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

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.

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.

Pregnancy in women with sickle cell disease (SCD) is a life-threatening condition. In both high- and low-income countries, there is an 11-fold increased risk of maternal death and a 4-fold increased risk of perinatal death. We highlight the epidemiology of SCD-specific and obstetric complications commonly seen during pregnancy in SCD and propose definitions for acute pain and acute chest syndrome (ACS) episodes during pregnancy. We conducted a systematic review of the recent obstetric and hematology literature using full research articles published within the last 5 years that reported outcomes in pregnant women with SCD. The prevalence of acute pain episodes during pregnancy ranged between 4% and 75%. The prevalence of ACS episodes during pregnancy ranged between 4% and 13%. The estimated prevalence of pulmonary thromboembolism in women with SCD during pregnancy is approximately 0.5 to 1%. ACS is the most common cause of death and is often preceded by acute pain episodes. The most crucial time to develop these complications in pregnancy is during the third trimester and postpartum period. In a pooled analysis from studies in low- and middle-income settings, maternal death in women with SCD is approximately 2393 and 4300 deaths per 100 000 live births with and without multidisciplinary care, respectively. In comparison, in the US and northern Europe, the general maternal mortality rate is approximately 23.8 and 8 deaths per 100 000 live births, respectively. A multidisciplinary SCD obstetrics care approach reduces maternal and perinatal morbidity and mortality in low- and middle-income countries.

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for high-risk hematological malignancies such as acute myeloid and lymphocytic leukemia, myelodysplastic syndrome, and myeloproliferative disorders. Alternative donor transplantation from either haploidentical (haplo-SCT) or cord blood donor (CBT) is an established therapeutic alternative for patients who need transplants but lack a human leukocyte antigen-matched donor. Although haplo-SCT (mainly non-T-cell-depleted haplo-SCT with posttransplant cyclophosphamide) is increasing while CBT is decreasing worldwide (Figure 1), recent developments in CBT, especially cord blood expansion and other strategies to improve engraftment and immune reconstitution post-CBT, make CBT still a valuable option. This article discusses the 2 options based on the currently available data, focusing on adults, and tries to give some clues to help the transplant physician choose a haploidentical vs a cord blood donor. Given the limited numbers of published or ongoing well-designed randomized controlled trials comparing haplo-SCT to CBT and the overall similar clinical results in the available, mostly registry-based, and single-center studies, with substantial heterogeneity and variability, the decision to perform haplo-SCT or CBT in a given patient depends not only on the patient, disease, and donor characteristics and donor availability (although most if not all patients should have in principle an alternative donor) but also on the transplant physician's discretion and, most importantly, the center's experience and preference and ongoing protocols and strategies.

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 treatment landscape in acute myeloid leukemia (AML) is rapidly evolving, with multiple new therapies approved in recent years. However, the prognosis for patients with high-risk genetic subsets of AML remains poor, and the development of more effective treatment options for these patients is ongoing. Three of these high-risk AML patient subsets include TP53-mutated AML, FLT3-internal tandem duplication (ITD)-mutated AML, and AML harboring rearrangements affecting the KMT2A locus (KMT2A-r AML). The prognosis for TP53-mutated AML remains poor with both intensive and targeted regimens, including those incorporating the BCL-2 inhibitor, venetoclax. Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for these patients, but posttransplant relapse rates remain high. Patients with FLT3-ITD-mutated AML continue to have suboptimal outcomes with standard therapies and experience high rates of relapse following transplant. KMT2A-r AML is also associated with poor outcomes with current treatment approaches, and effective standards of care are lacking for patients with relapsed/refractory disease. This article discusses current treatment approaches, along with the investigational agents being explored for the treatment of these 3 AML subsets, focusing primarily on agents that are further along in development.

Co-incident venous thromboembolism and thrombocytopenia are frequent in patients with active malignancies. The optimal approach for anticoagulation in patients with cancer and thrombocytopenia is not established. Different strategies are often utilized including dose-reduced anticoagulation dictated by degree of thrombocytopenia or transfusing platelets in order to facilitate therapeutic anticoagulation. This minireview provides an overview of the data and we outline our approach toward anticoagulation in patients with venous thromboembolism and thrombocytopenia in the setting of cancer.