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Prognostic factors in secondary adult HLH
AB
Figure 4. Survival outcomes according to hemophagocytic lymphohistiocytosis risk score. (A) Overall survival according to risk score. (B) Cumulative incidence of progression according to risk score. Low risk (score 0-1), intermediate risk (score 2), high risk (score ≥3). OS: overall survival; CIP: cumulative incidence of progres- sion.
patients according to variables such as age, thrombocy- topenia, EBV-association, and high ferritin level, which were significant factors for poor overall survival in multi- variate analysis. As we observed a high probability of relapse or refractory disease in high-risk patients, early intervention with salvage therapy and allogeneic HCT should be considered in selected patients. In contrast to high-risk or relapsed patients, we also observed patients who showed good responses to initial steroid therapy alone. Response to steroid alone was expected in some patients with an infection other than EBV, an autoimmune disease, or HLH of unknown cause. We may, therefore, consider delaying etoposide in some HLH patients with- out EBV and those with an autoimmune disease.
Although the distinction between primary and second- ary HLH is obvious, several genetic abnormalities found in adult patients support the hypothesis that many cases of secondary HLH have an underlying genetic predisposi- tion.34-36 This issue will remain challenging unless we can assess patients for the presence of genetic defects in every suspicious case, and more genes associated with cytotoxic function may be identified in the future.37 We were unable to check for all possible genetic abnormalities, except for some patients with negative results for UNC13D and PRF1 mutations, and we lack reference data regarding gene defects in adult patients. We, therefore, hypothe- sized that all enrolled patients without gene study data were cases of secondary HLH unless they did not satisfy HLH-2004 criteria.5 In addition, all patients enrolled in this study were diagnosed based on increased histiocytosis
with active hemophagocytosis in a bone marrow study, although previous reports showed that 30% of HLH cases may not present with hemophagocytosis in an initial bone marrow study.3,38 Conversely, severely ill patients not sat- isfying the diagnostic criteria for HLH sometimes present with bone marrow hemophagocytosis.39 As we initially identified HLH patients based on bone marrow results, it is possible that we missed some HLH patients without evidence of bone marrow hemophagocytosis or who did not undergo a bone marrow examination.
HLH is a rare disease for which well-organized prospec- tive studies are lacking: analysis of prognostic factors for secondary HLH is, therefore, difficult and few data are available for risk-stratification. Although our data originat- ed from a retrospective study, patients were consistently treated and managed, and the number of patients was suf- ficient for the final analysis. As we excluded cases of malignancy-associated HLH, treatment response to proto- cols and survival outcomes were relevant for risk-stratifi- cation. Our prognostic risk model should be validated by larger studies. Combinations of several predictive factors at diagnosis and 8-week treatment response can allow cli- nicians to identify patients at high risk of disease progres- sion, and second-line therapy including allogeneic HCT should be considered earlier in the course of treatment.
Acknowledgments
This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1020370).
References
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4. Lee JS, Kang JH, Lee GK, Park HJ. Successful treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with HLH-94 protocol. J Korean Med Sci. 2005;20(2):209-214.
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