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Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis
Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study
Article first published online: 27 JUN 2006
Copyright © 2006 American Cancer Society
Volume 107, Issue 3, pages 613–619, 1 August 2006
How to Cite
Morimoto, A., Ikushima, S., Kinugawa, N., Ishii, E., Kohdera, U., Sako, M., Fujimoto, J., Bessho, F., Horibe, K., Tsunematsu, Y., Imashuku, S. and for the Japan Langerhans Cell Histiocytosis Study Group (2006), Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis. Cancer, 107: 613–619. doi: 10.1002/cncr.21985
- Issue published online: 18 JUL 2006
- Article first published online: 27 JUN 2006
- Manuscript Accepted: 2 MAR 2006
- Manuscript Revised: 27 FEB 2006
- Manuscript Received: 12 JAN 2006
- Langerhans cell histiocytosis;
The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group-96 (JLSG-96) protocol was conducted prospectively from 1996 to 2001 in Japan.
Newly diagnosed children with multifocal LCH were classified into 2 groups: a single-system multisite (SS-m) group and a multisystem (MS) group. All patients initially were treated on Protocol A, which consisted of 6 weeks of induction therapy with combined cytosine arabinoside, vincristine (VCR), and prednisolone (PSL) followed by 6 months of maintenance therapy. Patients who had a poor response to the induction of Protocol A were switched to a salvage regimen (Protocol B), which consisted of an intensive combination of doxorubicin, cyclophosphamide, VCR, and PSL.
In total, 91 patients were treated, including 32 patients in the SS-m group and 59 patients in the MS group. At the median 5-year follow-up, 96.9% of patients in the SS-m group and 78.0% of patients in the MS group had good response status. Diabetes insipidus developed in 3.1% of patients in the SS-m group and in 8.9% of patients in the MS group. The overall survival rate at 5 years for the SS-m and MS groups was 100% and 94.4% ± 3.2%, respectively.
The JLSG-96 protocol attained very low mortality for pediatric patients with multifocal LCH. Cancer 2006. © 2006 American Cancer Society.
Langerhans cell histiocytosis (LCH) occurs primarily in childhood and is a rare clonal disorder of Langerhans cell proliferation, which is among the antigen-presenting cells that originate in bone marrow.1 LCH develops as unifocal lesions (28%) or multifocal lesions (72%) at various sites, such as bone, skin, lymph nodes, liver/spleen, thymus, central nervous system (CNS), etc.2 Multifocal LCH lesions occur as a single-system multisite (SS-m) type or as a multisystem (MS) type.
LCH can be managed by observation or local therapy in patients who have unifocal LCH with generally excellent outcomes; however, systemic chemotherapy is required for patients who have multifocal LCH lesions, which includes corticosteroids, vinblastine (VBL), vincristine (VCR), etoposide (VP-16), 6-mercaptopurine (6-MP), methotrexate (MTX), cytosine arabinoside (Ara-C), or a combination of these drugs.3 In the literature, 5 reports are available that deal with therapeutic trials (treatment studies) in >50 patients with LCH who had multifocal disease.4 In those studies, the median survival rate was 80% (range, from 71% to 93%),5–9 and the median survival rate among patients who had organ dysfunction was especially low (from 34% to 62%) in 3 early reports.5–7 Furthermore, a retrospective epidemiologic survey that was performed in Japan from 1986 to 19902 revealed that nearly 20% of patients with multifocal LCH died. These results clearly indicate the need for better clinical trials. However, the optimal drug treatment combination and the optimum length of the treatment remain to be determined. In particular, low induction rates and high recurrence rates after initial treatment are associated with a poor prognosis in patients with multifocal LCH.8, 9 In addition, late sequelae, such as diabetes insipidus (DI), orthopedic complications, CNS disorders, or secondary leukemia associated with VP-16, also become major problems during or after systemic chemotherapy.10–12
To overcome these unfavorable and unsatisfactory treatment results in pediatric patients with multifocal LCH, the Japan LCH Study Group (JLSG) conducted a prospective, multicenter cooperative protocol (JLSG-96) for these patients in Japan. The protocol confirmed that the outcome of pediatric patients with multifocal LCH can be improved by treatment with multidrug, intensified chemotherapy.
MATERIALS AND METHODS
In total, 96 Japanese children of age <15 years with newly diagnosed, multifocal LCH were registered consecutively for treatment on the JLSG-96 protocol between 1996 and 2001. Diagnoses were confirmed by histopathologic findings in affected organs, which were positive for either S-100, or CD1a antigen, or both. The patients were divided into 2 an SS-m group and an MS group. The SS-m type was defined as multiple affected lesions in only a single organ, and the MS type was defined as multiple affected lesions in several organs. Bone lesion(s) accompanied by adjacent soft tissue were defined as a single organ. Risk organ involvement was defined as follows: for the liver/spleen, hepatomegaly or splenomegaly judged on clinical findings (≥3 cm under the costal margin) with or without functional impairment; for the lungs, the presence of characteristic findings on a chest computed tomography (CT) scan with or without respiratory symptoms; and, for the hematopoietic system, the presence of cytopenia in the peripheral blood (as defined by Lahey13) with or without bone marrow changes.
Of 96 registered patients, 5 patients were excluded because of protocol violations (2 patients), misdiagnosis (1 patient), missing follow-up data (1 patient), or death before the initiation of treatment (1 patient); thus, 91 patients were eligible for the study, including 32 patients with SS-m type lesions (SS-m group) and 59 patients with MS type lesions (MS group). Characteristics of these 91 patients are shown in Table 1. The median age at diagnosis was 2.3 years in the SS-m group and 10 months in the MS group. In the SS-m group, 29 patients (93.5%) had bone lesions, 2 patients had lymph node lesions, and 1 patient had skin lesions. In the MS group, skin was the most commonly involved organ in 48 patients (81.4%), followed by bone in 39 patients (66.1%). Three patients (5.1%) had DI at diagnosis. Two-thirds of patients (69.5%) in the MS group had risk organ involvement. The patients were followed for a median of 5 years (range, 2.8–8.4 years).
|Characteristic||SS-m group||MS group|
|No. of patients||32||59|
|Age at diagnosis, y|
|Involved organs (no. of patients)|
|No. of patients with risk organ involvement (%)||0||41 (69.5)|
All patients were treated initially on Induction Arm A, which consisted of a 6-week treatment with combined Ara-C, VCR, and prednisolone (PSL) followed by 6 months on the Maintenance Arm A regimen (combined Ara-C, VCR, PSL, MTX, and PSL) for a total treatment duration of 30 weeks (Table 2). The patients who demonstrated a poor response in Induction Arm A were switched to a salvage regimen, Induction Arm B, which consisted of a 6-week, intensive combination of combined doxorubicin (ADR), cyclophosphamide (CPM), VCR, and PSL followed by 6 months on the Maintenance Arm B regimen (alternating between combined ADR, VCR, PSL, combined MTX, PSL and combined CPM, VCR, PSL every 2 weeks). For patients who were switched to Arm B, the total duration of therapy was 36 weeks, and the cumulative dose of ADR was set at 210 mg/m2.
|Protocol A (induction and maintenance therapy for newly diagnosed patients)|
|Induction Arm A|
|Ara-C, VCR, and PSL (AraVP)|
|Ara-C (100 mg/m2 per day as a 6-h drip) on Days 1–5|
|VCR (0.05mg/kg per day IV) on Day1|
|PSL (2 mg/kg per day orally) on Days 1–5|
|Every 2 wk × 3 courses|
|Maintenance Arm A|
|Ara-C (150 mg/m2 per d as a 2-h drip) on Day 1|
|VCR (0.05mg/kg per d IV) on Day1|
|PSL (2 mg/kg per d orally) on Days 1–4|
|b) MTX and PSL|
|MTX (1 mg/kg per d IV) on Day1|
|PSL (2 mg/kg per d orally) on Days 1–3|
|Alternate every 2 wk (a,b,a,b) for 6 mo|
|Protocol B (salvage therapy for poor responders to Induction Arm A)|
|Induction Arm B|
|ADR, CPM, VCR, and PSL|
|ADR (35 mg/m2 per d IV) on Day 1|
|CPM (10 mg/kg per d IV) on Days 1–5|
|VCR (0.05 mg/kg per d IV) on Day 1|
|PSL (2 mg/kg per d orally) on Days 1–5|
|Every 2 wk × 3 courses|
|Maintenance Arm B|
|a) ADR, VCR, and PSL|
|ADR (35 mg/m2 per d IV) on Day 1|
|VCR (0.05 mg/kg per d IV) on Day1|
|PSL (2 mg/kg per d orally) on Days 1–5|
|b) MTX and PSL|
|MTX (3 mg/kg per d as a 1-h drip) on Day1|
|PSL (2 mg/kg per d orally) on Days 1–3|
|c) CPM, VCR, and PSL|
|CPM (10 mg/kg per d IV) on Day 1|
|VCR (0.05 mg/kg per d IV) on Day1|
|PSL (2 mg/kg per d orally) on Days 1–5|
|Alternate every 2 wk (a,b,c,b,a,b,c,b) for 6 mo|
Treatment response was evaluated 6 weeks after the start of induction therapy in all patients. A good response (GR) at the 6-week evaluation was defined as the disappearance of signs or symptoms of disease except for radiologic findings of bone lesions (because the complete resolution of bone lesions at this point is not possible), a partial response (PR) was defined as regression >50% of signs or symptoms of disease without organ dysfunction and new lesions, a nonresponse (NR) was defined as regression <50% of signs or symptoms of disease with or without organ dysfunction and the absence of new lesions, and progressive disease (PD) was defined as progression in the signs or symptoms of disease and/or the appearance of new lesions. A GR and a PR to the Induction Arm A regimen were considered responses, and a NR and a PD were considered poor responses. A physician-in-chief at each institute evaluated the treatment response according to the protocol definition. However, when the evaluator had difficulty, the chairman of the study center (S.I.) was consulted to make a final determination. Reactivation was defined as the appearance of new lesions or enlargement of old lesions. At the end of Maintenance Arm A or Arm B therapy, patients were classified with an insufficient response if they did not obtain a GR. Events were defined at the time points of poor response to induction therapy, insufficient response, reactivation, secondary malignancy, and death.
Event-free survival (EFS) and overall survival (OS) were estimated by using Kaplan–Meier analysis, with the results presented as rates (%) ± standard error, and risk factors were compared by using the log-rank test. To compare prognoses between patients with or without risk organ involvement, the Fisher exact test was employed. P < .05 was considered statistically significant.
Treatment outcomes for patients in the SS-m group are shown in Figure 1. A GR was obtained with the Induction Arm A regimen in all but 1 patient (96.9%). This exceptional patient, who had NR, attained a GR with the Induction Arm B regimen. Two patients had reactivation during Maintenance Arm A treatment, and 7 patients had reactivation off therapy. The 5-year OS rate was 100%, and the 5-year EFS rate was 68.5% ± 8.3% in patients who received the Arm A protocol alone and 71.6% ± 8.0% in patients who received the Arm A and Arm B protocols combined (Fig. 2).
Treatment outcomes for patients in the MS group are shown in Figure 3. Forty-five of 59 patients (76.3%) had a GR/PR with the Induction Arm A regimen. Among those 45 patients, 8 patients were switched to other treatment regimens at the end of or before the completion of Maintenance Arm A treatment because of reactivation or insufficient response, whereas 37 patients (62.7%) attained a GR at the end of Maintenance Arm A treatment. Finally, 17 patients (28.8%) maintained a GR, whereas the remaining 20 patients had reactivation off therapy. Among those 20 patients, the time from the initiation of treatment to first reactivation ranged from 9 months to 30 months (median, 13 months), the number of reactivations ranged from 1 to 4 (median, 1.5 reactivations), and the most frequently reactivated organ was bone (55%), followed by skin (45%), and pituitary gland (25%). The Induction Arm B regimen was employed as treatment for the majority of these patients. Table 3 shows that, in 14 poor responders to the Induction Arm A regimen, 9 patients (64.3%) subsequently had a GR/PR to the Induction Arm B regimen. Among those 9 patients, 3 patients had reactivation or insufficient response during Maintenance Arm B, and 6 patients attained and maintained a GR. Of the 5 patients who did not respond even to the Induction Arm B regimen, 2 patients were rescued with cord blood stem cell transplantation, and 3 patients received treatment with alternative combination chemotherapy, including 1 patient who was rescued and 2 patients who died of disease. Taken together, a GR at any point of the clinical course was documented in 53 patients (89.8%) in the MS group. Among those 53 patients, 24 patients (45.3%) experienced ≥1 episode of reactivation. The 5-year OS rate was 94.4% ± 3.2%, and the 5-year EFS rate was 28.8% ± 5.9% in patients who received the Arm A protocol alone and 39.0% ± 6.3% in patients who received the Arm A and Arm B protocols combined (Fig. 4). In patients who had risk organ involvement, the initial response rate to Induction Arm A and the incidence of attaining a GR were low compared with patients who did not have risk organ involvement (response to Induction Arm A: 28 of 41 patients vs. 17 of 18 patients, respectively; P = .044; GR: 35 of 41 patients vs. 18 of 18 patients, respectively; P = .16). However, the 5-year OS rate and the incidence of reactivation or DI were similar between the patients with and without risk organ involvement (91.6% ± 4.7% vs. 100%, respectively; 14 of 35 patients vs. 10 of 18 patients, respectively, and 3 of 41 patients vs. 3 of 18 patients, respectively), whereas 5-year OS rate was relatively better for responders than for poor responders to the Induction Arm A regimen (97.1% ± 2.9% vs. 85.7% ± 9.4%, respectively; P = .065).
|Patient no.||Age, Years||Involved organs*||Response to induction B||Response to maintenance B||Further treatment and response||Outcome and survival, months|
|117||0.4||S, LN, L/S, Lu, H||PD||—||VBL/VP-16/PSL (PD)||D (5)|
|64||0.8||L/S, H||PD||—||CBSCT (GR)||A (≥66)|
|49||1.1||S, B, LN, L/S, H||NR||—||CSA/ADR/CPM/VCR/PSL (PD)||D (8)|
|46||0.3||S, Lu,||NR||—||VBL/ADR/VP-16/PSL (GR)||A (≥77)|
|116||0.5||S, B, LN, T, L/S, Lu, H||NR||—||CBSCT (GR)||A (≥41)|
|70||0.8||S, B, H||PR||Insuf||VBL/MTX/6MP/PSL (PR)||A (≥64)|
|90||5.2||T, Lu||PR||React||VBL/MTX/6MP/PSL (PR)||A (≥59)|
|93||2.0||S, L/S, H||PR||React||VBL/MTX/6MP/PSL (GR)||A (≥64)|
|45||0.3||S, B, LN, Lu,||PR||GR||—||A (≥77)|
|91||0.3||S, B, Lu||PR||GR||—||A (≥61)|
|51||0.7||S, B, LN, L/S, H||GR||GR||—||A (≥74)|
|107||15.0||B, LN||GR||GR||—||A (≥45)|
|122||2.3||S, B, Lu, H||GR||GR||—||A (≥38)|
|126||2.2||S, B, Lu, H||GR||GR||—||A (≥37)|
In the current study, no patients developed serious treatment-related toxicity that required discontinuation of the protocol, and no patients developed secondary malignancies. At the last follow-up, 31 of 32 patients in the SS-m group (96.9%) were classified with a GR, and the remaining patient was classified with stable but active disease off therapy. Conversely, 46 of 59 patients in the MS group (78.0%) were classified with a GR, 10 patients (16.9%) were classified with stable but active disease (3 patients on therapy and 7 patients off therapy), and the remaining 3 patients (5.1%) died of progressive disease. Two of those deaths occurred in patients who were poor responders to the Induction Arm A regimen (see Table 3, Patients 117 and 49). The remaining patient, who was age 8 months and had hematologic involvement at onset, initially had a GR to the Induction Arm A regimen and then had reactivation to bone 2.4 years after onset. Although he was treated with the Induction Arm B regimen, he died of multiple organ failure in association with subsequent hematologic and hepatic involvement. DI developed as long-term sequelae after diagnosis in 1 patient (3.1%) in the SS-m group and in 5 patients (8.9%) in the MS group. In total, DI was noted in 9 of 91 patients (9.9%), including 1 patient in the SS-m group and 8 patients in the MS group. Degenerative CNS disease developed in 3 patients, including 1 patient in the SS-m group and 2 patients in the MS group. Details on these patients were published previously.14
Our therapeutic results appear to be comparable to those from 2 protocol studies in pediatric patients with LCH that were published previously: the Deutsche Arbeitsgemeinschaft für Leukaemieforschung Histocytosis X (DAL-HX)-83/90 protocol study and the LCH-I protocol study. The former was a nonrandomized protocol in which patients who had single-system and multisystem LCH received combined VBL, VP-16, and PSL for 12 months,8, 15 and the latter was a 6-month randomized study in patients who had multisystem LCH that compared the efficacy of VBL and VP-16.9 The intensity of the induction therapy regimen was greater in the DAL-HX study than in the LCH-I study. To our knowledge, the JLSG-96 study is the first prospective, nonrandomized clinical trial in Japan for pediatric patients with multifocal LCH. This trial consisted 7.5 months of treatment on an induction regimen of combined Ara-C, VCR, and PSL, which was used previously in a Dutch study,16 in association with a combination of ADR, CPM, VCR, and PSL as the salvage regimen. We chose these drug combinations, because we expected to obtain better response rates by avoiding VP-16, which is associated with a potential leukemogenic adverse effect. The disease extent categories and response criteria that were used for analysis in the current study were almost identical to those used in the 2 studies described above.8, 9
The outcomes of out patients in the SS-m who were treated on the JLSG-96 protocol were comparable to the results achieved in the DAL-HX study (Table 4).15 The initial response rates and the incidence of developing DI after diagnosis were similar in both studies. None of the patients who had multifocal bone disease died. However, the reactivation rates were relatively higher in our JLSG-96 study than in the DAL-HX study (28.1% vs. 17.6%, respectively), which may be associated with the shorter treatment duration in our study (7.5 months vs. 12 months, respectively). In our study, 7 of 29 patients (24.1%) had reactivations, mostly occurring within 6 months off therapy (Fig. 2). Because of the high reactivation rates, our most recent protocol (JLSG-02) employs a longer treatment duration of 1 year.
|Variable||SS-m group||MS group|
|No. of patients||34||32||63||143||59|
|Median age at diagnosis, y||3.9||2.3||0.9||1.5||0.9|
|Duration of therapy, mo||12||7.5||12||6||7.5|
|Initial response rate (%)†||94.1||96.9||79.4||53.1||76.3|
|Reactivation after CR (%)‡||17.6||28.1||30.0||50.0||45.3|
|Status at last follow-up (%)|
|Developed DI after diagnosis (%)||2.9||3.1||11.9||14.2||8.9|
|Secondary malignancy (%)||0||0||0||1.4||0|
|Follow-up (median years)||8.7||5.2||7.5||4.9||5.0|
Conversely, the outcomes among patients in our MS group who were treated on JLSG-96 were comparable with both the DAL-HX study8 and the LCH-I study9 (Table 4). The rates of initial response and a GR status at last follow-up in our study were as high as those rates in the DAL-HX study but were better than those rates in the LCH-I study. The incidence of developing DI after diagnosis was approximately 10% in all 3 studies. However, the mortality rate (5.1%) was significantly lower in our study compared with the rates in the DAL-HX and the LCH-I studies (approximately 20%), which were similar to the historic Japanese data.2
The lower mortality rate in our study cannot be explained by a greater proportion of low-risk patients, because the majority of patients in our study were younger (median age, 0.9 years) than patients in the other studies and had risk organ involvement. When the outcomes of patients who had risk organ involvement were analyzed, initial response rates to Induction Arm A and the incidence of attaining a GR were low, but the survival rate was similar to that of the patients without risk organ involvement, indicating that these high-risk patients subsequently were rescued by salvage therapy in our study.
Response to the initial 6 weeks of therapy reportedly is an important indicator of survival,9, 17 and >90% of responders by 6 weeks survived in all 3 studies, whereas most of the patients who died were poor responders at 6 weeks (9 of 12 patients in the DAL-HX study, 24 of 29 patients in the LCH-1 study, and 2 of 3 patients in the current JLSG-96 study). Increasing the response rate at the induction of treatment and the prompt rescue of poor responders to initial therapy are imperative to improve therapeutic results for pediatric patients with multifocal LCH. We applied our Arm B protocol—a salvage regimen—for such poor responders. This rescue protocol resulted in the survival of 12 of 14 poor responders (85.7%) in our JLSG-96 study. In contrast, 30.8% and 64.2% of poor responders survived in the DAL-HX and LCH-I studies, respectively. Thus, our very low mortality rates appear to result at least in part from the high response rates to the Induction Arm A regimen and the high rescue rates with the Arm B regimen.
Some aspects of our the current results were unsatisfactory, namely, the low EFS rate (<40%) and the high reactivation rate (45.3%) in the MS group. To improve the quality of life for pediatric patients with LCH, we have modified our treatment protocol. Our ongoing protocol (JLSG-02) has been revised as follows; first, we have increased the initial dosage of PSL (2 mg/kg per day continuously for 4 weeks) from that in the JLSG-96 protocol (2 mg/kg per day for 5 days every 2 weeks); second, we added cyclosporine A to the Arm B Induction regimen for patients with PD; and third, we extended the treatment duration from 7.5 months to 1 year. Because rescuing patients with PD who have MS-type LCH is crucial for improving their survival rate, experimental trials that include more aggressive therapy, such as combination chemotherapy with 2-chlorodeoxyadenosine and high-dose Ara-C18 or hematopoietic stem cell transplantation with myeloablative or reduced intensity conditionings,19, 20 must be carried out carefully. These therapies should be incorporated into future protocols for patients with refractory and progressive LCH in well designed, large-scale clinical studies.
The authors thank the many physicians who participated in the Japan Langerhans Cell Histiocytosis Study Group-96 study, Professor Tohru Sugimoto for promoting their research activities, and Yasuko Hashimoto for her excellent secretarial assistance.
- 2Langerhans cell histiocytosis and hemophagocytic syndrome in Japan; epidemiological studies. Int J Pediatr Hematol Oncol. 1994; 1: 241–246., , , .
- 4Langerhans cell histiocytosis: a clinical update. In: WeitzmanS, EgelerRM, editors. Histiocytic Disorders of Children and Adults; Basic Science, Clinical Features and Therapy. Cambridge: Cambridge University Press; 2005: 95–129., , .