Intensive Chemotherapy Followed by Hematopoietic Stem Cell Rescue for Refractory or Recurrent Primary Central Nervous System (PCNSL) or Intra Ocular Lymphoma (IOL). Results of a Multicentric Phase II Study.

Background: Median survival of relapsing PCNSL after salvage treatment with conventional radiotherapy is 10 months.

Methods: The Société Française de Greffe de Moëlle-Thérapie cellulaire conducted a prospective multicenter trial of intensive chemotherapy followed by autologous hematopoietic stem-cell rescue (IC+HCT) in patients with refractory of recurrent primary central nervous lymphoma or intraocular lymphoma. Patients aged 18 to 65 were included in the study between January 2000 and December 2005. Patients with refractory or recurrent PCNSL received two cycles of salvage treatment, followed, when chemosensitive, by IC+HCT. Salvage treatment consisted of two cycles of CYVE with cytarabine (2g/m²/d days 2 through 5 and 50mg/m²/d days 1 through 5 in a 12-hour infusion) and etoposide (200 mg/d days 2 through 5). IC consisted of thiotepa (250 mg/m²/d days −9 through −7), busulfan (10 mg/kg (total dose) days −6 through −4), and cyclophosphamide (60 mg/kg/d days −3 and −2).

Results: Forty-three patients (22 females; 21 males, median age = 52, range 23–65) were included in 12 French centers. All the patients received high dose Methotrexate based first-line chemotherapy. Fourteen patients received cranial radiotherapy as part of first-line treatment. Patients were included in the study for a relapse (n= 22), a refractory disease (n=19), a partial response after first-line treatment (n=2). At inclusion in the study, diagnosis were PCNSL (n=38) with concomitant IOL (n=5); isolated IOL (n= 5). Response was not evaluable in 3 patients because of treatment-related death. Twenty patients (47%) achieved an objective response after salvage treatment. Treatment failed in 20 patients. Twenty-seven patients underwent IC+ HCT. The reasons for no IC+HCT were: SAE (n=5) including 3 deaths; absence of response (n=6); failure to collect stem cells (n=2); severe neurotoxicity (n= 2); unrelated death (n=1). After IC+HCT, disease status was CR (n=24); PD (n=1); not yet evaluated (n=2). Eleven patients in PD after CYVE salvage chemotherapy were maintained in the IC+HDT program according to physician decision. Interestingly, 10 of them achieved CR after IC+HCT. With a medium FO of 23.5 months, 22 patients were alive. Median overall survival was 18 months. Ten patients relapsed after HCT. After IC+HCT, median OS was not reached and median DFS was 38 months. Causes of deaths were: progression of disease (n=15); neurotoxicity (n=1); TRD (n=5)

Conclusion: Salvage therapy with IC+HCT in refractory or recurrent PCNSL leads to similar results than in relapsing systemic non-Hodgkin’s lymphoma and compares favourably to radiotherapy. CR could be obtained after IC for patients in PD after salvage therapy, suggesting that the mechanism of resistance is not only lymphoma cells-related, but might be related to specific properties of the blood-brain barrier.