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.

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

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

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.

MPN Symptoms Mimic Other Conditions, Open Communication Is Key

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

February 14, 2024

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.

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.

Disc wins orphan drug tag for rare blood cancer

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

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.

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.