Pediatric secondary Chronic myelogenous leukemia in a patient with Hemophagocytic lymphohistiocytosis carrying UNC13D,LYST and ITK variantChengshuang Huang1, 2, 3 Pei Huang1, 3 Xi Luo1, 3 Zhixu He1, 3 Yan Chen1, 31Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, 563000, China2Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, PR China3Department of Pediatrics, Guizhou Children’s Hospital, Zunyi, 563000, ChinaAddress correspondence to: Yan Chen, MD, The Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou, 563000, China, [email protected], +86-0851-28608293Short title: Pediatric secondary CML in a patient with HLHKeywords: Hemophagocytic lymphohistiocytosis; Secondary CML; Chemotherapy; Genetic screeningText: 839 wordsNumber of Tables: 1

Objective: To establish a prediction Nomogram based on prognostic factors for children with hemophagocytic lymphohistiocytosis (HLH). Methods: A retrospective analysis of pediatric HLH cases diagnosed at the Affiliated Hospital of Zunyi Medical University between January 2012 and December 2022 was conducted. Cox regression analysis was used to identify prognostic factors for pediatric HLH patients. The C-index, ROC curve, and AUC were used to evaluate the discrimination of the model. The DCA was used to evaluate the clinical application value of the model. Results: A total of 133 cases of secondary pediatric HLH patients were included in this study, with 45 deaths and 88 survivors. Univariate analysis showed that age ≤ 2 years, PLT ≤ 50×10 9/L, HB ≤90 g/L, AST ≥ 200 U/L, CK-MB ≥ 50 U/L, LDH ≥ 1000 U/L, SF ≥1500 μg/L, PT ≥ 20 s, APTT ≥ 40 s, hypoalbuminemia, hypofibrinogenemia, mechanical ventilation, splenomegaly, ARDS, respiratory failure,CNSL, shock, DIC, pulmonary hemorrhage, and gastrointestinal bleeding are risk factors for the survival of those secondary pediatric HLH patients ( P <0.05), while blood purification therapy may be a protective factor for HLH prognosis ( P = 0.049). Multivariable Cox showed that CNSL (HR = 3.18, 95%CI = 1.72-5.89), PLT ≤ 50×10^9/L (HR = 2.16, 95%CI = 1.11-4.19), hypoalbuminemia (HR=2.65, 95%CI=1.14-5.17), and hypofibrinogenemia (HR = 2.48, 95%CI = 1.19-5.14) were independent risk factors for the outcome of children with HLH, while the use of blood purification therapy (HR = 0.32, 95%CI = 0.16-0.64) was an independent protective factor. A Nomogram prediction model was constructed using R software, and the ROC curve , C-index, and calibration curve showed good discrimination and fit of the model. The DCA curve showed that the model had good clinical applicability. Finally, based on the Nomogram score and HR value, the subjects were divided into three groups, and it was found that the mortality rate in the high-risk group was significantly higher than that in the low-risk group. Conclusion: The development of a Nomogram to predict the prognosis of secondary pediatric HLH patients has good discrimination and accuracy and may have good clinical application value.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease. This case report describes a secondary chronic myelogenous leukemia (CML) in a nine-year-old male after treatment with a combination of etoposide (VP16), steroids and cyclosporin for HLH. VP16 can potentially induce leukemia, and single nucleotide polymorphisms may be involved in the pathogenesis of CML. We speculate that genetic backgrounds combined with chemotherapeutic drugs lead to secondary CML. This case report alerts physicians to the importance of genetic screening and the rare side effects of VP16 in children with HLH.