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

Racial, ethnic, and socioeconomic survival disparities have been well-demonstrated across population-based and clinical trial datasets in pediatric hematologic malignancies. To date, these analyses have relied on trial-collected data such as race, ethnicity, insurance, and zip code. These exposures serve as proxies for factors such as structural racism, genetic ancestry, and adverse social determinants of health (SDOH). Systematic measurement of SDOH and social needs-and interventions targeting these needs-are feasible in pediatric oncology. We use these data to present a roadmap for the next decade of health equity research to identify actionable mechanisms and develop a portfolio of interventions to advance equitable outcomes across pediatric hematologic malignancies.

Monoclonal gammopathies of clinical significance (MGCS) are a heterogeneous group of disorders characterized by the presence of an indolent B-cell or plasma-cell clone producing a toxic monoclonal immunoglobulin resulting in end-organ dysfunction. MGCS is a clinicopathologic diagnosis that requires the demonstration of a monoclonal immunoglobulin in the correct clinical setting. The most common MGCS syndromes are renal, neurologic, and cutaneous, although hematologic and multi-organ MGCS syndromes are also increasingly recognized. Therapy most commonly targets the underlying clonal population; immunoglobulin-targeting therapies as well as complement and cytokine antagonists have emerged for selected MGCS syndromes and may be temporizing in a subset of patients. Other chapters review renal and neurologic MGCS; this chapter focuses on hematologic and multi-organ MGCS syndromes.

TP53-mutated myeloid disease is a constellation of abnormalities seen in both de novo and therapy-related acute myeloid leukemia and myelodysplastic syndrome. Historically, this group of disorders has had a poor prognosis. Newer treatment combinations allow patients to be treated with less toxicity. If response to induction therapy is achieved, fit and willing patients should be considered for allogeneic hematopoietic cell transplantation (HCT). The addition of allogeneic HCT to the treatment approach has modestly improved outcomes compared to chemotherapy alone, more so for those patients with disease control. Tailoring the conditioning regimen and maintenance therapy may improve outcomes in TP53 myeloid patients. In addition to chemotherapy, disease-modulating and immunological treatments continue to be studied to further improve outcomes.

The management of immune thrombocytopenia (ITP) is continuously evolving with the development and introduction of newer therapies and a better understanding of the disease. Corticosteroids still represent the cornerstone of first-line treatment. Patients who fail to achieve remission with a short course of corticosteroids require subsequent therapy. Most guidelines recommend starting with either a thrombopoietin receptor agonist (TPO-RA), rituximab, or fostamatinib since these agents have been investigated in randomized trials and have well-characterized efficacy and safety profiles. Patients' involvement to reach a shared decision regarding choice of therapy is essential as these treatments have different modes of administration and mechanisms of action. Less than 10% will fail to respond to and/or be intolerant of multiple second-line therapeutic options and thus be considered to have refractory ITP and require a third-line therapeutic option. Such patients may require drugs with different targets or a combination of drugs with different mechanisms of action. Combining a TPO-RA and an immunomodulatory agent may be an appropriate approach at this stage. Many studies have been conducted during the last 2 decades investigating the efficacy and safety of combinations strategies for first and later lines of therapies. Yet none of these are recommended by current guidelines or have gained wide acceptance and consensus.

Treatment of immune thrombocytopenia (ITP) has evolved over the last 20 years in response to our increased understanding of the pathophysiology of this complex immune disorder. New treatments in development have taken advantage of our evolving understanding of the biology of this disease to target new mechanisms and expand the available ways in which to approach patients with this disorder. This review focuses on novel therapeutics in the ITP pipeline and discusses the pathophysiology of ITP that has led to their development.

Classification of acute leukemia involves assigning lineage by resemblance of blasts to normal progenitor cells. This approach provides descriptive information that is useful for disease monitoring, provides clues to pathogenesis, and can help to select effective chemotherapeutic regimens. Acute leukemias of ambiguous lineage (ALAL) are those leukemias that either fail to show evidence of myeloid, B-lymphoid, or T-lymphoid lineage commitment or show evidence of commitment to more than 1 lineage, including mixed-phenotype acute leukemia (MPAL). The different treatment regimens for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) make ALAL a challenge both diagnostically and therapeutically. Current classification criteria have reduced the reported incidence of mixed lineage leukemias by emphasizing fewer markers and categorizing some biphenotypic leukemias with recurrent cytogenetic abnormalities as other entities. Several recent studies have explored the genomic and epigenetic landscape of MPAL and emphasize the genomic heterogeneity of MPAL. Two classification proposals of myeloid malignancies recently been published and include International Consensus Classification and fifth edition of the World Health Organization Classification of Haematolymphoid Tumours. Our review aims to discuss the diagnostic challenges in the setting of classification updates, recent genomic studies, and therapeutic strategies in this poorly understood disease.

Refractory autoimmune mutilineage cytopenias can present in childhood associated with chronic nonmalignant lymphoproliferation (splenomegaly, hepatomegaly, and/or lymphadenopathy). Cytopenias due to peripheral destruction and sequestration have been well recognized since the 1950s and are often lumped together as eponymous syndromes, such as Evans syndrome and Canale-Smith syndrome. Though their clinical and genetic diagnostic workup may appear daunting, it can provide the basis for early intervention, genetic counseling, and empirical and targeted therapies. Autoimmune lymphoproliferative syndrome (ALPS), activated phosphatidylinositol 3-kinase delta syndrome (APDS), and many other related genetic disorders are otherwise collectively known as inborn errors of immunity (IEI). They present in early childhood as refractory autoimmune cytopenias due to immune dysregulation leading to lymphadenopathy, splenomegaly, and increased susceptibility to lymphoma. More recently, controlled clinical trials have shown that some of these immune system disorders with hematological manifestations might be more readily amenable to specific targeted treatments, thus preventing end-organ damage and associated comorbidities. Over the last 20 years, both rapamycin and mycophenolate mofetil have been successfully used as steroid-sparing long-term measures in ALPS. Current therapeutic options for APDS/PASLI (phosphoinositide 3-kinase [PI3K]-associated senescent T lymphocytes, lymphadenopathy, and immunodeficiency) include the orally bioavailable PI3Kδ inhibitor, leniolisib, which was licensed by the US Food and Drug Administration (FDA) in 2023 for use in individuals older than 12 years as a targeted treatment. Paradigms learned from patients with rare genetic disorders like ALPS and APDS may help in exploring and streamlining molecular therapy strategies in the wider group of IEIs presenting with refractory cytopenias and lymphoproliferation.

Interferon alpha (IFN-α) is a fascinating molecule with many biological properties yet to be fully understood. Among these properties, several have demonstrated usefulness for targeting malignant cells, including hematopoietic cells from patients with myeloproliferative neoplasms. Indeed, IFN-α has been used for decades across all myeloproliferative neoplasms, but only recently a new form, ropegIFN-α2b, was approved to treat patients with polycythemia vera. Many phase 2 and more recently phase 3 studies have demonstrated IFN-α's promise in treating patients with essential thrombocythemia and early-stage myelofibrosis. In addition, although not approved in that situation, IFN-α is the only cytoreductive therapy that can be used during pregnancy. Today, IFN-α is a key medicine for polycythemia vera and essential thrombocythemia, while its place in the management of myelofibrosis must be better defined. The advantages of IFN therapy include a well-known safety profile, high rates of clinical and molecular responses, and a unique ability to deeply reduce the mutant allele burden of most of the driver mutations causing myeloproliferative neoplasms. Recent preliminary data from prospective studies suggest that molecular responses may be correlated with prolonged event-free survival, raising the hope that IFN therapy may ultimately alter the natural history of many diseases.

Antibody-based and cell-based novel immunotherapies, such as bispecific T-cell engagers (BiTE), antibody-drug conjugates, or chimeric antigen receptor (CAR) T cells are currently standard treatment options for patients with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). To date, CD20-targeting monoclonal antibodies and the CD19-targeting BiTE's blinatumomab have been established elements of frontline therapy, either in patients with CD20+ ALL or in patients with measurable disease (MRD) following conventional chemotherapy. Recently, blinatumomab has also demonstrated a survival benefit in patients with MRD-negative ALL. Based on the observed high response rates and improved survival outcomes in patients with R/R ALL, antibody-based immunotherapies are being prospectively studied in the upfront setting, particularly in older adult patients, where even age-adapted conventional chemotherapies are still associated with significant rates of early death, treatment-related toxicity, and poor prognosis. In these approaches, conventional chemotherapy has been replaced or reduced and supplemented by immunotherapeutic agents, resulting in promising outcomes that form the basis for evaluating and defining new treatment standards.