Reduction In Spleen Volume Research Articles

A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.

TPS7086 Background: Patients (pts) with myelofibrosis (MF) have a reduced life-expectancy compared to age-matched controls. Several oral Janus Kinase (JAK) inhibitors such as ruxolitinib (RUX) have been approved by the US FDA based on improvements in symptom burden and spleen volume reduction compared to physician’s choice of best available therapy. However, duration of response to these agents is generally time-limited and treatment with JAK inhibitors is not considered to have disease-modifying potential. Additionally, median overall survival after RUX discontinuation is only 11-14 months. Thus, novel mechanism-based therapies for pts with disease progression on RUX are needed. JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A, which is also upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been implicated in MF pathogenesis. Finally, we and others have shown that combination of the CDK4/6 inhibitors and RUX had synergistic effects in murine models of MF (Rampal et al., CCR 2021) providing the preclinical rationale for this trial. Methods: This multicenter, phase I dose-escalation trial (NCT05714072) evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. Among the currently FDA-approved CDK4/6 inhibitors, abemaciclib was chosen for combination therapy due to less myelosuppressive effects compared with other CDK4/6 inhibitors. Inadequate response to RUX is defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms, as defined by the presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS. Following a conventional “3+3” dose-escalation design, pts will be treated with increasing doses of abemaciclib and stable doses of RUX (10mg or 15mg BID). The primary endpoint is to determine the maximum tolerated dose of RUX + abemaciclib. Secondary endpoints include measures of efficacy. Exploratory endpoints include changes in allele fraction of driver mutations, gene expression profiling, and clonal architecture to identify biomarkers of response, mechanisms of resistance, and to assess for any disease-modifying effects of the combination therapy. This trial is open to enrollment at Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Clinical trial information: NCT05714072 .

A randomized, double-blind, phase 3 study of jaktinib versus hydroxyurea (HU) in patients (pts) with intermediate-2 or high-risk myelofibrosis (MF).

7015 Background: Ruxolitinib and HU are recommended by Chinese MF guideline for splenomegaly. There is an unmet need for new treatments. Jaktinib, a novel JAK and AVCR1 inhibitor, showed promising activity on splenomegaly, anemia, and MF symptoms in a phase 2 study (NCT03886415). Here we present the interim results of a phase 3 study, which assessed the efficacy and safety of jaktinib compared to HU. Methods: Pts aged ≥ 18 with primary or post-ET/PV MF, DIPSS Int-2 or high risk, and no prior or ≤10 days’ treatment with a JAK inhibitor were enrolled and randomly assigned (2:1) to receive jaktinib 100 mg bid plus HU placebo or HU 0.5g bid plus jaktinib placebo, stratified by DIPSS risk status (Int-2 or high risk). One interim analysis was pre-specified to be conducted when 70 pts completed the week (wk) 24 visit or met the criteria for treatment termination before wk 24. The primary endpoint was the proportion of pts with a spleen volume reduction of ≥ 35% from baseline (SVR35) at wk 24, measured by MRI/CT images and assessed centrally. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with a ≥ 50% reduction in Total Symptom Score (TSS50), improvement of anemia, safety, etc. Results: This interim analysis (cut-off: April 8, 2022) included 47 pts receiving jaktinib and 23 receiving HU. 66.0% (jaktinib) and 69.6% (HU) had a baseline hemoglobin (Hb) < 100 g/L. 59.6% (jaktinib) and 69.6% (HU) were JAK2V617F positive. The SVR35 rates at wk 24 were 72.3% for jaktinib vs. 17.4% for HU ( p≤0.0001). The best spleen response rates were 80.9% of jaktinib-treat pts vs. 26.1% of HU-treated pts ( p≤0.0001). The median maximum percentage change from baseline in spleen volume were -46.59% vs. -18.50%. The TSS50 rates at wk 24 were 63.8% for jaktinib vs. 43.5% for HU ( p = 0.1163). 5 of 7 jaktinib-treated and two of 5 HU-treated pts who required RBC transfusion at baseline achieved a ≥50% decrease in RBC transfusion by wk 24. In transfusion-independent pts with baseline Hb ≤100 g/L, 39.3% for jaktinib and 15.4% for HU had a ≥20 g/L Hb increase. The most common grade ≥3 hematological treatment emergent adverse events (TEAEs) (jaktinib vs. HU) were anemia (25.5% vs. 43.5%), thrombocytopenia (17.0% vs. 39.1%), leukopenia (2.1% vs. 21.7%), neutropenia (2.1% vs. 21.7%) and decreased lymphocyte count (2.1% vs. 13.0%). Most common non-hematological TEAEs were upper respiratory tract infection (21.3% vs. 21.7%), elevated bilirubin (12.8% vs. 26.1%), fever (12.8% vs. 21.7%) and diarrhea (10.6% vs. 21.7%), predominantly of grade 1 or 2. TEAEs leading to treatment discontinuation occurred in 8.5% of jaktinib and 17.4% of HU. Conclusions: Jaktinib demonstrated significant clinical benefits over HU in MF pts for spleen response with improved symptom response and less cytopenias. Jaktinib may be a new treatment option for MF pts, especially for those with anemia. Clinical trial information: NCT04617028 .

Effects of hyperventilation on oxygenation, apnea breaking points, diving response, and spleen contraction during serial static apneas

PurposeHyperventilation is considered a major risk factor for hypoxic blackout during breath-hold diving, as it delays the apnea breaking point. However, little is known about how it affects oxygenation, the diving response, and spleen contraction during serial breath-holding.Methods18 volunteers with little or no experience in freediving performed two series of 5 apneas with cold facial immersion to maximal duration at 2-min intervals. In one series, apnea was preceded by normal breathing and in the other by 15 s of hyperventilation. End-tidal oxygen and end-tidal carbon dioxide were measured before and after every apnea, and peripheral oxygen saturation, heart rate, breathing movements, and skin blood flow were measured continuously. Spleen dimensions were measured every 15 s.ResultsApnea duration was longer after hyperventilation (133 vs 111 s). Hyperventilation reduced pre-apnea end-tidal CO2 (17.4 vs 29.0 mmHg) and post-apnea end-tidal CO2 (38.5 vs 40.3 mmHg), and delayed onset of involuntary breathing movements (112 vs 89 s). End-tidal O2 after apnea was lower in the hyperventilation trial (83.4 vs 89.4 mmHg) and so was the peripheral oxygen saturation nadir after apnea (90.6 vs 93.6%). During hyperventilation, the nadir peripheral oxygen saturation was lower in the last apnea than in the first (94.0% vs 86.7%). There were no differences in diving response or spleen volume reduction between conditions or across series.ConclusionsSerial apneas revealed a previously undescribed aspect of hyperventilation; a progressively increased desaturation across the series, not observed after normal breathing and could heighten the risk of a blackout.

Abstract CT261: A Phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis

Abstract Background Myelofibrosis (MF) is a myeloproliferative neoplasm that commonly harbors acquired somatic gene mutations in JAK2, CALR, or MPL. In the Phase 3 COMFORT-1 trial, which enrolled 309 patients (pts) with JAK inhibitor-naïve MF, ruxolitinib (RUX) showed spleen volume reduction of ≥35% (SVR35) and an improvement of 50% or more in the total symptom score (TSS50) in 42% and 46%, respectively compared to placebo. Activity has been shown with the combination of selinexor (SEL) plus RUX in preclinical studies. Methods XPORT-MF-034 is an open-label, Phase 1/2 study (NCT04562389) to evaluate the safety and efficacy of SEL plus RUX in treatment-naïve MF pts. SEL is evaluated at 2 dose levels, 40mg and 60mg once-weekly plus twice daily RUX in 28-day cycles. For nausea, all pts receive prophylaxis with a 5-HT3 antagonist prior to each SEL dose and as needed. Primary endpoints are to determine maximum tolerated dose, recommended Phase 2 dose (RP2D), and safety. Secondary endpoints include spleen and symptom response, and hemoglobin stabilization and improvement. The efficacy population for spleen and symptom evaluable pts included those who had a spleen assessment or at least one symptom score available, respectively, at baseline and the W12 or W24 timepoint. Results As of Oct 21, 2022, 24 pts have received at least one dose of 40mg or 60mg weekly SEL with RUX twice daily as per standard of care. Median age was 64 years old (range 44-77) and 11 pts had primary MF, 6 had post-ET MF, and 7 had post-PV MF. DIPSS risk category was int-1, int-2, and high risk for 7, 11, and 6, respectively. The median daily dose of ruxolitinib received was 20 mg. In efficacy evaluable pts, 63% (12/19) and 92% (11/12) achieved SVR35 at W12 and W24, and 83% (10/12) and 67% (4/6) achieved TSS50 at W12 and W24. Among the 11 pts who had a baseline hemoglobin level <10 g/dL, the median hemoglobin level decreased by 0.6 g/dL from baseline to W12 and increased by 0.8 g/dL from baseline to W24. The most common adverse events (AEs) were nausea (75%), anemia (63%), fatigue (58%), and thrombocytopenia (54%). The most common Grade ≥3 AEs were anemia (38%), thrombocytopenia (21%), neutropenia (17%), and atrial fibrillation (13%). Two pts discontinued treatment due to treatment-related AEs (G3 thrombocytopenia, G3 peripheral neuropathy) and no treatment-related deaths were reported. Conclusions To date, in pts with treatment-naïve MF, the novel combination of SEL and RUX has been reasonably well-tolerated with a generally manageable safety profile and has shown encouraging activity in spleen and symptom responses, in addition to hemoglobin stabilization. Updated safety and efficacy, including symptom data amongst those pts non evaluable for TSS50 at the time of the Oct data cutoff, as well as RP2D, will be available for presentation at AACR 2023. Citation Format: Haris Ali, Ashwin Kishtagari, Keri Maher, Sanjay Mohan, Karen Ansaldo, Xulong Wang, Kamal Chamoun, Josef T. Prchal, Srinivas K. Tantravahi. A Phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT261.

Abstract CT242: A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis

Abstract Introduction: Patients (pts) with primary and secondary myelofibrosis (MF) have a reduced life expectancy. While several oral Janus Kinase (JAK)-1/2 inhibitors such as ruxolitinib (RUX) have demonstrated improvements in symptom burden and spleen volume reduction compared to physician choice of best available therapy leading to their approval by the US FDA, responses to these agents are generally time-limited. Additionally, these agents are not considered to be disease-modifying and survival in pts after RUX discontinuation is poor with a median survival of 11-14 months. Thus, novel mechanism-based therapies for pts with suboptimal response or progression on RUX are needed. Preclinical Rationale: JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A in preclinical models and CDC25A expression is upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D also play a role in MF pathogenesis and drive myeloproliferation. Finally, combination of the CDK4/6 inhibitor ribociclib and RUX demonstrated reduction in spleen and liver size when compared to RUX alone in murine models, suggesting synergy (Rampal et al., CCR 2021). Methods: This multicenter, phase I dose-escalation trial evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. 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 1 symptom score ≥5 or 2 symptom scores ≥3 using the screening MPN-SAF TSS. This study follows a conventional “3+3” dose-escalation design, in which pts on a stable dose of RUX (10mg or 15mg BID) with sufficient baseline platelet and absolute neutrophil count will be treated with increasing doses of abemaciclib. Abemaciclib was chosen due to less myelosuppression compared with other CDK4/6 inhibitors. The pre-study dose of ruxolitinib will be maintained to determine the maximum tolerated dose of the combination of RUX+ abemaciclib. The primary endpoint is to determine the safety and tolerability, and to identify the recommended phase II dose of abemaciclib in MF pts on a stable dose of RUX. Secondary endpoints include overall response rate, progression-free and overall survival, and duration of response per the modified International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) 2013 consensus definitions. Correlative studies are planned to identify biomarkers predictive of response to RUX + abemaciclib, mechanisms of resistance (e.g., MAP kinase pathway activation), and any disease-modifying effects of combination therapy. Citation Format: Jan P. Bewersdorf, Srdan Verstovsek, Andriy Derkach, Lucia Masarova, Naveen Pemmaraju, Eytan M. Stein, Michael Mauro, Raajit Rampal, Prithviraj Bose. A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT242.

Abstract 6274: Preclinical characterization of the BET inhibitor, INCB057643, in combination with ruxolitinib for treatment of myeloproliferative neoplasms (MPN)

Abstract Patients with MPNs share common characteristics including overproduction of myeloid cells and chronic inflammation. In MPNs, bromodomain and extra-terminal (BET) proteins can bind to acetylated chromatin to regulate the activity of transcription factors such as NF-kB, leading to overproduction of inflammatory cytokines. Dysregulation of transcriptional gene expression can drive disease defining characteristics, therefore, targeting BET proteins could be an attractive therapeutic approach. In preclinical models, BET inhibitors decreased inflammatory cytokine production and restored hematopoietic cell differentiation. Combination of BET inhibitors with the JAK1/2 inhibitor, ruxolitinib, resulted in further reduction in cytokine production and bone marrow fibrosis (Kleppe M. Cancer Cell 2018). Here, we investigate a novel, orally bioavailable BET inhibitor, INCB057643, for the treatment of MPN in combination with ruxolitinib. INCB057643 is a potent and selective inhibitor of the BET family. In binding assays, INCB057643 selectively inhibited both BRD4 bromodomains, BD1 and BD2, with IC50 values of 39 nM and 6 nM, respectively. INCB057643 comparably inhibited both NF-kB reporter activity and MYC protein levels. Nascent transcript analysis on the JAK2 V617F-mutant cell line SET2 showed decreased transcription of genes linked to inflammation, alone and in combination with ruxolitinib. These data suggest that INCB057643 and ruxolitinib can be used in combination to effectively suppress the pathogenic gene program driving chronic inflammation. Functionally, INCB057643 inhibited proliferation of SET2 cells at nanomolar concentrations. In a SET2 xenograft model, combination of INCB057643 and ruxolitinib potently inhibited tumor growth. Similarly, in the MPLW515L-driven MPN mouse model, INCB057643 in combination with ruxolitinib resulted in a greater reduction in spleen volume, compared to that achieved with single agent treatment. Meso scale discovery assays on MPN-patient-derived CD34+ cells and whole blood using INCB057643 showed inhibition of NF-kB-mediated production of cytokines such as IL-8. In addition, flow cytometry-based analysis on MPN-patient-derived CD34+ cells showed that INCB057643 in combination with ruxolitinib decreased pathogenic megakaryopoiesis, and increased terminal erythroid differentiation. Our data demonstrate that the combination of the BET inhibitor, INCB057643, with ruxolitinib can restore normal hematopoietic differentiation, reduce inflammatory gene expression, and inhibit pathogenic cell differentiation in preclinical models of MPN. INCB057643 is currently being evaluated in clinical studies as monotherapy and in combination with ruxolitinib in patients with MPN. Acknowledgments: Michelle Pusey and Gaurang Trivedi contributed equally to this study. Citation Format: Michelle Pusey, Gaurang Trivedi, Bob Collins, Nina Zolotarjova, Pat Feldman, Monica Bomber, Jacob Ellis, Kristy Stengel, Cynthia Timmers, Hamza Celik, Matt Stubbs, Jeff Jackson, Scott Hiebert, Susan Wee, Sunkyu Kim. Preclinical characterization of the BET inhibitor, INCB057643, in combination with ruxolitinib for treatment of myeloproliferative neoplasms (MPN). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6274.

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies.

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS). This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12months from diagnosis) before ruxolitinib initiation. The analysis included 525 patients (ruxolitinib: ≤12months, n=84; >12months, n=216; placebo/BAT: ≤12months, n=66; >12months, n=159); the median age was 65.0-70.0years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p=.0610; 44.0% vs. 26.9% at Week 48, p=.0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p=.022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%-73%] vs. 57% [95% CI, 49%-64%]; hazard ratio, 1.53; 95% CI, 1.01-2.31; p=.0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT. These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS. Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue. Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments. Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment. Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B.

BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

Особливості хірургічної техніки мезопортального шунтування та ефективність методу в лікуванні дітей з портальною гіпертензією

Modern methods of surgical treatment of the prehepatic form of portal hypertension (PPH) aim to prevent bleeding from esophagus varicose veins and to restore liver portal perfusion. The use of mesoportal shunt (MPS) in patients with PPH is limited by the presence of favorable anatomy in the latter. The standardization of the diagnostic procedures volume, stages of surgery technical performance will help to significantly improve the results of treatment of children with PHP, to which indications for the MPS were established. Purpose - to evaluate the possibility of performing, efficiency and safety of MPS in children with portal hypertension, the degree of esophageal varicose veins involution and reducing the spleen volume reduction. Materials and methods. Case histories of 20 children who underwent surgical treatment of PPH by means of MPS in the period from January 2010 to June 2022 were retrospectively studied. The median follow up was 85.6±14.17 months. The surgical technique used is presented in detail. Results. Male predominance is seen (12 boys, 8 girls) in the study group. The average age at the moment of diagnosis was 7.6±0.88 years. In 13 (65%) cases, an episode of bleeding from varicose veins of the esophagus was the first clinical manifestation. Endoscopic examination revealed II-III degree esophageal varices in 17 (85%) children. All patients had splenomegaly with an average spleen volume of 507.7±67.7 cm3. 8 (40%) patients had severe hypersplenism. The median MPS operational time was 326 (95% CI 300-371) minutes. In 7 (35%) cases shunt thrombosis occured, in 1 (14.2%) case thrombectomy was performed. The overall MPS efficiency of 70% was reached. None of the patients of the follow up group had recurrency of esophageal bleeding. Conclusions. The possibility of performing the MPS depends on favorable anatomy; CT is the optional diagnostic method to detect it, but the role of direct intraoperative visualization and the performance of intraoperative intrahepatic portography remains highly valuable. The 5-year MPS survival rate was 72.2±10.6%. 1 year after surgery, MPS resulted into the involution of the esophageal varices (p<0.001) and a decrease in the volume of the spleen (p<0.001). The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Safety and Efficacy of Fedratinib in Patients with Primary (P), Post-Polycythemia Vera (Post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) Previously Treated with Ruxolitinib: Primary Analysis of the FREEDOM Trial

Introduction: Fedratinib is an oral selective Janus kinase (JAK) 2 inhibitor approved for treatment (tx) of patients (pts) with MF, including those previously treated with ruxolitinib (RUX). In the single-arm phase 2 JAKARTA2 trial (NCT01523171), fedratinib 400 mg once daily improved spleen volume and MF symptom burden in pts with MF resistant/intolerant to prior RUX (Harrison et al. Am J Hematol 2020). Long-term data are lacking due to early termination. The ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518) further evaluates the safety and efficacy of fedratinib in pts with MF previously treated with RUX and includes proactive strategies to mitigate gastrointestinal (GI) adverse events (AEs), thiamine level decreases, and potential encephalopathy (including Wernicke's encephalopathy [WE]). Methods: Eligible pts aged ≥ 18 years with PMF, post-PV MF, or post-ET MF with ≥ 3 months prior tx with RUX were enrolled in the study. Pts were required to have Dynamic International Prognostic Scoring System (DIPSS) intermediate- or high-risk MF, Eastern Cooperative Oncology Group performance status ≤ 2 and baseline platelet count ≥ 50 x 109/L. Pts were treated with fedratinib 400 mg once daily in continuous 28-day cycles until lack of efficacy, intolerance, or disease progression, and followed for 12 months after end of tx (EOT). AE mitigation strategies included prophylactic use of antiemetics and symptomatic use of antidiarrheals, thiamine supplementation, surveillance for encephalopathy, and adjusting preferred time of day for fedratinib administration. Results: Thirty-eight pts were enrolled and treated. Due to accrual challenges during the COVID-19 pandemic, the study was capped early, and data lost statistical power due to reduced sample size. At the database cutoff (November 29, 2021), median tx duration was 38 weeks, 13 pts had tx ongoing, and 25 pts had discontinued tx. At baseline, median age was 68.5 years, 23 (60.5%) pts had a diagnosis of PMF, 9 (23.7%) post-PV MF, and 6 (15.8%) post-ET MF, with DIPSS assessment of intermediate-1 risk in 13 (34.2%) pts, intermediate-2 risk in 18 (47.4%) pts, and high risk in 7 (18.4%) pts. Baseline median spleen volume was 1831.6 mL. A total of 9/35 (25.7%) evaluable pts met the primary endpoint of ≥ 35% spleen volume reduction (SVR) by magnetic resonance imaging/computed tomography at end of cycle (EOC) 6; 13 (37.1%) pts had ≥ 35% SVR when missing EOC6 assessments were imputed with last observation carried forward (LOCF) method (Table). In addition, 9 (25.7%) pts achieved a ≥ 35% SVR before or after EOC6, for a best overall response of ≥ 35% SVR in 22 (62.9%) pts up to end of tx. With a ≥ 25% SVR threshold, 24 (68.6%) pts had a response with LOCF at EOC6. Of ≥ 35% SVR responders, 19/22 (86.4%) maintained durable response at data cutoff (Figure). In secondary endpoints, 21/36 (58.3%) and 16/36 (44.4%) evaluable pts showed ≥ 50% reduction in total symptom score (TSS) at EOC3 and EOC6, respectively. A total of 34/38 (89.5%) pts had 1 tx-emergent AE related to study medication; 3 (7.9%) were serious AEs. Anemia and thrombocytopenia were reported in 23 (60.5%) and 13 (34.2%) pts, respectively. GI AEs were reported in 34 (89.5%) pts, with nausea, vomiting, and diarrhea reported in 15 (39.5%), 7 (18.4%), and 15 (39.5%) pts, respectively. Most GI AEs were grade 1/2 and occurred during cycle 1, and decreased in the subsequent cycles. Grade 1/2 decreases in thiamine levels were reported in 6 pts after initial tx; all instances were treated and resolved at next assessment. No pts required tx discontinuation due to low thiamine levels. There were no cases of WE reported. There were 2 deaths during tx and 7 during follow-up; none were related to study medication. Conclusions: Clinically relevant and durable spleen and symptom responses were observed in FREEDOM study participants, with a majority of responders showing durable SVR at data cutoff. This supports the use of fedratinib in pts with MF previously treated with RUX. One limitation of the study was small pt sample size. In this first fedratinib study proactively assessing a GI mitigation strategy and thiamine monitoring, results showed GI AEs were easily mitigated and no WE was reported. Study support: This study was supported by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Ruxolitinib for Treatment of Symptomatic Chronic Myelomonocytic Leukemia (CMML): Results of a Multicenter Phase II Clinical Trial

Introduction CMML is a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with poor overall survival (OS). Like primary myelofibrosis, a large subset of CMML patients suffer from disease-related symptoms and splenomegaly that contribute to morbidity. We have demonstrated that CMML is molecularly characterized by hematopoietic stem and progenitor cell hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). As the sentinel kinase required for GM-CSF signaling, JAK2 represents a rational therapeutic target in CMML and pharmacologic inhibition has demonstrated activity in preclinical models and in a phase I/II clinical trial. The overall response rate in that trial was 38% by MDS/MPN IWG criteria and 43% of patients (pts) with baseline splenomegaly achieved a spleen response by palpation. However, that clinical trial did not systematically or objectively measure symptom burden or radiographic splenomegaly. Here, we report results of our second phase II clinical trial with ruxolitinib for treatment of CMML objectively measuring spleen responses and symptom improvement. Methods This was a phase II prospective multicenter study. Key eligibility criteria included confirmed diagnosis of CMML and having either symptomatic splenomegaly and/or a myeloproliferative neoplasms symptom assessment form (MPN-SAF) total score (TSS) >17, ANC ≥ 250/ul, and platelets ≥35,000 u/l. Ruxolitinib was administered at 20 mg po BID at the previously identified RP2D. Dose adjustments/holding occurred for both hematological and non-hematological parameters. The primary endpoint was clinical benefit or better response per International Working Group (IWG) criteria for MDS/MPNs and symptom improvement was assessed using the MPN-SAF TSS. Pts were treated at least for 16 weeks if no clear progression and those deriving a clinical benefit could continue on study. Serial blood counts, chemistry and bone marrow assessment were conducted to assure safety and assess efficacy. Spleen volume was measured by CT imaging and the percentage of spleen volume reduction (SVR) was captured. Daily measurements of the MPN-SAF were performed for up to 17 weeks while on study. Results A total of 29 pts were enrolled at 4 centers (Moffitt, John Hopkins, Cleveland Clinic and Dana Farber) between September 2019 and June 2022. The median age was 74 (63-87) years. The majority were white (93%) and male (62%) consistent with the known demographics of CMML. Most pts had CMML-0 (62%) and proliferative CMML (69%) by the French American British group criteria. Fifty nine percent were high risk by the Mayo Clinic CMML risk model. Two patients had prior hypomethylating agent treatment and two had prior hydroxyurea. The most common somatic mutations at baseline were TET2 (79%), SRSF2 (68%) and ASXL1(48%). NRAS (21%), CBL (37%), and JAK2 (21%) were seen at higher proportions than previously reported likely due to study inclusion criteria. The median duration of follow up was 16 months and at the data cut off 8 pts remains on treatment. The median duration on treatment was 4 mo (.5-23 mo). Treatment-related adverse events and reasons for discontinuation are similar to that reported in the initial phase 1/2 study. The overall response rate by MDS/MPN IWG criteria was 17%: 10% (3) partial response and 7% (2) marrow response; 69% (20) had stable disease and 14% (4) were not yet evaluable. In addition, a clinical benefit was achieved in 66% of pts (19/29). Among 20 pts evaluable for spleen response, 30% (6/20) achieved ≥ 35% SVR measured by CT scan and 10/20 (50%) had 10% or more SVR (Figure 1a). Fifty four percent of patients achieved MPN-SAF TSS >50% reduction at 60 days and all but four patients demonstrated an improvement in MPN-SAF TSS (Figure 1b). The estimated median overall survival was 24 months (95% CI 9-39). Conclusions Ruxoltinib demonstrated meaningful clinical activity in CMML patients with splenomegaly and/or high disease symptom burden. Two thirds of patients achieved clinical benefit, 33% had ≥ 35% SVR, and 54% had a reduction in TSS>50%. The overall survival compares favorably to historical data among higher risk CMML and the magnitude of symptomatic benefit is similar to that observed in primary myelofibrosis. Collectively, our data suggests that ruxolitinib is a viable therapeutic for patients with symptomatic CMML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pelabresib (CPI-0610) As Add-on to Ruxolitinib in Myelofibrosis: Durability of Response and Safety Beyond Week 24 in the Phase 2 MANIFEST Study

Background: Myelofibrosis (MF) is largely characterized by bone marrow (BM) fibrosis, splenomegaly and cytopenias. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (eg NF-κB target genes, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. Although the current standard of care for MF is treatment with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX), many patients (pts) experience a suboptimal response to RUX monotherapy or must discontinue treatment due to cytopenias and therefore there is a significant unmet need for new therapies in this population. 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). Aims: In the ongoing, open-label Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. In Arm 2 of MANIFEST, pts with suboptimal/lost response to RUX are treated with PELA as 'add-on’ to RUX. In this abstract we will discuss results from the September 2021 data cut; updated data with longer follow-up on efficacy (≥35% reduction in spleen volume from baseline [BL; SVR35], ≥50% total symptom score reduction from BL [TSS50], duration of response and BM fibrosis improvement) and safety data from the planned July 2022 data cut will be presented. Methods: Pts in Arm 2 are stratified as transfusion dependent (TD; Arm 2A) and nontransfusion dependent (non-TD; Arm 2B). The primary endpoints are conversion from TD to transfusion independence (TI) in Arm 2A (TD cohort) and SVR35 at Week (Wk) 24 for Arm 2B (non-TD cohort). The secondary endpoints include TSS50 per MF Symptom Assessment Form v4.0 at Wk 24 and SVR35 at Wk 24 in Arm 2A (TD cohort). BM biopsies to assess BM fibrosis, durability of responses and safety data are evaluated. Data reported here are from the September 2021 data cut. Results: At Wk 24 in Arm 2 (N=86), 20% (16/81) of pts achieved SVR35 (Figures 1 and 2); 17% for Arm 2A (TD cohort) and 26% for Arm 2B (non-TD cohort). SVR35 at any time was achieved by 30% (24/81) of pts. At Wk 24, 27% (22/81) pts achieved ≥25% reduction in spleen volume from BL (SVR25); 26% (14/54) pts in Arm 2A (TD cohort) and 30% (8/27) pts in Arm 2B (non-TD cohort). Median spleen volume reduction for the full Arm 2 cohort was -18% at Wk 24. Durable (up to Wk 60) spleen volume reductions were observed as depicted in mean spleen volume change over time, and spleen volume reduction deepened over time (Figure 1). Twenty percent (16/80) pts had SVR35 response at Wk 48. In Arm 2A (TD cohort), the TD to TI rate was 16% (6/38). TSS50 at Wk 24 was 37% (30/81); 36% for Arm 2A (TD cohort) and 39% for Arm 2B (non-TD cohort). A total of 54% (46/86) of pts achieved TSS50 at any time. Median total symptom score reduction was -47% at Wk 24. As of data cut off, the median follow-up time was 24.4 (23.0-30.7) months and median treatment duration was 14.0 (8.4-20.6) months. After 24 wks of treatment, BM fibrosis improvement by ≥1 grade was achieved in 26% of evaluable pts by central pathology review; 50% of pts maintained the improvement at the next available assessment or longer. A total of 39% of pts achieved ≥1 grade improvement at any time (best response). The two most common hematologic treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia, reported in 52% (Grade ≥ 3: 33%) pts, and anemia, reported in 27% (Grade ≥ 3: 19%) pts. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely a reason for treatment discontinuation. A total of 20 pts (23%) reported TEAEs that led to PELA discontinuation. Serious adverse events reported in ≥3 pts were anemia (6 pts), respiratory tract infections (4 pts) and urinary tract infections (3 pts). Conclusions: Based on these preliminary Phase 2 data, PELA as 'add-on’ to RUX in pts with a suboptimal/lost response to RUX monotherapy resulted in durable splenic and symptom responses, deepening of spleen responses over time, and was generally well tolerated. Additionally, improvement in BM fibrosis, as a marker of disease modification, was observed in 39% of treated pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Quantitative MRI Identifies Heterogeneous Bone Marrow Treatment Responses in a Mouse Model of Myelofibrosis

Myeloproliferative neoplasms (MPNs), a class of blood cancers, typically arise from mutations in the thrombopoietin receptor (MPL), JAK2, or calreticulin that constitutively activate JAK/STAT signaling in hematopoietic stem and progenitor cells. Myelofibrosis (MF), the most aggressive of the MPNs, can arise as a primary neoplasm or secondary to other MPNs. MF is characterized by progressive fibrosis of bone marrow (BM), destruction of the hematopoietic niche, and eventual BM failure. Recently, the focus of treatment in MF has shifted toward restoration of healthy BM architecture and a functional hematopoietic niche rather than focusing solely on alleviating symptoms. Accomplishing this paradigm shift in drug development and therapy requires new approaches to monitor spatial and temporal changes in BM in patients during treatment. We present a quantitative magnetic resonance imaging (MRI) approach to analyze key pathologic changes in BM in a mouse model of MPN driven by MPLW515L. To evaluate disease extent, progression, and response to therapy in mice, we use anatomical MRI for spleen volume and three quantitative MRI metrics for BM: 1) apparent diffusion coefficient (ADC), 2) proton density fat fraction (PDFF), and 3) magnetization transfer ratio (MTR). PDFF and ADC assess the fat content and water movement of the BM and are useful in identifying cellularity changes such as hypercellularity in MPNs and MF. MTR probes changes in macromolecular structure, such as those observed with increasing fibrosis in MF. We used quantitative MRI to measure response to treatment in BM and change in spleen volume in response to three drugs: ruxolitinib (JAK1/2 inhibitor), fedratinib (JAK2 inhibitor), and navitoclax (BCL-2/BCL-xL inhibitor). Within 10 days after starting treatment, diseased spleen volumes in the ruxolitinib group (~3.5x healthy volume) had the greatest average reduction in spleen volume measured by MRI (-73.5% ± 11.4%) followed by the fedratinib group (-52.7% ± 16.7%). Interestingly, the spleens of every ruxolitinib-treated mouse displayed consistent and prolonged spleen volume reductions, while only a subset of mice in the other treatment groups (~70% fedratinib mice; ~33% navitoclax mice) demonstrated reductions in spleen volume. Despite the robust spleen response in ruxolitinib-treated mice, only some of the mice (~60%) exhibited sustained changes in BM ADC, MTR, and PDFF signals expected with reversion to healthy BM (decreased ADC, decreased MTR, and increased PDFF). In mice treated with fedratinib or navitoclax, even fewer mice (~40% and ~33% respectively) showed reversion toward healthy BM. Importantly, we observed spatial heterogeneity of BM response within the tibia of single mice, where proximal and distal tibia regions often responded disparately (~49% of cases). Because improving BM cellularity and fibrosis is increasingly the target of therapy in MPNs and in MF specifically, there is a distinct need for better techniques for longitudinally evaluating variations in treatment efficacy in living subjects. In this study, we demonstrate that the combination of three quantitative MRI metrics (ADC, PDFF, and MTR) can detect the impact of therapy on the BM in a preclinical mouse model of MPN/MF. Interestingly, we identified pronounced heterogeneity at multiple levels during treatment: 1) differences in changes in spleen volume versus BM; 2) disparate treatment responses of mice within a treatment group; and 3) contrasting regional treatment responses of the BM within a single mouse. Because these quantitative MRI metrics are directly translatable to clinical medicine and can identify variations in treatment efficacy in BM, both between and within subjects, this study sets the stage for future drug development and analysis of therapeutic interventions on the BM of patients with MF.

Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Introduction: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. Expression of PIM-1 is significantly upregulated in MF hematopoietic cells, supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a highly selective oral investigational PIM-1 kinase inhibitor. When administered alone and in combination with ruxolitinib, TP-3654 reduced spleen size and BM fibrosis in JAK2V617F and MPLW515L murine MF models (Dutta, 2021). In addition, TP-3654 decreased cytokine response genes and serum TGF-b in progenitor cells and JAK2V617F mice, respectively. TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. Methods: This Phase I/II study evaluates the safety and efficacy of TP-3654 monotherapy in patients with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor treatment; grade ≥2 BM fibrosis; platelet count ≥25x109/L; absolute neutrophil count ≥1x109/L; splenomegaly; and ≥2 measurable symptoms. The study aims to identify the maximum tolerated dose and/or recommended Phase II dose using a Bayesian logistic regression model (BLRM) with overdose control, and to assess clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement, and BM fibrosis reduction), safety, pharmacokinetic, and pharmacodynamic markers in peripheral blood and BM biopsies. Results: As of 11 July 2022, 8 patients were enrolled across 5 dose levels in the dose escalation phase. At baseline, median age was 70 years (range, 61 to 77), median spleen volume was 2370 cm3 (range, 1189 to 4407), median total symptom score was 19 (range, 4 to 62), median platelet count was 120 x109/L (range 68 to 237), median hemoglobin was 10.1 g/dL (range, 5.9 to 13.7), and two patients were transfusion-dependent. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitor treatment was 35 weeks (range, 13 to 269). Six patients had JAK2V16F mutation, 2 patients had CALR mutation. The median duration of TP-3654 treatment was 21 weeks (range, 1 to 45). No dose-limiting toxicities occurred. Treatment-related adverse events (TRAEs) occurring in >20% of patients included mild to moderate nausea, vomiting, and diarrhea. Grade ≥ 3 TRAEs included only 1 case of vomiting. No hematological TRAEs were reported. No discontinuation due to AE occurred. SVR was observed in 5 out of 6 evaluable patients (median best change -14%, range -3.2% to -35%) (Figure 1). Symptom improvement was observed in 5 out of 6 evaluable patients (median best change -70%, range -32 to -100%). A panel of cytokines were evaluated in plasma samples obtained at baseline and during TP-3654 treatment. Reductions in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) were observed after TP-3654 treatment (Figure 2). Patients with higher cytokine reductions correlated with higher reduction in total symptom score. Enrollment is ongoing, updated data will be presented. Conclusions: The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PACIFICA: A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician's Choice in Patients with Primary or Secondary Myelofibrosis and Severe Thrombocytopenia

Background: Myelofibrosis is a rare bone marrow disorder that is characterized by clonal proliferation of myeloid cells and bone marrow fibrosis. Myelofibrosis belongs to the group of BCR/ABL1 negative myeloproliferative neoplasms. Patients with myelofibrosis and severe thrombocytopenia (platelet counts <50x109/L) are generally older, with more advanced disease and increased risk of bleeding, higher rates of anemia and complex/unfavorable cytogenetics, and shortened overall survival compared to patients with higher platelet counts. So far, treatment options for patients with myelofibrosis and severe thrombocytopenia are limited due to the high incidence of treatment-related thrombocytopenia when other JAK inhibitors are used. Pacritinib is an oral JAK2/IRAK1/ACVR1 inhibitor with demonstrated clinical activity in myelofibrosis in two phase 3 studies and a phase 2 dose-finding study; all included patients with severe thrombocytopenia. The PACIFICA trial (NCT03165734) is designed to confirm efficacy and safety of pacritinib 200 mg twice daily vs physician's choice (P/C) therapy in patients with myelofibrosis and severe thrombocytopenia. Study Design: PACIFICA is a multinational, multicenter, randomized, controlled phase 3 trial of pacritinib vs P/C in adults with primary or secondary myelofibrosis with DIPSS intermediate- or high-risk disease, ECOG performance status 0-2, platelet counts <50 x 109/L, limited prior JAK2 inhibitor therapy (up to 270 days of low-dose ruxolitinib or up to 90 days of any JAK2 inhibitor), or JAK2 inhibitor naïve, and not candidates for stem cell transplant (Figure 1). Additional exclusion criteria include recent grade ≥2 cardiac or hemorrhagic events, left ventricular ejection fraction <50%, QTc >450 msec, or use of medications that increase risk of hemorrhage or QTc prolongation. Patients are randomized 2:1 to continuous pacritinib 200 mg twice daily or P/C (low-dose ruxolitinib [no more than 10 mg/day], danazol, corticosteroids, or hydroxyurea). Following regulatory feedback an amendment was initiated, and the study was updated to have co-primary endpoints involving both spleen volume reduction (SVR) and total symptom score (TSS). The co-primary endpoints are the proportion of patients achieving a ≥35% SVR and the proportion achieving a ≥50% reduction in modified TSS from baseline at week 24. To account for co-primary endpoints, the sample size was adjusted from 348 to 399 patients to provide 85% power to detect a difference between pacritinib and P/C. Secondary objectives include Patient Global Impression of Change response at week 24, overall survival, and safety. Tertiary endpoints include leukemia-free survival, hematologic improvement, fatigue improvement (based on PROMIS v.1.0 - Fatigue - Short Form 7a), changes in biomarkers and gene expression, and proportion of patients who experience a major adverse cardiac event (MACE). Given the US approval of pacritinib, PACIFICA is currently enrolling outside of the US at ~100 sites worldwide. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BMS-986158, a Potent BET Inhibitor, As Monotherapy and in Combination with Ruxolitinib or Fedratinib in Intermediate- or High-Risk Myelofibrosis: First Results from a Phase 1/2 Study

Background Bromodomain and extraterminal (BET) proteins play a role in cancer-cell proliferation, survival, and oncogenic progression, providing a rationale for using inhibitors of BET as anticancer drugs. BET inhibitors (BETi) alone and in combination with Janus kinase (JAK) inhibitors have been demonstrated to reduce inflammatory signals and disease burden in mouse myelofibrosis (MF) models, and combined inhibition of BET-mediated pathways and the JAK-STAT pathway has shown additional benefits for patients (pts) with MF. BMS-986158 is an orally bioavailable, potent, and selective small-molecule BETi that has demonstrated a dose-proportional pharmacokinetic profile with linear increases in exposure, as well as time- and dose-dependent modulation of BET target gene expression (Hilton J et al. Ann Oncol 2018;29(suppl 8):1429). BMS-986158 is being evaluated in pts with MF, alone and in combination with the JAK inhibitors ruxolitinib (RUX) or fedratinib (FED), in the CA011-023 study (NCT04817007). Here, we present initial safety and efficacy data from the dose-escalation parts (1A and 1B) of this study. Methods CA011-023 comprises a dose-escalation phase with BMS-986158 + RUX in RUX-naive pts (Part 1A) or BMS-986158 + FED in pts with previous RUX treatment (Part 1B), and a dose-expansion phase at the Recommended Phase 2 Dose (RP2D) evaluating BMS-986158 + RUX (Part 2A) or BMS-986158 ± FED (Part 2B). Eligible pts had primary or secondary MF, splenomegaly (spleen volume ≥ 450 cm3), ECOG performance status ≤ 2, and Dynamic International Prognostic Scoring System risk scores of intermediate-1 with symptoms, intermediate-2, or high. Planned dose levels for pts in Part 1A are BMS-986158 2.0 mg, 3.0 mg, and 4.5 mg once daily (QD) 5 days on/2 days off and RUX 15 mg twice daily. For pts in Part 1B, planned dose levels are BMS-986158 0.5 mg, 0.75 mg, 1.25 mg, and 2.0 mg QD 5 days on/2 days off and FED 400 mg QD. Primary objectives in the dose-escalation phase are assessment of safety and tolerability and determination of the maximum tolerated dose and/or RP2D of BMS-986158 in combination with RUX or FED. Secondary objectives include spleen volume reduction (SVR) from baseline. Assessment of pharmacodynamic markers, such as JAK2 variant allele, is an exploratory objective. Results As of May 31, 2022, 13 pts were treated, 6 with BMS-986158 + RUX (median 66 years [range, 36-81]; 100% male) and 7 with BMS-986158 + FED (median 62 years [range, 37-77]; 57% male). Grade 1/2 treatment-related adverse events (TRAEs) were reported in 3 (50%) pts in the BMS-986158 + RUX group and in 2 (29%) pts in the BMS-986158 + FED group. Grade 3 TRAEs considered to be related to the combination treatment reported in the BMS-986158 + RUX group were thrombocytopenia (2 pts [33%]), and neutropenia and hypertension (1 pt each [17%]). Grade 3 TRAEs considered to be related to the combination treatment in the BMS-986158 + FED group were anemia (2 pts [29%]) and thrombocytopenia (1 pt [14%]). No grade 4/5 TRAEs were reported for either combination. One dose-limiting toxicity (DLT; grade 3 thrombocytopenia leading to dose reduction of BMS-986158) was reported at the 2.0 mg dose level of BMS-986158 + RUX on cycle 1 day 19. No DLTs have been reported in pts treated with BMS-986158 + FED. No serious TRAEs or TRAEs leading to treatment discontinuation have been reported. Importantly, SVR was observed at Week 12 in all evaluable pts across both treatment groups and continued to deepen at Week 24 in evaluable pts. In the BMS-986158 + RUX group, 4/5 (80%) pts met SVR35 at week 12, and 2/2 (100%) pts met SVR35 at week 24. In the BMS-986158 + FED group 0/3 (0%) pts met SVR35 at week 12, and 1/2 (50%) pts met SVR35 at week 24 (Table 1). Pts with post-baseline spleen volume by MRI in Part 1B were treated at lower BMS-986158 dose levels (0.5 mg and 0.75 mg 5 days on/2 days off) compared to Part 1A (2 mg 5 days on/2 days off). Analysis of JAK2 variant allele frequency and determination of RP2D are ongoing. Conclusions Most TRAEs were grade 1/2 in severity, while grade 3 TRAEs were successfully managed with dose delays or modifications without leading to treatment discontinuation. Initial results demonstrate that BMS-986158 in combination with RUX or FED produced robust SVR in pts with MF, with responses that deepened beyond Week 12 under continued treatment. Enrollment is continuing in the dose-escalation cohorts to establish RP2D for both combinations. 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

An Updated Analysis on Safety and Efficacy of Avapritinib in Patients with Advanced Systemic Mastocytosis from the Explorer Clinical Study: Long-Term Efficacy and Safety

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm driven by KIT D816V mutations in ~95% of patients. Advanced SM (AdvSM) includes three subtypes: aggressive SM (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN; most common), all typically with poor prognoses. Avapritinib, an oral, highly selective inhibitor of KIT D816V, is approved in the USA for treatment of adult patients with AdvSM, and in Europe after ≥1 prior systemic therapy. Avapritinib is not recommended for the treatment of patients with AdvSM with platelet counts of <50×109/L. The aim of the multi-center, international, phase 1 EXPLORER (NCT02561988) clinical study was to determine maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and tolerability. Earlier data from this and the phase 2 PATHFINDER (NCT03580655) studies showed rapid, deep, and durable responses to avapritinib treatment regardless of prior therapy, AdvSM subtype, or presence of high-risk mutations. Here we present long-term analyses from EXPLORER showing sustained efficacy, deepening responses, mature progression-free survival (PFS), updated overall survival (OS), and consistent safety profile. Methods: Analyses included patients aged ≥18 years with centrally confirmed AdvSM who initiated 30-400 mg once daily avapritinib. Primary endpoints were MTD and RP2D, safety, and tolerability. Secondary endpoints included overall response rate (ORR) per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria defined as complete remission with full (CR) or partial (CRh) recovery of peripheral blood counts, partial remission, or clinical improvement, as well as changes in objective disease burden measures (bone marrow mast cell [BM MC] burden, serum tryptase, KIT D816V variant allele fraction [VAF], and spleen volume), PFS, and OS. Results: As of April 5, 2022, 69 patients with AdvSM were enrolled; 12% (n=8) had ASM, 19% (n=13) MCL, and 70% (n=48) SM-AHN. Median age (range) was 67 years (34-83), 59% were male, 30% had Eastern Cooperative Oncology Group performance status 2-3, and 59% had prior systemic therapy. Median duration of treatment (range) was 23 months (2-67); after 24 weeks most patients (69%) were receiving 100 mg or 200 mg daily. ORR (95% confidence interval [CI]) per mIWG-MRT-ECNM criteria for evaluable patients (N=57) was 77% (64-87) (Table) with ORR of 100% (40-100), 85% (55-98), and 72% (56-85), for ASM, MCL, and SM-AHN subtypes, respectively. There were 4 additional CRs (n=57) since the previous analysis of 53 evaluable patients at median follow-up of 23 months and ORR of 75%. Median duration of response (DOR) for all responders was not reached (NR). In patients with no prior therapy, median DOR (95% CI) was 38 months (22-not evaluable [NE]) and NR for patients with at least one prior therapy. Most patients had observed reductions in objective measures of disease burden including ≥50% reduction in BM MC burden (94%, n=61/69), serum tryptase (99%, n=68/69), KIT D816V VAF (75%, n=50/69), and ≥35% reduction in spleen volume (83%, n=55/69). 52 (80%) patients had total clearance of neoplastic BM MC aggregates. Median PFS (95% CI) in response-evaluable patients was 49 months (31-NE). With a median follow-up of 45 months, only 17 (25%) patients had disease progression, including 7 who progressed to acute myeloid leukemia. Median OS was NR in all AdvSM, ASM, and MCL, and was 46.9 months (95% CI 29.6-NE) in SM-AHN (Table, Figure). The most frequent treatment-related adverse events (TRAEs; any grade) were periorbital edema (64%), anemia (42%), thrombocytopenia (36%), nausea (33%), and peripheral edema (33%). Grade ≥3 TRAEs were observed in 74% of patients. There were no additional intracranial bleeding events since previous reports. Cognitive effects were experienced by 44% of patients, mostly grade 1 and 2. There was no negative impact on clinical efficacy despite 73% of patients having dose reductions or 83% having dose interruptions due to TRAEs. TRAEs led to discontinuations in 27% of patients. Conclusions: At almost 4 years of follow-up, survival benefit was ongoing with median OS not reached. Among all patients treated with avapritinib, rapid, durable responses were observed. Avapritinib was generally well tolerated with a safety profile consistent with previous reports. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Avapritinib As First-Line Therapy in Patients with Advanced Systemic Mastocytosis: Efficacy and Safety from the Pathfinder Clinical Study

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm driven by the KIT D816V mutation in ~95% of patients. Patients with advanced SM (AdvSM) have a poor prognosis and treatment options are limited. Avapritinib, an oral, potent, highly selective inhibitor of KIT D816V, is approved in the USA for treatment of adults with AdvSM, and in Europe after ≥1 prior systemic therapy. Avapritinib is not recommended for the treatment of patients with AdvSM with platelet counts <50×109/L. Data from the multi-center, international, phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) clinical studies demonstrated that responses to avapritinib treatment were rapid, deep, and durable regardless of prior therapy, AdvSM subtype, or presence of high-risk mutations. Here we present analyses from patients with AdvSM treated with avapritinib as first-line therapy in PATHFINDER. Methods: Analyses included adult patients with centrally confirmed AdvSM without prior antineoplastic treatment for AdvSM (treatment-naïve) who initiated 200 mg once-daily avapritinib in the PATHFINDER study. The primary endpoint was overall response rate (ORR), centrally evaluated according to the modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria defined as complete remission with full (CR) or partial (CRh) recovery of peripheral blood counts, partial remission (PR), or clinical improvement (CI). Secondary endpoints included, but were not limited to, mean change from baseline measures of disease burden (bone marrow mast cell [BM MC] burden, serum tryptase, blood KIT D816V variant allele fraction [VAF], and spleen volume), duration of response (DOR), time to response (TTR), overall survival (OS) and safety. Results: As of April 20, 2021, 107 patients with centrally confirmed AdvSM were enrolled, of whom 38 were treatment-naïve; 18% (n=7/38) had ASM, 74% (n=28/38) SM-AHN, and 8% (n=3/38) MCL. Median age (range) was 68 years (39-88), 53% were male, 16% had Eastern Cooperative Oncology Group performance status 2-3, and 95% exhibited KIT D816V. In 25 of 38 (66%) mIWG-MRT-ECNM response-evaluable patients, the ORR (95% CI) was 84% (n=21/25; 64-96) with 32% (n=8/25) achieving CR or CRh, 48% (n=12/25) achieving PR, and 4% (n=1/25) CI (Table). The median TTR (range) was 2.0 months (0.3-12.2). Median DOR across all subtypes was not reached at the time of analysis; however, the DOR rate (95% CI) was 100% (100-100) at 12 months and 86% (60-100) at 18 months. For patients with ASM, the DOR rate was 100% (100-100) at 12 and 18 months. In patients with SM-AHN, the DOR rate was 100% (100-100) at 12 months and 83.3% (53.5-100) at 18 months. After a median follow-up of 9.7 months, median OS in all patients was not reached. The OS rate was 96% (95% CI: 87-100) at 12 months and 88% (95% CI: 71-100) at 24 months. The OS rate at 12 months was 100% for patients with ASM or MCL and 94% (84-100) for patients with SM-AHN. At 24 months, OS rate was 86% (67-100) for patients with SM-AHN. In almost all patients, reductions of ≥50% in measures of disease burden including reduction in BM MC burden (84%, n=32/38), serum tryptase (95%, n=36/38), KIT D816V VAF (89%, n=34/38), and ≥35% reduction in spleen volume (66%, n=25/38) were observed. Total clearance of neoplastic MC aggregates in BM was achieved in 63% of patients (n=24/38). The most frequent (≥25% of N=38) treatment-related adverse events (TRAEs) were (any grade, grade ≥3) periorbital edema (53%, 5%), thrombocytopenia (45%, 21%), peripheral edema (37%, 3%), and anemia (26%, 13%). In total, 7 (18%) patients experienced cognitive effects, all grade 1 or 2; no intracranial bleeding events and no treatment-related deaths were reported. 28 (74%) patients had dose reductions and 25 (66%) had dose interruptions due to TRAEs. Thrombocytopenia was the most common TRAE leading to dose reduction (21%, n=8/38) and dose interruption (26%, n=10/38). 4 (10%) patients discontinued treatment due to TRAEs; 1 discontinuation each was due to neutropenia, thrombocytopenia, cognitive effects, and worsening weight loss. Conclusions: Avapritinib demonstrated a high level of efficacy as the first-line therapy for patients with AdvSM across all disease subtypes with an ORR of 84% and an OS rate of 88% at 2 years. Avapritinib treatment with a 200 mg once-daily starting dose was generally well-tolerated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fedratinib Induces Cytokine Changes Correlating with Clinical Response in Ruxolitinib Exposed Myelofibrosis Patients: Biomarker Analysis from the Freedom Trial

Background: Myelofibrosis (MF) is characterized by driver mutation (JAK2, CALR and MPL) mediated hyperactivity of the JAK-STAT signaling pathway, bone marrow fibrosis, impaired hematopoiesis, and splenomegaly /extramedullary hematopoiesis. Ruxolitinib (rux), a JAK inhibitor (JAKi), is the standard of care for higher risk MF patients. In 2019, the US FDA approved Fedratinib, a second JAKi that binds to both the ATP and substrate binding sites of the JAK2 kinase domain. The phase II JAKARTA2 study demonstrated that fedratinib is clinically efficacious in previously rux exposed patients. In the current work, through biomarker analysis of the phase 3b FREEDOM data, we sought to identify changes to the cytokine profile in fedratinib treated, previously rux exposed patients. In addition, we explored potential mechanism of fedratinib efficacy. Methods: In the FREEDOM study, patients (N=38) received fedratinib (400 mg/day) once daily in 28-day cycles until lack of efficacy, intolerance, or disease progression. Primary endpoint was proportion of subjects with ≥35% reduction of spleen volume assessed by magnetic resonance imaging (MRI) at the end of cycle 6 (SVR35). In the FREEDOM biomarker cohort, mutational detection was performed in immunomagnetically-enriched CD66+ myeloid cells using the MLL myeloid panel targeting 74 genes. Variants and indels were called using Pisces and Pindel, followed by annotation to COSMIC, ClinVar, gnomAd (non-cancer), and dbNSFP data bases. Clinically relevant somatic mutations were considered for analysis. Rules-Based Medicine's (RBM) HumanMAP v2.0 panel targeting 85 cytokines was used to measure changes in serum cytokine levels. 51 cytokines with variance > 0.3 on aggregated data were used for analysis. Pearson correlation analysis was used to compute Rho values between response and cytokine changes. Kinome screen was performed using the thermofisher Lanthascreen Eu kinase binding assay and the reaction biology kinome assay. Results and discussion Therapy related disease modifying effect in MF is currently being explored through ability to control variant allele frequency (VAF), reduce inflammation, minimize bone marrow fibrosis, in conjunction with restoration of normal hematopoiesis. In our study, JAK2 V617F mutation was detected in 48% (N=13/27) of total mutational biomarker cohort (N=27/38). However, response was independent of JAK2 V617F mutational status thereby decoupling this mutation with response/disease modification at cycle 6. As a next step, we evaluated if fedratinib treatment results in cytokine alterations that correlate with clinical response. Cytokine evaluation and paired analysis between cycle 1 and end of cycle 6 revealed increases in adiponectin, carcinoembryonic antigen (CEA), EPO and ferritin and decrease in EN-RAGE, IL-16, IL-18, IL1RA, TIMP-1, TNFR2, MPO, VCAM1 and VEGF (P < 0.001). Correlation analysis revealed adiponectin, CEA, ferritin, haptoglobin, erythropoietin and CCL18 to have significant correlation (P < 0.05) with response. The responders had the largest alteration in cytokine levels coupling these cytokines to response. Overall, fedratinib upregulates anti-inflammatory cytokines and reduces inflammatory cytokines which could contribute to symptom burden control and spleen volume reduction. These results in a rux exposed patient cohort suggests that fedratinib could have a differentiated profile from rux. To further investigate these differences, we performed kinome screens with two in vitro assays. Results indicate that fedratinib has a broader kinase inhibitory profile than rux. Thus, fedratinib could modulate additional signaling pathways explaining potential efficacy in rux exposed patients. Conclusion: Our biomarker analysis in previously rux exposed patients, shows that fedratinib triggers cytokine changes that correlate with response independent of mutational status. This suggests that at least at early timepoints, cytokine changes could be a potential biomarker for disease modifying effect. In addition, our in vitro analysis differentiates rux and fedratinib based on the inhibited kinases and altered biological pathways. Taken together our results indicate that while both rux and fedratinib are JAK inhibitors, they are well differentiated allowing fedratinib to be effective in previously rux exposed patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal