Intensification of induction therapy and prolongation of maintenance therapy did not improve the outcome of pediatric Langerhans cell histiocytosis with single-system multifocal bone lesions: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study

Abstract

Langerhans cell histiocytosis (LCH) with single-system (SS) multifocal bone (MFB) lesions is rarely fatal, but patients may experience relapses and develop LCH-associated sequelae. To evaluate effect on outcomes of pediatric multifocal LCH, we tested a treatment protocol modified from the Japan Langerhans Cell Histiocytosis Study Group (JLSG)-96 study. We assessed the outcomes of all consecutive newly diagnosed pediatric patients with LCH with SS-MFB lesions who were treated with JLSG-02 protocol in 2002-2009. JLSG-02 was modified from JLSG-96 as follows: increased prednisolone dosage at the induction phase and extension of maintenance therapy duration from 24 to 48 weeks. In total, 82 patients with a median follow-up duration of 8.0 years were eligible for analysis. At 6 weeks, 92.7% responded to induction; however, 27.6% of responders experienced relapses. In total, 4.8% developed central nervous system-related sequelae, including central diabetes insipidus and neurodegeneration, which were associated with relapse. None of the patients died. The 5-year event-free survival rates were not different between JLSG-02 and -96 cohort (66.7 vs. 65.1%; p = 0.697). Modification of previous treatment protocol did not contribute to improvement of outcomes in LCH with SS-MFB lesions.

Central diabetes insipidus in pediatric patients with Langerhans cell histiocytosis: Results from the JLSG‐96/02 studies

“…The JLSG‐96 and ‐02 multicenter, clinical trials for children with multifocal LCH are described in detail elsewhere . The studies were approved by the institutional review board of the Kyoto Prefectural University of Medicine, at which the JLSG registration office is located, and written informed consent was provided by all patients or legal guardians prior to inclusion.…”

“…Multifocal LCH cases are subdivided into two types: single‐system multisite (SS‐m) and multisystem (MS). Previous studies demonstrated excellent overall survival rates in LCH patients treated with the intensive chemotherapy regimens of the Histiocyte Society (LCH‐I, LCH‐II, LCH‐III) or the Japan LCH Study Group (JLSG‐96, JLSG‐02). However, LCH is associated with various permanent consequences, which result in long‐term impairments in quality of life.…”

Indomethacin is an effective treatment in adults and children with bone Langerhans cell histiocytosis (LCH)

“…Many different therapeutic strategies have been used for bone LCH. 1,2 Among less toxic and more effective regimens, indomethacin was found to be an effective analgesic and, subsequently, its effectiveness in reversing the disease process in children with symptomatic bone LCH, at diagnosis, or after reactivation, was demonstrated. [3][4][5] The rationale of its use is based on the mechanism of action of indomethacin, a non-steroidal anti-inflammatory drug that inhibits the cyclooxygenase 1 and 2 enzymes, involved in the arachidonic acid-prostaglandin pathway.…”

“…However, there are still chronic myeloid leukaemia (CML) patients who are sequentially resistant to different TKIs and even worse therapies in BCR-ABL1-positive B cell acute lymphoblastic leukaemia (B-ALL). 1 Ponatinib is the only registered third-generation TKI effective against almost all single BCR-ABL1 kinase domain (KD) mutations, including the gatekeeper T315I. Unfortunately, clinical and in vitro studies have shown that certain compound mutations (CMs, two or more nucleotide substitutions that change one or multiple codons) confer resistance to ponatinib, [2][3][4] but with inconsistent reports.…”

“…Recently, a multicentre study reported that NGS-based screening provides a more accurate picture of BCR-ABL1 KD mutations in CML and suggest incorporating it in clinical decision algorithms. 1 Nevertheless, the dynamic kinetics of ponatinib-resistant mutations have been scarcely investigated. Here we report the dynamic evolution of ponatinib-resistant mutations observed in heavily TKItreated patients monitored by NGS-based mutation screening.…”