Exploration of treatment in childhood Langerhans cell histiocytosis based on inflammatory and tumorous symptoms: A Pilot study

doi:10.21203/rs.3.rs-3122576/v1

Background: The outcome of multisystem childhood Langerhans cell histiocytosis (LCH), especially risk organ (RO) involvement patients, treated by the international traditional schemes had not been satisfactory and had a high incidence of reactivation with late sequelae. We observed that patients with different clinical symptoms showed different therapeutic responses to different drugs, suggesting that the method of grouping and selecting treatment strategies based only on the number of organs involved is inadequate. Based on the definition of LCH as an inflammatory myeloid tumor, this study innovatively divided children with LCH into inflammatory symptoms’ group and tumor symptoms’ group, and given different intensity treatment regimens accordingly, to explore a more appropriate treatment strategy.

\Methods: According to the clinical manifestations, 37 cases of children were divided into Group A (inflammatory symptoms) and Group B (tumor symptoms). Initial treatment, Group A used vindesine (VDS) and methylprednisolone (PSL); Group B used VDS, PSL, pirarubicin(THP) and cyclophosphamide (CTX). Treatment response was evaluated 6 weeks after the start of induction therapy in all patients, which assessed according to two criterias consisting of disease status and clinical scores of symptoms.

Results: Clinical scores pre- and post-treatment were 1.22 ± 0.547 and 0.00 ± 0.00 in Group A compared with 14.79 ± 1.686 and 1.00 ± 1.563 in Group B. Patients in both groups were all able to successfully enter maintenance treatment without progressive disease state. The overall survival (OS) of 4-year follow-up was 100% in both groups. The 4-year event-free survival (EFS) was 94.4% in Group A and 89.5% in Group B, respectively. There were no obvious adverse events in Group A, and the main adverse events in Group B were alopecia and non-lethal hematological toxicity.

Conclusion: Stratification according to patients’ clinical symptoms, with low-intensity treatment for inflammatory symptoms (mild manifestations) and intensive treatment with multiple drugs for tumor symptoms (severe manifestations), is a positive exploration that simplifies stratification method, achieves good long-term remission of the disease, and obtains a higher survival rate and quality of life, which seemed to be more appropriate for LCH patients.

Langerhans cell histiocytosis

inflammatory

tumorous

symptoms

treatment

children

Langerhans cell histiocytosis (LCH) is the most common histiocytic disease, with an incidence of about 5/1,000,000 in children, and WHO classifies it as an inflammatory myeloid neoplasiar.^, LCH can involve various organs of the body, and its clinical symptoms and prognosis are variable, the course of which varying from spontaneous regression and resolution to rapid progression and death or repeated recurrence and recrudescence with the risk of permanent consequences.

The International Society of Histiocytosis (HS) LCH I - IV scheme divides LCH into single system (SS) involvement, multisystem (MS) involvement, and whether there is involvement of risk organ (RO. Including liver, spleen and blood system). A treatment strategy based on vinblastine (VBL) and glucocorticoid (prednisone, PRED) was established, and the efficacy was evaluated according to the response after 6 weeks of initial treatment, and entered maintenance treatment for 1 year. The JLSG − 96 protocol from the Japan LCH Study Group (JLSG) used a similar approach to disease classification as LCH III, adopted intensive initial treatment plan of various chemotherapy drugs, including Arm A (vincristine, methylprednisolone, cytarabine) and Arm B (cyclophosphamide, doxorubicin, methotrexate, etc.), evaluated after 6 weeks of treatment, and entered maintenance therapy for half a year.

According to the literature,^4–5 SS-LCH patients can achieve a very excellent prognosis with only weak or even no treatment. The overall survival (OS) of MS-LCH patients treated with LCH III was 80%, in which RO- patients achieved 95% long-term remission and RO + patients responded poorly and not successfully entered maintenance phase; and event-free survival (EFS) was 50–60% in MS-LCH RO+. MS-LCH treated by the JLSG-96 developed similar OS and EFS. Therefore, the therapeutic responses of MS-LCH, especially RO + patients, treated by the above traditional schemes had not been satisfactory and had a high incidence of reactivation with late sequelae.

Our center started to diagnose and treat pediatric patients with LCH in the 1990s, with about 30–40 cases per year. The LCH III or JLSG-96 regimens were used alone firstly, and then since 2012, these two classic regimens were gradually integrated and refined, which formed the prototype of the treatment regimen in this study. Better results were obtained in terms of efficacy compared to the previous either alone.

During the treatment of LCH, we observed that patients with different clinical symptoms showed different therapeutic responses to different drugs, suggesting that the method of grouping and selecting treatment strategies based only on the number of organs involved is inadequate. At the time of initial diagnosis, there were two widely different clinical presentation tendencies, namely, inflammatory symptoms (milder clinical presentation) and tumor symptoms (more severe clinical presentation), corresponding specific clinical symptoms of which shown in Table 1. The grouping approach to treatment, given low-intensity therapy for mild manifestations (inflammatory symptoms) and multi-agent combination of high-intensity therapy for severe manifestations (tumor symptoms), seems to be more appropriate and more profitable for LCH patients.

Therefore, based on the current international definition of LCH as an inflammatory myeloid tumor, this study attempts to group patients according to their clinical manifestations (inflammatory symptoms and tumor symptoms) and to give them the corresponding treatment, and to observe their efficacy and adverse effects, in order to explore more appropriate grouping and treatment options for LCH, reduce complications, and obtain a higher survival rate and quality of life. The grouping and corresponding treatment protocol of this study is named LCH-GZWC-2018 (Wang).

Patients

In total, 41 Chinese children of age < 16 years with newly diagnosed in our centre ,were registered consecutively for treatment on this protocol between March 2017 and May 2021.Diagnoses were confirmed by histopathologic findings in affected organs, which were positive for either S-100, or CD1a antigen, or both.^4,^,^, All study participants signed an informed consent was approved by the ethics committee of Guangzhou Women and Children’s Medical Center.

Grouping

In this study, various clinical symptoms are divided into inflammatory symptoms and tumor symptoms. Inflammatory symptoms included rash, oral lesions, ear canal lesions, symptoms of bone damage, gastrointestinal symptoms, pulmonary symptoms, liver symptoms, endocrine system symptoms and central nervous system symptom, etc. Tumor symptoms involved noninfectious persistent fever, infiltrated symptoms, hematologic symptoms, etc. Detailed clinical manifestations of each symptoms were shown in Table 1. According to the symptoms, the patients were divided into 2 an inflammation symptom group (Group A) and a tumor symptom group (Group B). Group A only showed inflammatory symptoms, while Group B was complicated with tumor symptoms.

Table 1

Inflammation symptoms and tumor symptoms
Symptom	Involved organs and manifestations
Inflammatory symptoms	• Rash • Ear canal lesions: otorrhea or suspected hearing impairment • Bone damage: pain, limited mobility, hollow mass of the calvarium, eosinophilic granuloma of the long bones,scoliosis or vertebral compression fracture • Gastrointestinal symptoms: diarrhea, failure to thrive or evidence of malabsorption • Pulmonary symptoms: cough, shortness of breath • Liver symptoms: jaundice, low whiteness proteinemia, etc. • Endocrine system symptoms: short stature, growth failure precocious or delayed puberty,hypothyroidism • Central nervous system symptoms: diabetes insipidus, neurodegenerative changes
Tumor symptoms	• Noninfectious persistent fever • Infiltrated symptoms: gingival or palatal swelling, splenomegaly, mass of body or organ, lymphadenopathy • Hematologic symptoms: leukopenia, thrombocytopenia, anemia not explained by other causes

Treatment Protocols

All patients were given a 6-week initial treatment and a 12-month maintenance treatment. Group A was treated with vindesine(VDS) and methylprednisolone (PSL), and patients with simple bone lesions were included, including multiple bone lesions, weight-bearing bone involvement, anterior bone, skull base patients with bone involvement; Group B regimen intensive combination of combined VDS, PSL, pirarubicin (THP) and cyclophosphamide (CTX), Table 2. After 6 weeks, the patient was assessed to achieve non-active disease (NAD) or activity-better (better), activity-stable (stable), who could enter the maintenance phase of treatment. If the patient was defined as activity-progressive, salvage regimen treatment was given, Fig. 1. During the initial treatment, if some tumor symptoms failed to disappear, vemurafenib (Vemur) was added, and if some inflammatory symptoms failed to disappear, methotrexate (MTX) was added.

Table 2

Protocol of LCH-GZWC-2018 (Wang)
Group A
Initial treatment(duration of 6 weeks)
VDS	3mg/m ²	IV	D1 D8 D15 D22 D29 D36
PSL	2mg/kg	oral	D1-D28, D29-42 tapering week by week
Maintenance treatment(duration of 12 months)
VDS	3mg/m ²	IV	1 time per 3 weeks
PSL	2mg/kg	oral	5 days per 3 weeks
Group B
Initial treatment(duration of 6 weeks)
VDS	3mg/m ²	IV	D1 D8 D15 D22 D29 D36
PSL	2mg/kg	oral	D1-D28, D29-42 tapering week by week
THP	20mg/m ²	IV	D1 D15 D29
CTX	10mg/kg	IV	D1-5 D15-19 D29-33
MTX*	25mg/m ²	oral	1 time per week
Vemur#	15-20mg/kg	oral	2 times per day
Maintenance treatment(duration of 12 months)
VDS	3mg/m ²	IV	1 time per 3 weeks
PSL	2mg/kg	oral	5 days per 3 weeks
THP	20mg/m ²	IV	1 time per 6 weeks (W1, W7, W13,W19)
CTX	10mg/kg	IV	1 time per 6 weeks (W4, W10, W16,W22)
6MP	50mg/m ²	oral	1 time per day
MTX*	25mg/m ²	oral	1 time per week
Vemur#	15-20mg/kg	oral	2 times per day
VDS, vindesine; IV, intravenous; PSL, methylprednisolone; THP, pirarubicin; CTX, cyclophosphamide; MTX, methotrexate; Vemur, vemurafenib; 6MP, 6mercaptopurine.
*Additional use when inflammatory symptoms do not improve; #Additional use when tumor symptoms do not improve

Evaluation Criteria

Treatment response was evaluated 6 weeks after the start of induction therapy in all patients, which assessed according to two criterias consisting of disease status and clinical symptoms therapeutic efficacy.^, Disease status was defined as follows in Table 3: recovered, all symptoms and signs subsided; better, symptoms and signs improved, no new lesions; stable, some symptoms and signs persist without new lesions; progressive, progression of pre-existing symptoms and signs and/or emergence of new lesions. Recovered was defined as NAD; while better, stable and progressive were determined as active disease (AD). Comparing the clinical scores at the primary diagnosis and after 6-weeks initial treatment to show whether the clinical symptoms have improved after the application of the protocol, which is used to assess the symptoms therapeutic efficacy. The items of clinical score for each symptom are shown in Table 4.

Table 3

LCH disease status assessment
Non-active disease (NAD)
Recovered	All symptoms and signs subsided
Active disease (AD)
Better	Symptoms and signs improved, no new lesions
Stable	Some symptoms and signs persist without new lesions
Progressive*	Progression of pre-existing symptoms and signs and/or emergence of new lesions
*Progression of isolated bone damage is defined as appearance of new bone lesions or lesions in other organs.

Table 4

Clinical score of symptoms
Symptom	Performance	Score
Inflammatory symptoms
Rash (area of rash)	> 25%	2
	5–25%	1
	< 5%	0
Ear canal lesions	Pus, itching, oozing	2
	Hearing abnormalities	1
	None	0
Bone damage	Pain, abnormal posture	1
Bone damage	None	0
Gastrointestinal symptoms	Diarrhea	1
Gastrointestinal symptoms	None	0
Pulmonary symptoms	Need oxygen	2
	Symptomatic, no need for oxygen	1
	None	0
Liver symptoms (Child-Pugh classification)	Grade C	3
	Grade B	2
	Grade A	0
Endocrine system (excluding diabetes insipidus)	Replacement therapy	2
Endocrine system (excluding diabetes insipidus)	No replacement therapy required	0
Central nervous system symptoms	Central nervous system mass or diabetes insipidus	3
	Decreased urine output	1
	Asymptomatic	0
Tumor symptoms
Non-infectious fever	≥ 38 ℃	3
Non-infectious fever	None	0
Gingival or palatal swelling	Loose teeth, swollen gums	1
Gingival or palatal swelling	None	0
Splenomegaly	Flat umbilicus under spleen ribs	3
	Spleen subcostal > 2 cm	2
	Spleen subcostal < 2 cm	1
	Spleen under rib	0
Mass of body or organ	Mediastinal mass	3
Mass of body or organ	No placeholder	0
Lymphadenopathy	Lymph nodes > 2cm	2
Lymphadenopathy	Lymph nodes < 2 cm	0
Hematologic symptoms	Hemoglobin < 110g/l or platelet < 140×10 ⁹ /l	3
Hematologic symptoms	normal	0

Statistical Analyses

The results were calculated using SPSS 21.0 for mean (\(\stackrel{-}{\text{x}}\)) and standard deviation (SD). The measurement data between the two groups were analyzed by paired samples T test, the enumeration data were analyzed by the chi-square test, and the EFS was analyzed by Kaplan-Meier. A significant difference was defined at p value < 0.5. Adverse reactions were assessed according to CTCAE v4.0.

Patient Characteristics

Of 41 registered patients, 4 patients were excluded because of less than 12 months of follow-up. Thus, 37 patients were eligible for the study, including 18 patients with only inflammatory symptoms (Group A) and 19 patients with developed to tumor symptoms (Group B). Characteristics of these 37 patients are shown in Table 5. The patients in both groups were more common in males. The median age at diagnosis was 3.3 years in the Group A and 1.0 year in the Group B. The onset age of Group B was younger than that of Group A. In the Group A, all 18 patients (100%) had bone damage; Rash, ear canal lesions ,gastrointestinal symptoms, liver symptoms and Central nervous system symptoms were found in 1 patient (5.6%) each. In the Group B, fever and hematologic symptoms were the most commonly clinical manifestations in 19 patients (100%), followed by rash and liver symptoms in 17 patients (89.5%). Splenomegaly and pulmonary symptoms were also common in 16 (84.2%) and 12 patients (63.2%), respectively. The remaining symptoms such as ear canal lesions, bone damage and gastrointestinal symptoms were less than 50%. All patients were followed up for a median of 38 months (range, 21.34–71.47 months).

Table 5 Patient Characteristics

Characteristics	Group B	Group A
No. of patients	18	19
Age at diagnosis, y
Median	3.3	1.0
Range	0.5 - 11.1	0.6 - 3.6
Gender
Male	11（61.1%）	10（52.6%）
Female	7（38.9%）	9（47.4%）
Follow-up, m
Median	38.08	38.93
Range	21.34 - 43.73	22.52 - 71.47
Inflammatory symptoms (no. of patients)
Rash	1（5.6%）	17（89.5%）
Ear canal lesions	1（5.6%）	8（42.2%）
Bone damage	18（100%）	7（36.8%）
Gastrointestinal symptoms	1（5.6%）	5（26.3%）
Pulmonary symptoms	0	12（63.2%）
Liver symptoms	1（5.6%）	17（89.5%）
Endocrine system symptoms	0	1（5.3%）
Central nervous system symptoms	1（5.6%）	3（15.8%）
Tumor symptoms (no. of patients)
Fever	0	19（100%）
Gingival or palatal swelling	0	1（5.3%）
Splenomegaly	0	16（84.2%）
Mass of body or organ	0	2（10.5%）
Lymphadenopathy	0	4（21.1%）
Hematologic symptoms	0	19（100%）

Clinical Scores Of Symptoms

Group A had clinical scores of 1.22 ± 0.547 and 0.00 ± 0.00, while Group B had clinical scores 14.79 ±1 .686 and 1.00 ± 1.563, respectively, at the primary diagnosis and after 6-weeks initial treatment (Figure 2). The scores of two groups before and after treatment, analyzed by paired sample T test, were statistically significant (Table 6). This indicated that the clinical symptoms were significantly improved or even subsided after initial treatment of this protocol.

Table 6 Evaluation of Treatment Effectiveness

	Group A	Group B
No. of patients	18	19
Clinical scores (± SD)
At the primary diagnosis	1.22 ± 0.547	14.79 ±1 .686
After the initial treatment	0.00 ± 0.00	1.00 ± 1.563
p value	< 0.01	< 0.01
Disease status
NAD/better/stable	18 (100%)	19 (100%)
Progressive	0	0
Subsistence analysis
4 -year EFS (%)	94.4%	89.5 %
Event (diabetes insipidus)	1 (5.5%)	2 (10.5%)
Event’s time, M	4.54	18.64 / 20.25
4 -year OS (%)	100%	100%
Treatment-related adverse effects (Grade III or above of CTCAE 4.0 )
Hair loss	5 (27.8%)	18 (95%)
Fever	0	2 (10.5%)
Intestinal obstruction	1 (5.6%)	0
Hematological damage
Anemia	0	12 (63.2%)
Thrombocytopenia	0	14 (73.7%)
Cardiac dysfunction	0	0
Hepatic dysfunction	0	0

Four-year Survival Analysis

The OS of 4-year follow-up was 100% in both groups. After initial treatment and maintenance treatment, the 4 -year EFS of the two groups was 94.4% in Group A and 89.5% in Group B, respectively (Figure 3), demonstrated good EFS. The main factor affecting EFS is the occurrence of diabetes insipidus. As shown in Table 6, Group A had one case (5.5%) of first-episode diabetes insipidus at follow-up, whereas Group B had two cases (10.5%), with the time of this event being 4.54, 18.64 and 20.25 months after treatment, respectively. These 3 patients were able to survive for a long time with little impact on their lives after endocrine replacement therapy. Both OS and EFS were superior to the two before mentioned classical protocols.

Treatment-related Adverse Effects

Based on CTCAE 4.0 or later, treatment-related adverse reactions of grade III and above that occurred with this protocol are demonstrated in Table 6. In Group A, there were few adverse reactions, and all of them could tolerate chemotherapy. One patient developed intestinal obstruction, and the related pharmacogenomics examination showed CEP72 TT mutation. The main adverse reactions in Group B were alopecia and non-lethal hematological toxicity.

On average, only 8% of pathological "Langerhans cells (LCs)" were found in LCH lesions, and the rest of the lesions consisted of multiple inflammatory infiltrates. Immunologically, diseased cells share certain features with resting epidermal LC, including high levels of CD207+ and CD1A+ expression, but also with features of activated LC, including expression of T- cell costimulatory molecules and proinflammatory cytokines. expression, thereby causing a "cytokine storm".^12,13,14,15LCH lesions are characterized by inflammatory disease.

At the same time, LCH lesions also have many classic features of malignant tumors.¹⁶ CD1a+ cells in LCH lesions were identified as clonally proliferating cells.¹⁷ The lesion site presents manifestations of malignancy-related mechanisms, such as tumor immune escape enriched in regulatory T cells, increased tumor pro-inflammatory cytokines that promote local and systemic inflammatory responses, and expression of metalloproteinases that promote invasion and metastasis ^18,19 and overexpression of BCL2L1.²⁰ The high mutation rate of BRAF-V600E in LCH lesions provides a favorable basis for classifying LCH as a neoplastic disease.¹³ In recent years, with the progress of research in genetics, ERK cell signaling pathway, etc., and the research on the disease mechanism of LCH, WHO classifies the disease as inflammatory myeloid tumor.¹⁵

LCH III⁴ and JLSG-96 protocol,⁵both applied the number of involved organs and the risk of involved organs as stratified treatment strategy, have achieved good results in the treatment of SS-LCH, but there is still an urgent need to improve the survival rate of MS-LCH. An interesting phenomenon was observed during the application of the above two regimens in the treatment of disease. When the disease is mainly manifested as inflammatory symptoms, such as systemic rash, multiple bone lesions, pus and exudate from the outer ear, long-term diarrhea, pneumonia, etc, even with MS involvement, the disease progresses slowly and the severity is lower. Once tumor symptoms appear, such as long-term fever, splenomegaly, anemia, thrombocytopenia, and mediastinal mass, even though there are fewer systems involved, the rash is mild, and the disease progresses rapidly, severe, and even fatal.

Based on the observed phenomena, we tried to group patients according to their symptoms. Adjustments were made in scoring systems, disease status assessments.⁹^,¹⁰ In the judgment of blood system involvement, in addition to the involvement of at least two lineages of cells, some patients continued to show simple anemia before or after treatment (excluding chemotherapy drugs and nutritional reasons) without leukopenia and thrombocytopenia, and they were still judged as blood system involvement. In the liver evaluation, the method of judging the liver size (liver subcostal distance) was discarded, and the Child-Pugh liver function evaluation method was used. In terms of bone damage consideration, not only the situation of special parts such as anterior bones, skull base bones, and vertebrae were considered, but also whether the affected bones are functional bones and load-bearing bones are used as evaluation factors in this protocol. The involvement of these bones can affect the patient's quality of life later, which is sometimes overlooked or recommended to be observed in previous classical protocols. Therapeutic replacement of new alkaloids (VBL, VCR) with less neurotoxic VDS and doxorubicin (ADR) with less cardiotoxic THP, the dose was reduced to 20 mg/m².

After stratification according to inflammatory or tumor symptoms, patients in the inflammatory symptom group, treated with VDS+PSL only, have achieved good long-term EFS without the addition of targeted agents, regardless of the presence of BRAF mutation. Only one patient with CEP72 TT mutation developed drug-related intestinal obstruction, which resolved within a short time after discontinuation of VDS. The patient was treated with reduced doses of VDS in the remaining phase of regimen without reoccurrence of intestinal obstruction. No significant adverse effects occurred in any of the remaining cases in Group A. his protocol demonstrates a treatment strategy with low chemotherapy toxicity, good tolerability, short hospitalization days and low cost.

Patients in the tumor symptom group, given intensive treatment with multiple drugs at the beginning, were able to control the disease progression rapidly, and all of them could reach NAD after 6 weeks of initial treatment, and then entered the maintenance phase of treatment, which also could achieve good long-term EFS. This protocol reduced the dose of anthracyclines, with a cumulative THP dose of only 160 mg/m², (compared to the cumulative ADR of 210 mg/m² in JLSG-96). Cardiac function and ECG were routinely monitored during the course of treatment, and no abnormalities were found. Most of the treatment-related adverse effects were alopecia and hematological toxicity. The majority of patients in Group B have reached grade 4 (CTCAE) hematologic toxicity in the third week of this regimen, at which point we effectively reduced the incidence of infectious complications by suspending treatment. After the neutrophil count returned to 0.5×10⁹/L or above, the regimen was continued.

The time of first-episode diabetes insipidus in Group A was significantly earlier than in Group B, approximately 1 year earlier. This may be related to the involvement of the skull base bones in this Group A patient, which needs to confirm by more cases, however, it reminds us that we should pay more attention to the urine volume and water intake of patients with skull base bones involvement during the follow-up. The event’s time of the 2 cases in Group B occurred after 18 months from treatment (i.e., 6 months after drug withdrawal), which may require us to consider whether a 1-year maintenance treatment is still inadequate and whether longer maintenance treatment would be more beneficial.

During the course of treatment, in both Group A and Group B, we found that liver symptoms such as hepatomegaly, elevated liver enzymes and elevated bilirubin would be present for a long period in some patients, but the liver function assessment remained at Grade A or B (according to Child-Pugh classification), which did not lead to disease progression and affect their long-term survival. Based on prior clinical experience, we have learned that glucocorticoid monotherapy or combined with low cytotoxic agents (e.g., VDS) can already significantly slow down the progression of biliary sclerosis without the intensive treatment with multiple drugs for purely hepatic symptoms. The above confirms the aforementioned interesting finding that when the disease is mainly manifested as inflammatory symptoms, except for either tumor symptoms, it will be slower progression, lower severity and less intensive treatment required, despite manifesting as MS or even combined dangerous organ involvement.

This study not only simplified the stratification method but also obtained promising clinical results by stratifying 37 cases of children with LCH and giving treatments corresponding to different intensities. It has proposed a new grouping method and corresponding treatment strategy, which may be a more suitable stratified treatment method for patients with LCH. This is a bold attempt and exploration of the methodology based on the in-depth practice of the classical program and the full integration of clinical experience. This study will continue to collect cases with the aim of ongoing refining and supplementing the protocol.

CTX: cyclophosphamide; EFS: event-free survival; JLSG: Japan LCH Study Group; LCH: Langerhans cell histiocytosis; MS: multisystem; NAD: non-active disease; OS: overall survival; PSL: methylprednisolone; RO: risk organ; SS: single system; THP: pirarubicin; VDS: vindesine.

Ethics approval and consent to participate

In accordance with the ethical standards of the Declaration of Helsinki, All study participants signed an informed consent was approved by the ethics committee of Guangzhou Women and Children’s Medical Center.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This research was sponsored by the National Key Research and Development Program of China(grant numbers 2022YFC2705003), National Natural Science Foundation of China (grant numbers 82100199) and Guangzhou Municipal Health Technology General Guidance Project (grant numbers 105208407058).

Authors' contributions

JW and HL co-designed the study, enrolled patients, analyzed results, wrote the manuscript and contributed to the data registration and statistical analysis; QZ, RH and XL enrolled patients and statistical analysis data. All authors revised the paper and approved the submitted version.

Acknowledgements

The authors would like thank our center's medical staff participating in the treatment of children with LCH for years, and leadership of our center for their support, encouragement and cultivation.

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Exploration of treatment in childhood Langerhans cell histiocytosis based on inflammatory and tumorous symptoms: A Pilot study

Status:

Version 1

Abstract

Figures

INTRODUCTION

MATERIALS AND METHODS

Patients

Grouping

Treatment Protocols

Evaluation Criteria

Statistical Analyses

RESULTS

DISCUSSION

CONCLUSIONS

Abbreviations

Declarations

References

Status:

Version 1