　We diagnosed a female infant with Langerhans cell histiocytosis (LCH) who was refractory to conventional chemotherapy. She showed refractory inflammation that was complicated with hemophagocytic lymphohistiocytosis (HLH) during LCH chemotherapy; therefore, we changed the protocol to HLH2004 (dexamethasone, cyclosporine A and VP16). However, there were no signs of hematological recovery. We therefore performed cord blood transplantation with reduced-intensity conditioning, and she achieved complete remission for over 2 years. As salvage therapy for refractory LCH, hematopoietic stem cell transplantation may be a good therapeutic choice, especially when LCH is complicated with HLH

Kanamitsu, Kiichiro

Muraoka, Michiko

Oda, Megumi

Shimada, Akira

Washio, Kana

Okayama University Digital Information Repository

A Case of Refractory Langerhans Cell Histiocytosis Complicated with Hemophagocytic Lymphohistiocytosis Rescued by Cord Blood Transplantation with Reduced-intensity Conditioning

Okayama University Scientific Achievement Repository

L angerhans cell histiocytosis (LCH) is a rare dis-ease with various clinical presentations from localized to disseminated features.  Patients with multi-system LCH who are very young at onset with risk organ involvement,  or whose disease is refractory to conventional chemotherapy,  have shown poor out-comes [1 , 2].  For these high-risk patients,  2-CdA or clofarabine is administered as a rescue therapy [3 , 4]; the alternative approach is allogenic stem cell transplantation (HSCT).  Several reports have suggested that HSCT with reduced-intensity conditioning (RIC) improved the outcome of LCH patients [5-9].Hemophagocytic lymphohistiocytosis (HLH) is also a rare complication of LCH.  Although there have been only a few reports on LCH patients complicated with HLH,   the prognosis seems to be very poor when HLH occurs in refractory LCH patients [10].   We report the case of an infant with multisystem LCH complicated with HLH who was refractory to che-motherapy,  but was successfully treated by cord blood transplantation (CBT) with RIC.  The benefits of CBT with the RIC regimen are discussed.Case ReportA one-year-old girl exhibited a recurrent fever refractory to antibiotics with left cervical lymphade-nopathy as well as a skin rash on her head lasting five months.  She was admitted to our hospital for further examination and treatment.  At admission,  she had a high fever with tachypnea and tachycardia.  Physical Acta Med.  Okayama,  2017Vol.  71,  No.  3,  pp.  249-254CopyrightⒸ 2017 by Okayama University Medical School.http ://escholarship.lib.okayama-u.ac.jp/amo/Case ReportA Case of Refractory Langerhans Cell Histiocytosis Complicated with Hemophagocytic Lymphohistiocytosis Rescued by Cord Blood Transplantation with Reduced-intensity ConditioningKana Washioa,  Michiko Muraokab,  Kiichiro Kanamitsua,  Megumi Odaa,   and Akira Shimadaa＊aDepartment of Pediatrics,  Okayama University Hospital,  Okayama 700-8558,  Japan bDepartment of Pediatrics,  National Hospital Organization Fukuyama Medical Center,   Fukuyama,  Hiroshima 720-8520,  JapanWe diagnosed a female infant with Langerhans cell histiocytosis (LCH) who was refractory to conventional che-motherapy.  She showed refractory inflammation that was complicated with hemophagocytic lymphohistiocy-tosis (HLH) during LCH chemotherapy; therefore,  we changed the protocol to HLH2004 (dexamethasone,  cyclosporine A and VP16).  However,  there were no signs of hematological recovery.  We therefore performed cord blood transplantation with reduced-intensity conditioning,  and she achieved complete remission for over 2 years.  As salvage therapy for refractory LCH,  hematopoietic stem cell transplantation may be a good thera-peutic choice,  especially when LCH is complicated with HLH.Key words:  langerhans cell histiocytosis (LCH),  hemophagocytic lymphohistiocytosis (HLH),  hematopoietic stem cell transplantation (HSCT),  reduced-intensity conditioning (RIC),  refractoryReceived October 11, 2016; accepted December 15, 2016.＊Corresponding author. Phone : +81-86-235-7249; Fax : +81-86-221-4745E-mail : pajj236e@okayama-u.ac.jp (A. Shimada)Conflict of Interest Disclosures: No potential conflict of interest relevant to this article was reported.examination revealed bilateral massive cervical lymph-adenopathy,  hepatomegaly,  skin rash of bilateral postauricular lesions and inguens.  Her blood test showed severe anemia,  coagulopathy,  elevation of C-reactive protein,  and hypoalbuminemia.  Soluble IL-2 receptor and liver fibrotic marker levels were ele-vated (Table 1).  Computed tomography showed mas-sive cervical lymphadenopathy,  hepatomegaly,  and 250 Washio et al. Acta Med.  Okayama　Vol.  71,  No.  3A BCDTable 1　 Blood examination on admissionWBC 5,410 /µl TP 4.4 g/dlNeu 41 % Alb 2.1 g/dlHb 5.9 g/dl T.Bil 0.59 mg/dlPlt 22.5 ×104/µl D.Bil 0.09 mg/dlAST 9 U/lFibg 649 mg/dl ALT 2 U/lPT-INR 1.27 ALP 197 U/lAT3 62 % γGTP 9 U/lFDP 10.1 µg/ml CHE 45 U/lLD 168 U/lslL2-R 5,410 U/mlType 4 collagen 4.2 ng/dl UN 6.4 mg/dlHyaluronic acid 94.8 ng/dl CRTN 0.19 mg/dlAFP 2.5 ng/dlT.Cho 127 mg/dlTG 131 mg/dlferritin 169.1 ng/dlCRP 10.7 mg/dlBlood test of the patient on admission.  Abnormal data represented by thick letters.  It showed severe anemia,  coagulopathy,  elevation of CRP,  and hypoalbuminemia.  Soluble lL-2 receptor and liver ﬁbrotic marker levels were elevated.Fig. 1　 Images of computed tomogra-phy on admission.  A,  3D reconstruction showed multiple bone lesions on the skull;  B,  Lymphadenopathy and hepatomegaly were observed; C,  Lung lesions were observed.  We could not tell whether they were caused by an infection or LCH; D,  She also had bone lesions on her verte-brae.infiltration of the lower lung area (Fig. 1).  Multiple punched-out bone lesions were observed on the temporal bone,  orbit,  vertebra,  and pelvis.  Bone mar-row aspiration resulted in a dry tap.  Abnormal cells with rich cytoplasm were observed on the smear sam-ple,  but there was no sign of hemophagocytosis.  Patho-histologic examination of a cervical lymph node revealed a proliferation of polymorphic and dysplastic abnormal cells stained positively with S100 and CD1a,  which had replaced the normal lymphatic tissue.  From these results,  the patient was diagnosed with LCH (Fig. 2A).    We started administration of prednisolone (PSL) and chemotherapy following the Japan LCH Study Group (JLSG)-02 induction A protocol [1].  She returned to an afebrile state,  and the lymphadenopathy was gradually reduced; however,  the skin rash and hepatomegaly were still present.  After 3 weeks,  she developed recurrent fever with pancytopenia,  elevation of serum ferritin,  biliary enzyme,  and progressive coagulopathy (Table 2).  Bone marrow aspiration revealed massive hemophagocytosis and hypocellular marrow (Fig. 2B).  Epstein-Barr virus and cytomegalo-virus were negative on RT-PCR.  We diagnosed her with secondary HLH following LCH,  and changed the pro-tocol to HLH2004 (dexamethasone,  cyclosporine A and VP16) [11].  After 1 month,  her peripheral ferritin level was around 800 ng/ml,  and neutropenia contin-ued.  She achieved an afebrile state only with the use of acetaminophen for pain control.  Hemophagocytosis was observed in her bone marrow,  and there was no sign of normal hematopoiesis; therefore,  we consid-ered performing HSCT (Fig. 3).  She had no HLA-matched related donor,  and received 8 / 8 HLA-matched cord blood transplantation (CBT) with RIC.  We chose fludarabine (Flu; 180 mg/sqm) and mel-June 2017 LCH with HLH Rescued by RIC-CBT 251A.  Patho-histologic examination of cervical lymph nodeB.  Bone marrow aspiration; May-Grunwald Giemsa staining （onset of HLH）HE CD1a S-100Fig. 2　 A.  Patho-histologic examination of the cervical lymph node on admission.  The normal lymphatic tissue was replaced with a proliferation of polymorphic and dysplastic abnormal cells stained positively with S100 and CD1a.  B.  Bone marrow aspiration at the onset of hemophagocytic lymphohistiocytosis.  May-Grunwald Giemsa staining was performed.phalan (L-PAM; 140 mg/sqm) as the conditioning regimen.  We also intensified the conditioning with antithymocyte globulin (ATG; 2.5 mg/kg) and low-dose cyclophosphamide (CY; 100 mg/sqm) as immu-nosuppressants.  Successful engraftment was confirmed by bone marrow examination on day 33,  and short tandem repeat revealed over 95% donor type.  After neutrophil engraftment,  we gradually reduced PSL dos-age,  and there was no sign of refractory fever or hemophagocytosis.  Stage 1 skin rash was the only symptom of graft-versus host disease.  Neither virus reactivation nor fungal infection was observed.  She was discharged 3 months after CBT,  and no recurrence of LCH or HLH has been observed during a follow-up of more than 2 years.DiscussionLCH is a rare clonal disorder characterized by the proliferation and accumulation of clonal CD1a-positive immature dendritic cells,  accompanied by the infiltra-tion of various inflammatory cells [1 , 2].  The clinical presentation of LCH is highly variable,  ranging from benign localized to disseminated aggressive disease,  which may be fatal.  Patients under 2 years of age at onset who have involvement of one ore more ‘risk organs’ including the hematopoietic system,  liver,  spleen,  and lung,  or are refractory to conventional che-motherapy have a poor outcome with a survival rate of less than 30% at 2 years [5].Macrophage activation and secondary HLH are rarely reported in association with LCH.  Blaise et al.  reviewed 30 LCH cases that had pathological signs of macrophage activation [10].  They concluded that mul-tisystem LCH and young age are factors for macrophage activation.  Of the 7 patients who had fully developed HLH,  4 died.  Therefore,  the complication of HLH might increase the mortality rate of high-risk LCH [10].In our patient,  high risk organs such as the liver,  bone marrow,  and lung were involved.  She also had suffered inflammation,  her disease was refractory to conventional chemotherapy,  and finally she developed HLH during the clinical course.  After one month of HLH 2004 therapy,  she could not achieve remission of LCH or HLH.  She had hypertension and hyperglyce-mia as complications of the diseases and therapies,  sug-gesting the progression of endothelial disorder.  We expected that her prognosis would be very poor; there-fore,  we planned salvage HSCT as soon as possible.  Several studies have described the application of HSCT for refractory LCH.  In those reports,  myeloab-lative conditioning appears to be related with high treatment-related-mortality rate [5 , 9].  However,  other reports have suggested that HSCT with RIC could be a promising salvage therapy for refractory LCH [5-9].  Kudo et al.  reported that HSCT with a Flu + L-PAM 252 Washio et al. Acta Med.  Okayama　Vol.  71,  No.  3Table 2　 blood examination at the onset of HLHWBC 960 /µl TP 3.7 g/dlNeu 4 % Alb 2.0 g/dlHb 6.9 g/dl T.Bil 1.31 mg/dlPlt 13.3 ×104/µl D.Bil 0.49 mg/dlAST 5 U/lFibg 919 mg/dl ALT 2 U/lPT-INR 1.25 ALP U/lAT3 81 % γGTP 9 U/lFDP 5.3 µg/ml CHE 18 U/lLD 80 U/lslL2-R 2,492 U/mlUN 7.9 mg/dlEBV-PCR 0 Copies/µgDNA CRTN 0.14 mg/dlCMV-PCR 0 Copies/µgDNAT.Cho mg/dlTG 188 mg/dlferritin 897.5 ng/dlCRP 13.2 mg/dlBlood test of the patient on admission.  Abnormal data represented by thick letters.  It showed rapidly progressed anemia and neutropenia,  elevation of CRP,  ferritin,  and soluble IL-2 receptor It also showed hypoalbuminemia.  No evidence of reactivation of EBV nor CMV.regimen was safely and successfully performed in 15 refractory LCH patients [7].  We chose cord blood stem cell transplantation; therefore,  we intensified the con-ditioning with ATG and low-dose CY as an immuno-suppressant to avoid engraftment failure.   Fortunately,  our patient had no severe complications with HSCT,  showed successful engraftment,  and has been in com-plete remission for over 2 years.In conclusion,  immune system recovery by HSCT with RIC may be a treatment option for refractory LCH with HLH.  HSCT with RIC as a possible salvage ther-apy for refractory LCH should be considered.  Acknowledgments.　The authors would like to thank the following for their clinical support for this patient: Dr. Takuo Noda and Dr. Takanori Oyama (pediatric surgeon),  Dr. Takehiro Tanaka (pathologist),  Mrs. Yoshimi Hino,  Mr. Takahide Takahashi,  Mr. Masahide Imada and Toshiyuki Watanabe (technicians of the clinical laboratory department).  All are affiliated with the Okayama University Hospital.References 1. Morimoto A,  Shioda Y,  Imamura T,  Kudo K,  Kawaguchi H,  Sakashita K,  Yasui M,  Koga Y,  Kobayashi R,  Ishii E,  Fujimoto J,  Horibe K,  Bessho F,  Tsunematsu Y and Imashuku S: Intensiﬁed and prolonged therapy comprising cytarabine,  vincristine and pred-nisolone improves outcome in patients with multisystem Langerhans cell histiocytosis: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study.  Int J Hematol (2016) 104: 99-109. 2. Abla O,  Egeler RM and Weitzman S: Langerhans cell histiocyto-sis: Current concepts and treatments.  Cancer Treat Rev (2010) 36: 354-359. Improved outcome of refractory Langerhans cell histiocytosis in June 2017 LCH with HLH Rescued by RIC-CBT 253A.  Before CBTB.  After CBTFig.  3　 Clinical course after admission.  A.  Before transplanta-tion.  B.  After transplantation.  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A Case of Refractory Langerhans Cell Histiocytosis Complicated with Hemophagocytic Lymphohistiocytosis Rescued by Cord Blood Transplantation with Reduced-intensity Conditioning

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