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He J, Connors J, Meador A, Xu S, Meador H, Jiang H, Fueyo J, Gomez-Manzano C, Friedman GK, Zaky W, Sadighi Z, Slopis JM, Ahmad AH. Immunotherapy-related neurotoxicity in the central nervous system of children with cancer. Neuro Oncol 2025; 27:625-643. [PMID: 39535217 PMCID: PMC11889721 DOI: 10.1093/neuonc/noae243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Indexed: 11/16/2024] Open
Abstract
Significant gaps remain in our understanding of immunotherapy-related neurotoxicity in pediatric patients, largely because much of our knowledge comes from studies in adults. Accurately identifying the adverse effects of immunotherapy in children is also challenging, owing to variations in terminology and grading systems. Moreover, the manifestation of immunotherapy-related neurotoxicity differs greatly across different diseases, various modalities, dosages, and delivery methods. Combining immunotherapy with other treatments might improve outcomes but introduces new complexities and potential for increased toxicities. Additionally, pediatric patients with intracranial malignancy have unique responses to immunotherapies and distinct neurotoxicity compared to those with extracranial malignancy. Consequently, we must enhance our understanding of the pathophysiology, prevalence, severity, and management of immunotherapy's neurotoxic effects in this vulnerable group. This review consolidates the current knowledge of immunotherapy-related neurotoxicity in pediatric oncology, highlighting various types of neurotoxicity including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor inflammation-associated neurotoxicity (TIAN), among others. Furthermore, we examine the unique features of neurotoxicity associated with adoptive cellular therapy (ACT), antibody-based therapies, immune checkpoint inhibitors (ICIs), oncolytic viruses (OV), and cancer vaccines.
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Affiliation(s)
- Jiasen He
- Section of Pediatric Neuro-Oncology, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jeremy Connors
- Section of Stem Cell Transplant, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Andrew Meador
- Texas A&M University School of Medicine, Bryan, Texas, USA
| | - Shuo Xu
- Section of Pediatric Hematology Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Heather Meador
- Section of Pediatric Neuro-Oncology, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hong Jiang
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Juan Fueyo
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Candelaria Gomez-Manzano
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gregory K Friedman
- Section of Pediatric Neuro-Oncology, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wafik Zaky
- Section of Pediatric Neuro-Oncology, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zsila Sadighi
- Section of Pediatric Neuro-Oncology, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - John M Slopis
- Section of Pediatric Neuro-Oncology, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ali H Ahmad
- Section of Pediatric Critical Care, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Yin Y, Zhang W, Zhao L, Li Y, Huang M, Han Y, Wu X. Development and validation of a predictive model for diagnosing EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis. BMC Cancer 2025; 25:397. [PMID: 40045277 PMCID: PMC11881351 DOI: 10.1186/s12885-025-13788-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/21/2025] [Indexed: 03/09/2025] Open
Abstract
PURPOSE This study aims to identify distinguishing factors between EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis and non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis. Additionally, we developed and validated a predictive diagnostic model based on these factors. METHODS To evaluate the early identification of individuals with EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis versus non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis, we carried out a retrospective cohort research. The medical records system included 148 individuals' diagnoses of EBV-associated hemophagocytic lymphohistiocytosis between 2015 and 2023. RESULTS In this study, 148 patients were included, 75 of whom had non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis and the remaining 73 had EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis. The highest AUC, with a good predictive value, was found for IL-10 > 39.87 pg/ml in separating EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis from non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis. The diagnosis of EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis was influenced by platelets < 33.5*109/L, IL-6 > 20.79 pg/ml, and IFN-γ > 12.12 pg/ml as independent variables. These factors were combined with the predictive value of IL-10 > 39.87 pg/ml to establish the predictive model of the nomogram for diagnosis. The training set's and validation set's areas under the ROC curves were 0.825 and 0.812, respectively, showing that the model had good discrimination, a well-calibrated model, and a clinically valid model as indicated by the clinical decision curve. CONCLUSION The results of this study showed that the prediction model based on platelets < 33.5*109/L, IL-6 > 20.79 pg/ml, IFN-γ > 12.12 pg/ml, and IL-10 > 39.87 pg/ml could more accurately distinguish between EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis and non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis. This could aid clinicians in the early detection and convenient individualization of treatment for EBV-associated hemophagocytic lymphohistiocytosis.
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Affiliation(s)
- Yuhong Yin
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Wenzhi Zhang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Lizhen Zhao
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Ying Li
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Minchun Huang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Yu Han
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Xiaoyan Wu
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
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Zoref-Lorenz A, Witzig TE, Cerhan JR, Jordan MB. Malignancy-associated HLH: mechanisms, diagnosis, and treatment of a severe hyperinflammatory syndrome. Leuk Lymphoma 2024:1-9. [PMID: 39656557 DOI: 10.1080/10428194.2024.2436037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/24/2024] [Accepted: 11/25/2024] [Indexed: 12/17/2024]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by uncontrolled immune activation. While traditionally associated with genetic mutations affecting cytotoxic function, recent advances have highlighted the prevalence and significance of HLH in adults, particularly in hematologic malignancies. This review focuses on malignancy-associated HLH (M-HLH), a complex and challenging condition with a poor prognosis. The review explores four main subtypes of M-HLH: (1) HLH as the initial presentation of malignancy, (2) Chemotherapy Associated HLH, (3) Cytokine Release Syndrome (CRS) Associated HLH-like Syndrome, and (4) immune effector cell-associated HLH-like syndrome. Diagnosis is complicated by overlap with cancer symptoms and limitations of existing criteria. The Optimized HLH Inflammatory (OHI) index shows promise in early identification of hyperinflammation in new-onset hematologic malignancies. Treatment approaches must balance controlling hyperinflammation with addressing the underlying malignancy. Emerging therapies, including targeted agents like anakinra, ruxolitinib, and emapalumab, offer new management possibilities. This review examines the current understanding of M-HLH pathophysiology, diagnostic approaches, and treatment strategies for each subtype. It underscores the critical need for further research to unravel underlying mechanisms and establish evidence-based treatment protocols. Given the complexity of M-HLH, international collaborative efforts are essential to advance knowledge and improve patient outcomes.
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Affiliation(s)
- Adi Zoref-Lorenz
- Meir Medical Center, Hematology Institute, Tel Aviv University, Tel Aviv, Israel
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Thomas E Witzig
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - James R Cerhan
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Michael B Jordan
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Division of Bone Marrow Transplantation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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4
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Zhang Q, Yu Q, Chen Q, Dong H, Fang M, Liu N, Li W, Wang H, Zhao N, Zhu X, Zhang K, Zhou C. Prevalence, trends, and outcomes of hematological malignancies in patients with hemophagocytic lymphohistiocytosis. Hematology 2024; 29:2431397. [PMID: 39585795 DOI: 10.1080/16078454.2024.2431397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/11/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUNDS Hemophagocytic lymphohistiocytosis (HLH) is an acute, rapidly progressive systemic inflammatory disorder that often occurs secondary to hematological malignancies among other conditions in adults. Although the annual incidence of HLH is increasing, detailed epidemiological knowledge of HLH is still limited, especially in patients with hematological malignancies. OBJECTIVES To analyze the impact of hematological malignancies on the epidemiology and outcomes of HLH. STUDY DESIGN Data from the National Readmission Database (NRD) from 2011 to 2020 were analyzed to explore the epidemiological trends and in-hospital outcomes of HLH patients, particularly those with hematological malignancies. RESULTS Our analysis included 7579 HLH hospitalizations, with hematological malignancies implicated in 24.01% of cases. Our findings reveal a steady increase in HLH diagnoses from 145 cases in 2011 to 1848 in 2020, with the proportion linked to hematological malignancies remaining consistent. Patients with hematological malignancies-associated HLH exhibited higher rates of in-hospital mortality (31.6%) than those without (14.4%), and a higher 30-day readmission rate, underscoring a critical need for early detection and treatment revision. CONCLUSIONS Despite the increasing awareness and diagnosis of HLH, the prognosis of patients with HLH associated with hematological malignancies remains poor, highlighting the urgent need for improved management strategies and therapeutic interventions.
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Affiliation(s)
- Qi Zhang
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Qiuyan Yu
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Qian Chen
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Hongjing Dong
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Min Fang
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Na Liu
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Wen Li
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Hui Wang
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Nan Zhao
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Xunxun Zhu
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Kui Zhang
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, People's Republic of China
| | - Chi Zhou
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
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Liedgens P, Heger JM, Sieg N, Garcia Borrega J, Naendrup JH, Simon F, Johannis W, Hallek M, Shimabukuro-Vornhagen A, Kochanek M, Böll B, Eichenauer DA. Marked hyperferritinemia in critically ill cancer patients. Eur J Haematol 2024; 113:493-500. [PMID: 38937785 DOI: 10.1111/ejh.14263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/29/2024]
Abstract
OBJECTIVES To investigate characteristics and outcomes of critically ill cancer patients with marked hyperferritinemia. METHODS A single-center retrospective analysis comprising cancer patients with a ferritin level >10.000 μg/L treated in the intensive care unit (ICU) between 2012 and 2022 was conducted. RESULTS A total of 117 patients were included in the analysis. The median age was 59 years (range: 15-86 years). Females accounted for 48% of cases. 90% of patients had a hematologic malignancy. The median maximum ferritin level was 27.349 μg/L (range: 10.300-426.073 μg/L). The diagnostic criteria of septic shock were fulfilled in 51% of cases; 31% of patients had hemophagocytic lymphohistiocytosis (HLH) according to the HLH-2004 criteria. Mechanical ventilation, renal replacement therapy and the use of vasopressors were necessary in 59%, 35% and 70% of cases, respectively. The ICU, hospital, 90-day and 1-year survival rates were 33.3%, 23.1%, 23.7% and 11.7%. Patients with septic shock had a worse survival than those without septic shock (p = .001); the survival of patients who fulfilled the HLH-2004 criteria did not differ from those who did not (p = .88). CONCLUSION Critically ill cancer patients with marked hyperferritinemia have poor outcomes. The present data may help to make informed decisions for this patient group.
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MESH Headings
- Humans
- Middle Aged
- Aged
- Female
- Critical Illness
- Male
- Adult
- Aged, 80 and over
- Neoplasms/complications
- Neoplasms/blood
- Neoplasms/mortality
- Neoplasms/diagnosis
- Hyperferritinemia/diagnosis
- Hyperferritinemia/etiology
- Hyperferritinemia/blood
- Adolescent
- Retrospective Studies
- Young Adult
- Ferritins/blood
- Prognosis
- Intensive Care Units
- Lymphohistiocytosis, Hemophagocytic/diagnosis
- Lymphohistiocytosis, Hemophagocytic/mortality
- Lymphohistiocytosis, Hemophagocytic/blood
- Lymphohistiocytosis, Hemophagocytic/etiology
- Lymphohistiocytosis, Hemophagocytic/therapy
- Shock, Septic/blood
- Shock, Septic/mortality
- Shock, Septic/etiology
- Shock, Septic/diagnosis
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Affiliation(s)
- Paul Liedgens
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
- Krankenhaus Porz am Rhein, Department of Internal Medicine, Cologne, Germany
| | - Jan-Michel Heger
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
- Mildred Scheel School of Oncology Aachen Bonn Cologne Dusseldorf (MSSO ABCD), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Noelle Sieg
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Jorge Garcia Borrega
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Jan-Hendrik Naendrup
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Florian Simon
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Wibke Johannis
- Faculty of Medicine and University Hospital Cologne, Institute for Clinical Chemistry, Cologne, Germany
| | - Michael Hallek
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Alexander Shimabukuro-Vornhagen
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Matthias Kochanek
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Boris Böll
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
| | - Dennis A Eichenauer
- University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany
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Johnson WT, Epstein-Peterson ZD, Ganesan N, Pak T, Chang T, Dao P, Moskowitz AJ, Stuver RN, Ghione P, Galasso N, Khan N, Palomba ML, Caron PC, Kumar A, Tamari R, Lue JK, Noy A, Falchi L, Intlekofer AM, Gyurkocza B, Perales MA, Scordo M, Herskovits AZ, Salles G, Vardhana SA, Horwitz SM. Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis. Haematologica 2024; 109:2998-3003. [PMID: 38752279 PMCID: PMC11367207 DOI: 10.3324/haematol.2023.284179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 05/07/2024] [Indexed: 09/03/2024] Open
Abstract
Not available.
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Affiliation(s)
- William T Johnson
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY.
| | - Zachary D Epstein-Peterson
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Nivetha Ganesan
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Timothy Pak
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital-Weill Cornell Medical College, New York, NY
| | - Tiffany Chang
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Phuong Dao
- Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alison J Moskowitz
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Robert N Stuver
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Paola Ghione
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Natasha Galasso
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Niloufer Khan
- Department of Hematology and Hematopoietic Cell Transplant, Lymphoma Division, City of Hope Comprehensive Cancer, Duarte, CA
| | - M Lia Palomba
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Philip C Caron
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Anita Kumar
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Roni Tamari
- Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA; Department of Medicine, Adult Bone Marrow Transplant and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jennifer K Lue
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Ariela Noy
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Lorenzo Falchi
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Andrew M Intlekofer
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Boglarka Gyurkocza
- Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA; Department of Medicine, Adult Bone Marrow Transplant and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Miguel-Angel Perales
- Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA; Department of Medicine, Adult Bone Marrow Transplant and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael Scordo
- Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA; Department of Medicine, Adult Bone Marrow Transplant and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - A Zara Herskovits
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gilles Salles
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
| | - Santosha A Vardhana
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Steven M Horwitz
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY
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Siddik NA, Abd Rahim SNH, Jamaluddin J, Yuhana MY. Hemophagocytic Lymphohistiocytosis Associated With T-cell Lymphoma in Pregnancy: Diagnostic Conundrum Unveiled. Cureus 2024; 16:e66170. [PMID: 39233937 PMCID: PMC11372851 DOI: 10.7759/cureus.66170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2024] [Indexed: 09/06/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) during pregnancy is a rare and often misdiagnosed disease. The clinical manifestations are non-specific, contributing to a high maternal mortality rate. This case report details the presentation of a 31-year-old pregnant woman with high-grade fever initially treated as an infection-related condition. The diagnostic challenge arose from the rarity of HLH, its variable clinical presentation, and the lack of specificity in clinical and laboratory findings. Despite numerous tests and escalation of therapies, the patient, unfortunately, succumbed to HLH associated with T-cell lymphoma. This case report aims to raise awareness of HLH, emphasizing its challenging definition. Malignancy-associated HLH is not uncommon, and early identification and treatment are paramount to prevent progressive tissue damage, organ failure, and mortality. The atypical presentation of HLH as a clinical manifestation of T-cell lymphoma underscores the need for vigilance in diagnosing this potentially fatal syndrome.
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Affiliation(s)
| | | | | | - Muhamad Yazli Yuhana
- Infectious Disease, Kumpulan Perubatan Johor (KPJ) Healthcare University, Nilai, MYS
- Infectious Disease, Kumpulan Perubatan Johor (KPJ) Ampang Puteri Specialist Hospital, Ampang, MYS
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8
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Wei S, Chen H, Deng X, Jiang P, Wang J. A case report of hemophagocytic lymphohistiocytosis induced by toripalimab plus chemoradiotherapy in cervical cancer. Heliyon 2024; 10:e33816. [PMID: 39040237 PMCID: PMC11261852 DOI: 10.1016/j.heliyon.2024.e33816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/24/2024] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening clinical syndrome characterized by immune hyperactivation. Unlike primary HLH, immune checkpoint inhibitor (ICI)-triggered HLH is not well described, and there is a lack of theranostic guidelines. Herein, we first reported the successful management of PD-1 inhibitor-associated HLH in locally advanced cervical cancer. Case presentation We report a case of HLH in a 47-year-old patient with International Federation of Gynecology and Obstetrics (FIGO) IIIC1r cervical cancer who received toripalimab, a programmed cell death-1 receptor inhibitor, combined with chemoradiotherapy. The patient developed pyrexia, splenomegaly, leukopenia, anemia, thrombocytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, reduced NK cell activity, elevated sCD25 levels, and hemophagocytosis in a bone marrow aspirate. Our patient was successfully treated with methylprednisolone, indicating that immune-induced HLH might respond to glucocorticoids, and is still alive with a complete response of the tumor. Conclusion Considering the possibility of HLH is needed in patients receiving ICIs to detect rare toxicities at an early stage when the patient develops uncontrollable fever, cytopenia, and splenomegaly, our multidisciplinary treatment modality contributed to the early diagnosis and successful management of HLH, avoiding progressive tissue damage and organ failure. Whether glucocorticoids are used alone or not for immune-associated HLH needs further investigation.
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Affiliation(s)
| | | | - Xiuwen Deng
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, PR China
| | - Ping Jiang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, PR China
| | - Junjie Wang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, PR China
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9
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Jin Z, Miao Y, Zhang J, Zhang J, Wang C, Lu X, Miao Y, Sun M, Zhang Y, Zhuang Y, Ni H, Xu J, Zhuang W, Zhao M, Zhu J, Xu M, Lin G, Hua H, Xie X, Xu M, Jia T, Zhai L, Gu W, Shan Q, Wang Z, Shen Q, Zhang X, Li J, Shi W. The clinical significance and prognostic value of serum beta-2 microglobulin in adult lymphoma-associated hemophagocytic lymphohistiocytosis: a multicenter analysis of 326 patients. Ann Hematol 2024; 103:2257-2266. [PMID: 38270644 DOI: 10.1007/s00277-024-05631-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/15/2024] [Indexed: 01/26/2024]
Abstract
To investigate the prognostic impact of serum beta-2 microglobulin (B2M) in adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). The clinical and laboratory characteristics of 326 adult patients in a multicenter cohort with lymphoma-associated HLH with available baseline serum B2M levels were retrospectively analyzed. A total of 326 cases were included in this study, and the median serum B2M level was 5.19 mg/L. The optimal cut-off of serum B2M was 8.73 mg/L, and the cases with serum B2M level >8.73 mg/L were older and had a more advanced stage, lower levels of platelets, albumin, and fibrinogen, and higher creatinine level. The serum B2M >8.73 mg/L, creatinine ≥133 μmol/L, fibrinogen ≤1.5 g/L, agranulocytosis (<0.5 × 109/L), severe thrombocytopenia (<50 × 109/L), and high Epstein-Barr virus DNA copy number were found to have independent prognostic values in all patients, and the serum B2M >8.73 mg/L was also an independent prognostic factor in patients with creatinine <133 μmol/L. Finally, a prognostic scoring system was established based on independent prognostic factors of all patients and categorized the patients into three groups with significant prognostic differences. This study confirmed that the serum B2M level can be an independent prognostic factor in lymphoma-associated HLH and established a prognostic scoring system to predict patients' survival.
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Affiliation(s)
- Ze Jin
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Zhang
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
| | - Jing Zhang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
| | - Chunling Wang
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The First People's Hospital of Huai'an, Huai'an, China
| | - Xuzhang Lu
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Affiliated Changzhou No.2 Hospital of Nanjing Medical University, Changzhou, China
| | - Yuqing Miao
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Yancheng First People's Hospital, Yancheng, China
| | - Miao Sun
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Jingjiang People's Hospital, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang, China
| | - Yunping Zhang
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Yun Zhuang
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Wu Xi People's Hospital, Wuxi, China
| | - Haiwen Ni
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingyan Xu
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Wanchuan Zhuang
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Second People's Hospital of Lianyungang, Lianyungang, China
| | - Min Zhao
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Wuhu Second People's Hospital, Wuhu, China
| | - Jianfeng Zhu
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
| | - Min Xu
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China
| | - Guoqiang Lin
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Huai'an Hospital Affiliated to Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an, China
| | - Haiying Hua
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiaoyan Xie
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Maozhong Xu
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, China
| | - Tao Jia
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The First People's Hospital of Lianyungang, Lianyungang, China
| | - Lijia Zhai
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Affiliated Hospital of Yangzhou University, Yangzhou, China
| | - Weiying Gu
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Qiurong Shan
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Shuyang Traditional Chinese Medicine Hospital, Shuyang, China
| | - Zhi Wang
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, Wuxi Second People's Hospital, Wuxi, China
| | - Qiudan Shen
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China
- Department of Hematology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
| | - Xiaohui Zhang
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China.
- Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
| | - Jianyong Li
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China.
| | - Wenyu Shi
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China.
- Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis Association Lymphoma Group (JHA-LG), Nanjing, China.
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10
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Al-Yousuf H, O'Nions J, Wilson AJ, Gohil S, Manson JJ, Payne EM. Safety and efficacy of anakinra in hemophagocytic lymphohistiocytosis associated with acute leukemia. Haematologica 2024; 109:1947-1950. [PMID: 38299608 PMCID: PMC11141663 DOI: 10.3324/haematol.2023.283879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 01/22/2024] [Indexed: 02/02/2024] Open
Abstract
Not available.
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Affiliation(s)
- Hannah Al-Yousuf
- Department of Hematology, University College London Hospitals, London.
| | - Jenny O'Nions
- Department of Hematology, University College London Hospitals, London
| | - Andrew J Wilson
- Department of Hematology, University College London Hospitals, London
| | - Satyen Gohil
- Department of Hematology, University College London Hospitals, London
| | - Jessica J Manson
- Department of Hematology, University College London Hospitals, London
| | - Elspeth M Payne
- Department of Hematology, University College London Hospitals, London, United Kingdom; UCL Cancer Institute, London, United K ingdom.
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11
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Yang CL, Chen X, Zhou HJ, Wu WC, Zou LQ. Clinical Efficacy of Programmed Cell Death Ligand 1 Antibody in Treatment of Extranodal Natural Killer/T-Cell Lymphoma With Hemophagocytic Lymphohistiocytosis. J Hematol 2024; 13:46-51. [PMID: 38644986 PMCID: PMC11027771 DOI: 10.14740/jh1242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/25/2024] [Indexed: 04/23/2024] Open
Abstract
Extranodal natural killer/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (ENKTCL-LAHS) is a rare disease with poor prognosis. Currently, there are no well-established treatments for LAHS. Almost 50% of patients experience relapsed or refractory disease to anti-hemophagocytic lymphohistiocytosis (HLH) treatment, and the regimen for salvage therapy is limited. We report a case of ENKTCL-LAHS that was successfully treated with a programmed cell death ligand 1 (PD-L1) antibody (sugemalimab) alone and provide a literature review on existing ENKTCL-LAHS treatment options. A 31-year-old man with relapsed ENKTCL complicated by HLH was admitted to our hospital. Following the administration of the PD-L1 antibody sugemalimab, fever was resolved, Epstein-Barr virus (EBV) DNA copy number was negative, and HLH-related blood biochemical markers were decreased in the patient. Consequently, the patient achieved complete remission with a progression-free time (PFS) of 44 months. The prognosis of ENKTCL-LAHS is extremely poor, and the clinical treatment of ENKTCL-HLH is challenging. No previous reports exist regarding the use of PD-L1 antibodies in ENKTCL-LAHS treatment. This study is the first to report a patient with ENKTCL-LAHS treated with the PD-L1 antibody alone, who achieved a long PFS of 44 months. Our results suggest the effectiveness and safety of sugemalimab in the treatment of ENKTCL-LAHS; however, more clinical cases are required for validation. The PD-L1 antibody presents a novel treatment option for patients with ENKTCL-LAHS and warrants further clinical promotion.
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Affiliation(s)
- Chun Li Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Chen
- Division of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Jie Zhou
- Division of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wan Chun Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Li Qun Zou
- Division of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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12
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Tso ACY, Acharyya S, Fong SZ, Lee LK, Sreekanth SV, Fan BE, Chan SWS, Ong KH. A Retrospective Review of Secondary Hemophagocytic Lymphohistiocytosis (HLH) and Dengue-associated HLH from a Teaching Hospital in Singapore. Clin Hematol Int 2024; 6:116-127. [PMID: 38817699 PMCID: PMC11086992 DOI: 10.46989/001c.94954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 09/23/2023] [Indexed: 06/01/2024] Open
Abstract
Real-world data on the outcome of Asian patients with secondary hemophagocytic lymphohistiocytosis (HLH), especially on dengue-associated HLH, are limited to small case series. This is a retrospective records review of adult patients with secondary HLH between 2015 and 2020. Thirty-two adult patients were followed up for a median of 6.6 months (range 0.1 - 75 months). 15 had underlying lymphomas, and 12 had viral infections. Hemophagocytosis was seen in 28 of 29 patients with a bone marrow biopsy. 100% and 76.5% of patients with and without an underlying malignancy required HLH-directed therapy and blood product transfusion. 12 of 15 patients with lymphomas were treated with additional chemotherapy. Patients with malignancy-associated HLH had poorer survival than non-malignancy-associated HLH (median overall survival (OS) 1.5 months versus not reached, p-value 0.003). The 1-year survival rates of patients with malignancy-associated HLH, HLH with unknown etiologies, and infection-associated HLH were 0.133 (95% CI: 0.036 - 0.484), 0.400 (95% CI: 0.137 - 1.000) and 0.833 (95% CI: 0.647 - 1.000), respectively. Malignancy significantly increased the risk of death compared to infection-associated HLH (HR 9.37, p-value 0.003). Eight patients were diagnosed with dengue-associated HLH with a median HSCORE of 240 (98-99% probability of HLH). Their mean ferritin was 34,740 ng/mL. Three patients required blood product transfusion, 5 required corticosteroids and/or etoposide, with a median duration of treatment of 31 days. Their overall survival rate was 87.5%. Our study highlights the stark contrast in the survival of secondary HLH patients with and without an underlying malignancy. We also present one of the world's most extensive case series of dengue-associated HLH.
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13
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Song Y, Zhou F, Li X, Du F, Wang Z, Bai L, Yao Y, Liu L, Ma X, Chen S, Wu D, He X. Myelodysplastic syndrome associated-haemophagocytic lymphohistiocytosis: A retrospective study of 15 cases in a single centre. Br J Haematol 2024; 204:1096-1099. [PMID: 38036428 DOI: 10.1111/bjh.19232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 12/02/2023]
Affiliation(s)
- Yue Song
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Fei Zhou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xiaoli Li
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Feng Du
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Ziyan Wang
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Liyun Bai
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Yifang Yao
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Limin Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xiao Ma
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Suning Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xuefeng He
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
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14
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Knauft J, Schenk T, Ernst T, Schnetzke U, Hochhaus A, La Rosée P, Birndt S. Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH): a scoping review unveils clinical and diagnostic patterns of a lymphoma subgroup with poor prognosis. Leukemia 2024; 38:235-249. [PMID: 38238443 PMCID: PMC10844097 DOI: 10.1038/s41375-024-02135-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome driven by pathologic activation of cytotoxic T-lymphocytes and macrophages. Despite advances in diagnostics and management, adult patients with lymphoma-associated HLH (LA-HLH) harbor particularly poor prognosis and optimal treatment remains challenging. As systematic data on LA-HLH are scarce, we aimed to synthesize research evidence by thorough analysis of the published literature in PubMed (MEDLINE-database) within the context of a scoping review. Of 595 search results, 132 articles providing information on 542 patients were reviewed and analyzed. Median patient age was 60 years (range, 18-98) with male predominance (62.7%). B- and T-NHL were equally represented (45.6% and 45.2%), Hodgkin's lymphoma was reported in 8.9% of the cases. The majority of patients (91.6%) presented in Ann-Arbor-Stages III and IV, and bone marrow infiltration was observed in a significant proportion of patients (61.5%). Soluble CD25 levels were markedly elevated (median 10,000 U/ml), with levels beyond 10,000 U/ml indicating unfavorable prognosis for 30-day and overall survival. 66.8% of the patients died after median 5.1 months. LA-HLH remains a clinical challenge requiring specialized management. Timely diagnosis and appropriate lymphoma-specific treatment are of utmost importance to enhance patient outcomes.
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Affiliation(s)
- Johanna Knauft
- Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Thomas Schenk
- Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Thomas Ernst
- Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Ulf Schnetzke
- Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Andreas Hochhaus
- Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany
| | - Paul La Rosée
- Klinik für Innere Medizin II, Onkologie, Hämatologie, Immunologie, Infektiologie und Palliativmedizin, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany
| | - Sebastian Birndt
- Klinik für Innere Medizin II, Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
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15
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Govindarajan A, Venter F, Chaudhry A, Kaur H, Cobos E, Petersen G. Colorectal Carcinoma-An Anomalous Trigger of Adult Hemophagocytic Lymphohistiocytosis. J Investig Med High Impact Case Rep 2024; 12:23247096241273131. [PMID: 39345128 PMCID: PMC11457184 DOI: 10.1177/23247096241273131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/02/2024] [Accepted: 07/14/2024] [Indexed: 10/01/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare but often fatal condition characterized by a hyperinflammatory immune response leading to multiorgan failure. It is predominantly observed in the pediatric population and can be classified as familial or acquired HLH. The latter is more common in adults, often associated with malignancy, infection, or autoimmune diseases. Among acquired HLH cases, hematologic neoplasms account for the majority, with only a few isolated reports documenting solid neoplasms as the cause. Herein, we present a case of adult HLH associated with colorectal adenocarcinoma, which, to the best of our knowledge, is only the second reported case of HLH associated with this type of cancer.
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Affiliation(s)
- Ameish Govindarajan
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Kern Medical, Bakersfield, USA
| | | | | | | | - Everardo Cobos
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Greti Petersen
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Kern Medical, Bakersfield, USA
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Zoref-Lorenz A. Inpatient recognition and management of HLH. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2023; 2023:259-266. [PMID: 38066887 PMCID: PMC10727013 DOI: 10.1182/hematology.2023000509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is one of the life-threatening emergencies that a hematologist may be called upon to diagnose and manage. It is a hyperinflammatory process that develops in patients with genetic abnormalities, hematologic malignancies, chronic inflammatory states, or infections. The main clinical challenges are recognizing HLH, determining whether the immune response is aberrant or appropriate, and deciding upon therapy. Patients may present with fever, central nervous system symptoms, cytopenias, or elevated liver enzymes. Recognizing HLH is challenging because its features overlap with numerous systemic disorders, thus requiring a high level of suspicion and timely investigations to confirm the diagnosis and detect the underlying trigger. Once HLH is diagnosed, careful consideration of immunosuppressive therapy's potential benefit versus harm is necessary. Such therapy can sometimes be tailored to the underlying trigger. In the acute setting, the competing pressures of completing a thorough diagnostic process (including evaluation for the presence of lymphoma and infection) and the need for expedited treatment must be balanced. During the management of an HLH patient, continuous vigilance for the presence of as-yet unrecognized disease triggers, monitoring response, and identifying emerging complications is critical. This review will discuss the recognition and management of HLH in the inpatient setting.
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Affiliation(s)
- Adi Zoref-Lorenz
- Hematology Institute, Meir Medical Center, Kfar Saba, Israel
- Division of Immunobiology, Cincinnati Children's Medical Center, Cincinnati, OH
- School of Medicine, Tel Aviv University, Tel Aviv, Israel
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17
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Jaan A, Khalid F, Firoze Ahmed AM, Salman A, Meghal T, Du D. Hemophagocytic Lymphohistiocytosis and Pancreatic Cancer: A Rare Association. J Community Hosp Intern Med Perspect 2023; 13:68-71. [PMID: 37868670 PMCID: PMC10589035 DOI: 10.55729/2000-9666.1225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 05/20/2023] [Accepted: 06/02/2023] [Indexed: 10/24/2023] Open
Abstract
Introduction Hemophagocytic lymphohistiocytosis (HLH) or hemophagocytic syndrome (HPS) is a life-threatening and relatively rare condition that usually presents as a multisystem febrile illness. It is associated with excessive activation of the immune system and hypercytokinemia, leading to an unregulated aggregation of macrophages and lymphocytes. Here, we present the first likely case of HLH with metastatic pancreatic carcinoma being the underlying etiology. Case A 44-year-old male with past medical history significant for heart transplant for which he was on tacrolimus, End-Stage Renal Disease (ESRD) on hemodialysis, recently treated CMV viremia, and necrotizing pancreatitis presented to the emergency with complaints of chills, decreased appetite, worsening non-bloody emesis, and dull left upper quadrant abdominal pain with radiation to the back for four days. No shortness of breath, fever, diarrhea, or blood in the stool was reported. Vitals on admission were blood pressure of 90/61 mmHg, a heart rate of 110 beats per minute, temperature of 98.1 °F, and respiratory rate of 18 per minute. Physical exam was significant for scleral icterus, decreased bibasilar breath sounds, moderate abdominal tenderness in the left flank and left upper abdominal quadrant without any palpable mass, and 1+ bilateral pedal edema. The remainder of the physical examination was benign. Electrocardiogram (EKG) showed sinus tachycardia without any ischemic changes, and chest x-ray showed mild pulmonary edema. Initial blood workup revealed WBC at 8.3 k/uL, hemoglobin of 10.2 g/dL, platelet count of 90 k/uL, and BUN/creatinine of 45/5.8 (baseline 40/5.0). Cardiac workup showed an elevated high sensitivity troponin level of 2479 pg/mL and brain natriuretic peptide (BNP) of 600 (0-100 pg/mL). The hepatobiliary profile showed an aspartate transaminase (AST) level of 2645 U/L, an alanine transaminase (ALT) of 2935 U/L, alkaline phosphatase (ALP) of 106 U/L, and lipase of 61 U/L, with total and conjugated bilirubin of 3.5 mg/dL and 2.1 mg/dL, respectively. Transthoracic echocardiogram (TTE) showed reduced left ventricular size with hyperdynamic systolic function. Computerized tomography (CT) scan of the abdomen (Fig. 1) revealed numerous new pulmonary nodules, ring-enhancing lesions within the liver, hyperenhancement of the pancreas with walled-off necrosis, and splenomegaly. Microbiological work-up was positive for cytomegalovirus (CMV) serologies (IgM and IgG) but absent viral load on Polymerase Chain Reaction (PCR). The initial diagnosis was systemic inflammatory respiratory syndrome (SIRS), likely septic versus distributive in the setting of pancreatitis, demand mediated non-ST segment elevation myocardial infarction (NSTEMI), and shock liver. Tacrolimus was held, and the patient was started on broad-spectrum antibiotics including vancomycin and cefepime for sepsis of unknown origin along with vasopressors for hypotension, requiring admission to the medical intensive care unit. Blood and urine cultures were collected on admission which remained negative throughout the course of hospital. CA19-9 levels were found elevated at 5587 U/mL. Liver biopsy was consistent with poorly differentiated adenocarcinoma of pancreatic origin. Both Infectious Disease and Hematology were consulted due to broad differential diagnoses. Due to the patient's continued hemodynamic instability and nonresponsiveness to the antibiotics, HLH was suspected with supporting labs as follows: ferritin 55,740 ng/mL (22-322 ng/mL), triglycerides 177 mg/dL (30-150 mg/dL), and fibrinogen 244 mg/dL (173-454 mg/dL), thus conferring 70-80% probability of HPS based on H-score. Soluble IL-2 R levels came out at 19,188 pg/mL (ref range 175-858 pg/mL). The patient couldn't be started on HLH treatment due to initial concerns of underlying infection and the delay in results of soluble IL-2 Receptor (IL-2 R) levels. The infection as a possible etiology was ruled out due to negative blood and urine cultures and HLH was attributed to pancreatic cancer. A marrow biopsy couldn't be pursued as the patient died within a week of hospitalization. An autopsy was not performed as per family's request. Conclusion HLH can occur secondary to solid cell malignancies including those from the pancreas and should be kept high in the differential in critically ill cancer patients who are nonresponsive to antibiotics. H-score has been reported to be a more sensitive tool compared to the HLH protocol, especially if used earlier during the presentation. Further research is needed to compare diagnostic efficacy for HLH protocol verses H-score especially in critically ill patients as they might benefit from steroid trial.
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Affiliation(s)
- Ali Jaan
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY,
USA
| | - Farhan Khalid
- Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ,
USA
| | | | - Ahmed Salman
- Department of Hematology/Oncology, Rochester General Hospital, Rochester, NY,
USA
| | - Trisha Meghal
- Department of Hematology/Oncology, Monmouth Medical Center, Long Branch, NY,
USA
| | - Doantrang Du
- Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ,
USA
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Zhang Q, Zhu L, Zhou D, Li L, Xie W, Tan Y, Ye X. Risk factors and prognosis of early death in secondary hemophagocytic lymphohistiocytosis. Ann Hematol 2023; 102:2301-2308. [PMID: 37266671 DOI: 10.1007/s00277-023-05153-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/24/2023] [Indexed: 06/03/2023]
Abstract
The aim of our study was to summarize the clinical characteristics of early death patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), analyze the risk factors of early death, and analyze the survival of patients. The clinical characteristics of 324 newly diagnosed sHLH patients admitted to the First Affiliated Hospital of Zhejiang University Medical College and Zhejiang Provincial Cancer Hospital from January 2014 to February 2021 were analyzed retrospectively. Analyze the independent risk factors of early death, compare the secondary diseases and treatment methods of patients with early death group and non early death group, and analyze the survival of all patients with sHLH. Among the 324 newly diagnosed patients with sHLH, 134 died early, with an early mortality rate of 41.4%. Comparing the clinical characteristics of patients with early death group and patients with non early death group, logistic regression model was used to conduct multifactor analysis. Age > 60 years, Plt ≤ 20.0 × 109/L, APTT > 36.0 s and LDH > 1000.0 U/L were independent risk factors for early death of newly diagnosed sHLH patients (P < 0.05). Comparing the secondary diseases and treatment methods between early death group and non early death group, the proportion of sHLH patients secondary to lymphoma was higher in early death group than that in non early death group (P < 0.05). The proportion of sHLH patients secondary to connective tissue disease and infection was lower in early death group than that in non early death group (P < 0.05), and the proportion of sHLH patients used hormone combined chemotherapy was lower in early death group than that in non early death group (P < 0.05). The median follow-up time of all patients was 12.0 (1-65) months. The 5-year OS rates of patients with age > 60 years and age ≤ 60 years were 25.8% and 49.6% respectively (P < 0.001); The 5-year OS rates of patients with Plt > 20.0 × 109/L and Plt ≤ 20.0 × 109/L were 52.5% and 25.5% respectively (P < 0.001); The 5-year OS rates of patients with APTT > 36.0 s and APTT ≤ 36.0 s were 34.5% and 57.4% respectively (P < 0.001); The 5-year OS rates of patients with LDH > 1000.0 U/L and LDH ≤ 1000.0 U/L were 23.3% and 56.3% respectively (P < 0.001). Age > 60 years, Plt ≤ 20.0 × 109/L, APTT > 36.0 s and LDH > 1000.0 U/L are independent risk factors for early death of sHLH patients. The early mortality of lymphoma associated HLH (LA-HLH) patients is high, and early use of hormone combined chemotherapy can reduce the early mortality.
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Affiliation(s)
- Qiaolei Zhang
- Department of Hematology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No.38 Guangji Road, banshanqiao, Gongshu District, Hangzhou, 310003, Zhejiang, China
- Institute of Cancer and Basic Medicine(IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Lixia Zhu
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, No.79 Qingchun Road Hangzhou, Hangzhou, 310003, Zhejiang, China
| | - De Zhou
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, No.79 Qingchun Road Hangzhou, Hangzhou, 310003, Zhejiang, China
| | - Li Li
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, No.79 Qingchun Road Hangzhou, Hangzhou, 310003, Zhejiang, China
| | - Wanzhuo Xie
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, No.79 Qingchun Road Hangzhou, Hangzhou, 310003, Zhejiang, China
| | - Yamin Tan
- Department of Hematology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No.38 Guangji Road, banshanqiao, Gongshu District, Hangzhou, 310003, Zhejiang, China.
- Institute of Cancer and Basic Medicine(IBMC), Chinese Academy of Sciences, Hangzhou, China.
| | - Xiujin Ye
- Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, No.79 Qingchun Road Hangzhou, Hangzhou, 310003, Zhejiang, China.
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Song Y, Li X, He X, Zhou F, Du F, Wang Z, Chen S, Wu D. Dose-escalating ruxolitinib for refractory hemophagocytic lymphohistiocytosis. Front Immunol 2023; 14:1211655. [PMID: 37457729 PMCID: PMC10339381 DOI: 10.3389/fimmu.2023.1211655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder characterized by excessive secretion of cytokines. Even with the recommended HLH-94/2004 regimen, over 30% of patients remain refractory to frontline therapy or relapse after an initial response, leading to poor clinical outcomes. Ruxolitinib, a JAK1/2 inhibitor targets key cytokines in HLH, has shown promising therapeutic effects. However, there has been little attention given to patients who do not respond to ruxolitinib and whether an escalating dose can provide a resolution. Methods This study analyzed eight HLH patients who received dose-escalating ruxolitinib who had previously failed to respond to the general dose. The efficacy and safety were mainly analyzed. Results Overall, four out of eight (50%) patients achieved better remission after dose escalation. Two patients who only showed improvement with the general dose achieved complete remission (CR) after dose escalation, and the other two patients also achieved CR after dose escalation when they did not respond to the general dose. The median time to achieve the best overall response was 18.5 days (IQR 13.25-23.75 days). There was no correlation of treatment outcome with blood count, liver function, LDH, cytokines, ferritin levels, NK cell activity, or the time to initiation of ruxolitinib and maximum dosage. The etiology of HLH (p=0.029) and level of sCD25 (p=0.021) correlated with treatment response to dose-escalating ruxolitinib. The area of sCD25 under the ROC curve was 0.8125 (95% CI 0.5921 to 1.033, p=0.035) when using 10,000 pg/ml as the cut-off value for predicting therapeutic effects. After a median follow-up of 159 days, two patients died, and the estimated 2-month overall survival rate was 75%. Adverse effects possibly related to the dose-escalating of ruxolitinib included two cases of extremity pain and one of aminotransferase increased. No grade 3 or higher adverse events were reported. Conclusion This is the first comprehensive study on the use of dose-escalating ruxolitinib in HLH. Ruxolitinib at an escalated dose represent a viable and relatively safe solution for managing refractory HLH. The levels of sCD25 (with a cut-off of 10000pg/ml) can serve as an indicator for early consideration of chemotherapy during treatment.
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Affiliation(s)
- Yue Song
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xiaoli Li
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Xuefeng He
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Fei Zhou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Feng Du
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Ziyan Wang
- Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, Jiangsu, China
| | - Suning Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
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20
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West J, Stilwell P, Liu H, Ban L, Bythell M, Card T, Lanyon P, Nanduri V, Rankin J, Bishton M, Crooks C. 1-year survival in haemophagocytic lymphohistiocytosis: a nationwide cohort study from England 2003-2018. J Hematol Oncol 2023; 16:56. [PMID: 37237311 DOI: 10.1186/s13045-023-01434-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/29/2023] [Indexed: 05/28/2023] Open
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a lethal syndrome of excessive immune activation. We undertook a nationwide study in England of all cases of HLH diagnosed between 2003 and 2018, using linked electronic health data from hospital admissions and death certification. We modelled interactions between demographics and comorbidities and estimated one-year survival by calendar year, age group, gender and comorbidity (haematological malignancy, auto-immune, other malignancy) using Cox regression. There were 1628 people with HLH identified. Overall, crude one-year survival was 50% (95% Confidence interval 48-53%) which varied substantially with age (0-4: 61%; 5-14: 76%; 15-54: 61%; > 55: 24% p < 0.01), sex (males, 46%, worse than females, 55% p < 0.01) and associated comorbidity (auto-immune, 69%, haematological malignancy 28%, any other malignancy, 37% p < 0.01). Those aged < 54 years had a threefold increased risk of death at 1-year amongst HLH associated with malignancy compared to auto-immune. However, predicted 1-year survival decreased markedly with age in those with auto-immune (age 0-14, 84%; 15-54, 73%; > 55, 27%) such that among those > 55 years, survival was as poor as for patients with haematological malignancy. One-year survival following a diagnosis of HLH varies considerably by age, gender and associated comorbidity. Survival was better in those with auto-immune diseases among the young and middle age groups compared to those with an underlying malignancy, whereas in older age groups survival was uniformly poor regardless of the underlying disease process.
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Affiliation(s)
- Joe West
- University of Nottingham, Nottingham, UK
- National Disease Registration Service, NHS Digital, Leeds, UK
- Nottingham University Hospitals NHS Trust, Nottingham, UK
- Aarhus University, Aarhus, Denmark
| | - Peter Stilwell
- National Disease Registration Service, NHS Digital, Leeds, UK
| | - Hanhua Liu
- National Disease Registration Service, NHS Digital, Leeds, UK
| | | | - Mary Bythell
- National Disease Registration Service, NHS Digital, Leeds, UK
| | - Tim Card
- University of Nottingham, Nottingham, UK
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Peter Lanyon
- University of Nottingham, Nottingham, UK
- National Disease Registration Service, NHS Digital, Leeds, UK
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | | | - Judith Rankin
- National Disease Registration Service, NHS Digital, Leeds, UK
- Newcastle University, Newcastle upon Tyne, UK
| | - Mark Bishton
- University of Nottingham, Nottingham, UK.
- National Disease Registration Service, NHS Digital, Leeds, UK.
- Nottingham University Hospitals NHS Trust, Nottingham, UK.
| | - Colin Crooks
- University of Nottingham, Nottingham, UK
- National Disease Registration Service, NHS Digital, Leeds, UK
- Nottingham University Hospitals NHS Trust, Nottingham, UK
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21
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Lee JC, Logan AC. Diagnosis and Management of Adult Malignancy-Associated Hemophagocytic Lymphohistiocytosis. Cancers (Basel) 2023; 15:1839. [PMID: 36980725 PMCID: PMC10046521 DOI: 10.3390/cancers15061839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/08/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe, dysregulated inflammation driven by the inability of T cells to clear an antigenic target. When associated with malignancy (mHLH), the HLH syndrome is typically associated with extremely poor survival. Here, we review the diagnosis of secondary HLH (sHLH) syndromes in adults, with emphasis on the appropriate workup and treatment of mHLH. At present, the management of HLH in adults, including most forms of mHLH, is based on the use of corticosteroids and etoposide following the HLH-94 regimen. In some cases, this therapeutic approach may be cohesively incorporated into malignancy-directed therapy, while in other cases, the decision about whether to treat HLH prior to initiating other therapies may be more complicated. Recent studies exploring the efficacy of other agents in HLH, in particular ruxolitinib, offer hope for better outcomes in the management of mHLH. Considerations for the management of lymphoma-associated mHLH, as well as other forms of mHLH and immunotherapy treatment-related HLH, are discussed.
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Affiliation(s)
- Jerry C. Lee
- Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA;
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22
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Diaz L, Jauzelon B, Dillies AC, Le Souder C, Faillie JL, Maria ATJ, Palassin P. Hemophagocytic Lymphohistiocytosis Associated with Immunological Checkpoint Inhibitors: A Pharmacovigilance Study. J Clin Med 2023; 12:jcm12051985. [PMID: 36902771 PMCID: PMC10004618 DOI: 10.3390/jcm12051985] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/16/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Acquired hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition characterized by hyperactivation of macrophages and cytotoxic lymphocytes, combining a series of non-specific clinical symptoms and laboratory disorders. Etiologies are multiple: infectious (mainly viral) but also oncologic, autoimmune or drug-induced. Immune checkpoint inhibitors (ICI) are recent anti-tumor agents associated with a novel profile of adverse events triggered by immune system over-activation. Here, we sought to provide a comprehensive description and analysis of HLH cases reported with ICI since 2014. METHODS Disproportionality analyses were performed in order to further explore the association between ICI therapy and HLH. We selected 190 cases, 177 from the World Health Organization pharmacovigilance database and 13 from the literature. Detailed clinical characteristics were retrieved from the literature and from the French pharmacovigilance database. RESULTS The cases of HLH reported with ICI concerned men in 65% of cases with a median age of 64 years. HLH occurred in an average of 102 days after the initiation of ICI treatment and mostly concerned nivolumab, pembrolizumab and nivolumab/ipilimumab combination. All cases were considered serious. Most cases presented a favorable outcome (58.4%); however, death was reported for 15.3% of patients. Disproportionality analyses showed that HLH was seven times more frequently reported with ICI therapy than with other drugs and three times more than with other antineoplastic agents. CONCLUSIONS Clinicians should be aware of the potential risk of ICI-related HLH to improve the early diagnosis of this rare immune-related adverse event.
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Affiliation(s)
- Laurine Diaz
- Department of Medical Pharmacology and Toxicology, CHU Montpellier, Montpellier University, 34000 Montpellier, France
| | - Benjamin Jauzelon
- Internal Medicine & Immuno-Oncology (MedI2O), CHU Montpellier, 34000 Montpellier, France
| | - Anne-Charlotte Dillies
- Department of Medical Pharmacology and Toxicology, CHU Montpellier, Montpellier University, 34000 Montpellier, France
| | - Cosette Le Souder
- Department of Medical Pharmacology and Toxicology, CHU Montpellier, Montpellier University, 34000 Montpellier, France
| | - Jean-Luc Faillie
- Department of Medical Pharmacology and Toxicology, CHU Montpellier, Montpellier University, 34000 Montpellier, France
- Desbrest Institute of Epidemiology and Public Health (IDESP), Montpellier University, INSERM, 34000 Montpellier, France
| | - Alexandre Thibault Jacques Maria
- Internal Medicine & Immuno-Oncology (MedI2O), CHU Montpellier, 34000 Montpellier, France
- Institute for Regenerative Medicine and Biotherapy (IRMB), Montpellier University, 34000 Montpellier, France
| | - Pascale Palassin
- Department of Medical Pharmacology and Toxicology, CHU Montpellier, Montpellier University, 34000 Montpellier, France
- Correspondence: ; Tel.: +33-4-67336756; Fax: +33-4-67336751
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23
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La Marle S, Richard-Colmant G, Fauvernier M, Ghesquières H, Hot A, Sève P, Jamilloux Y. Mortality and Associated Causes in Hemophagocytic Lymphohistiocytosis: A Multiple-Cause-of-Death Analysis in France. J Clin Med 2023; 12:jcm12041696. [PMID: 36836229 PMCID: PMC9967667 DOI: 10.3390/jcm12041696] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/26/2023] [Accepted: 02/07/2023] [Indexed: 02/22/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome with an overall mortality rate of 40%. A multiple-cause-of-death analysis allows for the characterization of mortality and associated causes over an extended period. Death certificates, collected between 2000 and 2016 by the French Epidemiological Centre for the Medical Causes of Death (CepiDC, Inserm), containing the ICD10 codes for HLH (D76.1/2), were used to calculate HLH-related mortality rates and to compare them with the general population (observed/expected ratios, O/E). HLH was mentioned in 2072 death certificates as the underlying cause of death (UCD, n = 232) or as a non-underlying cause of death (NUCD, n = 1840). The mean age at death was 62.4 years. The age-standardized mortality rate was 1.93/million person-years and increased over the study period. When HLH was an NUCD, the most frequently associated UCDs were hematological diseases (42%), infections (39.4%), and solid tumors (10.4%). As compared to the general population, HLH decedents were more likely to have associated CMV infections or hematological diseases. The increase in mean age at death over the study period indicates progress in diagnostic and therapeutic management. This study suggests that the prognosis of HLH may be at least partially related to coexisting infections and hematological malignancies (either as causes of HLH or as complications).
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Affiliation(s)
- Solène La Marle
- Département de Médecine Interne, Hôpital de la Croix Rousse—Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, 69002 Lyon, France
| | - Gaëlle Richard-Colmant
- Département de Médecine Interne, Hôpital de la Croix Rousse—Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, 69002 Lyon, France
| | - Mathieu Fauvernier
- Département de Biostatistique-Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, 69000 Lyon, France
| | - Hervé Ghesquières
- Département d’Hématologie, Hôpital Lyon Sud—Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, 69495 Lyon, France
| | - Arnaud Hot
- Département de Médecine Interne, Hôpital Edouard Herriot—Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, 69003 Lyon, France
| | - Pascal Sève
- Département de Médecine Interne, Hôpital de la Croix Rousse—Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, 69002 Lyon, France
| | - Yvan Jamilloux
- Département de Médecine Interne, Hôpital de la Croix Rousse—Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, 69002 Lyon, France
- Lyon Immunopathology Federation (LIFE), Université Claude Bernard-Lyon 1, 69000 Lyon, France
- Correspondence: ; Tel.: +33-426-732-636
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Monti M, Marconi G, Ambrosini-Spaltro A, Gallio C, Ghini V, Esposito L, Antonini S, Montanari D, Frassineti GL. Hemophagocytic lymphohistiocytosis in gastric cancer: A rare syndrome for the oncologist. Case report and brief review. Front Oncol 2023; 13:1010561. [PMID: 36845741 PMCID: PMC9945267 DOI: 10.3389/fonc.2023.1010561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 01/10/2023] [Indexed: 02/10/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by uncontrolled activation of the immune system. HLH is a reactive mononuclear phagocytic response that occurs in association with a constellation of conditions such as malignancies and infections. The clinical diagnosis of HLH remains challenging because HLH can present with symptoms that significantly overlap with other causes of cytopenia, such as sepsis, autoimmune diseases, hematological cancers, and multiorgan failure. A 50-year-old man went to the emergency room (ER) for hyperchromic urine, melena, gingivorrhagia, and spontaneous abdominal wall hematomas. The first blood tests showed severe thrombocytopenia, alteration of the INR, and consumption of fibrinogen, and therefore, a diagnosis of disseminated intravascular coagulation (DIC) was made. A bone marrow aspirate showed numerous images of hemophagocytosis. With the suspicion of immune-mediated cytopenia, oral etoposide, intravenous immunoglobulin, and intravenous methylprednisolone were administered. Then, a diagnosis of gastric carcinoma was performed with a lymph node biopsy and gastroscopy. On the 30th day, the patient was transferred to the oncology ward of another hospital. On admission, he had serious piastrinopenia, anemia, hypertriglyceridemia, and hyperferritinemia. He was supported with a platelet transfusion and underwent a bone biopsy that showed a picture compatible with myelophthisis from diffuse medullary localization of a carcinoma of gastric origin. A diagnosis of HLH secondary to solid neoplasm was formulated. The patient started chemotherapy with oxaliplatin, calcium levofolinate, 5-fluorouracil bolus, 5-fluorouracil for 48 h (mFOLFOX6), and methylprednisolone. Six days after the third cycle of mFOLFOX6, the patient was discharged with the stabilization of his piastrinopenia condition. The patient continued chemotherapy with an improvement in his clinical conditions and normalization of hematological values. After 12 cycles of mFOLFOX, it was decided to start maintenance chemotherapy with capecitabine but, unfortunately, after only one cycle, HLH reappeared. The oncologist has to keep in mind the existence of HLH when there is an unusual clinical presentation of cancer, such as cytopenia affecting ≥2 lineages and alterations of ferritin and triglycerides other than fibrinogen and coagulation. Increased attention and additional research as well as a close collaboration with hematologists are needed to benefit patients with solid tumors complicated by HLH.
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Affiliation(s)
- Manlio Monti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy,*Correspondence: Manlio Monti,
| | - Giovanni Marconi
- Haematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | | | - Chiara Gallio
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Virginia Ghini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Luca Esposito
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Stefano Antonini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Daniela Montanari
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
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25
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Hegazy S, Moesch J, Guerrero A, Ho J, Karunamurthy A. Random Skin Biopsy Is a Useful Procedure in the Evaluation of Hemophagocytic Lymphohistiocytosis: A Case Report and Review of Literature. Am J Dermatopathol 2022; 44:925-928. [PMID: 36197063 DOI: 10.1097/dad.0000000000002301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
ABSTRACT Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome, characterized by aberrant activation of T lymphocytes and macrophages leading to hypercytokinemia. HLH can be familial or a result of various secondary etiologies. We present a case of a 46-year-old woman with a past medical history of multiple sclerosis on rituximab who presented as a transfer from an outside hospital with numerous clinical abnormalities including recurrent episodes of fever of unknown origin for 3 weeks, persistent leukocytosis, hypertriglyceridemia, and steatohepatitis. Given the uncertain nature of her illness, she underwent a random skin biopsy from the abdominal region to exclude hematolymphoid malignancy. Histopathology revealed a brisk histiocytic rich dermal infiltrate accompanied by perivascular lymphocytic infiltrate. The histiocytes were enlarged and positive for muraminadase and CD68 stains exhibiting hemophagocytosis focally. As per the HLH-2004 protocol, our patient met the diagnostic criteria of HLH. Concurrent bone marrow biopsy revealed similar rare hemophagocytosis. Cytogenetics and molecular studies were negative, supporting secondary HLH.
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Affiliation(s)
- Shaymaa Hegazy
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
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26
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Paolino J, Berliner N, Degar B. Hemophagocytic lymphohistiocytosis as an etiology of bone marrow failure. Front Oncol 2022; 12:1016318. [PMID: 36387094 PMCID: PMC9647152 DOI: 10.3389/fonc.2022.1016318] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of multiorgan system dysfunction that is caused by hypercytokinemia and persistent activation of cytotoxic T lymphocytes and macrophages. A nearly ubiquitous finding and a diagnostic criterion of HLH is the presence of cytopenias in ≥ 2 cell lines. The mechanism of cytopenias in HLH is multifactorial but appears to be predominantly driven by suppression of hematopoiesis by pro-inflammatory cytokines and, to some extent, by consumptive hemophagocytosis. Recognition of cytopenias as a manifestation of HLH is an important consideration for patients with bone marrow failure of unclear etiology.
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Affiliation(s)
- Jonathan Paolino
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
| | - Nancy Berliner
- Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Barbara Degar
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States,*Correspondence: Barbara Degar,
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27
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Rubio-Perez J, Rodríguez-Perez ÁR, Díaz-Blázquez M, Moreno-García V, Dómine-Gómez M. Treatment-related hemophagocytic lymphohistiocytosis due to atezolizumab: a case report and review of the literature. J Med Case Rep 2022; 16:365. [PMID: 36195892 PMCID: PMC9531226 DOI: 10.1186/s13256-022-03585-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 08/21/2022] [Indexed: 11/15/2022] Open
Abstract
Background Immune checkpoint inhibitors avoid inhibition of T-cell responses, upregulating antitumor immune response. Moreover, a dysregulation with hyperactive immune response can be caused, some of them underdiagnosed. Hemophagocytic lymphohistiocytosis is a rare and often fatal syndrome of uncontrolled and ineffective hyperinflammatory response that triggers an inflammatory cascade that can lead in many cases to death. Case presentation We report the case of a 67-year-old Caucasian man with stage IV lung adenocarcinoma who developed hemophagocytic lymphohistiocytosis after initiation of atezolizumab, an antagonist of programmed death-ligand 1. Even with early diagnosis and proper treatment, death occurs in approximately half of all cases reported. Conclusion Key markers are needed to better identify patients at risk of developing severe immune-related adverse events. In addition to key markers, a higher degree of suspicion and early intervention are needed to improve outcomes in acquired hemophagocytic lymphohistiocytosis, especially with the increasingly and expanding use of immune activation.
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Affiliation(s)
- Jaime Rubio-Perez
- Medical Oncology Department, University Hospital Fundacion Jimenez Diaz, Instituto de investigación sanitaria FJD, Madrid, Spain.
| | - Ángel Ricardo Rodríguez-Perez
- Medical Oncology Department, University Hospital Fundacion Jimenez Diaz, Instituto de investigación sanitaria FJD, Madrid, Spain.
| | - María Díaz-Blázquez
- Anatomic Pathology Unit Department, University Hospital Fundacion Jimenez Diaz, Madrid, Spain
| | - Victor Moreno-García
- Medical Oncology Department, University Hospital Fundacion Jimenez Diaz, Instituto de investigación sanitaria FJD, Madrid, Spain.,START Madrid-FJD, University Hospital Fundacion Jimenez Diaz, Madrid, Spain
| | - Manuel Dómine-Gómez
- Medical Oncology Department, University Hospital Fundacion Jimenez Diaz, Instituto de investigación sanitaria FJD, Madrid, Spain
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Li XY, Zhu SM, Li XY, Dong RS, Zhang AA, Li SJ, Geng YL. Reactive Hemophagocytic Lymphohistiocytosis Secondary to Ovarian Adenocarcinoma: A Rare Case Report. J Inflamm Res 2022; 15:5121-5128. [PMID: 36097636 PMCID: PMC9464022 DOI: 10.2147/jir.s376756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/09/2022] [Indexed: 11/23/2022] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH), a syndrome of immune hyperactivation and abnormal regulation that causes life-threatening inflammation, is mainly characterized by fever, hepatosplenomegaly, cytopenia, and other symptoms. Reactive HLH (rHLH) is typically secondary to immune deregulation caused by underlying rheumatologic, infectious, or malignant conditions. Malignancy-associated HLH (M-HLH) continues to be a critical health problem worldwide. Most malignancies associated with HLH are hematologic tumors, and M-HLH in non-hematologic tumors very rarely occurs. Case Report A 34-year-old Chinese woman had a history of persistent fever, acute dizziness, and bicytopenia. She was found to have developed bilateral ovarian cancer. Additional tests showed splenomegaly, hemophagocytes in the bone marrow, low natural killer activity, and hyperferritinemia, which met the diagnostic criteria put forth in the Histiocyte Society HLH-2004. The patient was treated with correcting anemia, increased platelets, and glucocorticoid therapy but showed no response. She progressively deteriorated and died 55 days later. Conclusion Hemophagocytic lymphohistiocytosis related to a solid tumor is extremely rare. To the best of the authors’ knowledge, the present case was the first to report rHLH secondary to ovarian adenocarcinoma. It is very significant for a better understanding of the disease mechanisms of HLH and should attract the attention of hematologists and other clinicians as the condition progresses and the cost of treating it increases.
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Affiliation(s)
- Xiao-Yan Li
- Department of Laboratory Medicine, Shanxi Province Fenyang Hospital, Fenyang, 032200, People's Republic of China
| | - Shu-Min Zhu
- Department of Laboratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
| | - Xin-Yuan Li
- Department of Laboratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
| | - Rui-Sheng Dong
- Department of Imaging Medicine, Shanxi Province Fenyang Hospital, Fenyang, 032200, People's Republic of China
| | - Ai-Ai Zhang
- Department of Laboratory Medicine, Shanxi Province Fenyang Hospital, Fenyang, 032200, People's Republic of China
| | - Shu-Jing Li
- Department of Radiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
| | - Yu-Lan Geng
- Department of Laboratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
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Zhou JC, Tan BB, Huang Y, Wu YY, Bai ZJ, Liang ML, Zhao WH. Intrathoracic infections in Hodgkin lymphoma (HL) patients may cooperate with HL to trigger hemophagocytic lymphohistiocytosis: A retrospective study. Medicine (Baltimore) 2022; 101:e29756. [PMID: 35777035 PMCID: PMC9239602 DOI: 10.1097/md.0000000000029756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Hodgkin lymphoma (HL)-related hemophagocytic lymphohistiocytosis (HLH) has been reported in the literature; however, there is almost no literature on the factors related to HL triggering HLH. One hundred forty patients with HL were retrospectively analyzed. The incidence of HL-related HLH (we call HL-related HLH as HL-HLH). And all HL-HLH patients in our cohort had HLH as the first manifestation and its clinical characteristics and the role of intrathoracic infection (ITI) in triggering HLH are discussed. The 140 patients with HL mainly included mixed-cellularity classic HL (MCCHL) in 81 (57.9%), nodular sclerosis classic HL (NSCHL) in 36 (25.7%), and lymphacyte-rich classic HL in 14 (10.0%) patients. Of the 137 patients who underwent chest computed tomography scans on admission, 44 had ITI, and most of these ITI were mildly ill and had no respiratory symptoms. Among 140 HL patients, 8 patients from MCCHL were diagnosed as HL-HLH. Among 81 MCCHL patients, 26 patients with ITI had a significantly higher incidence of HL-HLH than those without ITI (26.9% vs 1.8%, P = .002). The median survival time of 8 cases of HL-HLH was only 2 months. When HL patients were first admitted to the hospital, 5.7% had HLH as the first manifestation, and 32.1% had ITI. These ITI can cooperate with HL to trigger HLH, despite their mild illness. The prognosis of HL-HLH was poor.
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Affiliation(s)
- Ji-Cheng Zhou
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China
- *Correspondence: Ji-Cheng Zhou, Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021 Guangxi, P. R. China (e-mail: )
| | - Bin-Bin Tan
- Department of Hematology, Baise People’s Hospital, Baise, Guangxi, China
- *Correspondence: Ji-Cheng Zhou, Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021 Guangxi, P. R. China (e-mail: )
| | - Yan Huang
- Department of Hematology, Baise People’s Hospital, Baise, Guangxi, China
| | - Yin-Ying Wu
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China
| | - Zhen-Jie Bai
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China
| | - Min-Lan Liang
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China
| | - Wei-Hua Zhao
- Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China
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30
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Ojo A, Asemota J, Ojukwu S, Rajeh H, Bot A, Smith C, Laziuk K, Saleh M. B‑cell lymphoma‑associated hemophagocytic lymphohistiocytosis: A case report. Oncol Lett 2022; 24:246. [PMID: 35761945 PMCID: PMC9214690 DOI: 10.3892/ol.2022.13365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/23/2022] [Indexed: 11/16/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by an exaggerated but dysregulated immune response resulting in hyperinflammation, with a potential for progression to multiple organ dysfunction and failure. Infectious diseases, inflammatory disorders, malignancies and immunodeficiency syndromes are known triggers of HLH in adults. The present study reported the case of a middle-aged man with HLH triggered by B-cell lymphoma who was successfully treated with dexamethasone; etoposide, prednisone, vincristine, cyclophosphamide, hydroxy-doxorubicin and rituximab chemotherapy; and multiple intrathecal methotrexate with a good outcome.
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Affiliation(s)
- Ademola Ojo
- Department of Internal Medicine, Howard University Hospital, Washington, DC 20060, USA
| | - Joseph Asemota
- Department of Internal Medicine, Howard University Hospital, Washington, DC 20060, USA
| | - Somtochukwu Ojukwu
- Department of Internal Medicine, Howard University Hospital, Washington, DC 20060, USA
| | - Hmad Rajeh
- Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Amina Bot
- Department of Internal Medicine, Howard University Hospital, Washington, DC 20060, USA
| | - Caitlyn Smith
- Department of Pathology and Anatomical Sciences, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Katsiaryna Laziuk
- Department of Pathology and Anatomical Sciences, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Mohammed Saleh
- Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA
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31
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Zoref-Lorenz A, Yuklea M, Topaz G, Jordan MB, Ellis M. A Case of Chronic Lymphocytic Leukemia Complicated by Hemophagocytic Lymphohistiocytosis: Identifying the Aberrant Immune Response. J Gen Intern Med 2022; 37:1542-1546. [PMID: 35178648 PMCID: PMC9086000 DOI: 10.1007/s11606-022-07395-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 01/03/2022] [Indexed: 10/19/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may complicate hematologic malignancies. HLH and malignancies have common clinical features, and HLH diagnostic criteria (HLH-2004/Hscore) were not validated in this specific population. We describe a case of a 72-year-old patient with a history of chronic lymphocytic leukemia stable for over 10 years who presented with fever and cytopenia. After excluding infectious etiologies and the progression of her disease, HLH was diagnosed. The patient was treated with etoposide, dexamethasone, intravenous immunoglobulin, and rituximab. Despite initial clinical improvement, the patient deteriorated and developed pulmonary aspergillosis and CNS involvement that reflected uncontrolled HLH. The patient died 45 days after her presentation. An unusual feature of this case was that HLH was not triggered by infection, disease transformation, or treatment. This case emphasizes the challenges of differentiating the development of overwhelming HLH from other complications associated with hematologic malignancy.
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MESH Headings
- Aged
- Etoposide/therapeutic use
- Female
- Fever
- Humans
- Immunity
- Leukemia, Lymphocytic, Chronic, B-Cell/complications
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Lymphohistiocytosis, Hemophagocytic/complications
- Lymphohistiocytosis, Hemophagocytic/diagnosis
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Affiliation(s)
- Adi Zoref-Lorenz
- Hematology Institute, Meir Medical Center, Kfar Saba, Israel.
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA.
| | - Mona Yuklea
- Hematology Institute, Meir Medical Center, Kfar Saba, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Guy Topaz
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Internal Medicine C, Meir Medical Center, Kfar Saba, Israel
| | - Michael B Jordan
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA
| | - Martin Ellis
- Hematology Institute, Meir Medical Center, Kfar Saba, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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32
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Thompson JA, Schneider BJ, Brahmer J, Achufusi A, Armand P, Berkenstock MK, Bhatia S, Budde LE, Chokshi S, Davies M, Elshoury A, Gesthalter Y, Hegde A, Jain M, Kaffenberger BH, Lechner MG, Li T, Marr A, McGettigan S, McPherson J, Medina T, Mohindra NA, Olszanski AJ, Oluwole O, Patel SP, Patil P, Reddy S, Ryder M, Santomasso B, Shofer S, Sosman JA, Wang Y, Zaha VG, Lyons M, Dwyer M, Hang L. Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:387-405. [PMID: 35390769 DOI: 10.6004/jnccn.2022.0020] [Citation(s) in RCA: 198] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.
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Affiliation(s)
- John A Thompson
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | - Julie Brahmer
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | | | | | - Saurin Chokshi
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | | | | | | | | | - Benjamin H Kaffenberger
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | | | | | | | | | - Nisha A Mohindra
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Pradnya Patil
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | | | | | - Jeffrey A Sosman
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Vlad G Zaha
- UT Southwestern Simmons Comprehensive Cancer Center; and
| | | | | | - Lisa Hang
- National Comprehensive Cancer Network
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West J, Card TR, Bishton MJ, Lanyon P, Ban L, Bythell M, Elliss-Brookes L, Manson JJ, Nanduri V, Rankin J, Tattersall RS, Crooks CJ. Incidence and survival of haemophagocytic lymphohistiocytosis: A population-based cohort study from England. J Intern Med 2022; 291:493-504. [PMID: 34875131 DOI: 10.1111/joim.13432] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Haemophagocytic lymphohistiocytosis (HLH) is a rare hyper-inflammatory condition with poor outcomes. OBJECTIVES Few population-based estimates of the incidence and survival in adults exist. We aimed to provide these data for England. METHODS We used population-based linked data from primary care, secondary care, cancer registries and mortality databases in England to identify people diagnosed with HLH between 1 January 2000 and 31 December 2016. We calculated annual incidence rates by age and sex, modelled change in incidence over time with Poisson regression, calculated overall 1-year survival using Kaplan-Meier methods and estimated adjusted hazard ratios (HRs) of death using a Cox proportional hazards model. RESULTS We identified 214 patients with HLH. The reported age and sex-adjusted incidence increased twofold over the period, from around one to around two per million. Incidence was highest in those below 1 year (14.6 per million) and ≥75 years (2.2 per million), and lowest in those aged 15-44 years (0.8 per million). One-year survival varied by age and sex from 77% (95% confidence interval [CI] 63%-86%) in those <15 years to 30% (95% CI 14%-49%) in those ≥75. In patients with haematological cancer, the adjusted HR for death was 2.60 (95% CI 1.45-4.66) compared to patients with no malignant or rheumatological disease. CONCLUSION The incidence of HLH diagnosis in England has increased between 2000 and 2016 and occurs in all ages with varying underlying diseases. One-year survival varies substantially, being particularly poor in those aged over 75 years and those with haematological malignancy.
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Affiliation(s)
- Joe West
- Population and Lifespan Sciences, University of Nottingham, Nottingham, UK.,NIHR Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,National Disease Registration Service, NHS Digital, Leeds, UK
| | - Tim R Card
- Population and Lifespan Sciences, University of Nottingham, Nottingham, UK.,NIHR Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Mark J Bishton
- Department of Haematology, Nottingham City Hospital, Nottingham, UK
| | - Peter Lanyon
- Population and Lifespan Sciences, University of Nottingham, Nottingham, UK.,NIHR Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Lu Ban
- Evidera by PPD, London, UK
| | - Mary Bythell
- National Disease Registration Service, NHS Digital, Leeds, UK
| | | | - Jessica J Manson
- Department of Rheumatology, University College London Hospitals, London, UK
| | - Vasanta Nanduri
- Department of Paediatrics, Watford General Hospital, Watford, UK
| | - Judith Rankin
- National Disease Registration Service, NHS Digital, Leeds, UK.,Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Rachel S Tattersall
- Department of Rheumatology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Colin J Crooks
- NIHR Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,National Disease Registration Service, NHS Digital, Leeds, UK.,Translational Medical Sciences, University of Nottingham, Nottingham, UK
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34
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Xu W, Guo Z. Concurrence of hemophagocytic lymphohistiocytosis and small-cell lung cancer in bone marrow: A case report and literature review. SAGE Open Med Case Rep 2022; 10:2050313X221088146. [PMID: 35341097 PMCID: PMC8943551 DOI: 10.1177/2050313x221088146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 03/01/2022] [Indexed: 11/17/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis is a rare and almost universally fatal disease in
adults. A 60-year-old female patient presented to our hospital with a 3-day history of
weakness and anorexia. Physical examination revealed severe pallor without lymphadenopathy
or hepatosplenomegaly. The initial blood test showed a hemoglobin level of 2.6 g/dL and a
platelet count of 76 × 109/L. Later the patient experienced persistent high
fever for 1 week without any obvious infective symptoms. Biochemical examination revealed
hyperferritinemia and low natural killer cell viability. The bone marrow morphology showed
hemophagocytosis and infiltration with metastatic small-cell lung cancer. The patient was
diagnosed as small-cell lung cancer-related hemophagocytic lymphohistiocytosis.
Subsequently, she underwent chemotherapy with dexamethasone and etoposide. However, the
patient succumbed within 2 weeks of presentation due to rapidly progressive disease. In
conclusion, we reported the first hemophagocytic lymphohistiocytosis case with small-cell
lung cancer. It is critical to have early identification of hemophagocytic
lymphohistiocytosis in patients with small-cell lung cancer.
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Affiliation(s)
- Wenyan Xu
- Department of Hematology/Oncology, First Hospital of Tsinghua University, Beijing, China
| | - Zhenxing Guo
- Department of Hematology/Oncology, First Hospital of Tsinghua University, Beijing, China
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35
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Setiadi A, Zoref-Lorenz A, Lee CY, Jordan MB, Chen LYC. Malignancy-associated haemophagocytic lymphohistiocytosis. Lancet Haematol 2022; 9:e217-e227. [PMID: 35101205 DOI: 10.1016/s2352-3026(21)00366-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/08/2021] [Accepted: 11/15/2021] [Indexed: 01/13/2023]
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is an inflammatory syndrome that can occur with cancer (malignancy-associated HLH) or with immune-activating therapies for cancer. Patients with lymphoma appear to be at particularly high risk for malignancy-associated HLH. The familial form of HLH is characterised by uncontrolled activation of macrophages and cytotoxic T cells, which can be identified by genetics or specific immune markers. However, the pathophysiology of malignancy-associated HLH is not well understood, and distinguishing pathological immune activation from the laboratory and clinical abnormalities seen in cancer and cancer treatment is challenging. Emerging diagnostic tools, such as serum cytokine or chemokine concentrations, flow cytometry, and other functional measures, are discussed. Mortality remains high with current approaches. Targeted therapy, including blockade of specific cytokines such as IL-1, IL-6, and IFNγ, and inhibition of the JAK-STAT pathways might improve outcomes for some patients. Finally, we discuss a framework for thinking of malignancy-associated HLH within a larger umbrella concept of cytokine storm syndrome.
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Affiliation(s)
- Audi Setiadi
- Department of Pathology and Laboratory Medicine, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Adi Zoref-Lorenz
- Hematology Institute, Meir Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Division of Immunobiology, Cincinnati Children's Medical Center, Cincinnati, OH, USA
| | - Christina Y Lee
- Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael B Jordan
- Division of Immunobiology, Cincinnati Children's Medical Center, Cincinnati, OH, USA; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Medical Center, Cincinnati, OH, USA
| | - Luke Y C Chen
- Division of Hematology, Department of Medicine, Vancouver General Hospital, Vancouver, BC, Canada; Centre for Health Education Scholarship, University of British Columbia, Vancouver, BC, Canada.
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Zoref-Lorenz A, Murakami J, Hofstetter L, Iyer S, Alotaibi AS, Mohamed SF, Miller PG, Guber E, Weinstein S, Yacobovich J, Nikiforow S, Ebert BL, Lane A, Pasvolsky O, Raanani P, Nagler A, Berliner N, Daver N, Ellis M, Jordan MB. An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis. Blood 2022; 139:1098-1110. [PMID: 34780598 PMCID: PMC8854682 DOI: 10.1182/blood.2021012764] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/28/2021] [Indexed: 11/20/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004-defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.
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Affiliation(s)
- Adi Zoref-Lorenz
- Hematology Institute, Meir Medical Center, Kfar Saba, Israel
- Division of Immunobiology, Cincinnati Children's Medical Center, Cincinnati, OH
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jun Murakami
- Clinical Laboratory, Transfusion Medicine and Cell Therapy, University of Toyama, Toyama, Japan
| | - Liron Hofstetter
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel
| | | | - Ahmad S Alotaibi
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
- Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Peter G Miller
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Broad Institute of MIT and Harvard, Cambridge, MA
| | - Elad Guber
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pulmonary Institute, Meir Medical Center, Kfar Saba, Israel
| | - Shiri Weinstein
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Internal Medicine "D," Sheba Medical Center, Ramat Gan, Israel
| | - Joanne Yacobovich
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Sarah Nikiforow
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Benjamin L Ebert
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Broad Institute of MIT and Harvard, Cambridge, MA
- Howard Hughes Medical Institute, Bethesda, MD
| | - Adam Lane
- Department of Pediatrics, University of Cincinnati, and Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Oren Pasvolsky
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel
| | - Pia Raanani
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel
| | - Arnon Nagler
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Hematology Institute, Sheba Medical Center, Ramat Gan, Israel; and
| | - Nancy Berliner
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Naval Daver
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Martin Ellis
- Hematology Institute, Meir Medical Center, Kfar Saba, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael B Jordan
- Division of Immunobiology, Cincinnati Children's Medical Center, Cincinnati, OH
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
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Detecting HLH in hematologic malignancies. Blood 2022; 139:961-963. [PMID: 35175327 DOI: 10.1182/blood.2021014675] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/12/2021] [Indexed: 12/12/2022] Open
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Kim DW, Bukhari A, Lutfi F, Zafforoni F, Merechi F, Mustafa Ali MK, Gottlieb D, Lee ST, Kocoglu MH, Hardy NM, Yared J, Rapoport AP, Dahiya S, Law JY. Low utility of the H-Score and HLH-2004 criteria to identify patients with secondary hemophagocytic lymphohistiocytosis after CAR-T cell therapy for relapsed/refractory diffuse large B-Cell lymphoma. Leuk Lymphoma 2022; 63:1339-1347. [PMID: 35045791 DOI: 10.1080/10428194.2021.2024817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disorder. Use of chimeric antigen receptor T-cell therapy (CAR-T) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and secondary HLH. However, application of HLH scoring systems (H-score, HLH-2004 criteria) are not validated in this setting. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify patients with possible HLH post-CAR-T for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Only two of four patients with post CAR-T HLH met five or more of the diagnostic criteria for HLH by HLH 2004 criteria. In contrast all four post CAR-T HLH patients had a high H-score (>169); however, an additional ten patients that did not have HLH also had a high H-score. Thus, in this patient population, both scoring systems were demonstrated to have low prognostic significance in differentiating between high grade CRS and HLH.
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Affiliation(s)
- Dong Won Kim
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Ali Bukhari
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Forat Lutfi
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Facundo Zafforoni
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Fikru Merechi
- Department of Pathology, University of Maryland Medical Center, Baltimore, MD, USA
| | - Moaath K Mustafa Ali
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - David Gottlieb
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Seung T Lee
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Mehmet H Kocoglu
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Nancy M Hardy
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Jean Yared
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Aaron P Rapoport
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Saurabh Dahiya
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Jennie Y Law
- Department of Medicine, University of Maryland School of Medicine and Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
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Zhou L, Yu N, Li T, Ji H, Jiang L, Wang D, Xu B, Zhou X. Clinical characteristics and prognosis of 16 relapsed/refractory B-cell malignancy patients with CAR T-cell-related hyperferritinaemia. Front Oncol 2022; 12:912689. [PMID: 36313658 PMCID: PMC9600326 DOI: 10.3389/fonc.2022.912689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 09/21/2022] [Indexed: 12/08/2022] Open
Abstract
With the success of chimeric antigen receptor-modified (CAR) T-cell therapy for relapsed/refractory (r/r) B-cell malignancies, severe complications after CAR T-cell infusion have emerged as nonnegligible prognosis-related factors. However, the prognosis of patients with CAR T-cell-related hyperferritinaemia (HFA) is unclear. We report the efficacy and safety of CAR T-cell therapy in 16 r/r B-cell malignancy patients with CAR T-cell-related HFA. The rates of serum ferritin levels above 10,000 ng/ml during CAR T-cell therapy were 6.2% and 14.3% in B-cell non-Hodgkin's lymphoma (B-NHL) and acute B lymphocyte leukemia (B-ALL), respectively. These patients were characterized by an extremely high tumor burden and a high rate of extranodal involvement. In lymphoma, the complete remission (CR) rate was 37.5% (3/8), which was lower than that in the control group with the lowest value of ferritin (CR was 87.5% (7/8), P=0.0406), and it could also be seen that the OS of the control group (1-year OS rate 100%) had a better trend than HFA group (1-year OS rate 50%). In the B-ALL patients, the OS of the control group (1-year OS rate 100%) was higher than HFA group (1-year OS rate 45%, P=0.0189), although there was no significant difference in CR rate. High-grade CRS (≥3) occurred in 56.25% of the patients, and the mortality rate was 56.25%, which was significantly higher than control group (12.5% and 12.5%, P=0.009). The peak serum ferritin level in the patients who died of CRS was significantly higher than others (P=0.0168). Regardless of whether the CAR T-related MAS diagnostic criteria were met, there was no significant difference in ORR and OS in HFA group, however patients with MAS showed a higher rate of high-grade CRS. Interestingly, in our study, glucocorticoid intervention in HFA group showed little impact on expansion of CAR-T cells, whether compared with control group or compared within HFA group by dividing patients into high and low dosage subgroups based on the median dose of glucocorticoid. High mortality was observed in patients with CAR T-cell-related HFA. Early glucocorticoid intervention might be worth trying to improve the safety of CAR T therapy in these patients.
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Affiliation(s)
- Lanlan Zhou
- Department of Hematology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Nanzhou Yu
- Department of Hematology, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tongjuan Li
- Department of Hematology, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyan Ji
- Department of Hematology, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lijun Jiang
- Department of Hematology, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Wang
- Department of Hematology, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Xu
- Department of Hematology, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoxi Zhou
- Department of Hematology, Tongji Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Xiaoxi Zhou,
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Song Y, Yin Q, Wang J, Wang Z. Autologous Hematopoietic Stem Cell Transplantation for Patients with Lymphoma-Associated Hemophagocytic lymphohistiocytosis. Cell Transplant 2021; 30:9636897211057077. [PMID: 34743574 PMCID: PMC8579341 DOI: 10.1177/09636897211057077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory status. Lymphoma associated hemophagocytic lymphohistiocytosis (LAHS) is a kind of secondary HLH (sHLH). It suffers the worst outcome among sHLH. Allo-HSCT is often considered necessary. Autologous stem cell transplantation (auto-SCT) is widely used in the treatment of lymphoma, especially for high-risk NHL. There have been no clinical reports on the use of auto-SCT in LAHS in the past 20 years. METHODS We retrospectively evaluated 12 LAHS patients who received auto-SCT at our center from January 2013 to January 2020. Follow-up started at the date of LAHS diagnosis and ended at the date of death or last examination. Overall survival (OS) was calculated from the diagnosis of HLH to death of any cause. RESULTS The median period between diagnosis and auto-SCT is 6.7 months. All 12 patients achieved remission after transplantation. Follow-up to 1 January 2021, 8 patients remained disease-free, 4 patients relapsed and 2 of them died eventually. The median follow-up time is 20.9 months, and the median overall survival time has not been reached yet. The 3-year OS rates was 71%. Compared with LAHS patients who did not undergo transplantation during the same period (median OS time is 3.4 months), patients who underwent auto-SCT had a significantly better prognosis (P=0.001). Even if the lymphoma reaches CR after treatment, auto-SCT still provides a better prognosis compared to CR patients without transplantation (P=0.037). Compared with lymphoma patients without HLH who underwent auto-SCT during the same period, they had a similar prognosis (P=0.350). CONCLUSION LAHS, as a common type in secondary HLH, may have a better prognosis after removing the trigger of HLH. In this study, the autologous transplantation in LAHS can significantly improve the prognosis, and provide LAHS a similar prognosis as high-risk lymphoma without HLH.
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Affiliation(s)
- Yue Song
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qingxia Yin
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jingshi Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Song Y, Wang J, Wang Y, Wu L, Wang Z. Requirement for containing etoposide in the initial treatment of lymphoma associated hemophagocytic lymphohistiocytosis. Cancer Biol Ther 2021; 22:598-606. [PMID: 34724875 DOI: 10.1080/15384047.2021.1996139] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory status caused by a hereditary or acquired immunoregulatory abnormality. Lymphoma-associated hemophagocytic lymphohistiocytosis (LAHS) is a kind of secondary HLH (sHLH). It suffers the worst outcome among sHLH. However, there is no standard treatment strategy. The argument mainly focuses on whether an HLH-directed or malignancy-directed approach should initially be adopted. Etoposide is one of the key drugs in HLH treatment and also shows activity in lymphomas. We sought to identify the importance of containing etoposide in the initial treatment of LAHS. 66 patients diagnosed with LAHS in our center during the three years were divided into two groups according to whether the initial treatment involved etoposide or lymphoma-directed chemotherapy without etoposide. The remission rate of the initial etoposide group (52 patients) is significantly better than that of the no initial etoposide group (14 patients) (73.1% vs. 42.9%, p = .033). The two-month survival rate (79.8% vs. 46.8%, p = .035) and overall survival (median survival time 25.8 w vs. 7.8 w, p = .048) of the initial etoposide contained group is significantly better. Multivariate cox analysis revealed that for patients without EBV infection (37 cases), initial treatment with etoposide could significantly improve prognosis (p = .010, Exp(B) = 0.183), but for patients with positive EBV, it shows a tendency. Containing etoposide is beneficial in the initial treatment of LAHS, whether in the HLH-directed or lymphoma-directed strategy. It provides higher response rate, lower mortality rate, and better survival, especially for EBV negative patients.
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Affiliation(s)
- Yue Song
- Department and Institution: Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jingshi Wang
- Department and Institution: Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yini Wang
- Department and Institution: Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lin Wu
- Department and Institution: Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhao Wang
- Department and Institution: Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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42
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O'Brien O, Sibai H, Chang H. Hemophagocytosis arising during disease progression of chronic myelomonocytic leukemia. Int J Lab Hematol 2021; 44:25-26. [PMID: 34464027 DOI: 10.1111/ijlh.13685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/22/2021] [Accepted: 08/06/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Odharnaith O'Brien
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Hassan Sibai
- Department of Hematology and Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Hong Chang
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
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43
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Bishton MJ, Stilwell P, Card TR, Lanyon P, Ban L, Elliss-Brookes L, Manson J, Nanduri V, Earp K, Flower L, Amarnani R, Rankin J, Sen ES, Tattersall RS, Crooks CJ, Aston J, Siskova V, West J, Bythell M. A validation study of the identification of haemophagocytic lymphohistiocytosis in England using population-based health data. Br J Haematol 2021; 194:1039-1044. [PMID: 34386978 DOI: 10.1111/bjh.17768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/28/2021] [Indexed: 11/29/2022]
Abstract
We assessed the validity of coded healthcare data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. Out of 74 patients, 73 were coded D76.1 or D76.2 (positive predictive value 89·0% [95% Confidence Interval {CI} 80·2-94·9%]) with confirmed/probable HLH. For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97·8% [95% CI 88·2-99·9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case-finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. Five hundred and forty-one were coded D76.1 or D76.2 of whom 524 (96·9%) had HLH in the free-text cause of death. Of 157 coded D76.3, 66 (42·0%) had HLH in free text. D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic healthcare data in England can enable population-wide registration and analysis of HLH for future research.
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Affiliation(s)
- Mark J Bishton
- Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | | | - Tim R Card
- Population and Lifespan Sciences, University of Nottingham, Nottingham, UK.,NIHR Biomedical Research Centre, Nottingham, UK
| | - Peter Lanyon
- Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - Lu Ban
- Evidera by PPD, London, UK
| | | | | | | | - Kate Earp
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | | | - Judith Rankin
- Public Health England, London, UK.,Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Ethan S Sen
- Great North Children's Hospital, Newcastle upon Tyne, UK.,Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | - Colin J Crooks
- Public Health England, London, UK.,NIHR Biomedical Research Centre, Nottingham, UK.,Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
| | | | | | - Joe West
- Public Health England, London, UK.,Population and Lifespan Sciences, University of Nottingham, Nottingham, UK.,NIHR Biomedical Research Centre, Nottingham, UK
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Oh EJ, Yoon JH, Park KH, Bae HJ, Yun SJ, Min GJ, Park SS, Park S, Lee SE, Cho BS, Eom KS, Kim YJ, Lee S, Kim HJ, Min CK, Cho SG, Han K, Lee JW. Natural-killer cell cytotoxicity as a diagnostic and prognostic marker for adult patients with secondary hemophagocytic lymphohistiocytosis: a prospective phase II observational study. Ther Adv Hematol 2021; 12:20406207211020544. [PMID: 34104375 PMCID: PMC8172956 DOI: 10.1177/20406207211020544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 05/04/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) can be life-threatening if not detected and treated appropriately. The diagnosis of HLH can be confusing due to other similar febrile diseases that present with cytopenia. Natural-killer cell (NK)-cytotoxicity is an important diagnostic parameter for primary HLH; however, its role in secondary HLH in adults has not been well-elucidated. METHODS We prospectively enrolled 123 adult patients with febrile conditions accompanied by cytopenia or marrow hemophagocytosis. A diagnosis of HLH was based on HLH-2004 criteria and treated based on HLH-94 protocol. NK-cytotoxicity was calculated at the time of diagnosis by K562-cell direct lysis using flow-cytometry. RESULTS HLH (n = 60) was determined to be caused by Epstein-Barr virus (EBV) (n = 11), infection other than EBV (n = 16), malignancies (n = 19), and unknown (n = 14). Febrile diseases other than HLH (n = 63) were diagnosed as autoimmune disease (n = 22), malignancies (n = 21), infection (n = 12), non-malignant hematological diseases (n = 6), and unknown (n = 2). A lower NK-cytotoxicity level was observed at diagnosis in patients with HLH, compared with other causes of febrile disease (12.1% versus 26.2%, p < 0.001). However, NK-cytotoxicity had a borderline effect on diagnosis of HLH, with an area under receiver operation characteristic curve of 0.689. It also showed no significant role for the prediction of survival outcome. Multivariate analysis revealed that malignant disease and high ferritin level were related with poor survival outcome. In non-malignant disease subgroups, old age, EBV-association, and low NK-cytotoxicity were related with poor survival. CONCLUSIONS Febrile disease with cytopenia was associated with decreased NK-cytotoxicity, especially in adults with HLH; however, its diagnostic role for adult HLH is still arguable. The diagnostic criteria for adult HLH should be further discussed. TRIAL REGISTRATION Clinical Research Information Service [Internet]; Osong (Chungcheongbuk-do), Korea, Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); https://cris.nih.go.kr/cris/index.jsp; Feb, 16th 2016; KCT0001886 (KC15TISE0936).
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Affiliation(s)
- Eun-Jee Oh
- Department of Laboratory Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae-Ho Yoon
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Ki Hyun Park
- Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyun Joo Bae
- Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - So Jeong Yun
- Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Gi June Min
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Soo Park
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Silvia Park
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Eun Lee
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Byung-Sik Cho
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Seong Eom
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yoo-Jin Kim
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seok Lee
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hee-Je Kim
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang-Ki Min
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seok-Goo Cho
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyungja Han
- Department of Laboratory Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Wook Lee
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Naymagon L, Tremblay D, Mascarenhas J. The Efficacy of Etoposide-Based Therapy in Adult Secondary Hemophagocytic Lymphohistiocytosis. Acta Haematol 2021; 144:560-568. [PMID: 33827086 DOI: 10.1159/000514920] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/02/2021] [Indexed: 12/18/2022]
Abstract
Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank p = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633-1.799, p = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.
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Affiliation(s)
- Leonard Naymagon
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York, USA
| | - Douglas Tremblay
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York, USA
| | - John Mascarenhas
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York, USA
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Zhou YS, Cui YC, Yin MJ, Xie QW, Shen ZL, Shi HX, Ye YJ, Liang B. Gastric cancer complicated with hemophagocytic lymphohistiocytosis: case report and a brief review. J Gastrointest Oncol 2021; 12:892-899. [PMID: 34012677 DOI: 10.21037/jgo-20-432] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) comprises a group of severe immune function disorders that can lead to immune-mediated organ damage. There are two subtypes of HLH: primary and secondary. Secondary HLH is associated with infectious, oncologic, chemotherapeutic, and other underlying causes, and studies on HLH triggered by tumors have mainly focused on hematological malignancies. Secondary HLH in patients with solid tumors is rare. Here, we present two cases of gastric cancer complicated with HLH. The patient 1 was diagnosed as gastric cancer at stage I and got intractable fever after a distal subtotal gastrectomy without any evidence of infections or other complications. The patient 2 suffered from unresectable gastric adenocarcinoma and got fever, hemorrhagic rashes, and petechiae in mouth after six cycles of neoadjuvant chemotherapy. After detailed and comprehensive examinations, HLH was diagnosed in the two patients according to 2004 HLH diagnostic criteria, and the patients received treatment including immunosuppressive agents immediately. After therapy, the two patients showed partial remission, but both eventually died due to HLH relapse or progression of the primary tumor. The treatment regimen for HLH is intricate, and only a few relevant studies have focused on the treatment of cancer patients with HLH. The high mortality associated with this disease calls for more attention and additional research to improve the prognosis for these patients.
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Affiliation(s)
- Yu-Shi Zhou
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
| | - Yan-Cheng Cui
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
| | - Mu-Jun Yin
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
| | - Qi-Wei Xie
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
| | - Zhan-Long Shen
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
| | - Hong-Xia Shi
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Ying-Jiang Ye
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
| | - Bin Liang
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China
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Ascierto PA, Fu B, Wei H. IL-6 modulation for COVID-19: the right patients at the right time? J Immunother Cancer 2021; 9:e002285. [PMID: 33837054 PMCID: PMC8042594 DOI: 10.1136/jitc-2020-002285] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 01/08/2023] Open
Abstract
The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage-as defined clinically by C reactive protein levels higher than 75 mg/L.
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Affiliation(s)
- Paolo Antonio Ascierto
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
| | - Binqing Fu
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center; Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center; Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Sun Y, Blieden C, Merritt BY, Sosa R, Rivero G. Hemophagocytic lymphohistiocytosis and myelodysplastic syndrome: a case report and review of the literature. J Med Case Rep 2021; 15:98. [PMID: 33648567 PMCID: PMC7919086 DOI: 10.1186/s13256-020-02623-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/08/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and life-threatening cytopenias. Survival is poor, and management is pivotal on rapid identification of the disease. HLH is associated with hematologic malignancies, however correlation with myelodysplastic syndromes (MDS) is exceedingly unusual. Although minimizing overwhelming hyperinflammation by treating hemophagocytosis are central for HLH outcome, there is urgent necessity to identify potential initiating mechanisms that could assist in therapy design. CASE DESCRIPTION Here, we describe an elderly African American patient who developed rapid onset of cytopenias and coagulopathy associated with hepatic and bone marrow hemophagocytosis. We analyze four additional similar cases to isolate clinical, laboratory and cytogenetic findings expected in patients exhibiting concurrent HLH and MDS. HLH linked with MDS retains common HLH features associated with systemic hyperinflammation such as fever, hypotension, hepatosplenomegaly, hyperferritinemia, coagulopathy and rapidly evolving cytopenias. Typical MDS chromosomic abnormality such as trisomy 8 was frequently observed in our studied cases. CONCLUSION Our case describes difficulties while managing HLH in MDS patients. Diagnosis should be based on identifying HLH appropriate criteria and if possible karyotypic abnormalities normally observed in MDS.
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Affiliation(s)
- Y Sun
- Section of Hematology/Oncology, Baylor St Luke Medical Center, Houston, TX, 77030, USA
| | - C Blieden
- Department of Molecular and Human Genetics, Baylor Genetics, Baylor College of Medicine, Houston, TX, USA
| | - B Y Merritt
- Department of Pathology and Immunology, Baylor St. Luke's Medical Center, Baylor College of Medicine, Houston, TX, USA
| | - R Sosa
- Section of Hematology/Oncology, Baylor St Luke Medical Center, Houston, TX, 77030, USA.,The Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Gustavo Rivero
- Section of Hematology/Oncology, Baylor St Luke Medical Center, Houston, TX, 77030, USA. .,The Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
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Zheng XQ, Zhu HY, Wang JY, Fan L, Xu W, Li J. [Research progress of lymphoma associated hemophagocytic syndrome]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 41:788-792. [PMID: 33113618 PMCID: PMC7595859 DOI: 10.3760/cma.j.issn.0253-2727.2020.09.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- X Q Zheng
- Department of Hematology, Key Laboratory of Hematology of Nanjing Medical University, Jiangsu Province Hospital/The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - H Y Zhu
- Department of Hematology, Key Laboratory of Hematology of Nanjing Medical University, Jiangsu Province Hospital/The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Pukou CLL Center, Pukou Division of Jiangsu Province Hospital, Nanjing 211800, China
| | | | | | | | - Jianyong Li
- Department of Hematology, Key Laboratory of Hematology of Nanjing Medical University, Jiangsu Province Hospital/The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Pukou CLL Center, Pukou Division of Jiangsu Province Hospital, Nanjing 211800, China
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50
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Gudiol C, Lewis RE, Strati P, Kontoyiannis DP. Chimeric antigen receptor T-cell therapy for the treatment of lymphoid malignancies: is there an excess risk for infection? LANCET HAEMATOLOGY 2021; 8:e216-e228. [PMID: 33460558 DOI: 10.1016/s2352-3026(20)30376-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022]
Abstract
Therapy with genetically engineered chimeric antigen receptor (CAR) T cells targeting the CD19 antigen is promising for a number of refractory or relapsed B-cell malignancies. Information on the infectious complications of this immunotherapeutic strategy is scarce and difficult to interpret, as many factors influence infection incidence and outcomes. CAR T-cell therapy is usually given to patients with haematological cancers who have been heavily pretreated and are severely immunosuppressed. Moreover, the risk of infection is increased by the administration of lymphodepleting chemotherapy before CAR T-cell infusion, and by the development of complications such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, which are managed with anti-interleukin-6 antibodies, or corticosteroids, or both. On-target, off-tumour toxicities, such as B-cell aplasia, hypogammaglobulinaemia, and persistent or biphasic cytopenia, are common. In this Review, we evaluate the reported infectious complications of CAR T-cell therapy and associated risk factors and offer perspectives on its infection risk.
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Affiliation(s)
- Carlota Gudiol
- Infectious Diseases Department, Bellvitge University Hospital, IDIBIELL, University of Barcelona, Barcelona, Spain; Institut Català d'Oncologia, Barcelona, Spain; Spanish Network for Research in Infectious Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Russell E Lewis
- Unit of Infectious Diseases, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Paolo Strati
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dimitrios P Kontoyiannis
- Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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