Serologic characteristics of oxaliplatin antibodies in 15 patients with drug-induced immune hemolytic anemia.

BACKGROUND: Oxaliplatin, a third-generation platinum derivative is commonly used in combination treatment of metastatic colorectal cancer. Since 2008, it is the second most common cause of drug-induced immune hemolytic anemia (DIIHA) investigated in our laboratory. STUDY DESIGN AND METHODS: Samples from fifteen patients including nine (60%) with intravascular hemolysis, suspected of having DIIHA were studied for the presence of anti-oxaliplatin. Direct antiglobulin tests (DATs) and tests with oxaliplatin-treated red blood cells (RBCs) or untreated and enzyme-treated RBCs in the presence of oxaliplatin were performed. A pool of normal AB sera with no unexpected antibodies was used as a control for nonimmunologic protein adsorption (NIPA). RESULTS: Eleven (73%) of the fifteen patients had antibodies to oxaliplatin that reacted with drug-treated RBCs and untreated RBCs in the presence of drug by tube and/or gel method. Lower-titer reactivity (<20) obtained with four patients' sera and the corresponding pooled normal sera was most likely due to NIPA. Eighty seven percent (13/15) of the patients had positive DAT either with anti-IgG only (33%), IgG + C3d (40%), or C3d only (13%). Two patients had a negative DAT. No directly agglutinating antibody was observed with the pools of normal donor's sera in the presence of oxaliplatin. CONCLUSION: Anti-oxaliplatin can cause severe intravascular hemolysis. Complement can usually be detected on the patient's RBCs and anti-oxaliplatin can be detected in the patient's serum. RBC-bound albumin detection with anti-human albumin needs to be performed to confirm NIPA which could have contributed to the patient's hemolytic anemia.

Oxaliplatin-desensitization procedure is safe and feasible in an outpatient cancer unit in France.

This study was undertaken to assess the previously unevaluated safety and feasibility of oxaliplatin-desensitization procedure add a French ambulatory cancer unit, which is a current topic in oncology. Our findings demonstrated that oxaliplatin-desensitization was safe and feasible in our ambulatory cancer unit. In routine practice, all these procedures are done on an inpatient basis starting at least the day before. Those results could change oncological practices in France and improve patients' quality of life and lower costs associated with inpatient administration.

Oxaliplatin Treatment Alters Systemic Immune Responses.

PURPOSE: Oxaliplatin is a platinum-based chemotherapeutic agent demonstrating significant antitumor efficacy. Unlike conventional anticancer agents which are immunosuppressive, oxaliplatin has the capacity to stimulate immunological effects in response to the presentation of damage associated molecular patterns (DAMPs) elicited upon cell death. However, the effects of oxaliplatin treatment on systemic immune responses remain largely unknown. Aims of this study were to investigate the effects of oxaliplatin treatment on the proportions of (1) splenic T cells, B cells, macrophages, pro-/anti-inflammatory cytokines, gene expression of splenic cytokines, chemokines, and mediators; (2) double-positive and single-positive CD4+ and CD8+ T thymocytes; (3) bone-marrow hematopoietic stem and progenitor cells. METHODS: Male BALB/c mice received intraperitoneal injections of oxaliplatin (3mg/kg/d) or sterile water tri-weekly for 2 weeks. Leukocyte populations within the spleen, thymus, and bone-marrow were assessed using flow cytometry. RT-PCR was performed to characterise changes in splenic inflammation-associated genes. RESULTS: Oxaliplatin treatment reduced spleen size and cellularity (CD45+ cells), increased the proportion of CD4+, CD8+, and Treg cells, and elevated TNF-α expression. Oxaliplatin was selectively cytotoxic to B cells but had no effect on splenic macrophages. Oxaliplatin treatment altered the gene expression of several cytokines, chemokines, and cell mediators. Oxaliplatin did not deplete double-positive thymocytes but increased the single-positive CD8+ subset. There was also an increase in activated (CD69+) CD8+ T cells. Bone-marrow hematopoietic progenitor pool was demonstrably normal following oxaliplatin treatment when compared to the vehicle-treated cohort. CONCLUSION: Oxaliplatin does not cause systemic immunosuppression and, instead, has the capacity to induce beneficial antitumor immune responses.

Immunogenic cell death in anticancer chemotherapy and its impact on clinical studies.

The traditional view holds that apoptosis is non-immunogenic and does not induce an inflammatory response. However, recent studies have suggested that certain chemotherapeutic drugs that induce tumor cell apoptosis can induce immunogenic cell death (ICD) in cancer cells. This process is characterized by not only up-regulation of a series of signaling molecules in cancer cells, including expose of calreticulin (CRT), secretion of adenosine triphosphate (ATP) and release of high mobility group box 1 (HMGB1). In this review, we summarize recent progress in identifying and classifying ICD inducers; concepts and molecular mechanisms of ICD; and the impact and potential applications of ICD in clinical studies. We also discuss the contributions of ICD inducers in combination with other anticancer drugs in clinical applications.

The Contribution of the Basophil Activation Test to the Diagnosis of Hypersensitivity Reactions to Oxaliplatin.

Cytostatics, mainly oxaliplatin, are widely used to treat oncological diseases. There has been an increase in hypersensitivity reactions to these drugs, mostly IgE-mediated. Skin tests are the main diagnostic method used but they may induce irritant local reactions and contamination by health care professionals. The main goals of this work were to evaluate the contribution of the basophil activation test (BAT) as a diagnostic tool for hypersensitivity reactions to oxaliplatin, and to compare the expression of CD63 and CD203c molecules. BAT was performed with oxaliplatin in 6 oncological patients with previous documented hypersensitivity reactions to oxaliplatin and in 5 controls (4 oncological patients tolerant to oxaliplatin and 1 healthy control), assessing CD63 and CD203c expression on basophil population. We found higher values for the basophil activation percentage and mean stimulation index for CD203c expression with all oxaliplatin concentrations tested (most significant at 150 µg/mL: p = 0,0087; p = 0.0222) in the patients than in controls. The same did not occur, with statistical significance, for CD63 expression. When we compared the 2 activation markers in the patients, we observed a more enhanced expression of CD203c in both evaluations, with statistical significance at the 150-µg/mL concentration (p = 0,026; p = 0,0129). These data show a higher positivity of BAT with oxaliplatin in patients with previous hypersensitivity reactions, when compared to controls, suggesting that BAT may be a promising diagnostic method as an alternative to skin tests. CD203c appears to play a more prominent role than CD63, which is consistent with what is published in the literature.

Incidence and Risk of Oxaliplatin-Induced Hypersensitivity in Patients with Asymptomatic Prior Exposure: A Prospective Observational Study.

BACKGROUND: Oxaliplatin-related hypersensitivity reactions (HSRs), which can be life threatening, have introduced a dilemma regarding the use of chemotherapeutic agents. Because repeated exposure to oxaliplatin may increase the risk of sensitization, patients with a history of prior asymptomatic exposure require risk-stratified care. OBJECTIVE: This study aimed to elucidate the incidence and risk of oxaliplatin HSRs in patients with a history of asymptomatic prior exposure. METHODS: We performed a prospective observational study of patients who completed oxaliplatin-based chemotherapy between March 2013 and January 2015. Prior exposure to oxaliplatin, the oxaliplatin-free interval, reaction severity, eosinophil counts, and premedication were reviewed to assess the risk factors. RESULTS: A total of 793 patients were enrolled, among whom 148 (18.7%) experienced an HSR. The HSR incidence was 15.2% among oxaliplatin-naive patients but increased to 31.9% among those with a history of asymptomatic exposure and 75.0% among those with a history of oxaliplatin HSRs during the previous exposure, despite prophylaxis. The mean HSR onset cycle was earliest in the previous HSR group, followed by the previous asymptomatic exposure and nonexposure groups. The HSR severity also differed according to the previous exposure history and HSRs. In the multivariate analysis, prior exposure to oxaliplatin (odds ratio [OR], 3.78; 95% confidence interval [CI], 2.46-5.79) and a longer oxaliplatin-free interval (≥36 months; OR, 4.85; 95% CI, 1.60-14.37) were independent risk factors for HSRs. CONCLUSIONS: Previous exposure to oxaliplatin is a risk factor for earlier HSR onset and more severe and frequent HSR episodes, even if prior therapy was well tolerated.