Int J Hematol DOI 10.1007/s12185-015-1778-0
CASE REPORT
Successful treatment of adult Langerhans cell histiocytosis with intensified chemotherapy Mariko Minami1 · Takahiro Shima1 · Koji Kato1 · Hidetaka Yamamoto2 · Kenji Tsuchihashi1 · Seido Oku1 · Tomonori Shimokawa1 · Taro Tochigi1 · Goichi Yoshimoto1 · Kenjiro Kamezaki1 · Katsuto Takenaka3 · Hiromi Iwasaki3 · Yoshinao Oda2 · Toshihiro Miyamoto1 · Koichi Akashi1,3
Received: 22 October 2014 / Revised: 1 March 2015 / Accepted: 2 March 2015 © The Japanese Society of Hematology 2015
Abstract Langerhans cell histiocytosis (LCH) is a rare disease in adults. The treatment strategy for this condition remains controversial. Intensified systemic chemotherapy is required in pediatric patients with the multiple system form of LCH (MS-LCH) for aggressive forms of the disease. Recent clinical trials have shown that intensified chemotherapy for pediatric patients diagnosed with MS-LCH results in improved outcomes. However, whether the feasibility and efficacy of an intensified systemic chemotherapy regimen are also beneficial for adult patients with MS-LCH remains unclear. Here, we report two cases of adult MSLCH that were successfully treated with an intensified treatment protocol as used in pediatric patients. One patient fully completed the protocol, and has since maintained a complete response (CR) for 2 years following completion of the treatment. The other patient also achieved CR after induction therapy, and is now undergoing maintenance therapy in an outpatient clinic. The cases presented in this study suggest that intensified systemic chemotherapy as used for pediatric patients with MS-LCH is well tolerated and effective for adult patients as well.
* Koji Kato [email protected]‑u.ac.jp 1
Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3‑1‑1 Maidashi, Higashi‑ku, Fukuoka 812‑8582, Japan
2
Department of Anatomic Pathology, Pathological Sciences, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
3
Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
Keywords Langerhans cell histiocytosis · Adult · Chemotherapy
Introduction Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is a rare disease characterized by clonal proliferation of bone marrow-derived dendritic cells [1, 2]. For long, it has remained unclear if it is a reactive or a neoplastic disorder, although the finding of BRAF-V600E mutations in approximately half of LCH patients suggests it appears to be more appropriate to classify the disease as a neoplastic disorder [1, 3, 4]. LCH is divided into a localized or multifocal form based on the lesion. The former is called a single system type (SS-LCH) and the latter a multiple system type (MS-LCH). The incidence of pediatric LCH is rare with 2–5 cases per million, whereas that of adults is approximately 1–2 cases per million [1, 5]. The rarity of the disease has made it difficult for physicians to correctly diagnose the disease and choose the most appropriate treatment. Systemic chemotherapy is usually required for pediatric patients with MS-LCH and is associated with a poor prognosis [5–7]. However, the outcome of several clinical trials has shown that intensified induction chemotherapy provides a better outcome for pediatric patients with MSLCH [8]. Whether intensified chemotherapy is also effective for adult patients with MS-LCH remains unclear. In accordance with the pediatric protocol proposed by the Japan LCH Study Group (JLSG), we applied intensified chemotherapy (JLSG-02 protocol) to two adult patients diagnosed with MS-LCH with expectations of poor prognosis. Notably, both patients showed an excellent response, despite disease involvements in high-risk organs, typically associated with treatment resistance such as the liver and
13
M. Minami et al.
central nervous system (CNS). Our two cases suggest that the intensive pediatric protocol is both feasible and effective for adult patients with MS-LCH.
Case presentations Case 1 A 19-year-old male with pain in the left eye and headache consulted a nearby clinic in October 2010. There was a mass of 33 × 30 × 18 mm in the left great wing of his sphenoid bone, which infiltrated into the surrounding bone and soft tissue. He was referred to our hospital on January 2011 and on physical examination, no abnormality was found. A complete blood count (CBC) revealed normal. The lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) levels were within normal limits of 147 IU/L and 413.5 U/mL, respectively. A positron emission tomography–computed tomography (PET–CT) scan revealed a mass spreading from the left sphenoid sinus to the cranial base and upper side of the left orbit, with an abnormal uptake of SUVmax = 9.9. A neurosurgical biopsy from the left orbit revealed a diffuse S-100 protein and CD1a-immunopositive Langerhans cells (Fig. 1a, b, c). The inflammatory cells infiltrated the surrounding thickened collagenous tissue and cystic walls. MIB-1 staining index was 8.6 %. The patient was diagnosed with MS-LCH without a BRAF-V600E mutation using direct sequencing analysis. The patient had craniofacial bone lesions with soft tissue extensions, which are usually considered as “high central nerve system (CNS) risk” despite a negative result of LCH
Fig. 1 Langerhans cell histiocytosis (LCH). The tumor was characterized by a proliferation of histiocytes with cleaved nuclei and multinucleated giant cells infiltrated by eosinophils. Case 1 a Hematoxylin–eosin staining, original magnification 40× objective, b positive immunological staining for CD1a, c positive immunological staining for S-100 protein. Case 2 d Hematoxylin-eosin staining, magnification 40× objective, e positive immunological staining for CD1a, f positive immunological staining for S-100 protein
13
cells in his cerebrospinal fluid [9]. Therefore, the patient was treated with Induction Arm A according to the pediatric protocol of JLSG-02 [9], which consists of cytosine arabinoside (Ara-C), vincristine (VCR) and prednisolone (PSL) (Table 1). He developed grade 4 neutropenia and grade 3 thrombocytopenia, grade 1 liver dysfunction without life-threatening complications. After the induction, the tumor was reduced to 90 % of patients who responded within 6 weeks survived, while most of the patients who died poorly responded to the treatment [13]. This has led to the idea that intensified induction therapy may also improve the outcome of patients with MS-LCH. For example, the JLSG-96 study has shown promising results with the 5-year OS rate for MS-LCH at 95 %. However, a high relapse rate of 45 % in patients with MS-LCH was also problematic [13]. Therefore, to decrease the relapse rate, the induction chemotherapy is intensified in the recent JLSG-02 protocol and the period of treatment is prolonged from 7.5 months to 1 year in comparison with the JLSG-96 protocol [9, 13]. On the other hand, studies on adult MS-LCH have shown little progress because of the rarity of this disease. It has been reported that 30–40 % of MS-LCH patients did not receive chemotherapy when they are diagnosed, which partially owes to this rarity [6]. Systemic chemotherapy has been recommended for adult MS-LCH patients, although the optimal treatment strategy remains unclear. Administration of vinblastine (VBL) with or without steroids was the most frequent choice but no prospective study has been conducted [14]. In particular, for patients with CNS involvement, 2-chlorodeoxyadenosine (2-CDA) was a promising treatment [14–16]. However, the high risk of severe hematological toxicity and secondary hematologic malignancies prompted some to recommend 2-CDA as second-line therapy after VBL in relapsed or treatment-refractory patients. The JLSG-02 protocol for adult LCH patients has been prepared, which is called the Special C regimen and consists of 9 cycles of 6 mg/m2 (max. 6 mg) of VBL on
13
M. Minami et al. Fig. 2 Case 1 Computed tomography (CT) scanning at presentation (a) and after the induction treatment (b). The lesion in the left great wing of his sphenoid bone was reduced to
CASE REPORT
Successful treatment of adult Langerhans cell histiocytosis with intensified chemotherapy Mariko Minami1 · Takahiro Shima1 · Koji Kato1 · Hidetaka Yamamoto2 · Kenji Tsuchihashi1 · Seido Oku1 · Tomonori Shimokawa1 · Taro Tochigi1 · Goichi Yoshimoto1 · Kenjiro Kamezaki1 · Katsuto Takenaka3 · Hiromi Iwasaki3 · Yoshinao Oda2 · Toshihiro Miyamoto1 · Koichi Akashi1,3
Received: 22 October 2014 / Revised: 1 March 2015 / Accepted: 2 March 2015 © The Japanese Society of Hematology 2015
Abstract Langerhans cell histiocytosis (LCH) is a rare disease in adults. The treatment strategy for this condition remains controversial. Intensified systemic chemotherapy is required in pediatric patients with the multiple system form of LCH (MS-LCH) for aggressive forms of the disease. Recent clinical trials have shown that intensified chemotherapy for pediatric patients diagnosed with MS-LCH results in improved outcomes. However, whether the feasibility and efficacy of an intensified systemic chemotherapy regimen are also beneficial for adult patients with MS-LCH remains unclear. Here, we report two cases of adult MSLCH that were successfully treated with an intensified treatment protocol as used in pediatric patients. One patient fully completed the protocol, and has since maintained a complete response (CR) for 2 years following completion of the treatment. The other patient also achieved CR after induction therapy, and is now undergoing maintenance therapy in an outpatient clinic. The cases presented in this study suggest that intensified systemic chemotherapy as used for pediatric patients with MS-LCH is well tolerated and effective for adult patients as well.
* Koji Kato [email protected]‑u.ac.jp 1
Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3‑1‑1 Maidashi, Higashi‑ku, Fukuoka 812‑8582, Japan
2
Department of Anatomic Pathology, Pathological Sciences, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
3
Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
Keywords Langerhans cell histiocytosis · Adult · Chemotherapy
Introduction Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is a rare disease characterized by clonal proliferation of bone marrow-derived dendritic cells [1, 2]. For long, it has remained unclear if it is a reactive or a neoplastic disorder, although the finding of BRAF-V600E mutations in approximately half of LCH patients suggests it appears to be more appropriate to classify the disease as a neoplastic disorder [1, 3, 4]. LCH is divided into a localized or multifocal form based on the lesion. The former is called a single system type (SS-LCH) and the latter a multiple system type (MS-LCH). The incidence of pediatric LCH is rare with 2–5 cases per million, whereas that of adults is approximately 1–2 cases per million [1, 5]. The rarity of the disease has made it difficult for physicians to correctly diagnose the disease and choose the most appropriate treatment. Systemic chemotherapy is usually required for pediatric patients with MS-LCH and is associated with a poor prognosis [5–7]. However, the outcome of several clinical trials has shown that intensified induction chemotherapy provides a better outcome for pediatric patients with MSLCH [8]. Whether intensified chemotherapy is also effective for adult patients with MS-LCH remains unclear. In accordance with the pediatric protocol proposed by the Japan LCH Study Group (JLSG), we applied intensified chemotherapy (JLSG-02 protocol) to two adult patients diagnosed with MS-LCH with expectations of poor prognosis. Notably, both patients showed an excellent response, despite disease involvements in high-risk organs, typically associated with treatment resistance such as the liver and
13
M. Minami et al.
central nervous system (CNS). Our two cases suggest that the intensive pediatric protocol is both feasible and effective for adult patients with MS-LCH.
Case presentations Case 1 A 19-year-old male with pain in the left eye and headache consulted a nearby clinic in October 2010. There was a mass of 33 × 30 × 18 mm in the left great wing of his sphenoid bone, which infiltrated into the surrounding bone and soft tissue. He was referred to our hospital on January 2011 and on physical examination, no abnormality was found. A complete blood count (CBC) revealed normal. The lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) levels were within normal limits of 147 IU/L and 413.5 U/mL, respectively. A positron emission tomography–computed tomography (PET–CT) scan revealed a mass spreading from the left sphenoid sinus to the cranial base and upper side of the left orbit, with an abnormal uptake of SUVmax = 9.9. A neurosurgical biopsy from the left orbit revealed a diffuse S-100 protein and CD1a-immunopositive Langerhans cells (Fig. 1a, b, c). The inflammatory cells infiltrated the surrounding thickened collagenous tissue and cystic walls. MIB-1 staining index was 8.6 %. The patient was diagnosed with MS-LCH without a BRAF-V600E mutation using direct sequencing analysis. The patient had craniofacial bone lesions with soft tissue extensions, which are usually considered as “high central nerve system (CNS) risk” despite a negative result of LCH
Fig. 1 Langerhans cell histiocytosis (LCH). The tumor was characterized by a proliferation of histiocytes with cleaved nuclei and multinucleated giant cells infiltrated by eosinophils. Case 1 a Hematoxylin–eosin staining, original magnification 40× objective, b positive immunological staining for CD1a, c positive immunological staining for S-100 protein. Case 2 d Hematoxylin-eosin staining, magnification 40× objective, e positive immunological staining for CD1a, f positive immunological staining for S-100 protein
13
cells in his cerebrospinal fluid [9]. Therefore, the patient was treated with Induction Arm A according to the pediatric protocol of JLSG-02 [9], which consists of cytosine arabinoside (Ara-C), vincristine (VCR) and prednisolone (PSL) (Table 1). He developed grade 4 neutropenia and grade 3 thrombocytopenia, grade 1 liver dysfunction without life-threatening complications. After the induction, the tumor was reduced to 90 % of patients who responded within 6 weeks survived, while most of the patients who died poorly responded to the treatment [13]. This has led to the idea that intensified induction therapy may also improve the outcome of patients with MS-LCH. For example, the JLSG-96 study has shown promising results with the 5-year OS rate for MS-LCH at 95 %. However, a high relapse rate of 45 % in patients with MS-LCH was also problematic [13]. Therefore, to decrease the relapse rate, the induction chemotherapy is intensified in the recent JLSG-02 protocol and the period of treatment is prolonged from 7.5 months to 1 year in comparison with the JLSG-96 protocol [9, 13]. On the other hand, studies on adult MS-LCH have shown little progress because of the rarity of this disease. It has been reported that 30–40 % of MS-LCH patients did not receive chemotherapy when they are diagnosed, which partially owes to this rarity [6]. Systemic chemotherapy has been recommended for adult MS-LCH patients, although the optimal treatment strategy remains unclear. Administration of vinblastine (VBL) with or without steroids was the most frequent choice but no prospective study has been conducted [14]. In particular, for patients with CNS involvement, 2-chlorodeoxyadenosine (2-CDA) was a promising treatment [14–16]. However, the high risk of severe hematological toxicity and secondary hematologic malignancies prompted some to recommend 2-CDA as second-line therapy after VBL in relapsed or treatment-refractory patients. The JLSG-02 protocol for adult LCH patients has been prepared, which is called the Special C regimen and consists of 9 cycles of 6 mg/m2 (max. 6 mg) of VBL on
13
M. Minami et al. Fig. 2 Case 1 Computed tomography (CT) scanning at presentation (a) and after the induction treatment (b). The lesion in the left great wing of his sphenoid bone was reduced to
