High Rates of Polycythemia Vera Remission Seen With Ruxolitinib Plus Peg-IFN

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Andrea S. Blevins Primeau, PhD, MBA

Final results from the phase 2 COMBI II trial demonstrated high rates of remission of newly-diagnosed polycythemia vera (PV) after treatment with ruxolitinib plus pegylated-interferon-α2a (peg-IFN), according to a report published in Blood Advances.

The COMBI I trial previously demonstrated efficacy and safety of the combination of ruxolitinib with peg-IFN among patients who were refractory or intolerant to peg-IFN monotherapy and/or hydroxyurea.

“This study supports the previously described theory that combination therapy with ruxolitinib and peg-IFN may be one of the most promising treatment options in patients with myeloproliferative neoplasms,” the researchers wrote in their report.

In the investigator-initiated, single-center, phase 2 study, researchers treated 25 adult patients with newly-diagnosed PV with ruxolitinib and peg-IFN. All patients underwent pretreatment phlebotomies and patients who were high-risk, aged 60 or older, or who had a prior thrombosis also received hydroxyurea.

The primary endpoint was safety and secondary endpoints included complete remission (CR), peripheral blood count remission (PBCR), and bone marrow histologic remission (BMHR).

The median age of the patients was 70 years and 56% were male. The median number of phlebotomies from diagnosis to study entry was 3. There were 76% of patients who were considered high-risk, 20% had a prior thrombosis, and 12% had splenomegaly. The median hemoglobin was 13.8 g/dL and the median hematocrit was 0.44 IQR. The median variant allele fraction (VAF) of JAK2 V617F at baseline was 54 IQR.

Remission was achieved by 52% of patients by 12 months, with 12% of patients having achieved a CR. At 24 months, the overall remission rate was 56% and the CR rate remained at 12%.

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Janus kinase inhibitor monotherapy and combination therapies for myelofibrosis: what’s the current standard of care?

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Mahesh Swaminathana, Akhil Jain, Sungchul Daniel Choi & Naveen Pemmaraju
Received 10 Jun 2024, Accepted 23 Sep 2024, Published online: 03 Oct 2024

ABSTRACT

Introduction

JAK inhibitors (JAKi) have changed the treatment paradigm of myelofibrosis (MF). Currently, 4 JAKis are approved in the US as monotherapy (mono) to treat patients with MF. JAKis are also being studied in combination (combo) with novel agents. Herein, we review some of the key studies that evaluated JAKi as mono and combo in MF.

Areas covered

We performed a Pubmed search for ‘JAK inhibitors’ and ‘myelofibrosis’ from 1/2010 to 12/2023. For mono, we included only the unique phase II/III studies of the approved JAKi. Selective studies that evaluated JAKi in combo with the novel agents were also included.

Expert opinion

JAKis aim to provide clinical benefit to patients via spleen size reduction and MPN symptom improvement. In order to potentially increase clinical benefit for patients with MF, several novel agents are being partnered with ruxolitinib (RUX) with the ongoing hypothesis to augment greater measures of MF disease modification. The novel agents are either ‘added-on’ to RUX or as a combo in JAKi naïve patients. Also, the mutant-targeting era of therapies is now beginning with novel CALR-mutated, novel JAK2 V617F mutation-specific and type II JAK2i in the initial stages of drug development, representing a new approach to treatment.

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MPN Word of the Month: Platelets

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As we know, myeloproliferative neoplasms (MPNs) are a group of blood cancers that involve the overproduction of blood cells in the bone marrow. These conditions primarily include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). One of the primary features of certain MPNs, particularly essential thrombocythemia, is the abnormal production and function of platelets, that help with blood clotting and maintaining vascular integrity. Understanding the relationship between platelets and MPNs is crucial for diagnosing,
monitoring, and managing these disorders.

What Are Platelets?

Platelets, also known as thrombocytes, are small, disc-shaped cell fragments in the blood. Produced in the bone marrow by megakaryocytes, platelets are essential for hemostasis—the process that prevents excessive bleeding when blood vessels are injured. When a blood vessel is
damaged, platelets adhere to the site of injury, coagulate to form a plug, and interact with clotting factors to stabilize the clot, preventing further blood loss.

How Do Platelets Work In MPNs?

In MPNs, the bone marrow exhibits uncontrolled proliferation of hematopoietic stem cells, leading to the overproduction of various blood cells, including platelets. This dysregulation can significantly impact platelet function and count, resulting in both hemorrhagic and thrombotic complications.

Platelets in Essential Thrombocythemia (ET)
Essential thrombocythemia is characterized by an excessive production of platelets due to  mutations in genes such as JAK2, CALR, or MPL. In ET:

● High Platelet Counts: Patients often present with elevated platelet counts, sometimes exceeding one million platelets per microliter of blood. Despite the abundance of platelets, they may not function normally, leading to an increased risk of clotting (thrombosis) and bleeding (hemorrhage).
● Thrombotic Risk: Abnormally high platelet counts increase the likelihood of clot formation within blood vessels, potentially leading to complications such as stroke, heart attack, deep vein thrombosis (DVT), and pulmonary embolism.
● Bleeding Risk: Interestingly, patients with extremely high platelet counts can also experience bleeding issues. This is because the overproduction of platelets can lead to a depletion of von Willebrand factor (vWF), which is necessary for platelet adhesion,

Platelets in Polycythemia Vera (PV)
In PV, there is an overproduction of red blood cells, often accompanied by increased platelets and white blood cells:

● Platelet Dysfunction: Although the platelet count in PV is usually elevated, platelet function can be abnormal. This dysfunction can result in an increased risk of thrombosis even though there is a high platelet count.
● Thrombotic Events: Similar to ET, patients with PV have a higher risk of blood clots because the not only is there an increase in blood viscosity (from elevated red blood cell mass) there is also altered platelet function.

Platelets in Myelofibrosis (MF)
Myelofibrosis is marked by the replacement of bone marrow with fibrous tissue, impairing normal blood cell production:

● Variable Platelet Counts: Patients with MF may have either low (thrombocytopenia) or high (thrombocytosis) platelet counts, depending on disease progression and bone marrow function.
● Abnormal Platelet Function: Regardless of the platelet count, platelet function is often compromised, which leads to a higher risk of both bleeding and clotting events.

Platelets in Diagnosis and Management
The evaluation of platelet count and function is an important part of diagnosing and managing MPNs. Laboratory tests commonly used include:

● Complete Blood Count (CBC): To assess platelet count, red blood cell mass, and white blood cell count.
● Bone Marrow Biopsy: To examine marrow architecture and megakaryocyte proliferation, providing insight into the degree of myeloproliferation.
● Genetic Testing: To identify mutations in JAK2, CALR, and MPL genes, which are associated with different MPNs.
● Platelet Function Tests: In some cases, platelet aggregation studies may be used to evaluate platelet function, especially if bleeding complications are present.

The primary goal in managing MPNs is to minimize the risk of thrombotic and hemorrhagic events. Several treatment strategies are used to address abnormal platelets such as cytoreductive therapies, antiplatelet agents, JAK2 inhibitors, and close monitoring of blood counts.

Platelets play a central role in the diagnosis, progression, and care of myeloproliferative neoplasms. Understanding the complex interactions between platelets and MPNs is crucial for effective diagnosis, risk assessment, and management of these disorders. With appropriate
monitoring and individualized treatment strategies, the risks associated with abnormal platelet activity in MPNs can be managed, improving patient outcomes. For more information about MPNs visit our website at www.mpnadvocacy.com.

Choosing the Right JAK Inhibitor for Effective Myelofibrosis Treatment

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By Jordyn Sava
Fact checked by Sabrina Serani

With 4 JAK inhibitors approved in the US and additional agents in development, it is an exciting time for the field of myeloproliferative neoplasms (MPNs). Now, experts face the challenge of determining which treatment is best for each patient.

Ruxolitinib (Jakafi), an established JAK inhibitor, was first approved by the FDA in 2011,1 showing clear survival benefits. This was followed by the FDA approvals of fedratinib (Inrebic) in 2019,2 pacritinib (Vonjo) in 2022,3 and momelotinib (Ojjaara) in 2023.4

“Each [JAK inhibitor has] their place depending on the patient’s blood counts and other clinical factors,” explained Prithviraj Bose, MD, in an interview with Targeted OncologyTM.

With multiple JAK inhibitors available to choose from, a tailored approach ensures that each patient’s specific disease characteristics and comorbidities are considered to maximize efficacy and minimize toxicity during treatment.

In the interview, Bose, professor in the Department of Leukemia at MD Anderson Cancer Center, discussed the multiple JAK inhibitors available for the treatment of patients with MPNs.

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Ruxolitinib Could Be Useful in MF Care

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Leonardo Jaimes, MD

Ruxolitinib appears to produce durable responses and minimal adverse effects in patients with myelofibrosis (MF) in a real-world setting, according to a recently published study in Cancer.

Since its US Food and Drug Administration approval over a decade ago, the JAK1/JAK2 inhibitor ruxolitinib has become one of the most commonly used drugs for the management of MF-associated symptoms, the study team noted. Its approval is based on the results from the COMFORT study, which included only intermediate-2 and high-risk patients, they continued.

“However, intermediate-1 risk patients may carry a significant burden of disease and are increasingly treated with ruxolitinib in the real-life setting. Moreover, in some European countries (e.g., Germany) approval of ruxolitinib is not restricted to higher risk patients but rather to those with symptomatic disease (even when intermediate-1 or low risk),” the authors wrote.

Given the lack of studies investigating the effectiveness and safety of ruxolitinib in an intermediate-1 risk patient population and the small cohorts and short follow-up times used in previous studies, the research team aimed to assess the drug in a real-world clinical practice context.

The retrospective study included data from over 1000 patients with MF who had received ruxolitinib since 2013. Approximately 56% of the patients were intermediate risk-1.

The authors observed a 26% spleen response rate after six months of ruxolitinib in the intermediate risk-1 population and a 68% symptom response rate. Both rates were slightly inferior in patients with intermediate risk-2.

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Hypomethylating Agents Show Promise in Myelofibrosis Progression After alloHCT

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Andrea S. Blevins Primeau, PhD, MBA

Donor chimerism was restored with hypomethylating agent (HMA) treatment among some patients with myelofibrosis (MF) who relapsed after allogeneic hematopoietic cell transplantation (alloHCT), according to a small retrospective published in the journal Transplantation and Cellular Therapy.

These data suggest that HMA “is an option for patients in the future,” the researchers wrote in their report. “By promoting restoration of donor chimerism and clearance of pre-alloHCT somatic mutations, HMAs offer a capable therapeutic strategy for improving outcomes in this challenging patient population.”

In the single-center, retrospective study, the researchers analyzed data from the electronic health records of 12 patients with MF who relapsed after alloHCT between 2020 and 2023 and were subsequently treated with an HMA.

The median age of the cohort was 61 years and 33% of patients had primary MF, 41.7% had post-essential thrombocythemia MF, and 25.0% had post-polycythemia vera MF.

There were 92% of patients with disease classified as intermediate-2/high-risk by the Dynamic International Prognostic Scoring System (DIPSS) and 83% were considered high or very high risk by the Molecular International Prognostic Scoring System (MIPSS70+). There were 66.7%, 25.0%, and 16.7% of patients with JAK2, MPL, or CALR driver mutations, respectively, at diagnosis.

After transplantation, 99.9% of patients achieved donor chimerism at day 30 and 96.6% at day 100. Patients relapsed after alloHCT within a median of 282.5 days (range, 96-2388 days). The median donor chimerism before initiating an HMA was 57.82%.

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Shear Wave Elastography Distinguishes Myelofibrosis From Other MPNs

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Sep 25, 2024

 

Liver and spleen shear-wave elastography helped distinguish patients with myelofibrosis from healthy controls and those with essential thrombocytopenia, according to findings published in the Journal of Ultrasound. This suggests that the technique may help diagnose myeloproliferative neoplasms.

Researchers added that liver stiffness and spleen stiffness appeared to be linked with bone marrow fibrosis.

“Vibration-controlled transient elastography (VCTE) has proven to be a valuable tool in providing prognostic and staging information in patients with liver disease, greatly reducing the need for liver biopsy,” Vito Sansone, MD, Student, and colleagues wrote. “Spleen stiffness, similarly, has proven useful as a surrogate marker of portal hypertension. To date, however, the role of any of these techniques in the work-up of MPNs has not been established. …This study aims to investigate if values of liver and spleen stiffness measured with shear-wave elastography could help to differentiate MPNs from healthy controls and if there are significant differences in values of liver stiffness and spleen stiffness.”

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HTR1B Expression and Thrombosis in Patients With Myeloproliferative Neoplasms

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Vicki Moore, PhD

In this retrospective study, the researchers evaluated expression levels of HTR1B based on messenger RNA from peripheral blood mononuclear cells obtained from patients with newly diagnosed MPN, in addition to conducting other analyses. The researchers had a goal of evaluating possible differences in expression of this gene across MPN subtypes.

There were 85 patients with newly diagnosed MPN included in the analysis, with a median age of 57 years (range, 23-80). Among these patients, 28 had polycythemia vera (PV), 25 had essential thrombocythemia (ET), and 32 had primary myelofibrosis (PMF). Additionally, comparisons of HTR1B expression included 6 healthy volunteers.

Across MPN subtypes and control individuals, the expression of HTR1B did not significantly differ (P =.3089). However, there was large variation observed in expression levels. The researchers further examined expression levels in the context of other patient factors, including based on whether patients had a thrombotic or non-thrombotic history.

A total of 32 patients were considered to have thrombotic MPNs and 53 patients were considered to have nonthrombotic MPN, with median ages of 57 years in each group. Levels of HTR1B expression were significantly different when analyzed across groups organized by thrombotic MPN, nonthrombotic MPN, or status as control individuals.

The level of HTR1B expression appeared highest among patients with thrombotic MPNs, while levels appeared to not be significantly different between patients with nonthrombotic MPNs and control individuals. Among patients with thrombotic MPNs, there was no statistically significant difference observed in the level of fold-change in HTR1B expression by MPN subtype.

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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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