The CNS Relapse in T-Cell Lymphoma Index Predicts CNS Relapse in Patients with T- and NK-Cell Lymphomas.

Little is known about risk factors for central nervous system (CNS) relapse in mature T- and NK-cell neoplasms (MTNKN). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKN, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (N=182), of whom 91 had CNS relapse, we applied a LASSO Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (N=566). CNS relapse was most frequently observed in patients with PTCL, NOS (25%). Median time to CNS relapse and median overall survival after CNS relapse was 8.0 months and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (N=158) and high-risk (N=188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (HR 5.24, 95%CI 1.50-18.26, P=0.018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at highest risk of developing CNS relapse.

Impact of Race and Social Determinants of Health on Outcomes in Patients with Aggressive B-cell nHL Treated with CAR-T.

Healthcare disparities driven by multiple social, economic, and/or environmental factors lead to inequalities in health outcomes. CAR-T cell immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care utilization and outcomes in patients treated with CAR-T for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-T were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic and clinical data were collected and analyzed via Chi-squared and Kaplan-Meier analysis. Cox multivariable regression (MVA) was used to determine the impact of race/ethnicity and other variables on survival. 466 adult patients were included in our analysis. Median follow-up after CAR-T was 12.7 months. Median progression free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months, HR 1.56 [1.03-2.4], p=0.04) or Asians (2.7 months, HR 1.7 [1.02-2.67], p=0.04). Differences in median overall survival (mOS) were not significant. For Medicare (n=206) vs Medicaid (n=33) vs private insurance (n=219) vs self-pay (n=7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (p<0.001) and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (p<0.001), respectively. Collectively, our multi-center retrospective analysis showed that race and insurance status can impact outcomes for patients treated with CAR-T cell therapy.

Central Nervous System Relapse in T and NK cell Lymphomas.

PURPOSE OF REVIEW: T and NK cell lymphomas are relatively rare and heterogeneous forms of non-Hodgkin lymphoma that are associated with high rates of mortality. Central nervous system relapse carries significant morbidity, though management is largely extrapolated from literature in B cell neoplasms. As such, outcomes for central nervous system involvement in T/NK cell lymphomas are dismal with no standard of care. In this review, we discuss the epidemiology of central nervous system relapse in T/NK cell lymphomas and critically analyze available literature regarding prophylaxis and treatment. RECENT FINDINGS: Retrospective studies of central nervous system involvement in T/NK cell lymphomas have been limited by small sample sizes and heterogeneity of subtypes, though sites of extranodal involvement and disease subtypes are consistently reported as risk factors. Compelling evidence for the use of central nervous system-directed prophylactic therapy has not yet been established, though recent reports of central nervous system activity with novel agents may suggest promising therapeutic options. The overall rarity of T and NK cell lymphomas has precluded adequate study of prophylaxis and treatment of central nervous system relapse. Collaborative efforts are needed to better define strategies to address CNS disease in T/NK cell lymphomas. These should involve the use of targeted agents, which may hold an advantage over traditional cytotoxic drugs.

SOHO State of the Art Updates and Next Questions | Challenging Cases in Rare T-Cell Lymphomas.

Mature T- and NK-cell neoplasms (MTNKN) collectively represent a rare disorder, representing less than 15% of all non-Hodgkin lymphoma (NHL) cases and qualifying for orphan disease designation by the U.S. Food and Drug Administration (FDA). These consist of 9 families in the fifth revised WHO classification of lymphoid neoplasms, which are made up of over 30 disease subtypes, underscoring the heterogeneity of clinical features, molecular biology, and genetics across this disease group. Moreover, the 5 most common subtypes (peripheral T-cell lymphoma, not otherwise specified; nodal TFH cell lymphoma, angioimmunoblastic type; extranodal NK-cell/T-cell lymphoma; adult T-cell leukemia/lymphoma; and ALK-positive or -negative anaplastic large cell lymphoma) comprise over 75% of MTNKN cases, so other subtypes are exceedingly rare in the context of all NHL diagnoses and consequently often lack consensus on best practices in diagnosis and management. In this review, we discuss the following entities-enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and primary cutaneous ɣδ T-cell lymphoma (PCGD-TCL) - with an emphasis on clinical and diagnostic features and options for management.

Older Adults With Newly Diagnosed AML: Hot Topics for the Practicing Clinician.

Over the past decade, our understanding of AML pathogenesis and pathophysiology has improved significantly with mutational profiling. This has led to translational advances in therapeutic options, as there have been 10 new US Food and Drug Administration (FDA) approvals for AML therapies since 2017, half of which target specific driver mutations in FLT3, IDH1, or IDH2. These new agents have expanded the therapeutic armamentarium for AML, particularly for patients who are considered ineligible for intensive chemotherapy with anthracycline- and cytarabine-containing regimens. These new treatment options are relevant because the median age at diagnosis is 68 years, and outcomes for patients older than 60 years have historically been dismal. However, the optimal approach to incorporating novel agents into frontline regimens remains a clinical challenge, particularly with regard to sequencing of therapies, considering the role of allogeneic hematopoietic stem cell transplantation and managing toxicities.

Recent advances in targeted therapies in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.

Central Nervous System Progression/Relapse in Mature T- and NK-Cell Lymphomas.

Non-Hodgkin lymphomas (NHL) are cancers of mature B-, T-, and NK-cells which display marked biological heterogeneity between different subtypes. Mature T- and NK-cell neoplasms are an often-aggressive subgroup of NHL and make up approximately 15% of all NHL. Long-term follow up studies have demonstrated that patients with relapsed/refractory disease have dismal outcomes; in particular, secondary central nervous system (CNS) involvement is associated with higher mortality, though it remains controversial whether this independently confers worse outcomes or if it simply reflects more aggressive systemic disease. Possible risk factors predictive of CNS involvement, such as an elevated lactate dehydrogenase and more than two sites of extranodal involvement, may suggest the latter, though several studies have suggested that discrete sites of anatomic involvement or tumor histology may be independent risk factors as well. Ultimately, small retrospective case series form the basis of our understanding of this rare but devastating event but have not yet demonstrated a consistent benefit of CNS-directed prophylaxis in preventing this outcome. Nonetheless, ongoing efforts are working to establish the epidemiology of CNS progression/relapse in mature T- and NK-cell lymphomas with the goal of identifying clinicopathologic risk factors, which may potentially help discern which patients may benefit from CNS-directed prophylactic therapy or more aggressive systemic therapy.

Peri-CAR-T practice patterns and survival predictors for all CAR-T patients and post-CAR-T failure in aggressive B-NHL.

Most patients receiving chimeric antigen receptor T-cell therapy (CAR-T) for aggressive B-cell non-Hodgkin lymphoma (B-NHL) do not experience a durable remission. Several novel agents are approved to treat relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre- and post-CAR-T. We conducted a multicenter retrospective analysis to describe peri-CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n = 514) from 13 centers treated with CAR-T for B-NHL between 2015-2021 were included in the study. Survival curves were constructed using Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of the variables on survival outcomes. For all patients receiving CAR-T, a greater number of lines of therapy pre-CAR-T apheresis and bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). The median PFS and OS from the time of CAR-T cell infusion were 7.6 and 25.6 months, respectively. From the time of progression post-CAR-T, the median OS was 5.5 months. The median PFS of treatments administered in the first-line post-CAR-T failure was 2.8 months. Patients with refractory disease on day 30 had inferior OS and were less likely to receive subsequent treatment(s) than other patients with CAR-T failure. Allogeneic hematopoietic cell transplantation for selected patients at any time following CAR-T failure led to durable responses in over half of patients at 1 year. These data provide a benchmark for future clinical trials in patients with post-CAR-T cell progression, which remains an unmet clinical need.

The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target.

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a serine/threonine kinase that belongs to the DYRK family of proteins, a subgroup of the evolutionarily conserved CMGC protein kinase superfamily. Due to its localization on chromosome 21, the biological significance of DYRK1A was initially characterized in the pathogenesis of Down syndrome (DS) and related neurodegenerative diseases. However, increasing evidence has demonstrated a prominent role in cancer through its ability to regulate biologic processes including cell cycle progression, DNA damage repair, transcription, ubiquitination, tyrosine kinase activity, and cancer stem cell maintenance. DYRK1A has been identified as both an oncogene and tumor suppressor in different models, underscoring the importance of cellular context in its function. Here, we review mechanistic contributions of DYRK1A to cancer biology and its role as a potential therapeutic target.

Lithium and Therapeutic Targeting of GSK-3.

Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3.

DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.

Assessment of peripheral neutrophil functions in patients with localized aggressive periodontitis in the Indian population.

BACKGROUND: Localized aggressive periodontitis (LAP) patients exhibit abnormal neutrophil functions to a variety of environmental and host stimuli. The aim of the present study was to evaluate neutrophils chemotaxis, phagocytosis, microbicidal activity and superoxide generation in LAP patients of Indian origin. MATERIALS AND METHODS: Eleven LAP patients and nine healthy subjects were included in the study. Neutrophil chemotaxis was evaluated against an alkali-soluble casein solution using Wilkinson's method. Phagocytosis and microbicidal activity assay were performed using Candida albicans as an indicator organism. Nitrobluetetrazolium (NBT) test was used to assess superoxide generation by neutrophils using E. coli endotoxin. RESULTS: The chemotactic activity and phagocytic and microbicidal activity were observed to be significantly reduced (P < 0.01) in LAP neutrophils. On the contrary, superoxide generation was observed to be significantly increased (P < 0.01) in LAP neutrophils compared with healthy individuals. CONCLUSION: The results of the present study suggest that neutrophil functions, namely chemotaxis, phagocytosis and microbicidal activity, are deficient LAP patients. However, superoxide generation was significantly increased when stimulated by endotoxins, which may explain the tissue damage seen in LAP. These abnormal neutrophil functions may predispose to increased susceptibility for LAP. Further large-scale studies are required in the Indian population to ascertain the cause-and-effect relationship of defective host factors and aggressive periodontitis and to develop treatment strategies for more predictable periodontal treatment outcome.

Periodontal management of gingival enlargement associated with Sturge-Weber syndrome.

BACKGROUND: Sturge-Weber syndrome (encephalotrigeminal angiomatosis) is a rather uncommon congenital condition that is characterized by a combination of venous angioma of leptomeninges over the cerebral cortex and ipsilateral angiomatous lesions of the face and sometimes of the skull, jaws, and oral soft tissues. It is commonly referred to as Sturge-Weber syndrome after Sturge and Weber who first described this affliction in 1879. This article presents a case of Sturge-Weber syndrome associated with severe gingival enlargement, its management, and follow-up results. METHODS: A 15-year-old male patient was referred to the Department of Periodontics, Government Dental College and Hospital, for severe gingival enlargement. A detailed dental and medical history, clinical examination, and investigations confirmed the diagnosis of Sturge-Weber syndrome. This report reveals a classic presentation of the syndrome with emphasis on its oral manifestations. Periodontal management included thorough scaling and root planing followed by periodontal flap surgery to treat the gingival enlargement. Histopathologic examination of the excisional biopsy specimen revealed features suggestive of fibrous gingival enlargement. RESULTS: Reevaluation of the patient after 2 years showed remarkable (90%) reduction of the gingival enlargement in the maxillary arch and complete diminution (100%) in the mandibular arch. However, a slight recurrence was noted in the maxillary right quadrant. CONCLUSIONS: Sturge-Weber syndrome is clinically important to the periodontist because of its associated gingival vascular features and their complicating manifestations. Periodic systemic and oral examinations are recommended to identify and prevent any complications from the cranial and oral lesions.