Page 226 - Haematologica Vol. 110 - January 2025

LETTER TO THE EDITOR
Outcomes of patients with primary central nervous system lymphoma following CD19-targeted chimeric antigen receptor T-cell therapy
Primary diffuse large B-cell lymphoma of the central ner- vous system (PCNSL) is a rare but aggressive lymphoma typically confined to the brain, spinal cord, leptomenin- ges, cerebrospinal fluid and/or vitreoretinal space without systemic involvement.1,2 Although the prognosis of these patients has improved with evolving treatments,1 survival is poor for those who do not achieve a complete remis- sion (CR) following first-line treatment (i.e., primary re- fractory) or those who relapse after autologous stem cell transplantation (ASCT).3 There is still no consensus on the best salvage treatment for these patients,3 and different therapeutic strategies have been employed with modest success.3,4 CD19-targeted chimeric antigen receptor T-cell (CAR T) therapies are approved for systemic relapsed or refractory (R/R) diffuse large B-cell lymphoma.5-7 However, patients with PCNSL were not included in these pivotal trials, and patients with PCNSL are specifically excluded from the axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) labels.8 Since the approval of CAR T in the United States and Eu- rope, 4 small studies (N of patients=5-27) with relatively short follow-up reported on the preliminary activity and toxicity of CAR T in PCNSL.9-12 Herein we present an analysis of patients with R/R PCNSL who received commercial CAR T-cell therapy between January 2019 to March 2022 using data from the Center of International Blood and Marrow Transplant Research registry.
The study population included consecutive, consenting patients (≥18 years of age) with a diagnosis of R/R PCNSL who received commercially available CAR T-cell therapy (i.e., axi-cel or tisa-cel) during the index period. No patients were excluded based upon age, comorbidity, product type, or completeness of data. Patients from embargoed centers were excluded. The primary endpoint was overall survival (OS) defined as the time from CAR T infusion to death from any cause. Secondary endpoints included overall response rate (ORR) by day 100, progression-free survival (PFS) (defined as the time from CAR T to relapse/progressive disease (PD) or death from any cause, whichever occurs first, cumulative incidence of relapse or progression, non-relapse mortality (NRM), cause of death, cumulative incidence of any grade severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as defined by the ASTCT criteria13 at day 30 post CAR T infusion, and neutrophil and platelet recovery. The cumulative incidence function was used to estimate relapse/progression, NRM, CRS, and ICANS, and Kaplan-Meier estimators were used for
OS and PFS. The Institutional Review Board at the Medical College of Wisconsin approved this study.
Twenty-four patients meeting the eligibility criteria were analyzed (Table 1). At the time of CAR T infusion, median patient age was 57 years (range, 25-81), the majority were males (67%), and 10 patients (42%) had a Karnofsky per- formance score <90. The median number of prior therapies was 4 (range, 1-10), including 12 patients (50%) who had undergone a prior ASCT. Bridging therapy was utilized in 5 patients (20%), and 21 patients (88%) had active disease prior to CAR T infusion while 3 patients (12%) were in CR. Tisa-cel and axi-cel were infused in 21 (88%) and 3 (12%) patients, respectively.
Among 23 patients evaluable for response, the ORR was 61% (N=14) by day 100, including 3 patients (13%) with partial response and 11 patients (48%) with CR. The median fol- low-up from CAR T infusion was 26 months (range, 3-38). The 1- and 2-year OS were 55% (95% CI: 35-75%) and 50% (95% CI: 29-71%), and the 1- and 2-year PFS were 48% (95% CI: 28-69%) and 28% (95% CI: 9-51%), respectively (Figure 1). The cumulative incidence of disease relapse/progression was 72% (95% CI: 47-92%) and the NRM was 0% at two years. The cumulative incidence of neutrophil recovery at one month was 96% (95% CI: 79-100%) and platelet recov- ery at day 100 was 96% (95% CI: 79-100%). Sixteen patients (66.7%) developed CRS, with a median time to CRS onset of 3.5 days (range, 1-8). All cases of CRS were grade 1 or 2; no patients had grade ≥3 CRS. Eight patients (33%) devel- oped ICANS, with 5 patients (21%) experiencing grade 1 or 2 ICANS and 2 patients who received tisa-cel having grade ≥3 ICANS. The median time to onset of ICANS was six days (range, 1-9). Eleven patients died from disease recurrence or progression (92%), and one patient died from a bacterial infection (8%) after prior disease relapse/progression. There are limited data available on outcomes following CAR T for R/R PCNSL. Siddiqi et al.9 reported preliminary results on 5 patients with R/R PCNSL who were treated on a phase I trial evaluating a CD19 CAR T containing a novel CAR construct, demonstrating anti-tumor activity (CR: N=2; stable disease: N=2) and reassuring safety (ICANS grade 3: N=1). Frigault et al.10 also demonstrated promising safety and efficacy outcomes following treatment with tisa-cel in a cohort of 12 patients with highly refractory PCNSL. With a median follow-up of 12 months, 50% of patients achieved a CR and only one grade 3 ICANS was reported. Alcantara et al.11 reported a 6-month OS and PFS of 89% and 44%, respectively, among 9 patients with R/R PCNSL who received
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