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Clinical Lymphoma, Myeloma & Leukemia May 2022Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly,... (Review)
Review
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms and acute myeloid leukemia progression. Currently, allogeneic haematopoietic stem cell transplantation (AHSCT) therapy is the only curative option for MF patients. However, AHSCT is strictly limited due to the high rates of morbidity and mortality. Janus kinase 2 (JAK2) inhibitor Ruxolitinib is the first-line treatment for intermediate-II or high-risk MF patients with splenomegaly and constitutional symptoms, but most MF patients develop resistance or intolerance to Ruxolitinib. Therefore, MF treatment is a challenge for the medical community. This review summarizes 3 investigated directions for MF therapy: monotherapies of JAK inhibitors, monotherapies of non-JAK targeted agents, combination therapies of Ruxolitinib and other agents. We emphasize combination of Ruxolitinib and other agents is a promising strategy.
Topics: Anemia; Hematopoiesis; Humans; Primary Myelofibrosis; Splenomegaly
PubMed: 34903489
DOI: 10.1016/j.clml.2021.11.007 -
Clinical Genetics Apr 2023To suggest a unique missense variant candidate based on long-term ophthalmological changes and associated systemic signs described in five patients from two unrelated...
To suggest a unique missense variant candidate based on long-term ophthalmological changes and associated systemic signs described in five patients from two unrelated families affected by an autosomal dominant multi-systemic disorder including Retinal dystrophy, Optic nerve oedema, Splenomegaly, Anhidrosis and migraine Headaches, called ROSAH syndrome, related to a unique missense variant in ALPK1 gene. Observational longitudinal follow-up study of unrelated families. Clinical analysis of ophthalmological and systemic examinations was performed, followed by genetic analysis, including targeted Next Generation Sequencing (NGS) and Whole-Genome Sequencing (WGS). The ophthalmological phenotype showed extensive optic nerve swelling associated with early macular oedema and vascular leakage. The main associated systemic manifestations were recurrent fever, splenomegaly, anhidrosis, mild cytopenia, anicocytosis and hypersegmented polynuclear cells. WGS, shortened in the second family by the gene candidate suggestion, revealed in all patients the heterozygous missense variant c.710C>T; p.(Thr237Met) in ALPK1. The primary morbidity in ROSAH syndrome in this cohort appeared ophthalmological. Comprehensive, detailed phenotype changes aided by the advancement in genetic testing could allow an early genetic diagnosis of ROSAH syndrome and targeted treatment. The unique missense variant may be suggested as a target of gene correction therapy.
Topics: Humans; Splenomegaly; Follow-Up Studies; Hypohidrosis; Pedigree; Phenotype; Syndrome; Optic Nerve Diseases; Edema; Uveitis; DNA Mutational Analysis
PubMed: 36543582
DOI: 10.1111/cge.14286 -
Hematology. American Society of... Dec 2023Myelofibrosis is a devastating myeloid malignancy characterized by dysregulation of the JAK-STAT pathway, resulting in splenomegaly, constitutional symptoms, anemia,... (Review)
Review
Myelofibrosis is a devastating myeloid malignancy characterized by dysregulation of the JAK-STAT pathway, resulting in splenomegaly, constitutional symptoms, anemia, thrombocytopenia, leukocytosis, and an increased likelihood of progression to acute leukemia. The only curative option is allogeneic stem cell transplantation. The numbers of transplants have been increasing every year, and although there have been improvements in survival, there remain many unanswered questions. In this review, we will evaluate patient selection and appropriate timing for transplantation. We will cover the current prognostic scoring systems, which can aid in the decision of when to move forward with transplant. We will also review the different donor options, as well as the conditioning regimens. The peritransplant management of splenomegaly will be reviewed. We will discuss management of posttransplant complications such as loss of donor chimerism or disease relapse. Finally, we will review what is known about the outlook of patients who have undergone allogeneic stem cell transplant with regards to quality of life and long-term survival.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Janus Kinases; Primary Myelofibrosis; Quality of Life; Signal Transduction; Splenomegaly; STAT Transcription Factors; Transplantation Conditioning; Treatment Outcome
PubMed: 38066916
DOI: 10.1182/hematology.2023000453 -
European Journal of Internal Medicine Aug 2023
Topics: Humans; Splenomegaly; Splenectomy; Retrospective Studies
PubMed: 37137780
DOI: 10.1016/j.ejim.2023.04.031 -
Genetics in Medicine : Official Journal... Jul 2022This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results.
PURPOSE
This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults.
METHODS
A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics.
RESULTS
Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild.
CONCLUSION
Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD.
Topics: Adult; Carbon Monoxide; Double-Blind Method; Enzyme Replacement Therapy; Humans; Niemann-Pick Disease, Type A; Recombinant Proteins; Sphingomyelin Phosphodiesterase; Splenomegaly
PubMed: 35471153
DOI: 10.1016/j.gim.2022.03.021 -
Leukemia & Lymphoma May 2022Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis... (Review)
Review
Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.
Topics: Humans; Janus Kinase Inhibitors; Myeloproliferative Disorders; Primary Myelofibrosis; Splenomegaly; Treatment Outcome
PubMed: 34852713
DOI: 10.1080/10428194.2021.2010068 -
Expert Opinion on Pharmacotherapy Apr 2023Myelofibrosis is a hematologic malignancy with a variety of clinical manifestations including splenomegaly, which is present in approximately 80% of newly diagnosed... (Review)
Review
INTRODUCTION
Myelofibrosis is a hematologic malignancy with a variety of clinical manifestations including splenomegaly, which is present in approximately 80% of newly diagnosed patients. JAK inhibitors are the mainstay of pharmacologic treatment for splenomegaly in myelofibrosis, although spleen size reduction is not universal, and the duration of benefit is only moderately durable.
AREAS COVERED
We first discuss the pathobiology of splenomegaly in myelofibrosis before detailing approved and novel pharmacotherapies that can reduce spleen size while also highlighting non-pharmacologic approaches. In this review, efficacy of these treatments is measured solely by spleen volume reduction, acknowledging that other outcome measures such as symptom improvement and survival are also critical.
EXPERT OPINION
Currently, ruxolitinib can be administered to the majority of frontline patients although those with severe thrombocytopenia should receive pacritinib to address spleen burden. Momelotinib may be particularly well suited for patients with significant anemia and novel combination treatments in clinical development may improve the depth and duration of spleen responses. After frontline treatment failure, fedratinib, or pacritinib are commercial options for patients with persistent symptomatic splenomegaly. Novel agents given alone or in combination with a JAK inhibitor are being explored in trials, which may ameliorate splenomegaly and ultimately improve disease progression.
Topics: Humans; Splenomegaly; Primary Myelofibrosis; Bridged-Ring Compounds; Treatment Failure; Protein Kinase Inhibitors; Nitriles; Janus Kinase 2
PubMed: 36922391
DOI: 10.1080/14656566.2023.2192350 -
La Revue de Medecine Interne Dec 2023
Topics: Humans; Splenomegaly; Lymphohistiocytosis, Hemophagocytic; Fever
PubMed: 37550135
DOI: 10.1016/j.revmed.2023.07.004 -
Frontiers in Immunology 2023We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic...
We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in . IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1β), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon β (IFN-β); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans.
Topics: Humans; Leukocytes, Mononuclear; Interleukin-1 Receptor-Associated Kinases; Splenomegaly; Interleukin-6; Neuroinflammatory Diseases; Anemia; Mutation
PubMed: 37744344
DOI: 10.3389/fimmu.2023.1231749 -
La Revue de Medecine Interne Oct 2022Some common clinical situations, such as splenomegaly or lymphocytosis, or less common, such as autoimmune hemolytic anemia, cold agglutinin disease, or cryoglobulinemia... (Review)
Review
Some common clinical situations, such as splenomegaly or lymphocytosis, or less common, such as autoimmune hemolytic anemia, cold agglutinin disease, or cryoglobulinemia can lead to the diagnosis of splenic lymphoma. Splenic lymphoma is rare, mainly of non-hodgkinian origin, encompassing very different hematological entities in their clinical and biological presentation from an aggressive form such as hepato-splenic lymphoma to indolent B-cell lymphoma not requiring treatment such as marginal zone lymphoma, the most frequent form of splenic lymphoma. These entities can be challenging to diagnose and differentiate. This review presents different clinical and biological manifestations suspicious of splenic lymphoma and proposes a diagnosis work-up. We extended the strict definition of splenic lymphoma (lymphoma exclusively involving the spleen) to lymphoma thant can be revealed by a splenomegaly and we discuss the differential diagnosis of splenomegaly.
Topics: Anemia, Hemolytic, Autoimmune; Diagnosis, Differential; Humans; Lymphocytosis; Lymphoma, B-Cell, Marginal Zone; Splenic Neoplasms; Splenomegaly
PubMed: 35691756
DOI: 10.1016/j.revmed.2022.05.009