Category Archives: Research

JAK2 Mutations Rarely Found in Patients With MPN Living in High Altitude Areas Who Have Unprovoked Thrombotic Events

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Ryner Lai

JAK2 mutations are rarely found in patients with a myeloproliferative neoplasm (MPN) who have unprovoked thrombotic events — deep vein thrombosis (DVT), pulmonary embolism (PE), or atypical thrombosis — living in high-altitude regions, according to a study published in the International Journal of General Medicine. 

Thrombosis often serves as the initial manifestation of a MPN and is a significant contributor to both morbidity and mortality. JAK2 plays a role in influencing the proliferation of hematopoietic cells and the inflammatory signaling cascade; mutation in JAK2 is notably associated with higher rates of cellular proliferation and differentiation, as well as cytokine release. Patients with MPNs and JAK2 mutations typically have a raised risk of thrombosis when compared with their counterparts who do not have JAK2 mutations.

High-altitude living is associated with alterations in coagulation pathways and blood composition. Studies demonstrate that otherwise healthy individuals with high-altitude hypoxia are at an increased risk of developing idiopathic arterial and venous thrombosis. Scientists suspect that the high altitude can interact with background hereditary/acquired thrombophilia to further exacerbate the risk of initial/recurrent thrombosis.

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New Model Can Assess Blast Phase Progression Risk in Myeloproliferative Neoplasms

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November 12, 2024

Author(s): Alexandra Gerlach, Associate Editor

Researchers from Germany developed a model that utilizes 12 genetic markers to accurately distinguish patients with varying myeloproliferative neoplasms (MPNs) including chronic myeloid leukemia (CML) and BCR::ABL1 negative MPNs polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET). Using the model, clinicians can more precisely characterize their disease and determine their risk of progression to blast phase (BP).

Red blood cells and DNA strand | Image Credit: © GustavsMD – stock.adobe.com

MPNs are clonal disorders of the blood cells and bone marrow characterized by abnormal hematopoietic proliferation, which have been differentiated into 8 subclasses by the World Health Organization. However, the 4 classical types are CML, PV, PMF, and ET, characterized by mutations in the JAK2, CALR, or MPL driver genes.1,2

Diagnosis of a specific MPN is based on their unique morphology; for example, PV is distinguished by a hypercellular bone marrow and elevated hemoglobin level, compared with ET, which is characterized by megakaryocytic proliferation and increased platelet counts. However, this approach fails to acknowledge overlaps, borderline findings, or potential transitions to other MPN subtypes. Patients with PV and patients with ET can progress to post-PV or post-ET myelofibrosis (MF), underscoring the genetic intricacy of these disorders. There is also the risk of progression to BP, also called leukemic transformation, in which the presence of circulating or bone marrow blasts is ≥20%.2-4

In the study, the researchers aimed to use genetic markers to more effectively stratify CML, PV, PMF, and ET, as well as characterize patients with progression to BP. They developed a machine-learning model based on 12 genetic markers observed in routine analysis to accurately classify MPN subtypes and provide useful prognostic information in a user-friendly decision tree format for clinicians. Using data from over 500 patients, they were able to genetically characterize 355 individuals with 1 of the 4 classic MPNs.1

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Precipio Expands Bloodhound™ MPN Panel by Adding CALR Mutation Subtyping

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The unique assay enables laboratories to provide clinicians with more informed treatment decisions for their patients

| Source: Precipio, Inc.

NEW HAVEN, Conn., Oct. 08, 2024 (GLOBE NEWSWIRE) — Specialty cancer diagnostics company Precipio, Inc. (NASDAQ: PRPO) announces the launch of a new version of its Bloodhound MPN (Myeloproliferative Neoplasm) panel that is now able to distinguish between CALR type 1 and type 2 mutations. The CALR mutation data plays a critical role in disease prognosis and therapeutic decision-making. This differentiation aligns with the latest National Comprehensive Cancer Network (NCCN) guidelines released in August of this year (Version 2.2024—August 8, 2024).

This is the only quantitative PCR-based panel of its kind on the market that distinguishes between CALR Type 1 and Type 2 alongside the other genes relevant to the molecular evaluation of MPN.

“As science and discovery constantly evolve the diagnostic world, Precipio is committed to maintaining its competitive advantage and being at the forefront of our industry,” said Ilan Danieli, Precipio CEO. “Our customers and their patients will continue to benefit from access to cutting-edge technologies combined with the highest clinical value, enhancing patient care.”

Clinical Significance of CALR Subtyping in MPN Management
The inclusion of CALR mutation subtyping is a direct response to the evolving landscape of MPN patient care where understanding the specific type of CALR mutation can influence treatment strategies and outcomes.

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New Insights Emerge on Treatment Outcomes for Accelerated or Blast-Phase Myeloproliferative Neoplasms

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Tori Rodriguez, MA, LPC, AHC

In recent years, several new therapies approved by the US Food and Drug Administration for the treatment of acute myeloid leukemia (AML) have been used in the management of accelerated or blast-phase myeloproliferative neoplasms (MPN-AP/BP). However, due to a dearth of prospective data on the efficacy of these therapies in patients with MPN-AP/BP, there remains a lack of consensus regarding their use in this population.1

In a retrospective, multicenter cohort study published in Blood Advances, researchers aimed to address this gap by investigating outcomes among 202 patients with MPN-AP/BP who were diagnosed and treated in the current era of myeloid therapies.1

Study Findings

The results demonstrated a median overall survival (OS) of 0.86 years, with no significant differences observed by first-line treatment type. The most common frontline strategies were intensive chemotherapy, DNA methyltransferase inhibitor (DNMTi)-based regimens, and DNMTi plus venetoclax–based regimens.1

An analysis of 65 patients who went on to receive allogeneic hematopoietic stem cell transplant (allo-HSCT) revealed a median OS of 2.30 years from the time of transplant.

In an interview with Hematology Advisor, study co-author Evan Chen, MD, a medical oncologist at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School in Boston, Massachusetts, described 2 main takeaways from the findings: “First, outcomes of patients with MPN-AP/BP remain poor despite intensive chemotherapy and more recently developed, less-intensive venetoclax-based combinations. Second, a bone marrow transplant remains necessary for the possibility of long-term survival in the current treatment era for these patients.”

Despite the poor outcomes observed in this patient population, the present study found that “only 14% of patients were enrolled in clinical trials, and the criteria for assessing response in these patients is heterogeneous,” noted American Society of Hematology (ASH) media expert Ruben A. Mesa, MD, president and executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina.

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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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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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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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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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Managing Ruxolitinib-Associated Liver Toxicity in Patients With Myelofibrosis Requires a Nuanced Approach

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September 4, 2024

William J. Hogan, MBBCh, MRCPI

Key Points:

  • Ruxolitinib plays an important role in the treatment of symptomatic myelofibrosis, but its associated toxicities and adverse withdrawal effects can pose a challenge.
  • Myelofibrosis is linked with hepatic dysfunction, and ruxolitinib—despite its associated risks of hepatic transaminitis—may limit inflammation and progressive fibrosis, with liver injury resolution reported after treatment.
  • Overall, management of liver injury related to ruxolitinib depends on the cause and severity.

 

Question: In patients with myelofibrosis, how do you manage liver toxicity from ruxolitinib use beside dose de-escalation?

Answer: Ruxolitinib is a small-molecule JAK1/2 inhibitor that has an established role in the treatment of patients with symptomatic myelofibrosis, hydroxyurea-resistant polycythemia vera, and acute and chronic graft-versus-host disease. It has a potent anti-inflammatory effect that can provide very useful palliation of constitutional symptoms and splenomegaly in patients with myelofibrosis via inhibition of the JAK 1 and 2 pathways, which are involved in the production of inflammatory cytokines and hematopoietic growth factors.1-3 Common toxicities include myelosuppression, hepatic transaminitis, diarrhea, fatigue, headache, and peripheral edema. In patients with advanced myelofibrosis or florid inflammatory states, sudden withdrawal can lead to a systemic inflammatory response syndrome that can precipitate cardiopulmonary decompensation in frail patients, especially those with tenuous cardiopulmonary function, and corticosteroid prophylaxis or treatment may be required.4

In a mouse model of liver injury using carbon tetrachloride, JAK1/2 expression was implicated in progression of liver fibrosis. Inhibition of JAK1/2 downregulates downstream signaling, reduces progression to fibrosis, and even accelerates fibrosis reversal by inhibiting proliferation, migration, and activation of hepatic stellate cells in vitro.5 Myelofibrosis is associated with hepatic dysfunction by several mechanisms, including infiltration by hematopoietic stem cells (ie, extramedullary hematopoiesis [EMH]), portal vein thrombosis, and obliterative portal venopathy. EMH may respond favorably to ruxolitinib, and liver injury resolution after ruxolitinib treatment has been reported in patients with severe liver compromise related to myelofibrosis.6 These findings suggest that the drug may be able to reduce the consequences of inflammation—limiting progressive fibrosis in some circumstances—and may be of durable benefit in selected patients. A retrospective review of patients with liver injury and underlying myeloproliferative disorders treated with ruxolitinib and evaluated by biopsy demonstrated a variety of etiologies7; however, it is not always easy to determine how much is related to the underlying disease versus drug effects based on the biopsy findings, and this distinction is predominantly a clinical decision.

Liver toxicity typically manifests as mild hepatic transaminitis and can be exacerbated by drug–drug interactions. The incidence of hepatic transaminitis has been reported to be between 25% and 50%. Typically, these elevations are mild and self-limited, with < 1.5% of patients having values > 5 times the upper limit of normal. The drug is metabolized in the liver predominantly via the CYP3A4 pathway, and liver injury may be the result of the production of a toxic intermediate. Drug–drug interactions, such as with azole antifungals, can increase the effective exposure and enhance the potential for toxicity. Because suppression of intracellular signaling impairs immune response, suppression of viral replication may be impaired, increasing the potential for reactivation of quiescent viruses. This has been reported with reactivation of hepatitis B, resulting in clinically meaningful liver injury in patients who are at risk. It appears that the risk of viral reactivation with transaminitis and hyperbilirubinemia is greater in patients with HBsAg positivity, but reactivation has also been reported in those with anti-HBc. Efficacy with entecavir has been reported in treating viral reactivation and prophylaxis, so a nucleoside analog such as entecavir or tenofovir should be considered in patients who are at high risk.8-10

Management of liver injury related to ruxolitinib depends on the cause and severity. Identifying contributing causes, such as drug–drug interactions and prior viral hepatitis exposure and excluding other hepatotoxins are the initial imperative. Prior viral exposure with reactivation should be treated or prophylaxed when applicable. For mild transaminase elevations without hyperbilirubinemia, monitoring or temporary dose reduction may be appropriate. In more significant liver injury, dose interruption may be necessary. Consideration of an alternative JAK inhibitor may occasionally be warranted, as there does not appear to be significant evidence to suggest cross-reactivity between ruxolitinib and other JAK inhibitors. Of note, a retrospective review of liver injury occurring in patients with myeloproliferative neoplasms receiving ruxolitinib suggested a variety of potential etiologies, including those unrelated to the drug itself (EMH), in addition to obstructive portal vein apathy and drug-induced liver injury.

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