Clinical Dissection of Infectious Event Following ATG Treatment for Aplastic Anemia and Hypoplastic Myelodysplastic Syndrome Reveals Urgent Need for Anti-Aspergillus Prophylaxis

Background

Infection is the leading cause of death in patients with aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (hMDS). Prolonged neutropenia and lymphopenia followed by immunosuppressive treatment (IST) are the major risk factor for the development of infections. While IST responses occur after 3-6months after ATG treatment, aggravation of transient neutropenia and lymphopenia is provoked by ATG treatment. As such, increasing of mortality associated with infection is obviously predictable following ATG treatment. In this study, we analyzed the detailed infection profile so as to guide adequate prophylaxis after ATG treatment in AA and hMDS. More specifically, we studied the relation between invasive fungal infection (IFI) and treatment outcome and predictive factor of IFI after ATG treatment for AA and hMDS.

Patient and Methods

We retrospectively reviewed the medical records of AA and hMDS patients who were treated with rATG based immunosuppressive treatment between January 2005 to July 2016 in two institutions (Seoul National University Hospital and Seoul National University Bundang Hospital). Patients who did not complete the ATG course for 5days and visit the clinic after IST for at least 6months were excluded. Patients treated with hematopoietic stem cell transplantation within 6months after rATG administration were also excluded. The response was evaluated at 3 and 6 months after IST. Assessment of response to IST was performed according the criteria of European Group for Blood and Marrow Transplantation (EBMT). Infection events occurred within 6 months after rATG administration were studied. Only proven and probable IFIs were considered according to the European Organization for Research and Treatment of Cancer/Mycosese Study Group (EORTC/MSG) criteria. Overall survival (OS1) was defined as the time from diagnosis to last follow-up or death from any cause. The time of IST treatment to death was defined as OS2 and also evaluated. To assess t the optimal cut-off value of total white blood cells (WBCs), ALC (Absolute Lymphocyte Count) and ANC (Absolute Neutrophil Count), WBCs, ALC and ANC of the initiation of treatment, 3months after IST and 6months after IST were analyzed by using receiver operating characteristics (ROC) curves.

Results

A total of 139 patients (median age, 51.0; range 15-82, male:female 75:64) were evaluated. Eighty-two percent of the patients were SAA (n=114) at treatment. Response was observed in 97(CR 9.4 %, PR 60.4 %) patients at 3months and in 103 (CR 29.5%, PR 44.6%) patients at 6months after IST. A total of 88 infection events were observed in 75 patients and the most frequent infection was bacterial infection (40 cases, 45.4%). IFIs were observed in 26 cases and invasive aspergillosis (IA) was the most common fungal infection (23 cases, 88.4%). Other fungal infections included one proven mucormycosis by biopsy of nasal cavity and two yeast (Candida tropicalis and Candida albicans) fungemia. The most frequent organ involved by IFI was lung (21cases, 80.7%). The mean time to infection events was 1.6months in 75 patients and 2.0 month in 26 patients with IFIs. 33 patients died during the study period, and 26 of them were related with infection. 13 deaths were directly due to IFIs with median time of IST treatment to death was 17 weeks (range: 2-139weeks) and eight of them expired within 6months after IST. IFIs following ATG was significantly related with shorter OS (HR 4.4; CI 1.925-10.074; P= <0.0001). ALC less than 500/ml (sensitivity 71.4%; specificity 76.9%; AUC 0.768 CI₉₅ 0.630-0.906; P=0.002) at 3months after IST was a significant predictive factor for IFIs related death (OR 8.3; CI 2.167-32.044; P=0.002). Interestingly, infections other than IFI were not significantly related to infection related death or shorter OS.

Conclusion

Invasive fungal infection is the leading cause of death in patients who receive IST for AA or hMDS. Our findings strongly suggest need for antifungal prophylaxis such as posaconzole following ATG based IST in this population.