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Q. Zhang et al.
Our results demonstrate that RUX is effective and safe in pediatric patients with secondary forms of HLH. The rapid resolution of clinical symptoms and normalization of clinical laboratory parameters were observed. The OR rate at the end of the treatment protocol (day 28) was 83.3% (ten of 12 patients), with 66.7% (eight of 12 patients) in complete response, and all remained in CR until the data cutoff except for one who relapsed. No seri- ous adverse effects were reported. These findings sug- gested that RUX may serve as a potential first-line treat- ment option for secondary HLH, which can greatly reduce the toxic effects compared with intense chemotherapy. In addition, for patients who need biopsy analysis, RUX instead can provide more opportunities to find the original disease cause than corticosteroid-based therapy. Our study also showed that RUX had a quick effect, and for patients for whom RUX did not work well, we can probably identify this trend within approximately 3 days. Notably, the patients who had poor response to RUX after 3-7 days of treatment all responded well to the subsequent HLH-1994 regimen. This further suggests the possibility that we can attempt to use RUX first for approximately 3 days to determine the treatment response; for patients with poor efficacy, we can then combine it with chemotherapy regimen, which may not cause delayed treatment and poor prognosis. Future stud- ies are warranted to determine the viability of this idea. However, this does not mean that the efficacy of RUX is superior to that of HLH-1994/2004 regimen, which is also used to treat a major proportion of patients with primary HLH. Our main purpose is to sort suitable patients to avoid chemotherapy when possible, and make treatment available for patients deemed unsuitable for chemothera- py. We believe that RUX and standard chemotherapy may be two complementary first-line therapy strategies, as there are patients who cannot be solved by either RUX or chemotherapy. The key point is to find the specific HLH settings sensitive to RUX to guide better treatment in the future.
EBV-HLH accounts for approximately 60% of all pedi- atric HLH patients in China. EBV-HLH also accounts for a significant proportion of patients who are resistant to standard treatment and have a poor prognosis.31 No pre- vious studies have focused on the association between etiology and RUX treatment response. In addition, cur- rent ongoing trials investigating the use of RUX in HLH have not yet enrolled EBV-HLH patients.19 Therefore, our study focused more on to the relationship between EBV- HLH and RUX treatment. We enrolled eight EBV-HLH patients, the response rate was 100% (eight of eight), the CR rate was 75% (six of eight), and persistent EBV infec- tion in plasma of these subjects resolved rapidly. This suggests the possibility of RUX for treating EBV-HLH. However, one subject relapsed soon after CR, experi- enced disease recurrence 1 month after the subsequent HLH-1994 therapy, and finally died. This patient had CAEBV disease that induced HLH. For CAEBV patients with HLH signs, initiating HLH-directed treatment is required to suppress the life-threatening inflammatory process that underlies HLH. In our patient, RUX could transiently control her HLH condition, but was ineffec- tive for the CAEBV. Generally, in the absence of hematopoietic stem cell transplantation (HSCT), therapy for CAEBV, including other cytotoxic chemotherapy, can often delay the progression of disease at best, but over
time, the patients become refractory and progress to an irreversible stage.
It is interesting that patients in our study were able to clear the persistent EBV DNA in the plasma (initial con- centration 7.28×106-4.38×104copies/L) within 1 week after RUX treatment and had no EBV recurrence except for the CAEBV subject. We are not sure about the dura- tion of this EBV DNA decline, since T- or natural killer (NK)-cell infection is prone to reactivation, whereas all patients in this study exhibited multiple-cell-type EBV infection predominated by the T- or NK-cell subset. There are several explanations for this decrease in EBV DNA. First, it may be related to the EBV infection being either a first infection or a reactivation. Self-limiting is possible in patients with a first EBV infection like infec- tious mononucleosis. In addition, emapalumab (an anti– IFN-γ monoclonal antibody) has been reported to resolve persistent EBV infection in one patient, perhaps due to relief of immune paralysis caused by IFN-γ .23 As RUX can blunt numerous cytokines, including IFN-γ , the resolu- tion of the EBV infection in this study may also be attrib- uted to the relief of immune paralysis after RUX treat- ment, which primed the body immunity and ultimately resolved the EBV infection spontaneously. Moreover, evi- dence suggests that host cell stress such as oxidative stress, hypoxia and inflammation can induce EBV reacti- vation from latency.32 All of these factors may be removed after the excessive inflammation has been controlled by RUX, leading to a switch of EBV cycle from a lytic state to a latent state. In addition, we enrolled two patients with autoinflammatory diseases-associated HLH, but these two individuals had quite different responses to RUX, with one showing reversal of the HLH abnormali- ties soon and the other showing no improvement. Similarly, two patients of unknown etiology also showed two different kinds of responses. The RUX dose may not have been sufficient for these non-/poor-responders in this study. Moreover, the great heterogeneity of HLH, such as the etiology, clinical features and risk stratifica- tion, may also contribute to this difference. Therefore, further study is needed to optimize the clinical use of RUX, such as identifying some sensitive biomarkers.
In summary, our preliminary study provides further support for the possibility of RUX-based targeted therapy in pediatric patients with secondary HLH. Since patients with known CNS involvement were not enrolled in this study, we were unable to make statements on the effica- cy of ruxolitinib in the CNS. The number of patients in this study was small, and the observation time was rela- tively short. We are currently performing a large-scale, open-label, prospective trial on RUX monotherapy for pediatric HLH, which may answer more uncertainties and provide further evidence for RUX treatment as a first- line therapy in HLH.
Disclosures
No conflicts of interest to disclose.
Contributions
QZ conducted the data analysis and wrote the manuscript; RZ and ZGL contributed to the design of the study; AW, HHM, LZ, HYL, DW and YZZ performed the clinical aspects of the study; LC, WJL and YY performed laboratory tests and helped with data analysis; TYW helped with the study design. All authors read and approved the final manuscript.
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haematologica | 2021; 106(7)