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J.H. Yoon et al.
istered to 18 (14.3%) patients, while 23 (18.2%) patients were given dexamethasone alone. Patients who had mild symptoms and improved rapidly were treated with dex- amethasone alone and further therapy was not needed. In contrast, we were unable to administer cyclosporine and etoposide to patients with significant deterioration of organ function or a poor general condition. Of the 81 (64.3%) patients who achieved a complete response after treatments, 43 achieved this response by 4 weeks after treatment and the other 38 achieved it by 8 weeks or later. Of the 27 patients who relapsed, one relapsed between 4 and 8 weeks and 26 relapsed after 8 weeks during the course of treatment. After relapsing, most of the patients were treated with the HLH-94 protocol again. For relapsed EBV-HLH, we considered rituximab (n=6) or alemtuzum- ab (n=2) concomitantly, and two patients were treated with allogeneic HCT.
With regards to dynamic responses, 42 (34.4%) patients were early stable responders, 36 (29.5%) were late stable responders, 19 (15.6%) were unstable responders, and 25 (20.5%) were primary refractory non-responders (Table 1). Detailed responses according to causes of HLH are as follows. In patients with EBV-HLH, the overall response rate (complete plus partial responses) at 4 weeks was 75.5% (complete response in 16, partial response in 21) but decreased to 51.0% (complete response in 17, partial response in 8) at 8 weeks, and finally decreased to 30.6% (complete response in 15). The overall response rates at 4 weeks and 8 weeks for patients with HLH associated with infections other than EBV were 62.5% (complete response in 10, partial response in 5) and 75% (complete response in 14, partial response in 4), respectively, for those with autoimmune diseases, 82.3% (complete response in 9, partial response in 5) and 82.3% (complete response in 12, partial response in 2), respectively, and for those with HLH of unknown cause, 66.7% (complete response in 8, partial response in 16) and 66.7% (complete response in 19, partial response in 5), respectively. Patients with HLH associated with an autoimmune disease or infection other than EBV had superior 5-year overall survival rates (82.4% and 78.7%, respectively) and lower cumulative incidences
of progression (29.4% and 22.7%, respectively) compared to those of patients with EBV-associated HLH. The esti- mated 5-year overall survival rate and cumulative inci- dence of progression of patients with EBV-associated HLH were 25.1% and 77.5%, respectively (Figure 2).
Survival outcomes according to treatment response
Estimated 5-year overall survival rates of patients who achieved a complete response by 4 weeks (n=43) and 8 weeks (n=62) were 82.8% and 82.7%, respectively, while the overall survival rate of patients who achieved a partial response until 8 weeks (n=19) was 68.4% (Figure 3A,B). As we recognized four subgroups defined according to dynamic treatment response, there were 42 patients in the early stable responder group, 36 in the late stable respon- der group, 19 in the unstable responder group, and 25 in the non-responder group. Figure 3C,D presents the overall survival and cumulative incidence of progression curves of patients divided according to dynamic treatment response. Early stable responders and late stable respon- ders had 5-year overall survival rates of 80.7% and 73.7%, respectively, and 5-year cumulative incidences of progres- sion of 20.2% and 43.1%, respectively, while almost all patients in the unstable and non-responder groups died of disease progression (P<0.001).
Prognostic factors and risk stratification
We found that most parameters associated with HLH disease activity were predictive of survival outcomes, and many were correlated with each other. Age was correlated with albumin and alanine aminotransferase levels, EBV- association with triglyceride and fibrinogen levels, anemia with albumin levels, thrombocytopenia with prothrombin time, total bilirubin and erythrocyte sedimentation rate, and ferritin with prothrombin time, fibrinogen, erythro- cyte sedimentation rate, and lactate dehydrogenase levels. Multivariate analyses were performed using age, EBV- association, thrombocytopenia, ferritin, and dynamic treatment response after excluding correlated parameters (Table 2). Remaining an unstable responder or non- responder at 8 weeks was the most powerful predictive
AB
Figure 2. Survival outcomes according to the cause of secondary hemophagocytic lymphohistiocytosis. (A) Comparison of 5-year overall survival rates according to the cause of secondary hemophagocytic lymphohistiocytosis. (B) Comparison of cumulative incidences of progression after treatment according to the cause of sec- ondary hemophagocytic lymphohistiocytosis. OS: overall survival; HLH: hemophagocytic lymphohistiocytosis; EBV: Epstein-Barr virus.
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haematologica | 2019; 104(2)