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Biology of Blood and Marrow... Apr 2019Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently... (Review)
Review
Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
Topics: Cytokine Release Syndrome; Guidelines as Topic; Humans; Immunotherapy; Receptors, Antigen, T-Cell
PubMed: 30592986
DOI: 10.1016/j.bbmt.2018.12.758 -
Nature Reviews. Clinical Oncology Jan 2018Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and... (Review)
Review
Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.
Topics: Adult; Brain Diseases; Cytokines; Female; Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Syndrome
PubMed: 28925994
DOI: 10.1038/nrclinonc.2017.148 -
Current Opinion in Pediatrics Feb 2019Pediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted... (Review)
Review
PURPOSE OF REVIEW
Pediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors.
RECENT FINDINGS
It is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities.
SUMMARY
Novel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.
Topics: Child; Glioma; Humans; Neoplasm Grading
PubMed: 30531227
DOI: 10.1097/MOP.0000000000000717 -
Biology of Blood and Marrow... Apr 2019In this issue of BBMT, a multicenter group of investigators convened by the American Society of Blood and Marrow Transplantation outlines new consensus definitions and...
In this issue of BBMT, a multicenter group of investigators convened by the American Society of Blood and Marrow Transplantation outlines new consensus definitions and grading systems for the most common toxicities associated with immune effector cell therapies, including cytokine release syndrome and the newly named immune cell-associated neurotoxicity syndrome.
Topics: Cells, Cultured; Humans; Killer Cells, Natural
PubMed: 30615980
DOI: 10.1016/j.bbmt.2019.01.001 -
American Journal of Hematology May 2019CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy has demonstrated impressive results in B-cell malignancies, and CAR-T cell therapies... (Review)
Review
CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy has demonstrated impressive results in B-cell malignancies, and CAR-T cell therapies targeting other antigens are in development for other cancers. Cytokine release syndrome (CRS) and neurotoxicity can be life-threatening in a subset of patients. The severity of CRS and neurotoxicity can be impacted by the disease burden, lymphodepletion regimen, and CAR-T cell dose. Tocilizumab and corticosteroids have been used to manage these toxicities, enabling CD19 CAR-T cells to be administered without obvious compromise in efficacy. Consensus criteria for grading and managing toxicities will facilitate the widespread application of this treatment modality.
Topics: Antigens, CD19; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Neurotoxicity Syndromes; Receptors, Antigen, T-Cell
PubMed: 30784102
DOI: 10.1002/ajh.25445 -
In Vivo (Athens, Greece) 2019The risk factors, clinical features and non-hematological toxicity profiles during chemotherapy in acute lymphoblastic leukemia (ALL) patients treated in pediatric...
BACKGROUND/AIM
The risk factors, clinical features and non-hematological toxicity profiles during chemotherapy in acute lymphoblastic leukemia (ALL) patients treated in pediatric hematology centres were analysed.
MATERIALS AND METHODS
A total of 902/1872 children were reported as having grade 3 or 4 toxicity.
RESULTS
Among the analysed toxicities, infection and gastrointestinal and liver toxicities were the most common. The median follow-up was 6.8 years. Overall survival and event-free survival rates for the analysed group were lower than those reported for the group without grade ≥3 toxicity. In univariate analysis, we identified the number of toxic episodes, the risk group and remission status that had a significant impact on the outcome. Multivariate analysis demonstrated the risk group and the number of toxic episodes ≥3 to be statistically significant for the results.
CONCLUSION
The toxic profiles investigated in our report should be used in future efforts to decrease the burden of side effects during chemotherapy.
Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Testing; Humans; Immunophenotyping; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Severity of Illness Index
PubMed: 31280227
DOI: 10.21873/invivo.11608 -
Hematological Oncology Aug 2021National Comprehensive Cancer Network guidelines recommend radiation therapy (RT) for localized indolent non-Hodgkin lymphomas (iNHL). Many referring physicians avoid RT... (Comparative Study)
Comparative Study
National Comprehensive Cancer Network guidelines recommend radiation therapy (RT) for localized indolent non-Hodgkin lymphomas (iNHL). Many referring physicians avoid RT to the head and neck (HN) due to fears of toxicity. Very low-dose radiation (4 Gy) for select patients produces sustained local control and recently gained popularity. We compared early and late toxicities of standard 24-30 Gy to 4 Gy in patients with HN iNHL. We retrospectively analyzed 266 consecutive patients with HN iNHL receiving RT from 1994 to 2017. Patient characteristics, outcomes, and toxicities were collected from medical records. Early (≤2 months post-RT) and late (>2 months post-RT) toxicities were graded per Common Terminology Criteria for Adverse Events version 4. Grades 1-2 were defined as "low-grade" and 3-4 "high-grade." Toxicity incidence was compared between 4 and >4 Gy, grouped by treated site (orbit, nonorbital head, neck, skin) and early versus late. Median follow-up was 23 months (2-145) and 68 months (2-256) for 4Gy and >4 Gy cohorts, respectively. Median dose for the >4 Gy cohort was 30 Gy (10.5-54 Gy). Early and late toxicity incidences were lower in the 4 Gy cohort compared to >4 Gy across all RT-sites: early toxicity, orbit, 42% versus 96%; nonorbital head, 24% versus 96%; neck, 22% versus 94%; skin, 31% versus 87%; late toxicity, orbit, 20% versus 71%; nonorbital head, 6% versus 66%; neck, 6% versus 57%; skin, 0% versus 46% (4 Gy vs. >4 Gy, respectively). Toxicities among both cohorts were largely low-grade. High-grade early and late toxicities did not occur in the 4 Gy cohort. There was 1 high-grade early toxicity (Grade 3 dry mouth) and 17 high-grade late toxicities (Grade 3 cataracts) in the >4 Gy cohort. RT to HN for iNHL is associated with minimal short- and long-term toxicity and excellent local control among 4 Gy and >4 Gy treatments. In this setting, "toxicity" concerns should not deter oncologists from potentially curative RT. In select patients where toxicity remains a concern, very low dose 4 Gy could be considered.
Topics: Adult; Aged; Aged, 80 and over; Female; Head and Neck Neoplasms; Humans; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Grading; Radiotherapy Dosage
PubMed: 33733514
DOI: 10.1002/hon.2865 -
Cancer Jan 2017The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) is the universal framework for toxicity reporting in oncology trials. The...
BACKGROUND
The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) is the universal framework for toxicity reporting in oncology trials. The objective of this study was to develop a CTCAE-compatible modified barium swallow (MBS) grade for the purpose of grading pharyngeal dysphagia as a toxicity endpoint in cooperative-group organ-preservation trials for head and neck cancer (HNC). It was hypothesized that a 5-point, CTCAE-compatible MBS grade (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST]) based on the interaction of pharyngeal residue and laryngeal penetration/aspiration ratings would be feasible and psychometrically sound.
METHODS
A modified Delphi exercise was conducted for content validation, expert consensus, and operationalization of DIGEST criteria. Two blinded raters scored 100 MBSs conducted before or after surgical or nonsurgical organ preservation. Intrarater and interrater reliability was tested with weighted κ values. Criterion validity against oropharyngeal swallow efficiency (OPSE), the Modified Barium Swallow Impairment Profile (MBSImP™©), the MD Anderson Dysphagia Inventory (MDADI), and the Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) was assessed with a 1-way analysis of variance and post hoc pairwise comparisons between DIGEST grades.
RESULTS
Intrarater reliability was excellent (weighted κ = 0.82-0.84) with substantial to almost perfect agreement between raters (weighted κ = 0.67-0.81). DIGEST significantly discriminated levels of pharyngeal pathophysiology (MBSImP™©: r = 0.77; P < .0001), swallow efficiency (OPSE: r = -0.56; P < .0001), perceived dysphagia (MDADI: r = -0.41; P < .0001), and oral intake (PSS-HN diet: r = -0.49; P < .0001).
CONCLUSIONS
With the development of DIGEST, the MBS rating has been adapted to the CTCAE nomenclature of ordinal toxicity grading used in oncology trials. DIGEST offers a psychometrically sound measure for HNC clinical trials and investigations of toxicity profiles, dose responses, and predictive modeling. Cancer 2017;62-70. © 2016 American Cancer Society.
Topics: Barium; Deglutition; Deglutition Disorders; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; National Cancer Institute (U.S.); Pharynx; Psychometrics; Quality of Life; Reproducibility of Results; Surveys and Questionnaires; United States
PubMed: 27564246
DOI: 10.1002/cncr.30283 -
International Journal of Molecular... May 2023Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues...
Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications.
Topics: Humans; Adult; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Retrospective Studies; T-Lymphocytes; Thrombosis; Receptors, Antigen, T-Cell
PubMed: 37176053
DOI: 10.3390/ijms24098349 -
Diabetologia Jul 2018The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting... (Review)
Review
The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found >40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p'-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p'-DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p'-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking.
Topics: Animals; Benzhydryl Compounds; DDT; Diabetes Mellitus; Dichlorodiphenyl Dichloroethylene; Endocrine Disruptors; Glucose Tolerance Test; Humans; Phenols
PubMed: 29744538
DOI: 10.1007/s00125-018-4621-3