Venetoclax and Hypomethylating Agents as First-line Treatment in Newly Diagnosed Patients with AML in a Predominately Community Setting in the US.

BACKGROUND: Treatment with venetoclax + hypomethylating agents (HMAs) is standard-of-care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) aged ≥75 years, or with comorbidities precluding intensive chemotherapy. We describe real-world venetoclax + HMA treatment practices and outcomes in patients with ND AML in the US. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, US nationwide, de-identified database, and included adults with ND AML, initiating venetoclax + HMA treatment ≤30 days from diagnosis (June 1, 2018-January 31, 2020). Venetoclax treatment variables included dosing information, schedule modifications, and drug-drug interactions. The median venetoclax + HMA treatment duration and overall survival (OS) from venetoclax initiation to discontinuation, death, or end of follow-up (August 31, 2020) were examined by Kaplan-Meier analyses. RESULTS: Overall, 169 patients were included. The median age at diagnosis was 77 years; 85.2% of patients were treated in community practice. Ninety-five of 169 patients (56.2%) had evaluable bone marrow response data following the start of treatment; 53.7% were assessed approximately at the end of cycle 1. Following the first treatment cycle, treatment schedule modifications were recorded in 101 patients and dose changes in 56, primarily due to toxicity. The median treatment duration was 5.2 months; the median OS was 8.6 months (median follow-up was 7.2 months). Venetoclax dose changes did not modify efficacy outcomes, but longer median OS was associated with venetoclax treatment schedule modifications (P = .02). CONCLUSIONS: This study reflects early real-world experience with venetoclax + HMAs in a predominantly community setting and emphasizes the importance of appropriate venetoclax management in optimizing patient outcomes.

Primary Mediastinal B-cell Lymphoma Presenting as Chest Pain in a Young Woman and Treated with EPOCH-R.

Primary mediastinal B-cell lymphoma (PMBCL) is a rare type of diffuse large B-cell lymphoma, constituting 2-4% of non-Hodgkin lymphomas. Here we present a case of PMBCL initially presenting as pleuritic chest pain in an otherwise healthy 33-year-old woman. PMBCL typically presents as a large, fast-growing tumor limited to the mediastinum, making the iliosacral involvement in this case unusual. R-CHOP is the most commonly used chemotherapy regimen, although more aggressive therapies like EPOCH-R can spare the need for consolidative radiation therapy. PMBCL represents one of the greatest diagnostic and therapeutic challenges in malignant hematology.

Vosaroxin : a novel antineoplastic quinolone.

INTRODUCTION: The antineoplastic quinolone derivative vosaroxin (SNS-595, Sunesis, South San Francisco, CA, USA) was first described in 2002. It represents a novel class of anticancer drugs and is currently in a Phase III clinical trial for relapsed and refractory acute myeloid leukemia (AML). AML is the most common form of acute leukemia in adults and is increasing in incidence due to the aging of the American population. Despite advances in diagnosis, prognostic prediction, and treatment in younger age groups, there has been little improvement in survival among patients over 60 years of age, who make up the majority of those affected. AREAS COVERED: The development of vosaroxin, its mechanism of action, pharmacology, and metabolism, and the preclinical and clinical data to date will be covered. EXPERT OPINION: Despite its structural dissimilarity, vosaroxin has mechanisms of action similar to the anthracyclines and anthracenediones already in use for the treatment of AML. However, unlike these agents, vosaroxin is not a P-gp substrate, appears to be unaffected by overexpression of P-gp or TP53 mutations, and may be useful in the treatment of AML, especially in the elderly.

Conditional ablation of MHC-II suggests an indirect role for MHC-II in regulatory CD4 T cell maintenance.

Although the importance of MHC class II (MHC-II) in acute homeostatic proliferation of regulatory T (Treg) cells has been established, we considered here the maintenance and state of Treg cells in mice that are almost completely devoid of MHC-II in their periphery but still make their own CD4 T cells and Treg cells. The latter was accomplished by conditional deletion of a loxP-flanked MHC-II beta-chain allele using a TIE2Cre transgene, which causes a very high degree of deletion in hemopoietic/endothelial progenitor cells but without deletion among thymic epithelial cells. Such conditional MHC-II-deficient mice possess their own relatively stable levels of CD4+CD25+ cells, with a normal fraction of Foxp3+ Treg cells therein, but at a level approximately 2-fold lower than in control mice. Thus, both Foxp3low/- CD4+CD25+ cells, said to be a major source of IL-2, and IL-2-dependent Foxp3+ Treg cells are reduced in number. Furthermore, CD25 expression is marginally reduced among Foxp3+ Treg cells in conditional MHC-II-deficient mice, indicative of a lack of MHC-II-dependent TCR stimulation and/or IL-2 availability, and IL-2 administration in vivo caused greatly increased cell division among adoptively transferred Treg cells. This is not to say that IL-2 can cause Treg cell division in the complete absence of MHC-II as small numbers of MHC-II-bearing cells do remain in conditional MHC-II-deficient mice. Rather, this suggests only that IL-2 was limiting. Thus, our findings lend support to the proposal that Treg cell homeostasis depends on a delicate balance with a population of self-reactive IL-2-producing CD4+CD25+ cells which are themselves at least in part MHC-II-dependent.