Salvage therapy with 2-chlorodeoxyadenosine for refractory and relapsed pediatric Langerhans cell histiocytosis: an updated nationwide survey in Japan

Abstract

The prospective clinical trials conducted by the Histiocyte Society and the Japan LCH Study Group have markedly improved overall survival rates of pediatric patients with Langerhans cell histiocytosis (LCH). However, some patients were refractory to the first-line chemotherapy and more than one-third of patients experienced relapses. Salvage therapy for the refractory/relapsed (R/R) patients has not been standardized. Several reports revealed that 2-chlorodeoxyadenosine (2-CdA), a purine nucleoside analog, is highly effective for the R/R LCH patients with multisystem disease (MS), with risk of organ involvement (MS-RO +) as well as those without it (MS-RO–). For the MS-RO + patients, the LCH-S98 study revealed that 2-CdA monotherapy was insufficient for disease control (2-years overall survival [OS], 48.0%) [1]. The following LCH-S-2005 study revealed that 2-CdA (9 mg/m2, 5 days) with high dose cytarabine (Ara-C) (1.0 g/ m2, 5 days) demonstrated sufficient treatment response for the MS-RO + patients (non-active disease rate, 23/27 [85%]) [2]. For the MS-RO– patients, the 2-CdA monotherapy was effective in the LCH-S-98 study (2-years OS, 97.0%) and a recent French observational study (complete response, 5/44; partial response, 20/44; stable disease, 6/44; progressive disease, 5/44). We previously reported 17 R/R LCH patients receiving 2-CdA with or without Ara-C in this journal [3]. Here, we show the results of an updated survey and describe the outcomes in children with LCH treated with regimens containing 2-CdA for salvage in Japan. The LCH Committee of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) sent out questionnaires to all JPLSG affiliated hospitals, and retrospectively identified 52 R/R LCH patients (14 primary refractory and 38 relapsed) treated with 2-CdA regimens from 2005 to 2019. The two patients were already reported our previous study. The most common regimen was 5 mg/m2/day of 2-CdA given for 5 consecutive days every 3–4 weeks. Of these, 18 patients received 2-CdA combined with Ara-C (10 high-dose [over 1000 mg/sqm/day] and 8 intermediate-dose [200–500 mg/sqm/day]). Patients received median 6 courses and 2.5 courses of the 2-CdA therapy in the monotherapy and Ara-C combination groups, respectively. At the initiation of the 2-CdA therapy, 21 patients had MS-RO + disease (high-risk: HR) and the remaining 31 patients did not (lowrisk: LR). The LR group consisted of 18 had MS-RO– disease, 10 had multifocal bone disease, and 3 had singlesystem single-site disease (2 hypothalamus and 1 skin). In the HR group, 9 and 12 patients had primary refractory and relapsed disease, respectively. In the LR group, 5 and 26 had primary refractory and relapsed disease, respectively. Patients in the HR group received Ara-C combination therapy more frequently than those in the LR group (14/21 [67%] vs. 4/31 [13%]; P < 0.01). The response rates * Kenichi Sakamoto [email protected]