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

Allogeneic hematopoietic cell transplantation, gene therapy, and gene editing offer a potential cure for sickle cell disease (SCD). Unfortunately, myelodysplastic syndrome and acute myeloid leukemia development have been higher than expected after graft rejection following nonmyeloablative conditioning and lentivirus-based gene therapy employing myeloablative busulfan for SCD. Somatic mutations discovered in 2 of 76 patients who rejected their grafts were identified at baseline at much lower levels. While a whole-genome sequencing analysis reported no difference between patients with SCD and controls, a study including whole-exome sequencing revealed a higher prevalence of clonal hematopoiesis in individuals with SCD compared with controls. Genetic risk factors for myeloid malignancy development after curative therapy for SCD are currently being explored. Once discovered, decisions could be made about whether gene therapy may be feasible vs allogeneic hematopoietic cell transplant, which results in full donor chimerism. In the meantime, care should be taken to perform a benefit/risk assessment to help patients identify the best curative approach for them. Long-term follow-up is necessary to monitor for myeloid malignancies and other adverse effects of curative therapies for SCD.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States and Western Europe. Overall outcomes for patients with FL have continued to improve over the last several decades-most notably, with the addition of the CD20 monoclonal antibody rituximab to the treatment armamentarium. More recently, we have seen advances in the management of patients with relapsed/refractory FL with the approval of several new treatments including lenalidomide, axicabtagene ciloleucel, copanlisib, umbralisib, and tazemetostat. Unfortunately, there remains a group of patients for which treatment outcomes, especially overall survival (OS), are suboptimal. This group has been identified as patients who relapse within 24 months (POD24) of completion of chemoimmunotherapy (CIT). Data indicate that patients who relapse within this window have a 5-year OS of around 50%, compared to 80% for those who remain in remission beyond 24 months. POD24 patients have been included and evaluated in the studies of the novel agents mentioned. While not specifically designed to treat this high-risk group, early data suggest that outcomes are not significantly impacted by this designation, unlike CIT. While to date the optimal management of POD24 patients has not been elucidated, the future appears bright with the continued use of the approved agents and several others in clinical development.

Direct oral anticoagulants (DOACs) are commonly used oral factor Xa inhibitors in recent years. However, in some special clinical situations, the appropriate use of these anticoagulants may be of concern. In this article, we address the 5 commonly asked questions regarding their use for the treatment of venous thromboembolism, including in the setting of obesity, renal impairment, gastrointestinal (GI) malignancy, catheter-related thrombosis, and drug-drug interactions. Data on the use of DOACs in the presence of significant obesity or renal failure are mainly observational. Some DOACs are shown to have an increased risk of bleeding in patients with unresected luminal GI malignancy but not others, so selection of appropriate patients is the key. Furthermore, literature on the use of DOACs for catheter-related thrombosis or when drug-drug interactions are of concern is limited, and more research is welcome.

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by morphologic dysplasia, persistent cytopenia, and a variable risk of evolution to acute myeloid leukemia (AML). Risk stratification is crucial in a patient-centered approach to the treatment of MDS. Based on hematologic parameters and cytogenetic abnormalities, the Revised International Prognostic Scoring System is currently used for this purpose. In the past years, the use of massively parallel DNA sequencing has clarified the genetic basis of MDS and has enabled development of novel diagnostic and prognostic approaches. When conventional cytogenetics is combined with gene sequencing, more than 90% of patients are found to carry a somatic genetic lesion. In addition, a portion of patients has germline variants that predispose them to myeloid neoplasms. The recently developed International Consensus Classification of MDS includes new entities that are molecularly defined-namely, SF3B1-mutant and TP53-mutant MDS. The International Working Group for Prognosis in MDS has just developed the International Prognostic Scoring System-Molecular (IPSS-M) for MDS, which considers hematologic parameters, cytogenetic abnormalities, and somatic gene mutations. The IPSS-M score is personalized and can be obtained using a web-based calculator that returns not only the individual score but also the expected leukemia-free survival, overall survival, and risk of AML transformation. Providing an efficient risk stratification of patients with MDS, the IPSS-M represents a valuable tool for individual risk assessment and treatment decisions.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma that has traditionally been considered a subgroup of Hodgkin lymphoma. However, morphology, surface marker expression, genetics, and clinical course are different from classic Hodgkin lymphoma. While most patients experience indolent disease with slow progression, some patients can also have more aggressive disease. Nevertheless, outcomes are excellent, and excess mortality due to NLPHL is at most very low. The treatment of newly diagnosed NLPHL has historically mirrored that of classic Hodgkin lymphoma. However, evidence for deviations from that approach has emerged over time and is discussed herein. Less evidence is available for the optimal management of relapsed patients. So-called variant histology has recently emerged as a biological risk factor, providing at least a partial explanation for the observed heterogeneity of NLPHL. Considering variant histology together with other risk factors and careful observation of the clinical course of the disease in each patient can help to assess individual disease aggressiveness. Also important in this mostly indolent disease are the preferences of the patient and host factors, such as individual susceptibility to specific treatment side effects. Considering all this together can guide individualized treatment recommendations, which are paramount in this rare disease.

The incorporation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy significantly improved the outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). This was first shown with the addition of the first-generation TKI imatinib, which allowed more patients to be bridged to an allogeneic stem cell transplant (SCT) and led to superior long-term outcomes compared with chemotherapy alone. The use of second-generation TKIs (eg, dasatinib and nilotinib) has led to further improvement in outcomes of patients with Ph- positive ALL, with a long-term survival of 40% to 60% in several studies. Ponatinib is a third-generation, more potent TKI that results in high rates of molecular response and promising long-term survival even when allogeneic SCT is not routinely performed. While randomized data to support the TKI selection in Ph-positive ALL are lacking, data from single-arm studies suggest deeper molecular responses and superior survival outcomes with each successive generation of TKI. More recently, chemotherapy-free regimens with blinatumomab and TKIs have shown excellent results in the frontline setting and may represent an emerging paradigm shift in the treatment of Ph-positive ALL.

The choice of treatment for patients with multiple myeloma (MM) at first relapse/progression is based on many factors: (1) treatment-related factors, which include the regimen used during first induction, the quality and duration of first response achieved, toxicities from the first treatment, whether the patient underwent autologous stem cell transplant, and whether the patient was on maintenance at the time of relapse/progression; (2) disease-related factors, including disease presentation and pace of progression; and (3) patient-related factors, including functional age and performance status. The learning objectives are to present the treatment options for patients with MM upon their first relapse and to learn about various strategies for selecting an optimal treatment regimen.

The multifaceted pathophysiologic processes that comprise thrombosis and thromboembolic diseases take on a particular urgency in the hospitalized setting. In this review, we explore 3 cases of thrombosis from the inpatient wards: purpura fulminans, cancer-associated thrombosis with thrombocytopenia, and coronavirus disease 2019 (COVID-19) and the use of dose-escalated anticoagulation therapy and antiplatelet agents. We discuss the evaluation and management of purpura fulminans and the roles of plasma transfusion, protein C and antithrombin replacement, and anticoagulation in treating this disease. We present a framework for evaluating the etiologies of thrombocytopenia in cancer and review 2 strategies for anticoagulation management in patients with cancer-associated thrombosis and thrombocytopenia, including recent prospective data supporting the use of dose-modified anticoagulation based on platelet count. Last, we dissect the major clinical trials of therapeutic- and intermediate-dose anticoagulation and antiplatelet therapy in hospitalized patients with COVID-19, reviewing key recommendations from consensus guidelines while highlighting ways in which institutional and patient-tailored practices regarding antithrombotic therapies in COVID-19 may differ. Together, the cases highlight the diverse and dramatic presentations of macro- and microvascular thrombosis as encountered on the inpatient wards.

Since the introduction of tyrosine kinase inhibitors (TKIs) at the beginning of the millennium, the outlook for patients with chronic myeloid leukemia (CML) has improved remarkably. As such, the question of life expectancy and survival has become less problematic while quality of life and family planning have become more so. While TKIs are the cornerstone of CML management, their teratogenicity renders them contraindicated during pregnancy. In recent years, patients who satisfy standardized criteria can stop TKI therapy altogether, and indeed, in eligible patients who wish to become pregnant, these objectives overlap. However, not all patients satisfy these criteria. Some pregnancies are unplanned, and a number of patients are pregnant when diagnosed with CML. In these patients the way forward is less clear, and there remains a paucity of good evidence available to guide treatment. In this article, we summarize the relevant literature and provide a framework for clinicians faced with the challenge of managing CML and pregnancy.

Mast cell disorders include mastocytosis and mast cell activation syndromes. Mastocytosis is a rare clonal disorder of the mast cell, driven by KIT D816V mutation in most cases. Mastocytosis is diagnosed and classified according to World Health Organization criteria. Mast cell activation syndromes encompass a diverse group of disorders and may have clonal or nonclonal etiologies. Hematologists may be consulted to assist in the diagnostic workup and/or management of mast cell disorders. A consult to the hematologist for mast cell disorders may provoke anxiety due to the rare nature of these diseases and the management of nonhematologic mast cell activation symptoms. This article presents recommendations on how to approach the diagnosis and management of patients referred for common clinical scenarios.