Adult Langerhans cell histiocytosis and immunomodulatory drugs: Review and analysis of thirty-four case reports

Table 1 Recommendations for first-line therapy

Disease category	Treatment
Unifocal LCH
Skin	Local therapy (e.g., topical mustard nitrogen 20% in children)
	Phototherapy: PUVA, narrow band ultraviolet B
Bone	Intralesional steroid injection (40-160 mg methylprednisolone)
	Radiotherapy (in case of neurological deficit, soft tissue involvement)
Multifocal SS-LCH without “organ risk”
SS-LCH (bone lesions)	Zoledronic acid
SS-LCH (skin)	Methotrexate 20 mg per week p.o/i.v.
	Azathioprine 2 mg/kg/d p.o.
	Thalidomide 100 mg/die p.o. (skin or soft tissue multifocal SS-LCH if symptomatic)
Symptomatic MS-LCH without “risk organs”	Cytarabine 100 mg/m2 d1-5 q4w i.v.
	Etoposide 100 mg/m2 d1-5 q4w i.v.
	Vinblastin/Prednisone (“pediatric like schedule”)
MS-LCH with “risk organs”	2-CDA 6 mg/m2 d1-5 q4w s.c./i.v.
PLCH asymptomatic	Quit smoking
	Careful observation
PLCH symptomatic	Sistemic steroids
	Chemotherapy in case of progressive disease
	In case of severe respiratory failure or major pulmonary failure consider lung transplantation

"Risk organs" contains hematopoietic system, spleen, liver, and central nervous system. LCH: Langerhans cell histiocytosis. SS-LCH: Single-system Langerhans cell histiocytosis; MS-LCH: Multisystem Langerhans cell histiocytosis; P-LCH: Pulmonary Langerhans cell histiocytosis; PUVA: Psolaren plus ultraviolet A.

Table 2 List of case reports on immunomodulatory drugs in langerhans cell histiocytosis

Ref.	Publication year	Age	Sex	SS-LCH (1) MS-LCH (2)	Previous therapies	IMiDS dose1	Duration (mo)	Out come
Gnassia et al[27]	1987	32	F	1	No	50	60	NAD
Viraben et al[43]	1988	48	M	1	NA	300	1	NAD
Bensaid et al[19]	1992	29	F	2	No	100	3	ADR
Misery et al[33]	1993	67	M	1	No	200	3	NAD
Thomas et al[42]	1993	24	F	2	No	50	3	ADS
Thomas et al[42]	1993	59	F	2	Prednisone	50	18	ADS
Dallafior et al[23]	1995	65	F	1	Cladribin	200-100	10	NAD
Meunier et al[32]	1995	66	M	1	No	100	2	NAD
Bouyssou-Gauthier et al[21]	1996	68	M	2	Cyclophosph-mide/steroids	NA	NA	ADS
Gerlach et al[26]	1998	73	F	2	Etoposide/topi-cal mustard	200	12	ADR
Lair et al[29]	1998	33	F	2	RT/surgery	100	28	ADS
Claudon et al[22]	2002	44	F	2	Metotrexate/ste-roids	100	4	ADR
Kolde et al[28]	2002	23	M	2	No	500	3	ADS
Kolde et al[28]	2002	61	F	2	Prednisone	500	16	ADS
Mortazavi et al[35]	2002	29	M	2	No	100	2	ADS
Santillan et al[38]	2003	33	F	1	RT/surgery	100	12	NAD
Padula et al[36]	2004	31	F	1	RT/surgery	NA	NA	NAD
Sander et al[37]	2004	38	M	1	Cladribin	200	6	NAD
Mauro et al[31]	2005	73	F	2	CVP	100	7	ADR
Alioua et al[17]	2006	43	F	2	No	100	12	ADR
Moravvej et al[34]	2006	27	M	1	PUVA	100	3	ADR
Wollina et al[44]	2006	38	M	2	Cladribin	200	9	NAD
Broekaert et al[20]	2007	57	F	2	No	50	24	ADR
McClain et al[10]	2007	45	F	1	Vinorelbine/ prednisone	100	22	NR/PD
McClain et al[10]	2007	31	F	2	Vinorelbine/ prednisone/RT	100	0,5	NR/PD
McClain et al[10]	2007	21	F	2	Vinorelbine/ prednisone/RT	100	5	NAD
McClain et al[10]	2007	46	F	2	Vinorelbine/ prednisone/RT	100	12	NAD
Li et al[30]	2010	27	M	1	No	150	5	NAD
Fernandes et al[25]	2011	60	F	1	No	100	4	NAD
Shahidi-Dadras et al[39]	2011	20	M	1	Topical steroid	200	6	NAD
Szturz et al[41]	2012	35	M	2	Cladribin/ Cyclophospha-mide methilpredniso-lone/RT/CHO-EP/BEAM	Lena 25	9	ADR
El-safadi et al[24]	2012	59	F	1	Surgery/RT/ MTX	Lena 10	19	NAD
Subramaniyan et al[40]	2015	71	M	1	No	200	10	NAD
Ruiz Beguerie et al[18]	2017	56	F	1	No	150	12	NAD

¹Dose in mg/d. MS-LCH: Multisystem Langerhans cell histiocytosis; SS-LCH: Single-system Langerhans cell histiocytosis; RT: Radiotherapy; NAD: Nonactive disease; ADR: Active disease regressive; ADS: Active disease stable; NR/PD: Nonresponse/progression disease; MTX: Methotrexate; Lena 10: Lenalidomide 10 mg; Lena 25: Lenalidomide 25 mg; CVP: Cyclophosphamide, vincristine, prednisone; CHOEP: Cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone; BEAM: Carmustine, etoposide, cytarabine, and melphalan; PUVA: Photochemotherapy; NA: Not available; F: Female; M: Male; IMiDs: Immunomodulatory drugs.

Table 3 Clinical features of all 34 patients

Clinical features	All patients (%)
Female	21 (62)
Age at diagnosis mean (range)	45.3 (20-73)
Muco-cutaneous involvement	32 (94)
Multiorgan involvement	17 (50)
Lung involvement	3 (9)
CNS/pituitary involvement	8 (23.5)
Bone involvement	6 (18)
Lymph nodes involvement	3 (9)
Splenomegaly/hepatomegaly	2 (6)
Others sites involved (bone marrow, parotid gland)	2 (6)

CNS: Central nervous system.

Table 4 Previous treatments

Treatment before IMiDs	n (%)
None	14 (41)
Radiotherapy	8 (23.5)
Steroids	8 (23.5)
Vinorelbine	4 (12)
Surgery	4 (12)
Cladribin	4 (12)
Metotrexate	2 (6%)
Polichemotherapy regimens	2 (6)
Cyclophosphamide (single agent)	2 (6)
Topical drugs	2 (6)
Etoposide	1 (3)
PUVA	1 (3)

PUVA: Psolaren plus ultraviolet A; IMiDs: Immunomodulatory drugs.