Category Archives: Research

PharmaEssentia Completes Patient Enrollment for Phase 2b EXCEED-ET Trial in Essential Thrombocythemia and Phase 3b ECLIPSE-PV Trial in Polycythemia Vera

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June 25, 2024

PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TWSE: 6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology, oncology and immunology, today announced completion of enrollment for two clinical trials evaluating its ropeginterferon alfa-2b-njft (BESREMi ® ).

The Phase 2b EXCEED-ET trial (NCT05482971), which is evaluating the effectiveness and safety of ropeginterferon alfa-2b-njft in adult patients with essential thrombocythemia (ET), has exceeded the enrollment goal of 64 patients to include 91 patients. EXCEED-ET is evaluating people diagnosed with ET who are either treatment naïve or have received previous ET treatment with hydroxyurea or anagrelide but require a treatment change due to intolerance or because the previous treatment is no longer effective. This trial is being conducted in the United States and Canada and will use the accelerated dosing schedule (250, 350, 500 mcg). This accelerated dosing schedule has been previously assessed in Asian clinical trials.

The Phase 3b ECLIPSE-PV trial (NCT05481151), assessing the effectiveness and safety of two dosing regimens of ropeginterferon alfa-2b-njft in adult patients with polycythemia vera (PV), has also exceeded the enrollment goal of 100 patients to include 111 patients. ECLIPSE-PV is evaluating two ropeginterferon alfa-2b-njft doses, including the accelerated dosing schedule (as described above) in comparison to the current recommended dosing regimen. The ECLIPSE-PV study is being performed in the United States and Canada.

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Are thrombosis, progression, and survival in ET predictable?

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June 25, 2024

Ghaith Abu-Zeinah, Katie Erdos, Neville Lee, Ahamed Lebbe, Imane Bouhali, Mohammed Khalid, Richard T. Silver & Joseph M. Scandura

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) that originates from a hematopoietic stem cell harboring a mutated JAK2, CALR, or MPL gene, or none of these three mutations (10–15% are “triple negative”). Although considered the most indolent MPN, ET is linked to burdensome vasomotor symptoms, and potentially fatal complications that include thrombosis, hemorrhage, and disease progression to myelofibrosis and aggressive myeloid neoplasms. Prognostic measures to identify those at greatest risk for thrombosis, progression, and death in ET (events) are important for timely risk-adapted intervention with available treatments, and for development of interventional trials to improve event-free survival (EFS). But predicting risks of events in ET has been difficult because ET is an uncommon and clinically heterogenous chronic disease. Predicting progression and excess mortality is even more challenging because these events typically occur decades after ET diagnosis [1]. Thus, retrospective analysis of large cohorts with sufficiently long follow-up is required to identify prognostic measures to stratify risk in patients with ET.

Prognostic models have been developed to assess the risk of thrombosis (IPSET-thrombosis [2]) or overall survival (OS) in ET (IPSET-survival [3], MIPSS-ET [4], and triple A [AAA] [5]). This journal recently published two large retrospective ET cohorts: Gangat et al. at the Mayo Clinic (Mayo) [6] and Loscocco et al. at the Florence Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM) [7]. Both studies confirmed previously identified risk factors for thrombosis, progression and/or death in ET that include older age (Age ≥ 60), male sex, elevated white blood cell count (WBC > 11 × 109/L), elevated absolute neutrophil count (ANC ≥ 8 × 109/L), and low absolute lymphocyte count (ALC < 1.7 × 109/L) at the time of presentation. We evaluated these parameters and current risk models in our cohort of 328 adult patients with ET treated at the Weill Cornell Medicine (WCM) Silver MPN Center over a median follow-up of 6 years [8]. This cohort was rigorously defined according to the 2022 World Health Organization diagnostic criteria and therefore all patients had a diagnostic bone marrow biopsy and had alternative diagnoses scrupulously ruled out. The methods of data collection, retrieval, and analysis used were previously described [9], and cohort characteristics are included in Supplementary Table 1.

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Outcomes of the Myelofibrosis Symptom Tracking Survey

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We would like to thank the 147 patients who responded to a survey that targeted how people with
Myelofibrosis tracked their symptoms and then how they used the information they gleaned from
their tracking. You’ll never guess what we found.

Nearly 65 percent of respondents said they had never tracked their symptoms. When asked why,
a piece of the MF story unfolded. Some people acknowledged that the variability of both the
symptoms and their occurrence made it difficult to track, while others felt that bringing a focus to
their MF and symptoms each day undermined their mental health. A few mentioned that they
made mental notes of their symptoms, had their various doctors tracking symptoms, or just knew
innately when something changed. Several felt that there was no reason to track their symptoms,
this may be due in part to responses to another question that revealed only around 20 percent of
individuals were encouraged by their physician to keep track of their symptoms. Of those that
did track their symptoms, most did so with their own personal pen-and-paper accounting and
used a variety of approaches using numerical scales, happy and sad faces, or a more journaling
style.

After opening this little window into the MF experience. It was hard not to have additional
questions. For example, could symptom tracking be used as both a self-care practice and a tool of
empowerment? Ultimately, the tools and techniques that are most helpful come from the insight
and strength of those who experience MF every day. If symptom tracking is not the best way to
track symptoms to possibly share with your personal health care team, or the team you work with
during a clinical trial, what does work for you? We would love to learn more, and share what we
learn to benefit others. If you have a response to these questions or anything more you would like
to say on this topic, please email us at ngiocondo@mpnadvocacy.com.

Prospective Analysis Highlights Patterns of Progression to Myelofibrosis Following Essential Thrombocythemia Diagnosis

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June 17, 2024

Author(s): Caroline Seymour

Most patients with essential thrombocythemia (95.7%; 1184/1237) included in an analysis of the prospective, observational MOST study (NCT02953704) did not experience disease progression to myelofibrosis, but those who did were found to have had longer duration of disease, higher white blood cell counts, and lower hemoglobin levels at enrollment, according to findings presented at the 2024 EHA Congress.1

Of the 4.3% (n = 53) of patients who progressed to myelofibrosis, a pathologic diagnosis of the disease or grade 2 or greater fibrosis was the most common indicator (49.1%; n = 26) of disease progression, followed by new or worsening splenomegaly coupled with a combination of high white blood cell counts and low hemoglobin levels and platelet counts (22.6%; n = 12). Additional indicators were death from myelofibrosis, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML; 11.3%; n = 6) and circulating blasts above 1% with new or worsening splenomegaly (5.7%; n = 3); patients also met at least 2 progression criteria (11.3%; n = 6).

“These findings and further analyses of MOST data will add insight into disease progression in patients with essential thrombocythemia and facilitate clinical management of this patient population,” lead study author Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and vice dean of cancer programs at Wake Forest University School of Medicine in Charlotte, North Carolina, and coauthors wrote in the poster.

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Dr Gerds on the Clinical Implications of Pelabresib Plus Ruxolitinib in Myelofibrosis

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June 14, 2024

Author: Aaron Gerds, MD

Aaron Gerds, MD, assistant professor, medicine, Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, discusses the clinical implications of safety outcomes with of pelabresib (CPI-0610) plus ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis.

At the 2024 ASCO Annual Meeting, investigators presented updated safety and efficacy data from the phase 3 MANIFEST-2 trial (NCT04603495), which investigated pelabresib in combination with ruxolitinib in JAK inhibitor–naive patients with myelofibrosis. The study revealed significant reductions in splenomegaly with combination therapy compared with ruxolitinib alone at week 24, along with rapid, deep, and sustained spleen reduction. The combination therapy also generated a trend toward greater improvement in total symptom score and higher rates of deeper hemoglobin responses vs ruxolitinib monotherapy, with fewer patients requiring transfusions and fewer anemia-related adverse effects observed.

In this updated readout, patients receiving the combination experienced a significantly higher spleen volume response rate at week 24 compared with those receiving ruxolitinib alone. The combination therapy also resulted in more sustained spleen volume responses and greater reductions in total symptom score, although the difference in the latter did not reach statistical significance. Hemoglobin levels remained higher over time in the combination arm, and fewer patients in this arm required red blood cell transfusions. Improvements in bone marrow fibrosis and reductions in key inflammatory cytokines were also observed with the combination therapy.

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Observational Study Finds Progression Common in Lower-Risk Myelofibrosis

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June 14, 2024

Author(s): Sabrina Serani

Among patients with low- or intermediate-risk myelofibrosis (MF), a majority were reported to have disease progression over 4 years, and the rate of progression increased over time, according to findings from the prospective observational MOST study (NCT02953704) presented in a poster session at the 2024 EHA Congress. These findings provide important insight into the rates of disease progression for patients with lower-risk MF, a patient group with limited prospective data available on this topic.

A total of 232 patients with MF were enrolled, with 205 patients considered low or INT-1 risk due to being aged over 65 years alone comprising cohort A and 27 patients considered low or INT-1 risk for factors other than age only being evaluated in cohort B. In cohort A, 58.5% (n = 120) of patients experienced disease progression during the study, with the most common progression criteria being hemoglobin below 10 g/dL (47.5%). Further, 12 patients (10.0%) died due to disease progression and 6 (5%) had leukemic transformation. In cohort B, 29.6% (n = 8) of patients had disease progression during the course of the study.

Laboratory-defined criteria for progression in the MOST study included hemoglobin below 10 g/dL, platelet count below 100 × 109/L, less than 1% blasts, white blood cell count above 25 × 109/L, and leukemic transformation with greater than 20% blasts. Physician-reported criteria for progression were constitutional symptoms (weight loss, fever, sweats), new or worsening splenomegaly, 1 red blood cell transfusion during the study, physician-reported leukemic transformation, and death due to disease progression. The presence of at least 1 criterion was considered disease progression.

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Myeloproliferative neoplasms in the adolescent and young adult population: A comprehensive review of the literature

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Hannah Goulart, Lucia Masarova, Ruben Mesa, Claire Harrison, Jean-Jacques Kiladjian, Naveen Pemmaraju 

Abstract

Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR-ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well-tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts.

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Platelet proteome reveals potential mediators of immunothrombosis and proteostasis in myeloproliferative neoplasms

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Sarah Kelliher, Sara Gamba, Luisa Weiss, Zhu Shen, Marina Marchetti, Francesca Schieppati, Caitriona Scaife, Stephen Madden, Kathleen Bennett, Anne Fortune, Su Maung, Michael Fay, Fionnuala Ní Áinle, Patricia Maguire, Anna Falanga, Barry Kevane, and Anandi Krishnan

Myeloproliferative neoplasms (MPN) are chronic bone marrow malignancies characterised by clonal proliferation of hematopoietic precursors and elevated cell counts in peripheral blood. Patients with MPN are at risk of progression to myelofibrosis or acute leukemia and experience a substantial burden of
microvascular symptoms. However, thrombosis ( both arterial and venous), represents the leading
cause of morbidity and mortality for patients with PV and ET.

Translational studies have indicated that the platelet proteome influences pathways relating to immune
response, inflammation, and malignancy. Thrombocytosis and platelet hyperactivity are hallmarks of
MPN, however platelet count in isolation is not predictive of clinical outcome, and conventional
antiplatelet therapy does not fully mitigate thrombotic risk. A comprehensive picture of the MPN platelet
molecular profile is lacking and to date, no studies have evaluated the unbiased platelet proteome in a
sizeable clinical cohort of affected patients. In this present study, we performed untargeted quantitative
profiling of the platelet proteome in a large (n= 140) cohort of patients with PV and ET.

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Dr Kishtagari on JAK Inhibitor Selection for Myelofibrosis in the Community Setting

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John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses phase 3 of the SENTRY (NCT04562389) trial, a global, multicenter, phase 1/3 study evaluating the efficacy and safety of selinexor (Xpovio) when given in combination with ruxolitinib (Jakafi) in patients with JAK inhibitor treatment-naive myelofibrosis.

The study is being conducted in 2 phases. In phase 1, the open-label portion of the study, enrollment has been completed and the safety and recommended dose of selinexor plus ruxolitinib was studied. Phase 1a utilized a standard 3+3 design, and phase 1b was the dose-expansion part. Phase 3 of the trial is enrolling patients with JAK inhibitor treatment-naive myelofibrosis and randomizing them 2:1 to receive the combination therapy of selinexor with ruxolitinib or placebo with ruxolitinib.

In phase 3, the primary end points are the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24, and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24, as measured by the myelofibrosis symptom assessment form V4.0.

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Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis

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By: Aaron Gerds, Claire Harrison, Jean-Jacques Kiladjian, Ruben Mesa, Alessandro Vannucchi, Rami Komrokji, Prithviaj Bose, Marina Kremyanskaya, Adam Mead, Jason Gotlib, Shelonitda Rose, Fabian Sanabria, Niloufar Marsousi, Ana Giuseppi, Huijing Jiang, Jeanne Palmer , Kelly McCaul, Vincent Ribrag, Francesco Passamonti

Abstract:
The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in
cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B
were transfusion dependent (TD); patients in cohort 3A/3B had stable ruxolitinib treatment prior to
and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment
was extended if clinical benefit was observed at day 169. The primary endpoint was anemia response
rate (NTD, {greater than or equal to}1.5 g/dL hemoglobin increase from baseline; TD, transfusionindependence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary
endpoint. In cohorts 1 and 3A (NTD), 27% and 50% of patients respectively had mean hemoglobin
increase {greater than or equal to}1.5 g/dL from baseline. Among TD patients, ~50% had {greater
than or equal to}50% reduction in transfusion burden. Reduction in total symptom score was observed
in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had
{greater than or equal to}1 adverse event (AE); 47% had {greater than or equal to}1 treatmentrelated AE (TRAE; 11% grade {greater than or equal to}3), most frequently hypertension (18%),
managed with medical intervention. One patient had a serious TRAE leading to luspatercept
discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients,
ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept
improved anemia and transfusion burden across cohorts.

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