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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SOHO State of the Art Updates and Next Questions | Choosing and Properly Using a JAK Inhibitor in Myelofibrosis

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Michael J. Hochmanm, Colin A. Vale, Anthony M. Hunter

Abstract

Myelofibrosis (MF) is a chronic myeloid neoplasm characterized by myeloproliferation, bone marrow fibrosis, splenomegaly, and constitutional symptoms related to pro-inflammatory cytokine signaling. Biologically, MF is characterized by constitutive activation of JAK-STAT signaling; accordingly, JAK inhibitors have been rationally developed to treat MF. Following the initial approval of ruxolitinib in 2011, three additional agents have been approved: fedratinib, pacritinib, and momelotinib. As these therapies are non-curative, allogeneic stem cell transplantation remains a key treatment modality and patients with MF who are deemed candidates should be referred to a transplant center. This potentially curative but toxic approach is typically reserved for patients with higher-risk disease, and JAK inhibitors are recommended in the pre-transplant setting. JAK inhibitors have proven effective at managing splenomegaly and constitutional symptoms and should be started early in the disease course in patients presenting with these clinical manifestations; asymptomatic patients may initially be followed with close surveillance. Drug-related myelosuppression has been a challenge with initial JAK inhibitors, particularly in patients presenting with a cytopenic phenotype. However, newer agents, namely pacritinib and momelotinib, have proven more effective in this setting and are approved for patients with significant thrombocytopenia and anemia, respectively. Resistance or disease progression is clinically challenging and may be defined by several possible events, such as increasing splenomegaly or progression to accelerated or blast phase disease. However, with multiple JAK inhibitors now approved, sequencing of these agents appears poised to improve outcomes. Additionally, novel JAK inhibitors and JAK inhibitor-based combinations are in clinical development.

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Ruxolitinib Stands Out Among JAK2 Inhibitors for Myelofibrosis

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By Targeted Oncology Staff

In this virtual tumor board discussion, experts review the case of a 68-year-old woman diagnosed with primary myelofibrosis. The discussion focuses on recent data and emerging insights to guide clinical decision-making and explore the latest advances in treatment strategies for this challenging disease.

Prithvira J. Bose, MD: What are the first steps you would take for this patient, and how do you view multidisciplinary collaboration?

Julie Huynh-Lu, PA-C: Specific to [The University of Texas] MD Anderson [Cancer Center], the role of the physician assistant or nurse practitioner in the leukemia department is to evaluate the patient. Aside from doing a review of systems, I go over the myeloproliferative neoplasms [MPN] questionnaire with the patients to review any changes in their score. Whether they have started therapy or not, [we determine whether they] need to be on therapy based on their answers.

I do a physical assessment of the patient checking their spleen. We don’t order ultrasounds or CT scans on patients unless we’re unable to palpate due to pain in that area. I’ll measure the spleen size every time the patient comes in with a tape measure.

Having a second set of eyes evaluating the patient [is key] because some questions that I may ask, someone else may not—or the physician may ask questions that I may not know [to ask]. Collaboration among nurses, physician assistants or nurse practitioners, and physicians in compiling patient information ensures the best care for the patient.

We are lucky to have the MPN10 form in the Epic system on our flow sheet, and patients can fill out this form before they check in for their appointment. If they were unable to fill it out, I can go into that flow sheet, ask those questions, and fill it out with them. Then, the score [generates] for each patient.

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