THE IELSG-32 TRIAL: RANDOMIZED PHASE II TRIAL ON PRIMARY CHEMOTHERAPY WITH HIGH-DOSE METHOTREXATE AND HIGH-DOSE CYTARABINE WITH OR WITHOUT THIOTEPA, AND WITH OR WITHOUT RITUXIMAB, FOLLOWED BY BRAIN IRRADIATION VS HIGH-DOSE CHEMOTHERAPY SUPPORTED BY AUTOLOGOUS STEM CELLS TRANSPLANTATION FOR IMMUNOCOMPETENT PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA

Introduction: IELSG #32 is an international randomized phase II trial addressing the tolerability and efficacy of adding rituximab (R)±thiotepa (TT) to methotrexate (MTX)-cytarabine (ARAC) combination, followed by a 2nd randomization comparing consolidation with WBRT or HDC/ASCT in pts with PCNSL (NCT01011920). Herein, we report re- sults of the first randomization. Methods: HIV-neg pts 18-70 yo and ECOG PS ≤3 (PS ≤2 if age 66-70) with new histology-proven PCNSL and measurable disease were randomly assigned to receive 4 courses of MTX 3.5 g/m2 d1+ARAC 2 g/m2 x2/d d2-3 (arm A); or MTX-ARAC+R 375 mg/m2 d-5 & 0 (arm B); or MTX-ARAC-R+TT 30 mg/m2 d4 (arm C). ASC were collected after the 2nd course. Response was assessed after 2nd & 4th courses; pts with responsive disease were further ran- domized between WBRT and BCNU-TT conditioned/ASCT. Histology and neuroimaging were centrally reviewed. Primary endpoints were CRR (1st random) and 2-year FFS (2nd random). Sample size was esti- mated on the basis of 2nd random: with P0 65% and P1 85% (one-sided test; 5%; 95%), 52 patients/arm required. Results: 227 pts (median age 58 ys; 18-70) were enrolled in 52 centers of 5 countries; 8 pts were ex- cluded due to misdiagnosis, systemic disease or concomitant cancer. No differences in clinical presentation among 3 arms (A 75; B 69; C 75) were observed (Table 1). 733/876 (84%) planned courses were delivered. G4 hematological toxicity was more common in arm C, but infective complications were similar in the 3 arms. G4 non-hematological toxicities were rare. Chemotherapy was interrupted due to toxicity in 21 (9%) pts; 13 (6%) pts died of toxicity. ASC were successfully collected in 152/161 (94%) pts. Arm C was significantly more active, with a CRR of 49% and an ORR of 87%; 118 pts (A 35; B 35; C 48) were referred to 2nd random. At a median follow-up of 20 months (7-60), 111 pts remain failure-free (A 25; B 37; C 49), with 2-yr FFS of 34±6%, 52±6% and 64±6% (p=0.0006), respectively. 124 pts are alive (A 31; B 41; C 52), with 2-yr OS of 40±6%, 58±6% and 66±6% (p=0.01), respectively. Conclusions: The addition of TT and R to MTX-ARAC (MATRIX regimen) is associated with significantly improved response, FFS and OS rates in PCNSL pts. With the exception of greater hematological toxicity, MA- TRIX was not associated with higher rates of severe complications, al- lowed preservation of antimetabolites dose intensity, and permitted high rates of successful ASC collection.