Category Archives: Clinical Trial

Safety and Efficacy of Busulphan Based on Dosing Patterns in the Real‐World Management of Myeloproliferative Neoplasms

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March 2025

Ali Mahdi, Alexandros Rampotas, Patrick Roberts, Joanna Stokes

Abstract

Introduction
Myeloproliferative neoplasms (MPNs), such as polycythaemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are primarily treated by managing blood counts to reduce the thrombotic risk using cytoreductive agents. Busulphan, an oral alkylating agent, has been historically used for MPN management due to its myelosuppressive effects, but concerns about its risk of leukaemic transformation have limited its use.
Methods
This real‐world retrospective study evaluated the safety and efficacy of busulphan in 115 MPN patients across 13 UK hospitals. Responses in patients with ET and PV only were assessed using European LeukemiaNet (ELN) criteria.
Results
With a median age of 78 years, the overall response rate was 78.1%, with 29% of PV and 18% of ET patients achieving complete responses. Dosing regimens were similarly distributed between repeated single doses of busulphan (31%), courses of treatment lasting 1–4 weeks (30%) and continuous therapy for more than 4 weeks (35%). No cases of disease progression to acute leukaemia or myelofibrosis were recorded during the median follow‐up of 23 months. Adverse events were infrequent, with fatigue and cytopaenia being the most common (4% each).
Conclusion
Busulphan demonstrated a favourable safety profile and is a viable cytoreductive option, particularly for elderly patients who are intolerant to hydroxycarbamide.

Pelabresib Plus Ruxolitinib Improves Spleen Responses in Myelofibrosis

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By Roman Fabbricatore
Fact checked by Russ Conroy

Pelabresib (CPI 0610) in combination with ruxolitinib (Jakafi) significantly improved spleen responses and elicited robust clinical activity compared with placebo/ruxolitinib in patients with JAK inhibitor-naïve myelofibrosis, according to results from the phase 3 MANIFEST-2 trial (NCT04603495) published in Nature Medicine.1

Efficacy data from the trial revealed that the primary end point of spleen volume reduction of at least 35% at week 24 favored the investigational combination vs the placebo arm: 65.9% vs 35.2%, respectively (difference, 30.4%; 95% CI, 21.6%-39.3%; P <.001). Additionally, the mean percent change at week 24 in the respective arms was –50.6% (95% CI, –53.2% to –48.0%) vs –30.6% (95% CI, –33.7% to –27.5%). Spleen volume response was consistently higher with pelabresib vs placebo across predefined subgroups.

Furthermore, the hemoglobin response rate, defined as a 1.5 g/dl or greater mean increase, occurred in in 10.7% of the pelabresib arm (95% CI, 6.60%-14.90%) vs 6.0% of the placebo arm (95% CI, 2.85%-9.19%). Transfusions were received in the first 24 weeks of treatment in 27.6% and 37.5% of respective arms.

Greater reductions in NF-κB-regulated cytokines (–32.1% [95% CI, –34.9% to –29.2%] vs –19.4% [95% CI, –22.5% to –16.2%]), tumor necrosis factor (TNF; –43.5% [95% CI, –47.0% to –39.8%] vs –26.4% [95% CI, –30.5% to –22.1%]), and interleukin-6 (IL-6; –35.4% [95% CI, –44.2% to –25.2%] vs –14.5% [95% CI, –25.2% to –2.3%]) were seen in the investigational arm vs the placebo arm. Of note, a reduction in IL-8 levels was observed with pelabresib (–14.3% [95% CI, –22.3% to –5.5%]), but an increase was observed in the placebo arm (31.2% [95% CI, 17.5%-46.5%).

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Dr Rampal on ​Emerging Therapies Under Investigation in Myelofibrosis

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March 17, 2025

Author(s): Raajit K. Rampal, MD, PhD

Fact checked by: Ashling Wahner ,Chris Ryan

Raajit Rampal, MD, director of the Center for Hematologic Malignancies and director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, discusses emerging treatments for patients with myelofibrosis.

The therapeutic paradigm for myelofibrosis continues to expand with emerging treatment options, particularly with combination therapies, novel JAK inhibitors, and immunotherapeutic agents, Rampal begins. Among these, pelabresib (CPI-0610), a BET inhibitor, has completed phase 3 trials. Preliminary data from the phase 3 MANIFEST-2 trial (NCT04603495), which were presented in December 2023, demonstrated improved spleen responses and a trend toward better symptom management with the combination of pelabresib and ruxolitinib (Jakafi) vs placebo plus ruxolitinib in patients with JAK inhibitor–naive myelofibrosis. Updated findings from MANIFEST-2 were published in Nature Medicine in March 2025.

Beyond pelabresib, several other agents are currently in phase 3 trials for patients with myelofibrosis, Rampal says. Selinexor (Xpovio), which is currently FDA approved for the treatment of patients with relapsed/refractory multiple myeloma, is being studied in combination with ruxolitinib in patients with myelofibrosis in the phase 3 XPORT-MF-034 trial (NCT04562389). Additionally, navtemadlin (KRT-232), an MDM2 inhibitor, is undergoing clinical evaluation in patients with myelofibrosis. Notably, these trials are ongoing, and no conclusive data are available at this time, Rampal emphasizes.

The development of next-generation JAK inhibitors also represents a promising area of investigation, according to Rampal. These newer inhibitors are anticipated to demonstrate greater potency and selectivity compared with existing agents, though they remain in early-phase clinical trials, he notes.

Rampal states that one of the most exciting advancements in this setting is the emergence of immunotherapies. Calreticulin-targeted antibodies are currently being evaluated in clinical trials, and 2 candidates are in development, he reports. If these agents prove effective, they could significantly alter the treatment paradigm, he concludes.

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Promising New Treatment for Myelofibrosis Blood Cancer Using a Combination Targeted Therapy 

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By Julie Grisham

An international phase 3 clinical trial of a new drug combination for treating the blood cancer myelofibrosis found that adding a second, experimental drug to standard treatment was more effective than the standard treatment alone. Further, adding the second drug did not significantly increase side effects. Memorial Sloan Kettering Cancer Center (MSK) enrolled the most patients in the trial.

“This is one of the largest myelofibrosis clinical trials to date,” says MSK leukemia specialist Raajit Rampal, MD, PhD, lead author of the study, published March 10 in Nature Medicine. “There is a real unmet need for patients with this disease, and the findings from this trial represent an exciting advance.”

This study looked at adding an experimental drug called pelebresib to the drug ruxolitinib (Jakafi®), which is the current treatment for myelofibrosis. Both drugs are targeted therapies. Pelebrisib blocks the action of proteins involved in inflammation and cancer; ruxolitinib blocks a protein called JAK. This combination approach was based on ongoing research from the lab of MSK leukemia specialist and physician-scientist Ross Levine, MD.

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New MF Study Recruiting Participants for Its Phase 3 Portion

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Özge Özkaya, MSc, PhD
Publish Date

A phase 1/3 clinical trial testing the safety and efficacy of selinexor plus ruxolitinib in patients with myelofibrosis (MF) who are Janus kinase (JAK) inhibitor-naïve is now recruiting participants for its phase 3 portion.

The global, multicenter, 2-part study aims to recruit an estimated 350 participants with MF. Participants were all at least 18 years of age.

The study consists of an experimental phase 1a, experimental phase 1b, and experimental phase 3 portion.

In the experimental phase 1a portion, 1 group of patients were given 40 mg of oral selinexor once a week on days 1, 8, 15, and 22 of each 28-day cycle together with 15 or 20 mg of ruxolitinib twice a day based on their platelet count at baseline while another group was given 60 mg of oral selinexor on the same days and the same dose of ruxolitinib as the first group.

In the experimental phase 1b, patients were given either 40 or 60 mg of oral selinexor once a week on days 1, 8, 15, and 22 of each 28-day cycle and the same dose of ruxolitinib.

In the experimental phase 3 portion, patients will either be given a fixed starting dose of 60 mg of oral selinexor or a placebo once a week on days 1, 8, 15, and 22 of each 28-day cycle together with the same dose of ruxolitinib.

The primary outcome measures of the phase 1 portion of the trial was the maximum tolerated dose and recommended phase 2 dose of selinexor and the number of participants with adverse events by severity, nature, and occurrence.

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What to Know About Myeloproliferative Disorders Clinical Trials

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Medically reviewed by Julie Scott, DNP, ANP-BC, AOCNP — Written by Hope Gillette on March 6, 2025

Myeloproliferative disorders, now referred to as myeloproliferative neoplasms (MPNs), include a group of blood cancers that develop when bone marrow produces too many red blood cells, white blood cells, or platelets.

Some forms of MPNs, such as essential thrombocythemia (ET) respond well to current treatmentTrusted Source, but others, such as primary myelofibrosis, have fewer effective options.

Depending on the specific diagnosis you received, your healthcare team may recommend participating in an MPN clinical trial to expand your treatment possibilities.

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Protagonist and Takeda Announce Positive Topline Results from Phase 3 VERIFY Study of Rusfertide in Patients with Polycythemia Vera

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March 3, 2025

− Study met the primary endpoint, with a significantly higher proportion of clinical responders on rusfertide compared to placebo

− All four key secondary endpoints were met, including EU primary endpoint and patient-reported outcomes

− Rusfertide was generally well tolerated; no new safety findings were observed in the study

NEWARK, Calif. & OSAKA, Japan & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Protagonist Therapeutics, Inc. (“Protagonist”) (NASDAQ:PTGX) and Takeda (TSE:4502/NYSE:TAK) today announced positive topline results for the Phase 3 VERIFY study, in which phlebotomy-dependent patients with polycythemia vera (PV) were randomized to treatment with either rusfertide or placebo, as an add-on to standard of care treatment. The study met its primary endpoint and all four key secondary endpoints. Rusfertide is a first-in-class investigational hepcidin mimetic peptide therapeutic, which has received Orphan Drug designation and Fast Track designation from the U.S. Food & Drug Administration (FDA).

Key findings from the study include:

  • The primary endpoint of the study was met, with a significantly higher proportion of clinical responders1 among rusfertide-treated patients with PV (77%) compared to those who received placebo (33%) during weeks 20-32; p<0.0001. The primary endpoint of the study was the proportion of patients achieving a response, which was defined as the absence of phlebotomy eligibility.
  • The first key secondary endpoint, which is the pre-specified primary endpoint for European Union (EU) regulators, was also met, with a mean of 0.5 phlebotomies per patient in the rusfertide arm compared to 1.8 phlebotomies per patient in the placebo arm during weeks 0-32; p<0.0001.
  • The other three pre-specified key secondary endpoints, namely hematocrit control2 and patient-reported outcomes using PROMIS Fatigue SF-8a3 and MFSAF TSS-74, were also achieved with statistical significance.
  • Rusfertide was generally well tolerated in the Phase 3 VERIFY trial, and safety was in line with previous rusfertide clinical studies. No new safety findings were observed in the study. The majority of adverse events were grade 1-2 injection site reactions and all serious adverse events reported were deemed to be not drug related. There was no evidence of an increased risk of cancer in rusfertide-treated patients compared to those on placebo.

“The positive results of the Phase 3 VERIFY study across the primary and all key secondary endpoints provide compelling evidence of the potential for rusfertide as a first-in-class erythrocytosis-specific agent to address unmet medical needs in patients with PV who are unable to achieve adequate hematocrit control despite standard of care treatments,” said Arturo Molina, M.D., M.S., Chief Medical Officer of Protagonist. “We plan to submit additional details of these promising results for presentation at upcoming medical conferences in 2025. We are immensely grateful to the patients, study staff and principal investigators who made the VERIFY study possible.”

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Divesiran Is Tolerable and Shows Positive Early Signals in Polycythemia Vera

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February 26, 2025

Author(s): Kyle Doherty

Fact checked by: Megan Hollasch

Divesiran (SLN124), a novel small interfering RNA (siRNA), was safe and displayed signals of efficacy in the treatment of patients with polycythemia vera, according to findings from the phase 1/2 SANRECO trial (NCT05499013).1

Initial results from SANRECO presented during the 2024 ASH Annual Meeting showed that divesiran reduced phlebotomy frequency in patients (n = 21). A total of 79 phlebotomies occurred across all patients prior to dosing; there were 5 phlebotomies during the treatment period and 2 during follow-up among all patients. Divesiran also induced hepcidin in all patients and decreased hematocrit in all cohorts of patients treated.

Additionally, patients did not experience any dose-limiting toxicities. Most treatment-emergent adverse effects (TEAEs) were grade 1 in severity (84%) and there were no TEAEs above grade 2 reported. There were also no treatment-related serious AEs or TEAEs leading to treatment discontinuation.

Divesiran is a first-in-class GalNAc-conjugated siRNA that targets TMPRSS6, a negative regulator of the HJV/BMP/SMAD signaling pathway that induces hepcidin expression. The agent is designed to have a long duration of action, and, notably, it’s target sequence is unique to TMPRSS6 and was selected to maximize TMPRSS6 knock down. Investigators hypothesized that inhibiting TMPRSS6 would raise hepcidin levels and lower iron delivery to the bone marrow, leading to reduced erythropoiesis.

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Ropeginterferon Alfa-2b Effective in Phase 3 Essential Thrombocythemia Trial

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By Jordyn Sava
Fact checked by Jason Broderick

The SURPASS-ET trial (NCT04285086), evaluating ropeginterferon alfa-2b (Besremi) in patients with essential thrombocythemia (ET), has achieved its primary endpoint, demonstrating a durable clinical response as defined by modified European Leukemia Net (ELN) criteria.1

In the intent-to-treat (ITT) population, 42.9% (39/91) of patients treated with ropeginterferon alfa-2b had durable responses at 9 and 12 months vs 6.0% (5/83) of patients enrolled in the comparator arm who were treated with anagrelide (Agrylin) (P =.0001).

For the secondary end point, the JAK2 V617F allele burden decreased from 33.7% to 25.3% (-8.4%) in the ropeginterferon alfa-2b group over 12 months, compared with a reduction from 39.7% to 37.3% (-2.4%) in the anagrelide group. These findings indicate that ropeginterferon alfa-2b may provide a more pronounced effect on mitigating the underlying disease pathology relative to anagrelide.

“We are extremely proud of the SURPASS-ET phase 3 study outcome, which shows the potential of [ropeginterferon alfa-2b] as an important new treatment option for patients with ET, a rare blood cancer that drastically increases the risk of heart attack or stroke,” said Ko-Chung Lin, PhD, founder and chief executive officer of PharmaEssentia, in a press release. “The data highlight the broad potential to apply our innovative monopegylated, long-acting interferon technology as a significant step forward for treating ET, and potentially other myeloproliferative neoplasms, with non-chemotherapy treatments.”

For safety, ropeginterferon alfa-2b did not lead to any treatment-related serious adverse events. Overall, the agent had a manageable safety profile.

Full trial results, including additional pharmacokinetics and biomarker data, are expected to be presented at a later date.

“The results of the SURPASS-ET trial are significant,” said Albert Qin, MD, PhD, chief medical officer, PharmaEssentia, in a press release. “ET is a challenging condition associated with symptoms and risks of thrombosis and disease progression. These encouraging results highlight the potential of [ropeginterferon alfa-2b] to provide an effective and tolerable new treatment option that we believe could provide a substantial clinical benefit for patients with ET. We plan to submit these results to the FDA and other regulatory agencies as soon as possible in hopes of providing this potential new treatment option to patients with ET.”

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Ruxolitinib Combinations in MPNs: Updates From ASH

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January 8, 2025

Author(s): Mary Caffrey

Following its approval in 2011 for myelofibrosis (MF), ruxolitinib (Jakafi, Incyte) became the backbone of treatment for MF and later for polycythemia vera (PV), 2 of the 3 common myeloproliferative neoplasms (MPNs).

But although ruxolitinib improves survival outcomes and quality of life, some patients may not respond to therapy, while others may stop due to genetic mutations, disease progression, or other factors. For years now, investigators have been studying the Janus kinase (JAK) inhibitor in combination with other drugs, both in first-line treatment and refractory disease. Abstracts and oral presentations at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, offered updates on several combinations in the pipeline:

MANIFEST-2. Previous results from this phase 3 study (NCT04603495) of pelabresib, a selective bromodoman and extraterminal domain (BET) inhibitor, with ruxolitinib show it met its primary end point; in patients with MF not treated with a JAK inhibitor, a statistically significant higher proportion showed at least 35% reduction in spleen volume from baseline at week 24 with the combination vs ruxolitinib and placebo. Results presented at ASH showed those results were maintained after a median follow-up of 72 weeks, with a 48-week response rate of 57.0% for the combination vs 37.5% for ruxolitinib and placebo. An improvement in the Myelofibrosis Symptom Assessment Form total symptom score (TSS) by at least 50% was seen in 45.3% of patients receiving the combination vs 39.4% in the placebo group.1

Bomedemstat. An abstract at ASH reported on an ongoing phase 2 study (NCT05569538) involving bomedemstat combined with ruxolitinib in patients with advanced MF.2 Bomedemstat is an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), which plays a role in gene regulation; blocking this enzyme alters cell differentiation and growth. In August 2024, Merck announced the second phase 3 trial of bomedemastat in another MPN, essential thrombocythemia (ET).

The abstract authors noted that about 50% of patients with MF stop ruxolitinib after 3 years, mostly due to disease progression or cytopenia; median OS after discontinuation is 14 months.2 LSD1, they write, is “critical for self-renewal” of cancerous stem cells, and has shown promise as a single agent. This study reported on 2 cohorts: Cohort A had a suboptimal response to ruxolitinib, and cohort B patients had MF and were treatment naive. Patients in cohort A remained on the entry dose of ruxolitinib while cohort B started 10 mg twice per day; all patients received a starting dose of 0.4 mg/kg/day of bomedemstat. Dose adjustments were permitted every 4 weeks to achieve an optimal platelet count; downward titrations were done at any time for safety reasons. After a median of 61.7 weeks, in 40 evaluable patients, at week 24, 11 patients had at least a 50% improvement in TSS, with 25.9% in cohort A and 30.7% in cohort B; 17.5% had at least 35% spleen volume reduction, with 7.4% in cohort A and 38.5% in cohort B; and 50% of patients had stable or improved hemoglobin (51.9% in cohort A and 46.3% in cohort B). There were no safety signals or deaths related to the drug, the authors said.2

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