Low Circulating Mannan-Binding Leptin Levels Correlate with Increased Number of Febrile Episodes in Myeloma Patients Who Undergo High Dose Melphalan with Autologous Hematopoietic Stem Cell Transplantation and Do Not Receive Antibiotic Prophylaxis

Abstract 4457

Patients with multiple myeloma (MM) are at a higher risk of infections compared to general population. High dose melphalan (HDM) with autologous stem cell support (ASCT) is the recommended treatment for MM patients ≤65 years of age. Up to 80% of patients who undergo an ASCT develop neutropenic fever and up to one third of them have culture positive infections. The mannan binding leptin (MBL) pathway of the complement system is part of the innate immune system and seems to influence the risk of infections in cancer patients during treatment. In contrast to the classical complement pathway, MBL pathway is not antibody-dependent. MBL is a protein that belongs to the collectin family and is produced by hepatocytes. MBL acts via binding to the surface of bacteria, thus facilitating complement activation with formation of the membrane attack complex, leading to microbial lysis. In general population, 15–20% of people have MBL levels <500 mg/L, while even lower levels (<100 mg/L) are associated with increased frequency of infections. The impact of the MBL on the occurrence of infections during chemotherapy in malignant diseases has been explored in different studies with conflicting results. The aim of this study was to evaluate the impact of MBL levels on the risk of infections and on the risk of development of febrile episodes in patients with MM who receive HDM and ASCT.

We studied 100 MM patients who underwent an ASCT between 1996–2011 in a single center (Department of Clinical Therapeutics, University of Athens, Greece). All patients received prophylactic therapy with 200 mg fluconazole daily and 500 mg valacyclovir daily. Sixty-seven patients participated in a randomized study, where in the first arm patients received prophylactic antibiotics, including vancomycin at a dosage of 1 g once daily and ciprofloxacin at a dosage of 400 mg twice daily, while in the arm B there was no antibiotic prophylaxis. All patients received G-CSF 300 μ g twice daily from day of stem cell reinfusion to neutrophil counts >1500/mm³. In case of neutropenic fever, prophylactic antibiotics were interrupted and first line regimen was administered, including vancomycin 1g twice daily, amikacin 500 mg twice daily and ceftazidime 2 g TID. In case of failure of first line treatment, a second line antibiotic combination was administered, usually including a carbapenem and linezolide. Antibiotic regimens were also modified according to results of blood or urine cultures. MBL serum levels were measured in all patients on the day of mobilization, before the administration of cyclophosphamide, using an ELISA methodology (R&D Systems, Minneapolis, MN, USA).

Seventeen (17%) patients had MBL levels <500 mg/L. Of those, 11 received antibiotics prophylaxis and 6 did not. In general, there was no statistical difference regarding the development of fever or neutropenic fever between patients with MBL serum levels of <500 mg/L or ≥500 mg/L. However, among 17 patients with MBL levels of <500 mg/L, 6 /11 patients who received antibiotics prophylaxis developed a febrile episode compared to 6/6 patients who did not receive antibiotics prophylaxis and developed a febrile episode (p=0.049). There was no difference in the incidence of septicemia, the severity of infection, the number of days of hospitalization or the number of days with fever between patients with MBL serum levels of <500 mg/L or ≥500 mg/L. Nevertheless, patients with MBL levels <500 mg/L attained a lower response rate to first line therapy with antibiotics, i.e. lower percentage of fever resolution and higher incidence of necessitated administration of a second line antibiotic regimens, compared to patients with MBL levels of ≥500 mg/L (66.7% versus 88.9%, respectively; p=0.05).

The results of our study suggests that myeloma patients who underwent ASCT and had low levels of MBL had a lower response rate in first line antibiotic regimens, requiring more often administration of a second more advanced line of antibiotics. Furthermore, the administration of prophylactic antibiotics to these patients seems to reduce the number of febrile episodes. These observations underscores the importance of innate immune system in permitting antibiotics to exercise their protective effect in severely immunocompromised patients and raise the question about the necessity of administering prophylactic antibiotics in this subgroup of patients.