Navigating Cytoreduction in MPNs: Benefits, Risks, and Considerations

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Jordyn Sava

In an interview with Targeted Oncology, Douglas Tremblay, MD, discussed the significance of cytoreductive therapy in mitigating thrombotic risk in myeloproliferative neoplasms.

According to Douglas Tremblay, MD, cytoreductive therapy has emerged with a pivotal role in mitigating thrombotic risk in the treatment landscape of myeloproliferative neoplasms (MPNs), specifically essential thrombocytopenia (ET) and polycythemia vera (PV).

Despite the evident benefits, each therapy carries unique adverse effects, requiring the careful consideration of patient-specific factors in treatment administration. Deciding when to initiate cytoreductive therapy in patients with chronic MPNs relies on accurate risk assessment, with parameters such as age and prior thrombotic events often guiding treatment decisions.

Frontline therapies, such as hydroxyurea and interferon, manage blood counts for patients with ET and PV, and newer options are emerging, according to Tremblay, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai. However, the long-term implications focus on thrombosis prevention and disease progression.

Ongoing research endeavors aim to delve deeper into surrogate end points and novel therapeutic avenues, promising to further refine and revolutionize the management of MPNs.

In an interview with Targeted OncologyTM, Tremblay discussed the significance of cytoreductive therapy in mitigating thrombotic risk in MPNs, specifically ET and PV.

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JAK-STAT Pathway–Targeting Approaches in Myelofibrosis Are Evolving

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Raajit K. Rampal, MD, gave an overview of the classification, risk assessment, and current therapy options for patients with myelofibrosis.

Targeted Oncology: What is the latest understanding of the classification and pathogenesis of myeloproliferative neoplasms (MPNs)?

RAAJIT K. RAMPAL, MD, PHD: Nothing has changed in terms of the 2022 [World Health Organization] classification, unlike what has happened with myelodysplastic syndrome.1 JAK-STAT signaling is a hallmark of MPN pathogenesis, and all of the mutations that we’re aware of at the moment—JAK2, CALR [calreticulin], and MPL—function in the JAK-STAT pathway. MPL is the thrombopoietin receptor which complexes with JAK [Janus kinase].

CALR is interesting, because CALR was discovered in 2013 but we think at the moment CALR complexes with MPL and results in the aberrant activation of MPL, but CALR does traffic to the cell surface.2,3 That makes it a target for immunotherapy. That is the target of a couple of clinical trials; one is open [LIMBER (NCT06034002)] and the other is about to open, which is really interesting [and] could change everything in MPNs.

All that being said, there are still at least 8% to 15% of myelofibrosis cases that are “triple negative.”2,3 If you look at those cases by gene expression profiling, they have the JAK-STAT signature. The issue with those cases is that we haven’t identified the particular lesion that occurs there, but it is a JAK-STAT–activated lesion, regardless of what the actual driver is. Those are the important things to think about with regards to how the disease is driven.

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JNJ-88549968 by Johnson & Johnson for Essential Thrombocythemia: Likelihood of Approval

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JNJ-88549968 is under clinical development by Johnson & Johnson and currently in Phase I for Essential Thrombocythemia. According to GlobalData, Phase I drugs for Essential Thrombocythemia does not have sufficient historical data to build an indication benchmark PTSR for Phase I. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the JNJ-88549968 LoA Report. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

JNJ-88549968 overview

JNJ-88549968 is under development for the treatment of calreticulin (CALR)-mutated myeloproliferative neoplasms, essential thrombocythemia, neoplasms, leukemia and myelofibrosis. The therapeutic candidate is a bispecific antibody acts by targeting calreticulin and CD3.

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Identification of Novel Risk Variants of Inflammatory Factors Related to Myeloproliferative Neoplasm: A Bidirectional Mendelian Randomization Study

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Yang Li, Ting Sun, Jia Chen, Lei Zhang

Abstract

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427–0.964; p = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006–1.883; p = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002–0.084; p = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001–0.060; p = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

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Depression in patients with hematologic malignancies: The current landscape and future directions

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Thomas M. Kuczmarski, Lizabeth Roemer, Oreofe O. Odejide

February 13, 2024

Abstract

Patients with hematologic malignancies experience high rates of depression. These patients are vulnerable to depression throughout the disease trajectory, from diagnosis to survivorship, and at the end of life. In addition to the distressing nature of depression, it has substantial downstream effects including poor quality of life, increased risk of treatment complications, and worse survival. Therefore, systematic screening for depression and integration of robust psychological interventions for affected patients is crucial. Although depression has been historically studied mostly in patients with solid malignancies, research focusing on patients with hematologic malignancies is growing. In this article, we describe what is known about depression in patients with hematologic malignancies, including its assessment, prevalence, risk factors, and implications. We also describe interventions to ameliorate depression in this population. Future research is needed to test effective and scalable interventions to reduce the burden of depression among patients with blood cancers.

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MPN Symptoms Mimic Other Conditions, Open Communication Is Key

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Brielle Benyon

Myeloproliferative neoplasm (MPN) symptoms can often appear as another condition, making it essential that patients find a cancer care team that they trust and can have open communication with, according to Patrick Buxton.

Buxton, who is a clinical nurse manager at Fred Hutchinson Cancer Center in Seattle and a 2023 MPN Hero, explained that certain side effects like constant fatigue could mimic conditions such as depression. That is why it is important for patients to work with their oncology team to establish a baseline of lab results and symptoms and keep them up to date on how they are feeling.

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Significant Steps Forward in the Understanding and Treatment of MPNs

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Raajit Rampal, MD, PhD

February 13, 2024

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses some of the key takeaways from the 2023 American Society of Hematology (ASH) Annual Meeting and what he believes holds promise for the space in 2024.

This past year marked significant progress in the field of myeloproliferative neoplasms (MPNs) and highlights were presented at ASH 2023. Notably, 2 phase 3 trials were completed and 2 combination agents showed promising results. Additionally, several new non-JAK inhibitor drugs were highlighted, along with advancements in mastocytosis research.

Rampal explains that there is now excitement surrounding the emergence of small molecule inhibitors in clinical trials, which may offer potential insights. Moreover, the introduction of the first antibodies, particularly calreticulin antibodies from various companies, into clinical trials is anticipated to have a major impact, with insights expected to emerge soon.

These developments represent a significant step forward in the understanding and treatment of MPNs, offering hope for improved outcomes for patients in the near future.

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Gut Microbiota Differs in Patients With MPNs

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Ashley Chan

he gut microbiota in patients with myeloproliferative neoplasms (MPNs) showed a significant difference compared with healthy controls (HCs), according to a study published in the European Journal of Haematology, although patients with MPNs who have a specific driver mutation had a similar bacterial composition compared with HCs.

In particular, MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), pre-fibrotic myelofibrosis (pre-PMF) and primary myelofibrosis, have driver mutations, such as JAK2V617F, JAK2 exon, MPL or Calreticulin (CALR). Researchers found that patients with MPNs who are CALR-positive had the highest resemblance to HCs.

The study demonstrated that patients with MPNs have changes in the gut microbiota, which may be caused by their disease, which may include inflammation. This change in the microbiota has been shown to initiate and progress the disease, according to the study. Researchers also noted that the gut microbiota also affects the immune system, infection control and steady production of blood cells.

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Disc wins orphan drug tag for rare blood cancer

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February 12, 2024

By Jeanne Philpott

The US Food and Drug Administration (FDA) has granted an orphan drug designation (ODD) to US-based biotech Disc Medicine’s DISC-3405 to treat rare blood cancer polycythemia vera (PV).

Disc gained exclusive rights to develop and market the anti-TMPRSS6 (Transmembrane Serine Protease 6) humanized antibody in the US and other territories when it teamed up with Mabwell Therapeutics in a $412.5m licensing agreement in January 2023.

In October 2023, DISC initiated an ongoing Phase I clinical trial (NCT06050915) for DISC-3405, previously named MWTX-003 with data from the study now expected in H1 2024. The orphan drug designation comes after the drug had previously received fast-track designation from the FDA.

The 64-patient Phase I study is divided into groups receiving either a single or multiple doses of DISC-3405, or a placebo. In the single ascending dose (SAD) phase, two subjects serve as sentinels: one receives DISC-3405, and the other placebo. Additional subjects in the cohort are dosed at least 24 hours after the last sentinel dosing, following approval from the principal investigator. Subsequent multiple ascending dose (MAD) cohorts are enrolled only after a sufficient safety observation period for the SAD cohort, removing the need for sentinels in MAD cohorts.

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Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms

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Taylor B. Collins, Angelo B.A. Laranjeira, Tim Kong, Mary C. Fulbright, Daniel A.C. Fisher, Christopher M. Sturgeon, Luis F.Z. Batista, and Stephen T. Oh

Abstract

Myeloproliferative neoplasms (MPN) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induce a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated MPN disease burden including leukemic engraftment and splenomegaly in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only to primary MPN samples harboring ASXL1 mutations. Lastly, treatment of CD34+ hematopoietic/stem progenitor cells with PRMT6 inhibitor, EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.

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