Role of Biomarkers in the Management of Acute Myeloid Leukemia.

Despite many recent advances in treatment options, acute myeloid leukemia (AML) still has a high mortality rate. One important issue in optimizing outcomes for AML patients lies in the limited ability to predict response to specific therapies, duration of response, and likelihood of relapse. With evolving genetic characterization and improving molecular definitions, the ability to predict outcomes and long-term prognosis is slowly improving. The majority of the currently used prognostic assessments relate to molecular and chromosomal abnormalities, as well as response to initial therapy. These risk categories, however, do not account for a large amount of the variability in AML. Laboratory techniques now utilized in the clinic extend beyond bone marrow morphology and single gene sequencing, to next-generation sequencing of large gene panels and multiparameter flow cytometry, among others. Other technologic advances, such as gene expression analysis, have yet to demonstrate enough predictive and prognostic power to be employed in clinical medicine outside of clinical trials, but may be incorporated into the clinic in the future. In this review, we discuss the utility of current biomarkers, and present novel biomarker techniques and strategies that are in development for AML patients. Measurable residual disease (MRD) is a powerful prognostic tool that is increasingly being incorporated into clinical practice, and there are some exciting emerging biomarker technologies that have the potential to improve prognostic power in AML. As AML continues to be a difficult-to-treat disease with poor outcomes in many subtypes, advances in biomarkers that lead to better treatment decisions are greatly needed.

Induction of IL19 expression through JNK and cGAS-STING modulates DNA damage-induced cytokine production.

Cytokine production is a critical component of cell-extrinsic responses to DNA damage and cellular senescence. Here, we demonstrated that expression of the gene encoding interleukin-19 (IL-19) was enhanced by DNA damage through pathways mediated by c-Jun amino-terminal kinase (JNK) and cGAS-STING and that IL19 expression was required for the subsequent production of the cytokines IL-1, IL-6, and IL-8. IL19 expression was stimulated by diverse cellular stresses, including inhibition of the DNA replication checkpoint kinase ATR (ataxia telangiectasia and Rad3-related protein), oncogene expression, replicative exhaustion, oxidative stress, and DNA double-strand breaks. Unlike the production of IL-6 and IL-8, IL19 expression was not affected by abrogation of signaling by the IL-1 receptor (IL-1R) or the mitogen-activated protein kinase p38. Instead, the DNA damage­induced production of IL-1, IL-6, and IL-8 was substantially reduced by suppression of IL19 expression. The signaling pathways required to stimulate IL19 expression selectively depended on the type of DNA-damaging agent. Reactive oxygen species and the ASK1-JNK pathway were critical for responses to ionizing radiation (IR), whereas the cGAS-STING pathway stimulated IL19 expression in response to either IR or ATR inhibition. Whereas induction of IL1, IL6, and IL8 by IR depended on IL19 expression, the cGAS-STING­dependent induction of the immune checkpoint gene PDL1 after IR and ATR inhibition was independent of IL19. Together, these results suggest that IL-19 production by diverse pathways forms a distinct cytokine regulatory arm of the response to DNA damage.

Innate Immune Mechanisms and Immunotherapy of Myeloid Malignancies.

Similar to other cancers, myeloid malignancies are thought to subvert the immune system during their development. This subversion occurs via both malignant cell-autonomous and non-autonomous mechanisms and involves manipulation of the innate and adaptive immune systems. Multiple strategies are being studied to rejuvenate, redirect, or re-enforce the immune system in order to fight off myeloid malignancies. So far, the most successful strategies include interferon treatment and antibody-based therapies, though chimeric antigen receptor (CAR) cells and immune checkpoint inhibitors are also promising therapies. In this review, we discuss the inherent immune mechanisms of defense against myeloid malignancies, currently-approved agents, and agents under investigation. Overall, we evaluate the efficacy and potential of immuno-oncology in the treatment of myeloid malignancies.

B Cell Lymphomas of the GI Tract.

PURPOSE OF THE REVIEW: Primary GI lymphomas of B cell origin are a diverse group of lymphomas. In this article, we provide an overview of the diagnosis, pathologic and molecular features, and management of these varied lymphomas. RECENT FINDINGS: The most common primary GI lymphomas are diffuse large B cell lymphoma (DLBCL) and marginal zone lymphomas (MZL), but follicular lymphomas (FL), mantle cell lymphomas (MCL), post-transplant lymphoproliferative disorders (PTLD), and Burkitt lymphoma of the GI tract also occur. Many features of these lymphomas are similar to their nodal counterparts, but certain clinical and biological aspects are unique. Diagnostic and treatment strategies for these lymphomas continue to evolve over time. There are ongoing discoveries about the unique pathophysiology, molecular characteristics, and complications of primary B cell GI lymphomas that are already leading to improvements in management of this histologically diverse set of lymphomas.

Frontline Treatment for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Targeted Therapy vs. Chemoimmunotherapy.

PURPOSE OF REVIEW: The treatment options for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have expanded significantly in the last few years, including the use of new classes of oral small molecular inhibitors targeting the B cell receptor signaling pathway or the apoptosis machinery. Targeted therapy with or without immunotherapy has quickly emerged as a new standard for frontline treatment of CLL/SLL, though the previous standard chemoimmunotherapy (CIT) remains a treatment option. In this review, we present data from key clinical trials to evaluate the benefits and risks associated with different frontline treatment approaches. RECENT FINDINGS: We reviewed recently published and presented clinical trials on frontline CLL/SLL treatment, with particular focus on the comparison of CIT vs. targeted therapies, including inhibitors of Bruton's tyrosine kinase (BTK) or of the anti-apoptotic protein Bcl-2. Various BTK inhibitors as continuous treatment with or without anti-CD20 monoclonal antibodies have compared favorably to the conventional CITs in previously untreated CLL/SLL patients of various ages and comorbidities. Fixed duration treatment with the Bcl-2 inhibitor venetoclax combined with anti-CD20 monoclonal antibodies also showed superiority in clinical outcomes compared to CIT. Subgroup analysis interestingly showed that IgHV-mutated CLL/SLL might still derive similar benefits from CIT. Ongoing clinical trials are investigating combined targeted therapies of venetoclax plus a BTK inhibitor to try to further improve the efficacy while limiting the duration of treatment. Targeted therapies are becoming the new standard of care for frontline treatment of CLL/SLL although conventional CIT remains an option group of fit patients with low risk features. Novel strategies are being studied using targeted therapy combinations to optimize the depth of response in a time-limited fashion.

Controlling Phlebotomy Volume Diminishes PICU Transfusion: Implementation Processes and Impact.

BACKGROUND AND OBJECTIVES: Phlebotomy excess contributes to anemia in PICU patients and increases the likelihood of red blood cell transfusion, which is associated with risk of adverse outcomes. Excessive phlebotomy reduction (EPR) strategies may reduce the need for transfusion, but have not been evaluated in a PICU population. We hypothesized that EPR strategies, facilitated by implementation science methods, would decrease excess blood drawn and reduce transfusion frequency. METHODS: Quantitative and qualitative methods were used. Patient and blood draw data were collected with survey and focus group data to evaluate knowledge and attitudes before and after EPR intervention. The Consolidated Framework for Implementation Research was used to interpret qualitative data. Multivariate regression was employed to adjust for potential confounders for blood overdraw volume and transfusion incidence. RESULTS: Populations were similar pre- and postintervention. EPR strategies decreased blood overdraw volumes 62% from 5.5 mL (interquartile range 1-23) preintervention to 2.1 mL (interquartile range 0-7.9 mL) postintervention (P < .001). Fewer patients received red blood cell transfusions postintervention (32.1% preintervention versus 20.7% postintervention, P = .04). Regression analyses showed that EPR strategies reduced blood overdraw volume (P < .001) and lowered transfusion frequency (P = .05). Postintervention surveys reflected a high degree of satisfaction (93%) with EPR strategies, and 97% agreed EPR was a priority postintervention. CONCLUSIONS: Implementation science methods aided in the selection of EPR strategies and enhanced acceptance which, in this cohort, reduced excessive overdraw volumes and transfusion frequency. Larger trials are needed to determine if this approach can be applied in broader PICU populations.

Survivin is not required for the endomitotic cell cycle of megakaryocytes.

Survivin is a member of the chromosome passenger complex, which plays an important role in chromosome alignment, separation, and cytokinesis. Although survivin is required for the proliferation and survival of hematopoietic stem and progenitor cells, the extent to which it is necessary for endomitosis of megakaryocytes remains controversial. To determine whether survivin is required for polyploidization, we analyzed mice with a megakaryocyte-specific deletion. PF4-Cre/survivin(fl/fl) mice harbored normal platelet counts with megakaryocytes that reached ploidy states comparable with those of control littermates. The CD41(+) cells within these animals showed little excision but increased annexin V staining, implying that survivin is required for survival of megakaryocyte progenitors in vivo. In contrast, megakaryocytes in which survivin was excised ex vivo showed robust excision and an increased degree of polyploidization. These results demonstrate that survivin is necessary for survival of megakaryocyte progenitors, but is not required for polyploidization of committed megakaryocytes.