Page 67 - 2019_02-Haematologica-web

Prognostic factors in secondary adult HLH
cyclosporine.5,6,24 Final treatment response was evaluated after 8 weeks of induction according to the HLH-94 protocol. Patients exhibiting a complete response at 8 weeks were given mainte- nance therapy with low-dose steroids and cyclosporine for 2 to 4 more weeks, while patients who did not achieve a complete response or who were positive for EBV according to RQ-PCR (> 3-log) were considered for continuation therapy. If the EBV RQ- PCR level increased by at least 1-log with features of relapsing HLH, rituximab or alemtuzumab was given. Five patients who relapsed or had refractory disease were treated with allogeneic HCT using fludarabine (30 mg/m2/day for 5 days), busulfan (3.2 mg/kg/day for 2 days), and antithymocyte globulin (ATG, Thymoglobulin®, 2.5 mg/kg for 2 days).
Response assessment
Complete response was defined as resolution of all clinical signs and symptoms, as well as recovery of the complete blood count and normalization of abnormal laboratory findings associated with HLH. Progressive disease was identified when both cytope- nia and abnormal laboratory findings remained and partial response was defined when patients achieved either complete blood count recovery alone without normalization of laboratory findings or improvement of HLH-related laboratory findings alone without complete blood count recovery. We evaluated treatment response at 4 and 8 weeks after treatment, and also evaluated dynamic responses according to the response time and disease progression within 8 weeks. Patients with stable complete response at both 4 weeks and 8 weeks were classified as early sta- ble responders, patients who failed to achieve a complete response by 4 weeks but showed continuous response until 8 weeks were classified as late stable responders, patients who showed only transient response and eventually progressed until 8 weeks were defined as unstable responders, and patients exhibiting no response at all were classified as non-responders. Details on the statistical analysis are provided in the Online Supplementary Methods.
Results
Baseline characteristics of the patients
The causes of HLH in the 126 patients enrolled in this study were categorized as EBV-associated (n=49), infec- tion other than EBV (n=24), and autoimmune disease (n=17). Among the 49 cases of EBV-associated HLH, five were concomitantly related with an autoimmune disease. We were unable to identify related causes in 36 (28.6%) patients (Figure 1). The baseline characteristics of the patients and their responses to treatment are presented in Table 1. Fever was observed in all patients and 118 (93.6%) patients presented with splenomegaly. Infections other than EBV included hepatitis A virus (n=5), cytomegalovirus (n=2), Staphylococcus aureus (n=3), mycoplasma (n=3), parvovirus (n=3), human immunodefi- ciency virus (n=2), mycobacterium (n=2), malaria (n=2), amebiasis (n=1), anaplasmosis (n=1), Hantaan virus (n=1), herpes simplex virus (n=1), influenza virus (n=1), and enterococcus (n=1). Patients with Kaposi sarcoma caused by human immunodeficiency virus were considered to have malignancy-associated HLH. Autoimmune diseases and similar features included systemic lupus erythemato- sus (n=8), Kikuchi disease (n=6), Behçet syndrome (n=2), Sjögren syndrome (n=2), Graves disease (n=1), rheuma- toid arthritis (n=1), autoimmune hemolytic anemia (n=1), and ulcerative colitis (n=1). Among the 35 EBV-associated
HLH patients with available serology results, seven showed a recent primary infection, five reactivation, and 23 a past infection. In addition, initial bone marrow find- ings revealed that 36 out of 49 patients (73.5%) with EBV- associated HLH had active and frequent hemophagocyto- sis, while 17 out of the remaining 77 patients (22.1%) showed active hemophagocytosis.
Treatment outcomes according to causes of hemophagocytic lymphohistiocytosis
After excluding four patients (2 with hepatitis A and an unknown cause of HLH who showed a self-limiting dis- ease course, and 2 cases with progressive multi-organ fail- ure before treatment), 122 patients were treated. The HLH-94 protocol was applied in 81 (64.3%) patients: 23 (63.8%) with HLH of unknown cause, 40 (81.6%) with EBV-HLH, 13 (54.2%) with an infection other than EBV, and five (29.4%) with an autoimmune disease). Dexamethasone plus cyclosporine treatment was admin-
Table 1. Baseline characteristics and treatment outcome of patients with non-malignancy-associated secondary HLH (n=126).
Gender, male; n(%)
Age, years; median (range)
Time from symptom
to diagnosis, days; median (range)
Fever; n(%)
Splenomegaly; n(%)
Lowest level prior to therapy; median (range) Leukocytes (x109/L)
Neutrophils (x109/L)
Hemoglobin (g/dL)
Platelets (x109/L) Fibrinogen (mg/dL) Albumin (g/dL) Prothrombin time (%)
64 (50.8%)
45.0 (15-85)
13 (0 – 82) 126 (100%) 118 (93.6%)
2.39 (0.14-31.9) 1.08 (0.01-24.1) 9.3 (3.7-16.3) 44.0 (5-307) 215.0 (4 – 513) 2.8 (1.7-4.1) 69.0 (10-145)
Highest level within 4 weeks after treatment; median (range)
Ferritin (ng/mL)
Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Total bilirubin (mg/dL)
Lactate dehydrogenase (U/L) Triglyceride (mg/dL)
C-reactive protein (mg/dL)
Causes of HLH; n(%) EBV-associated
Median highest level (log) ≥ 5.0-log
< 5.0-log
Infection other than EBV Autoimmune disease Unknown cause
Treated patients; n(%) HLH94-based therapy Steroid + cyclosporine Steroid alone
4702 (278-214000) 196 (12-4990) 134 (5-5117) 1.17 (0.07-19.9) 1670 (285-30000) 173.5 (7-813) 4.9 (0.02-34.0)
49 (38.9%) 4.5 (2.7-7.5) 20 (41.0%) 29 (59.0%) 24 (19.0%) 17 (13.5%) 36 (28.6%)
122 (96.8%) 81 (64.3%) 18 (14.3%) 23 (18.2%)
81(64.3%)
42 (34.4%) 36 (29.5%) 19 (15.6%) 25 (20.5%)
Completeremissionachievedaftertreatments;n(%)
Treatment response at 8 weeks; n(%) Early stable responder
Late stable responder
Unstable responder
Non-responder
HLH: hemophagocytic lymphohistiocytosis; EBV: Epstein-Barr virus.
haematologica | 2019; 104(2)
271