Axi-cel for secondary CNS lymphoma

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) by the United States (US) Food & Drug Administration (FDA) and the European Medicines Agency (EMA).^1,2 The original ZUMA-1 study that these approvals were based on excluded patients with prior or active secondary central nervous system (CNS) lymphoma.³ However, real-world practice often differs from clinical trials and new treatment options, such as CAR T therapy, are required for patients with lymphoma who have CNS involvement. To evaluate the efficacy and safety of axi-cel treatment in patients with secondary CNS lymphoma, N. Nora Bennani, Mayo Clinic, Rochester, US, and colleagues conducted a retrospective analysis of the clinical outcomes of this patient population, on behalf of the US Lymphoma CAR-T Consortium. The results were presented at the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, US, and are summarized here.⁴

Study design and patient characteristics⁴

• Patients with prior or active secondary CNS lymphoma, treated at a participating US medical center, who were leukapheresed before September 30, 2018, with the intention to manufacture standard-of-care axi-cel (N = 298) were included in the analysis:
  • Data cut-off: August 31, 2019
  • Median follow-up: 13.8 months (range, 4–21)
• As shown in Table 1, the intention to treat (ITT) population was formed of 275 patients who received an axi-cel infusion
• Aims of the study:
  • Evaluate safety and efficacy of axi-cel in patients with a history of, or active, secondary CNS lymphoma
  • Compare safety and efficacy of axi-cel between patients with, and without, secondary CNS lymphoma

Table 1. Key data for study population

axi-cel, axicabtagene ciloleucel; chemo, chemotherapy; CNS, central nervous system; ITT, intention to treat; LD, lymphodepleting
	Secondary CNS lymphoma	No secondary CNS lymphoma
n	21	277
Product did not meet specification, n	0	7
Not dosed, n	3	20
Median time from leukapheresis to infusion, days (range)	28 (20–76)	26 (15–67)
Patients receiving LD chemo and axi-cel infusion, ITT population, n (%)	18 (86)	257 (93)

Of the patients with secondary CNS lymphoma (n = 21), at leukapheresis, 11 had a history of CNS disease and ten had active CNS disease. Three patients were not dosed with axi-cel. At the time of axi-cel infusion, ten patients with a history of CNS involvement and eight patients with active CNS were dosed. The figures below are for patients with a history of CNS versus active CNS disease:

• Bridging therapy given (n): 7/11 vs 9/10
• CNS-directed therapy given (n): 2/11 vs 8/10
• Secondary involvement distribution at time of axi-cel infusion:
  • Parenchymal disease: 2/10* vs 3/8
  • Leptomeningeal disease: 8/10* vs 4/8
  • Parenchymal and leptomeningeal involvement: 0/10* vs 1/8

*One patient had unknown secondary involvement distribution

As shown in Table 2, patients with CNS disease had higher Eastern Cooperative Oncology Group (ECOG) performance statuses and International Prognostic Index (IPI) scores, and there was an increased use of bridging therapy compared to patients without CNS disease.

Table 2. Patient demographics

Auto-SCT, autologous stem cell transplant; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, international prognostic index
	No CNS involvement	All cases with CNS involvement	Active CNS at time of infusion	Prior history of CNS
n	277	21	8	13
Median age, years (range)	60 (21–80)	58 (29–83)	60 (29–68)	58 (31–83)
Diagnosis DLBCL, %	67	86	75	92
High grade, %	21	24	20	27
Refractory, %	76	71	75	69
Median prior lines of therapy (range)	3 (2–11)	4 (2–6)	4 (3–6)	4 (2–6)
Auto-SCT	33	33	12.5	46
ECOG performance score ≥ 2, %	19	29	25	31
IPI score ≥ 3, %	53	67	63	69
Bridging therapy	51	76	88	69

Toxicities⁴

As shown in Table 3, patients with CNS involvement had a trend towards a higher rate of cytokine release syndrome, Grade 3 or higher, though immune mediated effector cell-associated neurotoxicity syndrome of any grade, or Grade 3 or higher, were similar between groups. Additionally, no seizures or cerebral edema in the CNS cohort were noted. Steroid use was higher in the CNS cohort.

Table 3. Toxicities in patients receiving axi-cel by CNS disease status

CNS, central nervous system; CRS, cytokine release syndrome; ICANS, immune mediated effector cells associated neurotoxicity syndrome
	No CNS involvement	All cases with CNS involvement	Active CNS at time of infusion	Prior history of CNS
n	277	21	8	13
CRS, any grade, %	93	86	100	77
CRS, grade ≥ 3, %	6	14	25	8
ICANs, any grade, %	93	86	100	77
ICANs, grade ≥ 3, %	28	33	50	23
Steroid use, %	49	62	63	62
Tocilizumab use, %	57	57	63	54

Responses⁴

In the modified ITT cohort of only patients who were dosed with axi-cel, there were no differences in response, as shown in Table 4, with six-month response rates similar between patients with and without CNS involvement (48% and 44%, respectively).

Table 4. Responses in the mITT population

CAR, chimeric antigen receptor; CNS, central nervous system; CR, complete response; mITT, modified intention to treat; PR, partial response
	No CNS involvement	All cases with CNS involvement	Active CNS at time of infusion	Prior history of CNS
n	257	18	8	10
Response rate, %	83	61	50	70
PR/CR rate at:
30 days, %	81	61	50	70
3 months, %	61	44	50	40
6 months, %	48	44	50	40

At 30 days, 3 months, and 6 months, data were missing for 7, 3, and 7 patients, respectively.

The six-month event-free survival rates were similar between groups:

• No CNS vs CNS disease: 56% vs 44%
• Hazard ratio: 1.44 (95% CI, 0.78–2.66), p= 0.24

Conclusion⁴

Axi-cel therapy in patients with secondary CNS disease in the real-world setting led to comparable rates of CAR T infusion, toxicity, and outcomes compared with patients without CNS disease. Limitations of this analysis, such as small sample size and short follow-up, prohibit strong conclusions that are applicable to clinical practice.  However, the data do support the further investigation of CAR T therapies in patients with a history of, or active, secondary CNS lymphoma.