CPX-351, a novel liposomal formulation of cytarabine and daunorubicine, represents the standard of care in fit patients with myelodysplasia-related changes (AML-MRC) and therapy-related Acute Myeloid Leukemia (tAML). Considering its better safety profile than conventional intensive chemotherapy, we investigated its cost/benefit ratio, in terms of overall survival and of mortality, in a large multicentric series of AML-MRC and tAML receiving CPX-351 outside clinical trials between 2019 and 2022. Patients were classified in fit or unfit to intensive chemotherapy through a comprehensive evaluation of age, comorbidities and performance status by adopting SIE/SIES/GITMO criteria. Disease risk was defined according to the ELN2017 classification. Before treatment start, 328/403 (81.4%) were classified as fit, 75/403 (18.6%) as unfit. Three hundred and ninety-six had a full genetic/cytogenetic profile with 17 (4%) being categorized as favorable risk, 162 (41%) intermediate risk, and 217 (55%) adverse risk according to ELN2017. After induction, 230/403 patients (57.1%) achieved a complete remission, with no differences between fit (57.3%) and unfit (56%). However, the two groups significantly differed in terms of survival (median overall survival of 18 months vs 8 months for fit and unfit patients) and of 28- and 100-day mortality (4.6% vs 10.7% at 28 days and 14.3% vs 32% at 100-days for fit and unfit patients, respectively). In conclusion, the SIE/SIES/GITMO criteria discriminated patient subgroups with different short- and long-term outcomes after treatment with CPX-351. The update or design of dedicated fitness criteria could represent a future and valid strategy to optimize the use of this specific treatment.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although patients with FL have high response rates to therapy, most develop increasingly resistant disease. In addition, transformation into an aggressive lymphoma is associated with unfavorable outcomes. Many novel agents are under investigation, and early clinical data are encouraging. Aligning treatment with the underlying tumor biology and sequencing of therapies remain key clinical challenges. At the Lymphoma Research Foundation's biannual 2024 Follicular Lymphoma Scientific Workshop, experts convened to discuss the role of chemotherapy in the context of new therapies, the impact of early progression on treatment sequencing, novel endpoints in clinical trials, disease biology and the tumor microenvironment, and new treatments on the horizon. This report focuses on updates in FL biology, first-line treatment, the role of progression of disease in 24 months (POD24), clinical trial design, and redefining cure in FL.

Chronic myelomonocytic leukemia (CMML) is characterised by monocytosis in blood and bone marrow and natural progression to acute myeloid leukemia (AML) in up to 30% of patients. The mutation landscape of CMML has been reported, and animal models that recapitulate its clinicopathologic features and progression are needed. We report a CMML zebrafish model based on transgenic SRSF2P95H expression that closely resembled the human disease. Hematological assessment of the transgenic animals showed myelodysplasia, monocytosis, and leukemia transformation. Transcriptomic analysis confirmed global splicing alterations and identified inflammatory phenotypes associated with activation of the cGAS-STING pathway. DNA damage, R-loop and dsDNA accumulation were evident. Inhibition of R-loop formation or cGAS-STING axis significantly reduced gene expression associated with inflammation and immune activation and mitigated the leukemia phenotype. The inflammatory effects and their response to treatment were recapitulated in human hematopoietic stem and progenitor cells (HSPC). Collectively, our findings showed a pathogenetic link between SRSF2P95H and cGAS-STING activation in CMML and its vulnerability to therapeutic intervention.

Pyroptosis is a form of programmed cell death characterized by the cleavage of gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of pro-inflammatory cytokines. In this study, we performed immunohistochemistry for cleaved GSDMD, GSDME-N-terminal, and GSDMC in two different cohorts of diffuse large B-cell lymphoma (DLBCL), and analyzed their prognostic and immune impact. The results showed frequent cleaved GSDMD (GSDMD-N-terminal) expression. Only cytoplasmic GSDMD-N-terminal expression correlated with significantly better patient survival in two cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry (mfIHC) results, we found that cytoplasmic GSDMD-N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T cell pyroptosis, lymphoma cell resistance to cell death, and phagocytosis by M2 macrophages were observed in cells with nuclear GSDMD-N-terminal expression. Bulk gene expression profiling and deconvolution analysis for patients with cytoplasmic GSDMD-N-terminal expression revealed downregulation of "Don't eat me" signaling genes, upregulation of many RNA genes, decreased frequency of "Inflammatory" lymphoma microenvironment subtype, increased abundance of prognostically favorable cell states and ecotypes, and decreased abundance of T cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of three gasdermin proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.

Menin inhibitors (MENINi) show promise for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1c). Outcomes after MENINi failure are poorly understood. To characterize the mutational landscape and subsequent outcomes, we conducted a multicenter retrospective study of adults from 4 U.S. centers with R/R AML after MENINi failure (relapse after response or primary refractory). The 84 patients (63% KMT2Ar, n=53; 23% NPM1c, n=19) who received MENINi were heavily pre-treated: 86% (n=72) had prior intensive chemotherapy (IC), 77% venetoclax (VEN, n=67), and 38% (n=32) allogeneic stem cell transplantation. After MENINi failure, 40% of patients (n=34) received supportive care. Of the 60% (n=50) that were treated, common regimens were hypomethylating agent (HMA)/VEN (26%, n=13), clinical trial (26%, n=13), and gilteritinib-based therapy (18%, n=9). The CR/CRi rate for non-trial therapies was 19% (n=7); ORR was 32% (n=12). All CR/CRi occurred with HMA/VEN (n=2, 15%), IC+VEN (n=4, 67%), or MENINi switching (bleximenib to revumenib, n=1, 50%). No FLT3-mutant patients responded to gilteritinib (0/6 gilteritinib-naïve). Median overall survival (mOS) from start of next therapy was 4.4 months; patients who achieved CR/CRi had mOS of 15.4 vs 3.4 months for non-responders (p=0.048). Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance.

Von Willebrand Disease (VWD) is the most common inherited bleeding disorder and is often diagnosed in the setting of heavy menstrual bleeding (HMB). Because estrogen upregulates von Willebrand factor synthesis, pregnancy and the management of menses may influence VWD testing and diagnosis. Throughout the lifespan, the management of women's reproductive health is frequently impacted by VWD. We seek to describe the interplay between VWD and women's reproductive health at three distinct phases in life: menarche and menstruation, maternal health and fertility, and menopause and aging. Planning for care requires screening for VWD in the setting of reproductive bleeding counseling patients about expectations, and monitoring for iron deficiency across all three phases. Hemostatic plans should be tailored to both factor levels and patient preference. Emphasis is placed on areas lacking vital data.

Loss-of-function mutations and deletions in core components of the epigenetic Polycomb Repressive Complex 2 (PRC2) are associated with poor initial treatment response in T-acute lymphoblastic leukemia (T-ALL), but the mechanisms that underpin resistance to individual therapies are unknown. We leveraged an isogenic T-ALL cellular model and primary patient data to investigate how PRC2 alterations affect signaling pathway activity in leukemia cells, and whether these changes may influence therapy response. Integration of transcriptomic, proteomic and phosphoproteomic results revealed markedly reduced activity of the WNT-dependent stabilization of proteins (WNT/STOP) pathway in leukemia cells lacking core PRC2 factor EZH2. Importantly, these results closely matched transcriptional readouts from T-ALL patient samples with PRC2 mutations and deletions. We discovered that PRC2 loss significantly reduced sensitivity to key T-ALL treatment asparaginase, and that this was mechanistically linked to increased cellular ubiquitination levels due to WNT/STOP suppression that bolstered leukemia cell asparagine reserves. These results also strongly correlated with transcriptional profiles of asparaginase resistance in an independent T-ALL patient cohort. We further found that asparaginase resistance in PRC2-depleted leukemic blasts could be mitigated by pharmaceutical proteasome inhibition, thereby providing a potential avenue to tackle induction treatment failure in these cases.

Systems-Based Hematology (SBH) is an emerging discipline focused on optimizing care delivery for patients with hematologic disorders within complex healthcare systems. Despite growing importance, the field lacks a formal definition, standardized curriculum, and clear career pathway, hindering widespread adoption and training of future SBH experts. We sought to define core principles, competencies, challenges, and future directions of SBH to identify foundational components for a potential educational curriculum. Semi-structured interviews were conducted with eight SBH experts. Expert participants were identified through their committee involvement with the American Society of Hematology. Five overarching themes emerged: The Accidental Expert: SBH careers have developed organically and reactively in response to pressing institutional needs, not through formal training; Defining the Unseen: experts define the field pragmatically by its function and roles; The SBH Toolkit: success requires a hybrid skillset combining clinical hematology expertise with Health Systems Science (HSS) principles; The Architect's Dilemma: the field's growth is hindered by interdependent challenges of building a curriculum, awareness, and securing resources; Charting the Future: the discipline is poised for growth, driven by increasing healthcare complexity and specialization.SBH represents the nexus of HSS principles and hematology care. Formalizing SBH requires a multi-pronged approach, including developing a standardized curriculum that equips learners with a hybrid skillset, creating clear value for health systems and patients, and fostering a community of practice through professional societies. These findings provide a foundational framework for developing educational resources and institutional support necessary to continue advancing SBH.

To improve the tolerability of post-transplant maintenance and outcomes despite poor risk disease genetics, we conducted a phase 1 study of venetoclax/FluBu2 RIC transplantation with tacrolimus/methotrexate GVHD prophylaxis followed by all-oral venetoclax/decitabine-cedazuridine (ven/dec-c) maintenance in poor-risk MDS/AML patients (N=30). 58% had prior venetoclax exposure and 63% were TP53-mutated; 15/19 had TP53 multi-hit state. At a median of +55 days, pre-emptive maintenance therapy with venetoclax (400 mg on days 1-14) and dec-c (decitabine 35 mg/cedazuridine 100 mg on days 1,3,5 or 1,2,3) was initiated for eight 42-day cycles in 26/30 (87%) patients (remaining 3 relapsed early, 1 withdrew). On maintenance, grade 3-4 neutropenia (96%) occurred though infections were rare (N=2). No DLTs occurred. 6-month acute GVHD grade II-IV rate was 13%. 1-year moderate/severe chronic GVHD rate was 31%. At a median follow up of 25.1-months (range,15-33), median OS and PFS were not reached. On maintenance, 2-year OS was 77% (95%CI,55-89), PFS 62% (95%CI,38-79), NRM 0%, and cumulative incidence of relapse 38% (95%CI,18-59). Exploratory studies identified 96% had pre-transplant NGS-MRD+, favorable survival in those with non-TP53 MRD+, and delayed conversion on maintenance in 11/18 (61%) in those with TP53 MRD+. PROs assessed in first 6-months of maintenance were stable except for emotional function, which improved (P=0.008). Trial is registered at clinicaltrials.gov/NCT03613532.

Ketamine is recommended as an opioid-sparing adjunct for sickle cell disease (SCD)-related pain management. Little is known regarding its use in hospitalized youth with SCD. We aimed to describe trends in ketamine administration and examine associations between ketamine administration and outcomes in hospitalized youth with SCD. We conducted a cross-sectional, multicenter study examining hospital admissions for youth with SCD from 44 children's hospitals in the US from 2016- 2023. Youth aged ≥6 months and older with SCD were identified using ICD-10 codes. Exposures included age, sex, race, payor, childhood opportunity index, hydroxyurea administration, and concomitant methadone, buprenorphine, or gabapentinoid administration. The primary outcome was ketamine administration during admission. Secondary outcomes included length of stay, days on intravenous opioids, all-cause 14-day readmission rates, and intensive care unit stays during admissions with ketamine administered during the first three days of hospitalization (early) and hospital day 4 or later (late). From 2016-2023, 4.5% (n = 3,391) of admissions for patients with SCD included ketamine administration, with prevalence increasing from 2.3% in 2016 to 5.7% in 2023 (p<0.001). Age groups ≥12 years and year of 2019 or later was associated with increased odds of ketamine administration. Admissions with ketamine administration were also more likely to have administration of methadone and hydroxyurea. Early versus late ketamine administration was associated with shorter LOS and fewer parental opioid days, indicating randomized controlled studies are needed to determine not only which patients benefit from ketamine but also the impact of early administration.

Malignancy-associated hemophagocytic lymphohistiocytosis (mHLH), a hyperinflammatory syndrome, has poor prognosis and no standard therapy. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-gamma, is approved for treating primary hemophagocytic lymphohistiocytosis (pHLH). REAL-HLH, a retrospective chart review conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with at least 1 dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with mHLH. Overall, 51/105 (48.6%) patients did not meet the pHLH classification criteria and were categorized as presenting with secondary HLH; 17/51 patients had underlying malignancy (mHLH). At HLH diagnosis, median age (range) was 15.0 (3.0-27.0) years, 6/14 (42.9%) patients with available data had a positive Optimized HLH Inflammatory index indicating pathologic inflammation; 9/17 (52.9%) had infections, and 10/17 (58.8%) received emapalumab in an intensive care unit. Emapalumab was primarily initiated for treating refractory (10/17; 58.8%) or progressive (3/17, 17.7%) disease. Most patients received HLH-related therapies before (16/17; 94.1%) and/or concurrent with (15/17; 88.2%) emapalumab. Most key laboratory parameters improved, and some (fibrinogen [11/13; 84.6%], absolute neutrophil count [6/10; 60%], and CXCL9 [7/8; 87.5%]), normalized or stabilized per physician assessment, following treatment with emapalumab-containing regimens. Overall survival at the end of follow-up and 12-month survival probability from emapalumab initiation were 23.5% and 22.1%, respectively. In conclusion, emapalumab-containing regimens improved or normalized most laboratory parameters in patients with mHLH. Future studies are warranted to establish appropriate emapalumab dosing and utility in this high-risk population.

Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to impact overall survival (OS). The influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium (PIDTC) from 1990-2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced intensity regimens were associated with lower T cell and myeloid donor chimerism, particularly when non-busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hotspot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS following HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This study was registered at www.clinicaltrials.gov as #NCT02064933.

The incidence of diffuse large B cell lymphoma (DLBCL) increases with older age. Thus, subgroup reporting for older adults in clinical trials is necessary to determine the relevance of novel therapy outcomes to this vulnerable population. This study assessed subgroup reporting of older adults (≥65 years) enrolled in Food and Drug Administration (FDA) and European Medicines Agency (EMA) registration trials for DLBCL between 2017 and 2023. Clinical efficacy endpoints for each trial were extracted from ClinicalTrials.gov registry data and study protocols. Primary and secondary publications reporting on included studies were identified through a systematic review process within Covidence. Ten therapies with 12 indications were approved between 2017 and 2023. Ninety-two publications were included for data extraction. The availability and completeness of older adult subgroup data relating to protocol-defined efficacy endpoints, as well as data relating to baseline patient characteristics, health-related quality of life outcomes, and toxicity outcomes, were assessed according to predefined criteria. Of the 12 primary endpoints, 10 (83.4%) were reported completely, 1 (8.3%) partially, and 1 (8.3%) was not reported among older subgroups. Of the 66 secondary endpoints, 25 (37.9%) were completely reported, 6 (9.1%) were partially reported, and 35 (53.1%) were unreported. Baseline characteristics, health related quality of life, and toxicities outcomes among older adults were mostly unreported. This analysis highlights a need for improvement in older adult subgroup reporting in DLBCL trials particularly among secondary endpoints.