Chronic Neutrophilic Leukemia

Although rare, myeloproliferative neoplasms can involve young patients and pose unique challenges for clinicians in diagnosis and therapy. The paper aims to review the biological markers of MPNs in pediatric populations-a particular group of patients that has been poorly studied due to the low frequency of MPN diagnosis.

Pitfalls in diagnosis include subjectivity in assessing neutrophil dysplasia and distinguishing true neoplastic neutrophilia from reactive neutrophilias that may be superimposed upon or occur as a manifestation of the progression of other myeloid neoplasms. Accurate distinction between neutrophilic myeloid neoplasms is important, as it helps guide patient management and may disclose specific genetic lesions amenable to targeted therapy.

P2, N=25, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2025 --> Apr 2026 | Trial primary completion date: Dec 2024 --> Apr 2025

P2, N=25, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting

No abstract available

We show that the T618I mutation also confers a survival advantage to neutrophils in an MCL1-dependent manner. Collectively, these data provide additional insights into the natural history of familial CNL arising from T618I CSF3R mutations and suggest that enhanced neutrophil survival also contributes to the high neutrophil count observed in patients with CNL.

We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.

Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease-modifying. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.

In conclusion, CSF3R mutations were found at a higher frequency in aCML patients than in previous studies, which might reflect ethnic differences. Additional studies are needed to confirm these findings and the relationship between CSF3R and CEBPA mutations.

Consequently, a combination of BCI with a MEK inhibitor successfully cured CSF3R-induced leukemia in a preclinical mouse model. Our findings underscore the pivotal role of DUSP1 in leukemic transformation driven by enhanced MAPK signaling and advocate for the development of a selective DUSP1 inhibitor for curative treatment outcomes.

There are also rarer forms such as chronic neutrophilic leukemia (CNL), which involves mutations in the CSF3R gene. However, rather than focusing on the differences between these alternate disease categories, this review aims to present a unifying molecular etiology in which these overlapping diseases are best understood as disruptions of normal hematopoietic signaling: specifically, the chronic activation of signaling pathways, particularly involving signal transducer and activator of transcription (STAT) transcription factors, most notably STAT5B, leading to the sustained stimulation of myelopoiesis, which underpins the various disease sequalae.

P1/2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

In the present study, the cellular and molecular effects of pharmacological inhibitors of aurora kinases, such as aurora A inhibitor I, AZD1152-HQPA, and reversine, were evaluated in Ba/F3 expressing the CSF3R mutation...Reversine more efficiently modulated genes associated with cell cycle and apoptosis compared to other drugs. In summary, our findings shed new insights into the use of AURKB inhibitors in the context of CNL.

No abstract available

The coexistence of these mutated genes and CSF3R mutations, as well as the different evolutionary sequences of clones, deepens the complexity of CNL molecular biology. The purpose of this review is to summarize the genetic research findings of CNL in the last decade, focusing on the common mutated genes in CNL and their clinical significance, as well as the clonal evolution pattern and sequence of mutation acquisition in CNL, to provide a basis for the appropriate management of CNL patients.

Ruxolitinib, a JAK2 inhibitor, provided a promising therapeutic effect in a phase II study...Anti-CD52 antibody, alemtuzumab, or anti-IL-5 antibody, mepolizumab, are promising drugs to control symptoms that are associated with hypereosinophilic syndrome. Allo-SCT is anticipated as a curative treatment for CEL, but the evidence of Allo-SCT for CEL is still limited. Further study is required to define the treatment strategy.

Prior to MN diagnosis, ten patients (67%) received etoposide and seven patients (47%) received autologous stem cell transplant (ASCT) (six with BEAM, one with cyclophosphamide plus total body irradiation). Herein we report the CI of MN in a cohort of patients with TCL, with particular attention to nodal TFH cell lymphomas given known CH mutations and the genotoxic stress of combination chemotherapy. As more patients have prolonged survival after initial therapy for TCL, further analysis, including baseline genetics and prospective characterization for clonal expansion and acquired mutations during therapy, could identify those at highest risk for developing a MN. Further characterization of our cohort and comparison to patients who did not develop a MN is ongoing.

The JAK1/JAK2 inhibitor, ruxolitinib, has shown clinical benefit in pts with MDS/MPN and pts harboring CSF3R mutations. Fedratinib demonstrates promising clinical efficacy in MDS/MPN and CNL pts with proliferative features. The safety profile is consistent with prior experience. Fedratinib's unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this pt population.

No abstract available

The patient was diagnosed using G-CSF-producing myeloma and was treated with daratumumab, lenalidomide, and dexamethasone. However, the clinical characteristics and long-term prognosis of G-CSF-producing myeloma remain unknown. Additional case gathering and investigations are required.

In this article, we report a case of CSF3R-mutated CMML and dissect this rare entity by reviewing the medical literature, with the intent to understand how this rare mutation shapes CMML's clinical and morphological phenotype. CSF3R-mutated CMML emerges as a rare entity meeting the ICC/WHO diagnostic criteria for CMML and simultaneously showing clinical-pathological and molecular traits of CNL and atypical chronic myeloid leukemia, rising an important and difficult diagnostic and therapeutical issue.

No abstract available

This suggests that CNL was clonally developed from the founding clone of MDS and CSF3R mutation contributes to the development of CNL in the present case. These findings provide insights into the pathology of CNL.

Using the same approach applied to other cell surface receptors, we identified an activating mutation, S489F, in the interleukin-31 receptor alpha chain (IL-31Rα). Combined, these results suggest a role for glycosylated hotspot residues in regulating receptor signaling, mutation of which can lead to ligand-independent, uncontrolled activity and human disease.

The prevalence and incidence of MPNs in Pakistan were derived using the number of patients visiting hospital. Thus, the prevalence reported here is not directly comparable with the entire country. Currently, there are no data in percentage of PV, ET, PMF, and JAK2(V617F) exon 14 mutation found significantly in Philadelphia -ve (non-BCR-ABL) myeloproliferative neoplasms.

Molecular aberrations involving protein tyrosine kinases have been used for the diagnosis, classification, detection of minimal/measurable residual disease, and target therapy. We review recent advances in molecular genetic aberrations in MPN with a focus on MPN associated with gene rearrangements or mutations involving tyrosine kinase pathways.

In this study, we found a statistically significant decrease in neutrophil, leukocyte, NLR and SIII values in the group receiving hydroxyurea. The decrease in SIII which includes neutrophil and platelet values was more remarkable. We think that the study should be evaluated together with cytokines in a larger patient group in order to mention the effect of hydroxyurea on inflammation more clearly.

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No abstract available

Not available.

PPM1D mutations are frequently associated with MN-pCT and older age and are observed in other hematolymphoid neoplasms. In contrast to the literature, de novo myeloid cases with PPM1D mutations were surprisingly frequent in this cohort. While there was no statistical significance, a trend did appear showing worse survival in MN-pCT patients compared with de novo myeloid neoplasms.

P2, N=40, Completed, Sidney Kimmel Cancer Center at Thomas Jefferson University | Active, not recruiting --> Completed

We identified four high-risk mutated genes, specifically CEBPA (β=2.26, HR=9.54, p=0.003), EZH2 (β=1.12, HR=3.062, p=0.009), NRAS (β=1.29, HR=3.63, p=0.048) and U2AF1 (β=1.75, HR=5.74, p=0.013) by multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.

Unfortunately, both trametinib and ruxolitinib exert cytostatic response and are rarely selective to leukemic clones. Our data provide evidence that enhanced Mapk signaling in leukemic cells are regulated by Dusp1 in CNL/aCML. In an analogy to "breaking the break", deletion of Dusp1 resulted in selective eradication of leukemic cells. Altogether, our data supports for developing selective Dusp1 inhibitor for curative treatment outcome.

Epigenetic priming with decitabine to induce DNA hypomethylation was investigated in a phase I trial for acute myeloid leukemia (AML) and has proven safe and feasible (Scandura et al Blood 2011)...Graft versus host disease (GVHD) - prophylaxis consisted of Alemtuzumab (total dose 60 mg for MUD and 30 mg for MRD), and Tacrolimus for 3-6 months post-transplant... Preconditioning treatment with 5-azacytidine as epigenetic priming is tolerable with a toxicity profile overall similar to conditioning with fludarabine/melphalan. But the addition of azacytidine at 75 mg/m2/daily (total 5 doses) causes significant renal toxicity, which abates with dose reduction. The PFS in this very high-risk population with historically high relapse rates is promising.

P2, N=40, Active, not recruiting, Sidney Kimmel Cancer Center at Thomas Jefferson University | Trial completion date: Jul 2021 --> Jan 2023

Recently, ruxolitinib has shown significant responses in patients with CNL; however, emergence of resistance might perturbate long-term management of the disease. The aim of this review is to summarize the clinical course and laboratory findings of CNL, highlight its pathogenesis and complex genetic landscape, and provide the context for the appropriate management of patients with CNL.

This upregulation of Myc can be reversed by LSD1 inhibitors. In summary, we find that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutant CSF3R through the upregulation of Myc-associated gene expression programs.