Usual and Unusual Manifestations of Familial Hemophagocytic Lymphohistiocytosis and Langerhans Cell Histiocytosis

Pediatric Clinics of North America

Volumn 64, Issue 1, 2017, Pages 91-109

  Erker, Craig ^a   Harker Murray, Paul ^a   Talano, Julie An ^a  

^a MEDICAL COLLEGE OF WISCONSIN   (United States)

Author keywords

Familial hemophagocytic lymphohistiocytosis (FHL); Hemophagocytic lymphohistiocytosis (HLH); Histiocytic disorders; Langerhans cell histiocytosis (LCH)

Indexed keywords

ALEMTUZUMAB; CLOFARABINE; CYCLOSPORIN; CYTARABINE; DEXAMETHASONE; ETOPOSIDE; FLUDARABINE; IMMUNOGLOBULIN; MELPHALAN; METHOTREXATE; PREDNISONE; STEROID; THYMOCYTE ANTIBODY; VINBLASTINE; VINCRISTINE;

AUTOSOMAL RECESSIVE DISORDER; BRAFV600E GENE; CASE REPORT; CHILD; CLINICAL FEATURE; CYTOTOXIC LYMPHOCYTE; DELAYED DIAGNOSIS; DENDRITIC CELL; DIFFERENTIAL DIAGNOSIS; DRUG TARGETING; GENE; GENE MUTATION; GENOTYPE; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HEMOPHAGOCYTIC SYNDROME; HUMAN; HUMAN CELL; HUMAN TISSUE; INFANT; LANGERHANS CELL HISTIOCYTOSIS; LIFE THREAT; MALE; MAP2K1 GENE; MUTATIONAL ANALYSIS; OVERALL SURVIVAL; PATHOGENESIS; PRESCHOOL CHILD; REVIEW; SALVAGE THERAPY; TREATMENT RESPONSE; DIAGNOSTIC ERROR; GENETICS; HISTIOCYTOSIS, LANGERHANS-CELL; LYMPHOHISTIOCYTOSIS, HEMOPHAGOCYTIC; RARE DISEASES;

CHILD; DELAYED DIAGNOSIS; DIAGNOSIS, DIFFERENTIAL; DIAGNOSTIC ERRORS; HISTIOCYTOSIS, LANGERHANS-CELL; HUMANS; LYMPHOHISTIOCYTOSIS, HEMOPHAGOCYTIC; RARE DISEASES;

EID: 84998773661     PISSN: 00313955     EISSN: 15578240     Source Type: Journal    
DOI: 10.1016/j.pcl.2016.08.006     Document Type: Review

References (100)

1. 1 Filipovich, A.H., Chandrakasan, S., Pathogenesis of hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 29:5 (2015), 895–902.
2. 2 Meeths, M., Horne, A., Sabel, M., et al. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatr Blood Cancer 62:2 (2015), 346–352.
3. 3 Janka, G.E., Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 166:2 (2007), 95–109.
4. 4 Zhang, L., Zhou, J., Sokol, L., Hereditary and acquired hemophagocytic lymphohistiocytosis. Cancer Control 21:4 (2014), 301–312.
5. 5 Henter, J., Ehrnst, A., Andersson, J., et al. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr 82:4 (1993), 369–372.
6. 6 Ohadi, M., Lalloz, M.R., Sham, P., et al. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet 64:1 (1999), 165–171.
7. 7 Ericson, K.G., Fadeel, B., Nilsson-Ardnor, S., et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet 68:3 (2001), 590–597.
8. 8 Suga, N., Takada, H., Nomura, A., et al. Perforin defects of primary haemophagocytic lymphohistiocytosis in japan. Br J Haematol 116:2 (2002), 346–349.
9. 9 Cetica, V., Sieni, E., Pende, D., et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. J Allergy Clin Immunol 137:1 (2016), 188–196.e4.
10. Lee, S.M., Sumegi, J., Villanueva, J., et al. Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation. J Pediatr 149:1 (2006), 134–137.
11. 11 Podack, E.R., Lowrey, D.M., Lichtenheld, M., et al. Structure, function and expression of murine and human perforin 1 (P1). Immunol Rev 103:1 (1988), 203–211.
12. 12 Feldmann, J., Callebaut, I., Raposo, G., et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115:4 (2003), 461–473.
13. 13 zur Stadt, U., Schmidt, S., Kasper, B., et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 14:6 (2005), 827–834.
14. 14 zur Stadt, U., Rohr, J., Seifert, W., et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 85:4 (2009), 482–492.
15. 15 Menasche, G., Menager, M.M., Lefebvre, J.M., et al. A newly identified isoform of Slp2a associates with Rab27a in cytotoxic T cells and participates to cytotoxic granule secretion. Blood 112:13 (2008), 5052–5062.
16. 16 Gil-Krzewska, A., Wood, S.M., Murakami, Y., et al. Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells. J Allergy Clin Immunol 137:4 (2015), 1165–1177.
17. 17 Sayos, J., Wu, C., Morra, M., et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395:6701 (1998), 462–469.
18. 18 Parolini, S., Bottino, C., Falco, M., et al. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med 192:3 (2000), 337–346.
19. 19 Marsh, R.A., Bleesing, J.J., Chandrakasan, S., et al. Reduced-intensity conditioning hematopoietic cell transplantation is an effective treatment for patients with SLAM-associated protein deficiency/X-linked lymphoproliferative disease type 1. Biol Blood Marrow Transplant 20:10 (2014), 1641–1645.
20. 20 Tang, G., Minemoto, Y., Dibling, B., et al. Inhibition of JNK activation through NF-κB target genes. Nature 414:6861 (2001), 313–317.
21. 21 Rigaud, S., Fondanèche, M., Lambert, N., et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:7115 (2006), 110–114.
22. 22 Ghosh, S., Bienemann, K., Boztug, K., et al. Interleukin-2-inducible T-cell kinase (ITK) deficiency-clinical and molecular aspects. J Clin Immunol 34:8 (2014), 892–899.
23. 23 Alkhairy, O.K., Perez-Becker, R., Driessen, G.J., et al. Novel mutations in TNFRSF7/CD27: clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol 136:3 (2015), 703–712.e10.
24. 24 Li, F.Y., Chaigne-Delalande, B., Su, H., et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 123:14 (2014), 2148–2152.
25. 25 Allen, C.E., McClain, K.L., Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program 2015:1 (2015), 177–182.
26. 26 Zhang, K., Filipovich, A.H., Johnson, J., et al. Hemophagocytic lymphohistiocytosis, familial. Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (eds.) GeneReviews® [Internet], 2013, University of Washington, Seattle (WA), 1993–2016.
27. Chandrakasan, S., Filipovich, A.H., Hemophagocytic lymphohistiocytosis: advances in pathophysiology, diagnosis, and treatment. J Pediatr 163:5 (2013), 1253–1259.
28. 28 Tesi, B., Lagerstedt-Robinson, K., Chiang, S.C., et al. Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis. Genome Med 7:1 (2015), 1–13.
29. 29 Zhang, K., Jordan, M.B., Marsh, R.A., et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 118:22 (2011), 5794–5798.
30. 30 Sieni, E., Cetica, V., Santoro, A., et al. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3. J Med Genet 48:5 (2011), 343–352.
31. 31 Zhang, K., Chandrakasan, S., Chapman, H., et al. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood 124:8 (2014), 1331–1334.
32. 32 Zhang, M., Bracaglia, C., Prencipe, G., et al. A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis. J Immunol 196:6 (2016), 2492–2503.
33. 33 Feldmann, J., Le Deist, F., Ouachée-Chardin, M., et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol 117:4 (2002), 965–972.
34. 34 Haddad, E., Sulis, M.L., Jabado, N., et al. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood 89:3 (1997), 794–800.
35. 35 Janka, G., Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 63 (2012), 233–246.
36. 36 Janka, G.E., Hemophagocytic syndromes. Blood Rev 21:5 (2007), 245–253.
37. 37 Henter, J., Horne, A., Aricó, M., et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:2 (2007), 124–131.
38. 38 Allen, C.E., Yu, X., Kozinetz, C.A., et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 50:6 (2008), 1227–1235.
39. 39 Trottestam, H., Horne, A., Arico, M., et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: Long-term results of the HLH-94 treatment protocol. Blood 118:17 (2011), 4577–4584.
40. 40 Horne, A., Trottestam, H., Aricò, M., et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol 140:3 (2008), 327–335.
41. 41 Lee, G., Lee, S.E., Ryu, K., et al. Posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors. Blood Res 48:4 (2013), 258–265.
42. 42 Thompson, P.A., Allen, C.E., Horton, T., et al. Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 52:5 (2009), 621–625.
43. 43 Marsh, R.A., Vaughn, G., Kim, M.O., et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood 116:26 (2010), 5824–5831.
44. 44 Mahlaoui, N., Ouachee-Chardin, M., de Saint Basile, G., et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics 120:3 (2007), e622–e628.
45. Abla, O., Weitzman, S., Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition. Hematology Am Soc Hematol Educ Program 2015:1 (2015), 565–570.
46. 46 Monsereenusorn, C., Rodriguez-Galindo, C., Clinical characteristics and treatment of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 29:5 (2015), 853–873.
47. 47 Stålemark, H., Laurencikas, E., Karis, J., et al. Incidence of Langerhans cell histiocytosis in children: a population-based study. Pediatr Blood Cancer 51:1 (2008), 76–81.
48. 48 Ehrhardt, M.J., Humphrey, S.R., Kelly, M.E., et al. The natural history of skin-limited Langerhans cell histiocytosis: a single-institution experience. J Pediatr Hematol Oncol 36:8 (2014), 613–616.
49. 49 Simko, S.J., Garmezy, B., Abhyankar, H., et al. Differentiating skin-limited and multisystem Langerhans cell histiocytosis. J Pediatr 165:5 (2014), 990–996.
50. 50 Guyot-Goubin, A., Donadieu, J., Barkaoui, M., et al. Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000–2004. Pediatr Blood Cancer 51:1 (2008), 71–75.
51. 51 Totadri, S., Bansal, D., Trehan, A., et al. The 5-year EFS of multisystem LCH with risk-organ involvement is suboptimal: a single-center experience from India. J Pediatr Hematol Oncol 38:1 (2016), e1–e5.
52. 52 Arkader, A., Glotzbecker, M., Hosalkar, H.S., et al. Primary musculoskeletal Langerhans cell histiocytosis in children: an analysis for a 3-decade period. J Pediatr Orthop 29:2 (2009), 201–207.
53. 53 Titgemeyer, C., Grois, N., Minkov, M., et al. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83-and 90-study. Med Pediatr Oncol 37:2 (2001), 108–114.
54. 54 Kamath, S., Arkader, A., Jubran, R.F., Outcomes of children younger than 24 months with Langerhans cell histiocytosis and bone involvement: a report from a single institution. J Pediatr Orthop 34:8 (2014), 825–830.
55. 55 Aricò, M., Astigarraga, I., Braier, J., et al. Lack of bone lesions at diagnosis is associated with inferior outcome in multisystem Langerhans cell histiocytosis of childhood. Br J Haematol 169:2 (2015), 241–248.
56. 56 Haupt, R., Nanduri, V., Calevo, M.G., et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society—Late Effects Study Group. Pediatr Blood Cancer 42:5 (2004), 438–444.
57. 57 Grois, N., Pötschger, U., Prosch, H., et al. Risk factors for diabetes insipidus in Langerhans cell histiocytosis. Pediatr Blood Cancer 46:2 (2006), 228–233.
58. 58 Donadieu, Jf, Thomas, C., Brugieres, L., et al. A multicentre retrospective survey of Langerhans' cell histiocytosis: 348 cases observed between 1983 and 1993. Arch Dis Child 75:1 (1996), 17–24.
59. 59 Morren, M., Vanden Broecke, K., Vangeebergen, L., et al. Diverse cutaneous presentations of Langerhans cell histiocytosis in children: a retrospective cohort study. Pediatr Blood Cancer 63:3 (2015), 486–492.
60. 60 Gadner, H., Heitger, A., Grois, N., et al. Treatment strategy for disseminated Langerhans cell histiocytosis. Med Pediatr Oncol 23:2 (1994), 72–80.
61. 61 Kapur, P., Erickson, C., Rakheja, D., et al. Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease): ten-year experience at Dallas Children's Medical Center. J Am Acad Dermatol 56:2 (2007), 290–294.
62. 62 Nakahigashi, K., Ohta, M., Sakai, R., et al. Late-onset self-healing reticulohistiocytosis: pediatric case of Hashimoto-Pritzker type Langerhans cell histiocytosis. J Dermatol 34:3 (2007), 205–209.
63. Stein, S.L., Paller, A.S., Haut, P.R., et al. Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series. Arch Pediatr Adolesc Med 155:7 (2001), 778–783.
64. 64 Lau, L., Krafchik, B., Trebo, M.M., et al. Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 46:1 (2006), 66–71.
65. 65 Battistella, M., Fraitag, S., Teillac, D.H., et al. Neonatal and early infantile cutaneous Langerhans cell histiocytosis: comparison of self-regressive and non-self-regressive forms. Arch Dermatol 146:2 (2010), 149–156.
66. 66 Gadner, H., Minkov, M., Grois, N., et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121:25 (2013), 5006–5014.
67. 67 Lahey, M.E., Prognostic factors in histiocytosis X. J Pediatr Hematol /Oncol 3:1 (1981), 57–60.
68. 68 Braier, J., Latella, A., Balancini, B., et al. Outcome in children with pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 43:7 (2004), 765–769.
69. 69 Idbaih, A., Donadieu, J., Barthez, M., et al. Retinoic acid therapy in “degenerative-like” neuro-Langerhans cell histiocytosis: a prospective pilot study. Pediatr Blood Cancer 43:1 (2004), 55–58.
70. 70 Barthez, M.A., Araujo, E., Donadieu, J., Langerhans cell histiocytosis and the central nervous system in childhood: evolution and prognostic factors. results of a collaborative study. J Child Neurol 15:3 (2000), 150–156.
71. 71 Grois, N., Prayer, D., Prosch, H., et al., CNS LCH Co-operative Group, Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128:Pt 4 (2005), 829–838.
72. 72 Donadieu, J., Rolon, M., Thomas, C., et al. Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study. J Pediatr 144:3 (2004), 344–350.
73. 73 Wnorowski, M., Prosch, H., Prayer, D., et al. Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 153:1 (2008), 127–132.
74. 74 Harmon, C.M., Brown, N., Langerhans cell histiocytosis: a clinicopathologic review and molecular pathogenetic update. Arch Pathol Lab Med 139:10 (2015), 1211–1214.
75. 75 Mc Dermott, R., Ziylan, U., Spehner, D., et al. Birbeck granules are subdomains of endosomal recycling compartment in human epidermal Langerhans cells, which form where langerin accumulates. Mol Biol Cell 13:1 (2002), 317–335.
76. 76 Valladeau, J., Ravel, O., Dezutter-Dambuyant, C., et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 12:1 (2000), 71–81.
77. 77 Yeom, J., Lee, C., Shin, H.Y., et al. Langerhans’ cell histiocytosis of the spine: analysis of twenty-three cases. Spine, 24(16), 1999, 1740.
78. 78 Huang, W.D., Yang, X.H., Wu, Z.P., et al. Langerhans cell histiocytosis of spine: a comparative study of clinical, imaging features, and diagnosis in children, adolescents, and adults. Spine J 13:9 (2013), 1108–1117.
79. 79 Willman, C.L., Busque, L., Griffith, B.B., et al. Langerhans'-cell histiocytosis (histiocytosis X)–a clonal proliferative disease. N Engl J Med 331:3 (1994), 154–160.
80. 80 Yu, R., Chu, A., Chu, C., et al. Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343:8900 (1994), 767–768.
81. 81 Badalian-Very, G., Vergilio, J.A., Degar, B.A., et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116:11 (2010), 1919–1923.
82. 82 Chakraborty, R., Hampton, O.A., Shen, X., et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 124:19 (2014), 3007–3015.
83. Berres, M.L., Lim, K.P., Peters, T., et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211:4 (2014), 669–683.
84. 84 Haroche, J., Cohen-Aubart, F., Emile, J.F., et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121:9 (2013), 1495–1500.
85. 85 Haroche, J., Cohen-Aubart, F., Emile, J.F., et al. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. J Clin Oncol 33:5 (2015), 411–418.
86. 86 Arceci, R.J., Biological and therapeutic implications of the BRAF pathway in histiocytic disorders. Am Soc Clin Oncol Educ Book, 2014, e441–e445.
87. 87 Chellapandian, D., Shaikh, F., van den Bos, C., et al. Management and outcome of patients with Langerhans cell histiocytosis and single-bone CNS-risk lesions: a multi-institutional retrospective study. Pediatr Blood Cancer 62:12 (2015), 2162–2166.
88. 88 Sessa, S., Sommelet, D., Lascombes, P., et al. Treatment of Langerhans-cell histiocytosis in children. experience at the Children's Hospital of Nancy. J Bone Joint Surg Am 76:10 (1994), 1513–1525.
89. 89 Haupt, R., Minkov, M., Astigarraga, I., et al. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer 60:2 (2013), 175–184.
90. 90 Hadfield, P.J., Birchall, M., Albert, D., Otitis externa in Langerhans' cell histiocytosis—the successful use of topical nitrogen mustard. Int J Pediatr Otorhinolaryngol 30:2 (1994), 143–149.
91. 91 Steen, A., Steen, K., Bauer, R., et al. Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 145:1 (2001), 137–140.
92. 92 Allen, C.E., Flores, R., Rauch, R., et al. Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer 54:3 (2010), 416–423.
93. 93 Ehrhardt, M.J., Karst, J., Donohoue, P.A., et al. Recognition and treatment of concurrent active and neurodegenerative Langerhans cell histiocytosis: a case report. J Pediatr Hematol Oncol 37:1 (2015), e37–e40.
94. 94 Imashuku, S., Fujita, N., Shioda, Y., et al. Follow-up of pediatric patients treated by IVIG for Langerhans cell histiocytosis (LCH)-related neurodegenerative CNS disease. Int J Hematol 101:2 (2015), 191–197.
95. 95 Allen, C.E., Ladisch, S., McClain, K.L., How I treat Langerhans cell histiocytosis. Blood 126:1 (2015), 26–35.
96. 96 Minkov, M., Steiner, M., Pötschger, U., et al. Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. J Pediatr 153:5 (2008), 700–705.e2.
97. 97 Donadieu, J., Bernard, F., van Noesel, M., et al. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood 126:12 (2015), 1415–1423.
98. 98 Simko, S.J., Tran, H.D., Jones, J., et al. Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer 61:3 (2014), 479–487.
99. 99 Jun, Y., Quan, Q.M., Bin, W., et al. Haploidentical parental hematopoietic stem cell transplantation in pediatric refractory Langerhans cell histiocytosis. Pediatr Transpl 18:4 (2014), E124–E129.
100. 100 Veys, P.A., Nanduri, V., Baker, K.S., et al. Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol 169:5 (2015), 711–718.