Pentraxin 2 (PTX-2; serum amyloid P component), a circulating endogenous regulator of the inflammatory response to tissue injury and fibrosis, is reduced in patients with myelofibrosis (MF). ...Zinpentraxin alfa (RO7490677, PRM-151) is a recombinant form of PTX-2 that has shown preclinical antifibrotic activity and no dose-limiting toxicities in phase I trials. We report results from stage 1 of a phase II trial of zinpentraxin alfa in patients with intermediate-1/2 or high-risk MF. Patients (n=27) received intravenous zinpentraxin α weekly (QW) or every 4 weeks (Q4W), as monotherapy or an additional therapy for patients on stable-dose ruxolitinib. The primary endpoint was overall response rate (ORR; investigatorassessed) adapted from International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria. Secondary endpoints included modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) change, bone marrow (BM) MF grade reduction, pharmacokinetics, and safety. ORR at week 24 was 33% (n=9/27) and varied across individual cohorts (QW: 38% 3/8; Q4W: 14% 1/7; QW+ruxolitinib: 33% 2/6; Q4W+ruxolitinib: 50% 3/6). Five of 18 evaluable patients (28%) experienced a ≥50% reduction in MPN-SAF TSS, and six of 17 evaluable patients (35%) had a ≥1 grade improvement from baseline in BM fibrosis at week 24. Most treatment-emergent adverse events (AE) were grade 1-2, most commonly fatigue. Among others, anemia and thrombocytopenia were infrequent (n=3 and n=1, respectively). Treatment-related serious AE occurred in four patients (15%). Overall, zinpentraxin alfa showed evidence of clinical activity and tolerable safety as monotherapy and in combination with ruxolitinib in this open-label, non-randomized trial (clinicaltrials gov. Identifier: NCT01981850).
Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical mast cells in one or several organs/tissues, often accompanied by mast cell activation. Whereas in ...children the disease manifestations are mostly limited to the skin, in adults the disease is usually systemic (systemic mastocytosis; SM) and involves the bone marrow and/or other internal organs. Several variants of SM have been defined. Whereas most patients have indolent SM, some patients have advanced SM, which underlines the complexity of SM. In 2002, a European consortium of clinicians and scientists initiated a multidisciplinary, multi-national cooperative network, termed the 'European Competence Network on Mastocytosis' (ECNM), with the aim to improve diagnosis and therapy of patients with mastocytosis and other mast cell activation disorders. Since then, members of the ECNM have organized Annual Meetings in several European countries. The present article provides a summary of advances in the field presented during the 17th Annual ECNM meeting held in Salzburg in October 2019.
Predicting disease progression remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive ...interventions. Here, profiling the three chronic subtypes of myeloproliferative neoplasms (MPNs), we identify the blood platelet transcriptome as a proxy strategy for highly sensitive progression biomarkers that also enables prediction of advanced disease via machine-learning algorithms. The MPN platelet transcriptome reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy. Subtype-specific markers offer mechanistic and therapeutic insights, and highlight impaired proteostasis and a persistent integrated stress response. Using a LASSO model with validation in two independent cohorts, we identify the advanced subtype MF at high accuracy and offer a robust progression signature toward clinical translation. Our platelet transcriptome snapshot of chronic MPNs demonstrates a proof-of-principle for disease risk stratification and progression beyond genetic data alone, with potential utility in other progressive disorders.
Display omitted
Platelet transcriptome yields progressive markers across MPN subtypesLasso-penalized multinomial regression model predicts advanced MPNsImpaired protein homeostasis and an integrated stress response feature in MPN progression
Shen et al. leverage two independent MPN patient cohorts to identify progressive platelet transcriptomic markers, which also enable an externally validated prediction for advanced MPNs. The platelet RNA-seq data identify impaired protein homeostasis in MPN progression and offer potential targets of therapy.
...the suggestion to patients that they have an MC disorder beyond (or in addition to) MCAS is not without consequences. Suggestion of an MC disorder can lead to unjustified anxiety and fear for ...patients, especially when the concept of MCAS is understood as synonymous to systemic mastocytosis, which can lead to hematologic malignancy. ...in those without typical clinical symptoms, there can be increased costs and health care use in an effort to implicate MCs in pathology. ...if the diagnosis is applied, referral centers must be prepared to evaluate these patients and eliminate diseases in the differential diagnosis.
Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an ...important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase (CP) in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis (BC), characterized by aberrant activation of β-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving β-catenin activation. Here we show that BC CML myeloid progenitors, in particular GMP, serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells (LSC). Notably, cDNA sequencing of Wnt/β-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3β, axin 1, β-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3β kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors. Moreover, BC CML progenitors with misspliced GSK3β have enhanced β-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3β reduces both in vitro replating and leukemic engraftment. We propose that CP CML is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3β in GMP LSC, enabling unphosphorylated β-catenin to participate in LSC self-renewal. Missplicing of GSK3β represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.
COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This ...analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.
Disease Overview
The eosinophilias encompass a broad range of non‐hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with the potential for end‐organ damage.
Diagnosis
...Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109/L, and may be associated with tissue damage. After the exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, molecular testing and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm.
Risk Stratification
Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2022 World Health Organization and International Consensus Classification endorse a semi‐molecular classification scheme of disease subtypes. This includes the major category “myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions” (MLN‐eo‐TK), and the MPN subtype, “chronic eosinophilic leukemia” (CEL). Lymphocyte‐variant HE is an aberrant T‐cell clone‐driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.
Risk‐Adapted Therapy
The goal of therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1.5 × 109/L) without symptoms or signs of organ involvement, a watch and wait approach with close follow‐up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Pemigatinib was recently approved for patients with relapsed or refractory FGFR1‐rearranged neoplasms. Corticosteroids are first‐line therapy for patients with lymphocyte‐variant HE and HES. Hydroxyurea and interferon‐α have demonstrated efficacy as initial treatment and in steroid‐refractory cases of HES. Mepolizumab, an interleukin‐5 (IL‐5) antagonist monoclonal antibody, is approved by the U.S Food and Drug Administration for patients with idiopathic HES. Cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. Targeted therapies such as the IL‐5 receptor antibody benralizumab, IL‐5 monoclonal antibody depemokimab, and various tyrosine kinase inhibitors for MLN‐eo‐TK, are under active investigation.
Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the ...molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses. Here, we report an RNAi-assisted protein target identification (RAPID) technology that individually assesses targeting of each member of the tyrosine kinase gene family. We demonstrate that RAPID screening of primary leukemia cells from 30 patients identifies targets that are critical to survival of the malignant cells from 10 of these individuals. We identify known, activating mutations in JAK2 and K-RAS, as well as patient-specific sensitivity to down-regulation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS. We also describe a previously undescribed, somatic, activating mutation in the thrombopoietin receptor that is sensitive to down-stream pharmacologic inhibition. Hence, the RAPID technique can quickly identify molecular vulnerabilities in malignant cells. Combination of this technique with whole-genome sequencing will represent an ideal tool for oncogenic target identification such that specific therapies can be matched with individual patients.
High oxygen affinity hemoglobins (Hbs), characterized by a decreased ability to release oxygen to the tissues and a left-shifted oxygen dissociation curve, are a rare cause of secondary ...erythrocytosis. Here, we report a base substitution in the β-globin gene at codon 89 (AGT>AGG) in a kindred with familial erythrocytosis resulting in Hb Vanderbilt, a high oxygen affinity variant.
PDF
