Hematology. American Society of Hematology. Education Program最新文献

Allogeneic hematopoietic cell transplantation, gene therapy, and gene editing offer a potential cure for sickle cell disease (SCD). Unfortunately, myelodysplastic syndrome and acute myeloid leukemia development have been higher than expected after graft rejection following nonmyeloablative conditioning and lentivirus-based gene therapy employing myeloablative busulfan for SCD. Somatic mutations discovered in 2 of 76 patients who rejected their grafts were identified at baseline at much lower levels. While a whole-genome sequencing analysis reported no difference between patients with SCD and controls, a study including whole-exome sequencing revealed a higher prevalence of clonal hematopoiesis in individuals with SCD compared with controls. Genetic risk factors for myeloid malignancy development after curative therapy for SCD are currently being explored. Once discovered, decisions could be made about whether gene therapy may be feasible vs allogeneic hematopoietic cell transplant, which results in full donor chimerism. In the meantime, care should be taken to perform a benefit/risk assessment to help patients identify the best curative approach for them. Long-term follow-up is necessary to monitor for myeloid malignancies and other adverse effects of curative therapies for SCD.

Chemotherapy-induced thrombocytopenia (CIT) is common, resulting in increased bleeding risk and chemotherapy delays, dose reduction, and treatment discontinuation, which can negatively affect oncologic outcomes. The only agent approved by the US Food and Drug Administration to manage CIT (oprelvekin) was voluntarily withdrawn from the market by the manufacturer, leaving few options for patients. Therefore, patients experiencing CIT present a significant clinical challenge in daily practice. The availability of thrombopoietin receptor agonists has led to formal clinical trials describing efficacy in CIT as well as a rather extensive body of published observational data from off-label use in this setting but no formal regulatory indications for CIT to date. The accumulated data, however, have affected National Comprehensive Cancer Network guidelines, which now recommend consideration of TPO-RA clinical trials as well as off-label use of romiplostim. This review article details the evidence to date for the management of CIT with thrombopoietin receptor agonists (TPO-RAs), discussing the efficacy data, the specific circumstances when treatment is warranted (and when it is generally unnecessary), and safety considerations. Specific recommendations regarding patient selection, initiation, dosing, titration, and discontinuation for TPO-RA therapy in CIT are given, based on published data and expert opinion where evidence is lacking.

Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of acute lymphoblastic leukemia (ALL) before their fifth birthday. ML-DS originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as transient abnormal myelopoiesis (TAM) that is caused by cooperation between trisomy 21-associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor GATA1. Around 10% of neonates with DS have clinical signs of TAM, although the frequency of hematologically silent GATA1 mutations in DS neonates is much higher (~25%). While most cases of TAM/silent TAM resolve without treatment within 3 to 4 months, in 10% to 20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. By contrast, DS-ALL, which is almost always B-lineage, presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene (60%), often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.

The myelodysplastic syndromes (MDS) are a heterogeneous group of malignant hematopoietic stem cell disorders characterized by ineffective growth and differentiation of hematopoietic progenitors leading to peripheral blood cytopenias, dysplasia, and a variable risk of transformation to acute myelogenous leukemia. As most patients present with lower-risk disease, understanding the pathogenesis of ineffective hematopoiesis is important for developing therapies that will increase blood counts in patients with MDS. Various inflammatory cytokines are elevated in MDS and contribute to dysplastic differentiation. Inflammatory pathways mediated by interleukin (IL) 1b, IL-6, IL-1RAP, IL-8, and others lead to growth of aberrant MDS stem and progenitors while inhibiting healthy hematopoiesis. Spliceosome mutations can lead to missplicing of genes such as IRAK4, CASP8, and MAP3K, which lead to activation of proinflammatory nuclear factor κB-driven pathways. Therapeutically, targeting of ligands of the transforming growth factor β (TGF-β) pathway has led to approval of luspatercept in transfusion-dependent patients with MDS. Presently, various clinical trials are evaluating inhibitors of cytokines and their receptors in low-risk MDS. Taken together, an inflammatory microenvironment can support the pathogenesis of clonal hematopoiesis and low-risk MDS, and clinical trials are evaluating anti-inflammatory strategies in these diseases.

The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular diagnostic for hemophilia, followed by the development of recombinant clotting factor replacement therapy. Now gene therapy beckons on the back of decades of research that has brought us to the final stages of the approval of 2 products in Europe and United States, thus heralding a new era in the treatment of the hemophilias. Valoctocogene roxaparvovec, the first gene therapy for treatment of hemophilia A, has been granted conditional marketing authorization in Europe. Another approach (etranacogene dezaparvovec, AMT-061) for hemophilia B is also under review by regulators. There are several other gene therapy approaches in earlier stages of development. These approaches entail a one-off infusion of a genetically modified adeno-associated virus (AAV) engineered to deliver either the FVIII or FIX gene to the liver, leading to the continuous endogenous synthesis and secretion of the missing coagulation factor into the circulation by the hepatocytes, thus preventing or reducing bleeding episodes. Ongoing observations show sustained clinical benefit of gene therapy for >5 years following a single administration of an AAV vector without long-lasting or late toxicities. An asymptomatic, self-limiting, immune-mediated rise in alanine aminotransferase is commonly observed within the first 12 months after gene transfer that has the potential to eliminate the transduced hepatocytes in the absence of treatment with immunosuppressive agents such as corticosteroids. The current state of this exciting and rapidly evolving field, as well as the challenges that need to be overcome for the widespread adaptation of this new treatment paradigm, is the subject of this review.

The multifaceted pathophysiologic processes that comprise thrombosis and thromboembolic diseases take on a particular urgency in the hospitalized setting. In this review, we explore 3 cases of thrombosis from the inpatient wards: purpura fulminans, cancer-associated thrombosis with thrombocytopenia, and coronavirus disease 2019 (COVID-19) and the use of dose-escalated anticoagulation therapy and antiplatelet agents. We discuss the evaluation and management of purpura fulminans and the roles of plasma transfusion, protein C and antithrombin replacement, and anticoagulation in treating this disease. We present a framework for evaluating the etiologies of thrombocytopenia in cancer and review 2 strategies for anticoagulation management in patients with cancer-associated thrombosis and thrombocytopenia, including recent prospective data supporting the use of dose-modified anticoagulation based on platelet count. Last, we dissect the major clinical trials of therapeutic- and intermediate-dose anticoagulation and antiplatelet therapy in hospitalized patients with COVID-19, reviewing key recommendations from consensus guidelines while highlighting ways in which institutional and patient-tailored practices regarding antithrombotic therapies in COVID-19 may differ. Together, the cases highlight the diverse and dramatic presentations of macro- and microvascular thrombosis as encountered on the inpatient wards.

Since the introduction of tyrosine kinase inhibitors (TKIs) at the beginning of the millennium, the outlook for patients with chronic myeloid leukemia (CML) has improved remarkably. As such, the question of life expectancy and survival has become less problematic while quality of life and family planning have become more so. While TKIs are the cornerstone of CML management, their teratogenicity renders them contraindicated during pregnancy. In recent years, patients who satisfy standardized criteria can stop TKI therapy altogether, and indeed, in eligible patients who wish to become pregnant, these objectives overlap. However, not all patients satisfy these criteria. Some pregnancies are unplanned, and a number of patients are pregnant when diagnosed with CML. In these patients the way forward is less clear, and there remains a paucity of good evidence available to guide treatment. In this article, we summarize the relevant literature and provide a framework for clinicians faced with the challenge of managing CML and pregnancy.

Mast cell disorders include mastocytosis and mast cell activation syndromes. Mastocytosis is a rare clonal disorder of the mast cell, driven by KIT D816V mutation in most cases. Mastocytosis is diagnosed and classified according to World Health Organization criteria. Mast cell activation syndromes encompass a diverse group of disorders and may have clonal or nonclonal etiologies. Hematologists may be consulted to assist in the diagnostic workup and/or management of mast cell disorders. A consult to the hematologist for mast cell disorders may provoke anxiety due to the rare nature of these diseases and the management of nonhematologic mast cell activation symptoms. This article presents recommendations on how to approach the diagnosis and management of patients referred for common clinical scenarios.

Molecular therapy with tyrosine kinase inhibitors (TKIs) has significantly reduced the indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in chronic myeloid leukemia (CML). Treatment-free remission can be obtained in about 50% of patients with an optimal response. However, cure rates up to 90% are restricted to patients receiving HSCT. Timing is essential since HSCT in the early stages of the disease has the best outcome. Patients in a more advanced phase (AdP) than chronic-phase (chP) CML undergo HSCT with suboptimal outcomes, and the gap between chP and AdP disease is widening. First-line therapy should start with first- or second-generation (G) TKIs. Patients failing treatment (BCR-ABL1 transcripts of greater than 10% at 3 and 6 months and greater than 1% at 12 months) should be switched to second-line TKIs, and HSCT should be considered. Patients not responding to 2G-TKI therapy as well as patients in an accelerated phase (AP) or blast crisis (BC) are candidates for HSCT. Therapy resistant BCR-ABL1 mutations, high-risk additional cytogenetic abnormalities, and molecular signs of leukemia progression should trigger the indication for HSCT. Patients who, despite dose adjustments, do not tolerate or develop severe adverse events, including vascular events, to multiple TKIs are also candidates for HSCT. In AdP CML, TKIs do not show long-lasting results, and the outcome of HSCT is less optimal without pretransplant therapy. In these patients the induction of chP2 with TKIs, either alone (AP) or in combination with intensive chemotherapy (BC), followed by HSCT should be pursued.