Very High Efficiency of ICE (Ifosfamide-Carboplatin-Etoposide) in Relapse/Refractory (R/R) Primary Central Nervous System (PCNSL) and Vitreo-Retinal (VRL) Non Hodgkin Lymphoma. a LOC Network Multicenter Retrospective Study on 58 Cases

Background : R/R PCNSL and VRL carry a very poor prognosis (i.e. 4,5 months, Jahnke, J neuro-oncol 2006)). Autologous stem-cell transplantation (ASCT) is effective in this setting but essentially if the disease is in good response (CR and PR). Since recent recommendations for first line treatment recommend high dose Mtx and AraC, new salvage chemotherapies must use other drugs. ICE regimen contain three drugs known to pass the blood-brain barrier  and is validated in R/R systemic lymphoma but not in PCNSL/VRL.

Methods:  From June 2010 to May 2015, all relapse/refractory PCNSL and VRL already treated by Mtx and AraC in 5 departments of haematology or neuro-oncology in France, where treated by ICE: ifosfamide (5g/m² at day 2), carboplatine (AUC 5 at day 2) and etoposide (100mg/m²/d days 1 to 3) every 3 to 4 weeks. ASCT with thiotepa-busulfan-cyclophosphamide was proposed when possible.

Results: Fifty-eight patients have been treated, 25 females and 33 males, median age was 64 [28-84]. Eight received rituximab at day 1 of each cycle. Twelve where refractory, 46 in relapse, with a mean progression free survival (PFS) of 159 days [0-1763] before ICE. Thirty patients (51%) were in second line, 12 (21%) in third, 4 in fourth. Localizations where CNS in 32 cases,  CNS + spinal fluid (SF) in 11, CNS + VR in 2, VRL in 9, SF in 3 and CNS+VR+SF in 1. Patients received a median of 3 cycles and 25 needed a dose reduction. Grade 3/4 WHO toxicities where: 29% neutropenic fever, 50% anemia, 69% neutropenia, 78% thrombocytopenia and 3 neurological reversible complications.  ASCT have been made in 19 patients (33%): 13 in CR, 4 in PR, 2 in progression. Response rate is 70% (48% CR and 22% PR). With a mean follow-up of 670 days, 25/41 patients in response relapsed (only 7/19 after ASCT), median PFS is 133 days (NR for ASCT), 35 patients died (30 by progression, 4 by sepsis and one by sudden heart arrest in PR). Median Overall survival (OS) was 238 days for all patients but was not reached in case of ASCT, mean follow up for surviving ASCT is 856 days [278-1628]).

Conclusion: ICE regimen is very effective in relapse/refractory PCNSL and LVR heavily treated by high dose Mtx and AraC, with a manageable toxicity. If ASCT is performed, OS is very high and relapses rare. ICE + ASCT can represent a new standard in this setting.