Navigating Cytoreduction in MPNs: Benefits, Risks, and Considerations

Posted on February 19, 2024February 19, 2024 by mpn_admin

February 16, 2024

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 Oncology^TM, Tremblay discussed the significance of cytoreductive therapy in mitigating thrombotic risk in MPNs, specifically ET and PV.

JAK-STAT Pathway–Targeting Approaches in Myelofibrosis Are Evolving

Posted on February 19, 2024February 19, 2024 by mpn_admin

February 15, 2024

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.

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

Posted on February 19, 2024February 19, 2024 by mpn_admin

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.

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

Posted on February 19, 2024February 19, 2024 by mpn_admin

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.

Significant Steps Forward in the Understanding and Treatment of MPNs

Posted on February 19, 2024February 19, 2024 by mpn_admin

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.

Gut Microbiota Differs in Patients With MPNs

Posted on February 14, 2024February 14, 2024 by mpn_admin

February 13, 2024

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.

Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms

Posted on February 13, 2024February 13, 2024 by mpn_admin

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.

CD123 As a Therapeutic Target in Accelerated and Blast Phase Myeloproliferative Neoplasms (MPNs)

Posted on February 12, 2024February 12, 2024 by mpn_admin

Melissa A. Babcook MD, PhD, Gerard Lozanski, MD, Sarah A. Wall MD, MPH

Background

CD123 expression in MPNs has been reported in case series and targeted in one phase I study of patients with chronic phase MPN. We describe the clinical phenotype of patients with accelerated (AP) or blast phase (BP) MPNs paired with CD123 co-expression on CD45(dim) myeloid blasts.

Methods

Subjects were identified by diagnosis in the Ohio State University Comprehensive Cancer Center Leukemia Tissue Bank (OSUCCC-LTB). Clinical data were collected by retrospective chart review with IRB approval. CD123 expression was measured by immunophenotyping of cryopreserved peripheral blood (PB) or marrow (BM) samples. Blasts were identified by CD45(dim) gating and co-expression of CD7/13/33/34/117/123 was measured. CD123 expression was stratified by quartile and correlation with clinical characteristics measured by Chi-square test.

Results

41 PB or BM samples from 24 subjects were identified from the OSUCCC-LTB. Nine subjects had paired PB and BM specimens, 6 had samples obtained at multiple timepoints. Median age at sample collection was 65.8 years (range 35.2-79.7) and median time from diagnosis was 13.1 months (range 0-96.5). Constitutional symptoms were present at collection for 24 samples (58.5%) and splenomegaly present for 20 samples (51.3%). At sample collection, 19.5% had never received treatment, 19.5% had been previously treated, and 61% were currently on treatment, most (n=16, 64%) with JAK inhibitor. 19 samples were obtained in chronic phase (46.3%), 9 in AP (22.0%), and 13 in BP (31.7%). 16 samples (39.0%) were from transfusion-dependent patients, most (68.8%) for both red blood cell and platelets. Median PB blasts were 3.2% (range:0-76) and BM blasts were 3% (range 0-82) by morphology. Molecular sequencing and karyotype were available for 18 (43.9%) and 27 (65.9%), respectively. The most common mutations identified were JAK2 (50%), ASXL1 (27.8%), SRSF2 (22.2%), CALR (16.7%), and TP53 (16.7%). Normal karyotype was found in 37%, 33.3% had complex karyotype, 11.1% had del 5q or 7q/-7, and 18.5% had del 13q or 20q. CD123 expression on the CD45-gated blasts ranged from 0.3-95.6% with a median value of 11.02%. CD123 expression is shown in figure 1. Figure 2a shows correlation between CD123 expression and disease phase (p < 0.01). Figure 2b shows CD123 expression correlation with ASXL1 mutation status (p =0.023). There were no statistically significant associations between CD123 expression and any other tested variables.

Conclusions

These data support a clinical trial targeting CD123 in high risk MPNs, defined by blasts >10% or the presence of ASXL1 mutation, an important subpopulation of patients in need of more effective and less toxic therapy than current standards of care that typically include cytotoxic chemotherapy.

Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study

Posted on February 12, 2024February 12, 2024 by mpn_admin

James T. England, Natasha Szuber, Shireen Sirhan, Tom Dunne, Sonia Cerquozzi, Madeleine Hill, Pierre J. A. Villeneuve, Jenny M. Ho, et al.

Abstract

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALR are uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.

NIH Analysis Reveals Rising Use of Complementary Health Approaches

Posted on February 12, 2024February 12, 2024 by mpn_admin

February 6, 2024

An analysis conducted by the National Institutes of Health’s National Center for Complementary and Integrative Health (NCCIH) reveals a substantial increase in the overall use of complementary health approaches by American adults from 2002 to 2022.

The study, published in the Journal of the American Medical Association, highlights a surge in the adoption of complementary health approaches for pain management over the same period.

Researchers utilized data from the 2002, 2012, and 2022 National Health Interview Survey (NHIS) to evaluate changes in the use of seven complementary health approaches, including yoga, meditation, massage therapy, chiropractic care, acupuncture, naturopathy, and guided imagery/progressive muscle relaxation.

The key findings include:

The percentage of individuals who reported using at least one of the seven approaches increased from 19.2% in 2002 to 36.7% in 2022.
The use of yoga, meditation, and massage therapy experienced the most significant growth from 2002 to 2022.
Use of yoga increased from 5% in 2002 to 15.8% in 2022.
Meditation became the most used approach in 2022, with an increase from 7.5% in 2002 to 17.3% in 2022.
Acupuncture, increasingly covered by insurance, saw an increase from 1% in 2002 to 2.2% in 2022.
Additionally, the analysis showed a notable rise in the proportion of U.S. adults using complementary health approaches specifically for pain management. Among participants using any of the complementary health approaches, the percentage reporting use for pain management increased from 42.3% in 2002 to 49.2% in 2022.

Despite the findings, the authors acknowledge study limitations, including decreasing NHIS response rates over time, possible recall bias, cross-sectional data, and differences in survey wording.

The study also highlights the role of factors such as higher quality research supporting the efficacy of complementary health approaches, the inclusion of these approaches in clinical practice guidelines for pain, and the expanded insurance coverage for approaches such as acupuncture, which has contributed to increased patient access.