Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis.

Myelodysplastic syndromes (MDSs) are chronic and often progressive myeloid neoplasms associated with remarkable heterogeneity in the histomorphology and clinical course. Various somatic mutations are involved in the pathogenesis of MDS. Recently, mutations in a gene encoding a spliceosomal protein, SF3B1, were discovered in a distinct form of MDS with ring sideroblasts. Whole exome sequencing of 15 patients with myeloid neoplasms was performed, and somatic mutations in spliceosomal genes were identified. Sanger sequencing of 310 patients was performed to assess phenotype/genotype associations. To determine the functional effect of spliceosomal mutations, we evaluated pre-mRNA splicing profiles by RNA deep sequencing. We identified additional somatic mutations in spliceosomal genes, including SF3B1, U2AF1, and SRSF2. These mutations alter pre-mRNA splicing patterns. SF3B1 mutations are prevalent in low-risk MDS with ring sideroblasts, whereas U2AF1 and SRSF2 mutations are frequent in chronic myelomonocytic leukemia and advanced forms of MDS. SF3B1 mutations are associated with a favorable prognosis, whereas U2AF1 and SRSF2 mutations are predictive for shorter survival. Mutations affecting spliceosomal genes that result in defective splicing are a new leukemogenic pathway. Spliceosomal genes are probably tumor suppressors, and their mutations may constitute diagnostic biomarkers that could potentially serve as therapeutic targets.

Therapeutic advances in the treatment of primary plasma cell leukemia: a focus on hematopoietic cell transplantation.

Primary plasma cell leukemia (pPCL) is an uncommon but aggressive plasma cell malignancy associated with frequent extramedullary involvement, high-risk cytogenetic abnormalities, and frequent organ dysfunction, ultimately resulting in poor prognosis. Here we review recent advances in our understanding of the molecular and biological aspects of PCL and summarize therapeutic progress occurring over the past 2 decades. pPCL is distinguished from secondary PCL arising from multiple myeloma. The molecular and immunophenotypic changes of pPCL are often distinct from those seen in secondary PCL and multiple myeloma. The availability of novel agents (ie, proteasome inhibitors and immunomodulatory agents) and the increasing use of hematopoietic cell transplantation strategies have resulted in better outcomes, although long-term survival remains poor. Development of complex treatment algorithms that combine novel agents as induction therapy, as part of conditioning regimens for hematopoietic cell transplantation (autologous or allogeneic), or as post-transplantation remission strategies are logical and may translate into improved survival in patients with PCL.

Evans Syndrome in the Context of Incomplete Systemic Lupus Erythematosus.

Evans syndrome is an autoimmune disorder characterized by the simultaneous or sequential occurrence of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura (ITP) with or without neutropenia. It can occur idiopathically or secondary to autoimmune or malignant processes. We are presenting a case of ITP with concurrent chronic hemolytic anemia and positive markers for systemic lupus erythematosus with no prior diagnosis of any rheumatological disorder.

Early Utilization of Intravenous Immunoglobulin in Heparin-Induced Thrombocytopenia for Limb Salvaging Purposes.

We present a case of a 28-year-old diabetic female who presented with high-burden lower extremity deep vein thrombosis (DVT) after previous exposure to unfractionated heparin (UFH). Heparin was discontinued, and non-heparin parenteral anticoagulant, argatroban, was started based on a high clinical suspicion of heparin-induced thrombocytopenia with thrombosis (HITT). The diagnosis of HIT was later proven by positive immune and functional assays. The severity of thrombocytopenia and the need for surgical intervention to salvage the limb prompted the use of intravenous immunoglobulin (IVIG) early on in the treatment course to recover platelet counts, halt the prothrombotic state, and prepare the patient for thrombectomy. The patient was put on direct oral anticoagulants (DOACs), apixaban, after thrombectomy, and platelet count recovery with no new thrombosis or bleeding episodes was reported after three months of follow-up.

Management of relapses after hematopoietic cell transplantation in T-cell non-Hodgkin lymphomas.

T-cell non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies that represent 10%-15% of all NHLs. The prognosis of relapsed T-cell NHL is poor, especially for those relapsing after an autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT). Disease relapse post auto-HCT is best managed on a clinical trial. In the absence of an investigational protocol, the choice of salvage therapies should take into account patient performance status, eligibility for an allo-HCT, and surface CD30 expression. CD30-directed therapies or aggressive salvage regimens can be used as a bridge to allo-HCT in medically fit patients. In the elderly or more infirm patients, single-agent therapies could be offered, aiming at palliation. Similarly, relapse after an allo-HCT is not uncommon and is a real challenge. Reduction in ongoing immune suppression or donor lymphocyte infusion are often considered in this setting to augment graft-versus-lymphoma (GVL) effects and can occasionally provide durable disease control. Clinical trials designed to investigate novel therapeutic agents with immunomodulatory properties to augment GVL effects (eg, histone deacetylase [HDAC] inhibitors, proteasome inhibitor, lenalidomide) or targeted therapies (eg, aurora A kinase inhibitors, anaplastic lymphoma kinase [ALK] inhibitors) are sorely needed to improve the dismal outcomes of T-cell NHL relapsing after an allo-HCT.