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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 249-254

Stem cell transplantation: A promising approach for pediatric patients with refractory multistage langerhans cell histiocytosis


1 Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh; College of Medicine, Taibah University, Madinah, Saudi Arabia

Date of Submission24-Nov-2020
Date of Decision23-Mar-2021
Date of Acceptance18-Jun-2021
Date of Web Publication18-Oct-2022

Correspondence Address:
Dr. Amal Alhejaili
Department of Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Center, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_223_20

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  Abstract 

BACKGROUND: Langerhans cell histiocytosis is a rare disorder leading to destruction of tissues as well as causing lesions in the body. LCH can be self-limiting to disseminated life threatening.
OBJECTIVES: We wanted to review data on presentation and outcome of our treatment efforts on patients with LCH diagnosed and treated at our institution.
MATERIAL AND METHODS: In this retrospective study involving 75 pediatric patients with LCH diagnosed between 1998 and 2018, we evaluated clinicopathological features, laboratory findings, treatment modalities and outcome.
RESULTS: In males median age at the time of diagnosis was 2.4 years. The median follow up was 63+/- 7.9 months. The most common presenting symptom was a bone lesion-related symptom. 57.3% were above 2 years of age at presentation while 38.7% below 2 years of age. 53% of cases had multisystem disease at diagnosis. Liver found to be most common organ involved. Treatment consisted of observation, surgery or chemotherapy. Vinblastine with steroid was the most common used chemotherapy regimen. 3 patients with progressive refractory disease underwent stem cell transplantation.
CONCLUSION: Overall survival was significantly lower in patients with liver involvement.

Keywords: Langerhans cell histiocytosis, pediatric, stem cell transplantation


How to cite this article:
AlFawaz I, Alhejaili A, Siddiqui K, Ayas M. Stem cell transplantation: A promising approach for pediatric patients with refractory multistage langerhans cell histiocytosis. J Appl Hematol 2022;13:249-54

How to cite this URL:
AlFawaz I, Alhejaili A, Siddiqui K, Ayas M. Stem cell transplantation: A promising approach for pediatric patients with refractory multistage langerhans cell histiocytosis. J Appl Hematol [serial online] 2022 [cited 2022 Dec 3];13:249-54. Available from: https://www.jahjournal.org/text.asp?2022/13/4/249/358707


  Introduction and Background Top


Historically, Thomas Smith published a case of 4½-year-old child with three large holes in the skull. These defects were thought initially to be congenital, but the published appearances of the skull lesions suggest Langerhans cell histiocytosis (LCH).[1] In 1973, the name LCH was introduced. This name was agreed upon to recognize the central role of the Langerhans cell.[2] LCH is a rare hematologic disorder that results from the clonal multiplication and accumulation of clonal CD1a+ CD207+ myeloid dendritic cells (histiocytes) amid an inflammatory background of macrophages, T-lymphocytes, and eosinophil cells that lead to the destruction of affected tissues.[3],[4],[5],[6] The clinical presentation of LCH is variable and challenging. Clinical presentation can be self-limited to disseminated life-threatening. The disease is divided into single system (SS, uni-or multi-focal) or multisystem (MS).[7] It can affect any system; LCH presented as genital lesions was reported in the literature.[8] Depending on the organs involved, patients are divided as high risk (lungs, liver, spleen, bone marrow) or as low risk (skin, bones, lymph nodes, gastrointestinal [GI] tract) that can be either unifocal or multifocal. There is a significant difference in mortality rates in the two risk groups. The organs most frequently affected were the skeleton (80%), the skin (33%), and the pituitary gland (25%).[9]

The diagnosis of LCH is based on the histologic and immunophenotypic examination of lesional tissue. The primary diagnostic feature is the morphologic identification of characteristic LCH cells. The inflammatory infiltrate contains various proportions of LCH cells, the disease hallmark, which are round and have characteristic “coffee-bean” cleaved nuclei and eosinophilic cytoplasm.[10] In addition, positive staining of the lesional cells with CD1a and/or langerin (CD207) is required for definitive diagnosis.[11]

According to the Histiocyte Society Risk Stratification which is published in 2009, SS may involve: bone: unifocal (single bone) or multifocal (>1 bone), skin, lymph node (not the draining lymph node of another LCH lesion), lungs, hypothalamic–pituitary/central nervous system, and others (e.g., thyroid, thymus). Approximately 65% of the patients have SS disease.[12],[13]

Current treatment of LCH includes topical steroids as the first-line treatment for localized disease of skin and bone. For multifocal SS or MS disease, systemic treatment with steroids and vinblastine for 12 months is the standard first-line regimen. Current researches are seeking more effective regimens because recurrence rates, which increase the risk of sequelae, are still high (30%–50%) in patients with MS disease.[10] An initial 6-week course of therapy with vinblastine and prednisone is suggested for all patients with MS-LCH, regardless of risk organ involvement. It is also recommended that all patients who have complete disease resolution after 6–12 weeks of initial therapy continue with maintenance therapy. Maintenance therapy consists of pulses of vinblastine and prednisone every 3 weeks and daily continuous 6-mercaptopurine for a total treatment duration of 12 months. It is recommended that patients who continue to experience involvement of risk organs after initial course 2 (12 weeks of therapy) are switched to salvage therapy. It is also recommended that patients without risk organ involvement who do not demonstrate improvement after course 2 be administered another course of therapy with alternative drugs. Salvage therapy options for high-risk patients include combined regimen of 2-chlorodeoxyadenosine (cladribine, leustatin) and cytarabine (Ara-C), as well as stem cell transplantation (SCT) after reduced-intensity conditioning regimen (RIC-SCT).[14],[15]

The prognosis for LCH varies. It depends on the form of the disease (SS-LCH vs. MS-LCH) as well as its location and response to chemotherapy. In unifocal LCH, the prognosis is good. There have been cases of spontaneous remission or symptoms subsiding after local treatment. In forms with multifocal bone involvement, relapses of the disease occur more often. The prognosis worsens significantly with the involvement of “risk organs” and the GI tract.[16],[17] Spontaneous regression of MS disease is rare but had been reported.[18]

In Saudi Arabia, the previous publications about LCH were case reports mainly. Moreover, there is only one pervious retrospective analytic review which was published in 1991 and included 21 pediatric patients with LCH. Overall disease-free survival was 84.2%.[19]

We report clinical presentation, treatment, and the outcome of the treatment for pediatric patients with LCH presenting at King Faisal Specialist Hospital and Research Center (KFSHRC) from 1998 to 2018.


  Methods Top


The medical records of 75 patients with LCH under 14 years of age diagnosed at KFSHRC, Riyadh, were identified. Data pertaining to the patients' clinical presentation, diagnostic interventions, pathological features, the disease (system involvement and risk stratification) treatment plan, and outcome were collected in a case report form. Complete blood count, hepatorenal profile, serum electrolytes, ferritin, total bilirubin, coagulation profile, and urine osmolality were checked in all patients. Bone marrow aspirate and biopsy studies were reviewed. The radiological studies regarding chest X-ray and skeletal survey, ultrasonography, computerized tomography, magnetic resonance imaging, and positron emission tomography were reviewed to evaluate the extent of disease. Clinical classification was based on the site and extent of the disease at the time of diagnosis; patient with one organ or system involved (unifocal or multifocal) will classified as SS and MS if more than one organ involved. Risk stratification was done according to organ involvement; patients are divided as high risk (lungs, liver, spleen, and bone marrow) or as low risk (skin, bones, lymph nodes, and GI tract). Organ dysfunction (liver, lung, and/or bone marrow) was diagnosed based on the criteria by Lahey. Hematological system dysfunction was defined as hemoglobin level below 10 g/dL and/or platelet count <100 × 109/L and/or total leukocyte count <4 × 109/L. Respiratory dysfunction was defined as a case of respiratory distress and/or interstitial infiltration on chest X-ray. Liver dysfunction was defined as hypoproteinemia (<5.5 g/dL), hypoalbuminemia (<2.5 g/dL), and/or prolongation of partial thromboplastin time (>40 s) and prothrombin time (>15 s or international normalized ratio >1.5) and/or hyperbilirubinemia (>1.5 mg/dL) and/or elevation in liver enzymes (alanine aminotransferase >40 IU/L, aspartate aminotransferase >33 IU/L). Further, hepatosplenomegaly was accepted as liver involvement.[20] Treatment included observation, local steroid therapy, chemotherapy, surgical excision of the lesion, or a combination of these modalities. Depending on the year of diagnosis, patients were treated by different ways of therapy before 1996 and by LCH-II protocol between 1996 and 2004 and LCH-III protocol after 2004.[21],[22] Assessment of disease state after completion of therapy was defined as no evidence of active disease if there is resolution of signs and symptoms; improved (regressive disease) if there is a regression of signs or symptom with no new lesions; persistent (stable) disease if there is a persistence of signs or symptoms with no new lesions; progressive disease if there is a progression of signs or symptoms and/or appearance of new lesions.

Statistical considerations

All nonnormal continuous data are presented as median with minimum and maximum points, while discrete data are provided as n (%). Kaplan–Meier survival curves were drawn to test for the significance of OS times between different groups using Breslow (generalized Wilcoxon) test. All P < 0.05 was considered statistically significant. OS was calculated from diagnosis to death or last visit. Event-free survival was calculated from diagnosis to death, progression of the disease, or recurrence, whichever came first, or last visit (censored). Comparison between the patient groups was made by log-rank test. All statistical analyses were conducted using IBM SPSS Statistics release 20.0 after data cleaning and quality assurance triggered by extreme and missing values.


  Results Top


Data of 75 patients with LCH diagnosed at KFSH, Riyadh, between January 1998 and December 2018 were reviewed. The median follow-up time was 63 ± 7.9 months with 95% confidence interval of 47.9–78.8 months. Boys represented 70.7% (n = 53) of the overall population, while girls represented 29.3% (n = 22). Median age at diagnosis was 2.4 years; 3.5 years in boys and 2.1 years in girls (P = 000 and 0.001, respectively). 57.3% (n = 43) were above 2 years of age at presentation, while 38.7% (n = 29) below 2 years of age. The most common symptom at presentation was a bone lesion-related symptom in 63 patients (84%) and then skin manifestations in 25 patients (33.3%). Most common bone manifestation is painful swelling in 70.7% (n = 53). Most common skin manifestations were scalp rash in 26.7% (n = 22) and then groin rash in 12% (n = 16). 73 (96%) had a histological diagnosis of LCH based on characteristics histological appearance of LCH lesions on hematoxylin and eosin and positive immunohistochemical staining with CD1a and/or S-100. Stage at presentation was SS in 35 patients (46.7%); 60% and 40% were unifocal and multifocal disease, respectively. While MS involvement at diagnosis was in 40 patients (53%); 48.9% and 51.1% had low risk and high risk, respectively. Liver was the most common organ involved in 17% (n = 13) followed by spleen 16% (n = 12) and then bone marrow in 14.7% (n = 11). The clinical and demographic characteristics of patients with LCH are listed in [Table 1].
Table 1: The clinical and demographic characteristics of patients with Langerhans cell histiocytosis

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Observation only was the option for only 9 patients (12.3%). Surgical excision was done for 6 patients (8.2%). Steroids with vinbalstine were given in 58 patients (79.5%) which was the most commonly used combination. Twenty-eight patients (38.3%) with SS disease out of 33 responded to the first line of therapy compared to 12 (17.8%) out of 40 patients with MS disease. Seventeen patients (23.2%) out of 40 with MS disease showed persistent and progressive disease compared to 4 (5.4%) patients out of 30 with SS. Relapse was more in MS group (12.3%) compared to in SS (1.4%).

Seventeen patients (23.3%) were positive for relapse. Thirteen patients (17.8%) showed progressive disease. The median relapse/progression-free survival time is 103.6 months. Relapse/progression-free survival is 49.5% ±7.8%. Forty-two patients were negative for relapse.

Relapse was more in the MS group (12.3%) compared to SS (1.4%). In our cohort; three patients underwent SCT. One patient diagnosed at the age of 2 years with progressive MS-LCH; SCT was done with reduced-intensity chemotherapy (REC). He had veno-occlusive disease of liver and cytomegalovirus antegenemia. He showed zero engraftment. Second patient was diagnosed with disseminated refractory LCH of liver, spleen, lung, and bone and he underwent allogeneic SCT with REC conditioning when he was 3 years of age. He suffered from multiple post-transplant complications, skin graft-versus-host disease, and multiple bacterial infections. He engrafted and was doing fine on follow-up. Third patient was 3 months old at diagnosis with MS-LCH of skin and bone and then she relapsed. She underwent autologous SCT, and she is doing fine on follow-up.

The overall survival (OS) in our cohort of the patients was observed to be 95.2%±2.7%.


  Discussion Top


Few single-center retrospective review studies of LCH in children have been published.[18] Our single-center review represented the experience of 20 years and includes 75 patients which put us in the fifth order among world regarding single-center publications after Yağcı et al. which includes 217 patients, Dhar et al. which includes 126 cases, Braier et al. with 123 cases, and Tuysuz et al. with 80 patients. However, we are the largest study among Arab area countries about pediatric LCH.[23],[24],[25] LCH is thought to be a nonhereditary disease. In our cohort, there was no familial predisposition as there was no positive family history of LCH. The median age at presentation was between 1 and 3 years with male predominance in line with most international publications. Median age at diagnosis was 2.4 years; 3.5 years in boys and 2.1 years in girls. Bone-related symptoms, especially painful swelling, are the most common presenting symptoms followed by skin-related symptoms in both age groups, i.e., below and above 2 years of age similar to most of articles, although in Dhar et al. the skin manifestation is the most common presenting symptom below 1 year of age.[26] We observed that the most commonly involved bones were skull bones, humerus, femur, and vertebrae. Similar percentages of bone involvement were previously reported.[25] Skin lesions range from single lesion to extensive scaly rash and icthyosis erythroderma. We found that one female patient presented with a single labia majora papule and other infant had whitish oral lesions.

Surprisingly, we found that the MS involvement at diagnosis was 53% (n = 40) compared to single system which represents 46.7% (n = 35).

In terms of organ involvement our results were similar to what has been published in the literature; in Braier et al.'s review, 18% of cases with MS disease have liver involvement; and in Yi et al.'s study, 45% of organ involvement was in liver.[23],[27] Liver involvement includes hepatic dysfunction (increased liver enzymes or albumin 3 times above upper limit of normal/hepatomegaly/secondary ascites/clotting factors abnormalities). Liver involvement is a known prognostic factor in LCH.[18] 46.7% (n = 7) of patients with hepatic involvement had progressive disease while only 20% (n = 3) resolved (P = 0.002). We found that all three patients died had a hepatic involvement (P = 0.007). OS of the patients with liver involvement was significantly lower than those without liver involvement (73.3%±13.2% vs. 100%, P < 0.001) [Figure 1].
Figure 1: Kaplan–Meier curve of overall survival of patients with liver involvement

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Diabetes insipidus was found in 22.7% (n = 17) which is similar to what had been reported in Broadbent et al. (24%).[1] A wide variety of treatment modalities were used in our study. Two patients were discharged against medical advice as their families refused to seek any treatment. Observation Only was the treatment of choice for nine patients (12.3%) and the surgery in six (8.2%). We observed excellent outcome (OS=100%) in both of these sub-groups. Steroids with vinblastine were given in 58 patients (79.5%) which was the most commonly used combination. Four patients received VP-16 etoposide before 2004. OS for patients who received VP-16 found to be 50% [Figure 2].
Figure 2: Overall survival of patients with different chemotherapy regimen

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Twenty-eight patients (38.3%) with SS disease out of 33 responded to the first line of therapy compared to 12 (17.8%) out of 40 patients with MS disease. 17 (23.2%) patients out of 40 with MS disease showed persistent and progressive disease compared to 4 (5.4%) patients out of 30 with SS.

Relapse was observed in 23.3%. The median relapse/progression-free survival time is 103.6 months. Relapse/progression-free survival is 49.5% ±7.8%.

Relapse was more in the MS group (12.3%) compared to SS (1.4%). OS in the SS group was 100% while 92.5% in the MS group (P = 0.1) [Figure 3].
Figure 3: Overall survival curve for patients according to the stage at diagnosis

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The survival rate has been improved to 75% after 2000 compared to 28% before 2000.[28]

SCT showed encouraging results with 100% 5-year OS in the 3 of our patients with refractory LCH in both autologous SCT and SCT with RIC. It was published that the 3-year OS of patients who received SCT with RIC regimen was 78%.[14] Autologous SCT is showing inferiority of outcome, but in our experience, the prognosis was excellent.[29]


  Conclusion Top


In Saudi Arabia, LCH has similar presentation to other parts of world. Our study shows favorable disease course in patients with SS-LCH. Those with MS disease, however, are more likely to have progressive/refractory disease. Liver involvement remains one of the strong prognostic factors. SCT is a promising approach for patients with refractory MS-LCH.

Ethical approval

This study was submitted to the Institutional Review Board of KFSHRC, Riyadh, Saudi Arabia, and was approved by the Research Advisory Committee through established procedures with Approval Number 2191006.

Informed consent

Data of interest collected from the patients' medical records were secured as governed by the institutional policies on patient confidentiality and privacy. No informed consents were obtained since this was a retrospective review of data and all data items collected were already documented in medical charts as part of the patients care and disease management documentation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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