Tisagenlecleucel is effective and safe in adult patients with relapsed/refractory primary CNS lymphoma

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma (NHL) confined to the brain, pia mater, eye, and/or spinal cord, although it is pathologically associated with systemic large B-cell lymphoma.
Neoplasms (LBCL) were similar, but newly diagnosed PCNSL had a worse prognosis than other NHL subtypes, with 5-year and 10-year overall survival (OS) rates of 29.
3% and 21.
6%, respectively
.

In general, patients with relapsed and refractory (R/R) PCNSL have a poor prognosis with a median OS of about 4 months and lack of effective salvage therapy
.

Real-world data from the International Center for Blood and Bone Marrow Transplantation Study (CIBMTR) demonstrate a lower incidence of severe immune effector cell-associated neurotoxicity syndrome (ICANS) in systemic lymphoma with Tisagenlecleucel, and results from a previous retrospective study demonstrating Tisagenlecleucel Safety and efficacy in secondary central nervous system lymphoma
.

Therefore, we conducted a prospective phase I/II study to evaluate the safety and efficacy of Tisagenlecleucel in patients with highly refractory PCNSL
.

Research Methods This phase I/II clinical study evaluated the efficacy and safety of Tisagenlecleucel in adult patients with R/R PCNSL
.

The Phase I study was designed to evaluate treatment-related toxicity in a PCNSL patient population at FDA-approved CAR-T doses (0.
6-6.
0 x 108 CAR+ T cells) in 6 patients, and an additional 6 patients were treated as part of a Phase II extension study
.

Patients included in the study must be 18 years of age or older with disease progression or relapse after high-dose methotrexate (HD-MTX)-based systemic therapy
.

Elderly (>60 years of age) patients were also eligible to participate in the study due to poor prognosis and if elderly patients were unable to tolerate first-line therapy due to grade 3+ renal or hepatic impairment
.

All patients required a confirmed diagnosis of PCNSL and no systemic disease
.

The patient received a lymphodepleting chemotherapy (LDC) regimen of fludarabine (25 mg/m2/d) and cyclophosphamide (250 mg/m2/d) on days -5, -4, and -3
.

All patients received seizure prophylaxis
.

In the absence of cytokine release syndrome (CRS)/ICANS, initiation of growth factor supportive therapy on day +7 was permitted
.

All patients required repeat baseline assessments before LDC and after any subsequent bridging therapy
.

The primary endpoint of the study was patient tolerability and toxicity, including CRS and ICANS grades
.

Study Results 1 Patient Characteristics The study enrolled 13 patients from December 2019 to the data cutoff date (November 2021), and 12 patients eventually received Tisagenlecleucel infusion
.

The median time from leukapheresis to infusion was 33 days (range: 27-37 days) in the 12 patients infused, and the median time from infusion to data cutoff was 12.
2 months (range: 3.
64-23.
5 months)
.

Baseline patient characteristics showed a median age of 63 years (range: 34-81 years) (see Table 1 for details)
.

All patients had disease progression or treatment failure after HD-MTX treatment; 3 patients had prior autologous hematopoietic stem cell transplantation (ASCT), and 4 patients had prior radiotherapy
.

All patients had lesions measurable by MRI and/or cytology/flow cytometry (FCM) prior to infusion
.

Table 1: Patient Baseline Characteristics 2 Patient Safety All patients required bridging therapy, including steroids, for symptomatic disease and disease-related brain edema after leukapheresis and before initiation of LDC therapy
.

Four of these patients required continued use of steroids for symptomatic disease characterized by left-sided weakness (patient 002), lower extremity weakness (patient 009), worsening cranial nerve deficits (patient 011), and refractory headache (patient 015) )
.

Three of the four patients requiring continuous steroid use were able to reduce steroids to physiologic doses at month 1 and achieve remission at the first assessment
.

All patients developed low-grade CRS and/or ICANS (Table 2)
.

Of the 12 patients infused with Tisagenlecleucel, grade 1 CRS occurred in 7 patients with a median of 4 days after Tisagenlecleucel infusion and a duration of 2 days
.

No patients required tocilizumab or other therapy
.

ICANS occurred in 6 of 12 patients (50%), all of whom received at least one dose of dexamethasone; median time to onset was 5 days and median duration was 3 days
.

Grade 1 ICANNs were observed in 3 (25%) patients, mainly manifesting as mild confusion
.

Grade 2 ICANS occurred in 2 patients (16.
7%), manifested by difficulty in word recall and decreased level of consciousness
.

Patient 002 developed grade 3 ICANS with worsening left-sided weakness
.

Table 2: The incidence of CRS and ICANS in patients 3 Patient efficacy Remissions were observed in 7/12 patients, including 6 complete remissions (CR) and 1 partial remission (PR) (Figure 1)
.

The median time from infusion to data cutoff was 12.
2 months, with 7/12 patients alive and 3/12 patients without disease progression
.

The median time to best response for patients at data cutoff was 3.
4 months
.

Cerebrospinal fluid (CSF) of all responders were negative for MYD88 by cytology, flow cytometry, IgH sequencing, and PCR; treatment response areas included large intraparenchymal masses and pia mater and CSF involvement
.

Figure 1: Evaluable patient efficacy and associated CRS/ICANS4 cell expansion and phenotype analysis after Tisagenlecleucel infusion.
Tisagenlecleucel cell expansion in peripheral blood was observed and measured by flow cytometry; T levels accounted for 18.
2% of CD45+ lymphocytes in peripheral blood (1226 CAR+ cells/μl) (Fig.
2, patient 008)
.

Patients showed predominantly CD4+ CAR-T amplification with varying degrees of memory phenotypes (TSCM, TCM, TEMRA, TEM, and TN) (Figure 2)
.

Markers of T cell clearance, such as PD-1, TIM-3 and LAG-3, were identified during peak expansion
.

All patients enrolled in the study who continued to respond showed B-cell aplasia (defined as <1% B cells in peripheral blood by flow cytometry)
.

Figure 2: Patient Peripheral Blood CAR-T Expansion and Phenotyping 5CSF and Cytokine Analysis CAR-T cell transport into the CSF was observed in all peripheral blood-expanded patients
.

CAR transgenic RNA levels were higher in the CSF of patients with the best response in CR (Fig.
3A)
.

According to the ratio of CAR expression to CD45+ cells, one patient showed relatively higher Tisagenlecucel levels in CSF than in peripheral blood (67.
2% vs 18.
2%, Figure 3B)
.

RNA analysis of CSF also found that patients whose best response was CR had increased expression of T-cell and macrophage gene pathways
.

Downregulation of genes associated with inflammatory cytokines (CCL4/CCL3), T-cell exhaustion (TOX), effector function (IKZF2), and a Jak family member (Tyk2) was also observed in patients who eventually achieved CR (Fig.
3C)
.

Concomitant with CNS-transported CAR-T cells, we also noted a trend toward increased serum and CNS inflammatory cytokines 1 week after Tisagenlecleucel infusion compared with pre-infusion baseline (Fig.
3D)
.

Figure 3: CSF and cytokine analysis results of pre/post-infusion samples Study Conclusions Overall, Tisagenlecleucel was well tolerated, with 42.
9% of initial responders having sustained remission, suggesting that Tisagenlecleucel is safe and effective in adult patients with R/R PCNSL
.

References Matthew J Frigault , Jorg Dietrich , Kathleen ME Gallagher, et al.
Safety and Efficacy of Tisagenlecleucel in Primary CNS Lymphoma: A phase I/II clinical trial.
Blood.
2022 Feb 15; blood.
2021014738.
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