Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis
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SUBMITTER: Oh S
PROVIDER: S-EPMC10561048 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.
| S-EPMC10778144 | biostudies-literature
Project description:We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis.
| S-EPMC4232180 | biostudies-literature
Project description:Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100 000× 10(9)/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a ≥35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a ≥50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT00745550.
| S-EPMC4490373 | biostudies-literature
Project description:Myelofibrosis (MF) is a myeloid malignancy associated with a heavy symptomatic burden that decreases quality of life and presents a risk for leukemic transformation. While there are limited curative treatments, the recent discovery of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway dysregulation has led to many clinical investigations for new treatment approaches. This review provides practical knowledge on the disease state, an overview of treatment options, and specifically focuses on the efficacy and safety of pacritinib in the management of MF. Pacritinib is a novel selective inhibitor of JAK2 and FMS-related tyrosine kinase 3 (FLT3) currently in Phase III trials for the treatment of MF. Thus far, studies have demonstrated clinical efficacy in reducing splenomegaly and constitutional symptoms. Common adverse events were gastrointestinal in nature, while hematologic toxicity was limited. However, it was announced that all ongoing clinical trials on pacritinib have been placed on hold by the US Food and Drug Administration in February 2016, due to concerns for increased intracranial hemorrhage and cardiac events. With comprehensive risk-benefit analysis of clinical trial data, the utility of pacritinib in the management of MF may be more clearly defined.
| S-EPMC4863690 | biostudies-literature
Project description:We evaluated pomalidomide with prednisone for myelofibrosis (MF) with significant anemia (hemoglobin < 10 g/dL). Patients (n = 29; 18 RBC-transfusion dependent) received 0.5mg pomalidomide daily in continuous 28-day cycles with prednisone given for the first 3 cycles only. Six (21%) patients responded (median response duration 11.4 months), including four who achieved RBC-transfusion-independence per the Delphi criteria and two who achieved clinical improvement (in platelets and spleen, respectively) per the International Working Group for Myelofibrosis Research and Treatment criteria. Grade 3 toxicity occurred in 1 patient (fatigue). Pomalidomide with prednisone is safe therapy with modest activity in patients with MF and anemia. ClinicalTrials.gov Identifier: NCT00946270.
| S-EPMC4157096 | biostudies-literature
Project description:Myelofibrosis (MF) has heterogeneous clinical manifestations, with some patients exhibiting a myelodepletive phenotype characterized by cytopenias and an absent or low JAK2V617F allele burden. Ruxolitinib may be less effective in these patients. We assessed the efficacy of pacritinib, a JAK2/IRAK1 inhibitor, in MF patients with low JAK2V617F allele burden. In this post hoc analysis of the PERSIST-1 and -2 trials, patients with MF randomized to pacritinib or best available therapy (BAT) were stratified by JAK2V617F allele burden quartile for spleen response of ≥35% and improvement in total symptom score of ≥50%. Five hundred thirty-six patients were included. Patients with lower JAK2V617F allele burden had smaller baseline spleens and lower hemoglobin and platelet counts as compared with higher allele burden patients. Among pacritinib-treated patients, spleen responses were observed across all JAK2V617F allele burden quartiles and in JAK2V617F- disease. No spleen responses were observed among BAT-treated patients with allele burden ≤50% or JAK2V617F- disease. The intention-to-treat response rate was significantly higher on the pacritinib arm for JAK2V617F- disease (23.0% vs 0%; P = .033), and for the lowest allele burden quartiles (0%-25%: 20.9% vs 0%, P < .001; 25%-50%: 15.4% vs 0%, P = .020). There were significantly more symptom responders with pacritinib vs BAT in the 0% to 25% and 25% to 50% cohorts. Pacritinib treatment led to superior spleen and symptom burden reduction compared with BAT in patients with absent or low JAK2V617F allele burden, suggesting that pacritinib may be uniquely suited for patients with myelodepletive MF.
| S-EPMC7724916 | biostudies-literature
Project description:Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.
| S-EPMC7509854 | biostudies-literature
Project description:BackgroundPacritinib (SB1518) is a highly selective kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. This multicenter phase 1/2 study evaluated the maximum tolerated dose (MTD), safety, and clinical activity of pacritinib in patients with myelofibrosis (MF) and other advanced myeloid malignancies.MethodsIn the phase 1 dose-escalation part of the study, 43 adults with advanced myeloid malignancies received pacritinib 100 to 600 mg once daily (QD). In the phase 2 part of the study, 31 adults with refractory or intermediate- or high-risk newly diagnosed MF and any degree of cytopenia received pacritinib 400 mg QD. The primary endpoint is a ≥35% reduction in spleen volume at week 24 as determined by magnetic resonance imaging.ResultsFive patients (11.6%) experienced a dose-limiting toxicity during cycle 1 of phase 1. The clinical benefit rate was 86.0% (13 patients achieving clinical improvement and 24 patients having stable disease). The MTD was established at 500 mg QD, and the recommended phase 2 dose was 400 mg QD. In phase 2, the primary endpoint was achieved by 23.5% of evaluable patients (4/17), with 47.4% (9/19) achieving a ≥50% spleen length reduction at week 24 as measured by physical examination. At week 24, 38.9% of evaluable patients (7/18) achieved a ≥50% decrease in MF Quality of Life and Symptom Assessment total score. Gastrointestinal toxicities were the most common adverse events and were predominantly grade 1/2 in severity. Grade 3/4 anemia was reported in 5/31 patients and grade 3/4 thrombocytopenia was reported in 3/31 patients. The most frequent AEs considered to be treatment related were diarrhea (28/31), nausea (15/31), vomiting (9/31), and fatigue (4/31). Grade 3 treatment-related AEs were reported in seven patients (22.6%), four of whom had diarrhea. No grade 4/5 treatment-related AEs were reported. No leukopenia, neutropenia, or lymphopenia were reported.ConclusionsPacritinib was well tolerated and demonstrated clinical activity in MF. The study suggests that pacritinib has unique characteristics, namely a lack of substantial myelosuppression and manageable side effects, making it an attractive target for further evaluation in MF.Trial registrationRetrospectively registered at www.clinicaltrials.gov (# NCT00719836 ) on July 20, 2008.
| S-EPMC5146859 | biostudies-literature
Project description:Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients. Thirty-three patients benefitting from PAC on clinical trial prior to the hold were allowed to resume therapy on an individual, compassionate-use basis. This study reports the detailed outcomes of 19 of these PAC retreatment patients with a median follow-up of 8 months. Despite a median platelet count of 49 × 109/L at restart of PAC, no significant change in hematologic profile was observed. Grade 3/4 adverse events of epistaxis (n = 1), asymptomatic QT prolongation (n = 1), and bradycardia (n = 1) occurred in three patients within the first 3 months of retreatment. One death due to catheter-associated sepsis occurred. The median time to discontinuation of PAC therapy on compassionate use for all 33 patients was 12.2 (95% CI 8.3-NR) months. PAC retreatment was associated with modest improvement in splenomegaly without progressive myelosuppression and supports the continued development of this agent for the treatment of MF second line to ruxolitinib or in the setting of treatment-limiting thrombocytopenia.
| S-EPMC6019145 | biostudies-literature
Project description:ImportanceMyelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib.ObjectiveTo compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia.Design, setting, and participantsFor this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly.InterventionsPatients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT.Main outcomes and measuresCoprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data.ResultsOverall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%).Conclusions and relevanceIn patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms.Trial registrationclinicaltrials.gov Identifier: NCT02055781.
| S-EPMC5885169 | biostudies-literature