VENLO, Netherlands & WILMINGTON, Del.–(BUSINESS WIRE)–Jun. 15, 2025– QIAGEN N.V. (NYSE: QGEN; Frankfurt Prime Standard: QIA) and Incyte (Nasdaq: INCY) today announced a new global collaboration to develop a novel diagnostic panel to support Incyte’s extensive portfolio of investigational therapies for patients with myeloproliferative neoplasms (MPNs), a group of rare blood cancers, including Incyte’s monoclonal antibody INCA033989, targeting mutant calreticulin (mutCALR), which is being developed in myelofibrosis (MF) and essential thrombocythemia (ET).
Positive Late-Breaking Data for Incyte’s First-in-Class mutCALR-targeted therapy INCA033989 in Essential Thrombocythemia Presented at EHA2025
WILMINGTON, Del.–(BUSINESS WIRE)–Jun. 15, 2025– Incyte (Nasdaq:INCY) today announced the first clinical data from two studies evaluating the safety, tolerability and efficacy of INCA033989, a novel, first in class, Incyte-discovered, targeted monoclonal antibody in patients with mutant calreticulin (mutCALR)-expressing myeloproliferative neoplasms (MPNs). These data – featured today in the Late-Breaking Oral Session (#LB4002) at the European Hematology Association 2025 (EHA2025) Congress in Milan, Italy – focus on the dose escalation portion of the studies in patients with high risk essential thrombocythemia (ET) who are resistant/intolerant to prior cytoreductive therapy.
The studies evaluated the safety and efficacy of INCA033989 in patients with ET as measured by hematologic response and reduction in mutCALR variant allele frequency (VAF).
Interferon Improves Myelofibrosis-Free Survival in AYA Patients with ET and PV
By Melissa Badamo – Last Updated: May 27, 2025
While cytoreductive drugs did not reduce thrombosis risk in adolescent and young adult (AYA) patients with essential thrombocythemia (ET) and polycythemia vera (PV), interferon “significantly improved” myelofibrosis-free survival (MFS) compared with other treatments, according to a study published in Leukemia.
The retrospective study explored the long-term complications and impact of cytoreductive drugs on patient outcomes, thrombotic risk, and progression to secondary myelofibrosis (sMF) in 348 patients diagnosed with ET (n=278) or PV (n=70) before the age of 25 years. The primary end points were MFS, thrombosis-free survival (TFS), and overall survival. Secondary end points included identification of risk factors associated with thrombotic events and progression to sMF.
In the ET cohort, 147 (53%) patients had JAK2 mutations, 43 (16%) had CALR mutations, 3 (1%) had MPL mutations, and 85 (30%) were triple negative (TN). All patients with PV had JAK2 mutations.
A total of 237 (68%) patients were treated with a cytoreductive drug, including 185 patients with ET (66.5%) and 52 patients with PV (74.3%). Patients received one line of therapy (n=97; 41%), two lines of therapy (n=82; 35%), or three or more lines of therapy (n=58; 24%). The most prescribed first-line treatments were hydroxycarbamide (n=126; 53%), interferon (n=55; 23%), anagrelide (n=52; 22%), and alternative drugs (n=4; 2%). The median follow-up was 8.5 years.
Thrombotic Risk
Forty-four patients presented 57 thrombotic events, with a risk of 1.9 per 100 patient-years. The 10- and 20-year probability of TFS was 86.8% and 78.8% for the entire cohort, 86.9% and 80.0% for patients with ET, and 84.4% and 76.3% for patients with PV.
In a multivariate analysis, elevated white blood cell count (>11 × 109/L; hazard ratio [HR], 2.7; P=0.012) and the absence of splenomegaly at diagnosis (HR, 5.7; P=0.026) were associated with increased risk for thrombosis.
Choice of first treatment did not correlate with differences in TFS. The 10- and 20-year TFS were 83.9% and 79.9% for interferon, 81.4% and 70.2% for hydroxycarbamide, and 91.6% and 76.3% for anagrelide (P=0.281)
How Essential Thrombocythemia and Polycythemia Vera Affect Blood Flow
May 27, 2025
Author(s): Dr. Tiziano Barbui
Fact checked by: Spencer Feldman
Excess blood cell production in two myeloproliferative neoplasms (MPNs) — essential thrombocythemia, or ET, and polycythemia vera, also known as PV — can impair circulation, according to Dr. Tiziano Barbui.
Barbui is a professor of hematology and founder of the department of hematology at Bergamo Hospital. He is currently the scientific director of clinical research foundation at Papa Giovanni XXIII Hospital, Bergamo, Italy.
In a video interview with CURE, Barbui explained that both diseases begin in the bone marrow and are marked by abnormal increases in blood cell counts. In polycythemia vera, red blood cells are overproduced, increasing blood viscosity and making it harder for blood to flow through small vessels. In essential thrombocythemia, the problem lies with excess platelet production.
Barbui emphasized that treatment is essential not only to relieve symptoms but also to prevent more serious complications linked to impaired blood circulation in both MPNs.
SVR With Pacritinib Is Linked With OS Benefit in Myelofibrosis With Thrombocytopenia
May 26, 2025
Author(s): Ashling Wahner
Fact checked by: Gina Mauro
The achievement of spleen volume response (SVR) of at least 10% (SVR10) at week 12 with pacritinib (Vonjo) was positively associated with overall survival (OS) in patients with myelofibrosis and thrombocytopenia, although more stringent SVR thresholds were not significantly associated with OS, according to findings from a post hoc landmark analysis of the phase 3 PERSIST-2 trial (NCT02055781).1
The investigators assessed OS among SVR responders vs nonresponders using 4 different SVR thresholds: at least 35% (SVR35), at least 20% (SVR20), SVR10, and greater than 0% (SVR0). The data, which were published in the European Journal of Haematology, showed that the greatest separation of OS curves between responders and nonresponders was observed among patients who received pacritinib (n = 89) at 200 mg twice daily and achieved SVR10 vs those who did not respond at that threshold (HR, 0.00; 95% CI, 0.00-0.14; P < .01). No deaths were observed among the responders, whereas 5 nonresponders died.
“We found that a significant association was not observed with more stringent SVR or total symptom score [TSS] thresholds, likely because the number of responders was lower, and thus a larger number of observations would be needed to detect statistical significance at such thresholds,” lead study author Helen Ajufo, MD, MS, of the Department of Medicine, Leukemia Service, at Memorial Sloan Kettering Cancer Center, in New York, New York, and coinvestigators explained in the paper.
SVR0 and SVR20 also conferred improved OS, although these more stringent response thresholds were less prognostic of the pacritinib survival benefit.
Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling
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.
Post Hoc Data Show Anemia Benefits, Reduced Transfusion Burden With Momelotinib in Myelofibrosis
Author(s): Chris Ryan
Fact checked by: Ashling Wahner
A post hoc analysis of a single-arm, phase 2 study (NCT02515630) and the phase 3 SIMPLIFY-1 (NCT01969838), SIMPLIFY-2 (NCT02101268), and MOMENTUM (NCT04173494) studies showed that momelotinib (Ojjaara) was associated with anemia-related benefits in most patients and a reduction in transfusion burden vs comparator treatments in patients with JAK inhibitor–naive and –experienced myelofibrosis.1
Findings published in Clinical Lymphoma, Myeloma & Leukemia showed that more than 77% of patients treated with momelotinib across the 4 trials experienced a numerical reduction in red blood cell (RBC) transfusion requirements during treatment compared with baseline.
“This [post hoc analysis] demonstrates that across all 3 phase 3 trials of momelotinib in myelofibrosis to date, at least 75% of patients treated with momelotinib either maintained or experienced improved transfusion intensities vs baseline,” lead study author Claire Harrison, MD, FRCP, FRCPath, a professor of myeloproliferative neoplasm and clinical director of Guy’s and St Thomas’ NHS Foundation Trust in London, United Kingdom, and colleagues wrote in the publication. “These results provide evidence that underscores the consistent anemia benefits provided by momelotinib for the majority of patients.”
In September 2023, the FDA approved momelotinib for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.2 This regulatory decision was supported by data from MOMENTUM and a subgroup of patients with anemia treated during SIMPLIFY-1.
Molecular Response to Therapy Linked With Event-Free Survival in PV
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 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%.
Evolving Myelofibrosis Treatments Aims to Fill Unmet Needs
May 21, 2025
Author(s): Ryan Scott
Fact checked by: Spencer Feldman
Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasms (MPN) and can occur as de novo disease. Myelofibrosis creates varying degrees of fibrosis and can cause driver mutations such as JAK2, CALR or MPL in approximately 90% of patients. These mutations cause constant activation of the JAK-STAT pathway, which can lead to uncontrolled cell growth.
Other mutations that can occur, such as ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1, may also affect how the disease develops and prognosis. Moreover, common symptoms of the disease include fatigue, night sweats, fever, bone pain, cachexia, pruritus, thrombosis, and bleeding. Although disease progression is the most common reason for death and occurs in approximately 20% of patients, many patients also face serious risks from other complications. These include heart problems, infections, or bleeding due to low blood counts.
To combat the unmet needs within the myelofibrosis treatment landscape, there have been a number of studies investigating novel treatments for JAK inhibitor-ineligible or relapsed/refractory patients. To further explore these investigations, and the current and future states of the treatment landscapes, investigators broke everything down in research published in the American Journal of Hematology.
Understanding the Present Landscape and Ongoing Studies
The discovery of genetic mutations, as well as the role of the JAK-STAT pathway in the treatment of MPNs has led to the development of oral KAK inhibitors. These drugs work by blocking overactive JAK signaling involved in disease progression and symptom burden.
One such drug being used is Rituxan (ruxolitinib), which is the first ever U.S. Food and Drug Administration (FDA)-approved JAK inhibitor for myelofibrosis, approved by the regulatory agency in 2011. The agent elicits effective for symptom relief and spleen size reduction in approximately 50% of patients who are treated with it.
Common side effects of Rituxan include anemia and low platelets; other non-blood-related side effects include fatigue, diarrhea and infections. Long-term use of the agent may also increase the risk of secondary cancers (like non-melanoma skin cancer) and round 40% to 50% of individuals discontinue the drug within three years due to side effects or lack of efficacy. However, stopping Rituxan is linked to new mutations and poorer outcomes.
Another agent used in the treatment of myelofibrosis is Inrebic (fedratinib), which was approved in 2019 by the FDA for both patients with newly diagnosed disease and those who are refractory and/or intolerant to Rituxan. This agent provides similar benefits to those seen with Rituxan, including reduction of spleen size and symptoms, but with frequent gastrointestinal side effects, like nausea, diarrhea and vomiting.
Notably, Inrebic carries a black box warning for risk of Wernicke’s encephalopathy, making monitoring essential. Additionally, treatment with the agent is less effective in patients who were on high-dose Rituxan prior to switching.
Vonjo (pacritinib) is another treatment which was approved in 2022 for patients with severe low platelet counts in the myelofibrosis treatment space. Unlike Rituxan and Inrebic, it can be used in high-risk patients with more advanced disease and cytopenias. In trials such as the PERSIST-1 and PERSIST-2 studies, Vonjo showed modest spleen and symptom response but improved transfusion independence.
Vonjo is currently being tested in the PACIFICA trial for patients with platelets less than 50 × 10⁹/L.
Finally, Ojjaara (momelotinib) is also being used in the treatment space for patients with this disease and was approved by the FDA in 2023. Ojjaara targets JAK1/2 and ALK2, with a unique effect on anemia. Trials, including the SIMPLIFY-1 and SIMPLIFY-2 studies, showed similar spleen responses to Rituxan but greater improvements in anemia and transfusion independence.
The MOMENTUM study confirmed Ojjaara’s improved both symptoms and anemia in symptomatic, anemic patients previously treated with a JAK inhibitor.
Ruxolitinib Plus Siremadlin Yielded Superior Spleen Volume Reduction in Patients With Myelofibrosis
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