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Elihu H. Estey, MD: Leukaemia expert, statistician, and gentle soul (July 15, 1946-October 8, 2021)

Bone Marrow Transplant

2021 Roland Walter

N/A

OBITUARY Elihu H. Estey, MD: leukemia expert, statistician, and gentle soul (July 15, 1946-October 8, 2021)

Leukemia

2021 Roland Walter

N/A

A regulatory T cell signature distinguishes the immune landscape of COVID-19 patients from those with other respiratory infections

Sci Adv

2021 Andrew Konecny; Jennifer Lund; Sarah Vick; Marie Frutoso; Raphael Gottardo; Florian Mair; Martin Prlic; Jim Boonyaratanakornkit; Evan Greene; Joshua Schiffer

[Figure: see text].

Molecular and pathology features of colorectal tumors and patient outcomes are associated with Fusobacterium nucleatum and its subspecies animalis

Cancer Epidemiol Biomarkers Prev

2021 Susan Bullman; Yi Lin; Jiayin Zheng; Amanda Phipps; Robert Steinfelder; Wei Sun; Barbara Banbury; Polly Newcomb; Conghui Qu; Li Hsu; Tabitha Harrison

BACKGROUND: Fusobacterium nucleatum activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. METHODS: We characterized F nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer (CRC) specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 CRC patients and assessed associations between F nucleatum presence and clinical characteristics, CRC-specific mortality, and somatic mutations. RESULTS: F nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors-particularly subspecies animalis. Presence of F nucleatum was associated with higher CRC-specific mortality (hazard ratio [HR], 1.97; P=0.0004). This association was restricted to non-hypermutated, microsatellite-stable tumors (HR, 2.13; P=0.0002) and those who received chemotherapy (HR = 1.92, CI: 1.07-3.45, p-value = 0.029). Only F nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with CRC-specific mortality (HR, 2.16; P=0.0016)-subspecies vincentii and nucleatum were not (HR, 1.07, P=0.86). Additional adjustment for tumor stage suggests that the effect of F nucleatum on mortality is partly driven by a stage shift. Presence of F nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, ERBB3 mutations, and suggestively associated with TP53 mutations. CONCLUSIONS: F nucleatum, and particularly subspecies animalis, was associated with a higher CRC-specific mortality and specific somatic mutated genes. IMPACT: Our findings identify the F nucleatum subspecies animalis as negatively impacting CRC mortality which may occur through a stage shift and its effect on chemoresistance.

Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update

J Clin Oncol

2021 John Thompson

PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. METHODS: A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. RESULTS: A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.

Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: a two-center observational study

J Immunother Cancer

2021 John Thompson

BACKGROUND: Current treatment guidelines for immune-mediated diarrhea and colitis (IMDC) recommend steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) for refractory cases. We aimed to compare the efficacy of these two SITs and their impact on cancer outcomes. METHODS: We performed a two-center, retrospective observational cohort study of patients with IMDC who received SITs following steroids from 2016 to 2020. Patients' demographic, clinical, and overall survival data were collected and analyzed. RESULTS: A total of 184 patients (62 vedolizumab, 94 infliximab, 28 combined sequentially) were included. The efficacy of achieving clinical remission of IMDC was similar (89% vs 88%, p=0.79) between the two groups. Compared with the infliximab group, the vedolizumab group had a shorter steroid exposure (35 vs 50 days, p<0.001), fewer hospitalizations (16% vs 28%, p=0.005), and a shorter hospital stay (median 10.5 vs 13.5days, p=0.043), but a longer time to clinical response (17.5 vs 13 days, p=0.012). Longer durations of immune checkpoint inhibitors treatment (OR 1.01, p=0.004) and steroid use (OR 1.02, p=0.043), and infliximab use alone (OR 2.51, p=0.039) were associated with higher IMDC recurrence. Furthermore, 3 doses of SIT (p=0.011), and fewer steroid tapering attempts (p=0.012) were associated with favorable overall survival. CONCLUSIONS: Treatment with vedolizumab as compared with infliximab for IMDC led to comparable IMDC response rates, shorter duration of steroid use, fewer hospitalizations, and lower IMDC recurrence, though with slightly longer time to IMDC response. Higher number of SIT doses was associated with better survival outcome, while more steroid exposure resulted in worse patient outcomes.

2021 Update Measurable Residual Disease in Acute Myeloid Leukemia: European LeukemiaNet Working Party Consensus Document

Blood

2021 Roland Walter; Brent Wood

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD working party evaluates standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a two-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next generation sequencing (NGS)-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate endpoint for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular- MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.

Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers

Neuro Oncol

2021 Aleena Arakaki; Eric Holland; Taranjit Gujral; Frank Szulzewsky

Patients with rare central nervous system (CNS) tumors typically have a poor prognosis and limited therapeutic options. Historically, these cancers have been difficult to study due to small number of patients. Recent technological advances have identified molecular drivers of some of these rare cancers which we can now use to generate representative preclinical models of these diseases. In this review, we outline the advantages and disadvantages of different models, emphasizing the utility of various in vitro and ex vivo models for target discovery and mechanistic inquiry and multiple in vivo models for therapeutic validation. We also highlight recent literature on preclinical model generation and screening approaches for ependymomas, histone mutated high-grade gliomas, and atypical teratoid rhabdoid tumors, all of which are rare CNS cancers that have recently established genetic or epigenetic drivers. These preclinical models are critical to advancing targeted therapeutics for these rare CNS cancers that currently rely on conventional treatments.

The genome-editing decade

Mol Ther

2021 Hans-Peter Kiem

N/A

Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy

Blood Adv

2021 Jenna Voutsinas; Nancy Miles; Cameron Turtle; David Maloney; Merav Bar; Jordan Gauthier; Alexandre Hirayama; Qian (Vicky) Wu

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies, however, is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy on a phase I/II clinical trial (NCT01865617), with primary endpoints of absolute neutrophil count (ANC) and platelet count at day-28 following CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75% respectively, at 28 days post-CAR T-cell infusion. Hematologic toxicity was noted in a significant subset of patients with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Utilizing debiased LASSO regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower pre-lymphodepletion platelet count as independent predictors for both decreased neutrophil and platelet counts following CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of IL-6 and lower day-28 counts; in contrast, higher serum concentrations of TGF-β were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery following CD19 CAR T-cell therapy.