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

Cold-reactive autoimmune hemolytic anemia (AIHA) is rare among the hemolytic anemias. It results when 1 of a variety of processes causes the generation of immunoglobulin M (IgM) autoantibodies against endogenous erythrocytes, resulting in complement activation and predominantly intravascular hemolysis. Cold AIHA is typically a primary lymphoproliferative disorder with marrow B-cell clones producing pathogenic IgM. More rarely, secondary cold AIHA (cAIHA) can develop from malignancy, infection, or other autoimmune disorders. However, in children cAIHA is typically post infection, mild, and self-limited. Symptoms include a sequelae of anemia, fatigue, and acrocyanosis. The severity of disease is variable and highly dependent on the thermal binding range of the autoantibody. In adults, treatment has most commonly focused on reducing antibody production with rituximab-based regimens. The addition of cytotoxic agents to rituximab improves response rates, but at the expense of tolerability. Recent insights into the cause of cold agglutinin disease as a clonal disorder driven by complement form the basis of newer therapeutic options. While rituximab-based regimens are still the mainstay of therapy, options have now expanded to include complement-directed treatments and other B-cell-directed or plasma-cell-directed therapies.

Globally, patients living with sickle cell disease are now surviving to reproductive age, with life expectancy approaching 50 years in most countries. Thus, reproductive options are now essential for patients living with the condition. However, it can be associated with maternal, delivery, and fetal complications. Outcomes may vary depending on the level of expertise and resources. In this piece we provide an optional guideline for managing sickle cell disease in pregnancy. The therapeutic option of serial exchange prophylactic transfusion has been offered in the context of a clinical trial (TAPS2).

The historically poor prognosis of patients with advanced systemic mastocytosis (AdvSM) and primary eosinophilic neoplasms has shifted to increasingly favorable outcomes with the discovery of druggable targets. The multikinase/KIT inhibitor midostaurin and the highly selective KIT D816V inhibitor avapritinib can elicit marked improvements in measures of mast cell (MC) burden as well as reversion of MC-mediated organ damage (C-findings) and disease symptoms. With avapritinib, the achievement of molecular remission of KIT D816V and improved survival compared with historical therapy suggests a potential to affect disease natural history. BLU-263 and bezuclastinib are KIT D816V inhibitors currently being tested in trials of AdvSM. In the new World Health Organization and International Consensus Classifications, the category of "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions" is inclusive of rearrangements involving PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1. While the successful outcomes with imatinib in FIP1L1::PDGFRA-positive cases and PDGFRB-rearranged neoplasms have become the "poster children" of these disorders, the responses of the other TK-driven neoplasms to small-molecule inhibitors are more variable. The selective FGFR inhibitor pemigatinib, approved in August 2022, is a promising therapy in aggressive FGFR1-driven diseases and highlights the role of such agents in bridging patients to allogeneic transplantation. This review summarizes the data for these approved and investigational agents and discusses open questions and future priorities regarding the management of these rare diseases.

As the aging population grows, so too does the number of well-tolerated antimyeloma therapies. Physicians will see an increasing volume of patients for subsequent lines of therapy, which could now extend this relationship for over a decade. For younger patients, treatment choices are infrequently impacted by concerns of fitness, but instead about effecting the deepest, most durable response. Older adults, in contrast, are more likely to experience under- than overtreatment, and therefore more objective (and ideally straightforward) ways to evaluate their fitness and ability to tolerate therapy will increasingly assist in decision-making. Post hoc analyses categorizing the fitness of trial patients in the modern treatment era globally demonstrate that even in highly selected populations, those that are recategorized as less fit or frail are consistently at higher risk of inferior outcomes and increased toxicities. Real-world data are comparatively lacking but do demonstrate that most patients with myeloma are not representative of those enrolled on clinical trials, generally more heavily burdened by comorbidities and more likely to be categorized as "less than fit." Simultaneously, the number of therapeutic options open to patients in the relapsed setting continues to grow, now including T-cell engagers and cellular therapies, with their unique toxicity profiles. The aim of this review is to summarize the available data, highlight some of the approaches possible to easily assess fitness and how results might inform treatment selection, and illustrate ways that patients' condition can be optimized rather than lead to exclusion from the more complex therapies newly available.

In this review, we present a clinical case report and discussion to outline the importance of long-term specific Fanconi anemia (FA) monitoring, and we discuss the main aspects of the general management of patients with FA and clinical complications. While several nontransplant treatments are currently under evaluation, hematopoietic stem cell transplantation (HSCT) remains the only therapeutic option for bone marrow failure (BMF). Although HSCT outcomes in patients with FA have remarkably improved over the past 20 years, in addition to the mortality intrinsic to the procedure, HSCT increases the risk and accelerates the appearance of late malignancies. HSCT offers the best outcome when performed in optimal conditions (moderate cytopenia shifting to severe, prior to transfusion dependence and before clonal evolution or myelodysplasia/acute myeloid leukemia); hence, an accurate surveillance program is vital. Haploidentical HSCT offers very good outcomes, although long-term effects on malignancies have not been fully explored. A monitoring plan is also important to identify cancers, particularly head and neck carcinomas, in very early phases. Gene therapy is still experimental and offers the most encouraging results when performed in early phases of BMF by infusing high numbers of corrected cells without genotoxic effects. Patients with FA need comprehensive monitoring and care plans, coordinated by centers with expertise in FA management, that start at diagnosis and continue throughout life. Such long-term follow-up is essential to detect complications related to the disease or treatment in this setting.

The application of genomic techniques, including cytogenetics and DNA sequencing, to decipher the molecular landscape of patients with myeloproliferative neoplasms (MPNs) has radically modified diagnostic approach and management through improved risk stratification. Three driver mutated genes (JAK2, MPL, CALR) are variably harbored by >80% of patients and associated with clinical characteristics, as well as major disease-related complications and different survival outcomes. Therefore, JAK2 V617F mutation is included in the revised International Prognosis Score of Thrombosis for Essential Thrombocythemia score for prediction of thrombosis in patients with essential thrombocythemia and prefibrotic primary myelofibrosis, while a CALR type 1 mutated genotype constitutes a favorable variable for survival in patients with myelofibrosis (MF). Novel, integrated clinical and cytogenetic/mutation scores (Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients with Primary Myelofibrosis [MIPSS70/v2], genetically inspired prognostic scoring system [GIPSS], Myelofibrosis Secondary to PV and ET- Prognostic Model [MYSEC-PM]) have been devised that guide selection of stem cell transplantation candidates with MF or help predict the risk associated with the transplant procedure (Myelofibrosis Transplant Scoring System), with greater performance compared with conventional scores based on hematologic and clinical variables only. On the other hand, several clinical needs remain unmet despite the great amount of molecular information available nowadays. These include the prediction of evolution to acute leukemia in a clinically actionable time frame, the identification of patients most likely to derive durable benefits from target agents, in primis JAK inhibitors, and, conversely, the significance of molecular responses that develop in patients receiving interferon or some novel agents. Here, we discuss briefly the significance and the role of genomic analysis for prognostication in patients with MPNs from a clinician's point of view, with the intent to provide how-to-use hints.

T-lineage acute lymphoblastic leukemia (T-ALL) is curable for most children and adolescent and young adult patients with contemporary frontline chemotherapy regimens. During the past decade, improved survival rates have resulted from the optimization of frontline chemotherapy regimens, the use of minimal residual disease (MRD) assessment for evaluating a patient's risk for relapse, and the intensification of treatment based on the persistence of MRD. Optimization of initial therapy is critical because relapsed T-ALL after initial intensive chemotherapy is incurable for most adult patients. Current T-ALL salvage chemotherapy regimens are minimally effective, and unlike in B-cell ALL, there are no approved antibody therapies or chimeric antigen receptor T-cell therapies for relapsed disease. Immunotherapy and small-molecule inhibitors are beginning to be tested in relapsed T-ALL and have the potential to advance the treatment. Until effective salvage strategies are discovered, however, intensive frontline therapy is required for cure. In this article I review the current frontline chemotherapy regimens for adult patients with T-ALL, summarize the novel targeted and immune therapeutics currently in early-phase clinical trials, and outline how these therapies are helping to define an optimal approach for T-ALL.

The prevention of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) continues to be one of the most contentious areas of lymphoma management. Outcomes for patients with secondary CNS lymphoma (SCNSL) have historically been very poor. However, in recent years improved responses have been reported with intensive immunochemotherapy approaches, and there is a growing interest in potential novel/cellular therapies. Traditional methods for selecting patients for CNS prophylaxis, including the CNS International Prognostic Index, are hampered by a lack of specificity, and there is accumulating evidence to question the efficacy of widely employed prophylactic interventions, including intrathecal and high-dose methotrexate (HD-MTX). Given the potential toxicity of HD-MTX in particular and the ongoing need to prioritize systemic disease control in high-risk patients, there is an urgent need to develop more robust methods for identifying patients at highest risk of CNS relapse, as well as investigating prophylactic interventions with greater efficacy. Here we review new evidence in this field from the last 5 years, focusing on the potential use of molecular diagnostics to improve the identification of high-risk patients, recent large data sets questioning the efficacy of HD-MTX, and the current approach to management of patients with SCNSL. We provide a suggested algorithm for approaching this very challenging clinical scenario.