bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventing relapse after CD19 CAR T-cell therapy for pediatric ALL: the role of transplant and enhanced CAR T cells
Authors: Talleur Aimee C. , Naik Swati , Gottschalk Stephen 
Published: December 2023

Abstract
CD19-specific chimeric antigen receptor (CAR) T-cell therapy has become an integral part of our treatment armamentarium for pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite initial remission rates of greater than 80%, durable remission occurs in only 40% to 50% of patients. In this review we summarize our current knowledge of the role of consolidative hematopoietic cell transplantation in the management of pediatric patients who achieved a minimal residual disease-negative complete response post CD19 CAR T-cell therapy. In addition, we review approaches to enhance effector function CD19 CAR T cells, focusing on how to improve persistence and prevent the emergence of CD19− B-ALL blasts.
The future paradigm of HMA + VEN or targeted inhibitor approaches: sequencing or triplet combinations in AML therapy
Authors: Venugopal Sangeetha , Watts Justin 
Published: December 2023

Abstract
The routine use of next-generation sequencing methods has underscored the genetic and clonal heterogeneity of acute myeloid leukemia (AML), subsequently ushering in an era of precision medicine–based targeted therapies exemplified by the small-molecule inhibitors of FLT3, IDH1/IDH2, and BCL2. This advent of targeted drugs in AML has broadened the spectrum of antileukemic therapies, and the approval of venetoclax in combination with a hypomethylating agent has been a welcome addition to our AML patients unable to tolerate intensive chemotherapy. Mounting evidence demonstrates that molecularly targeted agents combined with epigenetic therapies exhibit synergistic augmented leukemic cell kill compared to single-agent therapy. With such great power comes greater responsibility in determining the appropriate frontline AML treatment regimen in a molecularly defined subset and identifying safe and effective combination therapies with different mechanisms of action to outmaneuver primary and secondary resistance mechanisms in AML.
Management of aggressive lymphoma after CAR T-cell therapy failure
Authors: Nastoupil Loretta J. , Kambhampati Swetha 
Published: December 2023

Abstract
Several recent advances have affected the treatment landscape of diffuse large B-cell lymphoma. Chimeric antigen receptor (CAR) T-cell therapy has transformed the management of chemorefractory disease. Two randomized studies in early relapse disease have expanded the label to provide access to CAR T-cell therapy as early as second line for some patients. Despite the durable remissions that have been achieved, many patients will experience relapse. There is a growing population of patients previously treated with CAR T-cell therapy facing dismal outcomes. We review the prospective studies that inform treatment options in later lines and highlight the limited data examining outcomes with novel therapies after CAR T-cell failure. The treatment landscape is anticipated to continue to evolve with the emergence of bispecific antibodies that appear to be a promising approach, particularly after CAR T-cell therapy, although little is known about overlapping mechanisms of resistance. Enrichment for patients who have received prior CAR T-cell therapy on prospective trials is a critical unmet need to inform the preferred management for these high-risk patients.
Cytoreduction for ET and PV: who, what, when, and how?
Authors: Tremblay Douglas 
Published: December 2023

Abstract
Thrombotic complications are the primary contributor to morbidity and mortality in essential thrombocythemia (ET) and polycythemia vera (PV). Cytoreductive therapy is the main tool for primary or tertiary thrombosis prevention in these diseases. In general, high-thrombotic-risk patients and those with symptoms that may be ameliorated from cytoreductive therapy are candidates for this treatment, although the decision is highly individualized. Approved options for cytoreduction in ET and PV include hydroxyurea, long-acting interferons, anagrelide in ET, and ruxolitinib in PV. Selecting the ideal agent requires careful consideration of the toxicity profiles and individual treatment goals. In this review the existing literature on cytoreductive decisions in ET and PV is summarized, with an emphasis on risk-stratification, highlighting the need for personalized care in order to maximize the benefit of these therapies while minimizing toxicities.
Novel immunotherapies in the treatment of AML: is there hope?
Authors: Subklewe Marion , Bücklein Veit , Sallman David , Daver Naval 
Published: December 2023

Abstract
The success of allogeneic stem cell transplantation has demonstrated the potential for immunotherapy to treat acute myeloid leukemia (AML). Although alternative T-cell-based immunotherapies have shown efficacy, they also pose the risk of on-target off-leukemia hematotoxicity. So far, adoptive autologous or allogeneic chimeric antigen receptor (CAR) T/natural killer cell therapy is almost exclusively employed as a bridge-to-transplant strategy in the context of clinical trials. For now, clinical trials predominantly target lineage-restricted antigens, but emerging approaches focus on leukemia-associated/specific intracellular target antigens, including dual and split targeting strategies. Adapter CAR T cells and T-cell-recruiting bispecific antibodies offer transient exposure with enhanced safety and multitargeting potential against antigen-escape variants. However, these have yet to demonstrate sustained responses and should be used earlier to treat low leukemia burden, preferably if measurable residual disease is present. To address immune dysregulation and enhance T-cell fitness, novel CAR T and bispecific designs, along with combinatorial strategies, might prove essential. Furthermore, genetic associations with inflammatory bone marrow signatures suggest the need for tailored platforms in defined AML subtypes. The eagerly anticipated results of trials investigating magrolimab, an anti-CD47 antibody targeting the “do not eat me” signal in p53-mutated AML, should shed further light on the potential of these evolving immunotherapeutic approaches.
How old is too old? Frailty and geriatric assessments of older patients undergoing allogeneic HCT
Authors: Jayani Reena V. 
Published: December 2023

Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a curative-intent treatment for many hematologic malignancies but carries a significant risk of morbidity and mortality. An increasing number of older adults are receiving HCT, but current pretransplant evaluations overlook the unique vulnerabilities that older adults face. Oncology-specific geriatric and frailty assessments provide a comprehensive evaluation of older adults, help better weigh the risks of HCT with patients, and guide personalized optimization strategies to minimize vulnerabilities. Geriatric assessments evaluate seven domains: comorbidities, physical function, mental health, cognition, nutrition, medications, and social support. Frailty indices provide unique evaluations into a patient's overall status. Various standardized measures have been used to evaluate these areas in older adults prior to HCT. Different care models exist for the integration of geriatrics and geriatric principles into HCT evaluation: a multidisciplinary consultative clinic, a geriatrician alongside the HCT clinic, or a primary geriatric hematologist/transplant physician. Future studies are needed to investigate the use of geriatric assessments in selecting the conditioning regimen and intensity and measuring the impact of geriatric assessment–driven interventions on quality of life and toxicities post transplant.
Approaches to optimize outcomes in transplant recipients
Authors: Mishra Asmita 
Published: December 2023

Abstract
Curative therapy with an allogeneic hematopoietic cell transplant (HCT) can now be offered to a wider patient population due to improvements in donor selection, transplant conditioning regimens, and supportive care measures. However, risk of transplant-related morbidity and mortality remains, and thus appropriate transplant candidate workup pre-HCT for risk stratification and a management plan after HCT is crucial for success of the procedure. These include understanding and identifying risk of underlying malignant disease relapse, graft-versus-host disease, and infectious complications a patient may be predisposed toward, irrespective of allogeneic donor type. Progress in these domains with new therapeutic paradigms allows for development of a treatment plan prior to HCT to mitigate these potential risks tailored to the patient's case. Herein, we present case studies to focus on factors that influence decision-making in HCT and the approaches and strategies used to optimize post-HCT outcomes based on the individual HCT recipient's clinical scenario to improve on these high-risk scenarios.
Inflamed—HLH, MAS, or something else?
Authors: Kumar Ashish , Cournoyer Eily , Naymagon Leonard 
Published: December 2023

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive and maladaptive inflammation. Primary HLH is most frequently encountered in young children, and, without timely recognition and therapy, can lead to multiorgan failure and death. It is most often diagnosed using the HLH-2004 criteria and by identifying pathological mutations. However, the HLH-2004 criteria are not specific for HLH, and patients can easily fulfill these diagnostic criteria in other proinflammatory states in which HLH-therapy would not be indicated, including hematologic malignancies, infections, and rheumatologic disease. Therefore, great care must be taken to ensure that the specific disease associated with features of HLH is accurately recognized, as consequences of improper treatment can be catastrophic. We propose a diagnostic pathway for patients for whom HLH is on the differential (visual abstract). Importantly, in situations in which the initial diagnostic workup is equivocal or unrevealing, reevaluation for occult malignancy, infection, or rheumatologic disease would be prudent, as occult presentations may be missed on primary evaluation. Temporizing medications can be used in critically ill patients while awaiting secondary evaluation. By using this framework, clinicians will be able to more reliably discern primary HLH from other pro-inflammatory states and thus provide timely, appropriate disease-specific therapy.
Pyruvate kinase activators: targeting red cell metabolism in thalassemia
Authors: Kuo Kevin H.M. 
Published: December 2023

Abstract
Thalassemia is an inherited red blood cell disorder whereby the qualitative and/or quantitative imbalance in α- to β-globin ratio results in hemolysis and ineffective erythropoiesis. Oxidative stress, from the precipitated excess globin and free iron, is a major factor that drives hemolysis and ineffective erythropoiesis. Pyruvate kinase activity and adenosine triphosphate availability are reduced due to the overwhelmed cellular antioxidant system from the excessive oxidative stress. Mitapivat, a pyruvate kinase activator in development as a treatment for thalassemia, was shown to increase hemoglobin and reduce hemolysis in a small phase 2 single-arm trial of patients with α- and β-thalassemia. The ongoing phase 3 studies with mitapivat and the phase 2 study with etavopivat will examine the role of pyruvate kinase activators as disease modifying agents in thalassemia.
Minimal intensity conditioning strategies for bone marrow failure: is it time for “preventative” transplants?
Authors: Agarwal Suneet 
Published: December 2023

Abstract
Hematopoietic cell transplantation (HCT) can cure blood dyscrasias and reduce the risk of hematologic cancers in patients with inherited bone marrow failure syndromes (IBMFS). However, because of its high mortality rate, HCT is generally reserved until patients with IBMFS manifest life-threatening cytopenias or myeloid malignancy, at which point outcomes are poor. Screening tests that accurately predict transformation and enable timely intervention are lacking. These unknowns and risks limit the use of HCT in patients with IBMFS, sometimes until significant disease-related sequelae have occurred. A major goal for IBMFS is to reduce cellular therapy–related complications to the point that earlier intervention can be considered before significant transfusion exposure, occurrence of comorbidities, or malignant transformation. In recent decades, disease-specific allogeneic HCT trials have yielded significant improvements in outcomes in IBMFS conditions, including Fanconi anemia and dyskeratosis congenita. This is in large part due to marked reductions in conditioning intensity to address the increased sensitivity of these patients to cytotoxic chemotherapy and radiation. The success of these approaches may also indicate an ability to leverage intrinsic fitness defects of hematopoietic stem and progenitor cells across IBMFS disorders. Now with advances in tracking somatic genetic evolution in hematopoiesis and tailored minimal intensity conditioning regimens, this question arises: is it time for preventative HCT for IBMFS?
How to avoid early mortality in acute promyelocytic leukemia
Authors: Odetola Oluwatobi , Tallman Martin S. 
Published: December 2023

Abstract
Acute promyelocytic leukemia (APL), a phenotypically and genotypically unique subtype of acute myeloid leukemia, has seen unprecedented advances in its management since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide. However, the phenomenal pharmacologic conversion of this once highly fatal disease to one with a long-term survival exceeding 90% among patients who survive induction remains impaired by the significant incidence of early death (ED) reaching 30% in some real-world studies. The key driver for ED in APL is catastrophic hemorrhage with a proclivity for cranial sites. Most EDs in APL are currently considered preventable. Here, we discuss the concept of early death in APL and its characteristics. Importantly, we outline implementable strategies to reduce the incidence of ED. Early recognition of APL underpins these preventive measures as significant delays in the diagnosis increase the likelihood of ED. While early administration of ATRA is often taught to all hematology trainees, this lifesaving intervention is only possible if providers, including those in emergency departments and urgent/immediate care settings, are trained to have a high index of suspicion and competence to recognize the morphologic and clinical characteristics of the disease. Other proposed strategies tackle the complications that can be present at diagnosis or arise during induction therapy and address the issues of expert consultation and protocol adherence in the management of these patients. While some of these measures appear intuitive and others aspirational, widespread adoption could bring about an era of cure for almost every patient with APL.
How to assess hemostasis in patients with severe liver disease
Authors: Lisman Ton 
Published: December 2023

Abstract
Patients with advanced liver diseases frequently acquire profound alterations in their hemostatic system. Simultaneous changes in procoagulant and anticoagulant systems result in a reset in the hemostatic balance with a relatively neutral net effect, although there are notable hypocoagulable and hypercoagulable features in the hemostatic system in patients with liver disease. Laboratory and clinical studies have demonstrated that patients have a relatively well-preserved hemostatic system even though routine diagnostic tests of hemostasis (prothrombin time, platelet count) suggest a bleeding tendency. Routine diagnostic tests of hemostasis are unsuitable to assess the hemostatic status of patients with liver disease, as these tests are insensitive for the concurrent prohemostatic and antihemostatic changes in these patients. These tests are, however, frequently requested in patients with liver disease, as they are well established indicators of severity of liver disease. This paper will discuss commonly used diagnostic and research-type hemostatic tests and will outline how test results should be interpreted in patients with liver disease.
When to consider inherited marrow failure syndromes in adults
Authors: Gutierrez-Rodrigues Fernanda , Patel Bhavisha A. , Groarke Emma M. 
Published: December 2023

Abstract
The inherited bone marrow failure syndromes (IBMFS) are a heterogenous group of disorders caused by germline mutations in related genes and characterized by bone marrow failure (BMF), disease specific organ involvement, and, in most cases, predisposition to malignancy. Their distinction from immune marrow failure can often be challenging, particularly when presentations occur in adulthood or are atypical. A combination of functional (disease specific assays) and genetic testing is optimal in assessing all new BMF patients for an inherited etiology. However, genetic testing is costly and may not be available worldwide due to resource constraints; in such cases, clinical history, standard laboratory testing, and the use of algorithms can guide diagnosis. Interpretation of genetic results can be challenging and must reflect assessment of pathogenicity, inheritance pattern, clinical phenotype, and specimen type used. Due to the progressive use of genomics, new IBMFS continue to be identified, widening the spectrum of these disorders.
Provoked vs minimally provoked vs unprovoked VTE: does it matter?
Authors: Becattini Cecilia , Cimini Ludovica Anna 
Published: December 2023

Abstract
Venous thromboembolism (VTE) is a multifactorial disease, and its risk depends on exposure to risk factors and predisposing conditions. Based on their strength of association with a VTE episode, risk factors are classified as major or minor and determined using a temporal pattern to be transient or persistent. All patients with VTE should receive anticoagulant treatment for at least 3 months in the absence of an absolute contraindication. Beyond this period, selected patients may be candidates for an extended phase of anticoagulation aimed at secondary VTE prevention. The risk of recurrent VTE if anticoagulation is discontinued is probably the main driver of decision-making regarding extended treatment. The risk of recurrence after VTE associated with major risk factors is low if the risk factor is no longer present. In this case, treatment can be discontinued. If the major risk factor is persistent, anticoagulation should be continued. After VTE occurring in the absence of risk factors, anticoagulation should probably be continued indefinitely if the risk for bleeding is low and preferably with minimal effective doses of anticoagulants. VTE occurring after exposure to minor risk factors is probably the most challenging situation, especially if the clinical manifestation was acute pulmonary embolism. Understanding the actual role of minor risk factors in the occurrence of VTE helps in estimating the risk of recurrence and avoiding the dangers associated with unnecessary anticoagulation. The availability of safer strategies for anticoagulation could allow personalized strategies for secondary prevention of VTE.
Labor and delivery: DIC, HELLP, preeclampsia
Authors: Botero Juliana Perez , McIntosh Jennifer Jury 
Published: December 2023

Abstract
Hematologists are often needed to assist with the management of microangiopathic emergencies in pregnancy. A firm understanding of the diagnosis and management of preeclampsia with severe features, hemolysis elevated liver enzyme and low platelet syndrome, and disseminated intravascular coagulation, which are the most common causes of microangiopathic emergencies, is critical. However, being able to consider when other microangiopathic emergencies (acute fatty liver of pregnancy, congenital and acquired thrombotic thrombocytopenic purpura, complement mediated microangiopathy, antiphospholipid syndrome) should be considered is imperative. The hematologist and obstetric team should work together to optimize the care of common as well as rare hematologic emergencies.
Dual-targeted regimens for the frontline treatment of CLL
Authors: Ujjani Chaitra 
Published: December 2023

Abstract
The treatment landscape of chronic lymphocytic leukemia (CLL) has evolved considerably over the past decade due to the development of effective novel agents with varying mechanisms of action, including Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors. Extrapolating upon the success of anti-CD20–directed chemoimmunotherapy, a dual-targeted approach has been explored in treatment-naive patients with CLL. Anti-CD20 monoclonal antibody combinations with BTK inhibitors as well as BCL2 inhibitors have demonstrated superiority over traditional cytotoxic chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, and rituximab; bendamustine-rituximab; and obinutuzumab-chlorambucil. Impressive clinical benefit is seen in both younger and older patients, those with comorbidities, and, most importantly, those with poor prognostic features. Given this success, combinations of BTK inhibitors and venetoclax have been explored in clinical trials. These dual-targeted regimens provide remarkable efficacy while allowing for an all-oral approach and fixed duration of treatment. Current investigations under way are evaluating the utility of a triplet approach with the addition of obinutuzumab in comparison to a doublet approach.
Bispecific antibody therapies
Authors: de Assis Luiz Henrique , Fassi Daniel El , Hutchings Martin 
Published: December 2023

Abstract
Management of hematological malignancies is rapidly evolving from chemotherapy-based regimens toward targeted agents and immunotherapies, including bispecific antibodies (BsAbs). These novel and highly active treatments come with new side effect profiles. The hematological toxicities are common and potentially harmful, and the side effects have hitherto not been reviewed. With many BsAbs recently approved and entering routine clinical use, we have reviewed the rather limited published data and propose recommendations on the management of these toxicities. Our review of the available data confirms that hematological toxicities are among the most common toxicities, with potentially harmful consequences for the patients. Fortunately, hemophagocytic lymphohystiocytosis and disseminated intravascular coagulation are rare. Severe neutropenia and hypogammaglobulinemia are manageable, and their timely treatment and prevention may reduce morbidity and mortality.