Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

Vanessa A Fabrizio; Christine L Phillips; Adam Lane; Christina Baggott; Snehit Prabhu; Emily Egeler; Sharon Mavroukakis; Holly Pacenta; Jenna Rossoff; Heather E Stefanski; Julie-An Talano; Amy Moskop; Steven P Margossian; Michael R Verneris; Gary Douglas Myers; Nicole A Karras; Patrick A Brown; Muna Qayed; Michelle Hermiston; Prakash Satwani; Christa Krupski; Amy K Keating; Rachel Wilcox; Cara A Rabik; Vasant Chinnabhandar; Michael Kunicki; A Yasemin Goksenin; Kevin J Curran; Crystal L Mackall; Theodore W Laetsch; Liora M Schultz

doi:10.1182/bloodadvances.2021005564

. 2022 Jan 21;6(2):600–610. doi: 10.1182/bloodadvances.2021005564

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

Vanessa A Fabrizio ^1,^*, Christine L Phillips ^2,^3,^*, Adam Lane ², Christina Baggott ⁴, Snehit Prabhu ⁵, Emily Egeler ⁵, Sharon Mavroukakis ⁵, Holly Pacenta ⁶, Jenna Rossoff ⁷, Heather E Stefanski ⁸, Julie-An Talano ⁹, Amy Moskop ⁹, Steven P Margossian ¹⁰, Michael R Verneris ¹, Gary Douglas Myers ¹¹, Nicole A Karras ¹², Patrick A Brown ¹³, Muna Qayed ¹⁴, Michelle Hermiston ¹⁵, Prakash Satwani ¹⁶, Christa Krupski ^2,³, Amy K Keating ¹, Rachel Wilcox ¹¹, Cara A Rabik ¹³, Vasant Chinnabhandar ⁸, Michael Kunicki ⁴, A Yasemin Goksenin ¹⁵, Kevin J Curran ^17,¹⁸, Crystal L Mackall ^19,²⁰, Theodore W Laetsch ^6,^21,²², Liora M Schultz ^23,^✉

¹University of Colorado, Anschutz Medical Campus, Colorado Children’s Hospital, Aurora, CO;

²Department of Pediatrics, University of Cincinnati, Cincinnati, OH;

³Cincinnati Children’s Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, OH;

⁴Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;

⁵Stanford University School of Medicine, Stanford Cancer Institute, Center for Cancer Cell Therapy, Stanford, CA;

⁶Department of Pediatrics, The University of Texas Southwestern Medical Center/Children’s Health, Dallas, TX;

⁷ Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL;

⁸Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, University of Minnesota Medical School, Minneapolis, MN;

⁹Department of Pediatric Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI;

¹⁰Harvard Medical School, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Pediatric Hematology-Oncology, Boston, MA;

¹¹Children’s Mercy Hospital, Kansas City, MO;

¹²Department of Pediatrics, City of Hope National Medical Center, Duarte, CA;

¹³Department of Oncology, Sidney Kimmel Cancer Center at John Hopkins School of Medicine, Baltimore, MD;

¹⁴Emory University and Children’s Healthcare of Atlanta, Atlanta, GA;

¹⁵Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA;

¹⁶Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Medical Center, New York, NY;

¹⁷Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY;

¹⁸Department of Pediatrics, Weill Cornell Medical College, New York, NY;

¹⁹Division of Hematology and Oncology, Department of Pediatrics, Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA;

²⁰Division of Stem Cell Transplantation and Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA;

²¹Department of Pediatrics and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;

²²Division of Oncology, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA; and

²³Department of Pediatrics, Division of Hematology and Oncology, Stanford University School of Medicine, Stanford, CA

V.A.F. and C.L.P. are joint first authors.

Requests for data sharing may be submitted to Liora M. Schultz; e-mail: liora.schultz@gmail.com.

^✉

Correspondence: Liora M. Shultz, Stanford University School of Medicine, 1000 Welch Rd, Suite #300, Stanford, CA 94304; e-mail: lioras@stanford.edu.

^✉

Corresponding author.

PMCID: PMC8791593 PMID: 34794180

Key Points

CD19 CAR therapy for R/R EM disease, particularly CNS, offers a beneficial option with similar toxicity and survival to BM disease.
There was no increased cytokine release syndrome or neurotoxicity in patients with R/R EM disease, including active CNS disease at infusion.

Visual Abstract

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Abstract

Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (complete response) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both central nervous system (CNS)3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease before CAR therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range, <1-25 years), and in the non-CNS EM cohort it was 13 years (range, 2-26 years). In patients with CNS disease, 88% (35 of 40) achieved a complete response vs only 66% (10 of 15) with non-CNS EM disease. Patients with CNS disease (both with and without BM involvement) had 24-month OS outcomes comparable to those of non-CNS EM or BM only (P = .41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM-only patients (P = .92). No increased toxicity was seen with CNS or non-CNS EM disease (P = .3). Active CNS disease at time of infusion did not affect outcomes. Isolated CNS disease trended toward improved OS compared with combined CNS and BM (P = .12). R/R EM disease can be effectively treated with tisagenlecleucel; toxicity, relapse, and survival rates are comparable to those of patients with BM-only disease. Outcomes for isolated CNS relapse are encouraging.

Introduction

Acute lymphoblastic leukemia (ALL) is the most common malignancy occurring in children, and survival with risk-stratified therapy for B-cell ALL (B-ALL) approaches ≥90%.^1-3 However, for pediatric/young adult patients with relapsed or refractory (R/R) disease, the prognosis remains dismal.^4-6 CD19-specific chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for patients with R/R B-ALL.^7-14 Historically, relapsed extramedullary (EM) disease has been treated with a combination of chemotherapy, radiation, and often allogeneic stem cell transplantation (SCT), depending on the time interval from diagnosis to relapse.^15-19 Experience using CD19-specific CAR T-cell therapy for patients with R/R B-ALL presenting with central nervous system (CNS)3 disease, either isolated or in combination with bone marrow (BM) disease, or non-CNS EM is limited. This is in part because of exclusion of these patients from pivotal clinical trials, including ELIANA (Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients), due to concerns regarding increased toxicity with EM disease and subthreshold BM burden.^9,10

The tolerability and efficacy of CAR T cells in R/R ALL patients with EM disease are still undefined; however, a few reports expanding the treatment paradigm beyond BM disease and pivotal trials have shown effective trafficking of CAR T cells to sites of EM disease, encouraging its use for these patients.^20-23 Increased neurotoxicity in an adult cohort of patients with EM disease treated with a 1928z CAR construct has been reported.¹³ Another report of 27 pediatric patients described a higher rate of neurotoxicity in patients with CNS disease before lymphodepletion, although this cohort included a combination of patients who received either a 41BB or CD28z based CAR construct.²⁴ However, a report on the infusion of 7 patients with tisagenlecleucel who had isolated EM disease (negative or BM disease of <1%) showed no increased neurotoxicity and achievement of a complete response (CR) in all patients.²⁵ Patients receiving either CTL019 and CTL119 for relapsed CNS disease similarly show clearance of CNS disease without increased risk of neurotoxicity and similar survival rates compared with patients without CNS disease at infusion.²⁶ Herein, we report the results of patients who received tisagenlecleucel for R/R EM B-ALL disease as part of the multi-institutional Pediatric Real World CAR Consortium (PRWCC) and describe how patients with R/R EM disease have similar rates of toxicity and survival compared with patients with BM-only disease.

Methods

Study design

We conducted a retrospective analysis of pediatric and young adult patients with R/R B-ALL who were referred for tisagenlecleucel treatment for either isolated EM disease or combined BM + EM disease as part of the PRWCC multi-institutional consortium. Independent institutional review board approval was obtained by all centers, and data were collected by using the REDCap database, which is compliant with the Health Insurance Portability and Accountability Act of 1996. The study was conducted in accordance with the Declaration of Helsinki.

All patients with EM disease at tisagenlecleucel referral were comparatively analyzed against the remaining patients in the PRWCC consortium with BM-only disease. Patients with R/R CNS3 (CNS) disease or new-onset CNS3 disease at the time of referral for CAR T-cell therapy, as evident by the presence of leukemic blasts and ≥5 white blood cells/µL on flow cytometry or cytology from spinal fluid, were further stratified, with patients with isolated CNS3 (iCNS) separated from those with combined CNS + BM disease. To study the impact of active CNS3 disease at time of infusion on both toxicity and outcomes, the total CNS3 cohort (n = 40) was subdivided into active CNS3 disease at infusion (CNS⁺) vs CNS3 disease that cleared before infusion (CNS^–). Patients with CNS2 disease were not included in this CNS cohort and are instead included in the non-EM disease cohort (BM only). Patients with non-CNS EM disease, all of whom had active EM disease at time of lymphodepletion, were distinctly analyzed. The identification of non-CNS EM disease varied by center, imaging, and physician investigation.

Study end points

The primary outcomes of interest were overall survival (OS), relapse-free survival (RFS), and duration of B cell aplasia (BCA). Additional outcomes of interest were response rate assessed at day 28, toxicity, relapse rates, and CD19 antigen expression at relapse. CR was defined as ≤5% BM blasts by morphology, absence of circulating lymphoblasts, and no evidence of EM disease. Minimal residual disease negativity was defined as <0.01% abnormal B cells assessed by using flow cytometry. Relapse was defined as any (medullary or EM) evidence of morphologic, immunophenotypic, cytogenetic, and/or molecular recurrence of primary disease. CD19-positive B-cell recovery was defined as any detectable CD19-positive B cells (>1 cell/µL) on a peripheral blood lymphocyte flow cytometry panel. Toxicity grading was described according to guideline criteria standard to each institution, with cytokine release syndrome (CRS) graded by American Society for Transplantation and Cellular Therapy²⁷ and neurotoxicity (immune effector cell-associated neurotoxicity syndrome) graded by American Society for Transplantation and Cellular Therapy,²⁷ CRES (CAR T cell related encephalopathy syndrome),²⁸ and other.

Statistical analysis

For all analyses, the tisagenlecleucel infusion date was considered time 0, with a data cutoff of March 6, 2020. OS was defined as the time from infusion to death from all causes. Patients alive were censored at their last follow-up date. Time to relapse was defined as the time from the date of infusion to the date of disease relapse. RFS was defined as the time from infusion to any relapse or death. Patients who died before day 28 or did not achieve a CR were excluded from the RFS analysis. The duration of BCA was defined as time from infusion to loss of BCA, with SCT, if prior to loss of BCA or SCT without relapse, as a censored event.

Continuous and categorical data are summarized as median (interquartile range) and frequency. Differences among groups were assessed with Fisher’s exact test and Kruskal-Wallis tests for categorical and continuous data, respectively. Kaplan-Meier analysis was used to estimate OS, RFS, and duration of BCA. A comparative analysis was performed between the CNS, EM cohort, and rest of the cohort with BM-only disease. Differences in survival end points between groups were tested by using a log-rank test.

Results

Patient characteristics

From approval by the US Food and Drug Administration approval to March 6, 2020, a total of 184 evaluable patients were treated with tisagenlecleucel for R/R B-ALL and reported upon in the PRWCC. Fifty-five patients had R/R EM disease (CNS3 disease, n = 40; non-CNS EM disease, n = 15). Baseline characteristics of these cohorts are shown in Table 1. Patients with CNS disease were further stratified according to iCNS disease (n = 23) or combined CNS + BM (n = 17). The entire CNS cohort was also analyzed for presence of active CNS disease at time of infusion: CNS⁺ (n = 9) and CNS^– (n = 31). Sites of non-CNS EM disease at time of infusion included craniofacial (n = 6), bone (n = 3), testes (n = 3), soft tissue (n = 3), renal (n = 2), skin (n = 1), ocular (n = 1), and lung (n = 1) (Table 2). Patients with non-CNS EM disease had either no BM involvement (n = 6) or BM involvement (n = 9). The median duration of follow-up for the entire cohort was 335 days (range, 6-863 days).

Table 1.

Pre-tisagenlecleucel demographic characteristics of patients with R/R CNS disease, non-CNS EM disease, and the remaining cohort with isolated BM disease

Characteristic	CNS disease		P	CNS disease	Non-CNS EM	BM-only disease	P
Characteristic	iCNS (n = 23)	CNS + BM (n = 17)	P	iCNS + CNS + BM (n = 40)	(n = 15)	(n = 129)	P
Age at CAR infusion, y	11 (2-24)	10 (<1-25)	.85	10 (<1-25)	13 (2-26)	13 (<1-26)	.087
Sex (male/female)	18/5	13/4	1.0	31/9	9/6	71/58	.036
Initial NCI risk stratification			.72				.013
Low/standard	11	5		16	4	23
High/very high	9	7		16	6	74
Unknown	3	5		8	5	32
Initial cytogenetics risk			.70				.3
Favorable/intermediate	11	7		18	5	50
Unfavorable	7	3		10	3	53
Unknown	5	7		12	7	26
CNS status at diagnosis			.510				.17
CNS1	16	11		27	13	85
CNS2	4	4		8	1	32
CNS	2	0		2	0	1
Unknown	1	2		3	1	11
No. of relapses before CAR therapy			1.0				.003
0	1	0		1	1	29
≥1	22	17		39	14	100
No. of lines of treatment before CAR therapy			.69				.07
1	1	0		1	0	8
2	5	2		7	1	39
3	7	8		15	3	39
>4	10	7		17	11	43
Prior SCT	0	0	1.0	0	1	10	.16
Previous CRT/CSI	3	2	1.0	5	3	6	.037
Time from diagnosis to CAR infusion, mo	45 (4-135)	52 (5-94)	.76	51 (4-135)	50 (4-171)	27 (3-164)	.01
Time from relapse to CAR infusion, mo	3 (2-19)	2 (1-13)	.50	3 (1-19)	3 (1-12)	3 (0-12)	.10
Prophylactic levetiracetam			1.0				.13
Yes	16	11		27	6	67
No	7	6		13	9	60
Unknown	0	0		0	0	2

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CRT, cranial radiation; CSI, craniospinal radiation; iCNS, isolated CNS disease; NCI, National Cancer Institute.

Table 2.

Sites of the other non-CNS EM disease (n = 15)

Sites of EM disease at infusion^*
Craniofacial	6
Bone	3
Testes	3
Soft tissue	3
Renal	2
Skin	1
Ocular	1
Lung	1

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Patients can have >1 site of EM disease.

The median age at infusion of the CNS cohort was 10 years (range, <1-25 years), and in the non-CNS EM cohort it was 13 years (range, 2-26 years). Three patients with EM were diagnosed with high-risk infant ALL (CNS, n = 2; non-CNS EM, n = 1), but only one received their tisagenlecleucel infusion at <1 year of age to treat an on-therapy combined CNS + BM relapse. Disease refractory to upfront therapy was reported in only 2 patients treated with EM (CNS, n = 1; non-CNS EM, n = 1). The majority of patients had multiple lines of prior therapy, with 80% (32 of 40) of the CNS cohort having >3 lines of therapy before infusion with a median of 51 months (range, 4-135 months) between diagnosis and infusion. Similarly, 93% (14 of 15) of patients with non-CNS EM had >3 lines of therapy before infusion, with a median of 50 months (range, 4-171 months) between diagnosis and infusion. One patient from the entire EM cohort had pre-tisagenlecleucel SCT (non-CNS EM, n = 1; CNS, n = 0). Notably, only 12% of patients with CNS disease (n = 5) had prior cranial or craniospinal radiation before infusion. Remaining patients with BM-only disease had a shorter time from diagnosis to infusion, with a median of 27 months (range, 3-164 months) (P = .01). There was no difference in time from the most recent relapse to infusion between patients with either CNS disease (range, 2-5 months), non-CNS EM disease (range, 2-5 months), or BM-only disease (range, 2-3 months; all median, 3 months). Ninety-six percent of patients (53 of 55) with any EM disease received lymphodepletion with fludarabine (30 mg/m² per day × 4 days) and cyclophosphamide (500 mg/m² per day × 2 days). One patient had renal toxicity requiring a 50% dose reduction of lymphodepletion, and another patient did not receive any lymphodepletion due to pancytopenia (white blood cell count <0.2 K/µL) from preceding bridging chemotherapy

CNS3 disease

Response and toxicity.

Comparable to the response rate from the PRWCC infused cohort of 85%,²⁹ 88% (35 of 40) of patients with CNS disease achieved a CR (Table 3). Sixty-three percent (25 of 40) and 35% (12 of 40) of patients with CNS disease experienced any grade CRS or neurotoxicity, respectively. There was no difference in CRS grade between patients with iCNS compared with CNS + BM (P = .71) as well as patients with CNS⁺ compared with CNS^– (P = .55) (Table 4). Grade 3 or 4 neurotoxicity was not observed in any patients with iCNS, compared with 3 patients with CNS + BM disease (P = .22). Notably, no patients with active CNS⁺ disease at infusion experienced grade 3 or 4 neurotoxicity. Sixty-eight percent of patients with CNS disease (27 of 40) were given levetiracetam as prophylaxis before CAR T-cell therapy. There was no difference in the use of prophylactic levetiracetam between patients with iCNS (70% [16 of 23]) vs combined CNS + BM (65% [11 of 17]; P = 1.0). Treatment of toxicity (either CRS or neurotoxicity) in patients with CNS3 disease included tocilizumab (n = 10), steroids (n = 6), anakinra (n = 2), and siltuximab (n = 1).

Table 3.

Outcomes of patients with R/R CNS disease, non-CNS EM disease, and the rest of the cohort after tisagenlecleucel infusion

Outcome	CNS disease (n = 40)	Non-CNS EM disease (n = 15)	BM-only disease (n = 129)	P
CRS				.30
Grade 1	15	3	27
Grade 2	5	4	23
Grade 3	3	2	14
Grade 4	2	3	14
Grade 5	0	0	1
Unknown	1	0	0
ICANS				.39
Grade 1	9	2	8
Grade 2	2	0	5
Grade 3	1	0	7
Grade 4	2	0	2
Treatment of toxicity ^*				.14
Tocilizumab	10	5	31
Steroids	6	2	18
Other	2	0	4
Response				.35
No CR	4	4	15
CR (% MRD negative)	35 (97%)	10 (90%)	111 (95%)
Died before day 28	1	1	3
Relapsed post-CAR	15	6	45	.91
Site of relapse
CNS	5	0	0
CNS + BM	2	0	2
BM only	8	2	37
BM + other EM	0	2	4
Other EM disease	0	2	2
CD19-negative relapse	5/15	1/6	20/38	.025
Unknown	2	3	3
Time from infusion to relapse, d	101 (30-577)	95 (30-245)	90 (28-645)	.87
SCT post CAR	6	1	38	.06
Rationale for SCT post-CAR				.52
Preemptive	1	0	5
Loss of BCA	0	0	11
Refractory/relapse	4	1	16
MLL rearranged	1	0	2
Alive/dead	31/9	9/6	93/36	.40
Cause of death				.87
Relapse	7	5	26
Infection	2	0	4
CRS	0	0	1
Neurotoxicity	0	0	1
Transplant related	0	1	3
Cardiac related	0	0	1
Loss of BCA	10	8	39	.14
Time from infusion to loss of BCA, d	174 (36-266)	84.5 (29-396)	93 (28-545)	.23

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ICANS, immune effector cell-associated neurotoxicity syndrome; MLL, mixed-lineage leukemia; MRD, minimal residual disease.

Toxicity refers to either CRS or ICANS.

Table 4.

Outcomes of patients with R/R CNS disease categorized into separate cohorts

Outcome	CNS disease (n = 40)^*
Outcome	iCNS (n = 23)	CNS + BM (n = 17)	P	CNS⁺ (n = 9)	CNS^– (n = 31)	P
CRS			.71			.55
Grade 1	9	6		2	13
Grade 2	3	2		1	4
Grade 3	2	1		0	3
Grade 4	0	2		0	2
Unknown	1	0		1	0
ICANS			.22			1.0
Grade 1	5	4		3	6
Grade 2	2	0		1	1
Grade 3	0	1		0	1
Grade 4	0	2		0	2
Response			.07			.54
No CR	1	3		2	2
CR (% MRD negative)	22 (100%)	13 (92%)		7 (100%)	28 (96%)
Died before day 28	0	1		0	1
Relapsed post-CAR	7	8	.34	5	10	.26
Site of relapse			.18			.32
CNS	4	1		3	2
CNS + BM	0	2		0	2
BM only	3	5		2	6
BM + other EM	0	0		0	0
Other EM disease	0	0		0	0
CD19-negative relapse	2/7	3/8	1.0	1/5	4/10	1.0
Unknown	1	1		1	1
Time from infusion to relapse, d	178 (30-577)	61 (27-266)	.20	174 (30-577)	81.5 (27-206)	.54
SCT post-CAR	2	4	0.37	2	4	.60
Rationale for SCT post-CAR			0.23			.54
Preemptive	0	1		0	1
Loss of BCA	0	0		0	0
Refractory/relapse	1	3		2	2
MLL rearranged	1	0		0	1
Alive/dead	20/3	11/6	0.13	7/2	24/7	1.0
Cause of death			1.0			1.0
Relapse	2	5		2	5
Infection	1	1		0	2
CRS	0	0		0	0
Neurotoxicity	0	0		0	0
Transplant related	0	0		0	0
Cardiac related	0	0		0	0
Loss of BCA	5	5	0.72	3	7	.67
Time from infusion to loss of BCA, d	146 (36-192)	174 (148-266)	.48	114 (36-192)	174 (101-266)	.56

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ICANS, immune effector cell-associated neurotoxicity syndrome; MLL, mixed-lineage leukemia; MRD, minimal residual disease.

All 40 patients with R/R CNS disease were put into 2 separate cohorts to evaluate outcomes based on specific patient scenarios and important questions related to treating CNS disease.

Survival.

Twenty-three percent (9 of 40) of patients with CNS disease died after infusion. Causes of death included relapsed disease (n = 7) and infection (n = 2) (Table 3). No patients died of CRS or neurotoxicity. Patients with CNS disease had a 12- and 24-month OS of 75.7% (confidence interval [CI], 62.1-92.2) and 69.3% (CI, 53.4-90.1), respectively. Further comparison of patients with CNS disease revealed similar OS in patients with active CNS⁺ (71% [CI, 44.7-100] for both 12 and 24 months) and CNS^– disease that cleared before infusion (77.6%; CI, 63.1-95.6) and 67.9% (CI, 48.6-94.9) at time of infusion (P = .82) (Figure 1B). The 12- and 24-month OS probabilities were 80.8% (CI, 63.4-100) and 80.8% (CI, 63.4-100) for the iCNS cohort and 68.8% (CI, 49.2-96.2) and 57.4% (CI, 35.1-93.6) for the CNS + BM cohort (P = .12) (Figure 1C).

Figure 1. — **EM disease did not affect OS.** (A) Overall survival of patients with CNS3 disease, non-CNS EM disease, and BM-only disease (P = .41). (B) OS of patients with active CNS disease (CNS⁺) at time of infusion compared with those with CNS disease that cleared (CNS^–) before infusion (P = .82). (C) OS of patients with isolated CNS (iCNS) disease compared with those with combined CNS and BM disease (CNS + BM) (P = .12).

Relapse.

Overall, 38% (15 of 40) of patients with CNS disease relapsed post-tisagenlecleucel, 5 of whom experienced a CD19-negative relapse (Table 3). Two of these CD19-negative relapses were CNS3, one combined with a BM relapse and the other an isolated CNS relapse; the other 3 CD19-negative relapses were BM only. The 12-month RFS probabilities for the CNS⁺ and CNS^– cohorts were 68.6% (CI, 40.3-100) vs 57.5% (CI, 40.3-82.1) (P = .32) (Figure 2B). The 12-month RFS probabilities for the iCNS and CNS + BM cohorts were 66.1% (CI, 46.9-93.1) vs 49.5% (CI, 27.3-89.4), respectively (P = .63) (Figure 2C). The median time from infusion to relapse was 101 days (range, 30-577 days). Sites of relapse included iCNS (n = 5), combined CNS + BM (n = 2), and BM only (n = 8). A total of 6 patients with CNS disease underwent SCT post-CAR; 4 of 6 were due to relapsed disease. The 12-month RFS probability for all patients with CNS disease was 59.4% (CI, 43.7-80.7).

Figure 2. — **EM disease did not affect RFS.** (A) RFS of patients with CNS3 disease, non-CNS EM disease, and BM-only disease (P = .92). (B) RFS of patients with active CNS disease (CNS⁺) at time of infusion compared with those with CNS disease that cleared (CNS^–) before infusion (P = .32). (C) RFS of patients with isolated CNS disease (iCNS) compared with those with combined CNS and BM disease (CNS + BM) (P = .63).

B-cell aplasia.

Twenty-eight percent (10 of 35) of patients with CNS disease lost BCA, with a median time from infusion to BCA loss of 174 days (range, 36-266 days) (Table 3). The 12-month duration of BCA for the CNS cohort was 66.4% (CI, 49.3-89.5). There was no difference in duration of BCA between patients with CNS⁺ (64.3%; CI, 33.8-100) and CNS^– (67.3%; CI, 48.4-93.7) (P = .74) (Figure 3B). Similarly, no difference in the 12-month duration of BCA existed between patients with iCNS or CNS + BM disease compared with the rest of the cohort (67.7% [CI, 47.3-96.9] vs 62.9% [CI, 35.9-100]; P = .71) (Figure 3C).

Figure 3. — **EM disease did not affect the loss of BCA.** (A) The probability of BCA loss of patients with CNS3 disease, non-CNS EM disease, and BM-only disease (P = .14). (B) The probability of BCA loss of patients with active CNS disease (CNS⁺) at time of infusion compared with those with CNS disease that cleared (CNS^–) before infusion (P = .74). (C) The probability of BCA loss of patients with isolated CNS disease (iCNS) compared with those with combined CNS and BM disease (CNS + BM) (P = .71).