Dose Of Ruxolitinib Research Articles

Molecular Characterization of Response/Loss-of-Response to Ruxolitinib in Patients with Myelofibrosis

Background. Ruxolitinib (RUX) is standard of care for most patients (pts) with primary (PMF) and secondary (sMF) myelofibrosis. However, about half of responders lose benefits at 3-5y, associated with clonal progression, and have a dismal outcome thereafter. The molecular bases for response/loss of response to RUX have not been clarified yet. Aim. To explore genetic variables associated with response/loss of response to RUX in MF pts. Patients and Methods. All consecutive pts with WHO2016/IWG-MRT diagnosis of PMF/sMF, treated with RUX at our Center, were included. To the purpose of the study, response was stringently defined as achievement of spleen lenght reduction from LCM of >50% at any time point; non-responders (NR) were all the others. Loss-of-response was defined as the reappearance of >5cm splenomegaly, if the nadir under RUX was <5cm, and >50% increase if the nadir was >5cm. A custom NGS panel including complete CDS of 552 genes, selected for putative involvement in RUX response (belonging to JAK/STAT, MAPK, ERK pathways, inflammatory reactions, apoptosis) or associated with myeloid neoplasms, was designed. For RNAseq analysis, we used the R package DOSE and performed Over Representation Analysis (ORA) to identify over-represented biological functions/processes. Results. Baseline characteristics. A total of 171 pts were included, 52.1% PMF (15.8% prePMF, 36.5% overtPMF) and 82 sMF (46.9%; 29.2% PPV-, 17.7% PET-MF). DIPSS at RUX start was Int-1: 43.8%, Int-2: 39.8%, high: 16.4%. Median FU from RUX start was 3.5y (0.8-17.3y), median time on RUX was 2.4y (0.2-12y). Sixty-eight pts (39.8%) died, 39 (22.8%) while on RUX. AML developed in 13 pts (7.6%), 10 of which while on RUX. OS from RUX start was 5.8y (4.4-7.3y). JAK2V617F mut in 72.3%, MPLW515 7.6%, CALR 19.3% (12.8% Type1/like, 6.4% Type2/like), TN 2.3%. 68 pts (39.8%) were High Molecular Risk (HMR; ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1). Response to RUX. 93/171 pts (54.4%) were NR. Of the 78 responders (45.6%), 45 (57.7%) lost response (hence, R/L) after a median of 22.7 mo from RUX start, and 33 pts (43.3%) maintained response (hence, R/M) at last FU. Response outcome was influenced by RUX dose: 75.2% of NR and 64.4% of R/L had received <20 mg/die, compared with 63.6% of R/M who had received >30 mg/die. RUX stop (any reason) occurred in 24.2% of R/M, 62.2% R/L, 55% of NR (P=0.02). Baseline molecular predictors. Baseline molecular variables found to correlate with response/loss of response included: (i) HMR status, found in 51.1% R/L vs 24.2% R/M and 40.2% NR (P=0.04); (ii) >1 RAS pathway mutated gene (CBL, NRAS, KRAS, PTPN11), found in 30% NR, 5% R/L and 13.8% R/M (P=0.016); (iii) isolated CBL (n=8, 10.5%; P=0.02) and U2AF1 (n=5,6.7%; P=0.05) mutation, found exclusively in NR pts. Nor type nor variant allele frequency (VAF) of driver mutations impacted on response/loss of response. Serial mutational analysis. Among JAK2V617F mut pts, a partial molecular response (PMR, >50% VAF reduction; IWG-MRT criteria) was achieved by 18.6% of pts, after a median of 1.7y (1-5y). Median VAF reduction under RUX of pts with PMR was 71.3% (51-100%). A PMR occurred in 44.4% of R/M vs 14.8% of (R/L+NR), P=0.03. In 14 responder pts who were on stable dose of RUX since >1y and later became R/L, target NGS sequencing for 552 genes was performed using granulocyte DNA, collected at baseline (T0), at the time (+6mo) of response adjudication (T1) and at R/L (T2). A total of 91 mutated genes were acquired at T2 (mean gene number/pt, 2.5, range 1.0-16). Of these, 22 genes belonged to categories of "transcription regulator", 19 "cytokine mediator signaling", 14 "spliceasome/RNA processing", 11 "EGFR/TKI resistance" and 8 "chromatin regulators" (GO, KEGG, Reactome, Wikipathway). Serial, single cell analysis to interpret clonal hierarchy is ongoing, results will be presented at meeting. Pairwise RNAseq was performed in 4 pts with purified PB CD34+ cells collected at T1 and T2. By using a stringent FDR<0.1 value, enriched transcripts belonged to "RHO-GTPase" (n=88), "spliceasome" (n=40), "Type-2 interferon responses" (n=20), "IL12 stimulated gene and proteins" (n=14) categories. Conclusions. This study adds to the understanding of molecular mechanisms of response/loss of response to RUX by identifying baseline predictors and highlighting a set of involved genes/pathways, that remain to be validated.

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

Siremadlin, a Human Double Minute-2 (HDM2) Inhibitor, Added to Ruxolitinib after Suboptimal Response to Ruxolitinib Alone in Patients with Myelofibrosis: Results from Part 1 of the Phase 1/2 Adore Study

Introduction Ruxolitinib (RUX), a first-in-class Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for myelofibrosis (MF). However, ~50% patients (pts) discontinue RUX after ~3 years, including a third due to lack/loss of spleen response. Targeting additional pathogenic signaling pathways may provide superior disease control and potentially address underlying causes of disease. JAK2 mutations in MF induce expression of HDM2, which degrades tumor suppressor protein p53. Siremadlin (SIR), a potent and selective HDM2 inhibitor, restores p53-mediated apoptosis, which may promote clonal regression and spleen volume reduction (SVR). ADORE (NCT04097821) is a three-part phase 1/2 platform study assessing RUX in combination with 5 novel compounds, including SIR. We report results from the Part 1 (phase 1b) dose escalation cohort of SIR added to existing stable dose of RUX after suboptimal response to RUX alone. Methods Eligible pts had a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, splenomegaly (a palpable spleen ≥5 cm from the left costal margin or spleen volume ≥450 cm3 by MRI/CT scan), hemoglobin (Hb) level <11 g/dL (earlier protocol: <10 g/dL), and platelet count ≥75 × 109/L. Pts must have received RUX for ≥12 weeks (wks) (earlier protocol: ≥24 wks) and at a stable dose for ≥4 wks (earlier protocol: ≥8 wks) prior to first combination dose. Part 1 objective was to characterize the safety, tolerability, and recommended phase 2 dose (RP2D) of SIR added to RUX. Primary endpoint was incidence and severity of dose-limiting toxicities (DLT) within first 2 cycles; secondary objectives included characterization of the pharmacokinetic (PK) profile. Preliminary efficacy (change in spleen volume by MRI/CT scan from baseline [BL]), total symptom score (TSS) by MFSAF v4.0 and biomarkers were also explored. Pts were allocated to add SIR 20mg, 30mg or 40mg (orally once daily; days 1-5/28-day cycle) to their stable RUX dose (5-25mg twice daily). Adverse events (AEs) were coded by MedDRA and graded by CTCAE v5.0. Results In Part 1 SIR 20mg, 30mg and 40mg cohorts, 1/7, 9/10 and 1/6 pts were ongoing at data cut-off (April 13, 2022) respectively. The number of pts with DLTs after 2 cycles per number of evaluable pts was 0/6 at 20mg, 1/7 at 30mg (grade [G] 4 neutropenia and G4 thrombocytopenia in same pt), and 2/5 at 40mg (G3 and G4 thrombocytopenia). The most common AEs were gastrointestinal (GI) and hematologic (Table). RP2D was SIR 30mg/day. At 30mg, 5 pts experienced SIR-related GI toxicity; all events were G≤2; all lasted ≤4 days except for 1 case controlled with medication; 2 pts required concomitant medication for nausea, however, none discontinued treatment due to GI AEs. The most common hematologic AEs at 30mg were anemia, neutropenia, and thrombocytopenia. Two pts discontinued SIR 30mg due to G3 neutropenia and thrombocytopenia (for 1 pt) and G3 neutropenia (for 1 pt). At 30mg, 4/10 pts had completed a spleen volume assessment at 24 wks at time of data cut-off and all achieved SVR ≥35% from BL. At 20mg, 1/7 pts had SVR ≥35% at 24 wks. At 40mg, 3 pts discontinued prior to or did not complete spleen volume assessment at wk 24, limiting the availability of efficacy data (Figure). Symptom burden was low at BL across cohorts and subsequent TSS changes were highly variable between pts. SIR exposure increased with dose, with no relevant PK interactions between RUX and SIR observed. SIR increased growth/differentiation factor-15 (GDF15) expression, indicating target TP53 engagement. All pts were TP53 wildtype at BL. At data cut-off, SIR treatment resulted in the emergence of TP53 mutant clones in 1/7 pts at 20mg, 0/10 pts at 30mg and 1/6 pts at 40mg, at very low variant allele frequency (0.02-0.06) with unknown clinical significance. At 24 wks, 4/7 SIR-treated pts with available data had a decrease in JAK2 V617F mutational burden from BL (range 1.85-20.0%). Conclusions The RP2D of SIR is established as 30mg orally once daily on days 1-5/28-day cycle when added to the existing stable dose of RUX in pts with suboptimal response to prior RUX treatment. The addition of SIR 30mg was well tolerated, with low-G short-duration GI toxicity in contrast to an expected HDM2 inhibitor class effect. Other AEs were consistent with known RUX safety profile. Good tolerability at 30mg allowed pts to remain on SIR + RUX and to achieve robust spleen volume responses at 24 wks. The study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Add-on Parsaclisib to Ruxolitinib Therapy in Myelofibrosis Patients With Suboptimal Response to Ruxolitinib: Final Results From a Phase 2 Study

Background: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor and is effective in patients (pts) with myelofibrosis (MF). However, suboptimal or declining responses to RUX occur in a subset of pts, possibly due to persistent PI3K pathway activation with chronic JAK inhibitor therapy. Parsaclisib is a potent and highly selective next-generation PI3Kδ inhibitor. We conducted a phase 2 study (NCT02718300) evaluating add-on parsaclisib to stable doses of RUX, for pts with MF who experienced a suboptimal response to RUX (Yacoub A. HemaSphere 2021;5 Suppl 2:512). Here we report efficacy and safety results from the completed study. Methods: Eligible pts had primary or post-essential thrombocythemia/post-polycythemia vera MF with suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM], or palpable splenomegaly 5-10 cm below LSM and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 each using the Screening Symptom Form) after ≥6 months of RUX (5-25 mg twice daily; RUX stable dose, ≥8 wks). Pts remained on their stable RUX dose and were randomized to receive add-on parsaclisib 10 mg or 20 mg once daily (QD) for 8 wks and the same dose once weekly (QW) thereafter (QD/QW group), or parsaclisib 5 mg or 20 mg QD for 8 wks and 5 mg QD thereafter (all QD group) (Figure). Primary efficacy endpoint was change in spleen volume (SV) from baseline to wk 12 by MRI/CT scan. Key secondary endpoints included change in SV to wk 24, change in total symptom score (MFSAF-TSS, MPN-SAF-TSS), and safety. Results: Overall, 32 pts received parsaclisib QD/QW and 42 pts received parsaclisib all QD. Baseline median age was 68.0 (range 41.0-89.0) years and 47.3% of pts were male. The study has been completed. Median treatment duration was 336.5 days; median average daily dose was 5.0 mg/day for parsaclisib and 29.8 mg/day for RUX. Among all pts, 16 (21.6%) were rolled over to continue therapy in an open-label parsaclisib study after ending treatment in the present study. Other common reasons for pts discontinuing treatment were adverse events (13 [17.6%]) and progressive disease (10 [13.5%]); remainder discontinued for physician decision, pt decision, or "Other." Baseline median SV (cm3) was 2414.5 in QD/QW (n=29) and 1877.5 in QD (n=37); median MFSAF-TSS was 10.8 (n=28) and 16.3 (n=32) and median MPN-SAF-TSS was 25.5 (n=28) and 30.0 (n=37), respectively. Median percentage change in SV at wk 12 was −1.6 (n=28) in QD/QW and −15.4 (n=37) in QD, and at wk 24 was −2.5 (n=20) and −19.3 (n=29), respectively. Median percentage change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW and −32.8 (n=24) in QD, and at wk 24 was −10.0 (n=16) and −44.4 (n=18), respectively. Median percentage change in MPN-SAF-TSS at wk 12 was −19.2 (n=20) in QD/QW and −39.8 (n=30) in QD, and at wk 24 was −43.3 (n=15) and −60.8 (n=26), respectively. Responder analysis for these 3 efficacy variables is shown in the Table. Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. Grade 3/4 nonhematologic TEAEs occurring in >1 pt overall were pneumonia (n=5; 3 QD/QW, 2 QD), fatigue, hypoxia (each n=2; each 1 QD/QW, 1 QD), dyspnea (n=2, all QD), fall, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hypocalcemia (each n=2; all QD/QW). New-onset grade 3 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 11/42 pts (26.2%) in QD; grade 4 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 3/42 pts (7.1%) in QD. TEAEs of special interest included grade ≥3 ALT and AST (each n=2; all QD/QW), grade ≥2 diarrhea (n=4) and rash (n=1) (all QD/QW), and any-grade herpes simplex (n= 4; 1 QD/QW, 3 QD) and VZV infection (n= 3; 1 QD/QW, 2, QD). No colitis was reported. TEAEs led to parsaclisib interruption in 16/32 pts in QD/QW and 22/42 pts in QD, and RUX interruption in 5/32 and 8/42 pts, respectively. TEAEs led to parsaclisib discontinuation in 5/32 pts in QD/QW and 4/42 pts in QD, and RUX discontinuation in 2/32 and 2/42 pts, respectively. Conclusion: Final results from the phase 2 study demonstrate improvement in symptoms and SV with add-on parsaclisib in patients with MF having a suboptimal response to ruxolitinib. All daily dosing regimens were more efficacious than daily/weekly dosing. Combination therapy was associated with limited grade 3/4 AEs and TEAE-related discontinuations. Phase 3 studies using 5 mg QD parsaclisib together with ruxolitinib in naive MF patients and ruxolitinib-experienced patients are in progress. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II Study of a JAK1/2 Inhibitor Ruxolitinib for Systemic Chronic Active Epstein-Barr Virus Disease: An Investigator-Initiated Trial

Background: Systemic chronic active Epstein-Barr virus disease (sCAEBV) is a rare EBV-positive T- or NK-lymphoproliferative disease. Although the only curative treatment for sCAEBV available now is allogeneic hematopoietic stem cell transplantation (allo-HSCT), the presence of disease activity, persistent inflammation, at the time of allo-HSCT is associated with poor outcomes (Am J Hem.2022, 97, p780). STAT3 is constitutively activated contributing to cytokine production and cell survival of EBV-infected cells in sCAEBV (Oncotarget. 2019, 9, p31077). Thus, STAT3 inhibition by ruxolitinib, a JAK1/2 inhibitor, may be effective against disease activity of sCAEBV. Methods: We conducted an investigator-initiated trial of open-label, phase 2, prospective and multicenter to assess the efficacy and safety of ruxolitinib in sCAEBV patients with disease activity. The diagnostic criteria were as follows: elevated EBV-DNA load in the peripheral blood (PB) (>102.5 copies/µg DNA); EBV infected T or NK cells detected in affected tissues or PB; systemic inflammatory symptoms persisting for more than three months; exclusion of other possible diagnoses, such as immune deficiencies, autoimmune diseases, or lymphoma (Blood adv. 2021, 4, p2918). sCAEBV patients ≥13 y.o. with fever (≥ 37.5 ºC), and/or liver dysfunction (ALT ≥ 2.0 × ULN) were enrolled. Anti-VCA-IgM-positive patients were excluded. The initiation dose of ruxolitinib was 5-20 mg twice a day determined by the platelet count in PB. The treatment effects were classified as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). CR was defined as the disappearance of all the elements of disease activity such as fever, liver dysfunction, uveitis, progressive skin lesions, and vasculitis. PR was defined as the disappearance of at least one of the elements listed above. PD was defined as the conversion to active disease, exacerbation of active disease, or the development of overt T- or NK-cell lymphoma. SD was defined as presenting no progression. Ruxolitinib was administered for eight weeks. If CR was observed and allo-HSCT was scheduled, ruxolitinib was terminated early even if these events had occurred within less than eight weeks after initiating investigational drug administration. The primary endpoint of efficacy assessments was CR rate at eight weeks after the initiation of drug administration or at the time of early termination. Safety was assessed based on the frequency of adverse events defined by Common Terminology Criteria for Adverse Events, version 4.0. Results: Nine patients were enrolled between January 2019 and August 2021; five males and four females aged 13-64 y.o.; median age of 40 y.o. The types of EBV-infected cells were as follows: four were CD4, one was CD8, and four were CD56. Seven patients completed the study. Five among them received ruxolitinib for eight weeks and were treated as outpatients. Two patients fulfilled the criteria of early termination and each was treated for 35 and 12 days. The responses are shown in the figure. CR rate and OR rate after eight weeks or at early termination, the primary and the secondary endpoints were 28.6% (2/7) and 42.9% (3/7), respectively. No one showed progressive disease. One patient developed a grade 4 adverse event of oral bleeding during the treatment and resulted in discontinuing the administration of ruxolitinib on day 13. Seven patients received allo-HSCT. Five patients achieved undetectable level of EBV-DNA PB after allo-HSCT. Conclusion: The results indicate that ruxolitinib has demonstrated encouraging effects and is a potent therapeutic reagent against sCAEBV with active disease. Further analysis shall complete its assessment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combination Therapy with Ruxolitinib and Interferon in Newly Diagnosed Patients with Polycythemia Vera

Background: In the COMBI-I trial, we have shown that the combination treatment of Interferon-alpha-2a (IFN) and ruxolitinib is safe and efficacious in patients with polycythemia vera (PV) and myelofibrosis, who were mostly intolerant or refractory to IFN monotherapy. Interferon-alpha2 (IFN) has been used successfully for decades in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. However, 20-30% of patients are intolerant or show limited response to IFN treatment. Ruxolitinib is an anti-inflammatory agent and is used as first-line treatment in patients with myelofibrosis as well as second-line treatment in patients with PV. Combination therapy with the two agents may be more efficacious than monotherapy. Several reports suggest that after achieving a deep hematological and molecular response, treatment pause for several months to years is safe after IFN treatment. Therefore, an initial high-intensity regimen may help to control the disease allowing for treatment pause or low-dose IFN monotherapy. Herein, we report preliminary safety and efficacy data from the COMBI-II trial in patients with newly diagnosed PV. Aims: To evaluate the safety and efficacy of combination therapy with IFN and ruxolitinib in newly diagnosed patients with PV. Methods: A preplanned interim analysis after at least one year of treatment. Twenty-five patients with newly diagnosed PV were included. They were pretreated according to normal clinical standard with phlebotomies and, if high risk, hydroxyurea before inclusion and initiation of combination treatment. Hydroxyurea was withheld 1 week before initiation of treatment. Patients with severe kidney-, liver-, or heart disease were excluded. Initial therapy was IFN (Pegasys®) 45 μg sc/week and ruxolitinib (Jakavi®) 10 mg BID. The study duration was planned to be two years. Safety was assessed by registering all adverse events graded according to the CTCAE V 5.0. Efficacy was evaluated using the 2013 ELN and IWG-MRT response criteria. The JAK2V617F allele burden was measured using high-sensitivity real-time qPCR on whole blood with a lower detection limit of below 0.1%. Histological response, QoL data, and bone marrow MRI results will be presented in the final report. Results: Twenty-five patients with PV were included in 2019-2021. They had a median age of 70 years; 14 were females and 11 were males. Of the 25 patients, 19 patients were high-risk and 6 were low-risk; 5 patients had previous thrombosis. The median time from accepted referral to initiation of treatment was 67 days. The median follow-up time was 21 months. At time of data evaluation, 13 patients had completed 24 months, while 24 patients had completed 12 months of treatment. One patient was withdrawn from the study early due to the development of myelofibrosis 10 months after beginning treatment. One patient was diagnosed with follicular lymphoma 9 months after initiation of treatment. One patient had an acute myocardial infarction. No other thromboembolic events occurred. No grade 3-4 infections were observed. At follow-up, 19 patients were still receiving combination therapy. One patient was receiving concomitant hydroxyurea; 1 ruxolitinib monotherapy; 1 IFN monotherapy; 1 combination of hydroxyurea and IFN; and 1 hydroxyurea monotherapy. Grade 1-2 anemia was frequent and managed with dose reductions. The median doses of ruxolitinib and IFN at follow-up were 5 mg BID and 45 μg sc/2.week, respectively. High rates of complete hematological response were observed after 1 month of treatment (Figure 1). Three patients required phlebotomy after the first 2 weeks of treatment. The JAK2V617F allele burden was significantly reduced 3 months after the start of treatment, and continued to decline from a median of 47% (95%CI 35-59) at baseline to 6% (95%CI 3-12) after 24 months (figure 2);4 patients had a JAK2V617F allele burden < 1%, and 7 patients had a JAK2V617F allele burden below 5% at the latest measurement. No significant difference in JAK2V617F allele burden was observed between referral and initiation of the combination treatment. Conclusion: Combination therapy with IFN and ruxolitinib is relatively well tolerated and is highly efficacious in newly diagnosed PV patients with frequent normalization of cell counts and a marked reduction of the JAK2V617F allele burden. This therapy could lead to a subsequent long-term approach with low-dose interferon or treatment pauses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Dose-Escalation Study of the Oral Epichaperome Inhibitor, Zelavespib (ZEL) in Combination with Ruxolitinib (RUX), in Patients with Relapsed Myelofibrosis: Results of the Dose Escalation Stage

Background: ZEL (PU-H71) is an oral synthetic purine-scaffold epichaperome inhibitor that selectively binds to epichaperome complexes found in cancer cells via the altered ATP binding site of disease-associated heat shock protein (HSP90). ZEL has shown efficacy in cell line and mouse models of myeloproliferative neoplasm (MPN) and specifically myelofibrosis (MF) by disrupting JAK2 protein stability, resulting in dose-dependent inhibition of cell growth and signaling. JAK2 inhibitors are the only currently approved class of therapies for intermediate/higher risk MF, but there is still an urgent unmet medical need for 2nd line and beyond therapies. An emerging approach is the add-on/add-back strategy, with the addition of the second/novel agent in the setting of suboptimal response to JAKi monotherapy. In a prior trial of ZEL as IV monotherapy in an advanced malignancy study (including both solid and hematologic malignancies), ZEL demonstrated clinical activity in patients with lymphoma and MF. Based on this efficacy signal, the tolerability profile of ZEL in hematological malignancies, and the potential for synergy between mechanisms of action, a study with ZEL in combination with RUX was initiated. The present phase 1 study is the first to establish the safety, MTD, and preliminary efficacy of oral ZEL when added to RUX in MF (NCT03935555). Methods: Patients with primary, post-polycythemia vera or post-essential thrombocythemia MF were eligible if age ≥18 years, ECOG performance status ≤2, treatment with RUX >3 months prior to start with persistent or worsening splenomegaly and disease-related symptoms (by MPN-SAF TSS), adequate cardiac, hepatic and renal function, platelets ≥ 25,000/uL, ANC ≥500/uL, and no active ocular pathology. Oral solution of ZEL was administered daily in continuous 21-day cycles in combination with each patient's stable baseline RUX dose. The initial dose of ZEL was 50 mg with each subsequent cohort dose-escalating by 50 mg QD increments. DLTs were assessed in Cycle 1 (21 days). Response was assessed by IWG-MRT and ELN criteria. Results: Eleven patients have been enrolled: 3 patients each in the 50 and 100 mg cohorts, and 5 in the 150 mg cohort following DLT-driven cohort expansion. Median age was 69 years (range 59-78). Baseline RUX dose ranged from 5-25 mg bid, with a median of 15 mg. Median number of ZEL cycles administered was 4 (range 1-25). Most AEs were Gr 1 and 2 and the most frequent were abdominal pain, diarrhea and fatigue. Gr 4 thrombocytopenia in 2 patients (150 mg) met DLT criteria with platelet nadirs of 7K and 22K during cycle 1. One patient (150 mg with symptomatic improvement) developed Grade 3 bone marrow hypoplasia after 22 cycles of treatment, an SAE judged by the Investigator to be related to treatment. To date, 2 patients (1 each at 100 and 150 mg) demonstrated symptom improvement without significant reduction in spleen size. One patient (50 mg) had stable disease maintained for 20 cycles and successfully bridged to allogeneic stem cell transplant. Allele burden, cytokine profiles, flow cytometry for biomarkers, and PK analyses are in progress and will be presented. Conclusions: The ZEL dose 100 mg QD was well tolerated and was selected as the RP2D in combination with RUX. Although ZEL has not been shown to cause myelosuppression as monotherapy, further evaluation is necessary to understand possible effects on bone marrow and megakaryocyte function when used in combination with RUX. Further exploration of the therapeutic potential of oral ZEL in the treatment of MF and other MPNs, as monotherapy and with RUX, is warranted.

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

Real-World Experience with Ruxolitinib Therapy for Steroid Refractory Acute Graft Versus Host Disease

AM and SML contributed equally as co-first authors. KJ and DK contributed equally as co-senior authors. Background Acute graft versus host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplant (alloHCT) and is associated with significant morbidity and mortality. Steroid refractory aGVHD (SR-aGVHD) carries a particularly grim prognosis. Ruxolitinib has shown promise for treatment of SR-aGVHD in phase 2 and 3 trials; however, safety and efficacy data outside of the clinical trial setting is lacking. We performed a multicenter retrospective study to examine the response to ruxolitinib and its efficacy in patients with SR-aGVHD in a Canadian population. Methods and Patients This multicenter retrospective study includes patients that underwent alloHCT between 2015 and 2021, across five Canadian transplant centers in Calgary, Toronto, Vancouver, Quebec City, and Saskatoon. Patients were included in the study if they developed at least overall grade 2 aGVHD, met the criteria of SR-aGVHD, and were started on ruxolitinib for SR-aGVHD. Data was recorded on standardized forms by independent reviewers across the five sites. Survival outcomes were calculated by Kaplan-Meier. Treatment failure was defined as 1) treatment switch due to no response/no benefit, 2) non-relapse mortality (NRM), 3) relapse of primary disease, or 4) intolerance leading to discontinuation. Failure-free survival (FFS) was calculated from ruxolitinib start until the event of treatment failure or latest follow-up, while overall survival (OS) was calculated from the day of starting ruxolitinib therapy until death or latest follow-up. Results We reviewed 59 patients treated with ruxolitinib for SR-aGVHD. The median age at time of ruxolitinib therapy was 53 (range 21-70) years, and 54.2% of patients were male. The most common indication for alloHCT was acute leukemia (48.2%), followed by myeloproliferative disorder/myelodysplastic syndrome (28.8%), lymphoma/chronic lymphocytic leukemia (18.6%), and others (5.1%). Approximately half of patients were treated with myeloablative conditioning (50.8%). Donor type included matched unrelated (44.1%), matched related (23.7%), mismatched unrelated (15.3%), haploidentical (15.3%) and cord blood (1.7%). The median onset of aGVHD was 65 days post alloHCT (range 15-265). Prior to initiation of ruxolitinib, most patients had overall grade 3 aGVHD (57.6%) and 16.9% had overall grade 4 disease. Patients had a median Karnofsky Performance Status (KPS) of 80% (range 30-100%) prior to ruxolitinib initiation. A total of 36 patients (61.0%) obtained a complete response (CR) or partial response (PR) at 28 days. At day 56, 31 patients (52.5%) obtained a CR or PR. Patients that achieved a CR or PR at day 28 had a higher survival rate (69.2%), compared with patients that did not (31.6%) (p=0.037). In terms of long-term outcomes, with a median follow-up of 391 days, OS at 12 months was 41.5% (95% CI, 27.6-54.8%), with a median OS duration of 5.3 months (Figure A). The 12 months' FFS rate was 29.1% (95% CI, 16.1-43.3%), with a median FFS of 2.6 months (Figure A). Reasons for failure included NRM (39.0%), need for therapy switch (18.6%), relapse of primary disease (5.1%), and intolerance (3.4%; Figure B). Within 12 months after starting ruxolitinib, 14.8% of surviving patients were able to successfully taper off without flare of their aGVHD. By 24 months, 23.6% of surviving patients were able to taper off glucocorticoids (Figure 1A). Glucocorticoid dose decreased over time with a mean daily prednisone dose 1.486±0.072 mg/kg at day 0 of ruxolitinib, compared to 0.152±0.038 mg/kg after 6 months (p<0.001). Nineteen patients (32.2%) had an initial ruxolitinib dose of 10 mg twice daily (BID) while 37 (66.1%) were started on 5 mg BID, then escalated to 10mg BID within 3-7 days per the REACH1 study. There was no significant difference in OS observed between patients started on 10 mg BID compared to 5 mg BID. Conclusions In this Canadian real-world experience-based study, we observed similar response rate and FFS rate that was found in the REACH2 trial for SR-aGVHD treated with ruxolitinib. We also observed that NRM was the primary reason for treatment failure, and saw that ruxolitinib therapy for SR-aGVHD enabled successful tapering of prednisone. Overall, these data support clinical trial evidence for ruxolitinib as useful therapeutic option for SR-aGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Dose Ruxolitinib in Indian Haplo-Identical Transplant Patients with Steroid Refractory Acute Graft Versus Host Disease

Background: The number of allogeneic bone marrow transplants done in India is increasing by year. Unlike west, this region had got its own unique complications in the post-transplant period especially multi drug resistant gram negative bacterial sepsis reflecting in a higher transplant related mortality. With increasing number of Haplo-identical transplants, the problem of steroid refractory Graft versus host disease (GVHD) is a major reason for post-transplant morbidity and mortality. As most available immunosuppressive agents worsen cytopenia and in turn sepsis, we need a relatively safer method of managing steroid refractory GVHD in our setting. In this observational study, we used a lower dose of 5mg per day Ruxolitinib for a period of minimum 60 days post-transplant to look into clinical benefit. This dose was chosen considering the recovering platelet count and financial considerations in our resource limited setting. Method: This observational study was conducted from July 2019 to January 2022. A total of 11 steroid refractory GVHD Haploidentical transplant patients were chosen for data analysis that completed the scheduled dosage regimen of Ruxolitinib. Nine out of 11 patients were Acute Myeloid leukemia and two were Acute Lymphoblastic leukemia. The standard conditioning regimen in all was Fludarabine / Busulfan & Cyclophosphamide based conditioning. Additional GVHD medications used were PTCy, Tacrolimus, MMF and steroids with oral budesonide. Tab Ruxolitinib was started around Day +5 post steroids in people who were fitting into steroid refractory acyte GVHD at a fixed dose of 5mg OD for a minimum period of ten weeks. Two cases had one week dose interruption due to cytopenia. Results : At start of Ruxolitinib seven patients had Grade III gut and liver GVHD and rest four had grade II GVHD. Skin was grade II in all patients. When evaluated at Day +58 of Ruxolitinib, all patients were alive and nine of them were on tapering doses of steroids. All continued Tacrolimus at therapeutic doses. No excess bleeding or cytopenia requiring transfusion support happened during this period. As mentioned earlier two cases Ruxolitinib was stopped in view of platelet counts going below 20,000. On evaluation at day +100 post transplant, two patients continued to have grade II Liver, gut and skin GVH and one patient expired on day +48 to sepsis. Rest of eight patients had a Grade I skin, liver and gut GVHD and were able to continue Ruxolitinib further. We started Ruxolitinib taper in cases where steroids were stopped. As case numbers were very low and it's a pilot observation study, we didn't do detailed statistical analysis which may be misleading and give false promises. Conclusion: In our setup, we were finding it a difficulty to use the prescribed 10mg BD Ruxolitinib dose in adults due to fear of worsening cytopenia /sepsis and financial toxicity. We tried to observe the benefit of a lower dose in steroid refractory GVHD post Haplo-identical bone marrow transplant. No pharmaco-genetic assays were done and it's a very small sample size. This observational study revealed a better efficacy and tolerability of this dosing regimen in Indian Haplo-identical patients with a considerable response without compromising blood counts. The results are looking more promising to conduct this study in a bigger scale to benefit our patients from resource limited settings. Reference Zhao Y, Shi J, Luo Y, Gao F, Tan Y, Lai X, Yu J, Wei G, Huang H. Calcineurin Inhibitors Replacement by Ruxolitinib as Graft-versus-Host Disease Prophylaxis for Patients after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2020 May;26(5):e128-e133. doi: 10.1016/j.bbmt.2020.01.012. Epub 2020 Jan 23. PMID: 31982545.

Molecularly Targeted Combination Therapy for Advanced Phase Myeloproliferative Neoplasm: MPN-RC 119

Background: Patients with myeloproliferative neoplasms (MPNs) that develop accelerated (AP) or blast phase (BP) disease have poor outcomes and limited treatment options. The median overall survival (OS) for patients with MPN-BP is 3-5 months (Mesa, Blood 2005; Mascarenhas, CLML 2016), and 12 months for patients with MPN-AP. Myelofibrosis (MF) patients with 5-9% blasts in the peripheral blood (PB) have a similar outcome as patients with MPN-AP (Massarova, CLML 2021). IDH mutations occur in 20-25% of patients with MPN-BP and the acquisition of these mutations is associated with both an increased risk of leukemic transformation and reduced OS (Dunbar, blood 2020). IDH2R140Q-Jak2V617F mice treated with a combination of JAK1/2 inhibitor (ruxolitinib) and an IDH2 inhibitor (enasidenib) showed complete resolution of splenomegaly, normalization of blood counts, and blast resolution (McKenney, JCI 2018). Here we report the preliminary results of the first molecularly targeted therapy for MPN AP/BP patients harboring IDH2 mutations utilizing combination treatment with ruxolitinib and enasidenib. Methods: A phase 2, multicenter trial of combined ruxolitinib and enasidenib is being conducted in patients with MPN-AP/BP or MF in chronic phase (CP) with 4-9% PB blasts and an IDH2 Mutation (NCT04281498). MPN-AP/BP and MF-CP Patients receive enasidenib 100mg and 50mg daily respectively, with dose increases after cycle 1 for MF-CP. Initial ruxolitinib doses were determined based on platelet counts at enrollment for patients without previous ruxolitinib treatment or continuation of current treatment dose. Response assessment occurred every 3 cycles for MPN-AP/BP using modified Cheson criteria and every 6 cycles for MF-CP using IWG/ELN criteria. Results: Six patients have been enrolled (5 MPN-AP/BP and 1 MF-CP). 50% were male with a median age of 74 years (range 58-81). (Table 1). Patients were treated for a median of 5.5 cycles (1-13) with a median follow up of 26 weeks (2.7-53). At the time of reporting, two patients remain on trial. Four discontinued treatment; disease progression (n=1), physician discretion (n=1, after no response observed after 3 cycles), allogeneic stem cell transplant (n=1), withdrew consent (n=1). Grade 3/4 adverse events (AEs) were reported in five of the six (83%) patients. All grade 4 AEs were hematological events, as well as the majority of the grade 3 AEs. One patient (16.7%) had grade 3 liver function test abnormalities, one patient (16.7%) had grade 3 hyperbilirubinemia and one patient (16.7%) had grade 3 neutropenic fever. QT prolongation and evidence of a differentiation syndrome were not observed. AEs are summarized in Table 2. Of the five MPN-AP/BP patients, one pt was not evaluable for response (removed after 1 cycle due to disease progression). The ORR was 50% in the evaluable cohort and 40% in the intention to treat analysis. Two patients achieved complete remission (CR). One patient achieved CRi after 3 cycles and has maintained the response after 13 cycles, one patient achieved CRi after 3 cycles, and CR after 4 cycles, and has maintained the response after 9 cycles. Two patients had stable disease after 3 and 6 cycles. Conclusion: Combination treatment with ruxolitinib and enasidenib appear safe with manageable toxicity profile. The majority of grade 3/4 AEs were hematologic as expected in this advanced patient population. Results are encouraging and warrant continued evaluation of this IDH2 mutant defined poor prognostic group. Trial enrollment is ongoing and mature results will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Modulation of TGF-β Superfamily Signaling to Treat Myelofibrosis and Mitigate JAK Inhibitor Toxicity: A Report on the Phase 2 Study of Ker-050 in Participants with Myelofibrosis

Background: Myelofibrosis (MF) is a disorder characterized by unrestrained proliferation of myeloid precursors and dysfunctional Janus kinase (JAK) signaling. Hyperplastic and dysplastic megakaryocyte expansion in MF releases inflammatory cytokines. These cytokines promote fibroblast proliferation, bone remodeling, and marrow fibrosis, disrupting the osteohematopoietic niche and leading to ineffective and extramedullary hematopoiesis (Vainchenker et al. 2017). Clinical manifestations include splenomegaly, anemia, and often disabling constitutional symptoms. JAK inhibitors, such as ruxolitinib, have been shown to improve spleen size and symptoms, but are associated with dose-limiting anemia and thrombocytopenia, reducing their utility for many patients (Verstovsek et al. 2012). KER-050 is an investigational product designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. Preclinical studies have demonstrated that KER-050 induces erythropoiesis, increases platelet counts, improves bone mass, and prevents fibrosis. A preclinical study previously presented demonstrated that RKER-050 can reverse ruxolitinib-associated reductions in hemoglobin, hematocrit, and red blood cell count, indicating potential for KER-050 to mitigate ruxolitinib toxicity. In two clinical studies, including an ongoing study in participants with myelodysplastic syndromes (MDS), KER-050 has been well-tolerated. Accumulated clinical data demonstrate that KER-050 can stimulate erythropoiesis and thrombopoiesis in both healthy post-menopausal women and MDS participants with ineffective hematopoiesis. Here we present data from the first clinical study of KER-050 in participants with MF (NCT05037760). The objective of this study is to evaluate the potential of KER-050 as monotherapy and in combination with ruxolitinib to treat the underlying pathology of MF and mitigate JAK inhibitor-associated cytopenias. Methods: This ongoing Phase 2 open-label study is evaluating the safety, tolerability, pharmacokinetics PK), pharmacodynamics (PD), and efficacy of KER-050 administered with or without ruxolitinib in participants with primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF), and post-polycythemia vera myelofibrosis (post-PV MF) who have anemia (hemoglobin ≤ 10 g/dL or receiving transfusions). Part 1 involves parallel dose escalation arms (1A: monotherapy, 1B: combination with ruxolitinib) to evaluate the safety and tolerability of KER-050 and identify the dose(s) of KER-050 to be evaluated in Part 2 (Figure 1). Changes in hemoglobin, transfusion burden, spleen size, the Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF-TSS), PK and incidence of accelerated MF and acute myeloid leukemia are assessed as secondary endpoints. This study is also evaluating markers of multilineage hematopoiesis, bone remodeling, iron metabolism, inflammation, and marrow fibrosis. Frequency of ruxolitinib dose modification and quality of life will be explored. Results: Preliminary results from Part 1 will be presented. At the time of this writing, 5 patients have received KER-050 on study, 3 in Arm 1A and 2 in Arm 1B. Three participants have completed the dose-limiting toxicity (DLT) assessment period and no DLTs have been experienced. Data evaluated to date indicate a PD effect consistent with previous preclinical and clinical studies of KER-050. Summary: KER-050 is designed to alter TGF-β superfamily signaling, restoring balance to the osteohematopoietic niche and promoting multilineage hematopoietic differentiation. Here we present data from the first study of KER-050 in participants with MF evaluating the potential for KER-050 to impact key aspects of the MF disease state (anemia, spleen size, symptoms, progression), as monotherapy and in combination with ruxolitinib. The potential for KER-050 to mitigate ruxolitinib toxicity and related dose-reductions is being investigated. Exploratory analyses of the KER-050 impact on inflammation, bone remodeling, iron metabolism, and marrow fibrosis, as available, will be shared. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CTIM-16. PHASE 1 TRIAL OF RUXOLITINIB, TEMOZOLOMIDE, AND RADIATION IN HIGH-GRADE GLIOMAS

Abstract BACKGROUND Ruxolitinib is a small molecule inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. Dysregulation of the JAK/STAT pathway is associated with increased proliferation and survival of malignant cells. Preclinical evidence supporting inhibition of the JAK-STAT pathway arrogated glioma growth led to the design of this trial. METHODS Newly diagnosed patients with unmethylated MGMT HGG (arm 1) received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 was 10 mg twice daily, level 2 (15 mg twice daily), level 3 (20 mg twice daily), and level -1 was 5 mg twice daily. Patients with methylated MGMT HGG (arm 2) received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS 60 HGG were treated in the study and there was no dose-limiting toxicity. Survival data was calculated for 37 GBM patients. The OS for arm 1 was 18.17 months (10.15, NA) and was not reached for arm 2. The 1-year OS was 0.77 for all GBM patients, was 0.62 for arm 1 (unmethylated MGMT) and 0.93 for arm 2 (unmethylated MGMT). CONCLUSIONS A dose of 20 mg twice daily of ruxolitinib is safe with radiation and temozolomide. Preliminary survival data appears promising compared to the historical benchmarks for both the methylated MGMT and unmethylated MGMT groups. Genomic markers of response will be presented. A randomized phase 2 trial is planned.

High Incidence of Herpes Zoster in Patients Using Ruxolitinib for Myeloproliferative Neoplasms: Need for Prophylaxis.

High Incidence of Herpes Zoster in Patients Using Ruxolitinib for Myeloproliferative Neoplasms: Need for Prophylaxis.

Efficacy and Safety of Ruxolitinib in Polycythemia Vera

To evaluate the efficacy and safety of ruxolitinib in patients with polycythemia vera (PV). The clinical data of patients with PV treated with ruxolitinib in Peking Union Medical College Hospital from January 1, 2013 to December 31, 2019 were retrospectively analyzed. The starting dose of oral ruxolitinib was 10 mg twice daily and could be increased after 3 months of treatment if hematocrit (HCT) control was not achieved. HCT control was defined as HCT<45% in the absence of phlebotomy. Thirty-three patients (17 males and 16 females) were treated with ruxolitinib at a median age of 50 (21-72) years. JAK2V617F and JAK2exon12 alleles were detected in 31 and 2 patients, respectively. Before treatment, median hemoglobin level was 187 (166-208) g/L, median white blood cell and platelet level was 10.4 (5.0-15.8)×109/L and 457(237-677)×109/L, respectively. Totally 17 patients (51.5%) who were resistant to or intolerant of hydroxyurea were treated with ruxolitinib as second-line therapy, and 16 patients (48.5%) were treated with ruxolitinib as first-line therapy voluntarily. The median time since PV diagnosis to treatment of ruxolitinib was 47 (3-188) months. By December 31, 2019, all the patients continued to receive ruxolitinib. The median duration of ruxolitinib exposure was 19 (2-91) months. Both in the first-line therapy group and second-line therapy group, 15 cases (accounting for 93.8% and 88.2%, respecitvely) achieved HCT control. The median time from start of therapy to HCT control was 2.2 (0.8-11.6) months. One patient (3.0%) had disease progression after HCT control. The most common hematologic adverse events included anemia and thrombocytopenia, according to CTCAE classification, including 1 case of grade 1 anemia (3.0%) and 1 case of grade 2 thrombocytopenia (3.0%). There was no thromboembolic event occurred during the therapy of ruxolitinib. The remission rate of HCT in PV patients treated with ruxolitinib is high, and adverse reactions are rare. Ruxolitinib is effective in HCT control and generally well tolerated in patients with PV.

MPN-386 Real-World Ruxolitinib Treatment Pattern in Myelofibrosis Patients With Thrombocytopenia.

Ruxolitinib, the standard treatment for patients with myelofibrosis to reduce splenomegaly and improve myelofibrosis-associated symptoms, is associated with high rates of cytopenia effect. Thrombocytopenia, common in myelofibrosis patients, is associated with poor clinical outcomes, and its treatment confers a unique challenge. This real-world study characterized the disease and ruxolitinib treatment pattern in myelofibrosis patients with thrombocytopenia using US insurance claims data. Data from the IBM MarketScan® Medicare Supplemental Database were retrospectively analyzed to identify patients aged ≥18 years with ≥1 claim for ruxolitinib and ≥2 non-diagnostic medical claims for myelofibrosis from 2017 to 2019. The first ruxolitinib claim on or after the first myelofibrosis claim defined the index date. Patients who continuously enrolled in a health plan for 3 months before and 6 months after the index date were included. Clinical characteristics and ruxolitinib treatments were compared in myelofibrosis patients with or without a history of thrombocytopenia prior to ruxolitinib initiation. Overall, 136 myelofibrosis patients who received ruxolitinib treatment were included in the analysis. The median age was 61 years, 61% were male, 62% had primary myelofibrosis, and 38% had post-polycythemia vera or essential thrombocythemia myelofibrosis. Prior to ruxolitinib treatment, 57% of patients had a diagnosis of splenomegaly, 56% had anemia, 25% had thrombocytopenia, 19% had received RBC transfusion, and 7% had neutropenia. During ruxolitinib treatment, 25% of patients had a new diagnosis of thrombocytopenia, 22% had neutropenia, and 19% had anemia. Patients with versus without history of thrombocytopenia had more anemia (79% vs. 48%, P=0.001), more red blood cell transfusions (44% vs. 11%, P<0.001), and a lower mean starting dose of ruxolitinib (20 mg vs. 27 mg, P=0.005). History of anemia, leukocytosis, neutropenia, myelofibrosis type, and splenomegaly had no effect on the ruxolitinib starting dose. Myelofibrosis patients with versus without history of thrombocytopenia continued ruxolitinib treatment at lower doses. During ruxolitinib treatment, 57% of patients with versus 42% without history of thrombocytopenia experienced anemia (OR=1.88, P=0.43). History of thrombocytopenia was a major factor influencing ruxolitinib dose and was associated with history of anemia and neutropenia. Our findings underscore the need for more treatment options to manage myelofibrosis patients with thrombocytopenia.

Combined IFN-γ and JAK inhibition to treat hemophagocytic lymphohistiocytosis in mice

Familial hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disease caused by genetic defects in the granule-mediated cytotoxic pathway. Success of hematopoietic cell transplantation, the only cure, is correlated with the extent of disease control before transplantation. Unfortunately, disease refractoriness and toxicities to standard chemotherapy-based regimens are fatal in a fraction of patients. Novel targeted immunotherapies, such as IFN-γ blocking antibodies or ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, are promising but only partially effective at controlling disease. We asked whether combinations of cytokine-targeted therapies, using antibodies or JAK inhibitor, work synergistically to counteract HLH. Genetically predisposed mice were infected and treated with distinct combinations of immunotherapies. Disease outcome was monitored and compared to monotherapies. We showed that inhibiting IL-6 or IL-18 signaling in combination with IFN-γ blockade or ruxolitinib did not increase disease control compared to anti-IFN-γ antibodies or ruxolitinib monotherapies. In contrast, clinically relevant doses of ruxolitinib combined with low doses of anti-IFN-γ blocking antibodies corrected cytopenias, prevented overt neutrophilia, limited cytokinemia, and resolved HLH immunopathology and symptomatology. Our findings demonstrate that IFN-γ blockade and ruxolitinib act synergistically to suppress HLH progression. This supports the use of combined cytokine-targeted therapies as a bridge to hematopoietic cell transplantation in severe familial hemophagocytic lymphohistiocytosis.

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

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

P1044: REAL-WORLD RUXOLITINIB TREATMENT PATTERN IN MYELOFIBROSIS PATIENTS WITH THROMBOCYTOPENIA

Background: Ruxolitinib (RUX) is the standard treatment for patients (pts) with myelofibrosis (MF) to reduce splenomegaly and improve MF-associated symptoms. RUX treatment is titrated based on platelet counts and is associated with high rates of cytopenia effect. The incidence of moderate thrombocytopenia (platelet count <100 x 109/L) is about 25% in newly diagnosed MF pts; however, the prevalence is about 67% in all MF pts. Low platelet count has been identified as an important surrogate marker of survival in MF pts with associated poor clinical features. Thrombocytopenia is also an independent predictor in the Dynamic International Prognostic Scoring System plus (DIPPS plus), with an actual 1.4-fold increased risk of death. Thus, treatment of MF pts with thrombocytopenia confers a unique challenge and unmet medical need. Real world studies will provide a perspective on the current management of MF pts with thrombocytopenia. Aims: To characterize the disease and RUX treatment pattern in MF pts with thrombocytopenia using de-identified insurance claims data in the US. Methods: The IBM MarketScan® Medicare Supplemental Database data was retrospectively analyzed to identify pts aged ≥18 years with ≥1 claim for RUX and ≥2 non-diagnostic medical claims for MF (ICD-10 D47.4, D7581) from 2017–2019. The first RUX claim on or after the first MF claim defined the index date. Pts who continuously enrolled in a health plan for 3 months before the index date and 6 months after the index date were included. Clinical characteristics and RUX treatments were compared in MF pts with or without a history of thrombocytopenia prior to RUX initiation. Results: The database contained 136 MF pts who had received treatment with RUX. Median age was 61 years, 61% were male, 62% of pts had primary MF, and 38% had post-polycythemia vera or essential thrombocythemia MF. Prior to initial RUX treatment, 57% of pts had a diagnosis of splenomegaly, 56% had anemia, 25% had thrombocytopenia, 19% had received RBC transfusion, and 7% had neutropenia. During RUX treatment, 25% of pts had a new diagnosis of thrombocytopenia, 22% had neutropenia, and 19% had anemia. Pts with a history of thrombocytopenia also had more anemia (79% vs 48%, p=0.001) and more RBC transfusions (44% vs 11%, p<0.001) than those without a history of thrombocytopenia. History of thrombocytopenia was associated with a lower starting dose of RUX (average starting daily dose 20 mg vs 27 mg, p=0.005), whereas history of anemia, leukocytosis, neutropenia, MF type, and splenomegaly were found to have no difference in the RUX starting dose. In addition, MF pts with history of thrombocytopenia continued RUX treatment at lower doses compared with those without a history of thrombocytopenia. During RUX treatment, 57% of pts with history of thrombocytopenia experienced anemia compared with 42% in pts without history of thrombocytopenia (OR 1.88, p=0.43). Summary/Conclusion: In this real-world data analysis, history of thrombocytopenia was a major factor influencing the RUX dose for treatment of MF pts, consistent with prescribing data that RUX dose is adjusted based on platelet counts. These data show that pts with thrombocytopenia were treated with lower doses of RUX in clinical practice. Additionally, history of thrombocytopenia was associated with history of anemia; thus, these MF pts may be more prone to develop anemia during RUX treatment compared with pts without a history of thrombocytopenia. Our findings underscore the need for more treatment options to manage MF pts with thrombocytopenia. *Equal contribution.

P1047: REAL-WORLD SAFETY OF RUXOLITINIB IN PATIENTS WITH INTERMEDIATE OR HIGH RISK OF PRIMARY MYELOFIBROSIS, POST-POLYCYTHEMIA VERA MYELOFIBROSIS OR POST-ESSENTIAL THROMBOCYTHEMIA MYELOFIBROSIS IN CHINA

Background: Ruxolitinib, a potent and selective inhibitor of Janus kinase 1 (JAK1)/JAK2 tyrosine kinases, was approved for treatment of intermediate- and high-risk patients with myelofibrosis (MF) based on the findings from the pivotal studies, COMFORT I and II. Although an Asia regional study was conducted, the enrolled Chinese population was limited (N=63). Aims: We aimed to evaluate the safety profile and the treatment of ruxolitinib in Chinese patients with MF under routine clinical practice. Methods: This was a retrospective, non-interventional, multicenter, post-marketing surveillance study collecting data up to 48 weeks after ruxolitinib initiation. Patients aged ≥18 years with a confirmed diagnosis of intermediate or high-risk primary MF (PMF), post-polycythemia vera MF (PPV-MF) or post-essential thrombocythemia MF (PET-MF) who had received or were currently receiving ruxolitinib treatment per clinical judgment according to China approved label were included. Results: In total, 480 patients from 20 sites were enrolled and 428 patients completed the study treatment. The most reported reasons for treatment discontinuation were death (17.3%), adverse events (AE, 7.7%) and abnormal laboratory value (5.8%). Gender distribution were balance (male 51.6% vs female 48.4%) with median age of 61.0 years and median BMI of 22.5 kg/m2. Majority of the patients were diagnosed with PMF (69.8%), followed by PPV-MF (15.7%), and PET-MF (14.5%). The information on dosing and safety is detailed in Table 1. Ruxolitinib dosing was according to the local approved label (median initial daily dose 30.0 mg). The median time from first diagnosis to medication was 1.5 months. Overall, patients received ruxolitinib for a median of 11.1 months with median dose intensity of 28.7 mg/day. The most prescribed dose was 15 mg BID across varying durations of exposure to ruxolitinib (up to 48 weeks). A total of 196 (40.8%) patients had dose modification. On-treatment AE and serious AE (SAE) were reported in 361 (75.2%) and 57 (11.9%) patients, respectively. Of those, 60.2% and 6.0%, were related to study drug, respectively. The severity of majority of the AE were grade 2 and 3 (26.7 & 25.2%, respectively) while SAE were grade 3 & 4 (3.5% & 4.4%, respectively). A total of 4.0% and 2.3% of patients reported AEs and SAEs leading to discontinuation. The most commonly reported AEs were anemia (47.3%), decreased platelet count (22.1%), and abnormal liver function (12.7%). The most commonly reported SAEs were anemia (3.8%), platelet count decreased (1.0%), infectious pneumonia and pulmonary inflammation (both 0.8%). On-treatment AESI was reported by 18 (3.8%) patients, consisted of bleeding events (2.3%), serious or opportunistic infections (0.8%), and second primary malignancies (SPM, 0.6%). The SPM were pulmonary malignant tumors (n=2) and liver cancer (n=1). A total of 18 on-treatment deaths (MF progression=9, AE=4, and others=5) were reported. During the study period, we found that the number of patients with efficacy data were decreasing with time (baseline=183&116, Week 16=126 & 96, Week 32=90 & 62, Week 48=38 & 19 for spleen size measurement and total symptom score, respectively). This reflects the need for improve compliance in disease management. Image:Summary/Conclusion: This was the largest ruxolitinib real-world study in China. The safety profile of ruxolitinib in patients with intermediate- or high-risk PMF, PPV-MF, or PET-MF was generally consistent with previous global and Chinese studies of MF. The incidence of SPM was lower than that reported previously4. No new unexpected safety signals have been identified.