This phase 2 trial assessed high-dose IV ascorbic acid in TET2 mutant clonal cytopenia. Eight of 10 patients were eligible for response assessment, with no responses at week 20 by International Working Group Myelodysplasia Syndromes/Neoplasms criteria. This trial was registered at www.clinicaltrials.gov as #NCT03418038.

Cure rates for patients with acute lymphoblastic leukemia (ALL) have improved markedly in recent decades, in part because of risk stratification incorporating leukemia genomics, response to treatment, and clinical features to be able to determine at diagnosis which patients are more likely to relapse or have refractory disease. Although risk stratification is well developed for patients with B-lineage ALL, it remains challenging for those with T-lineage ALL (T-ALL). Prognostic factors validated across clinical trials and real-world data in T-ALL include age, central nervous system involvement, and measurable residual disease (MRD) response. Immunophenotype, including early T-cell precursor ALL, is widely used to classify T-ALL but is not consistently associated with outcome in multivariable risk models. Historically, few genetic alterations have been consistently associated with outcome, but recent comprehensive, large-scale genomic profiling has identified multiple genetic subtypes and alterations associated with outcome independent of MRD. This review highlights ongoing efforts to identify reliable prognostic biomarkers and underscores the potential of genomics-based classification to guide future T-ALL treatment strategies.

The B-cell lymphoma 2 inhibitor venetoclax has shown promise for treating acute myeloid leukemia (AML). However, identifying patients likely to respond remains a challenge, especially for those with relapsed/refractory (R/R) disease. We evaluated the utility of ex vivo venetoclax sensitivity testing to predict treatment responses to venetoclax-azacitidine in a prospective, multicenter, phase 2 trial. The trial recruited 104 participants with previously untreated (n = 48), R/R (n = 39), or previously treated secondary AML (sAML) (n = 17). The primary end point was complete remission or complete remission with incomplete hematologic recovery (CR/CRi) rate in ex vivo sensitive trial participants during the first 3 therapy cycles. The key secondary end points included the correlations between ex vivo drug sensitivity, responses, and survival. Venetoclax sensitivity was successfully assessed in 102 of 104 participants, with results available within a median of 3 days from sampling. In previously untreated AML, ex vivo sensitivity corresponded to an 85% (34/40) CR/CRi rate, with a median overall survival (OS) of 28.7 months, compared with 5.5 months for ex vivo resistant patients (P = .002). For R/R/sAML, ex vivo sensitivity resulted in a 62% CR/CRi rate (21/34) and median OS of 9.7 vs 3.3 months for ex vivo resistant patients (P < .001). In univariate and multivariate analysis, ex vivo venetoclax sensitivity was the strongest predictor for a favorable treatment response and survival. This trial demonstrates the feasibility of integrating ex vivo drug testing into clinical practice to identify patients with AML, particularly in the R/R setting, who benefit from venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04267081.

Platelets play crucial roles in hemostasis, thrombosis, and immunity, but our understanding of their complex biogenesis (thrombopoiesis) is currently incomplete. Deeper insight into the mechanisms of platelet biogenesis inside and outside the body is fundamental for managing hematological disorders and for the development of novel cell-based therapies. In this article, we address the current understanding of in vivo thrombopoiesis, including mechanisms of platelet generation from megakaryocytes (proplatelet formation, cytoplasmic fragmentation, and membrane budding) and their physiological location. Progress has been made in replicating these processes in vitro for potential therapeutic application, notably in platelet transfusion and bioengineering of platelets for novel targeted therapies. The current platelet-generating systems and their limitations, particularly yield, scalability, and functionality, are discussed. Finally, we highlight the current controversies and challenges in the field that need to be addressed to achieve a full understanding of these processes, in vivo and in vitro.

Complement-mediated thrombotic microangiopathy (CM-TMA) or hemolytic uremic syndrome, previously identified as atypical hemolytic uremic syndrome, is a TMA characterized by germ line variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement "biosensors" by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-TMA and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies immunoglobulin M (IgM)-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ∼50% of patients with CM-TMA who lack an alternative pathway "driving" variant and suggests at least a subset of CM-TMA is characterized by a breakdown of IgM immunologic tolerance.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive, yet curable, malignancy, but older patients are at higher risk of relapsed disease because they may not be eligible for full-intensity frontline chemoimmunotherapy or have comorbidities that limit standard treatments. Recent years have brought more treatment options than ever for this patient population, but it remains challenging to determine which can be safely and effectively offered to older patients. Formal determinations of fitness including geriatric assessments remain critical, but there is less guidance on how to best use this tool in the relapsed setting. Chimeric antigen receptor T-cell therapy is accessible to older patients, provided they can be supported through the intensive road to this treatment. If relapse occurs despite this or alternative therapies are preferred, many novel therapeutic options and combinations exist with some potential modifications for older adults, such as bispecific antibodies, tafasitamab and lenalidomide, polatuzumab-containing regimens, or loncastuximab tesirine. This article provides a summary of our approach to the management of this diverse population of older patients with relapsed or refractory DLBCL.

In 2023, 2 different gene therapies were approved for individuals with severe sickle cell disease (SCD). The small number of patients treated on the pivotal clinical trials that led to these approvals have experienced dramatic short-term reductions in the occurrence of painful vaso-occlusive crises, but the long-term safety and efficacy of these genetic therapies are yet to be ascertained. Several challenges and treatment-related concerns have emerged in regard to administering these therapies in clinical practice. This article discusses the selection and preparation of individuals with SCD who wish to receive autologous gene therapy, as well as the salient features of the care needed to support them through a long and arduous treatment process. I specifically focus on postinfusion care, as it relates to immune monitoring and infection prevention. Compared with allogeneic hematopoietic cell transplantation, delivering autologous gene therapy to an individual with SCD has distinct nuances that require awareness and special interventions. Using clinical vignettes derived from real-life patients, I provide perspectives on the complex decision-making process for gene therapy for SCD based on currently available data and make recommendations for evaluating and supporting these patients.

Secondary acute myeloid leukemia (sAML) has traditionally been used to designate any AML disease arising from an antecedent hematologic disorder or after prior cytotoxic or radiation therapy. We now know sAML comprises multiple disease entities with distinct clinical and biological features: AML, myelodysplastic related; myeloproliferative neoplasm-blast phase; and AML post-cytotoxic therapy. These entities largely represent adverse-risk phenotypes with the majority of patients experiencing suboptimal outcomes with standard therapeutic options. Given the aging general population and the increased life span of individuals receiving DNA-damaging agents for other medical conditions, the incidence of these diseases is steadily rising and now comprise ∼25% to 30% of all new AML diagnoses. Despite the plethora of novel agents approved for AML since 2017, many either are not applicable to sAML (ie, lacking a targetable mutation), have limited efficacy, or have not been studied in these specific entities. Furthermore, these patients are underrepresented in clinical trials, and novel therapeutic options are critically needed. Here, we present multiple patient cases exemplifying the new nomenclature and classification of the diseases comprising sAML and highlighting their diverse presentations. We provide our therapeutic approach for each clinical scenario and discuss the challenges of treatment with the currently available armamentarium.

No randomized trial has directly compared daratumumab and lenalidomide (D-R) maintenance with standard-of-care lenalidomide (R) alone after transplant. Herein, we report the primary results of the phase 3 AURIGA study evaluating D-R vs R maintenance in patients with newly diagnosed multiple myeloma (NDMM) who had very good or better partial response, were minimal residual disease (MRD)-positive (10-5) and anti-CD38-naïve after transplant. Two hundred patients were randomly assigned (1:1) to D-R (n = 99) or R (n = 101) maintenance for up to 36 cycles. The MRD-negative (10-5) conversion rate by 12 months from start of maintenance (primary end point) was significantly higher for D-R than R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% confidence interval [CI], 2.37-8.57; P < .0001). MRD-negative (10-6) conversion rate was similarly higher with D-R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P = .0002). At median follow-up (32.3 months), D-R achieved a higher overall MRD-negative (10-5) conversion rate (D-R, 60.6% vs R, 27.7%; OR, 4.12; 95% CI, 2.26-7.52; P < .0001) and complete response rate or better (75.8% vs 61.4%; OR, 2.00; 95% CI, 1.08-3.69; P = .0255) vs R. Progression-free survival (PFS) favored D-R vs R (hazard ratio, 0.53; 95% CI, 0.29-0.97); estimated 30-month PFS rates were 82.7% for D-R and 66.4% for R. Incidences of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were slightly higher with D-R than R. In conclusion, D-R maintenance achieved a higher MRD-negative conversion rate and improved PFS after transplant vs R, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT03901963.