Target therapies are widely used for treatment of various kinds of hematological malignancies. Since the cancer cells that are targeted, share the same markers with the non-cancerous cells of the immunological system, these therapies are often associated with infectious diseases that require the particular type of immune response for control. In this article, we report a case of Listeria monocytogenes bacteraemia complicating carfilzomib and daratumumab treatment for multiple myeloma. To the best of our knowledge, this is the first case report of listeriosis as a complication of monoclonal antibodies against CD38 and/or proteosome inhibitor therapy.
A 69-year-old Chinese woman with multiple myeloma was admitted to our hospital in December 2017 for carfilzomib and daratumumab therapy. The multiple myeloma was diagnosed in 2015 and she had failed autologous hematopoietic stem cell transplant performed in 2016. After relapse of multiple myeloma, she was started on carfilzomib, a newer proteasome inhibitor, since December 2016; and then daratumumab, an anti-CD38 monoclonal antibody, since August 2017. Three days after the third course of carfilzomib and daratumumab chemotherapy, she developed high fever up to 40°C with chills and rigors. There were no other localizing symptoms or signs. Total white cell count was 2.45 × 109/L, with neutrophil 2.05 × 109/L, and lymphocyte 0.25 × 109/L. Blood cultures were performed from the peripheral blood and the two lumens of the Hickman catheter and she was treated with empirical meropenem.
On Day 1 post-incubation, all three blood culture samples turned positive for a catalase-positive Gram-positive bacillus. The identity was confirmed to be L. monocytogenes by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The isolate was sensitive to penicillin (minimum inhibitory concentration 0.38 μg/mL by E-test). Meropenem was stopped and intravenous ampicillin and gentamicin were commenced. Systemic review revealed no gastrointestinal symptoms prior to the L. monocytogenes bacteremia and no symptoms or signs suggestive of meningitis or encephalitis. The patient denied intake of any potentially implicated food source. The fever settled after 3 days of intravenous antibiotics and ampicillin and gentamicin were continued for a total of 3 weeks. There was no relapse of listeriosis afterwards.
In the past decade, targeted therapies have revolutionized the treatment of various hematological malignancies, improving the prognosis as well as the quality of life for the patients. However, one of the major complications of targeted therapies is infectious complications, as the targets of the treatment are often the immune cells.1 Sometimes, infections that rarely occurred in these patients, even after chemotherapy, have emerged in patients with hematology after targeted therapies. For example, we recently reported a case series of Talaromyces marneffei infection in hematology patients who received monoclonal antibodies against CD20 or kinase inhibitors.2 In this article, we report the first case of listeriosis in a patient who received monocloncal antibodies against CD38 and proteosome inhibitor.
Listeriosis is an emerging complication in hematology patients receiving monocloncal antibodies against CD38 and proteosome inhibitor therapies. Listeriosis is a food-borne disease caused by L. monocytogenes or L. ivanovii, often due to ingestion of unpasteurized milk and dairy products as well as contaminated undercooked meat, ice-cream, salads, and other ready-to-eat items.3 However, in a significant proportion of patients, including the present case, the contaminated food source is not obvious. In immunocompetent hosts, it is usually a self-limiting febrile gastroenteritis. On the other hand, in patients of extremes of age (elderly and neonates), pregnant women, and other immunodeficiency states, it may lead to systemic sepsis with bacteremia (as in the present case), disseminated abscesses in multiple organs especially liver and spleen, and most severely central nervous system infections including meningitis, rhombencephalitis, cerebritis, and brain abscess.4 As L. monocytogenes and L. ivanovii are intracellular pathogens, the immunocompromised patients with listeriosis are often those with cell-mediated immunity defects, such as patients receiving corticosteroids, transplant recipients, and human immunodeficiency virus carriers.5 As for target therapies, agents such as alemtuzumab, rituximab, and etanercept have been reported to be associated with invasive listeriosis.6–9 However, in some of the reported cases, the patients received both the target therapies and other immunosuppressive agents. Therefore, the role of the target therapies was difficult to ascertain. In the present case, carfilzomib and daratumumab were the only immunosuppressive agents that the patient was receiving during the time for the development of listeriosis.
Based on the underlying mechanism of action, both daratumumab and carfilzomib may contribute to the susceptibility of our patient to listeriosis. Daratumumab is the first anti-CD38 monoclonal antibody available in the market, approved by U.S. Food and Drug Administration in 2016 for treatment of multiple myeloma. Anti-CD38 targets myeloma cells through antibody-dependent phagocytosis, antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. In addition, anti-CD38 can also eliminate immnosuppressive T-regulatory cells in order to augment cellular immunity against myeloma cells.10 CD38 is expressed most abundantly on myeloma cells, but is also found on neutrophils, monocytes, and natural killer cells.11 It was suggested in mice model that during L. monocytogenes infection, knocking out CD38 impaired migration of neutrophils and inflammatory monocytes to site of involvement and reduced their ability to control the bacteria.11 The deficiency was later attributed to the impairment of innate immunity for effective phagocytosis after knocking out CD38.12 However, the clinical association between anti-CD38 monoclonal antibody and listeriosis has not yet been reported before. Park et al. recently described infectious complications in 16 patients with refractory myeloma after receiving daratumumab monotherapy. Six out of 16 patients had Grade 3 or higher adverse events related to infection. One had Escherichia coli bacteraemia, three had lower respiratory tract infection, and two had upper respiratory tract infection. Of all the non-bacteraemic infective complications reported in this study, Streptococcus pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus were implicated.13 As for carfilzomib, a newer proteasome inhibitor in the same class as bortezomib, it was approved by U.S. Food and Drug Administration for relapsed or refractory multiple myeloma in 2012. Its mechanism of action is to prevent degradation of pro-apoptotic mediator of the myeloma cell, thus facilitating tumor cell death.14 It has been shown that bortezomib decreased T-cell proliferation and the function of natural killer cells and CD8+T-cells, which led to increased risk to herpes simplex virus and varicella-zoster virus infections.15 Based on these studies on bortezomib, carfilzomib probably has more suppressive effects than daratumumab on the cell-mediated immunity response, which is important in controlling Listeria infection. However, with the co-administration of daratumumab, it is difficult to conclude the contribution of carfilzomib to causing listeriosis in our patient. Individuals on target therapies should be warned to avoid high-risk food items while on these agents (https://www.foodsafety.gov/poisoning/causes/bacteriaviruses/listeria/index.html).
We report the first case of L. monocytogenes bacteremia and severe sepsis after receiving monoclonal antibodies against CD38 and proteasome inhibitor. Based on their respective mechanism of action, both carfilzomib and daratumumab may contribute to the occurrence of this complication, though the exact immunosuppressive effects of these agents are not yet well studied in the literature. Avoidance of high-risk food items after receiving targeted therapies would be prudent in order to prevent listeriosis. A high index of suspicion and use of empirical antibiotic regimens that cover listeria are also essential for the treatment of listeriosis in these patients.
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. Chan JFW, Chan TSY, Gill H, et al. Disseminated infections with talaromyces marneffei in non-AIDS patients given monoclonal antibodies against CD-20 and kinase inhibitors. Emerg Infect Dis 2015;21(7):1101–1106.
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