i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by, Catherine M. Broome, MD, Associate Professor of Medicine at Georgetown University School of Medicine, will provide expert guidance on diagnostic features, current treatment standards, emerging therapies, and supportive care strategies for patients with cold agglutinin disease (CAD). Start the activity now!
STATEMENT OF NEED
Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia (AIHA) in which antibodies cause hemolysis at cold temperatures, generally between 37º to 39º Fahrenheit. Approximately 1 in a million people are affected by CAD annually, with onset usually occurring between the ages of 40 and 80 years. Individuals commonly experience fatigue, dizziness, palpitations, and shortness of breath caused by the anemia; jaundice caused by degradation of hemoglobin into bilirubin; and sweating, coldness, or painful discoloration of their fingers, toes, ankles, and wrists triggered by exposure to cold (NORD, 2020). While progress has been made in recent years in understanding the pathogenesis of CAD, consensus recommendations based on randomized trials are needed for improving treatment outcomes and reducing symptom burden (Berentsen, 2021). In this Hematology/Oncology Fellows Lecture Series chaired by Catherine Broome, MD, Associate Professor of Medicine at Georgetown University School of Medicine, faculty will provide expert perspectives on optimizing the diagnosis, treatment, and supportive care of CAD.
TARGET AUDIENCE
Hematology fellows, attending faculty, and other health care professionals involved in the treatment of patients with cold agglutinin disease (CAD).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Evaluate the clinical and laboratory features of CAD that can inform timely and accurate diagnosis
Discuss the pathophysiology of CAD and the scientific rationale for targeting the classical complement pathway
Appraise the efficacy and safety of novel complement inhibitors for CAD as elucidated by recent studies
Assess strategies for managing anemia, cold-induced circulatory symptoms, and treatment-related adverse events to optimize the clinical outcomes of patients with CAD
Faculty
Catherine M. Broome, MD
Professor of Medicine
Georgetown University School of Medicine
Autoimmune hemolytic anemia (or autoimmune haemolytic anaemia; AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to insufficient plasma concentration.
Thrombophilias are hypercoagulable conditions that can be acquired or inherited. Most important hypercoagulable conditions =, testing procedures, duration of anticoagulation will be discussed here. Useful for Internal Medicine Boards and Hematology boards. Some aspects on duration of anticoagulation, HIT are high-yield for USMLE exams.
Autoimmune hemolytic anemia (or autoimmune haemolytic anaemia; AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to insufficient plasma concentration.
Thrombophilias are hypercoagulable conditions that can be acquired or inherited. Most important hypercoagulable conditions =, testing procedures, duration of anticoagulation will be discussed here. Useful for Internal Medicine Boards and Hematology boards. Some aspects on duration of anticoagulation, HIT are high-yield for USMLE exams.
leucodepletion is the removal of 99% leucocytes from the whole blood, pcv or platelets before transfusing into the donor.
this process many infections, transfusion reactions..
leucodepletion is the removal of 99% leucocytes from the whole blood, pcv or platelets before transfusing into the donor.
this process many infections, transfusion reactions..
Brugada syndrome (BrS) is an inherited cardiac disorder,
characterised by a typical ECG pattern and an increased
risk of arrhythmias and sudden cardiac death (SCD).
BrS is a challenging entity, in regard to diagnosis as
well as arrhythmia risk prediction and management.
Nowadays, asymptomatic patients represent the majority
of newly diagnosed patients with BrS, and its incidence
is expected to rise due to (genetic) family screening.
Progress in our understanding of the genetic and
molecular pathophysiology is limited by the absence
of a true gold standard, with consensus on its clinical
definition changing over time. Nevertheless, novel
insights continue to arise from detailed and in-depth
studies, including the complex genetic and molecular
basis. This includes the increasingly recognised
relevance of an underlying structural substrate. Risk
stratification in patients with BrS remains challenging,
particularly in those who are asymptomatic, but recent
studies have demonstrated the potential usefulness
of risk scores to identify patients at high risk of
arrhythmia and SCD. Development and validation of
a model that incorporates clinical and genetic factors,
comorbidities, age and gender, and environmental
aspects may facilitate improved prediction of disease
expressivity and arrhythmia/SCD risk, and potentially
guide patient management and therapy. This review
provides an update of the diagnosis, pathophysiology
and management of BrS, and discusses its future
perspectives.
BACKGROUND: Sequential Epstein-Barr virus (EBV)–positive B cell lymphoma to the initial diagnosis of angioimmunoblastic T cell lymphoma (AITL) is very rare, the exact mechanism and standard therapy of which is still being explored. CASE: A 50-year-old man was admitted to our hospital in January 2014 with a three-week history of enlargement of multiple lymph nodes. His initial pathological evaluation indicated AILT. The reactivation of EBV was observed during the immunosuppression therapy for AITL, accompanied by onset of subcutaneous nodules proven to be EBV-positive diffuse large B cell lymphoma (DLBCL) based on the pathological findings of rebiopsy. The patient was successfully treated with chidamide, a histone deacetylase (HDAC) inhibitor, and rituximab.
Conclusion: The sufficient surveillance for serum EBV and repeat biopsy is necessary for patients with AITL, and this treatment modality may become an active option.
Keywords: angioimmunoblastic T cell lymphoma, Epstein-Barr virus, HDAC inhibitor, non-Hodgkin lymphoma, peripheral T cell lymphoma
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Exploring Novel Treatments for Rett Syndromei3 Health
This slide deck, led by Timothy John Feyma, MD, Pediatric Neurologist at Gilette Children’s Hospital, will explore novel treatments and quality-of-life improvement strategies for children and adults with Rett syndrome.
STATEMENT OF NEED
Rett syndrome is a rare, debilitating neurodevelopmental disorder almost always associated with a spontaneous mutation in the methyl-CpG-binding protein 2 (MECP2) gene on the X-chromosome. Affected individuals experience loss of purposeful hand skills, abnormalities in gait, loss of spoken language, and stereotypic hand movements, with more severe manifestations including seizures, autistic features, autonomic nervous system dysfunction, breathing abnormalities, sleep disturbances, and cardiac abnormalities. While therapies for Rett syndrome are being investigated in clinical trials and have demonstrated modest benefit, no curative or effective disease-modifying treatments currently exist (Petriti et al, 2023). Therefore, the multidisciplinary team is challenged with the optimal management of complex comorbidities that persist throughout patients’ lives. This activity chaired by Timothy John Feyma, MD, Pediatric Neurologist at Gilette Children’s Hospital, will explore novel treatments and quality-of-life improvement strategies for children and adults with Rett syndrome.
TARGET AUDIENCE
Pediatric and adult neurologists, pediatricians, internists, family physicians, child and adult psychiatrists, nurse practitioners, physician assistants, nurses, and other health care professionals involved in the treatment of children and adults with Rett syndrome.
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to
Identify distinguishing features of Rett syndrome that can inform early and accurate diagnosis
Evaluate the safety, efficacy, and clinical utility of novel and emerging treatments for Rett syndrome in children and adults
Devise strategies to monitor and manage Rett syndrome symptoms in children and adults
Leveraging the Growing Arsenal of Adjuvant Therapies for Early-Stage NSCLCi3 Health
3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by, Dr. Helena A. Yu, Associate Attending Physician at Memorial Sloan Kettering Cancer Center, will provide insights into strategies for leveraging the growing arsenal of adjuvant therapies for early-stage non–small cell lung cancer (NSCLC), including treatment selection and adverse event management.
STATEMENT OF NEED
Lung cancer is the second most commonly diagnosed cancer and the leading cause of death for men and women worldwide. In the United States, non–small cell lung cancer (NSCLC) accounts for 81% of all lung cancer diagnoses (Cancer.net, 2023). Therapeutic options, survival rates, and outcomes for NSCLC are dramatically impacted by disease stage. For patients with early-stage disease, radical surgery is the mainstay of treatment; however, patients have a significant risk of relapse following surgery and local treatment. Numerous novel therapeutic approaches, including the use of molecular biomarkers and the development of targeted agents and immune checkpoint inhibitors, are under investigation for early-stage NSCLC, contributing to a growing arsenal of treatment options for this disease (Indini et al, 2020). In this visiting faculty meeting series chaired by Helena A. Yu, MD, Associate Attending Physician at Memorial Sloan Kettering Cancer Center, speakers will provide expert perspectives on diagnosis, identification of biomarkers, and efficacy and safety data of novel adjuvant therapies to improve survival outcomes for patients with early-stage NSCLC.
TARGET AUDIENCE
Medical oncologists, radiation oncologists, surgical oncologists, pulmonologists, nurse practitioners, physician assistants, oncology nurses, and other health care professionals involved in the treatment of patients with non–small cell lung cancer (NSCLC).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to
Identify the correct tumor stage and appropriate management approach for NSCLC based on the latest evidence
Distinguish biomarkers for early-stage NSCLC that can inform individualized treatment strategies
Appraise efficacy and safety data of novel adjuvant therapies for patients with NSCLC as elucidated by recent clinical trials
Apply strategies to prevent and mitigate adverse events associated with novel adjuvant therapies for early-stage NSCLC
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Leveraging the Growing Arsenal of Adjuvant
Therapies for Early-Stage NSCLC
Helena A. Yu, MD
Associate Attending Physician
Memorial Sloan Kettering Cancer Center
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Disclosures
Advisory board/panel: AbbVie, AstraZeneca, Black Diamond,
Blueprint, C4 Therapeutics, Cullinan, Daiichi Sankyo, Janssen, Taiho,
Takeda
Grants/research support: AstraZeneca, Black Diamond, Blueprint,
Cullinan, Daiichi Sankyo, Erasca, Janssen, Novartis, Pfize
Exploring Advances in the Early Diagnosis and Treatment of Alzheimer Disease ...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
In this slide deck, discover new insights into early diagnosis, emerging treatment modalities, and supportive care services for Alzheimer disease. An expert faculty member will discuss biological and clinical distinctions between mild cognitive impairment, dementia, and Alzheimer disease; methods for timely diagnosis; clinical trial data on novel monoclonal antibody therapies; prevention and management of side effects associated with monoclonal antibody therapies, including ARIA, and interdisciplinary support services for improving quality of life.
STATEMENT OF NEED
Alzheimer disease, the most common form of dementia among older adults, is a slowly progressive neurogenerative disease that affects approximately 6 million Americans aged 65 and older (Rajan et al, 2021). Symptoms of Alzheimer disease include memory loss, confusion, impulsive behavior, difficulty with language, mood and personality changes, hallucinations, and increased anxiety or aggression, with severe symptoms such as physical decline, difficulty swallowing, and inability to communicate developing as the disease progresses into its final stages (NIA, 2023). While new therapeutic agents have recently emerged to slow the progression of Alzheimer disease by targeting its underlying causes, the disease remains incurable, and the demands of day-to-day care place significant strain on both patients and their families and caregivers. Therefore, it is critical that clinicians remain up to date on early diagnosis, emerging treatment modalities, and supportive care services in order to provide optimal care for their patients. In this live webinar chaired by Nathaniel Chin, MD, Associate Professor of Medicine in the Division of Geriatrics and Gerontology at the University of Wisconsin-Madison, speakers will explore advances in the diagnosis and treatment of Alzheimer disease.
TARGET AUDIENCE
Geriatricians, neurologists, primary care physicians, psychiatrists, psychogeriatricians, nurse practitioners, physician assistants, nurses, and other health care professionals (HCPs) involved in the treatment of patients with Alzheimer disease (AD).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Utilize diagnostic methods that enable the timely identification of early Alzheimer disease (AD)
Evaluate the clinical utility of novel and emerging DMTs for the treatment of individual patients with early AD
Apply strategies to enhance interdisciplinary care for patients with early AD
Enhancing MRD Testing in Hematologic Malignancies: When Negativity is a Posit...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This expert CME-approved slide deck, presented by Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Cancer Center, will explore the current and emerging roles of MRD testing in hematologic malignancies. She presents the ongoing questions and latest data regarding the clinical utility of MRD testing in prognosis and treatment.
STATEMENT OF NEED
Measurable residual disease (MRD) is defined as the persistence of cancer cells at levels below morphologic detection after treatment. For patients with hematologic malignancies, MRD testing is increasingly being used to predict disease progression, monitor disease status, and evaluate treatment options (Dekker et al, 2023). Questions about current and future roles of MRD testing abound, including validation of assays, such as next-generation sequencing, machine learning, and flow cytometry; standardization of collection methods and modalities; considerations for clinical trial design and statistical analyses; and improved understanding of the roles of MRD status and depth of response across hematologic malignancies (Dekker et al, 2023; Baines et al, 2023). It is critical for members of the multidisciplinary cancer care team to stay up-to-date on the latest data regarding the clinical utility of MRD testing in prognosis and treatment. In this CME-approved activity, Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Cancer Center, will explore the current and emerging roles of MRD testing in hematologic malignancies.
TARGET AUDIENCE
Medical oncologists, hematologists, pathologists, and other health care professionals involved in the treatment of patients with hematologic malignancies.
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Distinguish the advantages and limitations of current MRD detection methods
Evaluate consensus recommendations on indications for MRD testing in hematologic malignancies
Explain the current and potential roles of MRD status and depth of response as a biomarker in clinical trials
Describe mechanisms of drug resistance/loss of response to BCMA-directed therapies
Assess the clinical utility of MRD in prognosis and treatment of selected hematologic malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma
Recurrent/Metastatic HNSCC: Harnessing Immunotherapy in Comprehensive Carei3 Health
i3 Health is pleased to make this slide deck from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck, presented by Glenn J. Hanna, MD, Director, Center for Cancer Therapeutic Innovation (Early Drug Development Program)
Medical Oncologist, Center for Head & Neck Oncology
Dana-Farber Cancer Institute, and Deborah Wong, MD, PhD, Associate Clinical Professor of Medicine, Division of Hematology-Oncology, UCLA Medical Center, was presented at a live educational event at the 2024 Multidisciplinary Head and Neck Cancers Symposium. It will provide expert perspectives on harnessing immunotherapy in recurrent/metastatic HNSCC to provide comprehensive care.
Slowing Progression of Chronic Kidney Disease Through Value-Based Carei3 Health
i3 Health is pleased to make this infographic from this activity available for use as a non-accredited self-study or teaching resource.
This two module CPE activity brings two leading pharmacists together to discuss the slowing progression of Chronic Kidney disease through value-based care.
In Module 1 of this activity, Jeff Sperry, PharmD, BCPS, Clinical Pharmacist at UCHealth Memorial Hospital, will explore risk factors contributing to CKD, efficacy and safety of novel therapies for slowing kidney function decline, and evidence-based strategies for management of CKD complications.
In Module 2 Justin J. Bioc, PharmD, BCPS, BCGP, RPh, Head of Clinical Pharmacy at Devoted Health, will explore the cost-effectiveness of novel therapies indicated to slow kidney function decline and strategies that maximize collaboration between payers and providers to optimize the care of patients with CKD.
Managing Immune-Related Adverse Events to Ensure Optimal Cancer Immunotherapy...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck, presented by Blanca Ledezma, MSN, NP, AOCNP® Nurse Practitioner
Hematology/Oncology
University of California, Los Angeles (UCLA) Health, will provide insight into the nurse’s view on managing immune-related adverse events to ensure optimal cancer immunotherapy outcomes.
Immune checkpoint inhibitors, which alter immune regulatory pathways and promote cell-mediated destruction of tumor cells, have revolutionized the treatment of cancer in recent years, with numerous therapeutic agents approved and several targets under investigation (Chennamadhavuni et al, 2022). However, up to 90% of patients receiving immune checkpoint inhibitors experience immune-related adverse events, which can affect a wide variety of organ systems and can occur at any time during treatment or even after treatment completion (NCCN, 2023). Immune-related adverse events are associated with significant morbidity as well as the risk of therapy discontinuation, which can have an unpredictable impact on patients’ disease course. Therefore, it is critical for nurses to understand the mechanism, identification, and timely management of immune-related adverse events (Shankar et al, 2022). In this activity presented by Blanca Ledezma, MSN, NP, AOCNP®, Nurse Practitioner at the University of California, Los Angeles (UCLA) Health, will provide insight into the nurse’s view on managing immune-related adverse events to ensure optimal cancer immunotherapy outcomes.
TARGET AUDIENCE
Oncology nurses, nurse practitioners, clinical nurse specialists, and other health care professionals involved in the management of patients with immune-related adverse events (IRAEs).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Discuss how the mechanisms of action of immunotherapies influence their safety profile
Identify risk factors predisposing patients to IRAEs
Distinguish IRAEs from chemotherapy- and targeted therapy-related adverse events
Coordinate with the interdisciplinary health care team to apply evidence-based guidelines and best practices in personalized nursing management plans for patients with IRAEs
Develop patient counseling strategies promoting awareness, self-monitoring, and escalated reporting of IRAEs
Virtual Tumor Board: Multidisciplinary Management of Advanced Soft Tissue Sar...i3 Health
i3 Health is pleased to make the Clinical Decision Aid from this activity available for use as a non-accredited self-study or teaching resource.
Gain insights and perspectives from this multidisciplinary panel of experts as they discuss cases and explore strategies to optimize treatment outcomes for patients with advanced soft tissue sarcoma. This distinguished Virtual Tumor Board features Shreyaskumar R. Patel, MD, Medical Director of the Sarcoma Center at the University of Texas MD Anderson Cancer Center; Kathleen Polson, NP, Nurse Practitioner at Dana-Farber Cancer Institute; and Brian Rubin, MD, PhD, Professor of Pathology at Cleveland Clinic Cancer Center
STATEMENT OF NEED
Sarcomas, which represent 1% to 2% of adult cancers, are a rare, heterogeneous group of neoplasms originating in the connective tissue. Soft tissue sarcomas, which begin in the muscle, tendons, fat, lymph, blood vessels, and nerves, encompass more than 80 histological subtypes. Approximately 25% of patients develop metastatic disease after curative-intent surgery, and for these patients, treatment options are limited and prognosis is very poor. In recent decades, the identification of genetic alterations in soft tissue sarcoma has led to the rise of targeted therapy, significantly expanding the therapeutic landscape. Remaining up to date on pathological characteristics and emerging data on novel therapies is crucial (Riskjell et al, 2023; NCI, 2023). In this Virtual Tumor Board, Shreyaskumar R. Patel, MD, Medical Director of the Sarcoma Center at the University of Texas MD Anderson Cancer Center; Kathleen Polson, NP, Nurse Practitioner at Dana-Farber Cancer Institute; and Brian Rubin, MD, PhD, Professor of Pathology at Cleveland Clinic Cancer Center, will present cases and explore multidisciplinary strategies to optimize treatment outcomes for patients with advanced soft tissue sarcoma.
TARGET AUDIENCE
Medical/surgical/radiation oncologists, pathologists, nurse practitioners, physician assistants, oncology nurses, and other health care professionals involved in the treatment of patients with soft tissue sarcoma.
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to
Distinguish patient and tumor characteristics that can inform personalized therapeutic approaches in soft tissue sarcoma
Evaluate emerging data on novel therapies for soft tissue sarcoma
Appraise multidisciplinary strategies to optimize treatment outcomes of patients with advanced soft tissue sarcoma
FACULTY
Shreyaskumar R. Patel, MD
Robert R. Herring Distinguished Professor of Medicine
Center Medical Director, Sarcoma Center
The University of Texas
MD Anderson Cancer Center
Kathleen Polson, NP
Nurse Practitioner
Dana-Farber Cancer Institute
Brian Rubin, MD, PhD
Professor of Pathology
Chairman, Robert J. Tomsich Pathology and Laboratory Medicine Institute
Cleveland Clinic Cancer Center
Pathology and Oncology Expert Perspectives in the Management of Triple-Negati...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck, presented by Dr. Ira Bleiweiss, Chief of Breast Pathology at the University of Pennsylvania, and Dr. Sara Tolaney, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, will feature expert pathology and oncology perspectives on the management of triple-negative breast cancer (TNBC), including case explorations and insights into frequently asked questions. Register today to hear these expert perspectives!
Statement of Need
Triple-negative breast cancer (TNBC) is an aggressive disease that accounts for approximately 10% to 15% of breast cancer diagnoses and is characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). TNBC is more common in Black women and in women under the age of 40 (ACS, 2023). Compared with other subtypes of invasive breast cancer, TNBC has high rates of metastasis and a poor prognosis. Due to the lack of hormone and receptor targets, therapeutic options are limited, and prognostication and treatment selection are complicated by the heterogeneity of the disease (Yang et al, 2022). In this live webinar, Dr. Sara Tolaney, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, and Dr. Ira Bleiweiss, Chief of Breast Pathology at the Hospital of the University of Pennsylvania, will provide expert oncology and pathology perspectives on evidence-based strategies for diagnosis, treatment, and adverse event management for patients with TNBC.
TARGET AUDIENCE
Medical oncologists, surgical oncologists, radiation oncologists, pathologists, nurse practitioners, physician assistants, oncology nurses, and other health care professionals involved in the treatment of patients with triple-negative breast cancer (TNBC).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Evaluate receptor and expression status for prognostication and treatment selection in TNBC
Differentiate the pathological characteristics of the various types of TNBC
Select optimal therapy for TNBC based on shared goals, biomarker testing, and clinical data on novel therapies
Discuss strategies for timely recognition and mitigation of adverse events associated with novel TNBC therapies
Current Standards and New Directions in the Treatment of Acquired Thrombotic ...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
Gain insight and expertise in this presentation on acquired thrombotic thrombocytopenic purpura. Spero Cataland, MD, Professor of Clinical Internal Medicine and Director of Benign Hematology at The Ohio State University, will provide guidance on current treatment standards and will discuss emerging therapies with the potential to improve patient outcomes in aTTP.
STATEMENT OF NEED
Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening thrombotic microangiopathy with a rapid onset and progression and a mortality rate of 10% to 20% with prompt treatment. Onset of aTTP is characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and a constellation of associated symptoms including hemorrhage, neurologic and renal manifestations, cardiac abnormalities, and mesenteric ischemia (Joly et al, 2017). Survivors of first aTTP events tend to have relapse events which need to be controlled. Rapid recognition and immediate appropriate treatment are critical for achieving optimized outcomes in aTTP. In this activity chaired by Spero Cataland, MD, Professor of Clinical Internal Medicine and Director of Benign Hematology at The Ohio State University, expert faculty will provide insightful guidance on current treatment standards and will discuss emerging therapies with the potential to improve patient outcomes in aTTP.
TARGET AUDIENCE
Hematology fellows, attending faculty, and other health care professionals involved in the treatment of patients with acquired thrombotic thrombocytopenic purpura (aTTP).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to
Evaluate the clinical and laboratory features of aTTP that can inform timely and accurate diagnosis
Discuss how ADAMTS13 activity can be used to guide the management of aTTP
Assess the mechanism of action, efficacy, and safety of novel anti-von Willebrand factor nanobodies in aTTP as elucidated by recent clinical trials
Evaluate novel treatment combinations and sequences with the potential to improve the outcomes of patients with aTTP
Expert Guidance on Current Standards and New Directions in Newly Diagnosed Mu...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
Presented by leading expert Urvi Shah, MD, Assistant Attending in the Myeloma Service at Memorial Sloan Kettering Cancer Center, this slide deck will explore guidance on current standards and new directions in newly diagnosed multiple myeloma.
STATEMENT OF NEED
An estimated 35,730 new cases of multiple myeloma are diagnosed in the United States annually, and 12,590 people die of the disease (Siegel et al, 2023). Characterized by clonal proliferation of malignant plasma cells in the bone marrow, multiple myeloma is associated with anemia, renal insufficiency, bone destruction, and hypercalcemia, all of which significantly impact patients’ quality of life. The development of novel therapies and combinations in recent years, including anti-CD38 antibodies, has provided numerous therapeutic options for newly diagnosed multiple myeloma. However, the optimal selection of induction therapy and subsequent treatment sequencing for individual patients remains a challenge. Additionally, factors including age, frailty, comorbidities, transplant eligibility, treatment-related toxicities, and supportive care needs complicate treatment decisions (Costello et al, 2022). This hematology/oncology fellows lecture series will explore expert guidance on current standards and new directions in newly diagnosed multiple myeloma.
TARGET AUDIENCE
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with multiple myeloma.
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Assess guideline-recommended treatment combination and sequencing strategies in NDMM
Evaluate the role of minimal residual disease (MRD) assessment in NDMM treatment
Review the mechanism of action, efficacy, and safety of anti-CD38 monoclonal antibodies in the treatment of NDMM
Discuss strategies to monitor and manage treatment-related toxicities and optimize survivorship care
Hitting the Target in HER2-Positive Metastatic Colorectal Canceri3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck will share the latest data and strategies for hitting the target in HER2-positive metastatic colorectal cancer. Dr. Christopher Lieu, Associate Professor at the University of Colorado Cancer Center, explores actionable targets to inform personalized care plans, guideline-recommended combination and sequencing strategies, adverse event monitoring and management, and more.
STATEMENT OF NEED
An estimated 153,020 new cases of colorectal cancer (CRC) are diagnosed annually, and 52,550 people die of the disease (Siegel et al, 2023). Approximately 22% of patients present with metastatic disease, which is associated with a dismal 5-year survival rate of 15% (SEER, 2022). Targeting biomarkers is a key strategy for expanding therapeutic options and improving outcomes in metastatic CRC. Human epidermal growth factor receptor 2 (HER2) amplification status and treatments targeting HER2 are some of the most recent additions to the arsenal of targeted therapy for this disease. This activity chaired by Christopher Lieu, MD, Associate Director of Clinical Research at the University of Colorado Cancer Center, will provide expert perspectives and practical guidance on treating HER2-positive metastatic CRC.
TARGET AUDIENCE
Oncologists, gastroenterologists, nurse practitioners, physician assistants, oncology nurses, and other health care professionals involved in the treatment of patients with colorectal cancer (CRC).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to
Distinguish actionable targets that can inform personalized care plans in metastatic CRC
Evaluate practice guidelines on treatment combinations and sequences for patients with metastatic CRC
Appraise emerging efficacy and safety data on novel targeted therapies for patients with HER2-positive metastatic CRC
Assess strategies for optimizing the safety and tolerability of novel targeted therapies for HER2-positive metastatic CRC
Leveraging BCMA-Directed Therapies for Improved Patient Outcomes in Relapsed/...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Rahul Banerjee, Assistant Professor at the University of Washington and Fred Hutchinson Cancer Center, will provide a case-based discussion on leveraging BCMA-directed antibody-drug conjugates, CAR T-cell therapies, and bispecific T-cell engagers to improve outcomes for patients with multiple myeloma in need of additional treatment options.
STATEMENT OF NEED
Multiple myeloma is a disease that remains incurable for most patients, many of whom become refractory to the majority of available treatments (Kumar et al, 2022). It is estimated that 35,730 new cases of multiple myeloma are diagnosed in the United States annually, and 12,590 people die of the disease (Siegel et al, 2023). Agents targeting B-cell maturation antigen (BCMA), including antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers, represent a promising therapy class for patients in need of additional treatment options, including those with higher genetic risk and heterogeneity (Kumar et al, 2022). This activity led by Rahul Banerjee, MD, FACP, Assistant Professor in the Division of Medical Oncology at the University of Washington and Fred Hutchinson Cancer Center, will provide strategies for leveraging BCMA-directed therapies for improved patient outcomes in relapsed/refractory multiple myeloma.
TARGET AUDIENCE
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with multiple myeloma (MM).
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Evaluate the mechanisms of action, efficacy, and safety of BCMA-directed therapies in relapsed/refractory MM
Assess guideline-recommended combination and sequential treatment strategies for relapsed/refractory MM
Identify risk factors for the development of treatment-specific adverse events with different classes of BCMA-directed therapies
Describe mechanisms of drug resistance/loss of response to BCMA-directed therapies
Examine the roles of gene expression profiling, soluble BCMA, and measurable residual disease (MRD) in clinical practice.
Optimizing Therapeutic Strategies in Castration-Resistant Prostate Canceri3 Health
This activity will discuss emerging efficacy and safety data on novel therapies for nmCRPC and mCRPC, strategies to manage adverse events, and the role of imaging studies and PSA testing in evaluating treatment response.
Optimizing Treatment Sequencing for Patients With Relapsed/ Refractory Multi...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Shaji Kumar, MD, Professor of Hematological Malignancies
Mayo Clinic Cancer Center, offers expert insight on the assessment of MM, emerging and current therapies, cutting edge approaches to personalized treatments plans, and much more.
Tailoring Therapy for Follicular Lymphoma Based on the Latest Evidencei3 Health
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Putting the Freeze on Cold Agglutinin Disease
1. Putting the Freeze on Cold Agglutinin Disease
Catherine M. Broome, MD
Professor of Medicine
Georgetown University School of Medicine
2. Disclosures
Advisory board or panel: Alexion, Alpine, Argenx, Sanofi, and Star
Speaker's bureau: Alexion and Sanofi
Grants/research support: Alexion, Alpine, Argenx, Novartis, Sanofi,
and Star
i3 Health has mitigated all relevant financial relationships
3. Learning Objectives
Evaluate the clinical and laboratory features of CAD that can inform
timely and accurate diagnosis
Discuss the pathophysiology of CAD and the scientific rationale for
targeting the classical complement pathway
Appraise the efficacy and safety of novel complement inhibitors for
CAD as elucidated by recent studies
Assess strategies for managing anemia, cold-induced circulatory
symptoms, and treatment-related adverse events to optimize the
clinical outcomes of patients with CAD
CAD = cold agglutinin disease.
4. Cold Agglutinin Disease (CAD)
Mullins et al, 2017; Berentsen et al, 2020.
CAD is generally diagnosed in 6th, 7th, and 8th decade of life, although it
has been diagnosed as young as age 30; slightly more common in women
CAD has an incidence range of 0.5-2.0 cases per million and an estimated
prevalence of 5-20 cases per million
Until recently, there was no data to suggest CAD incidence or prevalence
varied in different parts of the world. A multinational study in Europe in 2020
demonstrated that the prevalence and incidence of CAD were 4 times higher
in Norway compared with Lombardy, Northern Italy
This was the first-ever demonstration of a marked association between
climate and prevalence and incidence of CAD
5. Diagnosis of CAD
Swiecicki et al, 2013; Broome et al, 2022; Berentsen et al, 2020.
The diagnosis of CAD can be difficult, as these patients present with a
varied constellation of nonspecific symptoms such as fatigue,
shortness of breath, dyspnea on exertion, cold-induced circulatory
symptoms (Raynaud’s, livedo reticularis, acrocyanosis, and necrotic
lesions) anxiety, depression, and difficulty concentrating
In 1 large study of 191 patients, 115 (60.2%) had been diagnosed
within 1 year of clinical onset, but the longest time to diagnosis was 32
years
6. Definition of CAD
Ig = immunoglobulin; LPD = lymphoproliferative disorder; SLL = small lymphocytic leukemia; CLL = chronic lymphocytic leukemia.
Berentsen, 2016; Berentsen et al, 2020.
By accepted definition, CAD is
defined as the presence of cold
agglutinins, 90% IgM but may be IgG
or IgA, ± hemolysis and ± circulatory
symptoms in association with an
underlying, microscopic, clonal,
MYD88 L265P mutation–negative
low-grade B-cell lymphoproliferative
disorder
7. CAD versus Cold Agglutinin Syndrome (CAS)
DAT = direct antiglobulin test; C3d = complement protein 3d.
Berentsen, 2016.
Anemia
Hemolysis:
confirmed
Polyspecific DAT:
positive
Monospecific DAT:
positive for C3d
Cold agglutinin titer:
≥1:64
Primary cold agglutinin
disease
Secondary cold
agglutinin syndrome
Overt
malignancy?
Onset of anemia
before infection?
Yes
No
Secondary cold
agglutinin syndrome
No
Infection?
Yes
Yes
8. CAD: History and Physical Examination
SOB = shortness of breath.
Joly et al, 2022; Berentsen, 2016; Silberstein et al, 1986; Yamaguchi et al, 2022.
Fatigue: sometimes out of proportion to the degree of anemia
Circulatory symptoms precipitated by cold exposure (acrocyanosis, livedo
reticularis and Raynaud-like symptoms)
Shortness of breath or dyspnea on exertion
Acute hemolytic crisis in CAD
May demonstrate severe anemia, SOB, tachycardia, hemoglobinuria
Physical exam: pallor, jaundice, hepatomegaly, splenomegaly possibly
ulcerations or gangrene
9. Laboratory Findings in CAD: Anemia
Berentsen et al, 2020; Berentsen, 2020; Moreno Chulilla et al, 2009.
Anemia: almost universally present to some degree, although up to 10% of
patients can have no anemia due to brisk reticulocyte response
In a large observational study of 232 CAD patients, about 27% of patients
had severe anemia (hemoglobin <8 g/dL), 37% moderate (hemoglobin 8-10
g/dL), and 24% mild (hemoglobin 10 g/dL to lower limit of normal) at
presentation
Other considerations in evaluating anemia in CAD are bleeding; B12, folate,
or iron deficiency; and/or inappropriate erythropoietin response
10. Evaluation of Suspected CAD
Berentsen & Barcellini, 2021; Berentsen, 2021; Wongsaengsak et al, 2018.
Top image courtesy of John Lazarchick, ASH Image Bank, 2010.
Bottom image courtesy of Martin Heni and Sebastian Jonas Saur, ASH Image Bank 2013.
Peripheral blood smear: polychromasia,
anisocytosis, and spherocytes
Direct antiglobulin test (DAT) is the pivotal test in
evaluating CAD
The DAT will be strongly positive for C3 and negative
or weakly positive for IgG
If DAT is positive for C3, then a COLD AGGLUTININ
TITER should be performed on a sample that has
been kept warm to avoid precipitation of the cold
agglutinin and a false-negative result
The titer should be ≥1:64
11. Antiglobulin (Coomb’s) Testing
RBC = red blood cells.
Images courtesy of Catherine M. Broome, MD.
Direct Antiglobulin Test Indirect Antiglobulin Test
12. Bone Marrow Evaluation in CAD
MYD88 = myeloid differentiation factor 88; KMT2D = histone-lysine N-methyltransferase 2D; CARD = caspase recruitment domain family member 11.
Berentsen, 2021; Alaggio et al, 2022; Małecka et al, 2018.
Bone marrow evaluation is strongly advised in CAD at the time of diagnosis
and/or prior to initiating therapy
In CAD, the diagnostic bone marrow findings are a clonal, low-grade
lymphoproliferation distinct from lymphoplasmacytic lymphoma and marginal
zone lymphoma, currently recognized in the World Health Organization
(WHO) classification of hematolymphoid tumors
The MYD88 L265P mutation, present in nearly all cases of
lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia), is usually
not found in CAD. In contrast, KMT2D and CARD11 mutations are found
frequently
13. Typical Bone Marrow Findings in CAD
CD = cluster of differentiation; MUM1 = multiple myeloma 1; PAX5 = paired box 5;
BCL10 = B-cell lymphoma/leukemia 10.
Randen et al, 2014.
The figure illustrates the immunophenotypic findings in CAD-
associated lymphoproliferative disease
The lymphoid nodules consist mainly of B lymphocytes [(A),
anti-CD20 immunoperoxidase staining, 100X] and a
moderate amount of T lymphocytes [(B), anti-CD3
immunoperoxidase staining, 100X]
Plasma cells are mainly found in the periphery of the nodular
infiltrate and the parenchyma and express IgM and IgK [(C-
E), anti-IgM, anti-IgK, and anti-IgL immunoperoxidase
staining, respectively, 100X]
Lymphoid cells within the nodular lesions do not express
MUM1 but do variably express nuclear BCL10 and strongly
express PAX5 [(F–H), immunoperoxidase staining, 400X]
T lymphocytes in the lymphoid nodules are mainly CD4
helper cells whereas few CD8 cytotoxic cells are seen [(I–J),
immunoperoxidase staining for CD4 and CD8, respectively,
100X]
14. Hemolysis in CAD
LDH = lactate dehydrogenase.
Berentsen, 2021; Berentsen, 2020; Michalak et al, 2020; Barcellini & Fattizzo, 2015.
Chronic hemolysis is a common feature of CAD
In the steady state, it is almost exclusively an EXTRAVASCULAR hemolysis
mediated by opsonization of C3d-coated red blood cells in the liver
Acute hemolysis (occurs when there is upregulation of complement activity) is
mediated mainly by the membrane attack complex (C5b-9) and is
INTRAVASCULAR
Markers of hemolysis include:
Increased unconjugated bilirubin (extravascular)
Elevated LDH (intravascular)
Reduced haptoglobin (scavenger of free hemoglobin)
Increased reticulocyte count (indicator of bone marrow response to anemia)
16. Diagnostic Criteria for CAD
Berentsen, 2021.
Hemolytic anemia of variable severity (90% of cases) and peripheral
circulatory symptoms in most patients
DAT strongly positive for complement (C3d)
Cold agglutinin titer ≥64 at 4C
DAT negative or weakly positive for IgG
Monoclonal cold agglutinin (IgM-kappa present in 90% of cases)
Bone marrow evaluation showing primary CAD-associated
lymphoproliferative B-cell disorder
No overt clinical or radiological evidence of underlying disease (overt
malignancy, typically B cell lymphomas, acute infections, other systemic
autoimmune disorder)
17. Clinical Phenotype of CAD
Berentsen et al, 2020.
Hemolytic anemia with circulatory
symptoms grade 1 or absent (n=146)
Hemolytic anemia with circulatory
symptoms grade 2-3 (n=44)
Circulatory symptoms with compensated
hemolysis (n=20)
69.5%
21.%
9.5%
The majority of patients with CAD
present with hemolytic anemia
(N=210 patients with available data)
19. Agglutination
Slide courtesy of Catherine M. Broome, MD. image courtesy of John Lazarchick, ASH Image Bank, 2010. Image courtesy of Professor Erhabor Osaro. Licensed under CC BY-SA 4.0.
As the red blood cells circulate into the peripheral circulation, where temperatures are
below core body temperature, the cold agglutinin binds to the red blood cell membrane
polysaccharide antigen “I” or “i”
In the case of IgM antibodies, as the IgM forms pentamers the red blood cells are
drawn together in a process known as agglutination
Agglutination of red cells in small vessels in the periphery is responsible for circulatory
symptoms
Gross agglutination in test tube
Microscopic red cell agglutination Acrocyanosis
20. CAD: Mechanism of Disease
Berentsen, 2018; Shiiya & Ota, 2017.
Acrocyanosis-agglutination of red blood cells mediated by IgM
22. Anemia in CAD
Hb = hemoglobin; LLN = lower limit of normal.
Berentsen, 2020.
64% of patients with CAD have
baseline Hb <10 g/dL
Even patients with a normal Hb
have evidence of ongoing
hemolysis
The level of IgM (cold agglutinin)
does not linearly correlate with
degree of anemia
24%
Mild anemia
(Hb 10.0 g/dL - LLN)
12%
Compensated
(Hb ≥LLN)
27%
Severe anemia
(Hb <8.0 g/dL)
37%
Moderate anemia
(Hb 8.0-10.0 g/dL
Mean:
LDH 450 U/L
Bilirubin 43 μmol/L
IgM 4.2 g/L
Mean:
LDH 534 U/L
Bilirubin 47 μmol/L
IgM 5.5 g/L
Mean:
LDH 291 U/L
Bilirubin 31 μmol/L
IgM 5.8 g/L
Mean:
LDH 385 U/L
Bilirubin 37 μmol/L
IgM 6.7 g/L
23. Possible Consequences of CAD
Possible Consequences of CAD
Transfusions required
50% are considered transfusion-dependent for shorter or
longer periods
Elevated thromboembolic threat
• Increased risk of venous thromboembolism
(or other TEs)
• 62% higher incidence of thromboembolic events
Reduced quality of life
Mortality data
- Hill et al, 2019 (study in US)
- Danish Registry (Bylsma et al, 2019)
Patients diagnosed with CAD vs non-CAD, matched
population, have higher mortality rate
TE = thromboembolic events.
Berentsen, 2018; Broome et al, 2020; Bylsma et al, 2019; Hill et al, 2019.
24. CAD Imposes a Substantial Burden on Patients
Mullins et al, 2017; Su et al, 2020.
Health Care Resource Utilization
67%
100%
53%
100%
0
25
50
75
100
Hospital inpatient Outpatient Emergency room Pharmacy
Patients
(%)
Stanford Healthcare Study1
(N=15; 2008-2016)
36%
95%
26%
15%
74%
17%
0
25
50
75
100
Hospital inpatient Outpatient Emergency room
Patients
(%)
Optum-Humedica Database2
(N=410; 2006-2016)
25. Global Collaborative Efforts for Evidence-Based Treatment
Jäger et al, 2020; Berentsen et al, 2020; Bylsma et al, 2019; Natsuaki et al, 2018.
2017: first International Consensus Meeting
Berentsen et al (Norway vs Northern Italy study): largest study of
patients with verified CAD (n=232)
Bylsma et al (Danish study) showed CAD patients had increased
increased risk of TEs and increased mortality compared with the
general population cohort
Natsuaki et al (Japanese study) showed risk of thrombotic and
bleeding events
CAD
26. Risk of Thromboembolic Events in CAD Patients
Bylsma et al, 2019.
Based on Danish National Patient Registries (study period:
1999-2013)
Examined risk of TEs and mortality in CAD patients
CAD patients had increased
mortality compared with the
general population cohort
Risk of TEs was higher in the
CAD patient
Median survival: 8.5 years
Patients
diagnosed with
CAD
Matched
N 72 720
TEs at 1 year 7.2% 1.9%
at 3 years 9.0% 5.3%
at 5 years 11.5% 7.8%
Mortality rates
1 and 5 years after
diagnosis
17% and 39% 3% and 18%
27. Mortality Among Patients With CAD
Study period: January 2007-September 2018
651 CAD patients and 3,255 matched non-CAD
controls identified
For patients who experienced ≥1 TE
during the study period, mortality rate in
the CAD cohort was 23,684 vs 15,913 in
the matched-control cohort (P<0.001)
No TE ≥1 TE
CAD
cohort
Matched
non-CAD
cohort
P value
CAD
cohort
Matched
non-CAD
cohort
P value
value
Mortality rate
per 100,000
patients
14,184
(n=423)
10,176
(n=2,614)
<0.001
23,684
(n=228)
15,913
(n=641)
<0.001
Mean (SD) age
at death, years
76 (11)
(n=60)
82 (9)
(n=266)
<0.001
77 (13)
(n=54)
82 (7)
(n=102)
<0.001
Mortality Rates and Age at Death in Patients with No or ≥1 TE During the Study Period
SD = standard deviation.
Adapted from Hill et al, 2019.
28. Thrombosis in CAD
HR = hazard ratio; CI = confidence interval.
Broome et al, 2020.
608 patients with CAD and 5,873 matched comparison patients were identified from 2006 to 2016
Higher incidence of ≥1 TE in patients with CAD versus the comparison cohort (adjusted HR 1.94;
P<0.0001)
26.8% of patients with primary CAD and NO comorbidities experienced 1 or more TEs compared to 16.5%
of the comparator cohort
29.6%
14.6% 14.0%
7.6%
17.6%
5.2%
11.6%
3.7%
0
5
10
15
20
25
30
35
All TEs Venous… Cerebral…Arterial TEs
CAD cohort (n=608)
Non-CAD cohort
(n=5873)
Patients
(%)
Overall rates of arterial, venous, and
cerebral TEs
Number
of TEs
Patients
with
CAD, n
(%)
Patients
without
CAD, n
(%)
HR (95
% CI)
Adjusted
HR (95%
CI)
All CAD N=608 N=5,873
2.36
(2.01‐
2.76)
1.94
(1.64‐
2.30)
0
428
(70.4%)
4,840
(82.4%)
1+
180
(29.6%)
1033
(17.6%)
Primary
CAD
n=425 n = 4126
2.25
(1.84‐
2.75)
1.80
(1.46‐
2.22)
0
311
(73.2%)
3,446
(83.5%)
1+
114
(26.8%)
680
(16.5%)
29. Seasonality and CAD
HRU = health care resource utilization.
Röth, Fryzek, et al, 2022; Hansen et al, 2022.
In Röth et al’s study, patients with CAD had evidence of persistent
chronic hemolysis and anemia across seasons. The authors concluded
that the systemic burden of complement-mediated hemolysis, anemia,
thromboembolism risk, and HRU in CAD persist year-round, and
patients with CAD warrant close monitoring irrespective of the season
Hansen et al evaluated mortality and seasonality and
conclude that CAD is associated with an increased risk of
death during the colder months. They do concede that their
observational data does not allow for a direct causal inference
Spring
Summer
Autumn
Winter
30. Management of CAD
Management is largely unsatisfactory (with no approved
treatment)
Therapy is mainly directed at the degree of anemia
Avoidance of cold environments (<30º C in exposed skin
vessels)
Treat underlying disease (if possible)
Transfusion of RBCs if necessary
Sometimes effective emergency treatment needed
Steroids, alkylating agents, and splenectomy are not effective
RBC = red blood cell.
Gertz, 2007; Berentsen et al, 2007; Petz, 2008; Röth & Dührsen, 2010; Berentsen et al, 2015; Wouters & Zeerleder, 2015; Jäger et al, 2020.
31. Supportive Care of CAD
Avoidance of cold temperatures (warm clothing; avoidance of cold
drinks, ice cream, cold air, cold infusions/transfusions, etc)
Early and consequent antibiotic treatment of bacterial infections to
avoid hemolytic crisis
Transfusions (low plasma content, no plasma) when indicated (extremity
should be kept warm, in-line blood warmer)
Oral supplementation of folic acid (5 mg/d); vitamin B12 or iron
(if deficient)
Adequate hydration in critical hemolysis
Thromboprophylaxis with low–molecular weight heparin, etc, for
patients with acute/severe exacerbation of hemolysis
Gertz, 2007; Berentsen et al, 2007; Petz, 2008; Röth & Dührsen, 2010; Berentsen et al, 2015; Wouters & Zeerleder, 2015; Jäger et al, 2020.
32. Surgery and the CAD Patient
Yamaguchi et al, 2022; Bindu et al, 2017.
Particular attention must be paid to temperature control in
patients with high titers of cold agglutinins, since general
anesthesia causes hypothermia due to exposure to a cold
environment and anesthetic-induced impaired thermoregulation,
which causes vasodilation, inhibits vasoconstriction, and reduces
the metabolic rate by 20% to 30%
33. Preoperative Care for CAD Patients
Southern et al, 2019; Yamaguchi et al, 2022; Ji et al, 2021.
Hematology and anesthesiology consultations
Encourage patient to remain warm
Check preoperative labs
Arrange for warmed blood products and intravenous fluids
Have cross-matched blood products available
34. Intraoperative Care for CAD Patients
IV = intravenous
Southern et al, 2019; Ji et al, 2021.
Ensure all IV fluids and blood products are warmed
Use blankets and forced warm air devices
Ensure all intravenous and surgical fluids are kept warm
Transfuse warmed packed RBC as needed
35. Postoperative Care for CAD Patients
BMP = basic metabolic panel; CBC = complete blood count; CMP = complete metabolic panel.
Southern et al, 2019.
Daily blood work: BMP, CBC, CMP, haptoglobin, and LDH
Transfuse warmed packed RBC as needed
Inpatient hematology consultation and close outpatient follow-
up
37. CAD: First-Line Treatment Strategy
Rituximab monotherapy (375 mg/m2 weekly x4) in frail,
multimorbid patients
Response rate: only 50% effective
Partial responses: almost exclusively
Median duration: 12 months
Bendamustine-rituximab combination therapy (90 mg/m2 D1,
2)
Relatively fit patients: severely affected
4 cycles
Trial results yielded 78% response rate, 53% complete response,
response duration >88 months
Increases chance of adverse events
D = day.
Berentsen et al, 2004; Rossi et al, 2018; Berentsen et al, 2017; Berentsen et al, 2020.
38. Rituximab in CAD
OR = objective response; CR = complete response.
Berentsen et al, 2004; Schöllkopf et al, 2006; Berentsen et al, 2001; Jia et al, 2020; Berentsen, 2011.
Study/
publication
Drug(s)
studied
Study design
Patients/
courses of
therapy, n
OR CR
Hb
increase,
g/dL
Median
response
duration,
months
Toxicit
y
Blood, 2004;103
(8):2925-2928
Rituximab
Prospective,
nonrandomized
27/37 54% 4% 4.0
11
(observed)
Low
Leuk
Lymphoma,
2006;47(2):2532
60
Rituximab
Prospective,
nonrandomized
20/20 45% 5% 3.1
6.5
(observed)
Low
Anti-CD20 monoclonal antibody
2 uncontrolled trials with 54% and 45% response rates
All but 1 a partial response (PR)
Median time to response: 1.5 months
Median duration of response: 11 months
Low toxicity
39. Rituximab Plus Bendamustine in CAD
Berentsen et al, 2017; Berentsen et al, 2020.
Study/
publication
Drug(s) studied Study design
Patients/
courses of
therapy, n
OR CR
Hb
increase,
g/dL
Median
response
duration, mo
Toxicity
Blood,
2017;130
(4):537-541
Bendamustine +
rituximab
Prospective,
nonrandomized
45/45 71% 40% 3.7
>32
(observed)
Relatively low,
manageable
Blood,
2020;136(4):
480-488
Bendamustine +
rituximab
Follow-up, part
of larger study
45/45 78% 53%
Not
reevaluated
>88
(estimated)
Long-term:
low
Probability of sustained remission in patients who have
responded to 4 cycles of rituximab plus bendamustine
Bendamustine plus rituximab
71% response rate
40% complete response (CR)
31% partial response (PR)
33% patients with grade 3-4
neutropenia
>88 months median duration of
response in long-term follow-up
40. CAD: Second-Line Treatment Strategy
Fludarabine-rituximab (oral, 40 mg/m2)
For fit patients (not too young)
40 mg/m2 on Days 1-5
Higher response rate ~76% cases
Sustained remissions
Higher risk of long-term AEs
Bortezomib monotherapy (approved for MM and MCL)
1 cycle
Effective in 1/3 of patients
AE = adverse event; MM = multiple myeloma; MCL = mantle cell lymphoma.
Barcellini et al, 2020; Berentsen, 2018; Berentsen et al, 2020; Rossi et al, 2018; Velcade® prescribing information, 2022.
41. Rituximab Plus Fludarabine in CAD
Berentsen et al, 2010; Berentsen et al, 2020.
Study/
publication
Drug(s)
studied
Study design
Patients/
courses of
therapy, n
OR CR
Hb increase,
g/dL
Median
response
duration, mo
Toxicity
Blood, 2010;116
(17):3180-3184
Fludarabine
+ rituximab
Prospective,
nonrandomized 29/29 76% 21% 3.1
>66
(estimated)
Significant
Probability of sustained remission in patients who have
responded to 4 cycles of rituximab plus fludarabine
Uncontrolled prospective trial
76% of patients responded
21% complete response (CR)
55% partial response (PR)
Median time to response: 4
months
Median duration of response: 66
months
41% of patients had grade 3 or 4
hematologic toxicity
42. GIMEMA: Bortezomib in CAD
a1 patient achieved transfusion independence in spite of treatment stop.
b4 of 6 achieved transfusion independence.
Rossi et al, 2018.
Eligible patients received a single course of bortezomib (1.3 mg/m2 IV on Days 1, 4, 8, 11)
Phase 2 Prospective Study in Anemic Patients With Relapsed CAD
Patients enrolled N=21
• Transfusion-dependent: 10
• Hb <10 g/dL
Patients excluded n=2a
• Day 4 pulmonary
embolism
• Day 8 headache
Patients evaluable for
response n=19
Complete response
3 (15.8%)
Absence of anemia and
hemolysis, complete
resolution of clinical
symptoms
Partial response
3 (15.8%)
Stable increase in Hb level
by at least 2.0 g/dL,
improvement of clinical
symptoms and
transfusion independency
Refractory
13 (68.4%)
Failure to achieve
CR or PR
ORR
6/19 (31.6%)b
43. Daratumumab: Single-Case Study
IL = interleukin; IFN = interferon; TNF = tumor necrosis factor; TGF = transforming growth factor.
Zaninoni et al, 2021.
Daratumumab targets CD38-positive cells, expressed on plasma cells and
lymphoplasmacytes
Shows immunomodulatory influence on cytokines (IL-6, IL-10, IL-17,
IFN-γ, TNF-α, TGF-β)
Patient had long history of multitreated CAD (rituximab was ineffective) with
severe transfusion-dependent anemia, low cold agglutinin titer, and IgG
monoclonal gammopathy
Case indicates effectiveness ameliorating anemia and improving disabling
circulatory symptoms, although patient did not experience a complete response
Hb levels increased 3 g/dL resulting in transfusion independence
Disabling circulatory symptoms disappeared
Potential additional therapeutic option for the refractory disease
Effectiveness Ameliorating Anemia
44. Combination Therapy: Increases Response Rate
SAE = severe adverse event.
Berentsen et al, 2020.
Rituximab-bendamustine
Berentsen et al (n=232) Norway vs Italy study showed:
Improvement up to 78% (from 71%)
Complete response 53% (from 40%)
Response duration 88 months (7.3 yrs)
Limitations
≥25% will not respond
Patients continue to hemolyze
Awareness of SAEs
Risk of neutropenia
Infections may increase
CAD
45. Common Adverse Events
Berentsen 2020; Fouda & Bavbek, 2020.
Neutropenia, which can result in:
Infection
Concerns of long-term toxicities
Specifically with use of cytostatic agents, fludarabine and
bendamustine
Rituximab infusion reactions, at start
Anti–B-Cell Therapy for CAD
46. Unmet Medical Need
Berentsen, 2020; Gertz, 2007; Berentsen et al, 2007; Petz, 2008; Röth & Dührsen, 2010; Berentsen et al, 2015; Wouters & Zeerleder, 2015.
High frequency of persisting anemia/hemolysis
Immunochemotherapy is unsuccessful in at least 25% because
of treatment failure or toxicity
Small B-cell clone with low proliferation activity and difficult to
target efficiently
Need for rapid-acting therapy, especially in specific clinical
settings: acute and severe exacerbations due to infections,
major surgery, trauma, and cardiac surgery
CAD
51. DECADE: Eculizumab in CAD
ULN = upper limit of normal.
Röth et al, 2018.
First prospective trial of complement inhibition by eculizumab in CAD
12 patients with confirmed chronic CAD and 1 patient with acute CAS
requiring treatment of anemia, LDH >2X ULN
3 phase study 2-week screening (vaccination) 26-week treatment, 8-
week washout and observation
Median LDH decreased; Hb increased from 9.35 g/dL to 10.15 g/dL
8 patients became transfusion-independent; 3 maintained
No effect on circulatory symptoms
13 AEs possibly related to treatment
1 case of pneumonia probably related to treatment
No meningococcal infection occurred
Phase 2 Prospective Single-Arm Interventional 2 Center Trial
52. Eculizumab in CAD
Röth et al, 2018.
Therapy-related changes in lactate dehydrogenase levels
53. Eculizumab in CAD (cont.)
Eculizumab response in a patient with an acute
CAS. Urine of Patient 5 with severe intravascular
hemolysis and hemoglobinuria immediately before (A)
and 24 hours after (B) the first dose of eculizumab.
Therapy-related changes
in lactate dehydrogenase levels
Röth et al, 2018.
55. MAC
Pegcetacoplan (APL-2)
Gerber & Brodsky, 2022.
Lectin pathway
Activated by lectin and
mannose complex
Classical pathway
Activated by antigen-
antibody immune complex
Alternative pathway
Spontaneous
C3 convertase activation
APL-2 C3
C5
C3a
C3b
C5a
C5b
Inflammation
Inflammation
Cell removal
Antigen uptake
Cell lysis,
secretion,
death,
or proliferation
Factor b Factor D
Amplification
loop
56. Pegcetacoplan in CAD
SQ = subcutaneously.
Gertz et al, 2019; Grossi et al, 2018.
Phase 2, 48-week open-label trial in patients with primary AIHA
12 patients enrolled with CAD
Pegcetacoplan 270 mg/d SQ or 360 mg/d SQ
Interim analysis at Day 56
Mean Hb increased from 8.7 to 12.1 g/dL
Mean LDH, reticulocyte count and indirect bilirubin returned to
normal
75% experienced ≥1 AE
Pegcetacoplan increases Hb in CAD
Reduces intra and extravascular hemolysis
Appears safe and well-tolerated
57. CASCADE: Pegcetacoplan in CAD
Jilma et al, 2022.
Phase 3 Trial in Progress
Key Eligibility Criteria:
• Age ≥18
• Diagnosis of primary CAD
• Hb ≤9 g/dL
• Documented bone marrow
biopsy within 1 year of
screening
• Have been vaccinated against
S. pneumoniae, N.
meningitidis, H. influenzae
Pegcetacoplan
1,080 mg
2x week
Pegcetacoplan
1,080 mg
2x week
Pegcetacoplan
1,080 mg
2x week
Placebo
Part A
24-week double-blind
treatment period
Part B
24-week open-label
treatment period
Part C
Open-label
maintenance period
2:1 randomization
Primary end point
Hb level increase of ≥1.5 g/dL from baseline
which is maintained from Week 16 through
Week 24 without blood transfusion from Week 5
through Week 24
Secondary end points
• Change from baseline in Hb level
• Transfusion avoidance from Week 5 to Week 24
• Quality of life (QOL)
• Change in markers of hemolysis
• Number of transfusions from Week 5 to Week
24
24 48 96
Follow-up
period
Weeks 96-104
End of
treatment
-4
59. Sutimlimab Selectively Targets Complement C1s,
Ab = antibody.
Röth, Barcellini et al, 2021
Inhibiting Classical Complement Pathway Activation
C1 complex
C1q
C1r
C1s
Sutimlimab
Sutimlimab binds
C1s
Intravascular
hemolysis
Pathogen
Lysis
Extravascula
r hemolysis
Sutimlimab
(formerly BIVV009)
Humanized monoclonal Ab
IgG4 (S241P; L248E)
Inhibits classical complement
Lectin and Alternative
pathways remain intact
60. CARDINAL: Sutimlimab in CAD
Röth, Barcellini et al, 2021.
Open-Label Phase 3 Study: Patients With CAD and Recent History of Transfusion
Key eligibility criteria
• Baseline Hb ≤10 g/dL
• Active hemolysis: total
bilirubin above normal
• ≥1 blood transfusion within
6 months of enrollment
• No treatment with
rituximab within 3 months
or combination therapies
within 6 months
• CAS excluded
• Vaccinated against
encapsulated organisms
Sutimlimab
Dose <75 kg = 6.5 g
Dose ≥75 kg = 7.5 g
Weight-based IV on
Day 0 and Day 7
and then every 2 weeks
Sutimlimab
Every 2 weeks
Post-
treatment
follow-up
period
9 weeks
Part A (n=24)
26-week treatment
period
Part B (n=22)
Extension period
(up to 3 years)
Primary end point
Normalization of hemoglobin to ≥12 g/dL or
increase in hemoglobin by 2g/dL or more
without transfusion
Secondary end points
• Hemolysis markers
• QOL
• Transfusions needed
Screening/
observatio
n
period
6 weeks
61. 12
11
10
9
8
Mean
(±SE)
Hb
(g/dL)
45
30
40
35
Mean
(±SE)
FACIT-F
Sutimlimab Efficacy
SE = standard error; CP = classical pathway; FACIT-F = Functional Assessment of Chronic Illness Therapy – Fatigue.
Röth et al, 2019.
Correlation Between Key Response Measures and Classical
Complement Biomarkers
LLN
0.4
0.3
0.2
0.1
0.0
Mean
(±SE)
total
C4
(g/L)
25
15
10
0
20
5
Mean
(±SE)
Wieslab-CP
(%)
60
50
40
30
20
10
Mean
(±SE)
bilirubin
(µmol/L)
ULN
Weeks Weeks
62. Complement Activity and Inflammation
MCP = membrane cofactor protein; DAF = decay accelerating factor; CR1= complement receptor 1; C4BP = C4b binding protein.
Merle et al, 2015.
Classical pathway activation is an
inducer of systemic inflammation via
generation of C3a and C5a,
recruitment of neutrophils, endothelial
cell activation and platelet activation
63. 0
1
2
3
4
5
6
Mean
(±SEM)
IL-6
level
(pg/mL)
CARDINAL: Sutimlimab Phase 3 Ad Hoc Analysis
SEM = standard error of the mean; TAT = treatment assessment time point.
Weitz et al, 2020.
Correlation Between IL-6 Expression and Fatigue
Mean IL-6 levels (mean pg/mL [SEM]) declined
from baseline (3.21 [0.958]) to follow-up during
sutimlimab treatment; onset was as early as
Week 1 (2.70 [0.839])
By Week 3, mean (SEM) IL-6 levels were reduced
by more than half (1.56 [0.297]), rose slightly at Week
5 (1.88 [0.383]), and were lowest at the TAT (1.31
[0.201])
Decreased complement-mediated inflammation,
as demonstrated by IL-6 changes, occurred
concurrently with FACIT-Fatigue score improvements
over time
Suppression of classical complement pathway activity
and normalization of mean total C4 levels were
sustained with sutimlimab treatment over 25 weeks
Rapid and sustained decline of IL-6 levels concurrent
with FACIT-Fatigue improvement following sutimlimab treatment
0
10
20
30
40
50
60
-5
0
5
10
15
20
25
30
35
40
0 1 3 5 25
Week
Mean
(±SEM)
FACIT-F
score
Mean
(±SEM)
Wieslab-CP
(%)
0
0.1
0.2
0.3
0.4
No. of patients
IL-10: 21 19 18 18
FACIT-Fatigue: 22 21 20 20
C4: 23 22 22 21
CP: 24 22 22 21
18
20
21
21
IL-6 FACIT-Fatigue C4 CP
Mean
(±SEM)
total
C4
(g/L)
64. CARDINAL: Sutimlimab Trial Summary Analysis
Röth, Barcellini et al, 2021.
Sutimlimab is first-in-class selective inhibitor of the classical
complement pathway
Sutimlimab demonstrated rapid and sustained efficacy in CAD
Treatment with sutimlimab prevented hemolysis, significantly
increased Hb, and improved QOL (FACIT-F)
Targeting C1s in the classical complement pathway represents a novel
therapeutic approach for the management of CAD
Sutimlimab has the potential to change treatment practices for
patients with CAD
66. Adverse Events with Sutimlimab in CAD
TRAE = treatment-related AE; SLE = systemic lupus erythematosus.
Röth, Barcellini et al, 2021.
No serious adverse events were
determined to be related to
sutimlimab
Most common TRAE was infusion-
related reaction in 2 patients
Infections:
23 infections reported in 13 patients
No meningococcal infections
Serious infections were not
determined to be related to
sutimlimab
No clinical evidence of SLE or
autoimmune disease with
sutimlimab
CARDINAL Phase 3 Trial
Event
Total
(N=24)
All adverse events 124
Patients with ≥1 adverse event 22 (92%)
Patients with ≥1 treatment-related adverse
event
9 (37%)
Number of events 13
Serious adverse events 16
Patients with ≥1 serious adverse event 7 (29%)
Patients with ≥1 serious infection 2 (8%)
Patients who discontinued treatment or
study because of an adverse event
1 (4%)
Death 1 (4%)
67. CADENZA: Sutimlimab in CAD
Röth, Berentsen, et al, 2022.
Phase 3 Trial in Patients with no Recent History of Transfusion
Primary End Point Criteria
• Hemoglobin increase
≥1.5 g/dL [mean of
Weeks 23, 25, 26],
• Avoidance of
transfusion
• Avoidance of Study-
prohibited CAD therapy
[Weeks 5-26])
68. CADENZA: Sutimlimab in CAD (cont.)
Röth, Berentsen et al, 2022.
Randomized, phase 3 placebo-controlled trial in patients with
CAD who had no transfusions in the past 6 months
42 patients enrolled: 22 sutimlimab, 20 placebo
73% of patients on sutimlimab compared with 15% of patients
on placebo met the composite primary end point criteria
(hemoglobin increase ≥1.5 g/dL at treatment assessment
timepoint [mean of Weeks 23, 25, 26], avoidance of transfusion,
and study-prohibited CAD therapy [Weeks 5-26])
69. Adverse Events with Sutimlimab in CAD
TESAE = treatment-emergent serious AE.
Röth, Berentsen, et al, 2022.
14% (3 patients) in sutimlimab arm with TESAEs:
Febrile infection and increased IgM (1 patient), Raynaud’s (1 patient), cerebral
venous thrombosis (1 patient)
18 TEAEs of infection were reported by 10 patients (45%) in the
sutimlimab arm and 19 TEAEs of infection were reported in 10 patients
(50%) in the placebo arm
Adverse events occurring more often in sutimlimab group than in
placebo group:
Headache (22.7% vs 10%)
Hypertension (22.7% vs 0%)
Rhinitis (18.2% vs 0%)
Raynaud phenomenon (18.2% vs 0%)
Acrocyanosis (13.6% vs 0%)
CADENZA Phase 3 Trial
70. Efficacy of Sutimlimab in CAD
Röth, Berentsen et al, 2022.
CADENZA Phase 3 Trial
8
9
10
11
12
13
B 1 3 5 7 9 11 13 15 17 19 21 23 25 26
Weeks
Sutimlimab
n 22 22 21 22 19 20 17 19 17 18 19 19 18 19 19
n 20 19 19 19 19 19 19 19 19 19 19 19 20 19 19
Mean
(SE)
Hb
(g/dL)
Placebo
Impact on Anemia (Hb Level) and QOL (FACIT-Fatigue) With Sutimlimab
Compared With Placebo, From Baseline to Week 26
71. Efficacy of Sutimlimab in CAD (cont.)
BL = baseline; W26 = Week 26.
Röth, Berentsen et al, 2021.
At baseline:
More patients in the sutimlimab group
versus placebo group had cold-induced,
agglutination-mediated symptoms
(disabling circulatory symptoms,
acrocyanosis, Raynaud’s syndrome) and
hemoglobinuria
Patients in the sutimlimab group also had
higher IgM levels at baseline than
patients in the placebo group
At Week 26:
Substantial reductions in the incidence of
CAD symptoms were observed in the
sutimlimab group versus minimal
changes in the placebo group for
acrocyanosis, Raynaud’s syndrome, and
hemoglobinuria
CADENZA: Additional Exploratory End Points
40.9
26.3
22.7
10.5
13.6
5.3
36.4
15.8
20.0
26.3
15.0
21.1
0
0
10.0
5.3
0
10
20
30
40
50
BL W26 BL W26 BL W26 BL W26
Patients
(%)
Sutimlimab (n=22) Placebo (n=20)
Acrocyanosis Raynaud’s
syndrome
Disabling
circulatory
symptoms
Hemoglobinuria
n=9
n=4
n=5
n=5
n=5
n=3
n=2
n=4
n=3
n=1
n=8
n=2
n=3
n=1
Week
73. CADENZA: Conclusions Sutimlimab in CAD
TAT = treatment assessment timepoint.
Röth, Berentsen, et al, 2022.
Significantly more patients in the sutimlimab group vs the placebo
group met the primary efficacy criteria for a responder: Hb increase
≥1.5 g/dL at the TAT, and avoidance of transfusion and prohibited
CAD therapy from Weeks 5 to 26
Sutimlimab prevented hemolysis, increased Hb, and improved QOL
(FACIT-Fatigue), with no new safety concerns
The positive results of this double-blind, placebo-controlled study
demonstrate that sutimlimab is an effective therapeutic approach
regardless of transfusion history, thus supporting previously reported
data, across a wider population of patients with CAD
74. Cold Agglutinin–Mediated AIHA
Jäger et al, 2020; Röth, 2020; Berentsen, 2023; Berentsen et al, 2020.
Supportive care/therapy
Treat underlying disease
(if possible)
Supportive care/therapy
Clinical trial
(if possible)
Emergency situation
Eculizumab
Plasmapheresis
Rituximab
375 mg/m2 weekly x 4
(+ bendamustine for fit patients)
Rituximab
+ bendamustine
Clinical trial/experimental treatment
(sutimlimab, BIVV020, ibrutinib, venetoclax)
Rituximab
+ fludarabine or bortezomib mono
Primary CAD Secondary CAS
Asymptomatic Symptomatic
(anemia, transfusion, circulatory symptoms)
Watch &
wait
No response/relapse
Relapse
77. CADENCE Registry
Global Patient Registry will provide prospective longitudinal data
Launched 2019 to advance understanding of:
Patient demographics
Clinical presentation and characteristics
Comorbidities and disease burden
Patterns and use of CAD treatments
Long-term clinical outcomes
Patients’ health-related quality of life
Different geographic locations
Register your patient
https://coldagglutininnews.com/2021/01/07/cadence-registry
Cold Agglutinin Disease Real World EvidENCE Registry
Coldagglutininnews.com, 2021.
78. Key Takeaways
Recognizing symptoms and diagnosing are critical in CAD
Bone marrow positive for CAD LPD (B cells negative for MYD88 L265P
mutation)
NOT the indolent disease we once believed it was with increased risk
of thrombosis and mortality, which may be seasonal
CAD patients have evidence of hemolysis regardless of the season
CAD is a systemic inflammatory disease
Therapy decisions should be individualized to address symptoms;
consider comorbidities and patient preference
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Editor's Notes
Reference:
Berentsen S. How I manage patients with cold agglutinin disease. Br J Haematol. 2018;181(3):320-330. doi: 10.1111/bjh.15109.
References:
Berentsen S. How I manage patients with cold agglutinin disease. Br J Haematol. 2018;181(3):320-330. doi: 10.1111/bjh.15109.
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Bylsma LC, Gulbech Ording A, Rosenthal A, Öztürk B, Fryzek JP, Arias JM, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985. doi: 10.1182/bloodadvances.2019000476.
Hill QA, Punekar R, Arian JM, Broome CM, Su J. Mortality among patients with cold agglutinin disease in the United States: an electronic health record (EHR)-based analysis. Blood. 2019;134(suppl 1):4790. doi:10.1182/blood-2019-122140.
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Berentsen S, Barcellini W, D'Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488.
Bylsma LC, Gulbech Ording A, Rosenthal A, Öztürk B, Fryzek JP, Arias JM, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985. doi: 10.1182/bloodadvances.2019000476.
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Reference:
Bylsma LC, Gulbech Ording A, Rosenthal A, Öztürk B, Fryzek JP, Arias JM, Röth A, Berentsen S. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985. doi: 10.1182/bloodadvances.2019000476.
Hill QA, Punekar R, Arian JM, Broome CM, Su J. Mortality among patients with cold agglutinin disease in the United States: an electronic health record (EHR)-based analysis. Blood. 2019;134(suppl 1):4790. doi:10.1182/blood-2019-122140.
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Figure Legend:
Flowchart of patients enrolled. Response was evaluated at 3 months after treatment start. Hgb, hemoglobin; ORR, overall response rate.
Reference:
Zaninoni A, Giannotta JA, Gallì A, et al. The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease. Front Immunol. 2021;12:649441. doi: 10.3389/fimmu.2021.649441.
Reference:
Berentsen S, Barcellini W, D'Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488.
Relationship between lactate dehydrogenase response, eculizumab serum levels, and the thermal amplitude of the cold agglutinin. Difference in the lactate dehydrogenase level between the first and the last day of treatment (upper) and median eculizumab trough level between week 4 and week 26 of the treatment phase (lower) in relation to the thermal amplitude of the cold agglutinin in 12 patients with chronic CAD. Patients with or without a lactate dehydrogenase decrease ≥250 U/L are represented by solid or open circles, respectively.
This improvement in biomarkers of classical complement pathway activity from Week 1 onwards correlates well with the improvement seen in hemoglobin, bilirubin and the FACIT-Fatigue score.
Wieslab CP assay shows a drop in classical pathway activity,
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Which is reflected in the decline in bilirubin levels as complement mediated hemolysis is halted.
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C4 levels normalize with classical pathway inhibition,
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and likewise this is mirrored in the improvement in hemoglobin levels as well as FACIT-F scores.