Biology and Immunogenetics of Immune Effectors: Applications in Hematology and Cell Therapy

Immune effectors are the cells responsible for host response to cancer cells and germs. There is a stringent need to understand immune effectors biology to improve infectious disease management, particularly for patients affected by deep grade immunosuppression. During my research, I chose to investigate the role of Glucose-6-Phosphate Dehydrogenase (G6PD) on immune effectors biology, to evaluate its relevance for response to infectious agents. G6PD is a key enzyme of pentose-phosphate pathway, producing reducing power in the form of NADPH, that is essential for oxidative stress protection machinery. The typical manifestations of enzyme deficiency are acute hemolytic anemia (AHA) following exposure to drugs or food and neonatal jaundice. The enzyme is expressed in all cells, but typical manifestations are related to enzyme deficiency in red cells. G6PD deficiency impact on white cells is less studied; some authors postulated that enzyme deficiency confers susceptibility to infections, but evidences are controversial. I tried to study the role of this enzyme defect in patients with hematologic malignancies, a population characterized by deep grade immunosuppression. Bacterial infections are the leading cause of morbidity and mortality in hematologic patients with neutropenia. Fluoroquinolone prophylaxis was proved to be the only effective strategy to reduce febrile neutropenia, but the safety of this class of agents in patients with G6PD deficiency is questionable because of a claimed association with AHA. I retrospectively analyzed 242 patients treated with 628 intensive chemotherapy courses; 59 patients presented G6PD deficiency. All patients underwent fluoroquinolone prophylaxis. The primary endpoint was incidence of AHA. Secondary endpoints were incidence of febrile neutropenia, microbiologically and clinically documented infections and incidence of Gram Positive or Gram Negative infections. No episode of AHA was observed in the entire cohort. Incidence of microbiologically and clinically documented infection was similar, but incidence of invasive fungal disease (IFD; p<0.0001, HR 11.4, 95%CI 3.5-37.05) and Candida sepsis (p=0.008, HR 37, 95% CI 2.01-680.9) was higher in patients with enzyme deficiency. Interestingly, I observed a reduced incidence of febrile neutropenia in patients with G6PD deficiency (p=0.01, HR 0.46, 95%CI 0.25-0.8). These data suggest that fluoroquinolone prophylaxis in patients with G6PD deficiency, treated with intensive chemotherapy, is feasible and safe. Also, data about IFD incidence and febrile neutropenia suggest that G6PD may be important in susceptibility to opportunistic pathogens and host response in neutropenic patients. Next, I evaluated G6PD deficiency role in susceptibility to IFD in patients affected by acute myeloid leukemia (AML) undergoing intensive chemotherapy, that are the patients at higher risk of fungal infections. I investigate this point in a cohort of 108 patients; 28 harbored G6PD deficiency, whereas 80 were normal. The incidence of IFD was significantly higher in patients with G6PD deficiency compared to normal patients (35.7% vs 5%, p=0.0002, OR=10, 95%CI=2.96-37.5). Higher risk of mold infections (17.9% vs 5%, p=0.048, OR=4.1, 95%CI=1.0-16.6) and Candida sepsis (17.9% vs 0%, p=0.0009, OR=37.68%, 95%CI=2.0-707.1) was observed in patients with G6PD deficiency. These data suggest that the evaluation of G6PD activity may help to identify AML patients at higher risk of IFD, allowing to design more intensive surveillance and therapeutic strategies. The identification of G6PD deficiency as a risk factor for IFD in patients with AML results in an urgent need for strategies to properly manage this kind of patients at high risk of invasive mycoses. Next, I proposed an algorithm for correct identification, prophylaxis and treatment of IFD in patients with G6PD deficiency undergoing intensive chemotherapy for AML.