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

Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.

Ischemic priapism is a common but underrecognized morbidity affecting about 33% of adult men with sickle cell disease (SCD). The onset of priapism occurs in the prepubertal period and tends to be recurrent with increasing age. Significantly, priapism is associated with an unrecognized high burden of mental duress and sexual dysfunctions. The diagnosis of priapism is clinical. Many episodes of priapism will resolve spontaneously, but when an episode lasts longer than 4 hours, the episode is considered a urologic emergency requiring quick intervention with either corporal aspiration or shunt surgery. Only 3 randomized clinical trials (stilbesterol, ephedrine or etilefrine, and sildenafil) have been conducted for secondary priapism prevention in SCD. All 3 trials were limited with small sample sizes, selection biases, and inconclusive results after completion. The current molecular understanding of the pathobiology of priapism suggests a relative nitric oxide (NO) deficiency secondary to chronic hemolysis in SCD and associated phosphodiesterase type 5 dysregulation. We posit an increase in NO levels will restore the normal homeostatic relationship between voluntary erection and detumescence. Currently, 2 randomized phase 2 trials (1 double-blind, placebo-controlled trial and 1 open-label, single-arm intervention) are being conducted for secondary priapism prevention in men at high risk for recurrent priapism (NCT03938454 and NCT05142254). We review the epidemiology and pathobiology of priapism, along with mechanistic therapeutic approaches for secondary prevention of priapism in SCD.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a common subtype of B-lineage acute lymphoblastic leukemia (B-ALL) with increasing frequency across the age spectrum. Characterized by a kinase-activated gene expression profile and driven by a variety of genetic alterations involving cytokine receptors and kinases, Ph-like ALL is associated with high rates of residual disease and relapse in patients treated with conventional chemotherapy. In this case-based review, we describe the biology of the 2 major ABL-class and JAK pathway genetic subtypes of Ph-like ALL, discuss current diagnostic testing methodologies, and highlight targeted inhibitor and chemo/immunotherapy approaches under clinical investigation in children, adolescents, and adults with these high-risk leukemias.

Bacterial contamination of platelet units has been one of the most common transfusion-transmitted infections. Approximately 4 to 7 fatalities are being reported to the US Food and Drug Administration (FDA) annually, which cites bacterially contaminated platelet units as the cause. Over the past 3 decades, different mitigation strategies have been introduced to minimize the risk of morbidity and mortality related to contaminated platelet units. The process of platelet collection and manufacturing as well as storage at 20°C to 24°C contributes to higher prevalence of contaminated units. The risk of transfusing bacterially contaminated platelets can be lowered using different types of interventions. Prevention of bacterial contamination can be done by strict adherence to techniques that minimize contamination during unit collection. The detection of bacteria in platelet products can be improved with a combination of rapid testing and bacterial cultures that involve large volume and delayed sampling. Finally, pathogen reduction can inactivate bacteria or other pathogens present in the unit. This article describes different strategies that blood centers and transfusion services have undertaken since October 2021 to meet FDA guidance requirements. Market forces as well as feasibility of different FDA-proposed approaches have limited the number of practical solutions to just a few. In addition, the blood product availability required hospitals to adopt more progressive strategies to provide patients with needed platelet products.

The platelet collection and distribution system, based on volunteer nonremunerated donors, apheresis platelet collections, and primarily 1-directional distribution of platelets for up to 5-day room temperature storage at hospitals, typically performs well and provides therapeutic support for hundreds of thousands of patients annually. However, direct and indirect effects of the coronavirus disease 2019 pandemic, particularly during the Omicron wave, produced dramatic systemic failures and severe shortages. We propose 4 initiatives to reinforce the existing platelet pipeline and buffer the platelet supply against future unexpected disruptions.

Von Willebrand disease (VWD), the most common inherited bleeding disorder (IBD), disproportionately affects females, given the hemostatic challenges they may encounter throughout their lifetimes. Despite this, research about VWD remains grossly underrepresented, particularly compared to hemophilia, which is historically diagnosed in males. Structural sexism, stigmatization of menstrual bleeding, delayed diagnosis, and a lack of timely access to care result in an increased frequency of bleeding events, iron deficiency, iron deficiency anemia, and a decreased quality of life. However, we are only beginning to recognize and acknowledge the magnitude of the burden of this disease. With an increasing number of studies documenting the experiences of women with IBDs and recent international guidelines suggesting changes to optimal management, a paradigm shift in recognition and treatment is taking place. Here, we present a fictional patient case to illustrate one woman's history of bleeding. We review the evidence describing the impact of VWD on quality of life, normalization of vaginal bleeding, diagnostic delays, and the importance of access to multidisciplinary care. Furthermore, we discuss considerations around reproductive decision-making and the intergenerational nature of bleeding, which often renders patients as caregivers. Through incorporating the patient perspective, we argue for an equitable and compassionate path to overcome decades of silence, misrecognition, and dismissal. This path moves toward destigmatization, open dialogue, and timely access to specialized care.

Outcomes of allogeneic hematopoietic cell transplantation (HCT) for patients with advanced acute leukemia and myelodysplastic syndromes (MDS) remain uncertain. All published series include the important and often not stated selection bias that influences outcome. Performance status, patient age, prompt donor availability, risk phenotype of the leukemia, and tumor burden all influence the decision-making process about HCT with active disease. In addition, patients with MDS do not achieve a true pre-HCT complete remission, and thus much less stringent measures are used to indicate suitability for allografting in that disease. Post-HCT maintenance or investigational approaches for tumor depletion may improve the outcomes.

Allogeneic hematopoietic cell transplantation (alloHCT) often represents the only curative treatment for various malignant and nonmalignant disorders. Initially, the only suitable donors were considered human leukocyte antigen (HLA)-matched or partially matched relatives. The founding of international unrelated donor and umbilical cord blood registries expanded unrelated donor options and access for patients. In the absence of a matched sibling donor (MSD) with 13% to 51% availability, the current consensus recommends use of a matched unrelated donor (MUD) at HLA-A, B, C, and DRB1 with consideration of matching at HLA-DPB1 and -DQB1. MUD donor availability (donor willing and available to donate) ranges from 29% to 78% with African American patients on the lower end and white non-Hispanic patients with the highest likelihood of a match. Recent studies comparing donor to no-donor treatment options in malignant disease consistently point to substantially better outcomes following alloHCT. In the absence of an MSD or MUD, alternative donor choices turn to haploidentical related (Haplo), mismatched unrelated donor (MMUD), and umbilical cord blood (UCB). Novel strategies for alloHCT, including the use of posttransplant cyclophosphamide-based graft vs host disease prophylaxis, have expanded the safety and effectiveness of transplant procedures across HLA barriers using Haplo and MMUD. The less restrictive matching requirements for UCB transplant are well documented and allow for transplant across multiply mismatched HLA alleles. When all donor options are considered, nearly all patients have an available donor. Here we discuss the likelihood of donor availability, complete HLA match by available donor type, and current controversies warranting future research.

Curative therapies for sickle cell disease include allogeneic hematopoietic stem cell transplantation (HSCT) and gene-modified autologous stem cell transplantation. HSCT has been used for 30 years with success measured by engraftment, symptom control, graft-vs-host disease (GVHD) risk, organ toxicity, and immune reconstitution. While human leukocyte antigen-matched sibling donor (MSD) transplants have excellent outcomes, alternate donor transplants (unrelated/haploidentical) are just beginning to overcome GVHD and engraftment hurdles to match MSD. Gene therapy, a newly developed treatment, is undergoing careful evaluation in many trials with varying approaches. The risk/benefit ratio to the patient in relation to outcomes, toxicities, and mortality risk drives eligibility for curative interventions. Consequently, eligibility criteria for MSD transplants can be less stringent, especially in the young. Posttransplant outcome analysis after the "cure" with respect to organ function recovery is essential. While established damage such as stroke is irreversible, transplant can help stabilize (pulmonary function), prevent further deterioration (stroke), improve (neurocognition), and protect unaffected organs. Tracking organ functions postintervention uniformly between clinical trials and for adequate duration is essential to answer safety and efficacy questions related to curative therapies. Age-appropriate application/outcome analyses of such therapies will be the ultimate goal in overcoming this disease.