Real-world outcomes with tisagenlecleucel in CAYAs with R/R B-ALL

Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults (CAYAs) is associated with poor prognosis.¹ Tisagenlecleucel (tisa-cel) has been in commercial use for almost 5 years for the treatment of R/R B-ALL; however, available real-world data have been heterogeneous and limited across different institutions delivering tisa-cel.¹

Liora M. Schultz et al.¹ performed a retrospective, multi-institutional study across 15 institutions in the United States to collect data from tisa-cel experience to demonstrate real-world outcomes and influencing factors. The results of this study have been recently published in the Journal of Clinical Oncology, and we are pleased to provide a summary of key points.

Study design

A national consortium was established to allow cross-institutional reporting and analysis among 15 pediatric centers.

• Intent-to-treat (ITT) response analysis included 200 patients who underwent leukapheresis and cell shipment for planned standard-of-care tisa-cel regardless of receiving the treatment (Figure 1).
  • All patients who received tisa-cel (including through an expanded managed access protocol or individual investigational new drug approval) were evaluated for response, toxicity, and survival with a minimum follow-up of 28 days.
• Primary objective: Overall complete response (CR) rate at Day 28 following tisa-cel, measured by bone marrow (BM) and/or peripheral blood morphology and minimal residual disease
• Secondary objectives: Overall survival (OS) and event-free survival (EFS) at 6 and 12 months following tisa-cel
• Exploratory objective: Risk factors for response and survival

CRS, cytokine release syndrome; MAP, managed access protocol; s-IND, single-patient investigational new drug; SoC, standard of care; tisa-cel, tisagenlecleucel.
*Adapted from Schultz, et al.¹

Results

Of 200 patients, 185 received tisa-cel infusion; the median age at infusion was 12 years (range, 0–26 years). The median follow-up from tisa-cel therapy was 335 days (range, 6–863 days). The median number of prior therapy lines was three (range, 1–10), with a median duration of 33 months (range, 3–171 months). Most patients (83%) were treated for relapsed disease. Table 1 summarizes patient characteristics by infused and noninfused cohorts.

Table 1. Patient characteristics (N = 200)*

allo-HSCT, allogeneic hematopoietic stem cell transplantation; CAR, chimeric antigen receptor; MPAL, mixed phenotype acute leukemia. *Adapted from Schultz, et al.1
Characteristic, %	Infused (n = 185)	Noninfused (n = 15)
Sex
Male	60	60
Female	40	40
Cytogenetics
High risk	36	27
Ph-positive (p190 and p210)	5	0
Ph-like	13	13
MPAL	1	0
Intermediate risk	26	20
Low risk	13	13
Unknown	25	40
Prior lines of therapy, %
1–3	61	33
4–5	29	33
>5	10	33
Prior allo-HSCT	35	33
Prior CD19 therapy
Blinatumumab	18	40
CD19 CAR	3	0
Prior CD22 therapy
Inotuzumab	17	53
CD22 CAR	2	0
Disease status
Refractory without relapse	16	7
1 relapse	37	40
≥2 relapses	46	40

 Efficacy

The Day 28 CR rate was 79% (95% confidence interval [CI], 72–84) in the ITT population (excluding patients who did not receive tisa-cel due to CR from prior therapy; n = 197). Efficacy results from 184 infused evaluable patients are summarized in Table 2.

Table 2. Results from infused evaluable patients*

CI, confidence interval; CR, complete response; DoR, duration of response; EFS, event-free survival; MAP, managed access protocol; OS, overall survival; s-IND, single-patient investigational new drug. *Adapted from Schultz, et al.1
Response, % (95% CI)
Overall Day 28 CR rate (n = 184)	85 (79–89)
Patients who received MAP/s-IND	83
Patients with detectable disease prior to tisa-cel infusion (n = 134)	81 (73–86)
DoR at 6 months	75
DoR at 12 months	62
MRD negativity by flow cytometry in pts with morphologic CR (n = 153)	97
Survival outcomes
Median OS	Not reached
6-month OS, %	85
12-month OS, %	72
6-month EFS, %	62
12-month EFS, %	50

 Among responders:

• 37% relapsed (median time from infusion to relapse: 101 days, range, 30–645)
• 28% underwent post-CAR HSCT (median time from infusion to HSCT: 199 days, range 36–565)
  • 20 patients were in remission at the time of HSCT, while 19 patients proceeded to transplant following relapse post-tisa-cel.

In multivariate analysis, high burden disease (defined by ≥5% BM lymphoblasts, any circulating lymphoblasts and/or CNS3, or non-CNS extramedullary disease) was found to be significantly associated with a lower morphologic CR rate (73% vs 98% in low burden disease and 100% in undetectable disease; p < 0.0001). OS, EFS, and DoR at 6 and 12 months were also lower with high burden disease: 12-month OS was 58% (vs 85% in low burden disease and 95% in undetectable disease; p < 0.0001) and 12-month EFS was 31% (vs 70% in low burden disease and 72% in undetectable disease; p < 0.0001). Young age (3–10 years) at diagnosis (p = 0.006) and increased time from diagnosis to infusion (p < 0.001) were associated with improved OS.

Safety

Of 185 patients, 183 were evaluable for safety at Day 28 (incomplete data, n = 2). The results of safety analysis are provided in Table 3.

Table 3. Safety analysis*

AE, adverse event; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; PICU, pediatric intensive care unit; TLS, tumor lysis syndrome. *Adapted from Schultz, et al.1
AE	n, %
CRS (N = 183)
Any grade, %	63
Grade ≥3, %	21
Median CRS onset time, days (range)	5 (0–14)
Median duration of CRS, days (range)	4 (1–42)
Neurotoxicity (evaluable, n = 179)
Any grade, %	21
Grade ≥3, %	7
Cerebral edema, %	0.6
Cerebral hemorrhage, %	0.6
Median neurotoxicity onset time, days (range)	6 (3–25)
Median duration of neurotoxicity, days (range)	5 (1–203)
TLS (n = 175)
Yes, %	7
Grade 4 neutropenia persistent >28 days (evaluable, n = 147)
Yes, %	16
Infections (evaluable, n = 181)
≥1 infection, %	40
Median onset, days (range)	68 days (1–559)
CAR-related hospitalizations (overall cohort, n = 184)
Inpatient care, %	82
Median duration, days (range)	14.5 (1–75)
PICU, %	31
Median duration, days (range)	6 (1–33)

 A total of 51 patients died after tisa-cel infusion.

• Five patients died before Day 28, due to either leukemia, infection, cytokine release syndrome (CRS) or neurotoxicity.
• Other causes of death included infection, transplant complications and cardiac events.
• Non-relapse mortality was 7%.

In the univariate analysis, high disease burden was associated with increased CRS severity and higher rate of pediatric intensive care unit-level care compared with low burden disease and undetectable disease (p < 0.0001 for both). Relapse versus refractory status was also associated with increased CRS.

Conclusion

This study indicates that response and survival outcomes of tisa-cel in the real-world setting are similar to that seen in previous studies. Importantly, high disease burden is shown to be associated with inferior outcomes, suggesting high-risk disease may benefit from additional interventional approaches to optimize outcomes of CAR T-cell therapy.

Limitations of this study arise from its retrospective nature, differences in reporting across centers, and changes in definitions of disease response and relapse.