High-Dose Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation in Adulthood Histiocytocytic Disorders.

Background. Histiocytic disorders are clonal proliferations of antigen processing phagocytic or antigen presenting cells. Central nervous system (CNS) lesions outside pineal gland are rare and shared a poor prognosis with no optimal treatment defined yet. We hypothesized that high-dose chemotherapy (HDC) rescued by peripheral autologous hematopoietic stem cell transplantation (AHSCT) may help to control refractory CNS histiocytic disorders.

Patients and methods. Between 1997 and 2005, HDC/AHSCT was performed in patients with refractory CNS lesions of Langerhans Cell Histiocytosis (LCH, n=3) and Erdheim-chester disease (EDC, n=3). All patients were male with a median age of 36 years (range 23.8–45.9). They presented a long history of histiocytic disorder (6.5–15.8 years, median 7.6) and CNS involvement (0.4–7.4 years, median 4), with multisystemic disease in all but one, and refractory to 3–7 therapies (median 5) including surgery, corticotherapy, chemotherapy, 2-Cda, IFNa and Gleevec. Peripheral haematopoietic blood stem cells (PBSC) were harvested by leukapherisis, after steady-state granulocyte colony-stimulating factor mobilization (G-CSF 10 μg/kg/day). Conditioning regimen consisting in BCNU, 300 mg/kg at D-4, VP16, 60 mg/kg at D-3, and Melphalan 140 mg/m² at D-1, and was choosen to overcome blood brain barrier and because of the VP16 efficacy in histiocytic systemic disease. Response was assessed by the Histiocytic Society scoring system (Donadieu, 2004); disease was classified as non-active (NAD) (resolution of all signs and symptoms) or active (AD) [regressing disease (RD), stable disease (SD) or progressive disease (PD)], then response was considered as Better (NAD, RD), Intermediate (new lesion in 1 site, regression in another site, or SD) or Worse (PD).

Results. Although this population presented high risk of failure and toxicity due to advance CNS lesions, extensive tumour burden and prior therapy, the procedure was safe. PBSC were collected in all patients (3.31–13.13x10⁶ CD34+cells/kg). Toxicities included OMS grade 3 infections (n=6) and grades 3–4 mucositis (n=2) but no toxic related death. One patient had persistent PD at 14 months requiring new treatments. One patient had extra-CNS progressive disease and mild CNS response. Two patients achieved NAD: one at 14 months followed by local recurrence at 84 months, the 2^nd was still alive with NAD at 57 months. Two patients had RD: one secondarily progressed at 21 months and died at 31 months of infectious complication with persistent AD, the other were alive with ongoing RD at 4 months. Response was better when tumour burden was minimal and CNS lesions were craniofacial, skull bone or intracranial space occupying histiocytic infiltrates. For 2 patients, some response was also obtained on neurodegenerative brainstem lesions but partial and transient. Although initial response can be considered as Better in 4 cases and Worse in 2 cases, only 1 out of 6 patients had persistent NAD with a median follow-up of 22.4 months.

Conclusion. While this intensive therapy was used safely, its promising efficacy would be probably increased if performed earlier in disease evolution. Furthers studies are necessary to test this hypothesis.