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•Children with T-ALL treated in the COG AALL0434 had excellent EFS and OS independent of the ETP status.•Persistent leukemia after induction was a strong predictor of inferior outcome in patients with non-ETP T-ALL.

•Patients with CNS-1 and CNS-2 status have similar outcomes across 2 large studies with divergent therapies, including with and without CRT.•Patients with CNS-3 T-ALL treated with nelarabine had similar OS as CNS-1 and CNS-2, and thus should receive nelarabine as standard of care.

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone–derived cells as healthy experimental controls.

Glycoprotein VI (GPVI), the platelet immunoreceptor tyrosine activating motif (ITAM) receptor for collagen, plays a striking role on vascular integrity in animal models of inflammation and sepsis. Understanding ITAM-receptor signaling defects in humans suffering from sepsis may improve our understanding of the pathophysiology, especially during disease onset. In a pilot study, platelets from 15 patients with sepsis were assessed consecutively at day of admission, day 5 to 7, and the day of intensive care unit (ICU) discharge and subjected to comprehensive analyses by flow cytometry, aggregometry, and immunoblotting. Platelet function was markedly reduced in all patients. The defect was most prominent after GPVI stimulation with collagen-related peptide. In 14 of 15 patients, GPVI dysfunction was already present at time of ICU admission, considerably before the critical drop in platelet counts. Sepsis platelets failed to transduce the GPVI-mediated signal to trigger tyrosine phosphorylation of Syk kinase or LAT. GPVI deficiency was partially inducible in platelets of healthy donors through coincubation in whole blood, but not in plasma from patients with sepsis. Platelet aggregation upon GPVI stimulation increased only in those patients whose condition ameliorated. As blunted GPVI signaling occurred early at sepsis onset, this defect could be exploited as an indicator for early sepsis diagnosis, which needs to be confirmed in prospective studies.

•Successful pregnancies are possible among female alloHCT recipients, although birth rate is more than six times lower than in the general population.•Key factors increasing the chance of motherhood were younger age at HCT, non-malignant disease, no TBI or dose <8Gy and RIC/NMA conditioning

1The level of MRD in the bone marrow at the end of induction correlates with event free survival in T cell lymphoblastic lymphoma.2MRD at the end of induction may be one of the few prognostic variables for event free survival in pediatric T cell lymphoblastic lymphoma

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell’s palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ~20% of newly diagnosed FL in which the detection rate of t(14;18) is only ~50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an “advanced-stage signature” in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a “localized-stage signature” had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.

Introduction: After receiving frontline chemotherapy for classical Hodgkin lymphoma, up to 30% of patients (pts) relapse. Salvage chemotherapy and autologous stem cell transplantation (ASCT) are the standard of care. Immune Checkpoint inhibitors (ICIs) have become essential to salvage therapy with improved complete response (CR) rates. However, ICIs have been linked to an increased risk of engraftment syndrome (ES), reported in as many as 68-78% of cases (Moskowitz et al. 2021; Park et al. 2021), while others have reported lower rates 3-12% (Bryan et al. 2023; Mei et al. 2022). The variability is connected to the definition of ES. The more stringent Spitzers criteria require 3 major (non-infectious fever (NIF), skin rash, pulmonary edema, or hypoxia) or 2 major and 1 minor criteria within 96 hours of engraftment, while the more lenient Maiolino criteria require a NIF with skin rash, pulmonary infiltrates, or diarrhea. Early diagnosis of ES and early intervention with corticosteroids is important to minimize toxicity during the ASCT. Here, we evaluate ES incidence at our institution during ASCT with or without the inclusion of ICI during salvage therapy.

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Following the approval of blinatumomab in 2015 T-cell recruiting bispecific antibodies (BsAbs) became the established standard-of-care for relapsed or refractory (r/r) and minimal residual disease positive B-cell precursor acute lymphoblastic leukemia. More recently, there has been a notable increase in the approval of additional BsAb constructs for malignancies such as r/r follicular lymphoma, r/r large B-cell lymphoma, and advanced multiple myeloma (MM), with further approvals anticipated. Despite the clinical success, administration of BsAbs is commonly linked to dose-limiting immune-related adverse events (IrAEs), such as cytokine release syndrome, possibly compromising treatment efficacy. Hence, current BsAb as well as CAR T approvals integrate prophylactic and acute glucocorticoid (GC) application upon occurrence of IrAEs. Surprisingly, despite their immunosuppressive nature, GC administration had no negative impact on response or survival of MM patients receiving CAR T-cell therapy (Wang 2022). Based on these data, we hypothesize that the GC-mediated downregulation of BsAb-induced T-cell function has a dual effect: mitigating IrAEs and ameliorating T-cell exhaustion. Here we tested the effect of simultaneous administration of the GC dexamethasone (dexa) and a CD3xCD19 targeting BsAb on T-cell function and exhaustion.

Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 +and CD4 +CAR +T cells that has demonstrated efficacy and favorable safety based on clinical studies. Liso-cel is approved in the US for the treatment of adults with R/R LBCL after 1 or more lines of systemic therapy, but data describing outcomes in patients treated with liso-cel in the real-world setting are limited. We report real-world clinical effectiveness and safety of commercial liso-cel in patients with R/R LBCL based on a postmarketing study using data collected at the Center for International Blood and Marrow Transplant Research (CIBMTR).

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Introduction:The phase 2 KEYNOTE-C11 study (NCT05008224) evaluates the safety and efficacy of pembrolizumab (pembro) followed by AVD chemotherapy (chemotherapy) and pembro consolidation in patients with untreated, early unfavorable or advanced-stage cHL without radiotherapy. The criteria for study continuation were met at the pre-specified interim futility analysis after pembrolizumab induction and 2 cycles of AVD, with approximately 3 months of follow-up. We present results of an analysis of efficacy and safety in all enrolled patients with an additional 8 months of follow-up.

Background: Data on the clinical activity of venetoclax (ven) in lymphoplasmacytic lymphoma (LPL) are primarily limited to a phase 2 trial of ven monotherapy for a 2-year duration in 32 patients (pts) with relapsed/refractory IgM LPL who received a median of 2 prior treatments (tx), including 16 pts with prior BTK inhibitors (BTKi) (Castillo et al, JCO 2021). Overall response rate (ORR) was 84% and median progression-free survival (PFS) was 30 months (mos). We report the clinical activity of ven and prognostic factors associated with outcomes in a larger cohort.

INTRODUCTION:Recent data from the REMoDL-B trial show that addition of the proteasome inhibitor bortezomib to R-CHOP improves progression free survival (PFS) of patients (Pts) with activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) compared to R-CHOP, but peripheral neuropathy limited dose intensity. Relative to bortezomib, carfilzomib (K) displays comparable clinical activity in plasma cell neoplasms but does not cause neurotoxicity. K has preferential clinical activity in relapsed non-germinal center (non-GC) DLBCL treated with chemotherapy (Torka, et al. Blood Adv. 2023). To explore the safety and efficacy of K in combination with R-CHOP (KR-CHOP), we performed a phase I trial to identify the recommended phase 2 dose (RP2D) in all DLBCL Pts followed by a phase II extension exclusively in non-GC DLBCL.

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Introduction:In recent years, increasing evidence suggests an important role of tumor-infiltrating B lymphocytes (TIL-Bs) in cancer immunity. In various types of solid tumors, high density of TIL-Bs and presence of mature tertiary lymphoid structures consistently correlate with better prognosis and response to immune checkpoint blockade therapies. Diffuse large B-cell lymphoma (DLBCL) is a type of aggressive lymphoma arising from mature B cells. TIL-Bs have been identified in DLBCL based on single-cell gene-expression data in several previous studies, but their prognostic significance in DLBCL is unknown. In this study, we determined the clinical significance of TIL-B abundance and investigated the potential underlying mechanisms.

Background:Chimeric antigen receptor T (CAR-T) cell therapy has become the standard of care in patients with relapsed/refractory diffuse large cell lymphoma (R/R DLBCL), providing durable remission in 40% of patients. Lack of response is likely to be attributed to inter- and intra-patient variability, including PBMC heterogeneity and apheresis material composition, CAR-T infusion product, in-vivo expansion and activity of CAR-T cells and the development of tumor-intrinsic mechanisms. Current methods for evaluating CAR-T cell activation and potency have limited predictive value for clinical outcomes. To address this challenge, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) obtained from patients with R/R LBCL patients at the time of apheresis for the manufacturing of anti-CD19 CAR-T cell therapy. Methods: Between 10/2020 and 03/2022, 31 patients who underwent lymphopheresis were enrolled. Samples were obtained - 1) At day of lymphopheresis from peripheral blood; 2) On the day of infusion of CAR-T from the product; and 3) On day +7 after infusion from peripheral blood. All patients had day +30 PET-CT. In addition, PBMCs samples from healthy donors were used as control to analyze baseline characteristics compared to the DLBCL patients. PBMCs from patients of healthy donors were purified from frozen blood samples by density gradient separation, stained using human CD45 antibody and loaded onto a 10x Chromium system. libraries were generated using the 10X Genomics Chromium Single Cell 3' Kit. The data was processed and analyzed using the Seurat R package. The study was approved by the local Ethic committee. Results:Patient characteristics: 31 RR DLBCL patients (42% females; median age 72, range 47-81 years), all treated with CAR-T cells therapy as third line of therapy, participated in the study. All patients underwent lymphopheresis, followed by CAR-T production. Disease status at lymphodepletion was complete remission (CR, n=4, 13%), partial remission (n=6, 19%), and progressive disease (n=21, 68%) and patients received either tisagenlecleucel (n=20, 65%) or axicabtagene ciloleucel (n=11, 35%) . PET scan performed on day 30 post treatment revealed that 68% and 32% obtained CR, and PD, respectively. scRNA analysis revealed differences in PBMC composition between healthy donors and LBCL patients (Figure 1A), with lower levels of naïve and memory T cells and elevated levels of activated monocytes in LBCL patients, suggesting a shift towards an inflamed and pre-dysfunctional immune state. Categorization of LBCL patients into responders (PR/CR on day +30 PET-CT) and non-responders (PD on day +30 PET-CT) revealed differences in immune cell subsets between responders and non-responders (Figure 2A), with enriched inflammation-related pathways in non-responders, In contrast, responders exhibited a distinct healthy-like immune profiles, particularly high levels of naive T cells, similar to that obtained in their age matched healthy controls. Of note, non-responders showed alterations in immune cell subsets, including increased levels of T regulatory cells and effector NK cells. Furthermore, non-responders demonstrated a prominent inflammatory immune profile, characterized by gene pathways related to inflammation and activation, such as type I and III IFN-G, and TNFb response (Figure 1B). Notably, an IFN-G score was significantly higher in non-responder's monocytes subpopulations, compared to responders. Conclusions:These findings indicate that the success of CAR-T therapy could be determined by the molecular characteristics and subpopulation distribution of each patient's PBMC. The diverse immune profiles of DLBCL patients might impact the effectiveness of their immune cells in generating successful CAR-T products or providing a conducive environment for CAR T cells to combat cancer. Furthermore, these findings emphasize the potential of scRNA-seq in evaluating PBMC from CAR-T patients prior to treatment, allowing the potential calculation of an “immune potency score” associated with the probability of a positive outcome from CAR-T treatment of DLBCL patients. This score could potentially be used by oncologists in decision-making processes to determine the appropriate candidates for CAR-T therapy.

INTRODUCTION:Primary CNS lymphoma (PCNSL) is a rare lymphoma subtype. Treatment with whole brain radiotherapy (WBRT) resulted in high response rates but poor overall survival and modern therapy typically involves combination chemotherapy regimens that include rituximab and high dose methotrexate and, in some cases, followed by consolidative chemotherapy such as autologous stem cell transplantation (ASCT). However, there is no standard regimen, and the choice is institutional and/or physician preference. We performed a single institution retrospective study evaluating the outcomes of patients with PCNSL with focus on outcome stratified by POD24.

Introduction:Chimeric antigen receptor T-cell therapy (CAR T) is a novel therapy associated with a unique toxicity profile, namely cytokine release syndrome (CRS) occurring in (37-93%) of patients (pts) and immune effector cell associated neurotoxicity (ICANS) occurring in 23-67% of pts [Zahid, 2020]. Grading and management of these toxicities varies amongst institutions and patient populations. Furthermore, assessment of ICANS utilizes the Immune Effector Cell-Associated Encephalopathy (ICE) scoring system which includes 5-components that are dependent on a patient's English- speaking proficiency [Lee 2019]. We previously reported a higher-grade of neurotoxicity assessed in non-English speaking pts in a cohort of 127 pts at our institution [Melody, 2023]. We sought to confirm our previous findings by analyzing the impact of language spoken on the incidence, severity, and management including resource utilization for CAR T associated toxicities, in a larger multi-institutional cohort.

Background:DNA mismatch repair (MMR) deficiency (dMMR), which leads to genomic and microsatellite instability, is a biomarker that predicts response to immunotherapies and has variable prognostic effects for chemotherapies in solid tumors. The dMMR can be detected using gene sequencing or immunohistochemistry for four essential MMR proteins: MSH6, MSH2, MLH1, and PMS2. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Previous studies have suggested the role of MMR gene variants in DLBCL lymphomagenesis, yet the prognostic role of dMMR in DLBCL has not been well studied.

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Introduction:Chimeric antigen receptor T-cell therapy (CAR T) is an effective therapy in relapsed/refractory (R/R) large B-cell lymphoma (LBCL) but is associated with prolonged cytopenias, persistently low CD4 T-cells, and hypogammaglobulinemia (defined as serum IgG <500 mg/dL) resulting in an immunocompromised state post CAR T [Logue 2021]. Prophylactic antimicrobials and intravenous immunoglobulin (IVIG) have been utilized to mitigate infectious complications, but practices are not standardized. We sought to examine patterns of immune reconstitution and their impact on incidence, timing, and management of infection following CAR T.

Bispecific T-cell recruiting antibody constructs (BsAb) have shown clinical efficacy with Blinatumomab, a CD3xCD19 BiTE ® construct used for the treatment of relapsed or refractory B-cell precursor ALL. Despite the success of BsAbs in B-cell malignancies, the translation to a myeloid setting has been unsuccessful, independently of the chosen target antigen. For example, targeting CD33 has failed to provide long-term benefits. Several reports have demonstrated that the diverse genetic makeup of AML confers resistance to T-cell based immunotherapy. Mutations of TP53occur in 5-10% of patients with de novoAML and up to 50% in older patients with therapy related AML, thus highlighting its role as a potential resistance mechanism. We hypothesize, that genetic aberrations of TP53in AML contribute to cell intrinsic and cell extrinsic resistance against T-cell based immunotherapy approaches.

Introduction

Background:Despite the efficacy of venetoclax (VEN) in frontline CLL, optimal combination regimens and duration of treatment remain unclear. We hypothesized that cytoreduction with bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation for a fixed 1-year duration would be associated with an increased rate of undetectable minimal residual disease (uMRD) compared to historical controls and a reduction in the risk of tumor lysis syndrome (TLS). Here we report updated data from a fully-enrolled ongoing phase 2 multicenter, US, single-arm, open-label study (NCT03609593) designed to assess the safety and efficacy of BR-VR in previously untreated CLL patients (pts).

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