Infectious Complications of Monoclonal Antibodies Used to Treat Acute Leukemia and Multiple Myeloma
Gemtuzumab ozogamicin is approved for the treatment of acute myelocytic leukemia (AML). Gemtuzumab is conjugated to the toxin calicheamicin; upon internalization of the antibody-toxin conjugate in the target cell, calicheamicin binds to cell DNA and causes breaks in the DNA.45 Gemtuzumab targets CD33, an antigen found on myeloid precursor cells and AML blasts, and therefore prolonged, profound neutropenia is a major adverse event of therapy and occurs in essentially all patients.46,47 Neutropenic fever and sepsis are important potential sequelae.
Inotuzumab ozogamicin is approved for the treatment of acute B-cell lymphocytic leukemia (B-ALL). Inotuzumab targets CD22, a glycoprotein present on the blasts of most patients with B-ALL.48 Like gemtuzumab, it is conjugated to calicheamicin. Although CD22 expression is restricted to B cells, about half the patients in the pivotal phase 3 trial of inotuzumab ozogamicin developed neutropenia and were at risk for neutropenic fever and associated infection.49
Blinatumomab is the first approved bispecific T cell engager, indicated for the treatment of relapsed refractory B-ALL, comprised of monoclonal antibodies targeting CD19 on B cells and CD3 on cytotoxic T cells.50 Upon binding the targeted surface antigens, the CD3-positive T cells are activated and lyse the engaged B cells.50 An effect of T cell activation is cytokine release, which can result in fever and chills mimicking infection. In a phase 2 study of blinatumomab, 60% of patients developed fever.51 Cytokine release syndrome (CRS) is an important potential complication of BITE therapy, which in its most serious form is characterized by fever and hypotension; it is easily mistaken for serious infection. It is prudent to treat fever in neutropenic patients (ie, most of the refractory ALL patients treated with blinatumomab) with empiric antimicrobial therapy even if cytokine release is the suspected cause, since infections in neutropenic patients are so common. Neutropenia has not clearly been associated with blinatumomab, especially since its use is limited to patients likely to have started therapy neutropenic. Blinatumomab, by virtue of targeting CD19 on precursor and mature B cells as well as plasma cells, has been demonstrated to cause prolonged lymphopenia and hypogammaglobulinemia.50 Of note, opportunistic infections such as have been reported with rituximab anti-CD20 therapy have not been reported thus far with blinatumomab therapy. However, most patients receiving blinatumomab receive PCP prophylaxis because of recent steroid exposure with other chemotherapy regimens or for prevention of CRS. In the case of PML, the use of blinatumomab may not yet be great enough to know if there is an associated predisposition.
Daratumumab, approved in the treatment of refractory multiple myeloma, is a monoclonal antibody that targets CD38 on the surface of myeloma cells.52 The expression of CD38 is not limited to plasma cells; it is also found in low levels on lymphoid and myeloid cells.53,54 Opportunistic infections have not been reported in association with daratumumab therapy. In a phase 3 trial of lenalidomide and dexamethasone with or without daratumumab, neutropenia, fever, and upper respiratory infections were more frequent in the group that received daratumumab.55 In a phase 3 trial of bortezomib and dexamethasone with or without daratumumab, neutropenia, lymphopenia, fever, and upper respiratory infections were more frequent in the group receiving daratumumab.56 Another phase 3 trial studying bortezomib, melphalan, and prednisone with or without daratumumab reported increased frequency of upper respiratory infections and pneumonia in the daratumumab group but not neutropenia or fever.57
Infectious Complications of Monoclonal Antibodies Used to Treat Solid Tumors
Bevacizumab and Ramucirumab
Vascular endothelial growth factor (VEGF) is an important promotor of angiogenesis in tumor growth.58 Bevacizumab binds to VEGF-A, which is considered the most active of the VEGF family molecules.58 It is approved for the treatment of metastatic colorectal cancer, renal cell carcinoma, and non-small cell carcinoma of the lung, as well as glioblastoma multiforme.59 Ramucirumab binds to VEGF receptor-2 to block binding of VEGF-A to the receptor used for the treatment of advanced gastric carcinoma and metastatic colorectal carcinoma.58 A meta-analysis of randomized controlled trials of bevacizumab in a variety of malignancies demonstrated a statistically significant higher rate of any grade and high-grade infections in the bevacizumab group compared with controls.59 Another meta-analysis showed that bevacizumab is associated with an increased risk for neutropenia and febrile neutropenia compared with controls.60 An increased incidence of neutropenia has also been reported in several of the phase 3 trials of ramucirumab.58
Cetuximab and Panitumumab
Cetuximab and panitumumab target the epidermal growth factor receptor (EGFR) and are approved for the treatment of metastatic colorectal cancer, with cetuximab also approved for the treatment of head and neck squamous cell carcinoma.61 A meta-analysis of randomized controlled trials of these monoclonal antibodies showed that both cetuximab and panitumumab are associated with an increased risk for high-grade infection, and cetuximab is associated with an increased risk for febrile neutropenia.61 A separate meta-analysis that examined the risk for neutropenia in patients treated with cetuximab in randomized controlled trials showed that cetuximab was associated with an increased incidence of neutropenia compared with controls.62
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