Baseline characteristics
The medical records of 88 patients (median age 1.4 years, range 0.2–15 years) with non-malignancy associated secondary HLH were retrospectively reviewed. Causes of HLH were: EBV-associated (n = 30: recent primary infection n = 15, chronic active EBV infection n = 3, past infection n = 12), unknown cause (n = 19), infection other than EBV (n = 20:cytomegalovirus n = 10, brucella n = 3, Staphylococcus aureus n = 2, Streptococcus pneumoniae n = 2, Mycoplasm n = 1, parvovirus n = 1, herpes simplex n = 1), autoimmune disease (n = 13: systemic lupus erythematosus n = 4, juvenile rheumatoid arthritis n = 5, dermatomyositis n = 1, Kawasaki disease n = 2, anaphylactoid purpura n = 1), or immunodeficiency (n = 6: chronic granuloma n = 2, X-linked lymphocyte proliferative diseases n = 2, humoral immune deficiency n = 2). Baseline characteristics and treatment response for the included patients are summarized in Table 1. Fever was observed in all patients and 49 (55.7%) patients had splenomegaly. The median day of the peak values of ferritin is 7 days before initiation.
Table 1
Baseline characteristics and treatment outcomes of included patients (n = 88).
Characteristic | Value |
Gender (male), % | 50 (56.8%) |
Age, years old | 1.4 (0.2–15) |
Fever | 88 (100%) |
CMV % | 13 (14.8%) |
Leukocyte | 3.22 (0.25–36.47) |
Neutrophil | 1.195 (0.05–11.86) |
Platelet | 67.00 (7-562) |
Hemoglobin | 86.5 (31–131) |
Fibrinogen | 1.29 (0.27–4.56) |
Albumin | |
Ferritin | 3564.5 (132.0-591123.0) |
AST | 249.15 (21.0-9420.0) |
ALT | 207.50 (8.0-4953.0) |
LDH | 944.5 (156.0-5311.0) |
TG | 3.34 (0.39–13.56) |
CRP | 15.05 (0.25-161.54) |
GGT | 207.5 (7.0-1550.0) |
D-dimer | 2489.0 (129.0-35600.0) |
DIC % | 28 (31.8%) |
Splenomegaly % | 49 (55.7%) |
Jaundice % | 34 (38.6%) |
Bone marrow involvement % | 51 (58.0%) |
Hepatomegaly % | 65 (73.9%) |
Ascites % | 21 (23.9%) |
Lymphadenopathy % CR achievement after treatments | 28 (31.8%) 58 (65.9%) |
Therapy | |
HLH94/2004based therapy | 34 (38.6%) |
Steroid + IVIG | 8 (9.1%) |
Steroid | 22 (25%) |
Only observation | 23 (26.1%) |
Hematopoietic stem cell transplantation | 1 (1.1%) |
Causes of HLH | 56 (76.7%) |
EBV-associated | 30 (33.7%) |
Immunodeficiency | 6 (6.7%) |
Autoimmune disease (AID) | 13 (14.6%) |
Unknown cause and infection other than EBV | 40 (44.9%) |
Treatment response at 8 weeks | |
Early stable responder | 29 (33.3%) |
Late stable responder | 28 (32.2%) |
Unstable responder | 17 (19.5%) |
Non-responder | 13 (14.9%) |
Abbreviations: HLH, hemophagocytic lymphohistiocytosis; AST, aspartate aminotransferase; ALT, alanine transferase; LDH, lactate dehydrogenase; CRP, C-reactive protein; DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; CR, complete remission; EBV, Epstein-Barr virus; TG, triglyceride; GGT, gamma-glutamyl transpeptidase. |
Treatment outcomes
A total of 83/88 (94.3%) patients were treated. 65/88 (73.8%) (unknown cause n = 18, EBV infection n = 20, infection other than EBV n = 18, autoimmune disease n = 3, immunodeficiency n = 6) patients were administered therapy according to the HLH94 protocol. 5/88 (5.6%) patients were administered dexamethasone plus gamma globulin. 12/88 (13.6%) patients were administered dexamethasone alone. 1/88 (1.1%) patient underwent HCT. Dexamethasone alone with no further treatment was administered to patients who had mild symptoms and showed rapid improvement. 5/88 (5.6%) patients were not treated. Of these, 3 patients were without signs of HLH activity, and 2 patients died. Cyclosporine and etoposide were not administered to patients with substantially altered organ function or who were in a generally poor condition. 57/88 (64.7%) patients achieved complete response; of these, 30 patients achieved complete response at 4 weeks after treatment and 27 achieved complete response at 8 weeks or later. 3 patients relapsed; of these, 1 patient relapsed 8 weeks after treatment, 1 patient relapsed 4 months after treatment, and 1 patient relapsed 12 months after treatment. Relapsed patients had EBV-HLH, and were treated with rituximab (n = 1), alemtuzumab (n = 1), or allogeneic-HCT (n = 1) according to the HLH-94 protocol. Regarding dynamic response, 32/88 (36.4%) patients were early stable responders, 28/88 (31.8%) were late stable responders, 14/88 (15.9%) were unstable responders, and 13/88 (14.7%) were primary refractory non-responders.
Survival outcomes according to treatment response
5-year OS rates for patients with EBV-HLH and HLH due to an unknown cause and infections other than EBV were 80.0% and 77%, respectively, and higher than in patients with HLH from other causes (Fig. 1A).
Among all patients, 5-year OS rates for patients who achieved complete response at 4 weeks (n = 30) and 8 weeks (n = 57) were each 100%.5-year OS rates for patients who achieved partial response at 4 weeks (n = 38) and 8 weeks (n = 14) were 86% and 44.0%, respectively (Fig. 1B-C). 5-year OS rates for early stable responders and late stable responders were each 100% (Fig. 1D).
Among patients with EBV-HLH, 5-year OS rates for patients who achieved an early stable response, late response or non response were 100%, 100%, and 0.0%, respectively.
Prognostic factors and risk stratification
On univariate survival analysis, hemoglobin level, PLT, and albumin level at diagnosis, and dynamic treatment response were significantly correlated with survival outcomes. On multivariate analysis, non- response at 8 weeks was the most powerful predictor of poor OS. When treatment response was excluded, hemoglobin < 60 g/L and albumin < 25 g/L at diagnosis were associated with poor OS (Table 2). In patients with EBV-HLH, hemoglobin < 60 g/L at diagnosis was associated with poor OS.
Table 2
Univariate and multivariate analysis of parameters affecting OS in non-malignancy associated HLH
| Univariate analysis | | Multivariate analysis | | | |
| | Treatment response included | | Treatment response excluded |
5-year OS | P | HR(95%CI) | P | HR(95%CI) | P |
Age < 1 years old | 80.0% VS (69.0%) | 0.425 | | | | | | |
EBV-associated | 79.0% VS (67.0%) | 0.262 | | | | | | |
Hemoglobin < 60 g/L | 25.0% VS (77.0%) | < 0.001 | | | | | 3.22 (2.01–19.28) | 0.002 |
Platelet < 30 × 10^9/L | 36.0% VS (79.0%) | < 0.001 | | | | | 2.15 (0.88–5.24) | 0.093 |
ALT > 200 U/L | 73.0% VS (71.0%) | 0.935 | | | | | | |
TG > 2.5 mg/dl | 76.0% VS (62.0%) | 0.173 | | | | | | |
Fibrinogen < 1.5 | 66.0% VS (80.0%) | 0.170 | | | | | | |
Ferritin > 10000 | 75.0% VS (72.0%) | 0.744 | | | | | | |
Albumin < 25 g/L | 33.0% VS (82.0%) | < 0.001 | | | | | 7.71 (3.10-19.19) | < 0.001 |
Dynamic treatment response | | 0.010 | | | 0.010 | | | |
Early stable responder | 100% | | | 0.00 | | | | |
Late stable responder | 100% | | | 0.00 | | | | |
Unstable responder | 36% | | | 0.21(0.08–0.52) | | | | |
Non-responder | 0% | | | 1.0 | | | | |
Abbreviations: OS, overall survival; HLH, hemophagocytic lymphohistiocytosis; HR, hazard ratio; EBV, Epstein-Barr virus; ALT, alanine transferase; TG, triglyceride |
A prognostic risk score was established and weighted based on hazard ratios calculated for three parameters measured at diagnosis: hemoglobin < 60 g/L (2 points), platelets < 30 × 109/L (1 point), albumin < 25 g/L (2 points). Five-year OS of low-risk (score 0–1), intermediate-risk (score 2), and poor-risk (score ≥ 3) patients were 88%, 38%, and 22%, respectively (Fig. 2).