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

Marginal zone lymphomas (MZLs) represent about 7% of B-cell non-Hodgkin lymphomas and include 3 different subtypes-namely, extranodal (EMZL), nodal, and splenic (SMZL). The initial assessment requires specific diagnostic and staging procedures depending on organ-related peculiarities. In particular, although positron emission tomography/computed tomography was not initially recommended, recent data have reassessed its role in the routine staging of MZL, especially when only localized treatment is planned or there is a suspicion of histologic transformation. Recent findings have improved the risk stratification of MZL patients, highlighting the association of early progression after frontline therapy with worse overall survival. A significant fraction of MZL cases may be related to specific bacterial (ie, Helicobacter pylori in gastric EMZL) or viral infections (hepatis C virus), and in the earlier phases of disease, a variable percentage of patients may respond to anti-infective therapy. Involved-site radiotherapy has a central role in the management of localized EMZL not amenable to or not responding to anti-infective therapy. Although rituximab-based treatments (bendamustine- rituximab in advanced EMZL or rituximab monotherapy in SMZL) have demonstrated favorable results, the current therapeutic scenario is predicted to rapidly change as emerging novel agents, especially Bruton's tyrosine kinase inhibitors, have demonstrated promising efficacy and safety profiles, leading to their approval in the relapsed setting. Moreover, a large variety of novel agents (phosphatidylinositol 3-kinase inhibitors, chimeric antigen receptor T-cells, bispecific antibodies) are being tested in MZL patients with encouraging preliminary results.

Patients with chronic lymphocytic leukemia (CLL) refractory to covalent BTK and BCL2 inhibitors have a new unmet clinical need. Standard treatment options are able to obtain only limited and short-lasting disease control associated with reduced overall survival, and thus these patients have become ideal candidates for enrollment in clinical trials. Favorable results have been obtained with the use of noncovalent BTK inhibitors (roughly 70% overall response rate regardless of the actual resistance or intolerance to previous covalent BTK inhibitors) and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (with complete responses in up to 45% of cases and an undetectable measurable residual disease rate of 65% in the bone marrow). These 2 approaches should be considered valid options in this setting, although not yet approved. For young fit patients achieving remissions with salvage treatments, the option of allogeneic stem cell transplantation should be discussed as the outcome appears to be unaffected by number and type of previous targeted agents. Novel treatment strategies interfering with different mechanisms of CLL cell survival and proliferation are warranted, including small molecules with novel targets (eg, CDK9, MCL1, ERK inhibitors), CAR T cells targeting different antigens, CAR natural killer cells, or bispecific antibodies.

Abnormal bleeding in patients with liver disease may result from elevated portal pressure and varix formation, reduced hepatic synthesis of coagulation proteins, qualitative platelet dysfunction, and/or thrombocytopenia. Major mechanisms of thrombocytopenia in liver disease include splenic sequestration and impaired platelet production due to reduced thrombopoietin production. Alcohol and certain viruses may induce marrow suppression. Immune thrombocytopenia (ITP) may co-occur in patients with liver disease, particularly those with autoimmune liver disease or chronic hepatitis C. Drugs used for the treatment of liver disease or its complications, such as interferon, immunosuppressants, and antibiotics, may cause thrombocytopenia. Periprocedural management of thrombocytopenia of liver disease depends on both individual patient characteristics and the bleeding risk of the procedure. Patients with a platelet count higher than or equal to 50 000/µL and those requiring low-risk procedures rarely require platelet-directed therapy. For those with a platelet count below 50 000/µL who require a high-risk procedure, platelet-directed therapy should be considered, especially if the patient has other risk factors for bleeding, such as abnormal bleeding with past hemostatic challenges. We often target a platelet count higher than or equal to 50 000/µL in such patients. If the procedure is elective, we prefer treatment with a thrombopoietin receptor agonist; if it is urgent, we use platelet transfusion. In high-risk patients who have an inadequate response to or are otherwise unable to receive these therapies, other strategies may be considered, such as a trial of empiric ITP therapy, spleen-directed therapy, or transjugular intrahepatic portosystemic shunt placement.

Severe congenital neutropenias (SCNs) are rare diseases, and to date about 30 subtypes have been described according to their genetic causes. Standard care aims to prevent infections and limit the risk of leukemic transformation; however, several subtypes may have additional organ dysfunction(s), requiring specialized care. Granulocyte colony-stimulating factor and hematopoietic stem cell transplantation are now the bedrock of standard care. Better understanding of SCN mechanisms now offers the possibility of adapted therapy for some entities. An inhibitor of sodium glucose cotransporter, an antidiabetic drug, may attenuate glycogen storage disease type Ib and glucose-6-phosphatase catalytic subunit 3 neutropenias by clearing 1,5-anhydroglucitol, the precursor of the phosphate ester responsible for these SCNs. Chemokine receptor CXCR4 inhibitors contribute to reversing the leukocyte defect in warts, hypoglobulinemia, infections, and myelokathexis syndrome. All these new approaches use oral drugs, which notably improve quality of life. Additionally, improved research into clonal evolution has highlighted some ways to potentially prevent leukemia, such as stimulating somatic genetic rescue, a physiological process that might limit the risk of leukemic transformation.

Long-term survivors of pediatric hematologic malignancies are at elevated risk for neurocognitive impairment. Such impairment manifests in different ways at different times during survivorship, with deficits in processing speed, attention, and memory often appearing before deficits in executive function, intelligence, and academics. Survivors exposed to therapies that directly target the central nervous system (CNS), as is the case in acute lymphoblastic leukemia, may demonstrate subtle deficits during frontline therapy, and these deficits may grow and evolve over time. Survivors who do not receive CNS-directed therapies (eg, Hodgkin lymphoma) are also at elevated risk for neurocognitive impairment, although the influence on brain function is indirect through cancer therapy impact on systemic organ function vital to brain health (eg, cardiopulmonary morbidity). Over the course of the survivor's life span, the presence and impact of neurocognitive deficits will be determined by a complex interaction between premorbid development and environment, cancer therapy and clinical care, and posttreatment recovery and health. The timing and type of these treatment and health events will dictate the approach to screening and monitoring for neurocognitive impairment.

Allogeneic stem cell transplantation plays a central role in the management of fit adults with high-risk acute myeloid leukemia (AML) in first complete morphologic remission (CR1). Advances in both donor selection and transplant technology have both dramatically increased accessibility of transplant and led to significant reductions in transplant-related mortality over the past 2 decades. There has, however, been no concomitant reduction in the risk of disease relapse, which remains the major cause of transplant failure. Pivotal to the design of innovative strategies with the potential to reduce relapse risk is accurate identification of patients at the highest risk of disease recurrence. Multiple retrospective studies have identified an increased risk of disease relapse in patients allografted for AML in CR1 with evidence of pretransplant measurable residual disease (MRD). The prognostic significance of pretransplant MRD has been confirmed recently in prospective analyses. The optimal management of patients with evidence of pretransplant MRD remains a matter of conjecture with regard to 2 key issues. First, should the presence of pretransplant MRD delay a decision to proceed to transplant, allowing time for delivery of additional MRD-directed therapy prior to transplant? Second, to what extent can the intensity of the conditioning regimen or the magnitude of the graft-vs-leukemia effect be manipulated to improve the outcome of such patients?

Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders with clinical manifestations ranging from fatigue to life-threatening endomyocardial fibrosis and thromboembolic events. Given the broad differential diagnosis of HES, a comprehensive approach is needed to identify potential secondary (treatable) causes and define end-organ manifestations. Classification by clinical HES subtype is also useful in terms of assessing prognosis and guiding therapy. Corticosteroids remain the mainstay of initial therapy in the setting of acute, life-threatening PDGFR mutation-negative HES. Whereas the recent availability of eosinophil-targeted therapies with extraordinary efficacy and little apparent toxicity is changing the treatment paradigm, especially for idiopathic HES and overlap syndromes, questions remain unanswered regarding the choice of agent, impact of combination therapies, and long-term effects of eosinophil depletion. This review provides a case-based discussion of the differential diagnosis of HES, including the classification by clinical HES subtype. Treatment options are reviewed, including novel eosinophil-targeted agents recently approved for the treatment of HES and/or other eosinophil-associated disorders. Primary (myeloid) disorders associated with hypereosinophilia are not be addressed in depth in this review.

There are clinical issues of special importance and practice variation in the management of venous thromboembolism (VTE) and in the use of anticoagulants among hematologists who practice in Asia. In Asian-inherited thrombophilia, coagulation is disturbed due to loss-of-function mutations of protein S and protein C causing protein S and protein C deficiencies, whereas the gain-of-function factor V Leiden and prothrombin G20210A mutations are almost absent. Thrombophilia screening is not recommended in patients with VTE patients who have major provoking factors. However, it can be considered in unprovoked young patients with VTE who have a strong family history of VTE. Cancer is the most important acquired risk factor for VTE in Asians. Limited cancer screening at the initial presentation of unprovoked VTE is appropriate, especially in the elderly. Direct oral anticoagulants have been shown to have similar efficacy and reduce risk of major bleeding, including intracranial hemorrhage and bleeding requiring hospitalization, compared with warfarin. Most clinical trials evaluating therapies for treatment and prevention of VTE have included small numbers of Asian patients. Despite this lack of evidence, direct oral anticoagulants have been increasingly used in Asia for cancer-associated thrombosis. Individualized assessment of thrombotic and bleeding risks should be used for all hospitalized Asian patients when deciding on pharmacologic thromboprophylaxis. More research is needed to understand the factors that contribute to risks of VTE and anticoagulant-associated bleeding in Asian patients as these may differ from Western populations.

Myelodysplastic syndromes (MDS) are typically a hematologic malignancy of older adults characterized by dysplastic hematopoiesis, cytopenia(s), and risk of acute myeloid leukemia transformation. The treatment approach to MDS depends largely on risk stratification of an individual's disease, most commonly using the Revised International Prognostic Scoring System, which takes into account peripheral blood cytopenias and bone marrow blast percentage and cytogenetics. The current standard of care for patients with higher-risk MDS (HR-MDS) includes hypomethylating agents (HMAs), decitabine and azacitidine, and allogenic stem cell transplant for patients able to undergo this therapy. However, leukemic transformation remains a significant challenge, and outcomes with these current therapies are still dismal. There are several novel therapies in development aiming to improve upon the outcomes of single-agent HMA therapy using combination strategies with HMAs. Here we discuss the current standard of care for HR-MDS treatment and explore some of the most promising combination therapies coming out of the pipeline for HR-MDS.

Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.