Christian Grommes

Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma with a poor prognosis, high rate of refractory or relapsed (R/R) disease, and no established standard of care for R/R PCNSL. This phase 2 study evaluated the efficacy and safety of tirabrutinib, a potent, highly selective, second-generation Bruton tyrosine kinase inhibitor, in patients with R/R PCNSL in the US. In the open-label PROSPECT study, adults with R/R PCNSL whose disease progressed on or after ≥1 high-dose methotrexate-based therapy received once-daily oral tirabrutinib 480 mg. The primary endpoint was overall response rate (ORR), and secondary endpoints included complete response (CR) rate, duration of response (DOR), and time to response (TTR), as assessed by independent review committee. Safety was assessed by frequency and severity of treatment-emergent adverse events (TEAEs). Among 48 enrolled patients, median follow-up was 11.5 months, ORR was 67% (95% confidence interval [CI], 52-80), and CR rate was 44% (95% CI, 29-59). Median DOR was 9.3 months (95% CI, 4.6-14.6), and median TTR was 1.0 month (range, 0.9-3.7). Treatment-related TEAEs occurred in 36 patients (75%), most commonly anemia (19%), maculopapular rash (17%), fatigue (15%), neutropenia (15%), lymphocytopenia (15%), pruritus (15%), and other rash (15%). Grade ≥3 treatment-related TEAEs occurred in 13 patients (27%), most commonly neutropenia (8%) and maculopapular rash (6%). One death (bronchopulmonary aspergillosis) was treatment related. In patients with R/R PCNSL, once-daily oral tirabrutinib monotherapy resulted in rapid and durable responses and demonstrated a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04947319.

PURPOSE: A subset of brainstem gliomas harbor an isocitrate dehydrogenase 1/2 ( IDH1/2 ) mutation, which has important prognostic and treatment implications. We evaluated the radiographic features and the sensitivity of magnetic resonance spectroscopy (MRS) and cerebrospinal fluid cell-free DNA (CSF cfDNA) sequencing at detecting IDH1/2 mutations in a cohort of these tumors. METHODS: We identified IDH-mutant brainstem gliomas by retrospective chart review. IDH1/2 mutation was established by biopsy, CSF cfDNA sequencing, and/or the presence of a 2-hydroxyglutarate (2HG) peak by 3-Tesla MRS. RESULTS: Twenty-one patients with IDH-mutant brainstem gliomas were identified, 57% male with a median age of 26 (6-59) years. All tumors involved the pons and/or abutted the brachium pontis. Although 18 (86%) of 21 were nonenhancing, only one of 21 demonstrated T2-FLAIR mismatch. An IDH1/2 mutation was identified by biopsy in 17 and by CSF cfDNA sequencing in three; in the final patient, an IDH1/2 mutation was inferred by the presence of a 2HG peak. The sensitivity of MRS at identifying 2HG in patients with confirmed IDH1/2 mutations was 64.3% (95% CI, 35.1 to 87.2), which increased to 85.7% (95% CI, 42.1 to 99.6) when the study was performed before treatment. The 2HG peak was absent in all four patients with a repeat MRS after completion of radiation. IDH1/2 mutation was identified in four of seven patients who underwent sequencing of CSF cfDNA. In this cohort, median progression-free survival and overall survival were 57.6 and 90.4 months, respectively. An objective response to radiotherapy was observed in 76%. CONCLUSION: IDH-mutant brainstem gliomas have a characteristic clinical and radiographic phenotype. MRS is more sensitive than CSF cfDNA sequencing for noninvasively identifying the presence of an IDH1/2 mutation when performed before radiotherapy.

Background: High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL). Only ∼60% of patients achieve a complete response to first-line therapy with frequent relapses. The Bruton’s tyrosine kinase inhibitor ibrutinib has shown promising antitumor activity in recurrent/refractory PCNSL. Methods: The goal of the current single-center phase 2 trial was to explore whether the addition of ibrutinib to the combination of rituximab, methotrexate, procarbazine, and vincristine (R-MVP/i) increases complete response rate (CCR). Results: Thirty newly diagnosed PCNSLs were enrolled; median age 69 (range 41-79), median Eastern Cooperative Oncology Group (ECOG) = 1. Twenty-nine patients completed R-MVP/i, 1 withdrew consent after 2 cycles. A complete response (CR)/complete response unconfirmed (CRu) was achieved in 29 patients and a partial response in 1 for a CRR of 29/30 (97%, 95% CI: 83.3%, 99.8%). Treatment was well tolerated with no grade 5 toxicity observed. Eight patients experienced 13 grade 4 toxicities (lymphopenia [n = 3], neutropenia [n = 4], thrombocytopenia [n = 3], and white cell count decrease [n = 3]). The most common toxicities were thrombocytopenia, anemia, lymphopenia, and liver enzyme elevations. No Aspergillus or Pneumocystis infections occurred. No refractory disease was observed. For the 29 patients completing the trial, 19 received consolidation with cytarabine (Ara-C), 8 autologous stem cell transplant, 1 rituximab maintenance, and 1 was observed without maintenance or consolidation. At a median follow-up of 25.1 months (range 3.3-49.2), the median progression-free (PFS) and overall survival were not reached with a 2-year PFS of 84.2% (95% CI: 62.7%-93.9%). Conclusions: R-MVP/i was well tolerated and associated with excellent disease control and survival.

Background: Treatment options for recurrent/refractory central nervous system (CNS) lymphoma are limited but Bruton’s tyrosine kinase inhibitor ibrutinib has shown promise. To increase efficacy and reduce resistance, ibrutinib was combined with lenalidomide in a preclinical study and rituximab (R2I) in a phase Ib trial with expansion. Methods: Ibrutinib 560 mg (dose level 1) or 840 mg (levels 2–4) was administered daily; lenalidomide was dosed on days 1–21 at 10 mg (level 1 + 2), 15 mg (level 3), or 20 mg (level 4) daily; rituximab 500 mg/m2 was administered every 28 days. Rituximab was given for 6 cycles, lenalidomide for 12 cycles, and ibrutinib ongoing. Results: 25 patients were enrolled (3 each into dose levels 1–3; 6 into level 4; and 10 into the expansion cohort at level 4). The median age was 67 years (range 41–85) and the median Eastern Cooperative Oncology Group 1 (range 0–2). Patients had a median of 2 prior regimens (range 1–5). Common adverse events were thrombocytopenia, rash, and lymphopenia. No aspergillosis or grade 5 toxicities were observed. After 12.8 months of median follow-up, 20/25 (80%) showed a response with a median time to best response of 60 days (range, 25–615). Median progression-free survival (PFS) was 4.3 months (95% CI: 2.4–not reached) with a PFS12m of 37% (95% CI: 22%–63%). Median overall survival has not been reached. Patients with rash during treatment had improved PFS (HR: 0.17, 95% CI: 0.05–0.55, P-value = .003). Conclusions: R2I was tolerated well with high response rates and a short time to best respond. Median PFS was limited but 1/3 of patients had durable responses >12 months. This trial was registered at www.clinicaltrials.gov (NCT03703167).

Consolidation for primary central nervous system lymphoma (PCNSL) after induction chemoimmunotherapy include whole-brain radiotherapy (WBRT; ≤24 Gy reduced-dose [RD], >24 Gy standard-dose) and cytarabine, nonmyeloablative chemotherapy (NMC), or autologous hematopoietic cell transplantation (AHCT). Comparative outcomes are lacking. Outcomes from 1983-2020 were stratified by decade and Memorial Sloan Kettering Cancer Center recursive partitioning analysis (RPA) class. Clinicodemographic associations were analyzed by multinomial logistic regression. Progression-free survival (PFS) and overall survival (OS) were analyzed by proportional hazards. Of 559 patients, 385 (69%) were consolidated. Median follow-up and OS were 7.4 and 5.7 years, respectively. WBRT use declined (61% (1990s) vs 12% (2010s)), whereas AHCT (4% (1990s) vs 32% (2010s)) and NMC (27% (1990s) vs 52% (2010s)) rose. Compared with RPA 1, RPA 2 was more likely to receive NMC. Those with partial response to induction were less likely to receive AHCT (odds ratio, 0.36; P = .02). Among 351 with complete response to consolidation, only receipt of rituximab, methotrexate, procarbazine, and vincristine induction was associated with improved PFS (hazard ratio, 0.5; P = .006). Among RPA 1, median PFS and OS were not reached for AHCT or RD-WBRT, vs 2.5 and 13.0 years, respectively, after NMC. Among RPA class 3, median PFS and OS after RD-WBRT were 4.6 and 10 years, vs 1.7 and 4.4 years after NMC. No significant adjusted survival differences were seen across consolidation strategies. NMC is increasingly used in lieu of RD-WBRT despite a trend toward less favorable PFS. RD-WBRT can be considered in patients ineligible for AHCT.

Chimeric antigen receptor (CAR) T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extracranial lymphoma in which it can improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction before CART for CNSL (CNS-BRT). We identified patients with CNSL with non-Hodgkin B-cell lymphoma who received CNS-BRT before commercial CART. Cytoreduction from CNS-BRT was calculated as change in lesion size before CART. Twelve patients received CNS-BRT, and the median follow-up among survivors is 11.8 months (interquartile range, 8.5-21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All 10 patients with CNSL had progressive disease at the time of CNS-BRT. Of 12 patients, 1 experienced grade ≥3 cytokine release syndrome, and 3 of 12 patients experienced grade ≥3 immune effector cell–associated neurotoxicity syndrome. CNS-BRT achieved a 74.0% (95% confidence interval, 62.0-86.0) mean reduction in lesion size from baseline (P = .014) at a median of 12 days from BRT completion and before CART infusion. Best CNS response included 8 complete responses, 1 partial response, and 1 progressive disease. Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CART.

PURPOSE: High-dose methotrexate (HD-MTX) is the backbone of curative therapy for CNS lymphoma. Because of toxicity, MTX is administered in the inpatient setting along with hyperhydration and monitoring until MTX clearance is documented (3-5 days). Frequent hospitalizations result in patient time away from work, home, and exposure to potential iatrogenic/nosocomial complications. Here, we aim to demonstrate feasibility of HD-MTX administration in the outpatient setting with low-dose glucarpidase facilitating clearance. METHODS: This is a prospective nonrandomized study of outpatient HD-MTX followed by glucarpidase 2000u (ClinicalTrials.gov identifier: NCT03684980 ). Eligible patients had CNS lymphoma, creatinine 2 was administered once over 2 hours, preceded by standard hydration and followed by an additional 2 hours of dextrose 5% in water with NaHCO ₃ 75 mEq at 150 cc/h. Glucarpidase 2000u was administered once in the clinic 24 hours later. The primary end point was MTX level 48 hours after HD-MTX. RESULTS: Twenty doses of outpatient HD-MTX with glucarpidase were administered to seven patients. After 20 of 20 (100%) treatments, serum MTX levels were reduced to <100 nmol/L. Treatments were well-tolerated, and no admissions were required. One patient received additional outpatient hydration for elevated creatinine. Development of antiglucarpidase antibody was rare and did not affect treatment. CONCLUSION: Outpatient HD-MTX with glucarpidase is safe and well-tolerated and has the potential to alter standard treatment for CNS lymphoma.