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

Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematologic malignancy. With treatment advances, patients are living longer. However, the disease remains incurable. MM patients are started on a combination of antineoplastic agents with the aim of achieving disease remission. However, at some point patients will experience a relapse requiring another type of therapy. The attrition rate is high, and the periods of remission with each line of therapy become shorter as MM becomes biologically more complex and refractory to treatment. In other words, the initial induction strategy could have a significant impact on the patient's disease trajectory because this will likely be the best and most durable response for the patient. The upfront regimen for a new MM patient is determined based on disease-specific factors such as biology (cytogenetics, circulating plasma cells, extramedullary disease) as well as patient-related factors such as performance status, organ impairment, comorbidities, and fitness status. For patients considered fit, the treatment goal is to achieve maximum therapeutic efficacy to obtain the best disease response. The definition of fitness varies for each trial, and it is a subjective assessment by the provider. It does not necessarily correlate with whether a patient is considered transplant eligible. Patients may choose to defer transplant or may not be offered a transplant based on age cutoff geographically despite being fit. These patients are included in studies for transplant-ineligible patients. In this review, we evaluate the best induction regimen for MM patients fit for treatment.

POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a complex paraneoplastic syndrome related to a lambda-restricted low-tumor burden neoplasm. The diagnosis must be considered in the context of what might otherwise be believed to be a "monoclonal gammopathy of undetermined significance," with unusual features including, but not limited to, peripheral neuropathy, thrombocytosis, and extracellular volume overload. Once a diagnosis of POEMS syndrome is made, besides very specific supportive care, the treatments resemble those of multiple myeloma or solitary plasmacytoma of the bone. Based on case series, autologous stem cell transplant is still a favored therapy with durable remissions even without maintenance therapy. Even before the era of therapeutic monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor antibodies, 10-year overall survival approached 80%. Patients achieving a complete hematologic response have a progression-free survival of 88% even without maintenance therapy. Herein, a case of a patient with a less-than-average outcome is described to highlight some of the long-term challenges and complexities of managing patients with POEMS syndrome.

Treatment algorithms for severe aplastic anemia (SAA) are evolving. A hematopoietic cell transplant (HCT) from a matched sibling donor is preferred for younger patients with SAA, whereas immunosuppressive treatment (IST) has traditionally been recommended for older patients. Because of the toxicity and risk associated with HCTs from alternative donors (ie, matched unrelated donors, haploidentical donors, or umbilical cord blood units), this approach has generally been reserved for patients who have experienced relapse after IST or have proved refractory to it. However, the recent development of reduced-toxicity conditioning regimens and the use of posttransplant cyclophosphamide as prophylaxis for graft-versus-host disease have significantly reduced the risk of morbidity and mortality after HCT. These changes have also expanded the pool of donors such that alternative donors are now increasingly being used for HCTs for patients with SAA. With the use of these novel HCT regimens and improved supportive care practices, overall survival and disease-free survival after HCT have improved over the last few decades, and disease-free survival after HCT may now be superior to that after IST. Several ongoing clinical trials are evaluating the use of matched unrelated donors and have expanded the use of haploidentical donors in the up-front setting for treatment-naive patients, thereby challenging the equipoise that has existed in this field for decades. These advances may usher in a paradigm shift in the management of SAA in the coming years.

Plasmablastic lymphoma (PBL) is a rare and aggressive, usually CD20-negative, B-cell lymphoma with features between multiple myeloma and diffuse large B-cell lymphoma. Approximately 120 new cases are diagnosed annually in the United States, and there is a strong association with HIV infection and other immunosuppressive states. It affects mostly adult males, though PBL has been diagnosed in children and immunocompetent individuals. Epstein-Barr virus infection, MYC gene rearrangements, and other mechanisms appear to play a role in PBL lymphomagenesis. Given its rarity, PBL poses distinct diagnostic and therapeutic challenges. A timely diagnosis is essential and requires a high clinical suspicion and a thorough pathological evaluation. The clinical course is aggressive, with a high relapse rate and poor survival with standard therapies. More recently, better outcomes have been observed in patients with early-stage disease treated with combination chemotherapy followed by consolidative radiotherapy. Additionally, advanced disease outcomes may improve with the use of targeted agents, such as proteasome inhibitors and anti-CD38 monoclonal antibodies, when added to combination chemotherapy. Participation in clinical trials and multi-institutional collaboration will be essential to continue improving patient outcomes with PBL.

Hemophagocytic lymphohistiocytosis (HLH) and the related HLH-spectrum disorders macrophage activation syndrome, macrophage activation-like syndrome, and treatment-associated immune-effector-cell-associated HLH-like syndrome are extreme forms of too much inflammation (TMI). Adult patients with HLH associated with hematologic malignancies have a 70% to 80% mortality rate due to delayed diagnosis, prolonged immunosuppression with associated secondary infections, and disease recurrence. In recent years, educational efforts and epidemiological evolution have increased diagnostic awareness. This has been catalyzed by the COVID-19 pandemic, the first approved anti-interferon gamma antibody for primary relapsed/refractory HLH, advancements in the treatment of posttransplant graft-versus-host disease, and the broad availability of T-cell-engaging therapeutics. These truly challenging-to-diagnose entities under the cytokine storm umbrella confer TMI, causing multiorgan dysfunction and early death. Novel prognostic models, differential diagnosis with the help of advanced diagnostic algorithms, preemptive therapeutic interventions, and more individualized cytokine-directed treatment options have moved this previously neglected area in adult hematology to the forefront of the hematologist's daily practice.

T-cell engaging immunotherapies have transformed the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). First revolutionizing outcomes for relapsed and refractory disease, these therapies are now being incorporated and studied in the frontline setting. With the US Food and Drug Administration (FDA) approval of the CD19-directed bispecific T-cell engager (BiTE) blinatumomab for remission consolidation, the majority of patients with B-ALL receive blinatumomab in frontline therapy. Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is FDA approved for pediatric patients with B-ALL that is refractory or in second or greater relapse. With the same target, similar mechanisms of action, and some overlap in indications, the optimal placement and sequence of these immunotherapies remain unclear. Here we review the recent data and expanded use of blinatumomab and CAR T-cell therapy and discuss the role of CAR T-cell therapy in the current pediatric B-ALL treatment landscape, including in populations with relapsed/refractory disease and at very high risk of relapse.

Increasing use of clinical diagnostic genomic assays over the past 2 decades has enabled us to expand our understanding of the clinical spectrum of known diseases, as well as the genetic landscape and paradigms surrounding diverse clinical phenotypes. Taken together, this has provided significant insight into the pathobiology and genetic mechanisms driving human disease, ushering in a new era of molecular medicine. This review aims to help hematology providers understand how to conceptualize and strategize the appropriate use and interpretation of genomics tools in the context of other available forms of information and the evolving genetic concepts and paradigms relevant to their field.

Patients with acute myeloid leukemia (AML) often undergo allogeneic hematopoietic cell transplantation (HCT) as it represents a highly effective treatment to prevent relapse of their disease. While HCT is an important part of curative therapy for many AML patients, post-HCT relapse still occurs, and so post-HCT maintenance therapy is offered to some patients-often without any reliable evidence supporting its use. More and more molecularly targeted drugs are emerging in the field, and while there is randomized data supporting the use of FLT3 inhibitors in this setting, no other drug class has been convincingly shown to benefit these patients (yet). In acknowledgment of the fact that clinicians will continue to offer post-HCT maintenance in the hope of improving outcomes, this review focuses on the data (or lack thereof) directly supporting this practice, as well as some of the pitfalls that can be encountered with these drugs when used as maintenance.

Diagnosis of von Willebrand disease (VWD) is a challenge due to variability in laboratory assays, variability in patient von Willebrand factor (VWF) levels, and variability in the different types of VWD. Because of these challenges, it can be difficult to make the diagnosis, especially in young children. On the other hand, older individuals may carry a diagnosis of VWD and not truly have VWD, creating the necessity for thoughtful evaluation of patients for whom "undiagnosing" VWD is appropriate. The most important factor is clinical bleeding history, although repeated laboratory testing and individual considerations are also critical. More research is needed on aging and VWF to best understand this challenge.

Congenital thrombotic thrombocytopenic purpura (cTTP) arises from an inherited deficiency of ADAMTS13, causing a thrombotic microangiopathy with multisystemic sequelae. Acute cTTP relapse can cause arteriovascular thrombosis, and registry data suggest that later diagnosis and commencement of treatment are associated with increased morbidity. Undiagnosed or "nonovert" cTTP may also be associated with end-organ damage. Treatment is based on ADAMTS13 replacement, previously limited to plasma and factor VIII concentrates and now expanded to recombinant ADAMTS13, which can achieve higher peak and trough levels with smaller volumes. Now that treatment options are improved, we need to focus on prophylaxis and the clinical impact of this lifelong condition. Beyond treatment of acute TTP relapses, symptoms such as headaches, abdominal pain, and lethargy without overt laboratory relapse may reflect subacute TTP and herald later end-organ damage. We need further longitudinal data on how to optimize care. Key questions remain about prophylaxis and how to target optimal control of this condition through the alliance of improved treatment delivery and measures of clinical outcome.