Dose-Adjusted Teddi-R Induces Durable Complete Remissions in Relapsed and Refractory Primary CNS Lymphoma

Background: Primary CNS lymphoma (PCNSL) is an aggressive B-cell lymphoma that relies on chronic active B-cell receptor (BCR) signaling. Patients with chemo-refractory PCNSL or relapsed < 1y have a median OS of only 2-4 mos. Ibrutinib targets BCR signaling through inhibition of BTK. In a phase 1 study, we showed tumor reductions after a 14-day ibrutinib window in 94%, including complete remissions (CR) (Lionakis et al. Cancer Cell 2017). Further, ibrutinib added to anthracycline-based chemotherapy (DA-TEDDi-R) achieved CR in 86% of evaluable patients. Routine use of DA-TEDDi-R, however, is limited by our observation of 7 presumed or proven cases of Aspergillus when no fungal prophylaxis was given and in conjunction with high dose steroids. Herein, we report the durability of CR and PFS in relapsed/refractory patients with extended follow-up. Methods: Patients with untreated or relapsed/refractory PCNSL, age >18, and adequate organ function were enrolled. Previous BTK inhibitor, EBV+, and active pregnancy were excluded. Patients had baseline MRI brain, PET/CT brain and body, Ommaya placed, CSF analysis with flow cytometry, and ophthamologic evaluation. A window of ibrutinib x 14d was given in 3 cohorts at escalating doses (560mg, 700mg, 840mg) then repeat MRI to assess activity. After ibrutinib window, patients received up to 6 cycles of ibrutinib + TEDD-R (temozolamide, etoposide, doxil, dexamethasone, rituximab) with ICV or IT cytarabine. No pt received maintenance or consolidation. All remissions by MRI were confirmed with PET/CT brain and repeat CSF analysis. Surveillance brain MRI after treatment q3mos for 1y, q4mos x 1y, q6mos x 1y, then annually. Results:18 PCNSL patients with a median age 66 (range 49-87) were enrolled between August 2014 and March 2016. 5 patients were untreated, 2 relapsed, and 11 chemo-refractory. After a median potential f/u of 38.9m, the median PFS for all patients who received DA-TEDDi-R is 15.2m (95% CI:3.8-undefined) and the 2-yr PFS is 43.8% (95% CI: 19.8-65.6). Of 13 relapsed/refractory patients, 2 died from Aspergillus infection during the ibrutinib window; neither had fungal prophylaxis and both had high-dose steroids. 11 patients received a median of 5 cycles (range 1-6) of DA-TEDDi-R. Nine (82%) of these patients achieved CR/CRu. Notably, none of the 6 patients with relapsed/refractory PCNSL (1 relapsed, 5 refractory) in CR at the time of publication have relapsed or died. The median duration of CR in relapsed/refracto