PCNSL

Tisagenlecleucel in secondary CNS lymphoma

Although chimeric antigen receptor (CAR) T-cell therapy is improving outcomes of patients with non-Hodgkin lymphoma (NHL), it is not indicated for the use in patients with central nervous system (CNS) involvement. Due to concerns around neurotoxicity associated with the use of these products, CNS involvement was an exclusion criterion in previous clinical studies assessing the efficacy and safety of CAR T-cells.1

Matthew J Frigault from Massachusetts General Hospital, Boston, MA, US, and colleagues recently reported in Blood the results of a retrospective analysis of a small number of patients with high-grade B-cell NHL and secondary CNS involvement, who were treated with commercial tisagenlecleucel (tisa) at the Massachusetts General Hospital.2

Study design

Eight patients with CNS involvement received lymphodepleting chemotherapy with cyclophosphamide (250mg/m2) and fludarabine (25mg/m2) 5, 4, and 3 days before single infusion of tisa (0.6–6.0 x 108 cells). Patients received CNS-directed bridging therapy until lymphodepletion. Initial response was assessed 28 days after infusion by the treating physician in collaboration with a neuro-oncology specialist. Cytokine release syndrome (CRS) and neurotoxicity (NT) were evaluated by the treating physician according to the Lee criteria 2014 and CTCAE v5 and then retrospectively compared with the recent ASTCT 2019 guidelines.3,4

Table 1. Selected patient characteristics

Total number of patients

8

Median age

50 years (17–79)

Sex

Female

Male

 

4

4

NHL subtype

DLBCL

HGBCL

PMBCL

 

5

2

1

Site of CNS involvement at infusion

Parenchymal only

Leptomeningeal only

Both

 

3

3

2

Systemic disease at baseline

Yes

No

 

2

6

Median number of prior therapies

5 (3–6)

Number of patients with prior ASCT

1

ASCT, autologous stem cell transplant; DLBCL, diffuse large B-cell lymphoma; HGBCL, high-grade B-cell lymphoma; PMBCL, primary mediastinal large B-cell lymphoma

Main findings
  • Safety
    • Adverse events included grade 1 CRS and 1 NT event in a patient with progressive disease that were considered mainly due to CNS involvement rather CAR-T administration
    • Four patients experienced grade 1 neurotoxicity according to Lee 2014 assessment3, which was limited to one patient when assessed using new ASTCT guideline4
    • Patients did not require tocilizumab or high dose steroids for the management of CRS or NT
    • Prophylactic anticonvulsants were administered to all patients and no patients received growth factor support before Day 7
    • During therapy with CAR-T, two patients received concomitant maintenance with ibrutinib and one with ibrutinib plus steroids
  • Efficacy
    • CAR T-cell expansion was observed in patients with and without active systemic disease suggesting their ability to reach CNS
    • Treatment responses were seen as early as 3–4 weeks after infusion indicating kinetics of CAR T efficacy is similar between CNS and systemic disease
    • Two patients died due to progressive disease 3 and 25 days after CAR T-cell infusion. Two further patients achieved a CR with complete resolution of CNS disease. One patient with PR had a CR at Day+180, while another patient with PR had an ongoing response at Day +90
Table 2. Response and selected adverse events
  Max CRS/NT (ASTCT 2019)4 Response Follow-up
Patient 1 Grade 1 CRS PD leading to death NA
Patient 2 None CR, CSF (-) Systemic relapse at D90 with CNS (-) RT to focal relapse followed by resolution on D180 without additional CNS directed therapy
Patient 3 Grade 1 CRS PR, CSF (-) CR at D180
Patient 4 Grade 1 CRS PD RT and lenalidomide
Patient 5 Grade 1 CRS, NT* PD leading to death NA
Patient 6 Grade 1 CRS PD; Prior sitesresolved, new lesion CSF (+) Ibrutinib maintenance and RT to residual disease
Patient 7 Grade 1 CRS PR Ongoing response at D90
Patient 8 Grade 1 CRS CR Ongoing response at D90

CSF, cerebral spinal fluid; CR, complete response; D, days following CAR-T infusion; NA, non-applicable; PD, progressive disease; PR, partial response; RT, radiotherapy; *Not evaluable due to disease progression

Conclusion

This retrospective analysis points to the viability of tisa as a treatment option for patients with secondary CNS. Patients did not experience increased rates of CRS or NT while CNS responses were seen in half of the patients. The data presented in this retrospective study remain preliminary with a short follow-up but may pave the way for longer and larger prospective studies assessing the use of CAR T-cell therapy for the treatment of CNS disease. The authors are planning to explore this further in a pilot study of tisa in primary lymphoma.

References
  1. Karschnia P. et al., Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T-cells. Blood. 2019 May 16;133(20):2212-2221. DOI: 10.1182/blood-2018-12-893396
  2. Frigault M.J. et al., Tisagenlecleucel CAR-T Cell Therapy in Secondary CNS Lymphoma. Blood. 2019 Jul 18. pii: blood.2019001694. DOI: 10.1182/blood.2019001694.
  3. Lee D.W. et al., Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195. DOI: 10.1182/blood-2014-05-552729
  4. Lee D.W. et al., ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625-638. DOI: 10.1016/j.bbmt.2018.12.758
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