Clinical Characteristics and Prognostic Analysis of Testicular Relapse in Pediatric Acute Lymphoblastic Leukemia: A Retrospective Multicenter Study from China

Background: The incidence of testicular relapse in pediatric acute lymphoblastic leukemia (ALL) has been reduced to 2% or lower with the application of modern intensive chemotherapy. However, testes remain the second most common sites for relapsed ALL in children and the management of testicular relapse has not been fully depicted. Herein, we performed a multicenter retrospective study to analyze the clinical features and outcome of pediatric ALL with testicular relapse. Methods: Sixty-seven childhood testicular relapsed ALL patients were enrolled in this study from 13 centers in China. They were all initial treated with the CCCG-ALL-2015 protocol between January 2015 and December 2019. The clinical features, treatment regimens and outcomes of patients were collected. The overall survival (OS) was estimated by the Kaplan‑Meier methods and the differences between groups were compared by the log-rank test. Cox proportional‑hazards regression model was used for multivariate analysis to evaluate the influencing factors of OS. Results: The median age was 7 years old. The median time from initial diagnosis to testicular relapse was 37 months. Sixty-six patients (99%) were B-ALL. Forty-one patients (61%) were diagnosed as isolated testicular relapse and the remaining 26 patients (39%) were testis combined with bone marrow and/or central nervous system relapse. Eight of 67 patients were abandoned treatment. Fifty-nine patients (88%) accepted treatment with subsequent evaluation. The median follow-up was 33 months and the 4-year OS was 80.1%. Treatment were heterogenous, including chemotherapy alone, irradiation, orchiectomy, CD19-chimeric antigen receptor T (CAR‑T) cell therapy and hematopoietic stem cell transplantation (HSCT). The 4-year OS of patients treated with CAR-T cell therapy, orchiectomy and chemotherapy alone were 93.8%, 90.0% and 38.1% (P<0.05), respectively. The 4-year OS of patients accepted HSCT was 77.1%. The 4-year OS of patients with isolated testicular relapse and combined relapse were 87.9% and 68.4% (P=0.064), respectively. Among thirty-seven isolated testicular relapsed children, 19 patients (51%) accepted CD19-CART cell therapy and 10 patients (27%) accepted orchiectomy. The 4-year OS were 92.9% and 100% (P>0.05), respectively. Multivariate analysis identified combined relapse (HR=5.901, 95%CI 1.237-28.158) and chemotherapy alone (HR=6.322, 95%CI 1.393-28.702) were independent prognostic factors for 4‑year OS (all P<0.05). Conclusion: Testicular relapse of pediatric ALL mainly occurred 3 years after initial diagnosis. Patients with isolated testicular relapse had a favorable outcome. For isolated testicular relapse, CART cell therapy and orchiectomy were both effective. Orchiectomy would affect fertility, while CART cell therapy is safe and effective and has an advantage in improving life-quality of survivors. For the testicular relapsed patients, chemotherapy alone was less effective, CAR-T cell therapy and/or HSCT are suggested.