Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML.

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

Targeted testing of bone marrow specimens with cytoplasmic vacuolization to identify previously undiagnosed cases of VEXAS syndrome.

OBJECTIVE: To retrospectively identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) among male patients with bone marrow vacuolization using a clinically applicable, targeted-screening approach. METHODS: Bone marrow reports from 1 May 2014 through 18 February 2022 were reviewed for documentation of cytoplasmic vacuolization. Patients with acute leukaemia, lymphoma, metastatic solid tumour, amyloidosis or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome were excluded, as were those without clinical records available for direct chart review. Cases were rated for suspicion of VEXAS syndrome using a 5-point scale based on the presence of laboratory findings, clinical features and treatment response. Patients with available DNA material and moderate (three patients) or high (four to five patients) suspicion were tested for somatic UBA1 variants associated with VEXAS syndrome. RESULTS: A total of 315 reports from 292 unique patients included documentation of vacuolization. Following exclusion criteria, 64 patients underwent direct medical chart review to assess likelihood of VEXAS syndrome, for which 21 patients met moderate to high suspicion. Available DNA was present in eight patients, seven (87.5%) of whom had a pathogenic somatic UBA1 variant consistent with VEXAS syndrome. The distribution of cytoplasmic vacuolization in the bone marrow biopsy reports among patients with VEXAS syndrome were erythroid and myeloid precursors (6/7), erythroid precursors only (1/7) and myeloid precursors only (0/7). CONCLUSION: In this study, the utilization of a clinically applicable targeted-screening approach to test bone marrow specimens (with vacuolization) for the presence of previously undiagnosed VEXAS syndrome resulted in a positive detection rate of 87.5%.

Bispecific Antibodies for Non-Hodgkin Lymphoma Treatment.

OPINION STATEMENT: While there have been numerous advances in the field of non-Hodgkin lymphoma (NHL) over the last decade, relapsed and/or refractory (R/R) NHL remains a challenge and an area with unmet needs. T-cell redirecting immunotherapeutic approaches including chimeric antigen receptor (CAR) T-cells and bispecific antibodies (BsAbs) have the potential to revolutionize NHL therapy. BsAbs target CD3 on T-cells and CD19 or CD20 on malignant B-cells and have shown promises as a novel immunotherapy for NHL. The development of CD19 × CD3 BsAbs such as blinatumomab was met with significant challenges due to dose-limiting neurologic side effects. However, several CD20 × CD3 BsAbs including odronextamab, mosunetuzumab, glofitamab, and epcoritamab emerged recently. They have favorable toxicity profiles, with reduced cytokine release syndrome and neurotoxicity. In addition, all these BsAbs have demonstrated very promising efficacy in R/R NHL. With expansion and registrational studies actively ongoing, approvals of these agents for R/R NHL are anticipated in the near future. Some important questions pertinent to future clinical development of BsAbs include when and how to best utilize BsAbs in the management of R/R NHL, whether there is a role of BsAbs in treatment-naïve NHL, and how to combine BsAbs with other therapies. For example, whether BsAbs can be combined with cytotoxic chemotherapy effectively remains to be seen. A plethora of clinical studies will be needed to help address these questions, some of which are already ongoing. In addition, how do BsAbs compare to CAR T-cell therapy and how to choose and sequence between BsAbs and CAR T-cell therapy need to be addressed. While many of these critical questions remain to be answered in clinical studies, we believe the future of BsAbs in the NHL is very bright.

Successful treatment of recurrent CNS disease post-bone marrow transplant in children with familial hemophagocytic lymphohistiocytosis.

BACKGROUND: Central nervous system (CNS) involvement is a major cause of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis (HLH). Current standard of care for CNS disease utilizes high-dose systemic dexamethasone plus intrathecal methotrexate and hydrocortisone prior to transplantation. However, the morbidity and mortality remains high and there are no clear guidelines posttransplantation for screening and treatment of CNS disease. PROCEDURE: We report a single-center retrospective case series of five patients with familial HLH (FHLH) who had CNS involvement post-bone marrow transplantation (BMT). All patients were monitored with monthly lumbar punctures (LPs) prior to developing neurologic symptoms. Treatment utilized systemic dexamethasone for CNS disease control. RESULTS: Five patients were monitored with monthly or bimonthly surveillance LPs and treated with systemic dexamethasone to control CNS relapse post-BMT. All patients are alive, a median of 34 months posttransplant (range 14-66 months). Four patients have mild neurological deficits, including mild speech delay (3) and one patient who exhibited brainstem herniation on day 0, due to CNS HLH, has made a substantial recovery of function with residual deficits of focal weakness on the right side. One patient has no deficits. CONCLUSION: Our data support vigilant screening posttransplant for occult CNS disease prior to the development of symptoms and the use of systemic dexamethasone to reverse disease progression. Future prospective trials are needed to evaluate this treatment strategy.

Incidence of Central Nervous System Relapse in Primary Mediastinal Large B-Cell Lymphoma: Implications for Central Nervous System Prophylaxis.

BACKGROUND: Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL. Therefore, it may be expected that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL treated with standard chemoimmunotherapy. PATIENTS AND METHODS: This retrospective single center analysis included 154 patients with newly diagnosed PMBCL seen at Mayo Clinic. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. RESULTS: With a median follow-up of 39 months, 3 patients experienced CNS relapse, all associated with systemic relapse. The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI, 0.3%-4.6%) at 1 year and 2.21% (95% CI, 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n = 131), the incidence was 0.85% (95% CI, 0.1%-4.2%) at 1 year and 1.80% (95% CI, 0.3%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; 2 patients did not receive any CNS prophylaxis, while 1 patient received intrathecal CNS prophylaxis. CONCLUSION: The risk of CNS relapse in PMBCL appears to be very low after treatment with standard chemoimmunotherapy, suggesting routine CNS prophylaxis is not necessary.

Defining primary refractory large B-cell lymphoma.

ABSTRACT: Patients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have "primary refractory disease." However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological Resource cohort (MER; N = 949) or the Lymphoma Epidemiology of Outcomes cohort (LEO; N = 2755) from September 2002 to May 2021. Primary refractory LBCL was defined as no response (stable disease [SD]) or progressive disease (PD) during, or by the end of, frontline (1L) IC (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving CR at EOT to 1L IC (early relapse). In the MER cohort, patients with PPD had inferior overall survival (OS; 2-year OS rate: 15% MER, 31% LEO) when compared with other subgroups considered in defining primary refractory disease, EOT PR (2-year OS rate: 38% MER, 50% LEO) and early relapse (2-year OS rate: 44% MER, 58% LEO). Among patients receiving 1L IC with curative intent, we identified that patients with PPD are the key subgroup with poor outcomes. We propose a definition of primary refractory LBCL as SD or PD during, or by the end of, 1L treatment.

Multiomic analysis identifies a high-risk signature that predicts early clinical failure in DLBCL.

Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.

High-grade B-cell lymphoma, not otherwise specified: CNS involvement and outcomes in a multi-institutional series.

ABSTRACT: Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal = 6, parenchymal = 4, and both = 1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR = 3.5) and testicular (in men) or female pelvic (in women) involvement (OR = 8.1). There was no significant difference in survival outcomes between patients with HGBL NOS with (median PFS = 4 years) or without (median PFS = 2.4 years) baseline CNS involvement (P = 0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% vs 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-germinal center B-cell subtype, and "dual-expresser lymphoma" phenotype, however, high CNS IPI was not. The prognosis of relapsed HGBL NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and chimeric antigen receptor T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease.

Bacteremia in blood or marrow transplantation patients: clinical risk factors for infection and emerging antibiotic resistance.

Bacterial infections continue to be a leading cause of mortality and morbidity in patients who undergo blood and marrow transplantations (BMTs). The relative importance of different clinical features (donor type, graft cell source, and conditioning regimen) on the incidence and timing of posttransplantation bacterial infections is uncertain, but a detailed analysis could better guide prevention and therapy. We retrospectively analyzed the incidence and risk factors for early bacterial infections, as well as patterns of antibiotic resistance. We observed 613 bacteremic events among 349 of 834 patients who underwent BMT treated at the University of Minnesota from 2005 to 2010 (cumulative incidence 42%; 95% confidence interval [CI], 38-45). Donor type (allogeneic vs autologous) had the greatest impact on the incidence of bacteremia within 100 days posttransplantation. Among allogeneic transplantations, myeloablative (MA), compared to reduced-intensity conditioning (RIC) was associated with a significantly greater risk of bacteremia, as was the development of acute graft-versus-host disease (aGVHD). Additionally, patients who underwent BMT, compared to the contemporaneous hospital population, developed infections with more frequent resistance to antibiotics used in the treatment against commonly isolated bacterial organisms. These findings have important clinical implications regarding the use and selection of both prophylactic and empiric antibiotic regimens.

Evolving treatment patterns and improved outcomes in relapsed/refractory mantle cell lymphoma: a prospective cohort study.

Over the last two decades, the frontline therapy for mantle cell lymphoma (MCL) has evolved. However, the impact of subsequent lines of therapy on survival outcomes has not been well characterized. In this study, we investigated the treatment patterns and survival outcomes in patients with relapsed/refractory (R/R) MCL treated with second-line (2 L) therapy. Adult patients with newly diagnosed MCL from 2002 to 2015 were enrolled in a prospective cohort study. Clinical characteristics, 2 L treatment details, and outcomes were compared between patients who received 2 L treatment between 2003-2009 (Era 1), 2010-2014 (Era 2), and 2015-2021 (Era 3). 2 L treatment was heterogenous in all eras, and there was a substantial shift in the pattern of 2 L therapy over time. The estimated 2-year EFS rate was 21% (95% CI, 13-35), 40% (95% CI, 30-53), and 51% (95% CI, 37-68) in Era 1-3 respectively, and the 5-year OS rate was 31% (95% CI, 21-45), 37% (95% CI, 27-50), and 67% (95% CI, 54-83) in Era 1-3, respectively. These results provide real-world evidence on evolving treatment patterns of 2 L therapy based on the era of relapse. The changes in 2 L treatment correlated with improved EFS and OS, suggesting that treatment advances are associated with improved outcomes in patients with R/R MCL.

Multiomic Analysis Identifies a High-Risk Metabolic and TME Depleted Signature that Predicts Early Clinical Failure in DLBCL.

PURPOSE: 60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. PATIENTS AND METHODS: Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure. RESULTS: Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31] P < .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09] P < .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. CONCLUSION: This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Patterning, Reading, and Executive Functions.

Detecting a pattern within a sequence of ordered units, defined as patterning, is a cognitive ability that is important in learning mathematics and influential in learning to read. The present study was designed to examine relations between first-grade children's executive functions, patterning, and reading abilities, and to examine whether these relations differ by the type of pattern. The results showed that working memory correlated with reading fluency, and comprehension measures. Inhibition correlated only with the latter. Cognitive flexibility was correlated with patterning performance and with performance on object size patterns, whereas working memory was correlated with performance on symmetrical patterns and growing number patterns. These results suggest that the cognition required for completing patterns differs depending on the pattern type. Teachers may find it beneficial to place emphasis on the switching and working memory components of completing patterning tasks, depending on the type of patterns used in instruction.

Early Executive Function and Mathematics Relations: Correlation Does Not Ensure Concordance.

In this chapter, we address one potentially overlooked component of the relation between executive function (EF) skills and early mathematics, a relation for which there is widespread empirical support. Evidence for this relation has, thus far, been largely correlational. Here we emphasize that because positive correlations do not guarantee concordance among all members of a sample or population, a small but meaningful number of children may either fare well in mathematics despite poor EF skills, or may have strong EF skills despite weak mathematics skills. We propose that attention to different profiles of discordance for EF and mathematics may help identify individualized learning needs for students at risk for mathematics difficulties and disabilities.

The Relations Between Patterning, Executive Function, and Mathematics.

Patterning, or the ability to understand patterns, is a skill commonly taught to young children as part of school mathematics curricula. It seems likely that some aspects of executive function, such as cognitive flexibility, inhibition, and working memory, may be expressed in the patterning abilities of children. The primary objective of the present study was to examine the relationship between patterning and executive functioning for first grade children. In addition, the relations between patterning, executive functioning, mathematics, and reading were examined. The results showed that patterning was significantly related to cognitive flexibility and working memory, but not to inhibition. Patterning, cognitive flexibility, and working memory were significantly related to mathematical skills. Only patterning and working memory were significantly related to reading. Regression analyses and structural equation modeling both showed that patterning had effects on both reading and mathematics measures, and that the effects of cognitive flexibility were entirely mediated by patterning. Working memory had independent effects on reading and mathematics, and also effects moderated by patterning. In sum, these findings suggest that cognitive flexibility and working memory are related to patterning and express their effects on reading and mathematics in whole or in part through patterning.