Researchers Identify INCA033989 as a Potential Treatment for Myeloproliferative Neoplasms

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By Alexandra Gerlach, Associate Editor

Data from a study published in Blood demonstrates the therapeutic potential of INCA033989 as the first targeted therapy for myeloproliferative neoplasms (MPNs) that does not interfere with normal blood cell production. Existing therapeutic options for MPNs are effective at symptom management but have high discontinuation rates due to resistance and inadequate drug tolerability. The development of INCA033989 opens pathways to more effective, targeted options with disease-modifying potential without any negative impact on surrounding blood cells.1

The development of INCA033989 has positive implications for the evolving treatment landscape of patients with MPNs. Image Credit: © Anna – stock.adobe.com

MPNs are a group of malignancies characterized by the overproduction of red and white blood cells and is an umbrella for 6 different disease types: myelofibrosis (MF), essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Calreticulin (CALR) mutations are responsible for disease development in 20% to 30% of patients with MPNs, which can be either insertions or deletions in exon 9 of CALR. The mutated CALRprotein (mutCALR) is responsible for the stable interaction with thrombopoietin receptors (TPO-R), which are crucial for controlling blood cell production.2,3

Janus kinase (JAK) inhibitors, such as ruxolitinib (Jakafi; Incyte Corp), are the recommended treatment options for patients with MF or other MPNs; however, they are associated with adverse effects (AEs), namely grade 3 or 4 anemia. INCA033989 is a high affinity, fully human immunoglobulin G1 selective monoclonal antibody targeting mutCALR-driven oncogenesis to suppress TPO-R signaling, thereby preventing the proliferation and progression of disease. According to data from the original study announcing the development of this agent, there was an observed synergism between INCA033989 and ruxolitinib which resulted in the inhibition of cell proliferation and indicated the ability of INCA033989 to enhance the efficacy of ruxolitinib.3,4

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New Trial Sets Out to Test Treatment for Early Primary MF

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Özge Özkaya, MSc, PhD

A new randomized, double-blind, placebo-controlled, phase 3 clinical trial assessing the safety and efficacy of ropeginterferon alfa-2b, a new-generation pegylated interferon-based therapy, in patients with early and lower-risk primary myelofibrosis (MF) is now open.

The trial aims to recruit 150 such patients who are at least 18 years of age and will receive either up to 500 μg of subcutaneous ropeginterferon alfa-2b or a placebo every 2 weeks until 56 weeks.

The primary endpoints of the trial include clinically relevant complete hematologic response as measured by platelet count, white blood cell count, hemoglobin levels in peripheral blood, absence of thrombotic events, and no progression to acute myeloid leukemia, and symptom endpoint.

Secondary endpoints include bone marrow response, event-free survival or progression-free survival, molecular response in driver or relevant coexisting gene mutations, and safety.

“The study will provide important data for the treatment of early/lower-risk [primary] MF for which an anti-clonal, disease-modifying agent is highly needed,” the researchers wrote in an article that they published in the journal Annals of Hematology, which contains the details of the trial design.

The trial is not yet recruiting participants. It is estimated to start in October 2024 and be completed in August 2027.

Previous research has shown that ropeginterferon alfa-2b has favorable pharmacokinetics and safety profiles and requires less frequent injections than previous formulations of pegylated interferon alfa, the researchers noted.

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Korean Study Finds DOAC Use “Seems Effective” in Patients With MPNs

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September 25, 2024

Author(s): Mary Caffrey

A study based on a decade’s worth of Korean insurance data found that use of direct oral anticoagulants (DOACs) to address atrial fibrillation and venous thromboembolism in patients with myeloproliferative neoplasms (MPNs) is effective, with acceptable bleeding risk.

Patients with Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) face an elevated risk of arterial and venous thrombosis, due to the increased production of mature myeloid blood cells caused by their condition.1 The increased morbidity and mortality caused by atrial fibrillation (AF) and venous thromboembolism (VTE) among patients with MPNs has led the American College of Cardiology and the American Heart Association, among others, to recommend direct oral anticoagulants (DOACs) to prevent blood clots and reduce the risk of major cardiovascular events in patients with MPNs.2

However, a group of authors from Korea, writing in Cancer Research and Treatment, note that the actual amount of evidence regarding the use of DOACs in patients with MPNs is limited. This week, they published a study based on a decade’s worth of Korean insurance data. Based on an analysis of records from 368 patients with MPNs, they concluded that use of DOACs in this population “seems effective with an acceptable bleeding risk.”3

The authors write that a prior study, with very limited data, found the 1-year cumulative incidence of thrombosis was 5.5% and bleeding was 12.3% among patients with MPNs taking DOACs.3 They note their study population involved patients who were somewhat older (average age, 74 years) and had a higher CHA2DS2-VASc score, which evaluates a patient’s risk based on the presence of congestive heart failure, hypertension, age, diabetes status, history of stroke or transient ischemic attack, and vascular disease; risk is doubled if the patient is 75 years or older.

The Korean study was based on data from the Health Insurance Review and Assessment Service, which has information on inpatient and outpatient care for 50 million Koreans. Investigators pulled patient data from the period of January 1, 2011, to January 1, 2021. The cohort of 368 patients had the following characteristics:3

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Bose’s Guide to Ruxolitinib, Fedratinib, Pacritinib, and Momelotinib

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By Prithviraj Bose, MD

Prithviraj Bose, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, provides an overview of the different JAK inhibitors currently available for patients with myeloproliferative neoplasms.

Transcription:

0:09 | We have 4 JAK inhibitors approved for the treatment of myelofibrosis in the US. Important to note, pacritinib [Vonjo] is not approved outside the US. There is obviously a lot to say on this topic, especially, ruxolitinib [Jakafi] was approved in 2011, fedratinib [Inrebic] in 2019 and then pacritinib and momelotinib [Ojjaara], more recently, 2022 and 2023. But I think I will just hit some high points.

0:36 | So for ruxolitinib, the first thing I would say about that is that it is the JAK inhibitor with the most clearly demonstrated survival benefit in myelofibrosis. Now, is that an effect just of ruxolitinib and not of the others? We do not know that. It could be a class effect, but the data are the data and the data are that ruxolitinib is the one that has a clearly shown survival benefit. I think that needs to be considered as we use it, and it is usually the most frequently used frontline drug. Now, where you can get into trouble with ruxolitinib is with cytopenias, low blood counts, and this is a drug that you need to be able to dose well in order to get the benefit that you are seeking. The dose can get compromised by cytopenias.

1:29 | That is where I will tie that into the entry of pacritinib and momelotinib. These are easier to use in the setting of cytopenias. In fact, pacritinib has a label for platelets than 50, and momelotinib is for patients with anemia in myelofibrosis. So right there, you can see that they sort of have their place more in that cytopenic population, which could be frontline, or, more commonly, second-line, after ruxolitinib. I think those are great additions in the sense that you can give them at good doses despite low blood counts, which becomes difficult with ruxolitinib, like I just said. [They are] certainly very welcome additions to the arsenal.

2:12 | I will just say 1 last thing about fedratinib, which was the second one approved. This is a good drug, perhaps as good as ruxolitinib from an efficacy stand point, but really with no clear advantage over ruxolitinib. So, I do not use it in the frontline. I do use it, however, in post-ruxolitinib settings, where the blood counts are good. In those proliferative scenarios, as opposed to the cytopenic scenarios, in second-line and beyond, I do find fedratinib to be a useful drug. It has some toxicities that one has to pay attention to. All patients should get thiamine supplementation, stuff like that, but overall, I would say those are the kind of very high level points about the 4 drugs.

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Dr Amanam on Criteria for Selecting a JAK Inhibitor in Myelofibrosis

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September 23, 2024

Author(s): Idoroenyi Amanam, MD

Idoroenyi Amanam, MD, assistant professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses the criteria for selecting JAK inhibitors in the treatment of patients with myelofibrosis.

Ruxolitinib (Jakafi) was the first JAK inhibitor approved for the treatment of myelofibrosis by the FDA in 2011. Amanam notes that this approval was initially based on the agent’s demonstrated benefits in reducing splenomegaly and improving symptom burden, two critical factors that influence treatment outcomes in myelofibrosis. Since then, 3 additional JAK inhibitors have received FDA approval for the treatment of select patients with myelofibrosis: fedratinib (Inrebic) in 2019, pacritinib (Vonjo) in 2022, and momelotinib (Ojjaara) in 2023.

Amanam emphasizes that the ideal candidates for JAK inhibitors are patients experiencing significant symptom burden and splenomegaly. Patients presenting with myelofibrosis, particularly those with moderate to severe spleen enlargement and a high burden of disease-related symptoms, are likely to derive the most benefit from JAK inhibition, he continues.

Conversely, patients who are not experiencing splenomegaly or any symptom burden may have limited therapeutic gain from JAK inhibitors, and the use of these agents in these patients may expose them to unnecessary risks of adverse effects (AEs), he says. The most commonly reported AEs from JAK inhibitor treatment are cytopenias, such as anemia, thrombocytopenia, and leukopenia, Amanam notes.

To avoid these potential toxicities, Amanam stresses the importance of thorough patient evaluation and symptom assessment when considering JAK inhibitors, as the absence of these key criteria can reduce the overall efficacy of treatment and increase the potential for unnecessary AEs.

In clinical practice, Amanam explains the importance of personalized treatment strategies based on individual patient characteristics and risk profiles, prioritizing those who meet the established clinical benchmarks for symptom relief and splenic volume reduction.

Although JAK inhibitors can offer significant symptomatic relief for appropriately selected patients, they are not universally beneficial for all patients with myelofibrosis and should be used judiciously to optimize clinical outcomes, he concludes.

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Can Vaccines Be Developed for MPNs? Study Examines the Challenges

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September 18, 2024

Author(s): Mary Caffrey

Researchers from Bulgaria conduct an analysis of the potential for therapeutic vaccines in by comparing testing results for patients from their country with an international data set.

Despite their status as myeloid malignancies, myeloproliferative neoplasms (MPNs) have drawn interest from researchers as candidates for therapeutic vaccines. Giroux et al drew attention in Science in 2022 by investigating MPNs with calreticulin (CALR) mutations, which lack T cells to target this antigen.1 Specifically, Giroux’s team pursued the major histocompatibility complex (MHC-1) allele frequences they observed and developed a heteroclitic peptide vaccine to activate T cells against tumors.

Now, a team from Bulgaria follows Giroux with a statistical approach, with results appearing in Frontiers in Immunology.2 The group first made comparisons between patients with MPNs and healthy controls within the homogenous population of Bulgaria before completing a meta-analysis involving patients and healthy controls from the 1000 Genomes Project, an international effort to collect human genome samples.3

To start, the team established that human leukocyte antigen class I (HLA-I) and class II (HLA-II) alleles alter how JAK2 V617F and CALR mutations create cancer cells in MPNs, but that the role of immune response in MPNs is not well known. Thus, the team sought to explore the role of HLA genes in MPNs with CALR mutations. They conducted analyses involving 42 patients with CALR mutations and 158 with JAK2 V6127F mutations, as well as 1083 healthy controls.2

As the authors explained, mutations in 3 genes drive all MPNs; they are JAK2, CALR, and MPL. “These mutations originate at the level of hematopoietic stem cells, but, depending on the intrinsic and extrinsic factors, can lead to differential skewing of hematopoiesis predominantly into one of the myeloid lineages presenting clinically with 1 of the 3 phenotypes,” which they noted are essential thrombocythemia, polycythemia vera, and primary myelofibrosis.2

Mutations may appear just as cancer cells form but also before symptoms appear, in a status called clonal hematopoiesis of indeterminate potential, or CHIP; it may take a long time for CHIP to convert to malignancy, and different mutations follow different paths.

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Rovadicitinib Bests Hydroxyurea in Myelofibrosis

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Erin Clancy

The JAK2 inhibitor rovadicitinib proved more effective than hydroxyurea in patients with JAK inhibitor-naïve, intermediate-2 or high-risk myelofibrosis in a phase 2 trial presented at the ESMO Congress 2024.

These results “support the use of rovadicitinib as a new treatment option” for these patients, said study presenter Ling Pan, of West China Hospital, Sichuan University, in Chengdu, China.

The trial (NCT05020652) enrolled 105 patients with intermediate-2 or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. All patients had received no prior JAK inhibitor treatment and had palpable splenomegaly.

Patients were randomly assigned 2:1 to receive rovadicitinib at 15 mg twice daily plus placebo (n=72) or hydroxyurea at 0.5 g twice daily plus placebo (n=35). Baseline characteristics were well balanced between the arms.

Treatment continued for 24 weeks, at which point patients who achieved a spleen volume reduction of 35% or greater (SVR35) maintained treatment as assigned. Those who had not achieved SVR35 by week 24 received open-label rovadicitinib at 15 mg twice daily until treatment termination criteria were met.

At week 24, the SVR35 rate was 58.33% in the rovadicitinib arm and 22.86% in the hydroxyurea arm (P =.0006). The best spleen response rate during the study period was 63.89% with rovadicitinib and 31.43% with hydroxyurea (P =.0017).

The proportion of patients who achieved a 50% or greater reduction in total symptom score at week 24 was 61.11% with rovadicitinib and 45.71% with hydroxyurea (P =.136). The best symptom response rate during the study period was 77.78% with rovadicitinib and 54.29% with hydroxyurea (P =.0136).

Eighteen patients who initially received hydroxyurea but switched to rovadicitinib after week 24 were included in the safety analysis, so 90 patients were evaluable in the rovadicitinib arm and 35 patients were evaluable in the hydroxyurea arm.

The rate of treatment-emergent adverse events (TEAEs) was 97.78% in the rovadicitinib arm and 100% in the hydroxyurea arm. The rate of grade 3 or higher TEAEs was 51.11% and 77.14%, respectively. The rate of serious TEAEs was 31.11% and 40.00%, respectively.

The most common grade 3 or higher hematologic TEAEs (in the rovadicitinib and hydroxyurea arms, respectively) were platelet count decrease (20.00% and 17.14%) and anemia (28.89% and 60.00%). The most common grade 3 or higher non-hematologic TEAE was hyperkalemia (6.67%) in the rovadicitinib arm and weight gain (2.86%) in the hydroxyurea arm.

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Patients With Lower-Risk Myelofibrosis May Respond to Jakafi

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By Darlene Dobkowski, MA
Fact checked by Ashley Chan

Responses to treatment with Jakafi (ruxolitinib) were more frequent and durable in patients with intermediate-1 risk (low-risk) myelofibrosis, according to findings from a real-world study.

In addition, patients with intermediate-2 (high-risk) myelofibrosis had lower rates of toxicity from Jakafi treatment, as shown in findings from the study published in the journal Cancer.

After six months of treatment with Jakafi, spleen response rates were observed in 26.8% of patients, with symptom response rates in 67.9% of patients with intermediate-1 risk myelofibrosis.

“Splenomegaly (enlarged spleen) and symptoms may be extremely burdensome also in lower-risk patients, with approximately 40% of such patients starting [Jakafi] with a large splenomegaly and a high symptom score,” the study authors wrote. “This finding again supports how the clinical phenotype of [myelofibrosis] should guide the medical therapeutic approach, without being influenced by the prognostic risk category, which, in contrast, is essential instead for the transplant decision.”

Predictors of responses at six months after initiating treatment with Jakafi included no cytopenia (a condition with a lower-than-normal number of blood cells, which can include hemoglobin levels, platelets and white blood cells), no high-molecular-risk mutations and blasts less than 1%. Out of all these factors, high-molecular-risk mutations continued to have a significant association with responses.

According to The Leukemia & Lymphoma Society, blasts are immature blood cells that are a result of mutated stem cells multiplying uncontrollably. They do not mature into healthy blood cells, nor do they function as such. Abnormal blasts, over time, can surpass the bone marrow’s production of normal healthy blood cells.

At the start of the study, 595 of the 1,055 patients (56.2%) with myelofibrosis had intermediate-1 risk according to two different scoring systems used to classify risk (Dynamic International Prognostic Scoring System and Myelofibrosis Score With Constitutional Symptoms – Peripheral Myeloid Immaturity). Both of these scoring systems take into account certain factors like hemoglobin levels, platelet count, spleen size and symptoms.

The spleen was palpable (meaning that it is enlarged and could be felt through the abdominal wall) at the lower edge of the rib cage at less than 5 centimeters in 5.9% of patients, between 5 and 10 centimeters in 47.4% and greater than 10 centimeters in 39.7%. Of note, 54.1% of patients were highly symptomatic.

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Vonjo Improves Thrombocytopenia, Anemia in Patients With Myelofibrosis

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By Jax DiEugenio
Fact checked by Chris Ryan

Improvements in thrombocytopenia and anemia were observed in patients with myelofibrosis treated with Vonjo (pacritinib) in the real-world setting, as demonstrated in findings from a retrospective study presented at the 2024 SOHO Annual Meeting.

According to the National Cancer Institute, thrombocytopenia refers to a condition in which patients have a lower-than-normal number of platelets in the blood, and this can result in excessive bleeding from wounds and easy bruising. Anemia is a condition when patients have a low count of red blood cells.

Findings showed that patients with a platelet count below 100 x 109/L (which is considered low) at baseline (74 patients) experienced an early increase in platelet count following treatment initiation that was maintained throughout the observation period. Additionally, an early increase in median hemoglobin (a protein inside red blood cells that carries oxygen from lungs to tissues and organs) was reported in all patients, and this increase was sustained throughout the observation period. Patients with hemoglobin level of less than 8 g/dL (a level that indicates anemia) at the start of treatment (35 patients) experienced a hemoglobin increase of nearly 1 g/dL by day 30.

Notably, patients who received prior treatment with Jakafi (ruxolitinib; 69 patients) experienced an increase in platelet counts and hemoglobin levels following initiation of Vonjo. At baseline, the median platelet count and median hemoglobin level in this population was 91 x 109/L and 8.7 g/dL, respectively. At day 360, the median platelet count and median hemoglobin were 97 x 109/L and 10.4 g/dL, respectively.

“In addition to spleen and symptom benefits observed in previous clinical trials, real-world outcomes demonstrate stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis treated with [Vonjo],” lead study author Michael Marrone and colleagues, wrote in a poster presentation of the data. Marrone is an assistant professor in the College of Medicine, Department of Public Health Sciences, at the Medical University of South Carolina in Charleston.

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Novel approach may eliminate survival disparity in HSCT, greatly expand access

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September 17, 2024

Key takeaways:

  • Post-transplant cyclophosphamide prophylaxis reduced the OS disparity in matched vs. mismatched unrelated donor hematopoietic stem cell transplant.
  • The approach could expand access to HSCT.

Use of post-transplant cyclophosphamide prophylaxis to prevent graft-versus-host disease could greatly expand access to hematopoietic stem cell transplantation, according to results of a retrospective study.

An analysis of patients who received post-transplant cyclophosphamide (PTCy) showed no statistically significant difference in OS or GVHD-free RFS (GRFS) between patients with matched (8/8) or mismatched (7/8) unrelated donors.

The ability to find a suitable unrelated donor with a 7/8 HLA match is “much greater” than finding one with 8/8 HLA match, according to researcher Steven M. Devine, MD, chief medical officer at NMDP and senior scientific director at Center for International Blood and Marrow Transplant Research (CIBMTR), told Healio.

“For an African American patient, [chances] go from 30% to over 80%,” Devine said. “It’s even higher for Hispanic or Asian individuals — into the 90% range.

“If you can go even lower [to a 6/8 match or 5/8 match], you can pretty much find a volunteer unrelated donor for almost 100% of patients,” Devine added. “We are enabling a transplant for everyone, regardless of their ancestry.”

Access disparities

Allogeneic HSCT — used to treat multiple blood cancers and blood disorders — produces the best results when stem cells of a related or unrelated donor matches at 8/8 HLA markers at the HLA-A, -B, -C and -DRB1 genes, according to study background.

Only 30% of patients have siblings, who are HLA-identical matches and therefore could donate.

Non-Hispanic white individuals have a 79% likelihood of finding an unrelated matched donor in the NMDP registry. The rate is between 29% and 58% for people of other races and ethnicities.

“Historically, there’s been roughly a 10% lower chance of survival with each level of mismatch,” Devine said. “That’s why for years the focus has been on trying to find full matches for all patients.”

Cyclophosphamide, a chemotherapy drug used to treat a variety of solid tumors and hematologic cancers, has been repurposed for about 20 years to prevent GVHD after HSCT.

“It’s really revolutionized [stem cell transplant] because its use is associated with a much lower risk for both the acute and more chronic forms of GVHD,” Devine said. “It’s improved outcomes overall, and it’s allowed us to perform mismatched transplants both from related and unrelated donors. So, [for this study], we [wondered whether] those historical differences in outcomes between matched and mismatched transplant [are] as great as they were years ago now that we’re using PTCy.”

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