. 2018 May 2;131(26):2877–2890. doi: 10.1182/blood-2018-03-839753

Table 3.

Treatment strategies for patients with RDD

Treatment	Dose/schedule	Indication	Supportive evidence	Comments
Observation	NA	Uncomplicated adenopathy	Case series of 80 patients showed 50% spontaneous remission⁶⁷	Can consider observation for near-complete resection of unifocal lesions with minimal residual disease after surgery
		Asymptomatic cutaneous RDD
		Postoperatively for resected unifocal disease
Corticosteroids	Prednisone: 40-70 mg or 1 mg/kg per d followed by taper	Symptomatic nodal or cutaneous disease	Several case reports and case series with prednisone showing responses in orbital, CNS, and bone RDD and AHA-associated disease^69,70	Responses, when favorable, are unpredictable in their durability
	Dexamethasone: 8-20 mg per d followed by taper	Nonresectable or multifocal extranodal disease requiring systemic treatment	Dexamethasone was effective in CNS and nodal RDD in case reports^71,72	Optimal duration of treatment is not known because early relapse can occur
			Case report of intralesional steroids in orbital RDD⁷⁴	One reasonable approach is to treat to optimal response followed by slow taper
			No response to steroids in other case reports of orbital, tracheal, renal, or soft tissue RDD^75,76	After successful steroid treatment: consider second-line agents to maintain response
Surgical resection	NA	Unifocal extranodal disease	Case series with long-term remission after resection of isolated cutaneous and intracranial disease^31,69	Local recurrences can occur,^31,43 for which case systemic treatment should be considered
Surgical resection	NA	Symptomatic cranial, spinal, sinus, or airway disease
Sirolimus	2.5 mg/m² per d for 18 mo, then taper off over 6 mo		Prolonged CR in RDD with autoimmune cytopenia⁷⁷	Reasonable first choice in ALPS-associated RDD
Radiotherapy	30-50 Gy, lymphoma-like schedule¹⁰²	Refractory or symptomatic disease not amenable to resection, recurrent after resection, or with a contraindication to systemic therapy	Palliative benefit in case reports, including refractory soft tissue and orbital RDD with visual compromise⁹⁷ and for mass effect causing airway obstruction^67,103	No established fractionation schedule
Radiotherapy	30-50 Gy, lymphoma-like schedule¹⁰²			Can also be considered as adjuvant treatment after resection of cranial or spinal lesions with residual but not bulky disease
Chemotherapy
Cladribine	5 mg/m² per d for 5 d, every 28 d for up to 6 cycles	Severe, disseminated, or refractory disease	11 patients reported: 7 with CR, 1 with PR, and 3 with PD^13,51,90-92	Can cause myelosuppression with associated infections
Cladribine	5 mg/m² per d for 5 d, every 28 d for up to 6 cycles	CNS involvement		Can cause myelosuppression with associated infections
MTX or 6-MP/MTX	20 mg/m² per wk of MTX, alone or with 6-MP (50 mg/m² per d) or steroids	Multifocal, skin, or CNS RDD	PR or CR in refractory cases^79-85	Reasonable as maintenance therapy after surgery or steroids
MTX or 6-MP/MTX		Multifocal, skin, or CNS RDD	PR or CR in refractory cases^79-85	Optimal duration unknown
Vinca alkaloids	Standard doses; vinblastine usually combined with prednisone		Vincristine effective in 1 report of skin RDD⁸⁶	Variable responses
Vinca alkaloids			Several reports showing prolonged CR when combined with other agents^81-83	Optimal duration unknown
Immunomodulatory
Thalidomide	50-300 mg per d; variable duration	Refractory cutaneous RDD	Recent review: several reports with prolonged CR⁹⁴	Notable toxicities include skin rash and neuropathy
Thalidomide	50-300 mg per d; variable duration	Refractory cutaneous RDD	Variable responses	Optimal dose and duration unknown
Lenalidomide	Not known	Refractory disease	Sustained CR in an adult with multiply relapsed RDD⁹⁵	Myelosuppressive but less neuropathy and skin rash than thalidomide
Rituximab	500 mg/m² per dose every 1 or 2 wk for 2-6 cycles	For refractory nodal and immune-related RDD	Efficacy described in single case reports⁹⁶	Mechanism of efficacy is not understood
Rituximab	- alone or with chemotherapy	For refractory nodal and immune-related RDD	Efficacy described in single case reports⁹⁶	There are reports of refractoriness and relapses,^85,97 and therefore, reports of success are interpreted with caution
Imatinib mesylate	400-600 mg per d for 7 mo	Refractory/relapsed RDD	Anecdotal activity in 1 adult with refractory RDD⁹⁸	Variable responses
Imatinib mesylate	400-600 mg per d for 7 mo	Refractory/relapsed RDD	1 case of skin RDD was refractory⁹⁹	May work only in PDGFRα/β⁺ cases
Clinical trial (experimental)
Cobimetinib (NCT02649972)	Per trial guidelines	Refractory RDD	Substantial regression of abdominal masses in a single patient with KRAS p.G12R–mutated RDD¹⁰¹	Several case reports of successful treatment of ECD with cobimetinib^10,100
Clofarabine (NCT02425904)	25 mg/m² per d for 5 d, every 28 d for 6 cycles	Severe, disseminated, or refractory disease	3 patients: 2 with CR, 1 had PR⁹³	Myelosuppressive and expensive
Clofarabine (NCT02425904)	25 mg/m² per d for 5 d, every 28 d for 6 cycles	CNS involvement	3 patients: 2 with CR, 1 had PR⁹³	Prospective studies ongoing to determine optimal dosing, long-term efficacy, and toxicity

AHA, autoimmune hemolytic anemia; CR, complete response; 6-MP, 6-mercaptopurine; MTX, methotrexate; NA, not applicable; PD, progressive disease; PR, partial response.