STRENGTHS AND LIMITATIONS OF THIS STUDY

In this clinical trial, we intensify treatment with the addition of intrathecal chemotherapy and the replacement of dexamethasone with prednisone in patients with multisystem Langerhans cell histiocytosis (LCH) and with the addition of zoledronate for multifocal bone-LCH.

This is a nationwide, multicentre, non-randomised, phase II study in Japan.

As LCH is a rare disease, we could not design a randomised phase III trial.

This study will not provide long-term outcomes beyond 3 years.

Introduction

Over the past decades, the prognosis of Langerhans cell histiocytosis (LCH) has markedly improved. A large international study, including patients with LCH-I,1 LCH-II2 and LCH-III3 conducted by the Histiocyte Society, adopted vinblastine/prednisolone-based treatment, whereas the Japan LCH Study Group (JLSG) and Japanese Paediatric Leukaemia/Lymphoma Study Group (JPLSG) conducted other studies, including JLSG-96,4 JLSG-025 6 and JPLSG-LCH-12,7 adopting cytarabine-based treatment. Although the overall survival rates are better than 90%, high relapse rates and accompanying permanent consequences, such as central diabetes insipidus (CDI) and LCH-associated neurodegenerative diseases (LCH-ND), remain unresolved.

To improve event-free survival (EFS) and reduce permanent consequences in both LCH with multisystem (MS) disease and LCH with multifocal bone (MFB) disease, the Japan Children Cancer Group (JCCG) and the Japan Adult Leukaemia Study Group (JALSG) conducted a nationwide single-arm phase II clinical trial in newly diagnosed paediatric and adult patients. The main changes in this trial are as follows. First, based on previous reports that patients with high-risk LCH have elevated levels of inflammatory cytokines and chemokines and sometimes develop haemophagocytic lymphohistiocytosis,8 9 causing multiple organ failure, we replace the prednisolone normally administered in the initial 2 weeks of induction treatment for MS disease with dexamethasone (DEX), which has been shown to have stronger anti-inflammatory and antitumour effects in acute lymphoblastic leukaemia.10 In addition, we expect DEX to prevent neurodegeneration caused by intracranial inflammation because of its high penetration to cerebrospinal fluid.11 12 Second, central nervous system (CNS)-targeted therapy with intrathecal injection of cytarabine, common in acute leukaemia, is introduced for the first time in LCH due to previous reports indicating the direct involvement of tumour cells or histiocytes with the same oncogenic mutation as tumour cells in the development of permanent consequences in CNS.11 13 We choose cytarabine for intrathecal injection over methotrexate, which causes leucoencephalopathy in some patients,14 as it exerts a cytotoxic effect on myeloid cells and is the main drug in LCH clinical trials in Japan. Because the safety and effectiveness of intrathecal injections in children have been broadly verified in the treatment of leukaemia and this study aimed to administer intrathecal injections only three times without methotrexate, we judged that this treatment would have no safety issues.15

For MFB disease, zoledronic acid, which has been shown to be effective against LCH bone lesions in a small case series,16 17 will be administered to intensify the bone lesion treatment. Since bone lesions in LCH are infiltrated by giant osteoclast-like multinucleated cells and osteolytic activity is reported to be high in children with active LCH,18 19 it seems rational to use zoledronic acid to suppress osteoclasts.

Methods and analysisPurpose and study setting

This is a non-blinded, multicentre, single-arm phase II clinical trial in previously untreated, newly diagnosed paediatric (aged under 20 years) and adult (aged under 40 years) patients with LCH. Here, we evaluate the safety and effectiveness of chemotherapy intensification by comparing it with standard chemotherapy and JLSG-02 and JLSG-96 therapies for MS and MFB diseases, respectively.

Substitute DEX for prednisolone for the initial 2 weeks of induction treatment for MS.

Introduce intrathecal injections of cytarabine and prednisolone for MS disease.

Introduce zoledronic acid during maintenance therapy for MFB disease.

EndpointsSecondary endpoints

EFS (overall, by risk, by generation, by BRAF V600E gene mutation pattern at diagnosis, by BRAF V600E gene mutation pattern in bone marrow at diagnosis, by peripheral blood BRAF V600E gene mutation pattern at diagnosis, cases in which GR (good response)/PR (partial response) was obtained 6 weeks after the start of treatment and by reduction rate of BRAF V600E gene mutation in bone marrow or peripheral blood during treatment).

Overall survival (overall, by risk, by generation, by BRAF V600E gene mutation pattern at diagnosis, by BRAF V600E gene mutation pattern in bone marrow at diagnosis, by peripheral blood BRAF V600E gene mutation pattern at diagnosis, by initial treatment responsiveness and by reduction rate of BRAF V600E gene mutation in bone marrow or peripheral blood during treatment).

Progression-free survival (overall, by risk, by generation, by BRAF V600E gene mutation pattern at diagnosis, by BRAF V600E gene mutation pattern in bone marrow at diagnosis, by peripheral blood BRAF V600E gene mutation pattern at diagnosis, cases in which GR/PR was obtained 6 weeks after the start of treatment and by reduction rate of BRAF V600E gene mutation in bone marrow or peripheral blood during treatment).

Relapse rate (overall, by risk, by generation, by BRAF V600E gene mutation pattern at diagnosis, by BRAF V600E gene mutation pattern in bone marrow at diagnosis, by peripheral blood BRAF V600E gene mutation pattern at diagnosis, cases in which GR/PR was obtained 6 weeks after the start of treatment and by reduction rate of BRAF V600E gene mutation in bone marrow or peripheral blood during treatment).

Disease assessment and response rate in each treatment phase (overall, by risk).

Correlation between changes in LCH disease activity score and clinical prognosis.

Incidence of CNS-related late complications (overall, by risk, by generation, by BRAF V600E gene mutation pattern at diagnosis, by BRAF V600E gene mutation pattern in bone marrow at diagnosis, by peripheral blood BRAF V600E gene mutation pattern at diagnosis, by initial treatment responsiveness and by reduction rate of BRAF V600E gene mutation in bone marrow or peripheral blood during treatment)

Incidence of adverse events due to Common Terminology Criteria for Adverse Events (CTCAE)C V.5.0.

Treatment completion rate, number of intrathecal injections and number of zoledronic acid administrations.

Eligibility criteriaInclusion criteria

Patients histologically diagnosed with LCH.

Age at registration: 0–39 years.

The Lansky performance status score is 10 or more for patients aged less than 20 years and the Karnofsky performance status score is 10 or more for patients aged 20–39 years.

Patients with LCH with MS or MFB.

Previously untreated patients with newly diagnosed LCH (prior surgery and steroid therapy are allowed).

Patients who can submit diagnostic samples, including biopsy specimens and peripheral blood (PB) and/or bone marrow (BM) aspiration samples for central review.

Written informed consent for participation in this study will be obtained from patients or their legal guardians.

Exclusion criteria

Severe dysfunction in the liver, kidney, or cardiac system, which may make the study therapy difficult, except for dysfunction due to LCH, which is expected to improve with LCH treatment.

Grade 3 or higher (CTCAE V.5.0) intracranial haemorrhage.

CNS neurodegenerative diseases.

Patients with other malignancies or a history of other malignancies.

Patients weighing less than 2500 g.

Positive for HIV, hepatitis C virus or hepatitis B surface antigen.

Pregnant women or those who are planning to be pregnant.

Patients otherwise deemed unsuitable for this study by the investigators.

Central review for diagnosis and treatment evaluation

Pathological diagnosis: all patients will be pathologically confirmed to have LCH by a central review.

Molecular diagnosis: the presence of BRAF V600E mutation in the tumour, PB and/or BM will be centrally tested using droplet digital PCR.

Explorative evaluation: genomic analysis of MAPK pathways other than BRAF V600E and cytokine/chemokine and bone metabolism marker assays will be performed centrally by droplet digital PCR (or target sequence analysis) and assays will be performed using multiplex immunoassays or single ELISA.

Treatment procedures

This is a single-arm phase II clinical trial of both MS and MFB. The study design is shown in figure 1A and B and tables 1 and 2.

Figure 1

Treatment outlines of (A) the multisystem and (B) multifocal bone LCH. Ara-C, cytarabine; DEX, dexamethasone; IT, intrathecal administration of cytarabine plus prednisolone; LCH, Langerhans cell histiocytosis; MTX, methotrexate; PSL, prednisolone; VBL, vinblastine; 6-MP, 6-mercaptopurine; VCR, vincristine; ZOL, zoledronate acid.

Table 1

Treatment protocol of the LCH-19-MSMFB trial for multisystem disease

Table 2

Treatment protocol of the LCH-19-MSMFB trial for multifocal bone disease

MS disease

Both risk organ-positive and organ-negative patients with MS will receive an initial 6-week induction treatment course (induction A+id) comprising 2 weeks of administration of DEX, followed by 4 weeks of administration of prednisolone, vincristine and cytarabine and two intrathecal administrations of cytarabine/prednisolone. Patients with GR or PR who respond to induction therapy will receive 24 weeks of maintenance I+i consisting of prednisolone, cytarabine, vincristine, methotrexate and one intrathecal injection, followed by an additional 24 weeks of maintenance II comprising prednisolone, vinblastine, 6-mercaptopurine and methotrexate to complete the treatment (figure 1A and table 1). Patients who develop active disease progression (AD-p) or relapse during maintenance therapy will be excluded.

MFB disease

All patients with MFB disease will receive an initial 6-week induction treatment (induction A), comprising 6 weeks of prednisolone, vincristine and cytarabine. Patients with GR or PR responding to induction therapy will receive 24 weeks of maintenance I+z comprising prednisolone, cytarabine, vincristine, methotrexate and six zoledronic acid to complete treatment (figure 1B and table 2). Patients who develop AD-p or relapse during maintenance therapy will be excluded.

Evaluation criteriaInitial treatment response at the end of the 6 weeks of induction therapy

The initial treatment response (response to induction therapy) is classified into four categories: GR, PR, NR (no response) and PD (progressive disease), as previously reported.4–6 These categories are defined in more specific detail but are almost equivalent to the Histiocyte Society categories of NAD (no active disase), AD (active disease) better, AD intermediate and AD worse, respectively.20 Briefly, GR is defined as the disappearance of the signs and symptoms of LCH. PR is defined in patients who meet all the following criteria: (1) ≥30% decrease in the sum of the longest diameter of the LCH lesions according to the Response Evaluation Criteria in Solid Tumors guidelines,21 (2) partial regression (>50%) of skin or mucosal LCH lesions, (3) no new lesion of LCH compared with baseline and (4) disappearance of the risk of organ involvement (if initially present). NR is defined in patients meeting either of the following criteria: (1) ≤30% decrease in the sum of the longest diameter of the LCH lesions, (2) lesser regression (<50%) of skin or mucosa LCH lesions, (3) despite improvement of initial lesions, additional lesion occurs (except for lesions in risk organ) or (4) persistence of risk organ involvement. PD is defined as the worsening of signs or symptoms due to LCH and/or the appearance of new LCH lesions despite induction treatment.

Disease status during maintenance therapy

Disease status during maintenance therapy is classified into four categories: NAD, AD-r, AD-s and AD-p, as defined by the Histocyte Society.20

Sample size considerations

As a historical control, the JLSG-02 results are used in the EFS of patients with MS disease aged under 20 years, whereas those of JLSG-96 are used in MFB disease aged <20 years.

Based on the 3-year EFS rate of 45.8% (95% CI: 34.1 to 56.8) in the historical control of MS disease with risk organ involvement, we set the expected value at 66% with a threshold of 46%. Accounting for the exclusion of 10% of the cases, the sample size needed to achieve a one-sided significance level of 10% and a power of 80% was 36.

Similarly, based on a 3-year EFS rate of 66.7% (95% CI: 54.8 to 76.1) in the historical control of MS disease without risk organ involvement, we set the expected value at 78% with a threshold of 67%. After excluding 10% of cases, the sample size in this subgroup was set to 86. As for MFB disease, which showed a 3-year EFS rate of 69% (95% CI: 46.8 to 82.5) in historical control, we set the expected value at 85% with a threshold of 69%. Accounting for a predicted exclusion of 10% of cases, the sample size in this subgroup was set to 40.

Statistical analysis

We define the ‘full analysis set (FAS)’ and ‘per protocol set (PPS)’ for efficacy evaluation. The FAS is defined as all registered patients, excluding those who receive no protocol treatment and those with serious violations such as not providing consent. PPS is defined as patients with adequate administration of study treatment among the FAS population, excluding those who receive less than two intrathecal injections for MS disease and less than six doses of zoledronic acid for MFB disease. A ‘safety analysis set (SAF)’ is also defined. All registered patients—with the exception of those who receive no protocol treatment protocol—included in the SAF population.

Survival curves will be estimated using the Kaplan-Meier method and SEs will be calculated using Greenwood’s formula. To estimate the cumulative relapse rate and the incidence of permanent CNS consequences, we will use the cumulative incidence method with the counting process method to estimate SEs. CIs are set at 95%; however, for the primary endpoints, the lower limit of the 80% CI and the threshold will be compared for each subgroup.

Participating institutions

Approximately 170 departments from various institutions are participating in this study. All institutions belonged to either the JCCG or JALSG study groups.

Follow-up and study status

Patient enrolment was initiated on 1 June 2021 and is scheduled to end in March 2028. Data collection will end in March 2031.

Patient and public involvement

The patients and/or the public are not involved in the design, conduct, reporting, or dissemination of this study.

Ethics and dissemination

This trial will be performed in accordance with the ethical principles of the Declaration of Helsinki and the Clinical Trial Act. This study was reviewed by the National Hospital Organisation Review Board for Clinical Trials (Nagoya, Japan) and registered in the Japan Registry of Clinical Trials (jRCTs041210027, https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027) on 1 June 2021. Patient enrolment is scheduled to end in March 2028, while data collection will end in March 2031. Informed consent will be obtained from all the patients and/or their guardians before registration. All data will be collected confidentially by the investigators using an electronic data capture system. We will present the results of this trial at a conference and publish them in a peer-reviewed journal.

Discussion

Reducing the recurrence rate and permanent consequences such as CDI and LCH-ND are common issues that need to be resolved in patients with LCH. The significance of substituting prednisolone with DEX for the first 2 weeks of induction treatment for MS, introduction of intrathecal injection of cytarabine and prednisolone for MS, and addition of zoledronic acid during maintenance therapy for MFB will be clarified. Additionally, an exploratory analysis will identify issues for future clinical trials.

Ethics statementsPatient consent for publication

Not applicable.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.