THE ADDITION OF THIOTEPA AND RITUXIMAB TO HIGH DOSES OF ANTIMETABOLITES SIGNIFICANTLY IMPROVES OUTCOME IN PRIMARY CNS LYMPHOMA: THE FIRST RANDOMIZATION OF THE IELSG #32 TRIAL

Introduction: IELSG #32 is an international randomized phase-II trial addressing the tolerability and efficacy of adding rituximab (RM) ± thiotepa (TTP) to methotrexate (MTX)-cytarabine (ARAC) combination, followed by a 2nd randomization comparing consolidation with whole-brain irradiation (WBRT) or autologous stem cell transplantation (ASCT) in patients (pts) with primary CNS lymphoma (PCNSL) (NCT01011920). Herein, we report results of the first randomization. Methods: HIV-neg pts 18-70 years old and ECOG PS 0-3 (PS ≤2 if age 66-70) with new histology-proven PCNSL and ≥1 measurable lesion 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 + RM 375 mg/m2 d-5 & 0 (arm B); or MTX-ARAC-RM + TTP 30 mg/m2 d4 (arm C). ASC were collected after the 2nd course. Response was assessed after 2nd and 4th courses; pts with responsive or stable disease were randomized between WBRT and BCNU-TTP conditioned/ASCT. Histology and neuroimaging were centrally reviewed. Primary endpoints were complete remission rate (CRR; 1st randomization) and 2-year FFS (2nd randomization). Sample size was estimated on the basis of 2nd randomization: with P0 65% and P1 85% (one-sided test; α 5%; β 95%), 52 patients/arm required. Results: 227 pts (median age 58 yrs; 18-70) were enrolled in 52 centers of 5 European countries; 8 pts were excluded due to wrong diagnosis, systemic disease or concomitant cancer. No differences in clinical presentation among 3 arms (A 75; B 69; C 75) were observed (Table). 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 (Table). G4 non-hematological toxicities were rare. Chemotherapy was interrupted due to toxicity in 21 (9%) pts; 13 (6%) pts died of toxicity. ASC harvest was successful in 152/161 (94%) pts. Arm C was significantly more active, with a CRR of 48%, and an ORR of 87% (Table); 118 pts (A 35; B 35; C 48) were referred to 2nd randomization (59 pts/arm). At a median follow-up of 20 months (5-60), 110 pts remain failure-free (A 26 pts; B 36 pts; C 48 pts), with 2-year FFS of 36±6%, 52±6% and 64±6% (p=0.0008), respectively. Salvage therapy was delivered to 65% of failed pts, without difference in efficacy among arms. 126 pts are alive (A 32 pts; B 42 pts; C 52 pts), with 2-yr OS of 41±6%, 58±6% and 66±6% (p=0.01), respectively. Conclusions: The addition of TTP and RM to MTX-ARAC (MATRIX regimen) is associated with significantly improved response, FFS and OS rates in PCNSL pts. Although it’s associated with higher hematological toxicity, MATRIX was not associated with higher rates of severe complications, and allowed an adequate ASC collection in 94% of cases, with a maintained RDI of antimetabolites. A (n= 75) B (n= 69) C (n= 75) p Median age (range) 58 (18-70) 57 (24-70) 57 (29-70) NS Male 46 (61%) 44 (64%) 46 (61%) NS ECOG PS >1 27 (36%) 23 (33%) 24 (32%) NS Low IELSG risk 14 (19%) 12 (17%) 13 (17%) NS Intermediate IELSG risk 47 (63%) 44 (64%) 47 (63%) NS High IELSG risk 14 (19%) 13 (19%) 15 (20%) NS Intraocular disease 5 ( 7%) 1 ( 1%) 1 ( 1%) NS Meningeal involvement 2 ( 3%) 2 ( 3%) 3 ( 4%) NS Feasibility and Toxicity Actually delivered courses* 223 (74%) 236 (86%) 274 (91%) Relative dose intensity MTX 92% 84% 85% NS Relative dose intensity ARAC 87% 81% 80% NS Relative dose intensity RM - 82% 83% NS Relative dose intensity TTP - - 76% - G4 neutropenia* 99 (44%) 119 (50%) 153 (56%) 0.01 G4 thrombocytopenia* 116 (52%) 140 (59%) 200 (73%) 0.0001 G4 anemia* 9 ( 4%) 6 ( 3%) 14 ( 5%) NS G≥3 febrile neutrop./infections* 43 (19%) 31 (13%) 45 (16%) NS G4 hepatotoxicity* 6 ( 3%) 3 ( 1%) 1 ( 1%) NS G4 nephrotoxicity* 0 ( 0%) 0 ( 0%) 1 ( 1%) NS Toxic deaths§ 7 ( 9%) 3 ( 4%) 3 ( 4%) NS Autologous stem cell collection 48/51 (94%) 44/46 (96%) 60/64 (94%) NS Median of collected stem cells (x 106 CD34+ cells/kg bw) 12.3 15 8.2 NS Activity and efficacy Complete remission rate (95%CI) 23% (14-31) 31% (21-42) 49% (38-60) A vs. B: 0.29 A vs. C: 0.0007 B vs. C: 0.02 Overall response rate (95%CI) 53% (42-64) 74% (64-84) 87% (80-94) A vs. B: 0.01 A vs. C: 0.00001 B vs. C: 0.05 2-year Failure-Free Survival 36 ± 6% 52 ± 6% 64 ± 6% 0.0008 5-year Failure-Free Survival 15 ±10% 43 ± 7% 53 ±11% 0.0008 2-year Overall Survival 41 ± 6% 58 ± 6% 66 ± 6% 0.01 5-year Overall Survival 28 ± 7% 50 ± 7% 66 ± 6% 0.01 * Percentage on the number of delivered courses. § Percentage on the number of enrolled patients.