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J.H. Yoon et al.
cause of secondary HLH in this study. The prognosis of patients with EBV-associated HLH is expected to be better than that of those with malignancies or primary HLH, but if patients are not treated appropriately, their survival out- comes are dismal.26,27 Our data revealed that patients with EBV-associated HLH had similar responses to treatment in the early period but many relapsed afterward, which final- ly resulted in these patients having significantly inferior overall survivals and higher cumulative incidences of pro- gression compared to patients with HLH related to other causes. It is, therefore, important to decide on early sal- vage treatment, including allogeneic HCT, for poor responders with EBV-associated HLH. Previous reports suggested a role of acyclovir in the management of EBV- associated disease,28,29 but no relevant data are available on the additional effects of antiviral therapy.9 Salvage treat- ments include rituximab12,17,30 and alemtuzumab31 followed by allogeneic HCT.32,33 Although we used rituximab in six patients and alemtuzumab in two in the setting of relapsed disease, none of the patients showed a response to additional therapy suggesting that incorporation of rit- uximab into the HLH protocol might be an alternative approach as initial treatment in EBV-associated HLH. Of the three patients with relapsed/refractory EBV-HLH treated with allogeneic HCT, one died of relapse, one died of septic pneumonia, and one is alive without relapse.
We calculated survival outcomes of responders and non- responders at 4 weeks and 8 weeks, respectively, and
found that patients who did not achieve at least a stable partial response at 8 weeks had very high mortality. A recent prospective study investigating the effects of a sal- vage regimen using liposomal doxorubicin applied salvage chemotherapy for refractory patients who were defined as non-responsive to initial therapy at 2 weeks.18 However, our data show that patients who failed to achieve a com- plete response by 4 weeks after treatment could still achieve long-term survival if they exhibited a continuous and stable response until 8 weeks. The HLH-94 protocol recommends continuation therapy when disease is active at 8 weeks after initial therapy, and our study population included patients who proceeded to continuation therapy. Among our 21 patients who were given continuation ther- apy, 16 additional patients ultimately achieved a complete response and two of these patients were treated with allo- geneic HCT. There are no data comparing survival between patients receiving continuation therapy and other salvage regimens, or on the proper timing for allo- geneic HCT, especially in patients with EBV-HLH. However, as our data indicate that the course of EBV-HLH after relapse is very progressive, urgent preparation for allogeneic HCT is recommended. We also identified that the risk of relapse among patients with EBV-HLH was higher in those with an age >45 years, maximal EBV RQ- PCR higher than 5-log, and hyperbilirubinemia.
Apart from non-responders at 8 weeks, who have a par- ticularly poor outcome, we further identified high-risk
Table 2. Univariate and multivariate analyses for parameters affecting overall survival in non-malignancy-associated HLH.
Univariate analysis Multivariate analysis
Treatment response included Treatment response excluded
5-yearOS P HR P HR P
Age > 45 years old** (n=61, 49.4%)
EBV-associated**
(n=49, 45.9%)
Hemoglobin <9.0 g/dL (n=47, 42.5%)
Platelet count <35 x109/L **
(n=47, 36.8%)
Alanine aminotransferase >165 U/L (n=55, 32.2%)
Bilirubin >1.6 mg/dL
(n=51, 43.7%)
Albumin <3.0 g/dL (n=76, 49.4%)
Triglycerides >200 mg/dL
(n=50, 43.7%)
Ferritin >20,000 ng/mL** (n=26, 50.6%)
Fibrinogin <150 mg/dL
(n=45, 35.6%)
Dynamic treatment response** Early stable responder (n=42) Late responder (n=36)
Unstable or non-responder (n=44)
26.8% (vs. 74.9%)
25.1%
(vs. 69.3%) 38.7%
(vs. 75.6%) 32.8%
(vs. 64.7%) 67.7%
(vs. 40.6%) 30.1%
(vs. 68.5%) 34.2%
(vs. 80.8%) 38.1%
(vs. 61.4%) 23.1%%
(vs. 60.1%) 33.4%
(vs. 63.3%) 87.0%
73.7% 0.0%
< 0.001*
< 0.001*
< 0.001*
< 0.001*
0.0055*
< 0.001*
< 0.001*
0.0256*
< 0.001*
0.002*
< 0.001*
2.54 (1.4-4.7)
1.99
(1.1-3.5)
0.003*
0.016*
3.38 < 0.001* (1.9-6.1)
2.16 0.006*
(1.2-3.8)
2.20 0.004*
(1.3-3.8)
1.99 0.021* (1.1-3.6)
1.0 1.73 (0.6-5.2) 17.3 (6.5-45.9)
0.326
< 0.001*
OS: overall survival; HLH: hemophagocytic lymphohistiocytosis; HR: hazard ratio; EBV: Epstein-Barr virus; *P < 0.05. **Variables used in multivariate analyses were selected after excluding significant correlations: age, EBV-association, thrombocytopenia, hyperferritinemia, dynamic treatment response
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haematologica | 2019; 104(2)