Hematology-oncology Therapy Third Edition

[Oliverio Gallman]

Thethird edition of this book has been extensively expanded to discuss all aspects of cancer treatment side-effects in everyday life, covering a range of issues from skin problems to fertility problems, Divided in three major parts, the first part covers medical cancer therapy side effects, ranging from organ-related toxicities to drug group particularities. In the second part the adverse events in surgery are extensively discussed, covering issues in regular and robotic surgery and discussing indications and effectiveness. Finally, in the third part, the balance of efficacy versus toxicity in radiotherapy is discussed for different tumor types.

The reader will learn about the state of the art in cancer therapies and their side-effects as well as possible prevention. Chapters remain up to date via electronic updates and include all the latest progress in drug discovery, surgery and radiotherapy.

This is a very comprehensive work written by a team of world experts and edited by key opinion leaders. This book is aimed at medical, surgical and clinical oncologists but is a great resource for junior doctors, trainees, pharmacists and nurses.

Mario Dicato, Hematology-Oncology Service at Luxembourg Medical Center, Luxembourg, and Head of the Research Laboratory of the Luxembourg Foundation for Research on Cancer and Blood Disorders. M. Dicato trained at Lausanne University, completed his postgraduate training at the Universities of Geneva, Switzerland, Pittsburgh and Yale, USA. He did his fellowship (subspecialty training) in hematology at the Massachusetts General Hospital, Boston and was Clinical and Research Fellow in Medicine at Harvard University, Boston, USA.

Eric Van Cutsem, MD, PhD, is full professor and Head of the division of Digestive Oncology at University of Leuven, Leuven, Belgium (KUL) and University Hospitals Leuven. He became in 2018 doctor honoris causa of the Medical University of Warsaw, Poland. He is member of the Belgian Royal Academy of Medicine and president of the Belgian Foundation against Cancer and received in 2019 the ESMO Award. His research focuses on the development of new treatment strategies for GI cancers, including drug development and the identification of molecular markers and diagnostic tools. He has published more than 560 peer-reviewed articles, leading to more than 68500 citations and an H-Factor of 118. In 2013, Capital magazine ranked Prof Van Cutsem in the top three reputed colon cancer experts globally. Thomson Reuters ranks him in the top 1% for impact in his domain. He co-founded the ESMO GI/World Congress on Gastrointestinal Cancer, and is Chair of the meeting in Barcelona, Spain. He serves/served on the board or key committee of several international societies, including ESMO, ASCO, ENET, EORTC, ECCO, ESDO and of the patient advocacy groups, Europacolon and Digestive Cancers Europe

During the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment. ICI-related side effects occur via direct overactivation of the immune system, and patients can experience symptoms akin to autoimmune disease. These symptoms can range in severity from mild to severe and can be fatal. Advanced practice providers require a heightened awareness of the wide range of immune-related adverse events that can occur with ICI therapy.

Immune checkpoint inhibitors (ICIs) exert their effects through upregulation of the immune system (Sharma & Allison, 2020). The most common ICIs include those affecting cytotoxic T-lymphocyte antigen 4, programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1. Cytotoxic T-lymphocyte antigen 4 usually affects the immune system during the priming phase of T-cell activation, whereas PD-1 and programmed cell death-ligand 1 work with T-cell responses during the effector stage (Sharma & Allison, 2020). ICIs are approved for treatment for a variety of malignancies as single-agent therapy, as dual checkpoint inhibition, and in combination with chemotherapy or targeted therapy. The latest ICI to receive approval from the U.S. Food and Drug Administration is the lymphocyte activation gene 3 inhibitor relatlimab, which restores function of exhausted T cells during the effector phase (Tawbi et al., 2022). To date, lymphocyte activation gene 3 is approved in combination with nivolumab for the treatment of metastatic melanoma (Tawbi et al., 2022).

Because of the mechanism of action of ICIs, their adverse effect profile is vastly different than that for standard chemotherapy or targeted therapy. The most common immune-related adverse events (irAEs) are those affecting the skin (e.g., rash), gastrointestinal tract (e.g., diarrhea, colitis), liver (e.g., hepatitis), and endocrine system (e.g., thyroid, pituitary) (Michot et al., 2016). However, there are less common but more severe and life-threatening irAEs requiring early recognition and intervention.

This article reviews the recognition and management of the following three life-threatening irAEs: myocarditis, myositis, and myasthenia gravis. Although myocarditis, myositis, and myasthenia gravis can occur in isolation, they often occur together in a pair or triad and tend to have overlapping symptoms. This phenomenon is referred to as overlap syndrome or triple-hit syndrome (Lipe et al., 2021; Pathak et al., 2021). This syndrome has also been referred to clinically as triple M syndrome in reference to the three irAEs it encompasses. Because of the rarity of irAE-related side effects, the literature consists primarily of case series and retrospective reviews. Consequently, treatment and immunosuppression recommendations for diseases outside of irAEs are extrapolated from these case series.

This article reviews the presenting symptoms and workup of and treatment for myocarditis, myositis, and myasthenia gravis within triple M syndrome. The review is based on standards of care, guidelines, a case study, and retrospective reviews published from 2016 to 2023.

Workup includes physical examination, laboratory diagnostics, electromyography (EMG), and muscle biopsy, if indicated. Laboratory findings include elevated creatine kinase, aldolase, and troponin T (Saygin et al., 2022; Shelly et al., 2020). EMG will show changes consistent with myopathy in as many as 75% of cases, although there are reports of normal EMG in the context of other diagnostic findings concerning for myositis (Saygin et al., 2022). Patients may also have elevated aspartate and alanine aminotransferases (alanine transaminase and aspartate transaminase) because of presence in skeletal muscle cells, which can be confused with ICI-related hepatitis (Saygin et al., 2022). Myositis-specific antibodies are largely negative in ICI-related myositis (Saygin et al., 2022).

Once patients are clinically stable and creatine kinase and troponin T are downtrending, patients can be converted to oral prednisone, with dosing tapered during a period of four to six weeks. In addition, it is recommended that patients have weekly blood draws to monitor creatine kinase and troponin T levels and physical examination to assess for muscle weakness (Saygin et al., 2022; Shelly et al., 2020).

Once diagnosed, treatment for myasthenia gravis includes pyridostigmine, an acetylcholinesterase inhibitor; IVIG; PLEX; and immunosuppression, including corticosteroids (NCCN, 2023; Safa et al., 2019). Corticosteroid dosing with myasthenia gravis is lower than that for other irAEs because high-dose steroids may exacerbate myasthenia gravis (Zubair et al., 2022). For patients with myasthenia gravis exacerbation or rapid decompensation, intubation and ventilation may be necessary, with careful monitoring of respiratory status (Zubair et al., 2022). Following symptomatic improvement, tapering of steroids usually occurs from several weeks to a few months. In addition, IVIG can be administered simultaneously with steroids, which generally requires a longer taper over the course of many months (Zivelonghi & Zekeridou, 2021). Comanagement with a neurologist specializing in neuromuscular disorders is recommended for patients with myasthenia gravis (Zivelonghi & Zekeridou, 2021).

Triple M syndrome is the combination of myocarditis, myositis, and myasthenia gravis. As a rare complication of ICI therapy, this syndrome carries high rates of morbidity and mortality. Onset is typically rapid after the initiation of ICI therapy, often occurring after a single dose (Pathak et al., 2021). Advanced practice providers who routinely see patients with hematologic diseases or cancers need to be aware of early warning signs and symptoms of triple M syndrome so that they can initiate appropriate diagnostic workup. Figure 1 demonstrates how subtle the symptoms of triple M syndrome can be and how quickly they can escalate. If there is concern for any of these irAEs, diagnostic workup for all three syndromes is initiated (Lipe et al., 2021; Pathak et al., 2021). Although these three irAEs have substantial overlap in symptoms and diagnostic workup, subtle and significant differences exist that aid in confirming the diagnosis (Lipe et al., 2021; Pathak et al., 2021). Table 1 presents the recommended workup for each irAE encompassing triple M syndrome. Interpretation and discussion of results occurs between the primary hematology-oncology team and appropriate subspecialists to determine a plan for ongoing care. Patients with minor, nonspecific symptoms during initial workup may require hospitalization because they can deteriorate quickly and require a higher level of care, including transfer to the intensive care unit and telemetry (Lipe et al., 2021). Although high-dose steroids are the standard treatment for myositis and myocarditis, steroids can exacerbate myasthenia gravis, requiring interprofessional consultation (Safa et al., 2019; Zubair et al., 2022). Early workup to rule out myasthenia gravis can avoid additional morbidity. If myasthenia gravis is strongly suspected, or if the patient is experiencing severe myositis symptoms, treatment with IVIG or PLEX is recommended (NCCN, 2023). With rare exceptions, discontinuation of ICI therapy is recommended after patients develop one of these irAEs (NCCN, 2023).

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