Treatment Optimization for Children with De Novo and Relapsed Langerhans cell Histiocytosis (LCH) as Part of the International Collaborative Study LCH IV
Hematology, Oncology
Final Report Abstract
The trial LCH-IV-G-2016 was designed as a multi-center, randomized, controlled, open label, phase III study in children 0-18 years with de novo Langerhanscell histiocytosis (LCH) (Stratum I) or in relapsed LCH after completion of Stratum I (Stratum II). In Stratum I, the study determined whether prolongation (+/- intensification with 6-mercaptopurine (MP) or intensification with 6-MP without prolongation of maintenance therapy reduces the relapse rate/percentage of permanent consequences in patients with de novo LCH (Stratum I, Group 1: Multisystem LCH, Group 2: Single system LCH). The objective in Stratum II was to determine the efficacy of a new drug (indomethacin) given in maintenance therapy to prevent further reactivation/permanent consequences compared to the standard 6-MP + methotrexate (MTX) combination. As LCH is a relatively rare disease, it was clear that Germany alone did not have enough patients for sufficiently powered and meaningful results. Therefore, LCH-IV-G-2016 was closely related to the international study LCH-IV, and statistical analysis and calculation of sample size referred to the overall international study LCH-IV. LCH-IV-G-2016 was opened January 5, 2018, and enrollment of 250 patients over 72 months was planned. Five patients each were randomized in 2018 and 2019, 11 patients in 2020, 14 in 2021, and 1 in 2022. Due to insufficient recruitment, the study was prematurely closed on demand by the DFG. Recruitment was stopped May 15, 2022. Overall, 36 patients (13 girls and 23 boys) were enrolled in 14 centers in Germany. Median age (range) was 4 years 9 months (1 month to 16 years 5 months). Eight and 27 patients were stratified in Stratum I, group 1 and 2, respectively, and 1 patient in Stratum II. All but three patients (91.7%) received and completed the maintenance therapy as randomized. Early discontinuation was due to disease progression, adverse event (not listed as SAE), and parents´ decision not based upon medical problems (each n=1). Out of the 34 patients analyzed for efficacy, 7 patients (median age 6 years 3 months) experienced a relapse during maintenance (n=1) or during follow-up of two years (n=6) (20.6%). One patient was stratified I Stratum I, group 1, the other 6 in Stratum I, group 2. No death and no clinical SAE 3/4 was observed. Hematologic toxicity grade 3/4 was seen in two patients without clinical consequence. No safety concerns were expressed by the DSMB. The 36 enrolled patients (stratified in one of the 3 Strata, which consisted of 2 or 4 arms, respectively) is way too small to make any analysis possible regarding efficacy and safety. Nevertheless, the German patients will be included in the results of the international study and will help to have evidence based data whether prolongation/intensification of maintenance therapy in children and adolescents with LCH result in a benefit.
