Pacritinib Demonstrates Efficacy, Tolerability in Patients with Myelofibrosis and Thrombocytopenia

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October 16, 2024

Author(s): Alexandra Gerlach, Associate Editor

Pacritinib (Vonjo; CTI BioPharma Corp) demonstrated improved spleen volume reduction (SVR) and was tolerable in patients with myelofibrosis (MF) and thrombocytopenia, according to data published in the European Journal of Hematology. The findings offer deeper insights into the capabilities of Janus kinase (JAK) inhibitors to improve SVR and overall survival (OS), contradicting prior studies advising against use of JAK inhibitors for thrombocytopenia.1

Further studies are needed to identify the long-term safety and efficacy of the therapy.

Image Credit: © AkuAku – stock.adobe.com

Thrombocytopenia, a condition that occurs when blood platelet counts are too low, is a disease-related feature of MF that leads to poorer prognoses impacting both OS and leukemia-free survival. It can be caused by a variety of factors including ineffective hematopoiesis, splenic sequestration, and treatment-related effects. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curable treatment for MF but is only available for a minority of patients. However, the development of JAK inhibitors has expanded treatment options for patients with MF and may show promise for treatment of thrombocytopenia.2

Pacritinib is a JAK inhibitor used to treat intermediate or high-risk MF that targets JAK2 and FMS-like tyrosine kinase 3. It was approved by the FDA in 2022 for treatment of both primary and secondary MF in patients with platelet counts < 50 x 109/L. In the phase 3, randomized, controlled PERSIST-2 trial (NCT02055781), pacritinib demonstrated favorable efficacy and tolerability compared with best available therapy (BAT) in patients with MF and thrombocytopenia.3-5

In the study, approximately 300 patients with thrombocytopenia and primary or secondary myelofibrosis were randomized in a 1:1:1 ratio to receive either pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT. The primary end points included SVR of ≥ 35% reduction in spleen volume from baseline to week 24 as measured by MRI or computed tomography, as well as ≥ 50% reduction in the total symptom score from baseline to week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form 2.0.1,5

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Dr Klisovic on a Case Discussion of Momelotinib in Myelofibrosis With Anemia

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October 16, 2024

Author(s): Rebecca Klisovic, MD

Fact checked by: Ashling Wahner, Ryan Scott

Rebecca Klisovic, MD, chief medical information officer, University Hospitals Seidman Cancer Center, discusses 3 case studies about patients with myelofibrosis that were presented during an OncLive® State of the Science Summit™ on hematologic oncology, which she chaired.

The first case that was discussed was on a 71-year-old male patient with newly diagnosed myelofibrosis with splenomegaly, mild anemia, a high symptom burden, and intermediate-2–risk disease, Klisovic begins. The consensus among the panelists was that this patient required treatment due to his spleen size, symptoms, and anemia, she says. Although some oncologists who participated in the discussion considered using ruxolitinib (Jakafi) because of its early survival data, the panel predominantly favored momelotinib (Ojjaara), given this agent’s potential benefit in patients with anemia, she explains.

The second case was on a 62-year-old female patient with myelofibrosis who had already received ruxolitinib and had comorbidities including symptom scoring and a large spleen, according to Klisovic. This patient also had anemia, with a hemoglobin level of 7.2 g/dL, she reports. Therefore, the focus on improving anemia made momelotinib a clear treatment choice in this setting, she adds. Whereas other case presentations prompted treatment debates between the panelists, this case was more clear cut, especially since this patient was refractory to ruxolitinib, Klisovic emphasizes.

The third case was on a 54-year-old female patient with newly diagnosed myelofibrosis that was characterized by both anemia and thrombocytopenia, as well as a platelet count of 34/µL, Klisovic says. This discussion centered around the use of pacritinib vs momelotinib, informed by the patient’s low platelet count, she explains. Some discussants raised concerns about the patient’s eligibility for momelotinib clinical trials, which have enrollment criteria with varying platelet cutoffs, she notes. Despite these concerns, most participants favored the use of pacritinib (Vonjo) due to this agent’s efficacy in managing thrombocytopenia, she reports. However, some discussants noted that momelotinib could also be a viable treatment option for patients similar to the one in this case, depending on clinical trial criteria and individual patient factors, she concludes.

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Luspatercept Shows Promise in Alleviating Myelofibrosis-Associated Anemia

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Ryner Lai

Luspatercept shows promise in alleviating myelofibrosis-associated anemia and has a safety profile consistent with previous research, according to a study published in Blood Advances. 

The most common therapeutics in myelofibrosis include erythropoiesis-stimulating agents, androgens, corticosteroids, and lenalidomide. However, many of these are associated with significant adverse events (AEs). Researchers are investigating therapeutic agents that are highly effective against anemia while having an acceptable safety profile.

Luspatercept is an erythropoietin maturation agent that has been approved in the United States for treating anemia in some individuals with myelodysplastic syndromes or beta-thalassemia who need red blood cell (RBC) transfusion. This therapeutic has been shown to induce transfusion independence in approximately 38% of patients. Researchers sought to explore if the success of luspatercept can be replicated in myelofibrosis and conducted a study to assess its use in patients with myelofibrosis-associated anemia, with or without transfusion dependence.

Researchers reported results from a phase 2, multicenter, open-label trial that assessed the use of luspatercept in myelofibrosis. They recruited adult patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis who possessed an Eastern Cooperative Oncology Group performance status score of 2 or less and had evidence of anemia. Patients were divided according to their transfusion dependence status and whether they were on ruxolitinib therapy.

Participants received subcutaneous luspatercept at a dose of 1.0 mg/kg (with titration up to 1.75 mg/kg every 21 days for a total of 24 weeks). They were then assessed for their disease response at day 169; if they demonstrated clinical benefits, they could continue receiving luspatercept treatment for approximately 2 years longer. The primary endpoint of this study was anemia response at the end of the 24-week period.

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Selinexor Paves the Way for More Affordable, Effective Treatment Options in Myelofibrosis

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October 14, 2024

Author(s): Courtney Flaherty

Fact checked by: Caroline Seymour

Attempts to leverage drugs that are effective in combination, such as selinexor (Xpovio), as single agents for the management JAK inhibitor–naive myelofibrosis reflects the need for improved personalization of therapy according to individual factors, and mitigation of financial toxicities associated with standard JAK inhibitor–based regimens, according to Joseph M. Scandura, MD, PhD.

Selinexor, an oral exportin 1 inhibitor potentially targeting both JAK/STAT and non-JAK/STAT pathways, has previously demonstrated efficacy when used in combination with ruxolitinib (Jakafi) in the phase 1/3 SENTRY trial (XPORT-MF-034; NCT04562389). Results from the phase 1 portion of the trial showed a 35% or greater reduction in spleen volume (SVR35) at weeks 12 and 24 in 71% and 79% of patients treated with 60 mg of selinexor plus ruxolitinib in the intention-to-treat (ITT) population (n = 14), respectively. Moreover, 58% of patients who achieved symptom improvement of at least 50% (TSS50) at week 24 in the ITT population (n = 12) remained in response at the data cutoff of August 1, 2023.1,2

In July 2023, the FDA granted fast track designation to single-agent selinexorfor the treatment of patients with myelofibrosis, including primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis.3

Selinexor will be evaluated in combination with ruxolitinib in the phase 3 portion of SENTRY,1 and as monotherapy in the phase 2 SENTRY-2 study (XPORT-MF-044; NCT05980806) in JAK inhibitor–naive patients with myelofibrosis.4

“The big thing that differentiates the [SENTRY-2] study is that it’s testing selinexor [alone] and only adding the JAK inhibitor [to selinexor] when it is needed, and it matches the patients’ characteristics. It’s not a one-size-fits-all study,” said Scandura, who is an associate attending physician at NewYork-Presbyterian Hospital and an associate professor of medicine at Weill Cornell Medical College, Cornell University, in New York. “This allows patients to be treated similarly to clinical practice in the context of a clinical trial…and allows us to [learn whether] one of these drugs works much better with selinexor than the other.”

In an interview with OncLive®, Scandura discussed selinexor’s mechanism of action, reviewed clinical data supporting its potential use both alone and in combination with JAK inhibitors in myelofibrosis, and highlighted how approval of this agent as monotherapy could help alleviate financial burdens associated with JAK inhibitor–based regimens.

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Update: Ruxolitinib Beats Best Available Therapy in Treating Polycythemia Vera

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October 14, 2024

Author(s): Mary Caffrey

An updated meta-analysis confirms that ruxolitinib, the Janus kinase (JAK) 1/JAK2 inhibitor sold as Jakafi, offers improvements in key measures of efficacy compared with best available therapy (BAT) for patients with polycythemia vera (PV),1 a rare, slow-progressing disorder that causes the blood to make too many red blood cells.

Caused by a genetic mutation, PV is not typically fatal on its own, but it can cause dangerous blood clots and damage to the spleen. In a small number of cases, it progresses to more aggressive forms of blood cancer.

The latest results were reported in the journal APMIS,1 formerly known as Acta Pathologica, Microbiologica, et Immunologica Scandinavica.

The analysis followed a 2020 meta-analysis involving 16 studies that appeared in Blood Advances.2 That analysis included evidence from 4 randomized controlled trials and included 663 patients; the authors estimated a thrombosis incidence of 3.09% per year for ruxolitinib vs 5.51% for BAT, but noted that globally, this did not reach significance (P = .098). “A clinical trial on selected patients at high risk of thrombosis would be warranted, but its feasibility is questionable,” the authors wrote.2

The current analysis examines ruxolitinib’s efficacy and safety compared BAT in 1061 patients with PV and in hydroxyurea-resistant and intolerant patients with PV across 6 studies, with a cutoff of November 2023. The patients included 620 on BAT and 441 on ruxolitinib. According to the investigators:

  • Those taking ruxolitinib showed higher hematocrit control (P = .015) and treatment response (P = .04) compared to BAT.
  • Patients taking ruxolitinib had significantly improved Myeloproliferative Neoplasms-Symptom Assessment Form scores (MPN-SAF), P < .01.

However, on the safety front, patients with PV treated with ruxolitinib had higher rates of nonmelanoma skin cancer (P < .01), as has been previously documented.

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NCCN Guidelines for MPN Reflect New Drugs, Focus on Clinical Trials

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October 11, 2024

Author(s): Interview by Mary Caffrey

Understanding of myeloproliferative neoplasms (MPNs), a group of blood cancers that occur when a person’s bone marrow makes too many blood cells, has increased since discovery of the JAK2 mutation in 2005.1 Still, the first set of National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPNs, which include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), did not appear until 2017, and through 2022 there were few updates.

But since then, the NCCN Guidelines for MPNs have had multiple updates per year, with the latest in August 2024,2 a sign of increased activity in the field. In an interview with The American Journal of Managed Care® (AJMC®), Aaron Gerds, MD, MS, who chairs the panel handling the MPN updates, confirms that the more frequent updates reflect new approvals and more options for patients.

Aaron Gerds, MD, MS | Image credit: Cleveland Clinic

“We are regularly looking at the published literature and updates in the field in order to make sure that these guidelines are very nimble, and that they are adjusted to reflect current practice,” said Gerds, who is associate professor of medicine and deputy director for clinical research at the Cleveland Clinic Taussig Cancer Institute. Some guidelines might be updated every 5 to 10 years; but if there’s nothing new, “there’s not a lot of sense in updating things in a large way.”

Conversely, updates often occur when new therapies are approved or become available, Gerds said, as was the case in September 2023 when momelotinib (Ojjaara), the fourth Janus kinase (JAK) inhibitor, became available for the treatment of intermediate or high-risk MF, including primary MF or secondary MF, and post-PV, and post-ET in adults with anemia.3

The most recent update puts a major focus on clinical trials; in many circumstances, they are listed as the preferred option over FDA-approved therapies; in the AJMC interview, Gerds explains how a pair of phase 3 trials involving ruxolitinib combinations will produce results very soon.

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Precipio Expands Bloodhound™ MPN Panel by Adding CALR Mutation Subtyping

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The unique assay enables laboratories to provide clinicians with more informed treatment decisions for their patients

| Source: Precipio, Inc.

NEW HAVEN, Conn., Oct. 08, 2024 (GLOBE NEWSWIRE) — Specialty cancer diagnostics company Precipio, Inc. (NASDAQ: PRPO) announces the launch of a new version of its Bloodhound MPN (Myeloproliferative Neoplasm) panel that is now able to distinguish between CALR type 1 and type 2 mutations. The CALR mutation data plays a critical role in disease prognosis and therapeutic decision-making. This differentiation aligns with the latest National Comprehensive Cancer Network (NCCN) guidelines released in August of this year (Version 2.2024—August 8, 2024).

This is the only quantitative PCR-based panel of its kind on the market that distinguishes between CALR Type 1 and Type 2 alongside the other genes relevant to the molecular evaluation of MPN.

“As science and discovery constantly evolve the diagnostic world, Precipio is committed to maintaining its competitive advantage and being at the forefront of our industry,” said Ilan Danieli, Precipio CEO. “Our customers and their patients will continue to benefit from access to cutting-edge technologies combined with the highest clinical value, enhancing patient care.”

Clinical Significance of CALR Subtyping in MPN Management
The inclusion of CALR mutation subtyping is a direct response to the evolving landscape of MPN patient care where understanding the specific type of CALR mutation can influence treatment strategies and outcomes.

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JAK Inhibitors Diversify the Field of Myelofibrosis Symptom and Spleen Management

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October 8, 2024

Author(s): Ashling Wahner

Fact checked by: Courtney Flaherty

The wealth of JAK inhibitors available for managing myelofibrosis invites the development of increasingly personalized treatment plans based on individual patient needs and disease characteristics, according to Idoroenyi Amanam, MD.

“We’ve come a long way since ruxolitinib [Jakafi] was FDA approved,” Amanam said in an interview with OncLive®. “We have a better understanding of which patients benefit from JAK inhibitors, and we are clearer on the shortcomings of JAK inhibitors.”

In the interview, Amanam discussed how JAK inhibitors measure up against other available therapies in myelofibrosis; patient characteristics that are most likely to indicate benefit with JAK inhibitors; and which of these agents he is likely to choose based on patients’ platelet counts, symptom burden, and treatment history.

For instance, Amanam highlighted the importance of pacritinib (Vonjo) in the myelofibrosis treatment paradigm. Pacritinib was approved by the FDA in 2022 for the treatment of select adult patients with intermediate- or high-risk myelofibrosis with thrombocytopenia based on findings from the phase 3 PERSIST-2 trial (NCT02055781), in which 29% patients who received the agent achieved a spleen volume reduction (SVR) of at least 35%. Among patients who received best available therapy, the SVR rate was 3%.1

He also explained the role of momelotinib (Ojjaara) for patients with anemia. Momelotinib was FDA-approved in 2023 for the treatment of adult patients with intermediate- or high-risk myelofibrosis and anemia based on data from the phase 3 MOMENTUM trial (NCT04173494).2 In MOMENTUM, 25% of patients who received momelotinib (n = 32/130) experienced a Myelofibrosis Symptom Assessment Form 4.0 total symptom score reduction of at least 50% vs 9% of those who received danazol (Danocrine; n = 6/65), translating to a treatment difference of 16% (95% CI, 6%-26%; P < .0095).3

Amanam is an assistant professor in the Division of Leukemia in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

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Study Findings Suggest Use of Fedratinib as Treatment in the Second Line for Myelofibrosis

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October 3, 2024

Author(s): Alexandra Gerlach, Associate Editor

Fedratinib (Inrebic; Bristol Myers Squibb) demonstrates safety and efficacy as a second line Janus kinase inhibitor (JAKi) option to reduce spleen size after ruxolitinib (Jakafi; Incyte Corp) failure or intolerance in patients with myelofibrosis (MF), according to results from the FREEDOM2 trial (NCT03952039). The study compared treatment with fedratinib and the best available therapy (BAT) in intermediate- or high-risk primary MF.1

The results support the potential of fedratinib as a JAK-2 inhibitor in the second line as a therapeutic option for patients intolerant or resistance to ruxolitinib.

Image Credit: © NeuroGraphix Studio – stock.adobe.com

MF is an uncommon, fatal myeloproliferative neoplasm characterized by the overproduction hematopoietic stem cells, leading to increasingly reduced red blood cell production. As a result, many patients with MF, approximately 40%, have anemia at diagnosis, of which an estimated 25% are RBC transfusion dependent (TD). In most cases, patients will develop chronic anemia and TD as the disease progresses.2,3

Ruxolitinib is a JAKi approved by the FDA in 2011 and indicated for the treatment of patients with intermediate or high-risk myelofibrosis, including primary MF (PMF), post-polycythemia vera MF (post-PV MF) and post-essential thrombocythemia MF (post-ET MF). Despite its success for some patients, the response rate is less than 50% and survival rates after ruxolitinib discontinuation are poor. Many patients develop ruxolitinib intolerance and become relapsed or refractory.4,5

Fedratinib is an orally available, small molecule inhibitor of JAK-2, which is often mutated in patients with MF. It was approved in 2019 by the FDA as a therapeutic option for intermediate- or high-risk primary or secondary MF and has demonstrated clinically meaningful benefits for patients. In multiple preregistration trials, fedratinib resulted in reduction spleen size and improvement in symptoms in 40% to 50% of patients, including those who were resistant or intolerant to ruxolitinib.6

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Novel Biomarker Could Predict MF Progression

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Özge Özkaya, MSc, PhD

C-mannosyl tryptophan could be a novel biomarker to predict the progression of myelofibrosis (MF) in thrombocytosis of myeloproliferative neoplasms, according to a new study published in the journal Scientific Reports.

“Present studies evaluating C-mannosylation using this novel assay for progression to overt MF in [essential thrombocythemia] may provide promising future directions,” the researchers wrote.

To assess C-mannosyl tryptophan in human hematological diseases, the team, led by Shinobu Tamura, PhD, from the Wakayama Medical University in Japan, quantified the levels of the amino acid in the serum of 94 healthy people using hydrophilic interaction liquid chromatography.

They found that the platelet count was positively correlated with the levels of C-mannosyl tryptophan in the serum.

They then assessed the clinical significance of C-mannosyl tryptophan in thrombocytosis of myeloproliferative neoplasms, including essential thrombocythemia, by measuring the levels of the amino acid in the serum of 34 patients with thrombocytosis of myeloproliferative neoplasms and compared this to the levels in the serum of 52 patients with other hematological disorders.

They found that serum levels of C-mannosyl tryptophan were significantly higher in patients with thrombocytosis. Moreover, the amino acid’s serum levels were inversely correlated with anemia, which was related to MF.

Finally, the researchers analyzed the bone marrow biopsy samples of 18 patients with essential thrombocythemia and measured the levels of C-mannosyl tryptophan in their serum at the same time. They found that 12 patients with bone marrow fibrosis had significantly higher levels of C-mannosyl tryptophan compared to the 6 patients without bone marrow fibrosis.

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