Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Prior Invasive Aspergillosis

Background: Introducing a new antifungals and diagnostic procedures has improved prognosis of the invasive aspergillosis (IA) in hematological patients. The number of patients with IA who are candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) has increased. The influence of IA on survival and on allo-HSCT related complications has not been investigated in a prospective study.

Aim: to estimate impact of prior proven and probable IA on outcome of allo-HSCT compared to patients without IA.

Methods: In prospective observational single center study 362 allo-HSCT recipients (336 - first and 26 - second allo-HSCT) were included from Jan 2012 to Dec 2014. The median age was 34 y, males - 54%. Most of pts had high-risk acute leukemia (70%). Allo-HSCT with MUD were performed in 57%, MRD - 24%, haplo - 11%, MMUD - 8%, predominantly with RIC (80%). All patients with lesions in CT scan before allo-HSCT have undergone bronchoscopy with BAL microscopy, culture and GM test. EORTC/MSG 2008 criteria were used for the diagnosis of proven and probable IA as well as to evaluate response to therapy. "Active" invasive IA - IA diagnosed just before allo-HSCT. All patients were observed with the median 2 years follow up. We analyze status of pts before HSCT, donor types, source of HSCT, CMV status, conditioning regimens and type of immunosuppression, relapse or progression of IA, relapse of underlying disease, duration of antifungal therapy and prophylaxis, acute and chronic GvHD. The cumulative incidences were determined with cumulative incidence method. Differences between the two cohorts were verified with Gray test. Overall survival after allo-HSCT was estimated with Kaplan-Meier method and cohorts were compared by log-rank test.

Results: Incidence of IA before allo-HSCT was 20% (n=72/362). According to EORTC/MSG 2008 criteria 92% of pts had probable IA and 8% - proven IA. The main sites of IA were lungs - 95%, central nervous system - 3%, and colon - 3%, other sites were observed in a combination with lungs involvement: sinuses - 5%, spleen - 3%, and liver - 3%. The median time from IA to allo-HSCT was 3 months (3 days - 30 months). Antifungal therapy before allo-HSCT was used in 69% pts (voriconazole - 95%, other - 5%) with the median duration of therapy - 2 months. Complete response to antifungal therapy was registered in 19 (26%) patients, partial response or stabilization - 31 (43%), and "active IA" - 22 (31%). After allo-HSCT all patients received antifungal therapy with voriconazole (first line - 31%, continuation of treatment - 43%, and secondary prophylaxis - 26%). Median length of treatment was 166 days (37 - 394) with the median duration to effect 99 days (31 - 217). No toxicity of the antifungal treatment was registered. Cumulative incidence of relapse or progression of IA at 2 year after allo-HSCT was 14% (n=10). "Active" underlying disease before D+100 post transplant was the only risk factor for the relapse or progression of IA after allo-HSCT (6% vs 33%, p=0,007). 100-days OS after allo-HSCT was 77%, 2-year OS after allo-HSCT was 62%. There was no significant difference in OS in patients with or without IA prior to allo-HSCT (57% vs 65%, p=0,3). Duration of antifungal therapy before HSCT (<90 days vs ≥90 days), status of IA at the moment of HSCT ("active" IA vs PR vs CR), relapse/progression of IA after HSCT was not affected on 2-year OS after allo-HSCT in patients with prior IA.

Conclusions: Incidence of proven and probable invasive aspergillosis before allo-HSCT was 20%. Cumulative incidence of relapse or progression of the invasive aspergillosis after allo-HSCT was 14% and "active" underlying disease before D+100 post transplant was the only risk factor. Invasive aspergillosis prior to allo-HSCT did not impair the outcome of the procedure with effective diagnosis and prophylaxis being used.