Long Term Follow-up of Methotrexate and Cytarabine in Adult Patients with Langerhans Cell Histiocytosis

Background: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the proliferation and accumulation of mononuclear phagocytes across diverse tissues and organs. The optimal treatment strategy for adult LCH remains unclear. A comprehensive understanding of the long-term efficacy of various chemotherapy regimens in adult patients with LCH remains lacking. Our previous study (AJH 2020) demonstrated the remarkable efficacy of combined methotrexate and cytarabine (MA) therapy in patients newly diagnosed with LCH, with a median follow-up of 2 years. This study was designed to provide a comprehensive understanding of this therapeutic combination, which could pave the way for optimized treatment regimens for LCH, ultimately improving patient outcomes and quality of life.

Methods: This was a phase 2, prospective, single-center study evaluating MA as frontline treatment for adult patients with newly diagnosed LCH exhibiting multisystem disease (MS) or multifocal single-system (SS-M) involvement. The final patient was enrolled in the study in December 2020. Participants underwent MA therapy every 35 days for 6 cycles. Methotrexate (1 g/m²) was administered by 24 h infusion on day 1 and cytarabine (0.1 g/m²) by 24 h infusion for 5 days. After completion of 3 and 6 cycles of MA therapy, patients underwent comprehensive clinical evaluations, including physical examinations, laboratory investigations, and imaging, as appropriate for the LCH location. Subsequently, these evaluations were repeated every 3 months for disease monitoring. Non-active disease (NAD) was defined as the resolution of all signs and symptoms. Patients were classified as having active disease (AD), which was further subdivided into regressive disease (signs and symptoms improved [AD/better]), stable disease (SD [persistence of signs and symptoms]), and progressive disease (PD [progression, and/or appearance of new lesions]). The overall response rate (ORR) was defined as the percentage of patients who exhibited NAD or AD/better response to MA therapy. The primary endpoint was event-free survival (EFS), with events defined as a poor response (i.e., SD or PD) to MA, reactivation after MA therapy, and death from any cause.

Results: The study enrolled 95 treatment-naive patients with LCH, including an extended follow-up of 83 patients from our previous trial and 12 new cases. All patients underwent ≥ 1 course(s) of MA therapy, with a median of 6 courses (range, 1–6). Overall, 80 (84.2%) patients completed the treatment protocol, whereas 15 (15.8%) discontinued the protocol (14 patient decisions, 1 poor response). The median patient age was 32 years (range, 18–65 years). The ORR was 89.5%. The estimated six-year overall survival (OS) and EFS rates were 93.2% and 55.2%, respectively. Multivariate analysis revealed that splenic lesions at baseline (HR 0.114 [95% CI 0.019–0.678]; P=0.017) and age > 40 years at diagnosis (HR 0.137 [95% CI 0.026–0.737]); P=0.021) were associated with inferior OS. Seven patients died including 3 patients died from disease progression (23, 42, and 66 months, respectively, after the initiation of MA treatment), 1 patient died of follicular lymphoma 56 months after the initiation of the MA regimen, 1 patient died in an accident, and the cause of death in the remaining 2 patients was unclear. Liver (HR 0.478 [95% CI 0.251–0.911]; P=0.025), spleen (HR 0.414 95% CI 0.196–0.875]); P=0.021), and skin (HR 0.479 [95% CI 0.250–0.917]; P=0.026) involvement at baseline were poor prognostic factors for EFS. Thirty-eight patients experienced disease reactivation. In 25 cases, reactivation was confined to a single organ and 13 patients were reactivated in multiple systems. No degenerative central nervous system diseases were observed. Predominant toxicities included hematological adverse reactions. Neutropenia and thrombocytopenia were universally observed among the patients. Two additional patients developed a second primary malignancy (SPM) compared our previous study. One patient was diagnosed with follicular lymphoma 47 months after initiating the MA regimen, while another was diagnosed with acute lymphoblastic leukemia 91 months after initiation of the MA regimen. We did not find any correlation between BRAF status and outcomes or SPMs in our study.

Conclusion: The MA regimen was a valid and safe therapeutic approach for adult patients newly diagnosed with LCH.