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Blood Nov 2023Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with...
Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.
Topics: Humans; Polycythemia Vera; Primary Myelofibrosis; Thrombocytosis; Hydroxyurea; Thrombosis; Interferon-alpha; Leukemia, Myeloid, Acute; Janus Kinase 2
PubMed: 37729609
DOI: 10.1182/blood.2023021503 -
Advances in Pediatrics Aug 2023Acute leukemia is the most common malignancy in childhood, while chronic myeloid leukemia is rare, accounting for only 2% to 3% of all leukemia in childhood and 9% in... (Review)
Review
Acute leukemia is the most common malignancy in childhood, while chronic myeloid leukemia is rare, accounting for only 2% to 3% of all leukemia in childhood and 9% in adolescents, with an annual incidence of 1 and 2.2 cases per million in the two groups. The goal in Pediatrics is remission and cure with tyrosine kinase inhibitors (TKIs) and monitoring closely for long-term effects of TKI use.
Topics: Humans; Adolescent; Child; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 37422292
DOI: 10.1016/j.yapd.2023.04.002 -
Journal of Hematology & Oncology Jul 2023Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with... (Review)
Review
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with MF are at risk for reduced survival versus the general population and often experience burdensome signs and symptoms that reduce quality of life. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials. Over a decade later, ruxolitinib continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits of ruxolitinib. This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent JUMP, ROBUST, EXPAND, and REALISE trials; in pooled analyses; and in postmarketing analyses in the 10 years following approval. There is a focus on the occurrence of common hematologic and nonhematologic adverse events, with guidance provided on the management of patients with anemia or thrombocytopenia, including dosing strategies based on findings from the REALISE and EXPAND trials. Finally, to ensure a greater understanding of the safety profile of ruxolitinib, practical considerations are discussed.
Topics: Humans; Primary Myelofibrosis; Quality of Life; Janus Kinase 2; Nitriles; Pyrimidines
PubMed: 37501130
DOI: 10.1186/s13045-023-01471-z -
Autoimmunity Reviews Nov 2023Autoimmune Lymphoproliferative Syndrome (ALPS) is an autoimmune disease that has been reported in over 2200 patients. It is a rare, genetic disease where pathogenic... (Review)
Review
Autoimmune Lymphoproliferative Syndrome (ALPS) is an autoimmune disease that has been reported in over 2200 patients. It is a rare, genetic disease where pathogenic variants occur in the extrinsic pathway of apoptosis. Various mutations in different genes, such as FAS, FASL, and CASP10, can result in ALPS. Most commonly, pathogenic variants occur in the FAS receptor. This malfunctioning pathway allows for the abnormal accumulation of lymphocytes, namely CD3 + TCRαβ+CD4 - CD8- (double negative (DN) T) cells, which are a hallmark of the disease. This disease usually presents in childhood with lymphadenopathy and splenomegaly as a result of lymphoproliferation. Over time, these patients may develop cytopenias or lymphomas because of irregularities in the immune system. Current treatments include glucocorticoids, mycophenolate mofetil, sirolimus, immunoglobulin G, and rituximab. These medications serve to manage the symptoms and there are no standardized recommendations for the management of ALPS. The only curative therapy is a bone marrow transplant, but this is rarely done because of the complications. This review serves to broaden the understanding of ALPS by discussing the mechanism of immune dysregulation, how the symptoms manifest, and the mechanisms of treatment. Additionally, we discuss the epidemiology, comorbidities, and medications relating to ALPS patients across the United States using data from Cosmos.
Topics: Humans; Autoimmune Lymphoproliferative Syndrome; Autoimmune Diseases; fas Receptor; Splenomegaly; Mutation; Sirolimus; Lymphoproliferative Disorders
PubMed: 37683818
DOI: 10.1016/j.autrev.2023.103442 -
Current Problems in Diagnostic Radiology 2023Hepatosplenomegaly is commonly diagnosed by radiologists based on single dimension measurements and heuristic cut-offs. Volumetric measurements may be more accurate for...
Hepatosplenomegaly is commonly diagnosed by radiologists based on single dimension measurements and heuristic cut-offs. Volumetric measurements may be more accurate for diagnosing organ enlargement. Artificial intelligence techniques may be able to automatically calculate liver and spleen volume and facilitate more accurate diagnosis. After IRB approval, 2 convolutional neural networks (CNN) were developed to automatically segment the liver and spleen on a training dataset comprised of 500 single-phase, contrast-enhanced CT abdomen and pelvis examinations. A separate dataset of ten thousand sequential examinations at a single institution was segmented with these CNNs. Performance was evaluated on a 1% subset and compared with manual segmentations using Sorensen-Dice coefficients and Pearson correlation coefficients. Radiologist reports were reviewed for diagnosis of hepatomegaly and splenomegaly and compared with calculated volumes. Abnormal enlargement was defined as greater than 2 standard deviations above the mean. Median Dice coefficients for liver and spleen segmentation were 0.988 and 0.981, respectively. Pearson correlation coefficients of CNN-derived estimates of organ volume against the gold-standard manual annotation were 0.999 for the liver and spleen (P < 0.001). Average liver volume was 1556.8 ± 498.7 cc and average spleen volume was 194.6 ± 123.0 cc. There were significant differences in average liver and spleen volumes between male and female patients. Thus, the volume thresholds for ground-truth determination of hepatomegaly and splenomegaly were determined separately for each sex. Radiologist classification of hepatomegaly was 65% sensitive, 91% specific, with a positive predictive value (PPV) of 23% and an negative predictive value (NPV) of 98%. Radiologist classification of splenomegaly was 68% sensitive, 97% specific, with a positive predictive value (PPV) of 50% and a negative predictive value (NPV) of 99%. Convolutional neural networks can accurately segment the liver and spleen and may be helpful to improve radiologist accuracy in the diagnosis of hepatomegaly and splenomegaly.
PubMed: 37277270
DOI: 10.1067/j.cpradiol.2023.05.005 -
Journal of Clinical and Experimental... Sep 2023Follicular lymphoma is one of the most frequent lymphomas. Histologically, it is characterized by a follicular (nodular) growth pattern of centrocytes and centroblasts;...
Follicular lymphoma is one of the most frequent lymphomas. Histologically, it is characterized by a follicular (nodular) growth pattern of centrocytes and centroblasts; mixed with variable immune microenvironment cells. Clinically, it is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. It is biologically and clinically heterogeneous. In most patients it is indolent, but others have a more aggressive evolution with relapses; and transformation to diffuse large B-cell lymphoma. Tumorigenesis includes an asymptomatic preclinical phase in which premalignant B-lymphocytes with the t(14;18) chromosomal translocation acquire additional genetic alterations in the germinal centers, and clonal evolution occurs, although not all the cells progress to the tumor stage. This manuscript reviews the pathobiology and clinicopathological characteristics of follicular lymphoma. It includes a description of the physiology of the germinal center, the genetic alterations of BCL2 and BCL6, the mutational profile, the immune checkpoint, precision medicine, and highlights in the lymphoma classification. In addition, a comment and review on artificial intelligence and machine (deep) learning are made.
Topics: Humans; Lymphoma, Follicular; Artificial Intelligence; Neoplasm Recurrence, Local; B-Lymphocytes; Lymphoma, Large B-Cell, Diffuse; Translocation, Genetic; Tumor Microenvironment
PubMed: 37518274
DOI: 10.3960/jslrt.23014 -
Journal of Immunology (Baltimore, Md. :... Feb 2024Helminth infections are common in animals. However, the impact of a helminth infection on the function of hematopoietic stem cells (HSCs) and other hematopoietic cells...
Helminth infections are common in animals. However, the impact of a helminth infection on the function of hematopoietic stem cells (HSCs) and other hematopoietic cells has not been comprehensively defined. In this article, we describe the hematopoietic response to infection of mice with Schistosoma mansoni, a parasitic flatworm that causes schistosomiasis. We analyzed the frequency or number of hematopoietic cell types in the bone marrow, spleen, liver, thymus, and blood and observed multiple hematopoietic changes caused by infection. Schistosome infection impaired bone marrow HSC function after serial transplantation. Functional HSCs were present in the infected liver. Infection blocked bone marrow erythropoiesis and augmented spleen erythropoiesis, observations consistent with the anemia and splenomegaly prevalent in schistosomiasis patients. This work defines the hematopoietic response to schistosomiasis, a debilitating disease afflicting more than 200 million people, and identifies impairments in HSC function and erythropoiesis.
Topics: Humans; Mice; Animals; Bone Marrow; Hematopoietic Stem Cells; Hematopoiesis; Erythropoiesis; Spleen; Schistosomiasis
PubMed: 38169327
DOI: 10.4049/jimmunol.2300195 -
Expert Opinion on Drug Safety Jan 2024Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm hallmarked by deregulated proliferation of hematopoietic stem cells leading to prevalent expansion of red... (Review)
Review
INTRODUCTION
Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm hallmarked by deregulated proliferation of hematopoietic stem cells leading to prevalent expansion of red cell mass, increased rate of vascular events, splenomegaly, disease-associated symptoms, and risk of evolution to secondary myelofibrosis and blast phase. PV is pathogenetically associated with autonomously persistent activation of JAK2, which causes overproduction of blood cells and an inflammatory condition responsible for the clinical manifestations of the disease. Extensively supported by preclinical studies, targeting JAK2-dependent signaling represents a rational therapeutic approach to PV, finally leading to the approval of ruxolitinib, a JAK1/2 inhibitor.
AREAS COVERED (LITERATURE RESEARCH)
We analyzed reports of phase 2 and phase 3 trials with ruxolitinib in PV and relevant literature dealing with efficacy and safety aspects, including most recent real-world reports.
EXPERT OPINION
Ruxolitinib is the only JAK2 inhibitor approved for the treatment of PV with well-known efficacy for splenomegaly, symptoms, and potentially reduction of vascular events. The treatment regimen is notably manageable and safe, with the most prevalent side effects primarily encompassing myelosuppression, hyperlipidemia, non-melanoma skin cancer and infections, mainly reactivation of Herpes Zoster. These effects necessitate ongoing surveillance and proactive preventive measures.
Topics: Humans; Polycythemia Vera; Splenomegaly; Nitriles; Pyrimidines; Janus Kinase Inhibitors; Pyrazoles
PubMed: 38156903
DOI: 10.1080/14740338.2023.2299391