vs 50%), ≥1% peripheral blasts (45% vs 61%), and prior JAK2 inhibitor (48% vs 73%). Patients treated with pacritinib vs ruxolitinib achieved higher rates of SVR (22% vs 3%, p=0.02) and numerically higher rates of mTSS response (35% vs 19%; p=0.11) at week 24 (Figure 1A). A greater percentage of patients on pacritinib reported “much” or “very much” improved symptoms (35% vs 16%, p=0.06; Figure 1A). Among ruxolitinib-treated patients with an available PGIC measure at week 24, 50% reported either no improvement or worsening symptoms, while 76% of pacritinib-treated patients reported improvement (Figure 1B). After adjusting for imbalances in baseline characteristics, there was no diminution of treatment effect on SVR or mTSS, and the hazard ratio for survival on pacritinib vs ruxolitinib was 0.46 [95% CI: 0.15-1.43]. Fatal adverse events occurred at slightly lower rates on pacritinib vs ruxolitinib (8% vs 11%). Bleeding occurred at similar rates on pacritinib and ruxolitinib (43% vs 41%). There were low rates of herpes zoster reactivation (n=0 vs 1), fungal skin infection (n=0 vs 1), pulmonary aspergillosis (n=1 vs 0), deep venous thrombosis (n=0 vs 1), and pulmonary embolism (n=1 vs 0) on pacritinib and ruxolitinib, respectively. Image:Summary/Conclusion: Pacritinib yielded higher response rates and a similar safety profile to lower-dose ruxolitinib in patients with myelofibrosis who have moderate or severe thrombocytopenia.

S197: NAVITOCLAX PLUS RUXOLITINIB IN JAK INHIBITOR-NAÏVE PATIENTS WITH MYELOFIBROSIS: PRELIMINARY SAFETY AND EFFICACY IN A MULTICENTER, OPEN-LABEL PHASE 2 STUDY

Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients with myelofibrosis (MF) that improves disease symptoms in approximately 40% of patients with limited impact on disease biology. Many patients lose response over time, highlighting an unmet need for novel therapies. Navitoclax is a first-in-class, oral, small molecule that binds with high affinity to BCL-XL and BCL-2, key pro-survival proteins in the apoptotic pathway, and has a synergistic effect when used in combination with JAK inhibitors to enhance malignant cell death in MF. This ongoing, open-label, multicenter, phase II trial (NCT03222609) is evaluating the efficacy and safety of navitoclax with or without ruxolitinib in patients with MF and previously published data suggest clinically meaningful activity of the combination in patients with prior ruxolitinib failure (Pemmaraju et al., ASH 2020). Here, we report results from patients who were JAK inhibitor-naïve and treated with navitoclax and ruxolitinib combination therapy. Aims: N/A Methods: Enrolled patients had primary or secondary MF with splenomegaly (DIPSS ≥ Intermediate-1) and did not receive prior therapy with JAK-2 or bromodomain and extraterminal motif (BET) inhibitors. Patients initiated navitoclax at 100 mg once per day (QD) or 200 mg QD if baseline platelet count was ≤150 × 109/L or >150 × 109/L, respectively. Ruxolitinib was orally administered twice daily at a starting dose based on baseline platelet count as per the local ruxolitinib label. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from baseline at week 24. SVR35 was assessed at weeks 12, 24, and once every 24 weeks thereafter. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), bone marrow fibrosis reduction, and anemia response (per International Working Group criteria). Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 patients received navitoclax plus ruxolitinib. The median duration of follow-up was 6.1 (range, 1.9 to 18.6) months. Twenty-eight (88%) patients received a navitoclax dose of 200 mg, and 4 (13%) received 100 mg OD. The median age was 69 years (range, 44 to 83), median spleen volume was 1889.08 cm3 (range, 645.6 to 7339.6), and 38% had at least 1 prior line of therapy. The median navitoclax and ruxolitinib exposures were 24.1 (range, 5.1 to 80.9) and 24.1 (5.1 to 80.9) weeks, respectively. Thirty-one (97%) patients experienced ≥1 AE, 25 (78%) had Grade ≥3 AEs, and 6 (19%) had serious AEs. The most frequent Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). Three (9%) and 2 (6%) patients experienced an AE that led to navitoclax and ruxolitinib discontinuation, respectively, and 2 (6%; 1 progressive disease, 1 cardiac disorder unrelated to navitoclax) AEs led to death ≤30 days after the last dose of navitoclax. SVR35 was achieved by 52% of evaluable patients at week 24 (SVR35 in DIPSS Intermediate-2, 50%; High-risk, 33%) and by 76% at any time on the study (Table). The median time to first SVR35 was 12.1 (range, 11 to 47) weeks. Image:Summary/Conclusion: The combination of navitoclax and ruxolitinib was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in patients without prior JAK-2 inhibitor exposure. SVR35, anemia, and bone marrow fibrosis improved over time.

P1051: A PHASE 2 STUDY OF IMG-7289 (BOMEDEMSTAT) IN PATIENTS WITH ADVANCED MYELOFIBROSIS

Background: Lysine-specific demethylase-1 (LSD1) is an activity critical for the self-renewal of malignant myeloid cells and maturation of megakaryocytes, cells central to the pathogenesis of MF. Bomedemstat is an orally active LSD1 inhibitor that in mouse models ameliorated the hallmarks of MPNs and improved survival (Kleppe et al. 2015; Jutzi et al. 2018). Aims: IMG-7289-CTP-102 is an ongoing, global, open-label Phase 2 study evaluating bomedemstat dosed QD in MF patients (NCT03136185). Key eligibility criteria include patients intolerant, refractory, resistant, or inadequately controlled by approved therapy, and platelet count ≥100 x 109/L. Key objectives are safety and reduction of spleen volume (SVR) by MRI/CT and total symptoms scores (TSS) using the MPN-SAF instrument. Methods: Serial bone marrow (BM) biopsies and imaging studies are read centrally. 261 genes are serially sequenced to quantify changes in the allelic frequencies of mutations (MAF) and identify new mutations. The starting dose is 0.6 mg/kg/d titrating, as needed, to a platelet count of 50-75x109/L. Results: At 89 patients, the study is now fully enrolled: 46% primary MF, 33% post-essential thrombocythaemia-MF, 21% post-polycythaemia vera-MF. Median age is 68 (35-88) with 52% males. Prior treatment with ruxolitinib was reported in 83% (74/89); 46% had also received at least 1 additional treatment. 30% of patients (27/89) had received ≥1 RBC transfusion prior to dosing. By IPSS, 53% were high-risk, 40% int.-2, and 7% int.-1. At screening (N=103), sequencing to a mean depth of >1000 bp, JAK2 was mutated in 69%, CALR in 21%, MPL in 6%; 59% had ≥2 mutations of which 71% were high-molecular risk mutations in ASXL1, IDH1/2, EZH2, U2AF1, TP53 and/or SRSF2. At data cutoff (3 Feb 2022), the median duration of treatment is 28 weeks (2-131). Of patients for whom TSS data is available at 24 weeks in those with baseline values ≥20, 72% (18/25) had a reduction in TSS; 24% (6/25) reported a ≥50% reduction. Of patients evaluable for SVR (N=50), 64% had a reduction in spleen volume from baseline; in 28%, SVR was ≥20%. Of evaluable patients (N=41), 90% had stable (∆ <±1.0 g/dL) or improved (≥1.0 g/dL) hemoglobin. Of patients with BM fibrosis scoring post-baseline (N=52), 31% improved by 1 grade and 50% were stable. CCL5 and S100A8/A9 cytokines were elevated at baseline in 50% (16/32) and 78%, respectively; at Day 84, 81% and 68%, respectively, showed reductions of at least 10% and of those, 100% (CCL5) and 47% (S100A8/A9) normalized. In follow-up sequencing at around Week 24, of 60 mutant alleles in 32 patients, the mean MAF fell by 39% in 48%. JAK2 MAFs fell by 31% [SD 5%] in 46% (N=24); ASXL1 MAFs fell 40% in 71%. Clones with JAK2 and/or ASXL1 mutations were most affected. No new mutations have been identified and no patient has transformed to AML. The most common non-hematologic AEs reported by patients was dysgeusia in 36% (32/90) and diarrhoea in 34% (31/90). All dysgeusia events were grade 1/2 and 1 led to treatment discontinuation. Of 14 related SAEs, 4 were Grade 2, 9 Grade 3 and 1 Grade 4 (thrombocytopenia). Twenty-nine patients remain on bomedemstat. Early terminations due to AEs occurred in 18 (20%) patients (9 related to bomedemstat), and 13 discontinued for other reasons. There have been no safety signals, DLTs, or deaths related to drug. Summary/Conclusion: In patients with advanced MF, bomedemstat alone had an acceptable tolerability profile, relieved symptoms, reduced spleen volume and mutation burden while improving fibrosis and anemia without safety signals.

P1037: DOES EARLY INTERVENTION IN MYELOFIBROSIS IMPACT OUTCOMES? A POOLED ANALYSIS OF THE COMFORT I AND II STUDIES

Background: Myelofibrosis (MF) is characterized by cytopenias, splenomegaly, burdensome symptoms, and poor overall survival (OS). Few studies have investigated if earlier intervention with targeted MF therapies affects response and OS. In a pooled analysis of the COMFORT I and II trials of ruxolitinib (RUX), patients (pts) who received RUX at randomization or after crossover from placebo (PBO) or best available therapy (BAT) had improved OS. Aims: To assess the association of MF disease duration before treatment with disease outcomes using pooled COMFORT data Methods: COMFORT I (NCT00952289) and COMFORT II (NCT00934544) were phase 3 trials of RUX vs PBO or BAT, respectively, in pts with intermediate-2 or high-risk MF who provided written informed consent. In this post hoc analysis, data from RUX-treated pts in both studies were combined (RUX group), and data from the PBO/BAT arms were pooled (control group). Pt subgroups were defined based on disease duration before treatment initiation (≤12 mo or >12 mo from diagnosis). Assessments included frequency of thrombocytopenia (platelets [PLT] <100 Gi/L or PLT transfusion) and anemia (hemoglobin <100 g/L or red blood cell transfusion) events, spleen volume response (SVR; spleen volume reduction ≥35% from baseline [SVR35]), symptom response (MF-Symptom Assessment Form total symptom score [TSS] reduction ≥50% from baseline [TSS50]; available in COMFORT I only), and OS. OS was assessed using the Kaplan-Meier method; pts randomized to PBO/BAT were included in the PBO/BAT group regardless of crossover. A multivariable analysis (MVA) using a logistic regression model was used to examine factors associated with SVR. Results: There were 525 pts in the analysis (RUX: ≤12 mo, n=84; >12 mo, n=216; PBO/BAT: ≤12 mo, n=66; >12 mo, n=159). Median age across groups ranged from 65 to 70 y. Baseline clinical characteristics were generally similar across subgroups, but pts with shorter vs longer disease duration were slightly younger with higher blood counts. Among pts who received RUX, fewer thrombocytopenia events were observed among those treated earlier (≤12 mo vs >12 mo), with differences seen as early as Wk 4–8 on treatment (18% vs 33%) and sustained over time; a similar trend was observed for anemia events (Wk 4–8, 59% vs 72%). The proportion of pts with SVR35 was greater among those who initiated RUX earlier (≤12 mo vs >12 mo) at Wk 24 (48% vs 33%; P=0.0610) and 48 (44% vs 27%; P=0.0149; Table). A numerically greater proportion of pts who initiated RUX at ≤12 mo vs >12 mo achieved TSS50 at Wk 24 (56% vs 40%; P=0.0829; Table). OS at Wk 240 was improved among pts who initiated RUX at ≤12 mo vs >12 mo (63% [95% CI, 51%–73%] vs 57% [95% CI, 49%–64%]; P=0.0430; Table). Comparatively, OS was longer with RUX vs PBO/BAT regardless of disease duration. A sensitivity analysis using a 24-mo cutoff was also conducted but yielded weaker associations between disease duration and SVR, TSS, and OS. In the MVA, a significantly greater binary SVR was seen among pts with shorter (≤12 mo) vs longer (>12 mo) MF disease duration (odds ratio, 2.1; P=0.022). Image:Summary/Conclusion: These findings suggest that earlier RUX initiation in MF may improve clinical outcomes, including cytopenias, SVR, symptom burden, and OS. While “watch and wait” remains a common treatment approach for newly diagnosed patients, these data suggest that pts with MF may benefit from earlier intervention. Additional studies to further evaluate the impact of early intervention are warranted.

S192: SINGLE-CELL RNA PROFILING OF MYELOFIBROSIS PATIENTS REVEALS PELABRESIB-INDUCED DECREASE OF MEGAKARYOCYTIC PROGENITORS AND NORMALIZATION OF CD4+ T CELLS IN PERIPHERAL BLOOD

Background: Abnormal differentiation of the megakaryocytic (MK) lineage in conjunction with overproduction of proinflammatory cytokines (Ck), resulting in bone marrow fibrosis, anemia, extramedullary hematopoiesis and often hepatosplenomegaly, are the main biological and clinical characteristics of myelofibrosis (MF). Bromodomain and extraterminal domain (BET) proteins play a key role in the regulation of neoplastic myeloproliferation and proinflammatory Ck production. Pelabresib (CPI-0610) is a potent, selective BET inhibitor under investigation in MF patients (pts) as monotherapy and in combination with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) in the ongoing MANIFEST Phase 2 study (NCT02158858). Arm 1: pelabresib as monotherapy in RUX-intolerant, ineligible or refractory MF pts; Arm 2: pelabresib in combination with RUX as an ‘add-on’ in MF pts with suboptimal response to RUX; Arm 3: pelabresib combination therapy with RUX in JAKi-naïve MF pts. Pelabresib as monotherapy and in combination with RUX improved spleen volume reduction, symptoms and hemoglobin levels (Talpaz M, ASH 2020). The effects of pelabresib on hematopoietic stem/progenitor cells (HSPCs) and immune cell populations in MF pts are presented here. Aims: We aimed to characterize the cellular composition and transcriptional alterations occurring in peripheral blood (PB) obtained from MF pts enrolled in the MANIFEST trial. Methods: We performed single-cell RNA sequencing on 234,904 CD34+ HSPCs and 135,970 CD34- mature PB cells (Figure). Cells were obtained from a random pool of 20 pts (Arm 1 n=5, Arm 2 n=8, Arm 3 n=7), which included a baseline sample (BL) and samples collected during treatment (range: C3 through C12) for each pt. Mobilized PB cells from healthy donors (HD) were used as a control (n=11). Results: Analysis of CD34+ HSPCs at BL demonstrated a statistically significant increase of MK, neutrophilic and erythroid progenitors in MF pts compared with HDs and decreased numbers of myeloid and B cell lineage progenitors. Pelabresib as monotherapy and in combination with RUX led to a significant reduction of MK-, neutrophilic and erythroid progenitors as compared with BL in all pts analyzed. Analysis of CD34- cells from MF pts identified a significantly lower proportion of CD4+ T cells and increased numbers of erythroid cells at BL compared with HD. Individual pts also exhibited reduction in natural killer cells and CD16+ monocytes as well as elevated MK lineage cells. Pelabresib as monotherapy and in combination with RUX increased the proportion of CD4+ T cells, and more importantly, reduced MK lineage cells compared with BL in both treatment-naïve and RUX relapsed/refractory (r/r) pts. In MF pts at BL, a larger spleen volume was observed in pts with lower numbers of CD4+ T cells and increased numbers of MK- and myeloid CSF3R+ cells. Updated results of the cell composition analysis and transcriptional reprogramming during pelabresib treatment, as well as correlation with effects on cytokine plasma levels and clinical efficacy data, will be presented. Image:Summary/Conclusion: The single-cell profiling of a subset of MF pts enrolled in the MANIFEST study suggests that pelabresib alone and in combination with RUX induces an improvement of the myeloid-lymphoid imbalance in both JAKi-naïve and r/r MF pts. The observed effects of pelabresib on HSPCs from MF pts confirm the ex vivo activity on erythroid and MK differentiation of stem cells (Keller P, EHA 2021; Verstovsek S, ASH 2021) and implies a potential disease-modifying effect warranting further investigation.

Abstract CT541: Efficacy and safety of parsaclisib-ruxolitinib combination therapy in myelofibrosis patients (Pts) with low vs higher baseline platelet count (PC): A subgroup analysis of data from a phase 2 study

Abstract Background: Myelofibrosis (MF) pts often exhibit suboptimal response to chronic ruxolitinib therapy, possibly due to persistent PI3K pathway activation. In the ongoing phase 2 INCB 50465-201 trial (NCT02718300), add on parsaclisib (potent, highly selective PI3Kδ inhibitor) is showing preliminary efficacy in MF pts with suboptimal ruxolitinib response. JAK inhibitors (eg, ruxolitinib), are associated with thrombocytopenia; therefore, pts with low PC are commonly more difficult to treat. We present a subgroup analysis of efficacy and safety data from INCB 50465-201 by baseline PC. Methods: Eligible adults had primary/secondary MF with suboptimal response (palpable spleen &amp;gt;10 cm below left subcostal margin [LSM]; or palpable spleen 5-10 cm below LSM and active symptoms) after ≥6 months of ruxolitinib monotherapy (5-25 mg BID; stable dose ≥8 wks). Pts remained on their last stable ruxolitinib dose and received add on parsaclisib (10 or 20 mg QD for 8 wks; same dose QW thereafter) or parsaclisib (5 or 20 mg QD for 8 wks; 5 mg QD thereafter). For this analysis, spleen volume (SV), total symptom score (TSS) assessed by Myelofibrosis-Symptoms Assessment Form (MFSAF) v3.0 daily diary, and safety, were evaluated by baseline PC (low PC, 50-&amp;lt;100 × 109/L; higher PC, ≥100 × 109/L). Results: At data cutoff (8/27/2020), 67 pts were enrolled (low PC, n=21; higher PC, n=46; median age 68 y). For low vs higher PC, median prior duration of ruxolitinib use was 34.7 vs 14.9 months; baseline symptoms were worse for low PC vs higher PC (median [range] MFSAF-TSS, 21.4 [0.6-47] vs 10 [0-43]). For low vs higher PC, 9/18 (50.0%) vs 15/38 (39.4%) pts had SV reduction (SVR) ≥10% at wk 12; percentages of pts with SVR ≥10% were similar at wk 24 (6/17 [35.2%] vs 13/35 [37.1%]); 0 vs 1 pt had SVR ≥35% at wk 12; 2 vs 1 pt had SVR ≥35% at wk 24. Of pts with ≥10% SVR at wk 24, 4/6 with low PC and 9/13 with higher PC were on all daily dosing regimens. For low vs higher PC, median (range) percentage change in MFSAF-TSS was −20.5 (−56.6 to +17.1) vs −22.2 (−100 to +500) at wk 12; −26.1 (−54.7 to +2.4) vs −23.1 (−91.3 to +222.5) at wk 24. In both subgroups, nonhematologic treatment-emergent adverse events (TEAEs) were mostly grade 1/2. Most common (≥20%) TEAEs were dyspnea (33%), falls (33%), peripheral edema (29%), and nasal congestion (24%) for low PC; diarrhea (28%), nausea (24%), abdominal pain (24%), cough (20%), and fatigue (20%) for higher PC. For low vs higher PC, 9/21 (43%) vs 3/46 (7%) pts had parsaclisib dose interruption due to thrombocytopenia; 1 pt with low PC had ruxolitinib interruption due to thrombocytopenia. Conclusion: Add-on parsaclisib showed efficacy in pts from both low and higher baseline PC groups. Given the acceptable safety profile and efficacy of add-on parsaclasib, MF pts with both low and higher PC may be able to benefit from parsaclisib-ruxolitinib combination therapy. Citation Format: Abdulraheem Yacoub, Uma Borate, Raajit Rampal, Haris Ali, Eunice Wang, Aaron Gerds, Gabriela Hobbs, Marina Kremyanskaya, Elliott Winton, Casey O’Connell, Swati Goel, Stephen Oh, Gary Schiller, Albert Assad, Sue Erickson-Viitanen, Feng Zhou, Naval Daver. Efficacy and safety of parsaclisib-ruxolitinib combination therapy in myelofibrosis patients (Pts) with low vs higher baseline platelet count (PC): A subgroup analysis of data from a phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT541.