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   Table of Contents - Current issue
Coverpage
July-September 2019
Volume 2 | Issue 3
Page Nos. 53-125

Online since Thursday, August 22, 2019

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EDITORIAL  

Cancer immunotherapy for the immunosuppressed: Dissecting the conundrum of safety and efficacy p. 53
Joud Hajjar
DOI:10.4103/JIPO.JIPO_15_19  
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EXPERT OPINION Top

Immunotherapy use in patients with HIV and non-small-cell lung cancer: Current data p. 55
Katherine A Scilla, Alessandro Russo, Christian Rolfo
DOI:10.4103/JIPO.JIPO_13_19  
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ORIGINAL RESEARCH Top

Safety of immune checkpoint blockade in patients with cancer and preexisting autoimmune diseases and/or chronic inflammatory disorders p. 59
Mohsin Shah, Mazen N Jizzini, Imad E Majzoub, Aiham Qdaisat, Cielito C Reyes-Gibby, Sai-Ching Yeung
DOI:10.4103/JIPO.JIPO_11_19  
Background: Checkpoint blockade therapy, in the form of immune checkpoint inhibitors (ICIs), is increasingly being used to prolong survival in cancer patients, but its use is limited by the occurrence of immune-related adverse events (irAEs). These can be serious and occasionally fatal. However, the safety of ICIs is currently unknown in cancer patients with preexisting autoimmune diseases (PADs) and/or chronic inflammatory disorders (CIDs) such as eczema.Aim: The aim of this study is to evaluate the safety of ICIs in cancer patients with PAD and/or eczema at our institution. Patients and Methods: A retrospective study of cancer patients who presented to the Emergency Department between March 1, 2011, and February 29, 2016, after ICI therapy was previously conducted. Among these patients, those with PAD and/or eczema were further evaluated for safety by determining the occurrences of de novo irAEs or preexisting disease exacerbation. Results: Twenty-two cancer patients with PAD and/or eczema who received ICIs were reviewed, in which 15 were male (68%). Their median age was 63 years (range: 40–78 years). Most patients received anti-PD-1drugs (68%). Melanoma was the most common malignancy (45%). Autoimmune thyroiditis/primary hypothyroidism was the most common PAD. Four patients were receiving treatment for PAD at baseline using systemic corticosteroids, anti-inflammatory agents, and other immunosuppressants. Nineteen patients experienced de novo irAEs and/or PAD exacerbation. In three patients, the irAE was severe (grade ≥3). In six patients, the irAE or exacerbation was managed with systemic corticosteroids. Twelve patients experienced resolution of the de novo irAE or PAD exacerbation without the need to withhold or discontinue ICI therapy. The median time to last follow-up or death from the first dose of ICI was 16.8 months (range: 2–80 months). Death due to cancer progression was reported in 17 patients. Conclusion: Although de novo irAEs and PAD exacerbation were common, most patients with PAD and/or CIDs tolerated ICI therapy well.
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Rheumatic and musculoskeletal adverse events with immune checkpoint inhibitors: Data from the United States Food and Drug Administration adverse event reporting system p. 65
Xerxes N Pundole, Mayur Sarangdhar, Maria E Suarez-Almazor
DOI:10.4103/JIPO.JIPO_12_19  
Background: Despite their efficacy, immune checkpoint inhibitors (ICIs) can cause significant immune-related adverse events (irAEs). Rheumatic and musculoskeletal irAEs can be serious and adversely affect the quality of life. The full spectrum of irAEs is still emerging, and to represent and better understand their scope, we evaluated the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: We used AERSMine, an open-access web application to mine FAERS data across 11,919,342 patients from 2011 (first quarter) to 2018 (fourth quarter). Measures of disproportionality were calculated using well-established pharmacovigilance metrics, proportional reporting ratios, and safety signals (information component), in patients receiving ICI. Results: We analyzed 63,979 cancer patients for reports of ICI-associated AEs. Eighty-two percent of these reports were in relation with anti-PD-1 inhibitors. Rates of rheumatic and musculoskeletal AEs were higher in men and in patients >65 years of age. Several statistically significant AEs were identified, most in relation with PD-1 inhibitors. AEs with the highest number of reports included arthralgia (n = 1062), followed by myalgia (n = 532), myositis (n = 438), arthritis (n = 403), and rhabdomyolysis (n = 230). Novel AEs affecting the skeleton included compression fractures, fractures at various skeletal sites (rib, thoracic vertebral, and humerus), osteonecrosis of the jaw, osteitis, and osteomyelitis. Conclusion: A wide spectrum of rheumatic and musculoskeletal AE signals were detected within the FAERS data which may signify the emerging trends of irAEs post approval of ICI. Additional research to explore mechanisms and identify optimal management strategies of these AEs is warranted.
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REVIEW ARTICLES Top

Kaposi's sarcoma in the immunosuppressed p. 74
Nisha A Reddy, Steven R Mays, Omar Pacha
DOI:10.4103/JIPO.JIPO_10_19  
Kaposi's sarcoma (KS) is a virally induced tumor most commonly appearing in the immunosuppressed. It is caused by infection with human herpesvirus-8, which in healthy individuals causes no symptoms. However, in patients with weakened immune systems, such as in HIV and organ transplant patients, the virus can proliferate leading to KS. Following the introduction of antiretroviral therapy (ART) for HIV and AIDS, the prevalence of AIDS-related KS has fallen, but it has begun to appear in subsets of patients on treatment. Treatments for KS vary depending on the cause of immunosuppression. In the case of HIV, ART is the first-line treatment, but other therapies are initiated based on tumor response. In transplant patients, primary treatment involves stopping or reducing immunosuppression and similarly advancing to other therapies based on response. This presents a dilemma in many cases where chemotherapy will reduce an already-weakened immune system or in strengthening an immune system in patients at risk for transplant rejection. This review will focus on summarizing the effects of immunosuppression in HIV-related (epidemic) and iatrogenically immunosuppressed transplant patients with KS and its etiology, pathophysiology, current treatments, and management along with novel therapies.
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Common cutaneous neoplasms in patients with immunodeficiency: A case series p. 79
Suhair Al Salihi, Haider A Mejbel, Victor G Prieto, Phyu P Aung
DOI:10.4103/JIPO.JIPO_9_19  
Through humoral and cell-mediated mechanisms, the immune system plays a vital role in protecting every organ system. Disorders of the immune system may result in various cutaneous manifestations, including cutaneous malignancies. In patients with immunodeficiency, the risk of development of malignant cutaneous neoplasms is substantially increased. This increased risk may be due to oncogenic viruses that find a suitable microenvironment for tumorigenesis and cancer development. A subset of cutaneous malignancies that develop in patients with immunodeficiency may show aggressive clinical and biological behavior. Here, we report six cases of highly aggressive and deadly cutaneous neoplasms that arose in patients with a known history of immunodeficiency: two cases of Kaposi sarcoma in patients with immunosuppression due to human immunodeficiency virus infection; a case of Merkel cell carcinoma and a case of squamous cell carcinoma (SCC) in patients receiving immunosuppressive drugs after organ transplant; a case of multiple cutaneous tumors, including invasive melanoma, SCC, and sebaceous carcinoma, in a patient with hypogammaglobulinemia and a history of organ transplant; and a case of basal cell carcinoma and melanoma in situ in a patient with primary immunodeficiency.
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Review: The impact of HIV infection on cancer treatment with immunotherapy p. 85
Bruno Palma Granwehr
DOI:10.4103/JIPO.JIPO_14_19  
Human immunodeficiency virus (HIV) and cancer have been intimately linked since the first cases of HIV were identified after investigation of unusually high rates of Kaposi's sarcoma in patients without other risk factors. HIV not only impairs the immune system but also drives a chronic inflammatory response. The significance of the chronic inflammatory response has become more evident, as patients with HIV survive longer on antiretroviral therapy, developing cancers more typical of the aging population. Cancer treatment offered to patients with HIV includes traditional cytotoxic chemotherapy, surgery, and radiation. Some oncologists abbreviate courses or reduce doses of treatment in patients with HIV. The promising field of immunotherapy, exemplified by immune checkpoint inhibitors (ICIs), has revolutionized cancer care. Some of the first studies of ICIs conceived of these agents as an approach to overcome “immune exhaustion” in patients with HIV and other chronic viral infections. In fact, clinical trials are underway to assess the impact of ICIs on patients with HIV with low CD4 counts, despite virologic suppression. Experience with ICI in patients with HIV and cancer is limited, but available studies suggest that HIV remains well-controlled, with CD4 count stable to increasing and viral load stable to decreasing. Immune-related adverse effects have varied, with one case series reporting higher than expected rates, but immune reconstitution inflammatory syndrome has not been reported. In addition to these other therapies, stem cell transplant (SCT) has been demonstrated to be safe and effective. In selected patients with HIV, SCT has even led to the cure of HIV, as noted in two confirmed cases. The treatment of patients with HIV and cancer will benefit from clinical trials designed for this population, as well as new guidelines to aid oncologists in providing care for these patients. Collaboration between oncologists and HIV providers is essential in managing the treatment of HIV during cancer therapy, as well as addressing infectious and other complications that arise. This collaboration will lead to continued improvement in the management of this growing patient population.
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Neuromuscular weakness syndromes from immune checkpoint inhibitors: A case series and literature review p. 93
Ahmad Daher, Carlos Kamiya Matsuoka, Monica Elena Loghin, Marta Penas-Prado, Sudhakar Tummala
DOI:10.4103/JIPO.JIPO_3_19  
Immune checkpoint inhibitors (CPIs) (anti-cytotoxic T-lymphocyte antigen-4, anti-programmed death 1, and anti-programmed death-ligand 1) have transformed the landscape of cancer therapy. However, their increasing use has unleashed immune-related adverse events in various organs, among which neurologic ones, while rare, are increasingly being recognized and remain incompletely characterized. Herein, we report five patients with nonmelanoma cancers who developed weakness after receiving CPIs. The etiology was attributed to radiculoneuritis (one patient), myositis (one patient), Miller Fisher/myasthenia gravis (MG) (one patient), neuropathy/myositis/MG (one patient), and myositis/MG (one patient). Weakness developed after a median of two doses (range: 1–3) and 4 weeks (range: 3–10) from initiation of therapy. Two patients had severe manifestations without improvement while the other three experienced partial improvement despite discontinuation of the CPI (s) and initiation of immunosuppressive therapy. A review of literature identified 62 similar cases. This report highlights the challenges in the diagnosis and management of neurologic adverse events related to the use of CPIs. It also addresses the crucial need for early recognition, proper workup, and better biomarkers to help improve the outcomes of these adverse events.
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CASE REPORT Top

Eosinophilic fasciitis in a patient treated by atezolizumab for metastatic triple-negative breast cancer p. 101
Yacine Wissam, Laila Belcaid, Ruth Wittoek, Vanessa Smith, Amber Vanhaecke, Sofie De Schepper, Lennart Jans, Daphné t'Kint de Roodenbeke, Andrea Gombos, Sandrine Aspeslagh
DOI:10.4103/JIPO.JIPO_8_19  
Immune checkpoint inhibition has revolutionized the treatment for numerous cancer patients; however, the spectrum of immune-related adverse events (irAEs) remains to be fully uncovered. We report a 48-year-old woman who was treated in the Phase III IMpassion130 study (atezolizumab and nanoparticle albumin-bound [nab]-paclitaxel) for metastatic triple-negative breast cancer. She experienced a partial response after 3 months. Nevertheless, the patient presented with thickening of the skin and muscle fatigue in the distal extremities together with blood eosinophilia after 15 months. Skin biopsy and magnetic resonance imaging were diagnostic of eosinophilic fasciitis (EF). Symptoms clearly improved upon stopping atezolizumab, while tumor response is still ongoing after discontinuing treatment. We identified five other cases of EF during immunotherapy, all occurring after about 1 year and in contrast to our case, mostly accompanied by other irAEs. This highlights that even if EF is a rare irAE, timely recognition and management remains important.
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CONFERENCE PROCEEDINGS Top

Meeting Proceedings of the First Immuno-Oncology Society of India Conference (I-OSICON-2019), Mumbai, India p. 106
Jyoti Bajpai, Ram Abhinav Kannan, Hemant Malhotra, Vivek Radhakrishnan, Rakesh Jalali, Gaurav Narula, Amit Awasthi, Girdhari Lal, Rahul Purvar, Kumar Prabhash, Senthil Rajappa, Atul Sharma, Moni Kuriakose, Vikram Matthews, Reena Nair, Smruti Koppikar, Shubhda V Chiplunkar, Shripad Banavali
DOI:10.4103/2666-2345.265156  
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