Impact of prior invasive mycosis upon outcome of allogeneic hematopoietic stem cell transplantation in children and adults

Summary

Introduction

Implementation of new antifungals and diagnostic procedures has improved prognosis of the invasive fungal diseases (IFD) in hematological patients. The number of candidates for allogeneic hematopoietic stem cell transplant (alloHSCT) with known IFD is increasing. The role of IFD prior to alloHSCT is still a subject of controversy. There are no data concerning pediatric alloHSCT with prior IFD. The aim of the study is to estimate impact of prior IFD on outcome of alloHSCT.

Patients and methods

In our prospective study, 504 allo-HSCT recipients were included from Jan 2013 to Jul 2016. The median age was 24 y.o. [2 months to 76 years], children (<18 yo), 164; adults, 340; males, 52%. Most of the cases had initially high-risk acute leukemia (74.6%). Allo-HSCT from MUD was performed in 58.5%, MRD, in 22.5%; haplo, in 19%, predominantly treated by a RIC regimen (67%). All the patients with CT-detected lesions at the moment of transplantation underwent bronchoscopy with BAL microscopy; culture and galactomannan test. EORTC/MSG 2008 criteria were used for the diagnosis of proven and probable IFD, and evaluation of response to therapy. “Active IFD” means IFD diagnosed just before HSCT. The median follow up was 20 months. The primary endpoints were overall survival (OS) and incidence of relapse or progression of IFD after alloHSCT; secondary events were malignancy relapse, acute or chronic GvHD.

Results

The IFD incidence before alloHSCT was 15% (n=76). According to EORTS/MSG 2008 criteria, 90.8% of pts had probable and 9.2% proven IFD. Etiology of IFD prior to HSCT was as follows: invasive aspergillosis (IA), 75%; invasive candidiasis (IC), 13%; mucormycosis (Mu), 4%; Pneumocystis pneumonia (PCP), 1.3%, and combination of IA with Mu was found in 2 cases; invasive candidiasis was in 1 patient; PCP, 1 case. The main sites of infection were lungs, 95%. Other localizations were mostly combined with lung involvement: sinuses, 9%; spleen, 6%; liver, 6%; soft tissues, 3%. Antifungal therapy before alloHSCT was performed in 75% pts with median duration of 2 months. Complete response to antifungal therapy was in 38.2% pts, partial response or stabilization, in 35.5%. 26.3% pts had “active IFD”. After alloHSCT, all the pts received antifungal therapy or secondary prophylaxis according to IFD etiology. Cumulative incidence of relapse or progression of IFD after alloHSCT was 14.5%. Active underlying disease at the moment of HSCT was the only risk factor for relapse or progression of IFD after alloHSCT (11.5% vs 21.1%, p=0.03). We have not detected any significant differences in cumulative incidence of acute (p=0.28), chronic GVHD (p=0.25), and relapse (p=0.31) in study group as compared to pts without history of IFD. 3-year OS after alloHSCT was 67.5%. The impact of prior IFD upon overall survival in alloHSCT recipients was not statistically significant in all groups (60.5% vs 68.7%, p=0.1), and separately for children (50.0% vs 57.4%, p=0.32) and adults (63.3% vs 74.6%, p=0.09). The worst outcome was observed in pts with “active IFD” and active underlying disease at the moment of HSCT (3-year OS was 20%, p<0.001). However, in pts with “active IFD” and remission of underlying disease, OS was similar to survival rate of pts without a history of IFD (80% vs 68.7%, p=0.57).

Conclusions

Fifteen percent of patients had IFD prior to alloHSCT. Cumulative incidence of relapse or progression of IFD after alloHSCT was 14.5%. Prior IFD had no significant impact on alloHSCT-related complications and overall survival in children and adults. Active underlying disease at the moment of HSCT was the only risk factor for relapse or progression of IFD and impaired outcome of alloHSCT.

Keywords

Prior invasive fungal diseases, allogeneic hematopoietic stem cell transplantation, active invasive fungal diseases, antifungal therapy, clinical outcomes, children and adults.