Tag Archives: clinical trial

Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling

Posted on by

May 24, 2025

Sivahari Prasad Gorantla, Michael Rassner, Kirstyn Anne Crossley,…Robert Zeiser & Justus Duyster

Abstract

Ruxolitinib is a potent JAK1/JAK2 inhibitor, approved for the treatment of primary myelofibrosis (PMF) patients based on the concept of inhibition of oncogenic signaling. However, the effect of ruxolitinib on JAK2-V617F allelic burden is modest, suggesting that inhibition of JAK2-V617F signaling-driven clone expansion is not the main mechanism of action. We evaluate whether ruxolitinib mainly blocks the proliferation of the malignant clone or exerts its effects also by targeting non-malignant cells. Therefore, we develop two JAK2-V617F-driven myeloproliferative neoplasm (MPN) mouse models harboring ruxolitinib resistance mutations. Mice carrying ruxolitinib-resistant JAK2-V617F-driven MPN respond to ruxolitinib treatment similar to mice with ruxolitinib-sensitive JAK2-V617F MPN with respect to reduction of spleen size, leukocyte count and pro-inflammatory cytokines in the serum. Ruxolitinib reduces pro-inflammatory cytokines in both stromal cells and non-malignant hematopoietic cells. Using a rigorous ruxolitinib resistance mutation approach, we can prove that ruxolitinib acts independent of oncogenic JAK2-V617F signaling and reduces the main features of MPN disease such as spleen size and leukocyte counts. Our findings characterize the mechanism of action for ruxolitinib in MPN.

Read more

 

Molecular Response to Therapy Linked With Event-Free Survival in PV

Posted on by

May 23, 2025

Author(s): Jared Kaltwasser

Fact checked by: Rose McNulty

Molecular response to therapy appears to correlate with event-free survival in patients with early polycythemia vera (PV), according to a new analysis. The findings were published in a research letter in the journal HemaSphere.1

While clonal expansion of JAK2V617F-mutated hematopoietic stem cells is implicated in almost all cases of PV, the potential implications of molecular response to therapy (MR) as demonstrated by reduced frequency of the variant allele have been disputed, the authors explained.

The findings also show that ropeginterferon alfa-2b is an effective therapy for molecular response in early polycythemia vera. | Image credit: fotogurmespb.- stock.adobe.com

The question is difficult to study, they noted, since the early onset of PV is associated with nonspecific symptoms. However, the authors cited a 2023 study assessing ruxolitinib (Jakafi; Incyte) in patients with high-risk PV found molecular response was correlated with superior outcomes, including event-free survival (EFS).2

In the new report, researchers examined data from the phase 3 PROUD-PV study and its extension trial, CONTINUATION-PV, to see whether there was a meaningful relationship between MR and EFS in patients with early-stage PV.1

The PROUD-PV trial involved participants with low- or high-risk PV requiring cytoreduction who were treatment naive or who had been pretreated with hydroxyurea for less than 3 years without resistance or intolerance. Participants were randomized on a 1:1 basis to receive either ropeginterferon alfa-2b (Besremi; PharmaEssentia) or hydroxyurea for 12 months. In CONTINUATION-PV, participants remained in their same treatment arm, though control-arm patients were allowed to switch from hydroxyurea to any standard treatment.

The final analysis of CONTINUATION-PV included 95 participants in the ropeginterferon alfa-2b cohort and 74 in the hydroxyurea/best available therapy control group. The median treatment duration for the two study arms was 6.3 years and 6.0 years, respectively.

The authors found that patients in the ropeginterferon alfa-2b arm had a reduction of median JAK2V617F variant allele frequency from 37.3% at baseline to 8.5% at year 6, with 66.0% of patients achieving MR. Patients in that cohort spent a median cumulative proportion of time in MR of 66.7%.

Ruxolitinib Plus Siremadlin Yielded Superior Spleen Volume Reduction in Patients With Myelofibrosis

Posted on by

May 20, 2025

Author(s): Alexandra Gerlach, Associate Editor

Data from the ADORE trial (NCT04097821) suggest combining ruxolitinib (Jakafi; Incyte Corp) with novel agents such as siremadlin (HDM201, Novartis), rineterkib (LTT462; Novartis), sabatolimab (MBG453; Novartis), crizanlizumab (Adakveo; Novartis), or NIS793 (Novartis) was superior to ruxolitinib monotherapy in patients with myelofibrosis (MF). The investigators reported improved spleen volume reductions (SVR), which were greatest in patients treated with ruxolitinib in combination with siremadlin.1

3D visualization of red blood cells | Image Credit: © Thipphaphone – stock.adobe.com

MF is a disease that falls under the umbrella of myeloproliferative neoplasms, which is a group of diseases characterized by the overproduction of red blood cells, white blood cells, or platelets in the bone marrow. In MF, there is an ongoing reduced production of red blood cells that leads to bone marrow fibrosis, extramedullary hematopoiesis, recurrent splenomegaly, and anemia. Other symptoms can include fatigue, nocturnal sweats, bone pain, enlarged spleen, and weight loss. can arise as a main disease (primary MF) or as a subsequent condition to essential thrombocythemia (post-ET MF) and polycythemia vera (post-PV MF). In some cases, MF can progress to acute myeloid leukemia.2

Janus kinase (JAK) inhibitors, such as ruxolitinib, are the standard of care for treatment and management of MF-related complications and have yielded significantly favorable outcomes; however, they are associated with various adverse effects (AEs). Ruxolitinib was initially approved in 2011 for first-line treatment of patients with intermediate- and high-risk MF, but the agent is known to be highly associated with increased risk of persistent or worsening anemia. Despite its widespread use, approximately 70% of patients discontinue treatment after about 5 years, with a third citing an inadequate reduction in spleen volume as a key reason.3,4

ADORE is a randomized, open-label, phase 1/2 open platform study evaluating the safety and efficacy of 5 novel agents with ruxolitinib in patients with MF. The trial utilized an innovative open platform design and enrolled 44 patients in part 1 of the trial who were treated with ruxolitinib in combination with 1 of 5 investigational agents: siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. The largest cohort (n = 23) received the combination of ruxolitinib (orally at a dosage of 5 mg) and siremadlin (orally at a dosage of 10, 20, or 40 mg).1,4

Among those patients, the most common AEs were gastrointestinal issues, such as nausea and diarrhea, and hematologic toxicities, including thrombocytopenia, anemia, and neutropenia. Based on safety and efficacy findings, once-daily 30 mg siremadlin taken orally on days 1 through 5 of a 28-day cycle was chosen as the recommended phase 2 dose.4

Read more

Real-World Data Shows Favorable Efficacy and Safety With Busulfan for MPNs

Posted on by
Andrea S. Blevins Primeau, PhD, MBA
Publish Date

Busulfan treatment of myeloproliferative neoplasms (MPNs) demonstrated high response rates and infrequent adverse events (AEs), according to a study of real-world data from hospitals in the United Kingdom.

“Given the lack of prospective studies on the use of busulphan, our study contributes valuable real-world data on the safety and efficacy of busulphan which clinicians should find useful in managing this challenging cohort,” the researchers wrote in their report.

In the retrospective study, researchers analyzed data from 115 patients with MPNs from 13 hospitals. The median age of the cohort was 78 years and 44% of patients were male. The majority of patients had a diagnosis of essential thrombocythemia (ET) at 67%, followed by 24% with polycythemia vera (PV), 5% with MPN not otherwise specified, and 4% with myelofibrosis. JAK2 and CALR mutations were present among 62% and 13% of patients, respectively.

There were 16% of patients with a history of malignancy, including 8% of nonmelanoma skin cancers, and 8% with cancers that included those of the breast, prostate, lung, low-grade lymphoma, and melanoma.

One previous line of therapy (LOT) had been received by 13% of patients, 63% had 2 LOTs, 19% had 3 LOTs, and 5% had 4 LOTs. The most common previous cytoreductive therapy was hydroxycarbamide (78%), followed by anagrelide (16%), pegylated interferon (8%), P32 (3%), and ruxolitinib (2%).

The dosing regimens of busulfan included repeated single doses (31%) with a median dose of 38 mg, 1- to 4-week courses (30%) with a median dose 3.5 mg, and continuous therapy lasting more than 4 weeks (35%) with a median dose of 2 mg.

Our study contributes valuable real-world data on the safety and efficacy of busulphan which clinicians should find useful in managing this challenging cohort.

The median time from busulfan initiation to last follow-up or death was 23 months. There were 14% of patients who were alive with acceptable blood count control without any other cytoreductive therapy.

Read more

Strategic JAK Inhibitor Sequencing: Translating SIMPLIFY I/II Outcomes to Optimize Myelofibrosis Management

Posted on by

By Pankit Vachhani, MD
Edward Pearson, MD

Summary of Momelotinib Clinical Trials and Second-Line Applications

SIMPLIFY-1 (First-Line Setting)

  • Efficacy comparison with ruxolitinib in newly diagnosed myelofibrosis:
    • Spleen response: Momelotinib demonstrated spleen volume reduction
    • Symptom improvement: Not as robust as ruxolitinib
    • Anemia benefit: Preserved transfusion independence at week 24 vs baseline, while ruxolitinib showed slight decline
  • Clinical considerations for newly diagnosed myelofibrosis with moderate anemia:
    • Potential benefit of single-agent therapy (avoiding combination with erythropoiesis-stimulating agents)
    • When anemia contributes significantly to symptom burden, momelotinib may be preferable

SIMPLIFY-2 (Second-Line Setting)

  • Study design: Effectively a comparison of momelotinib vs ruxolitinib in previously treated patients
    • No washout period between treatments
  • Key outcomes:
    • Spleen response: Comparable between momelotinib and control (“a wash”)
    • Anemia: Clear advantage for momelotinib
    • Symptom control: Superior with momelotinib in the second-line setting
  • Expert opinion on optimal positioning:
    • Panel indicated greater preference for momelotinib in the second-line setting
    • Particularly valuable in patients with worsening anemia or diminishing spleen response on ruxolitinib
    • Setting appropriate expectations is crucial; emphasize anemia and symptom benefits rather than additional spleen reduction

Read more

Clinical Trial Aims to Test Tagraxofusp and Pacritinib Combination Therapy in Patients With MF

Posted on by
Özge Özkaya, MSc, PhD
Publish Date

A new study testing the combination of tagraxofusp and pacritinib in patients with myelofibrosis (MF) is now open.

The single-center, open-label, early phase 1, pilot trial aims to recruit 20 patients with MF who are at least 18 years of age and who have previously been treated with a Janus kinase (JAK) 1/2 inhibitor or in whom JAK1/2 inhibitor therapy is not appropriate, is contraindicated, or was declined.

Participants will be given 12 µg/kg of intravenous tagraxofusp once a day for 3 consecutive days and 200 mg of oral pacritinib twice a day starting at the 4th day of the second cycle and administered continuously with subsequent cycles starting on day 1 of each cycle.

The primary outcome measures will be a spleen volume reduction of 35% of more and the change in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score Version 2.0 (MPN-SAF TSS 2.0) from baseline to week 24.

Secondary outcome measures will include the number of participants with treatment-related adverse events, the change from baseline in anemia and platelet count, and any improvement in patients’ quality of life based on the global impression of change.

Tagraxofusp is a cytotoxin directed at CD123, and pacritinib is a small-molecule kinase inhibitor. The rationale of using these 2 drugs in combination is their compatible mechanisms of action targeting MF stem cells and the bone marrow. It is thought that the combination may lead to improvements in symptoms associated with myeloproliferative neoplasms and reduce splenomegaly.

Both agents have previously been studied in cases of mildly depleted bone marrow and were shown to be safe and led to hematological improvements.

The trial is not yet recruiting participants but aims to recruit 20 participants. It is estimated to be completed in December 2026.

Read more

Biomed Valley Discoveries Announces First Patient Dosed in Phase 1/2 Combination Study of Ulixertinib with Ruxolitinib (Jakafi®) in Patients with Myelofibrosis

Posted on by

Provided by GlobeNewswire  

— Dual targeting of JAK 1/2 (ruxolitinib) and ERK 1/2 (ulixertinib) may represent a novel treatment approach for myelofibrosis and possibly other myeloproliferative neoplasms

KANSAS CITY, Mo., April 28, 2025 (GLOBE NEWSWIRE) — Biomed Valley Discoveries (BVD), a clinical-stage biotechnology company guided by its founders’ intent of bringing hope for life to patients, today announced that the first patient has been dosed in a Phase 1/2 combination study of ulixertinib, BVD’s highly selective, first-in-class ERK 1/2 inhibitor with ruxolitinib, a JAK1/JAK2 inhibitor for the treatment of myelofibrosis, a rare type of bone marrow cancer that disrupts the body’s normal production of blood cells.

Raajit Rampal, M.D., Ph.D., a hematologist-oncologist with Memorial Sloan Kettering Cancer Center who specializes in the treatment of myeloproliferative neoplasms and leukemia, is the lead principal investigator for this investigator-initiated trial.

“We’re thrilled to announce the milestone of first patient dosed in this trial, and grateful for the opportunity to collaborate with Dr. Rampal and Incyte to explore the potential of ERK inhibition as a complement to JAK inhibition for the treatment of patients with myelofibrosis,” said Brent Kreider, Ph.D., President of BVD. “This trial helps further our commitment to fully interrogate the potential of direct ERK inhibition to address unmet patient needs in various cancer settings where MAPK signaling is implicated.”

Read more

Clinical Trials Can Open Doors for Patients With Myeloproliferative Neoplasms

Posted on by

By Kathryn Johnson, DNP, MSc, FNP-BC
Fact checked by Bridget Hoyt

Educating patients on the “risks and benefits” of clinical trials is a part of the pipeline for better treatment options in myeloproliferative neoplasms (MPNs) in which nurses can engage, said a nurse practitioner.

For patients with MPNs, clinical trials have paved the way for better treatment outcomes, increasing options vastly within a short amount of time. In an interview with Oncology Nursing News, Kathryn Johnson, DNP, MSc, FNP-BC, spoke to the importance of the development of these options and nurses’ role in making those possible.

As Johnson, a clinical program manager at Icahn School of Medicine at Mount Sinai New York, outlined, nurses can play a key part in informing patients on what to expect on clinical trials. She advised not only being prepared with information patients should know, but making time for patients to air their concerns and ask questions as well.

Johnson added that in the time that she has been working in oncology, multiple advancements have been made in the treatment of MPNs. She expects this trend to continue in the coming years.

Read more

Fedratinib Shows Promise in Long-Term MPN Success With Tolerable Toxicity

Posted on by

By Hany Elmariah, MD

A phase 1 trial investigated the safety and tolerability of maintenance therapy with the JAK2 inhibitor fedratinib (Inrebic) following allogeneic hematopoietic cell transplant (HCT) for myeloproliferative neoplasms (MPNs) and myelodysplastic syndrome/MPN overlap syndromes.

While HCT offers potential cure for MPNs, posttransplant relapse remains a significant challenge. Fedratinib, effective in myelofibrosis, with a favorable safety profile and oral administration, presents a rational strategy to reduce relapse and potentially prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect.

“Usually with fedratinib, the main toxicities are cytopenia, so low blood counts. We also see a fair amount of [gastrointestinal (GI)] toxicity, nausea, vomiting, or diarrhea,” said Hany Elmariah, MD, associate member at the Moffitt Cancer Center in the Department of Bone Marrow Transplant and Cellular Immunotherapy, in an interview with Targeted OncologyTM.

The study enrolled patients post-HCT who received fedratinib between days +60 and +100 for up to 1 year. The trial utilized a 3+3 design to determine the maximum tolerated dose (MTD). Eleven patients were evaluable for dose-limiting toxicities (DLTs). The MTD was identified as 400 mg daily. While no DLTs occurred within the 30-day window, 4 patients withdrew due to non-DLT adverse events. Notably, only 1 patient developed severe chronic GVHD. The median progression-free survival was 12.4 months, and the 1-year overall survival was 100%.

Read more

New Trial Will Assess Safety and Efficacy of MF Drug

Posted on by
Leonardo Jaimes, MD

Publish Date

A clinical trial aiming to determine the efficacy, safety, and pharmacokinetics of the experimental drug WJ01024 combined with ruxolitinib in patients with myelofibrosis (MF) is set to begin soon.

“Although the clinical efficacy of ruxolitinib tablets has been confirmed, only about half of MF patients can achieve the ideal therapeutic effect (≥35% reduction in spleen volume and ≥50% improvement in disease symptoms at 24 weeks),” the authors wrote. “Therefore, there is an urgent need for innovative drugs that can be combined with ruxolitinib tablets to enhance therapeutic efficacy and meet clinical needs,” they added.

WJ01024 aims to enhance the therapeutic efficacy of ruxolitinib through  XPO-1 inhibition. Previous in vitro studies have confirmed that the drug enhances ruxolitinib anti-cell proliferation activity, the researchers noted. Furthermore, preliminary studies on humans suggest that WJ01024 is effective as monotherapy for relapsing patients and those intolerant to JAK inhibitors, they added.

The trial will consist of a dose escalation and a dose extension phase (phase 1a and phase 2). Phase 1b will divide patients into three groups receiving 40 mg, 60 mg, and 80 mg of WJ01024, respectively. Phase 2 will be an open-label evaluation of the efficacy and safety of the recommended dose in combination with ruxolitinib.

The study will only include patients diagnosed with MF and with the international prognostic scoring system risk category of intermediate-1, intermediate-2, or high-risk. Patients in the accelerated blast phase or previous treatment with either JAK or XPO-1 inhibitors are not eligible for participation.

Read more