Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with both malignant and nonmalignant disorders. To select the optimal donor for allogeneic hematopoietic cell transplantation, the first step is to search for a matched sibling donor or a matched unrelated donor, both of which yield comparable outcomes in the current clinical landscape. Additional donor options include haploidentical donors, mismatched unrelated donors, and umbilical cord blood donors. Newer transplant approaches have refined the use of these donor sources to improve outcomes. Beyond human leukocyte antigen compatibility, several non-human leukocyte antigen factors influence optimal donor selection. These include donor age, the presence of donor-specific antibodies, cytomegalovirus status, and ABO blood type compatibility. Various graft engineering strategies have been developed. These include posttransplant cyclophosphamide, T-cell depletion techniques such as CD34+ selection, CD45RA depletion, and αβ T-cell depletion, T regulatory purification, and umbilical cord blood expansion. Optimizing the cell dose used in transplantation is also critical to improving outcomes. All of these strategies combined allow nearly every patient to find a donor with continued improvements in outcomes.

Combined hypomethylating agent (HMA) plus venetoclax (Ven) therapy enables most older patients with acute myeloid leukemia (AML) to achieve clinical remission. Key objectives are now aimed at developing new triplet combinations to circumvent mechanisms of resistance and extend remission longevity and, by extension, survival. Genomically agnostic approaches combine hypomethylating agents and venetoclax (HMA-Ven) with novel agents directed at oncogenic pathways critical for leukemic cell survival, proliferation, metabolism, or differentiation. Challenges faced in the development of new HMA-Ven triplets include competition from targeted inhibitors, biological heterogeneity of AML, potential for additive toxicity, reduced efficacy from modifications to the HMA-Ven backbone, and the higher bar for success in older AML beyond the current standard of care.

The treatment landscape for hemophilia has evolved rapidly over the past decade, with the approval of several therapies with novel mechanisms of action. Extended half-life factor concentrates and nonfactor therapies, including factor VIII mimetics and rebalancing agents, have reduced treatment burden while also improving bleed protection. Although these new therapies provide an unprecedented ability to personalize treatment and to meet changing needs across the life span for each individual, the complexity of these treatment considerations has made clinical decision-making and selection of the optimal treatment challenging for those living with hemophilia and their clinicians.

Monoclonal gammopathy of renal significance (MGRS) represents a clinical entity where clonal plasma or B-cell proliferative disorders secrete a monoclonal protein that leads to renal damage without meeting the diagnostic criteria for overt hematologic malignancies such as multiple myeloma or lymphoma. The diagnosis typically requires a kidney biopsy. MGRS subtypes are divided into 3 groups based on their pathologic findings: organized deposits, nonorganized deposits, and absence of immune deposits. Identifying the underlying clonal population of plasma cells or B cells is important to guide therapy. The standard of care for upfront treatment of light chain amyloidosis is daratumumab, cyclophosphamide, bortezomib, and dexamethasone. For other types of MGRS, the treatment depends on the underlying clone or the identified monoclonal protein. While light chain amyloidosis has validated response criteria, there are no uniform response criteria for other MGRS subtypes. Renal transplantation has been historically underutilized and represents a potentially transformative intervention in carefully selected patients who achieve good disease control using clone-directed therapy.

Sickle cell disease (SCD) remains the most common monogenic disorder worldwide, yet more than a century after its formal discovery, our treatment options and approach to care remain underdeveloped. Despite scientific progress, care for SCD continues to lag behind other chronic conditions, in part due to a lack of consensus on straightforward medical decision-making-driven by a persistent paucity of data and compounded by historical neglect, systemic inequities, and clinical heterogeneity. To truly serve this vulnerable population, we must move toward a more comprehensive, personalized approach to adult care-one that mirrors the individualized pain management plans routinely used in acute care settings. While much of the foundational work in SCD has been in pediatrics, this manuscript focuses on the adult population, where the burden of disease increases and access to specialized care declines. We emphasize the importance of considering genotype, hematologic profile, comorbid conditions, psychosocial context, and health literacy when developing treatment plans in shared decision-making with our patients. Ultimately, we hope this manuscript provides practical insights to help clinicians answer the daily complex questions surrounding sickle cell care: whom to treat and which interventions offer the most meaningful benefit for that particular patient.

The introduction of CAR (chimeric antigen receptor) T-cell therapy and bispecific antibodies into clinical practice has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM). Both modalities have shown impressive clinical efficacy with slightly different but overall manageable toxicity profiles. At present, two B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, are approved for standard use in the United States. There are currently 4 commercially approved bispecific antibodies: teclistamab, elranatamab, and linvoseltamab, which target BCMA, as well as talquetamab, which targets the GPRC5D antigen on the surface of plasma cells. In this review, we explore (a) the advantages and challenges of integrating CAR T-cell therapy earlier in the RRMM treatment course; (b) the safety and efficacy of bispecific antibodies and their evolving role in the current RRMM treatment paradigm; (c) practical considerations for both modalities, focusing on patient selection and supportive care strategies; and (d) recommendations for sequencing of T-cell redirecting therapies to maximize long-term outcomes.

Contemporary chemotherapy protocols have improved cure rates for children, adolescents, and young adults (CAYA) with T-lineage acute lymphoblastic leukemia (T-ALL) to greater than 80%. Unfortunately, outcomes for CAYA with relapsed and refractory disease, as well as older adults, remain poor. A key goal in the treatment of T-ALL therapy is preventing relapse; however, it is challenging to identify high-risk patients. Recently, several genomic initiatives have identified distinct biological subtypes of T-ALL and have correlated disease biology, including mutational status, transcriptional phenotype, and clonal drivers, with therapy response and outcome. The integration of genomic profiling into clinical diagnosis and treatment has promise to guide risk stratification, targeted therapy, and clinical trial design for high-risk patients. This review highlights the recently mapped genomic landscape of T-ALL, with particular emphasis on recently identified genomic molecular signatures, their utility in risk stratification, and targeted therapy selection for refractory cases.

The role of minimal residual disease (MRD) testing is well defined in curable hematological malignancies like acute lymphoblastic leukemia. However, in chronic lymphocytic leukemia (CLL), which is an incurable low-grade lymphoma, MRD is mostly investigational, especially in the relapsed setting. Newer techniques are trying to get to even deeper levels than before-for instance, 10-6 with sequencing. Here we describe the current techniques of MRD testing in CLL and explore the applications of these modalities in relapsed/refractory CLL in novel targeted therapies, cellular therapy, and other immunotherapies that can lead to deep and durable remissions, especially when used in combinations. More and more prospective interventional trials are now using MRD testing to inform decisions, and the data from these trials will further elucidate the best use of MRD testing in CLL patients. For now, MRD testing is not used for treatment decisions in the real world, although it can be done for monitoring in patients with high-risk genetics.

Rare B-cell malignancies pose a unique management challenge because of their rarity and aggressiveness. Given their low incidence, they require a high index of suspicion for diagnosis and necessitate specialized therapeutic approaches. Herein, we discuss 3 of those rare lymphomas: plasmablastic lymphoma, lymphomatoid granulomatosis, and intravascular lymphoma. Plasmablastic lymphoma is aggressive and often linked to immunosuppression, particularly in HIV- infected individuals. It is characterized by plasmablastic morphology lacking CD20 expression, extranodal disease, MYC rearrangement, and frequent Epstein-Barr virus infection. Recent advancements in treatment involve using novel agents like bortezomib, daratumumab, and B-cell maturation antigen-targeted therapy, which are improving outcomes; however, the prognosis for relapsed disease remains poor. Lymphomatoid granulomatosis is a rare, Epstein-Barr virus-driven B-cell disorder defined by angiocentric and angiodestructive infiltrates. It primarily affects the lungs but can also involve skin and the central nervous system, causing systemic symptoms. Treatment and prognosis vary by histologic grade; low-grade cases may be treated with immunomodulation, while high-grade cases generally require chemoimmunotherapy. Intravascular lymphoma involves malignant B cells proliferating in small blood vessels, leading to nonspecific clinical symptoms. Early diagnosis through tissue biopsy is crucial. The best remission chances come from rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy combined with central nervous system-directed treatment. New research is ongoing for relapsed cases.

Improved understanding of the molecular underpinnings of acute leukemia has led to advances in the detection of very low levels of leukemia-specific abnormalities, known as measurable residual disease (MRD). The limit of detection for modern next-generation sequencing and polymerase chain reaction-based assays is as low as 10-6, allowing for quantitative and longitudinal monitoring in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In the period surrounding allogeneic hematopoietic cell transplantation (HCT), detectable MRD is clearly associated with poor outcomes, primarily due to an increased risk of morphologic relapse. In this review, we address the use of maintenance therapy for patients with acute leukemia, including those who are MRD-positive prior to and following HCT. Post-HCT azacitidine may have a role for MRD-positive AML. In AML with FLT3-internal tandem duplication mutation, post-HCT gilteritinib and sorafenib can be evidence-based strategies to target MRD. In ALL, blinatumomab is a powerful tool to eradicate MRD in patients with Philadelphia (Ph)-positive or Ph-negative ALL; tyrosine kinase inhibitors are indicated for post-HCT management of Ph+ ALL. Despite these advances, the optimal duration and type of intervention still remain unknown for many patients with acute leukemia who have peri-HCT MRD.

Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia, a specific clonal B-cell disorder of the bone marrow, and a monoclonal gammopathy of clinical significance. Thus, CAD should be distinguished from cold agglutinin syndrome, a more heterogeneous cold hemolytic syndrome that occurs secondary to other clinical disease. Cold agglutinins in CAD are usually of the immunoglobulin M kappa class with a heavy chain variable region encoded by the IGHV4-34 gene segment. The hemolytic anemia is entirely mediated by classical complement activation, which also explains some additional clinical features, such as fatigue and acute exacerbations. Non-complement-mediated steps in pathogenesis are also essential, such as erythrocyte agglutination and, probably, coexistent cryoglobulin activity in some patients, resulting in cold-induced circulatory symptoms. Based on this heterogeneity, different clinical phenotypes can be defined and used to guide individualized treatment. Established therapies aim at targeting the pathogenic B-cell clone or the classical complement activation pathway. Novel and investigational therapies include Bruton's tyrosine kinase inhibitors, plasma cell-directed therapies, novel complement inhibitors, and entirely new approaches such as cytokine inhibitors and, possibly, antibodies specific for the VH4-34 protein sequence. Patients with CAD requiring therapy should be considered for clinical trials.

Hematologic malignancies are associated with an increased risk of venous thromboembolism (VTE) with aggressive lymphomas and multiple myeloma exhibiting the highest VTE incidence. The performance of VTE risk scores in hematologic malignancies remains suboptimal. Concomitant thrombocytopenia and coagulopathies complicate thrombosis prevention and management. This review synthesizes current evidence on anticoagulation in hematologic malignancies (excluding myeloproliferative neoplasms), outlines key clinical challenges, and proposes practical strategies to guide decision-making.

The treatment landscape of B-cell non-Hodgkin lymphoma (B-NHL) has been rapidly transformed by the emergence of T-cell engaging (TCE) therapies. Within the past decade, anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have moved from relapsed/refractory to second-line settings in aggressive large B-cell lymphomas and are now also approved for R/R follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia. More recently, bispecific antibodies with dual engagement of CD20 × CD3 have emerged as an alternative TCE option with regulatory approval as monotherapies in several relapsed/refractory B-cell lymphomas. Common investigational themes for TCE therapies include earlier integration in the treatment paradigm, testing combination approaches, and considering optimal sequencing approaches. Despite major progress, there remains opportunity for technical innovations that may improve efficacy, attenuate toxicity, and ease the sometimes complex logistics around treatment delivery. Alternative and multiantigen targets are being explored in CAR T-cell constructs as well as bispecific antibodies, with some of these approaches now in early-phase clinical trials. Strategies to improve CAR T manufacturing, optimize T-cell fitness, and design novel "armored" CAR T-cells designs are actively being tested in preclinical and early-phase clinical data. From a safety perspective, much progress has been made in reducing the burden of side effects and broadening access; however, barriers remain before TCE therapies can be widely available to all patients. This brief review addresses some of the latest strategies being tested to elevate TCE therapies as pillars of immunotherapy for B-NHL.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare but life-threatening disease caused by an autoantibody-mediated mechanism of deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Novel therapeutic principles have challenged the standard of care, consisting of therapeutic plasma exchange (TPE), glucocorticoids, and adjunct immunosuppressants. Anti-VWF therapy with caplacizumab has been shown to be effective in halting thrombotic microangiopathy earlier, preventing early relapses, and potentially lowering TTP-associated mortality. It has also opened avenues toward a more tailored treatment approach guided by ADAMTS13 activity levels and a treatment algorithm forgoing TPE. This article highlights the importance of an early diagnosis and early therapeutic interventions indiscriminate of the initial clinical presentation that ultimately enable a TPE-free treatment. Moreover, it discusses the approach to handling immunosuppression and anti-VWF therapy in cases with prolonged autoimmunity. Timely diagnosis and therapy are based on on-site ADAMTS13 testing and the immediate availability of anti-VWF therapy in an emergency situation while close monitoring of the clinical and laboratory response to anti-VWF-therapy informs the decision to forgo TPE. A novel standard of care comprising anti-VWF-therapy, glucocorticoids, and early immunosuppression with anti-CD20-agents with or without TPE in selected cases based on cases series and the MAYARI trial (NCT05468320) is currently being established.

Allogeneic hematopoietic stem-cell transplantation is a curative modality for hematologic malignancies, bone marrow failure syndromes, hemoglobinopathies, and other nonmalignant disorders. Graft-versus-host disease (GVHD)-in its acute or chronic form-is an important transplant complication. The effective prevention of GVHD is crucial to the success of allotransplantation. Acute GVHD is mediated by the recognition of recipient antigens by donor T lymphocytes, with the subsequent activation and proliferation of T cells and establishment of an inflammatory cytokine cascade. Chronic GVHD is mediated by T-cell, B-cell, and macrophage activation with eventual inflammation and fibrosis. Standard approaches for GVHD prevention have been calcineurin-inhibitor (CNI) based, while newer approaches have focused on adding in-vivo T-cell modulation to a CNI backbone with antimetabolites such as posttransplant cyclophosphamide (PTCy), checkpoint blocking agents such as abatacept, or mammalian target of rapamycin (mTOR) inhibition with sirolimus. Still other approaches focus on blocking T-cell trafficking to target organs via integrin blockade (vedolizumab), cytokine blockade (JAK inhibitors), and B-cell blockade for chronic GVHD prevention. The use of PTCy and abatacept have improved allotransplantation safety and efficacy with human leukocyte antigen (HLA)-mismatched as well as HLA-matched donors, thus expanding the donor pool greatly for patients of all ancestries, and ushering in a new era in transplantation where donors are available for almost every patient.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of complement dysregulation, predisposing patients to complications of intravascular hemolysis, thrombophilia, and marrow failure, with a high risk of mortality without treatment. Allogeneic stem cell transplantation is the only current cure but is typically reserved for marrow failure-predominant disease or when targeted therapies are not available. Terminal complement inhibition with eculizumab has significantly altered management and outcomes for patients with PNH, and the last several years have seen the development and approval of many new complement inhibitors with different molecular targets. Newer inhibitors may also provide options for extended time between doses, for self-administration, and for management of iatrogenic extravascular hemolysis, which can occur secondary to C5 inhibition. This essay reviews the various therapeutic options potentially available to PNH patients, the pros and cons of each treatment, considerations regarding the monitoring of side effects, and the possible complications, as well as breakthrough hemolysis and an approach to shared decision-making.

The options for frontline chronic lymphocytic leukemia (CLL) treatment continue to expand. Therapies include monotherapy with a Bruton's tyrosine kinase inhibitor (BTKi), doublet therapies such as venetoclax with intravenous obinutuzmab or an oral BTKi, and triplet therapy combining BTKi, venetoclax, and CD20 antibody. Treatment duration also is increasingly variable, from fixed duration to utilization of undetectable minimal residual disease (uMRD) to determine optimal treatment completion. Currently, the best option for an individual patient requires a multifaceted approach considering the individual's cytogenetics, comorbidities, and personal preferences, including time-limited therapy vs continuous treatment. In this article, we outline the current state of frontline CLL including ongoing questions and future directions.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with disparate outcomes. While about two-thirds of patients have historically been cured with standard frontline chemoimmunotherapy, those who relapse or are refractory have typically had poor outcomes. Early efforts to tailor treatment based on molecular subtypes categorized by gene expression profiling (germinal center-like and activated B-cell-like) or approximation by immunochemistry algorithms did not substantially impact therapy in DLBCL. Genomic profiling led to the discovery of up to 7 subtypes with shared genetic alterations. The LymphGen and DLBclass are classifiers that assign patients to these subtypes. A clinical trial is under design to specifically treat subtypes of DLBCL in the frontline setting with targeted therapies in combination with standard treatment. Importantly, some of the most efficacious therapeutic approaches in relapsed/refractory DLBCL (chimeric antigen-receptor T cells and bispecific antibodies) appear to work independently of molecular subtype, although these agents' effectiveness may be impacted by the tumor microenvironment. Bispecific antibodies are being studied in newly diagnosed patients in combination with standard chemoimmunotherapy regimens. While future treatment may incorporate drugs with novel mechanisms and/or immunotherapies in the frontline setting, targeting by molecular subtype continues to hold promise as our treatment regimens evolve. Potential strategies could include escalation with specific therapies when response is inadequate, de-escalation of chemotherapy with continuation or addition of targeted agents in those with early complete responses, and refined algorithms to select appropriate treatment in high-risk or relapsed/refractory disease.

Advances in the development of safe and effective treatments for hemophilia over the past century have significantly increased the life expectancy of persons with hemophilia (PwH). As a result, clinicians are now encountering age-related comorbidities that were previously uncommon in hemophilia care, including cardiovascular disease, malignancy, and renal disease. Managing this aging population of PwH requires addressing both the complications of hemophilia and the multifaceted effects of aging. Their care needs have become increasingly complex, requiring attention to broader aspects of health, such as liver and bone health, fall and fracture risk, and frailty. However, preventive care, including routine monitoring and treatment of these conditions, is a gap in the current care model for this population. Inadequate access to primary care physicians negatively impacts the management and prevention of chronic diseases in PwH, resulting in medical vulnerability. The focus of this review is to examine prevalent complications in the aging PwH. Case studies presented focus on identifying and reducing cardiovascular disease risk, weighing bleeding risk with stroke risk in the management of atrial fibrillation, and ensuring a multidisciplinary approach to address frailty, bone health, and orthopedic surgery in the aging PwH. As we enter a new era of therapeutics, hemophilia treatment centers will play an integral role in closing care gaps in helping PwH achieve optimal outcomes.

Combination therapies in acute myeloid leukemia (AML) are an area of current investigation due to the potential of overcoming resistance by targeting multiple pathways simultaneously. Triplet therapies combining hypomethylating agents, venetoclax, and targeted inhibitors are emerging as a promising therapy for older patients with AML unfit for intensive chemotherapy. These regimens have predominantly been studied in FLT3- and IDH1/2-mutated AML with attainment of high rates of measurable residual disease-negative composite remissions. Notably, patients with FLT3-internal tandem duplication and IDH1-mutated AML appear to garner a significant benefit from combination treatment due to poor duration of response to hypomethylating agents/venetoclax alone. While effective, the need to remain on indefinite therapy for individuals who are not stem cell transplant candidates and dose optimization/de-escalation strategies remain critical concerns. Herein, we aim to review the current treatment landscape of newly diagnosed and relapsed/refractory FLT3- and IDH1/2-mutated AML and the role of triplet regimens in these molecular subgroups.