Ruxolitinib combined with dexamethasone in adult patients with newly diagnosed Hemophagocytic lymphohistiocytosis: A single-center pilot trial

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive and life-threatening disease that can be classified into primary and secondary HLH, most adult patients have secondary HLH, and the main secondary causes are infection, rheumatic disease, and malignancy. The current first-line treatment regimen such as HLH-94 or HLH-2004 are largely extrapolated from pediatric HLH; however, the prognosis of adult HLH is worse than that of children.1, 2 In addition to its unsatisfactory efficacy, the toxicity of HLH-94/HLH-2004 regimens has resulted in relatively high treatment-related mortality,2 Therefore, more efficient and less toxic induction therapy is needed in secondary HLH. Excessive production of cytokines contributes to the pathogenesis of HLH. Recent studies have indicated that ruxolitinib, a small-molecule inhibitor of Janus kinases (JAKs), which are essential for cytokine signaling, may be therapeutic in HLH. A prospective study demonstrated that ruxolitinib is effective and safe in adults with secondary HLH,3 and all patients responded to ruxolitinib and survived for more than two months. Moreover, Lauren K. Meyer et al.4 demonstrated that hypercytokinemia of HLH reduces the apoptotic potential of CD8+ T cells, leading to relative dexamethasone resistance, and this apoptotic potential is restored both in vitro and in vivo upon exposure to ruxolitinib. Based on the above studies, we performed this single-center, pilot study to evaluate the efficacy and tolerability of Ru-D in adult patients with secondary HLH at the First Affiliated Hospital, College of Medicine, Zhejiang University. Patients enrolled in this study met the following criteria: (1) fulfilled at least five of the eight HLH-2004 criteria for HLH; (2) male or female, older than 18 years; (3) no prior chemotherapy treatment for HLH; and (4) signed an informed consent form before participating in the study. Patients who met any one of the following were ineligible: central nervous system involvement, presence of a malignancy, HIV infection, and pregnant women. Patients in this study underwent an 8-week period of treatment. The Ru-D regimen consists of ruxolitinib (15 mg twice daily for 8 weeks) and dexamethasone (initially 10 mg/m2 for 2 weeks followed by 5 mg/m2 for 2 weeks, 2.5 mg/m2 for 2 weeks, 1.25 mg/m2 for one week, and one week of tapering). For follow-up and salvage treatment, we employed the following criteria: (1) If patients did not respond to the Ru-D regimen after 7 days or relapsed at any point during treatment, they entered a rescue regimen such as HLH-94 or doxorubicin-etoposide-methylprednisolone (DEP); (2) If patients were diagnosed with lymphoma after enrollment, chemotherapy was immediately started; (3) After 8 weeks of treatment, if no recurrence and no HLH-related gene mutations were detected, treatment was discontinued, and these patients entered the follow-up stage; (4) Allo-HSCT was performed in patients who met the criteria for allo-HSCT. The primary endpoint was the overall response during treatment with the Ru-D regimen in this study. The overall response rate (ORR) included the percentage of patients with a complete response (CR), a partial response (PR), or an improvement in the measures of HLH. Efficacy was evaluated 7, 14, 28, and 56 days after initiating Ru-D therapy. The efficacy of treatment was assessed according to the evaluation criteria proposed by Franco et al5 Secondary endpoints were safety and tolerability, progression-free survival (PFS), overall survival (OS), and changes in biomarkers between baseline and post-treatment. Adverse events in this study were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE 5.0). From April 1, 2021 to May 31, 2021, a total of 8 patients were enrolled in this study. The main clinical characteristics of the patients enrolled are summarized in Table 1. All the patients were adults, and the median age was 48 years (range 23–77 years). Among the 8 patients, five were eventually diagnosed with lymphoma-associated HLH (LAHS) after enrollment. The remaining three included one bacterial infection-associated HLH and two cases of Epstein–Barr virus-associated HLH (EVB-HLH). Serum EBV-DNA copies were positive in seven patients (102–106 copies/mL) and were negative in the patient who was diagnosed with bacterial infection-associated HLH. The eight patients had ECOG performance status scores of 2 to 4, and most patients were steady at 3 or 4. Patients were followed up until June 30, 2022 or until death, with none lost to follow-up. Table 1 also shows the response outcomes in detail. The median follow-up time was 8.5 (range, 0.1–15.0) months. The ORR to the Ru-D regime was 87.5% (7/8), with 50% (4/8) showing CR, 25.0% (2/8) PR, and 12.5% (1/8) improvement in measures of HLH, 12.5% (1/8) no response (NR). Among the LAHS patients, one patient (20%) achieved CR, two patients (40%) achieved PR, and 1 patient (20%) achieved improvement in measures of HLH, and 1 patient (20%) NR. All the 3 non-LAHS patients achieved CR, and no recurrence has occurred so far. The OS was 75% (6/8) at 2 months, 50% (4/8) at 6 months and 37.5% at 12 months. Although the overall mortality rate was 62.5% (5/8), there was only one death directly related to HLH. The Ru-D treatment in our study was well tolerated, with no toxicities leading to dose reduction or discontinuation of treatment observed. Ruxolitinib has been reported to have a risk of hematological toxicity, which is difficult to evaluate because cytopenia is also the major clinical feature of HLH. We found that only 1 patient (12.5%) had grade III anemia during Ru-D therapy. Four additional patients (50%) developed grade II hematologic toxicity. Regarding infections, pneumocystis pneumonia (PCP) occurred in Patient 7 after 56 days of Ru-D treatment and was successfully cured by trimethoprim-sulfamethoxazole. Patient 6 had a history of baseline bronchiectasis and chronic pulmonary infection with PA before receiving Ru-D. During treatment, this patient suffered aggravation of pulmonary infection and presented with cough, sputum, and inflammatory exudation changes on lung imaging and positive sputum culture for PA, while the body temperature remained within normal limits. She was treated with cefoperazone-sulbactam against PA but had poor control of the infection, developed massive hemoptysis on Day 19, and died in 48 hours. For other patients, no unusual infections were observed. Secondary HLH in adults is a major clinical challenge due to its rapid progression and high mortality. The current first-line treatment strategies are the HLH-94 and HLH-2004 regimens, the ORR was approximately 70%. There were 8 patients enrolled in our study, whose ORR was 87.5%, which is higher than the patients treated with the HLH-94/HLH-2004 regimen. The survival of adult patients with HLH is poor, in a large, multicenter, retrospective study, the median OS in patients with malignancy-associated HLH was 2.8 months and for those with non-malignancy-associated HLH was 10.7 months.3 We also have retrospectively analyzed 205 patients seen between January 2011 and December 2015 in our hospital. The median OS was only 1.8 months, and most of these patients received HLH-94 as initial treatment.6 In this study, the median OS was 4.7 months in patients with LAHS, and all the patients with non-LAHS are now alive with a CR status for more than one year. In contrast to the above studies, this study demonstrated better short-term survival in both malignancy-associated HLH and non-malignancy-associated HLH patients. In our study, Ru-D regimen shows that it is an efficient and safe initial treatment for patients with LAHS, the rapid control of cytokine-driven inflammation gives these patients opportunity to confirm the diagnosis of lymphoma and bridge to chemotherapy. Although Ru-D regimen may improve short-term survival in LAHS patients, their long-term survival remains poor. More effective anti-lymphoma strategies may be the fundamental way to improve the prognosis of these patients. Overall, the Ru-P regimen was well tolerated in this study. Regarding hematologic toxicity, only 1 patient (25%) developed grade III hematologic toxicity. The peripheral blood cell counts of patients who responded gradually improved during Ru-D treatment. However, it should be noted that during Ru-D treatment, we found 2 cases of grade III or higher infection-related AE. Therefore, during Ru-D treatment, we should be aware of the aggravation of the original infection and new opportunistic infections. More experience is needed to assess the need for prophylactic anti-infective therapy in these patients. In summary, this study was a preliminary attempt at giving the Ru-D regimen to newly diagnosed adult HLH patients. Although the sample size was small and the follow-up time was relatively short. Given the rarity and high short-term mortality of adult HLH, the results of this study have some relevance indeed. Ru-D showed a high ORR and good safety and has the potential to become a first-line treatment for HLH in adults. De Zhou, Honghu Zhu, Jie Jin, Xiujin Ye, and Xianbo Huang designed the study; De Zhou, Xianbo Huang, and Mixue Xie analyzed the results; De Zhou and Xianbo Huang wrote the paper; De Zhou, Xiu jin Ye, Xianbo Huang, and Xueying Li performed the research; Xin Huang, Xiudi Yang, Li LI, Lixia Zhu, Jingjing Zhu, Xiaolong Zheng, Jianai Sun, Shuqi Zhao, Wenjuan Yu, Wanzhuo Xie, and Hongyan Tong collected the data and reviewed the paper. De Zhou, Xiujin Ye, and Xianbo Huang obtained funding. Honghu Zhu and Jie Jin provided administrative support. All authors read and approved the final manuscript. The authors thank the patients and their families, and medical staff who participated in this study. This work was supported by grants from Zhejiang Provincial Natural Science Foundation of China (No. LGF22H160040 and LZ22H080002), and Natural Science Foundation of China (No. 81900152). The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.