Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study

Tanya Siddiqi; David G Maloney; Saad S Kenderian; Danielle M Brander; Kathleen Dorritie; Jacob Soumerai; Peter A Riedell; Nirav N Shah; Rajneesh Nath; Bita Fakhri; Deborah M Stephens; Shuo Ma; Tatyana Feldman; Scott R Solomon; Stephen J Schuster; Serena K Perna; Sherilyn A Tuazon; San-San Ou; Eniko Papp; Leanne Peiser; Yizhe Chen; William G Wierda

doi:10.1016/S0140-6736(23)01052-8

. Author manuscript; available in PMC: 2025 Jan 22.

Published in final edited form as: Lancet. 2023 Jun 6;402(10402):641–654. doi: 10.1016/S0140-6736(23)01052-8

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study

Tanya Siddiqi

¹Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA (T Siddiqi MD); Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA (Prof D G Maloney MD); Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA (S S Kenderian MBChB); Division of Hematologic Malignancies & Cellular Therapy, Duke University Health System, Durham, NC, USA (D M Brander MD); Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA (K Dorritie MD); Department of Medicine, Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA, USA (J Soumerai MD); Section of Hematology/Oncology, Department of Medicine, The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA (P A Riedell MD); Cancer Center, Froedtert Hospital, Medical College of Wisconsin, Milwaukee, WI, USA (N N Shah MD); Stem Cell Transplantation Cellular Therapy and Acute Leukemia, Banner MD Anderson Cancer Center, Gilbert, AZ, USA (R Nath MD); Department of Medicine, Division of Hematology and Blood and Marrow Transplant, University of California San Francisco, San Francisco, CA, USA (B Fakhri MD); Internal Medicine and Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA (D M Stephens DO); Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA (Prof S Ma MD); T Cell Lymphoma Program, John Theurer Cancer Center at Hackensack Meridian Health, Hackensack Meridian Health School of Medicine, Hackensack, NJ, USA (T Feldman MD); Transplant and Cellular Immunotherapy Program, Northside Hospital Cancer Institute, Atlanta, GA, USA (S R Solomon MD); Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA (Prof S J Schuster MD); Bristol Myers Squibb, Princeton, NJ, USA (S K Perna MD, Y Chen PhD); Bristol Myers Squibb, Seattle, WA, USA (S A Tuazon MD, S-S Ou MS, E Papp PhD, L Peiser DPhil); Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA (Prof W G Wierda MD)

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¹, David G Maloney

David G Maloney

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¹, Saad S Kenderian

Saad S Kenderian

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¹, Danielle M Brander

Danielle M Brander

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¹, Kathleen Dorritie

Kathleen Dorritie

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¹, Jacob Soumerai

Jacob Soumerai

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¹, Peter A Riedell

Peter A Riedell

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¹, Nirav N Shah

Nirav N Shah

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¹, Rajneesh Nath

Rajneesh Nath

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¹, Bita Fakhri

Bita Fakhri

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¹, Deborah M Stephens

Deborah M Stephens

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¹, Shuo Ma

Shuo Ma

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¹, Tatyana Feldman

Tatyana Feldman

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¹, Scott R Solomon

Scott R Solomon

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¹, Stephen J Schuster

Stephen J Schuster

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¹, Serena K Perna

Serena K Perna

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¹, Sherilyn A Tuazon

Sherilyn A Tuazon

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¹, San-San Ou

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¹, Eniko Papp

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¹, Leanne Peiser

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¹, Yizhe Chen

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¹, William G Wierda

William G Wierda

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Contributors

TS and WGW contributed to the study concept or design, data acquisition, and data interpretation. DGM contributed to the study concept or design and data acquisition. SSK, DMB, KD, JS, PAR, NNS, RN, BF, DMS, SM, TF, SRS, and SJS contributed to data acquisition. SKP and SAT contributed to the study concept or design and data interpretation. S-SO and YC contributed to data analysis and data interpretation. EP and LP contributed to the study concept or design, data analysis, and data interpretation. SKP, SAT, S-SO, EP, LP, and YC accessed and verified the data. All authors had full access to the data, contributed to writing of the manuscript, approved the final version, and agree to be accountable for all aspects of the work.

^✉

Correspondence to: Dr Tanya Siddiqi, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA tsiddiqi@coh.org

PMCID: PMC11753452 NIHMSID: NIHMS2026426 PMID: 37295445

Abstract

Summary

Background

Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma.

Methods

We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1–2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 10⁶ (dose level 1) or 100 × 10⁶ (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198.

Findings

Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59–70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3–7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9–32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis).

Interpretation

A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable.

Funding

Juno Therapeutics, a Bristol-Myers Squibb Company.

Introduction

Chronic lymphocytic leukaemia and small lymphocytic lymphoma are among the most prevalent haematological malignancies in North America and Europe.¹ Targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and B cell lymphoma 2 (BCL2) inhibitors, alone or combined with CD20 monoclonal antibody, have shown efficacy.^2–6 However, patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma who experience intolerance to or disease progression after BTK inhibitor and BCL2 inhibitor treatment have no established standard of care and poor outcomes, indicating a crucial unmet need.^4,7–12

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8⁺ and CD4⁺ CAR⁺ T cells. The phase 1 dose-escalation portion of TRANSCEND CLL 004 (NCT03331198) established a liso-cel target dose of 100 × 10⁶ CAR⁺ T cells as the recommended phase 2 dose.¹³ Here, we report the primary analysis of the monotherapy portion of TRANSCEND CLL 004.

Methods

Study design and participants

TRANSCEND CLL 004 was a multicentre, open-label, single-arm, phase 1–2 study conducted in the USA. The study enrolled adults (aged ≥18 years) with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, previous BTK inhibitor treatment failure (stable disease or progressive disease as best response, progression after previous response, or discontinuation due to BTK inhibitor intolerance) or who were deemed ineligible for BTK inhibitor treatment, adequate organ function, and an Eastern Cooperative Oncology Group performance status of 0 or 1 (appendix pp 6–8). Patients with high-risk cytogenetics (three or more chromosomal abnormalities, del[17p], mutated TP53, or unmutated immunoglobulin heavy-chain variable gene) needed to have received at least two previous lines of therapy and patients with standard-risk features needed to have received at least three previous lines of therapy. Patients were excluded if they had active CNS leukaemia, Richter transformation, previous gene therapy, or allogeneic haematopoietic stem-cell transplantation in the preceding 100 days before leukapheresis.

The study was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. Institutional review boards at participating institutions approved the study protocol and amendments. All patients provided written informed consent before any study-related procedures. The study protocol is provided in the appendix (pp 48–224).

Procedures

All patients underwent leukapheresis for liso-cel production (appendix p 40). Bridging therapy for disease control (appendix p 9) was allowed at investigator discretion during liso-cel manufacturing. Patients were reassessed for measurable disease before receiving lymphodepleting chemotherapy (fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² intravenously daily for 3 days); 2–7 days later, they received a liso-cel intravenous infusion consisting of equal doses of CD8⁺ and CD4⁺ CAR⁺ T cells at the total target dose level (DL) of 50 × 10⁶ CAR⁺ T cells (DL1) or 100 × 10⁶ CAR⁺ T cells (DL2) in phase 1 and at DL2 in phase 2. There was no minimum lymphocyte cutoff for liso-cel manufacturing. Important protocol deviations are shown in the appendix (p 12).

Outcomes

The primary endpoint was complete response or remission, including complete response or remission with incomplete marrow recovery, based on independent review committee (IRC) evaluation per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria¹⁴ (iwCLL 2018; appendix pp 13–16) in the prespecified subset of efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (primary efficacy analysis set) at DL2, pooled from phase 1 and phase 2 portions of the study. Venetoclax failure was defined as discontinuation of venetoclax due to progression or intolerability, or no objective response within 3 months after initiating venetoclax, per investigator assessment. Key secondary efficacy endpoints for sequential hierarchical analyses were overall response rate and undetectable minimal residual disease (MRD) rate in blood in the primary efficacy analysis set at DL2. Other secondary endpoints were duration of response, time to response, progression-free survival, overall survival, and safety (type, frequency, and severity of adverse events and laboratory abnormalities). Additional secondary endpoints of health-related quality of life, health utility, and healthcare resource utilisation will be reported separately. Exploratory endpoints included undetectable MRD rate in marrow and cellular kinetics.

Efficacy was assessed per iwCLL 2018 by an IRC and investigators at study day 30 and months 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, and 48, or until disease progression or end of study (24 or 48 months; appendix pp 17–18). Complete response or remission (including with incomplete marrow recovery) and partial response or remission (including nodular partial response or remission) were confirmed with a reassessment at least 8 weeks later. MRD was assessed by next-generation sequencing using a clonoSEQ (Adaptive Biotechnologies, Seattle, WA, USA) assay. Undetectable MRD was defined as having less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes at one or more post-infusion timepoint. Patients with unknown MRD status (eg, next-generation sequencing assay calibration failure) were presumed to have detectable MRD, unless otherwise specified.

Duration of response was defined as time from first response (complete response or remission, including with incomplete marrow recovery, or partial response or remission, including nodular partial response or remission) to the earlier date of disease progression or death due to any cause. Duration of complete response or remission (including incomplete marrow recovery) was defined as time from first complete response or remission to the earlier date of disease progression or death due to any cause. Progression-free survival was defined as time from liso-cel infusion to the earlier date of disease progression or death due to any cause. Overall survival was defined as time from liso-cel infusion to the date of death due to any cause.

Neurological events were defined as investigator-identified neurological adverse events related to liso-cel. Adverse events, including neurological events and laboratory abnormalities, were coded using the Medical Dictionary for Regulatory Activities, version 25.1, and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Cytokine release syndrome was graded according to Lee 2014 criteria.¹⁵ For all adverse events, the most severe grade was used for those that occurred more than once in an individual patient. A treatment-emergent adverse event was defined as an adverse event that started any time within 90 days from initiation of liso-cel infusion. Any adverse event occurring after the initiation of another anticancer treatment or liso-cel retreatment was not considered a treatment-emergent adverse event. Cellular kinetics were analysed in blood samples by quantitative PCR¹⁶ to detect the liso-cel CAR transgene and by flow cytometry¹⁷ to assess peripheral CD19⁺ cells or CD19⁺ cell aplasia (defined as <3% of CD19⁺ cells in peripheral blood lymphocytes).

Statistical analysis

The primary endpoint was evaluated in the primary efficacy analysis set at DL2 (appendix p 19). Efficacy analyses were also conducted at each DL in the full efficacy set (all patients who received liso-cel and had measurable disease per IRC before infusion). The primary safety analysis was conducted in the full safety set (all patients who received liso-cel at DL1 or DL2). Patients were not included in the efficacy or safety analyses if they received non-conforming product, defined as any product wherein one of the CD8 or CD4 cell components did not meet one of the requirements to be considered liso-cel but was considered appropriate for infusion.

A minimum of 40 patients in the primary efficacy analysis set at DL2 (estimated enrolment of 120 patients in the full efficacy set at DL2) would provide at least 84% power at a 2·5% one-sided significance level to reject the null hypothesis that the proportion of patients with complete response or remission (including with incomplete marrow recovery) is 5% or less. The primary analysis was conducted when at least 40 patients in the primary efficacy analysis set at DL2 received liso-cel and responders had at least 6 months of follow-up from the initial response or had disease progression, died, or withdrew from the study. The primary and two key secondary endpoints were tested using the gatekeeping procedure to control the type I error rate (appendix p 41). Only if the hypothesis of the primary endpoint (complete response or remission [including with incomplete marrow recovery]; null hypothesis of ≤5%) was rejected at a one-sided significance level of 2·5%, the hypotheses of overall response rate (null hypothesis of ≤40%) and undetectable MRD rate in blood (null hypothesis of ≤5%) could be tested hierarchically. The hypothesis of overall response rate would need to be rejected at a one-sided significance level of 2·5% before the hypothesis of undetectable MRD rate in blood could be tested. Justifications for reference rates used in the hypothesis testing are provided in the appendix (p 10). Time-to-event endpoints were summarised with medians and 95% CIs using the Kaplan-Meier method. Statistical analyses were conducted using SAS version 9.4. This trial is registered with ClinicalTrials.gov, NCT03331198.

Role of the funding source

The funder of the study had a role in study design, data collection, data analysis, data interpretation, and writing of the report.

Results

Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis across 27 sites in the USA (appendix pp 4–5). Of the 137 leukapheresed patients, liso-cel was successfully manufactured for 131 (96%) patients and infused into 117 patients (full safety set), including 49 patients in the primary efficacy analysis set at DL2 (figure 1). Six patients died before treatment due to disease progression (n=1), unspecified adverse event (n=1), septic shock (n=1), anaphylaxis from bridging therapy (n=1), and unknown cause (n=2). The median time from leukapheresis to liso-cel infusion was 36 days (IQR 33–48; appendix p 20). Nine patients received DL1 at a median dose of 43·8 × 10⁶ CAR⁺ T cells (IQR 41·9–45·1) and 108 received DL2 at a median dose of 100·0 × 10⁶ CAR⁺ T cells (99·1–100·7; appendix p 21). At data cutoff (Sept 29, 2022), median on-study follow-up for the full safety set was 21·1 months (IQR 7·3–28·2). 14 patients were treated in the outpatient setting.

Figure 1: — BTK=Bruton tyrosine kinase. CAR=chimeric antigen receptor. DL1=dose level 1, 50 × 10⁶ CAR⁺ T cells. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. Liso-cel=lisocabtagene maraleucel. *At data cutoff (Sept 29, 2022), the conforming status of CAR T-cell product for one patient was not available in the dataset; therefore, the product for this patient was considered non-conforming and the patient was not included in the efficacy and safety analyses that required the receipt of conforming product; after data cutoff, it was confirmed that the patient received conforming product, so this patient will be included in future safety and efficacy analyses. †Safety analyses included all patients who received liso-cel; patients were not included in the safety analyses if they received non-conforming product, defined as any product wherein one of the CD8 or CD4 cell components did not meet one of the requirements to be considered liso-cel but was considered appropriate for infusion. ‡Data from the long-term follow-up study were included for the analyses of study duration, overall survival, and deaths. §Efficacy analyses included patients who received liso-cel and had measurable disease before liso-cel infusion based on independent review committee assessment; patients were excluded if they did not have baseline disease assessment completed or no longer had measurable disease on baseline disease assessment after anticancer therapy for disease control and before liso-cel infusion, or if they developed Richter transformation or mantle cell lymphoma before liso-cel infusion; patients were not included in the efficacy analyses if they received non-conforming product; retreatment with liso-cel was allowed for patients who had a complete response or remission (including with incomplete marrow recovery) with the first liso-cel treatment and subsequently progressed, including with Richter transformation; no independent review committee assessments were performed after retreatment; two patients received liso-cel retreatment in the full population. ¶Venetoclax failure was defined as discontinuation of venetoclax due to disease progression or intolerability and met indications for further therapy per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, or no objective response within 3 months of initiating venetoclax. ||The number of patients screened is unavailable for this subset because the patients’ disease characteristic was not necessarily recorded if they did not meet eligibility criteria.

In the full safety set (n=117), the median age was 65 years (IQR 59–70), 52 (44%) patients had bulky (≥5 cm) lymph nodes, and 97 (83%) had high-risk cytogenetics (table 1). Patients had a median of five lines of previous therapy (IQR 3–7), including BTK inhibitor (117, 100%), chemoimmunotherapy (101, 86%), and PI3K inhibitor (29, 25%); 103 (88%) were refractory to BTK inhibitor, 89 (76%) were refractory to venetoclax, and 70 (60%) had BTK inhibitor progression and venetoclax failure. 89 (76%) patients received bridging therapy during liso-cel manufacturing, primarily venetoclax (39, 44%) and obinutuzumab (25, 28%; appendix p 22). The demographic and baseline characteristics were similar between the full safety set and BTK inhibitor progression and venetoclax failure subset. The demographic and baseline characteristics of the six patients who did not have liso-cel successfully manufactured are provided in the appendix (p 23).

Table 1:

Demographics and baseline characteristics (safety set)

	Full population^*		BTK inhibitor progression and venetoclax failure subset^*

	DL2 (n=108)	Total (n=117)	DL2 (n=66)	Total (n=70)

Age, years	64 (59–70)	65 (59–70)	66 (59–70)	66 (59–70)
Sex
Female	32 (30%)	37 (32%)	16 (24%)	19 (27%)
Male	76 (70%)	80 (68%)	50 (76%)	51 (73%)
Race
White	92 (85%)	99 (85%)	56 (85%)	60 (86%)
Black or African American	3 (3%)	5 (4%)	1 (2%)	1 (1%)
Asian	1 (1%)	1 (1%)	1 (2%)	1 (1%)
Native Hawaiian or other Pacific Islander	1 (1%)	1 (1%)	0	0
Unknown	11 (10%)	11 (9%)	8 (12%)	8 (11%)
Ethnicity
Hispanic or Latino	2 (2%)	3 (3%)	1 (2%)	1 (1%)
Not Hispanic or Latino	98 (91%)	106 (91%)	59 (89%)	63 (90%)
Unknown	8 (7%)	8 (7%)	6 (9%)	6 (9%)
ECOG performance status at screening
0	47 (44%)	48 (41%)	26 (39%)	27 (39%)
1	61 (56%)	69 (59%)	40 (61%)	43 (61%)
Bulky lymph nodes (at least one lesion with the longest diameter of ≥5 cm)
Yes	48 (44%)	52 (44%)	30 (45%)	32 (46%)
No	51 (47%)	56 (48%)	28 (42%)	30 (43%)
Unknown	9 (8%)	9 (8%)	8 (12%)	8 (11%)
SPD, cm²
n	99	108	58	62
Median (IQR)	30·3 (17·1–81·4)	30·0 (16·7–80·1)	35·7 (21·9–88·2)	33·8 (21·9–81·4)
Lactate dehydrogenase, U/L	239·5 (197·0–325·5)	239·0 (197·0–322·0)	238·5 (197·0–322·0)	238·5 (197·0–322·0)
Rai disease stage
0–II	46 (43%)	48 (41%)	26 (39%)	27 (39%)
III or IV	54 (50%)	60 (51%)	34 (52%)	36 (51%)
Unknown or missing	8 (7%)	9 (8%)	6 (9%)	7 (10%)
Binet disease stage
A or B	43 (40%)	45 (38%)	25 (38%)	26 (37%)
C	46 (43%)	53 (45%)	27 (41%)	30 (43%)
Unknown or missing	19 (18%)	19 (16%)	14 (21%)	14 (20%)
High-risk cytogenetics
Any	91 (84%)	97 (83%)	57 (86%)	60 (86%)
del(17p)	46 (43%)	49 (42%)	31 (47%)	33 (47%)
Mutated TP53	50 (46%)	54 (46%)	33 (50%)	35 (50%)
Unmutated IGHV	50 (46%)	54 (46%)	29 (44%)	31 (44%)
At least three chromosomal aberrations	67 (62%)	72 (62%)	41 (62%)	44 (63%)
Previous lines of systemic therapy	5 (3–7)	5 (3–7)	5 (4–7)	5 (4–7)
Two	7 (6%)	7 (6%)	2 (3%)	2 (3%)
Three	21 (19%)	24 (21%)	7 (11%)	7 (10%)
Four	25 (23%)	27 (23%)	17 (26%)	18 (26%)
Five or more	55 (51%)	59 (50%)	40 (61%)	43 (61%)
Previous therapy
Previous BTK inhibitor	108 (100%)	117 (100%)	66 (100%)	70 (100%)
BTK inhibitor refractory^†	95 (88%)	103 (88%)	66 (100%)	70 (100%)
BTK inhibitor relapsed^‡	1 (<1%)	2 (2%)	0	0
BTK inhibitor intolerant only	12 (11%)	12 (10%)	0	0
Previous venetoclax	89 (82%)	94 (80%)	66 (100%)	70 (100%)
Venetoclax refractory^†	84 (78%)	89 (76%)	63 (95%)	67 (96%)
Venetoclax relapsed^‡	0	0	0	0
Venetoclax intolerant only	4 (4%)	4 (3%)	3 (5%)	3 (4%)
Previous BTK inhibitor and venetoclax	89 (82%)	94 (80%)	66 (100%)	70 (100%)
BTK inhibitor progression and venetoclax failure^§	66 (61%)	70 (60%)	66 (100%)	70 (100%)
Previous chemoimmunotherapy	93 (86%)	101 (86%)	58 (88%)	62 (89%)
Previous HSCT	6 (6%)	7 (6%)	6 (9%)	7 (10%)
Previous PI3K inhibitor	28 (26%)	29 (25%)	21 (32%)	22 (31%)
Received bridging therapy	84 (78%)	89 (76%)	53 (80%)	55 (79%)
Time from diagnosis to liso-cel infusion, months	132·5 (83·9–178·2)	128·9 (82·8–172·7)	143·1 (85·1–186·3)	138·5 (84·1–182·9)

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Data are n (%) or median (IQR). BTK=Bruton tyrosine kinase. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. ECOG=Eastern Cooperative Oncology Group. SPD=sum of the product of perpendicular diameters. TP53=tumour protein 53. IGHV=immunoglobulin heavy chain. HSCT=haematopoietic stem-cell transplantation. PI3K=phosphatidylinositol 3-kinase. Liso-cel=lisocabtagene maraleucel. CAR⁺=chimeric antigen receptor-positive.

Nine patients in the full population and four patients in the BTK inhibitor progression and venetoclax failure subset had small lymphocytic lymphoma.

^†

Refractory disease was defined as treatment failure (non-response) or progression within 6 months after the last dose of therapy.

^‡

Relapsed disease was defined as disease progression in a patient who had previously reached complete response or remission (including with incomplete marrow recovery) or partial response or remission (including nodular partial response or remission) for a period of at least 6 months.

^§

A patient was included if they progressed on a BTK inhibitor and met one of the following criteria: discontinued venetoclax due to disease progression or intolerability and disease met indications for further therapy per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria; or did not reach an objective response within 3 months of initiating therapy.

The primary endpoint of IRC-assessed complete response or remission (including with incomplete marrow recovery) rate in the primary efficacy analysis set at DL2 (n=49) was met at 18% (n=9; 95% CI 9–32; p=0·0006; table 2). The key secondary endpoint of overall response rate was 43% (n=21; 95% CI 29–58) and not statistically significant compared with the null hypothesis (p=0·39). Based on investigator assessment per iwCLL 2018, the rate of complete response or remission (including with incomplete marrow recovery) was 24% (n=12; 13·3–38·9) and the rate of overall response was 57% (n=28; 42–71), with an 87% concordance with IRC assessments. In 30 patients with del(17p), mutated TP53, or both, the rate of complete response or remission (including with incomplete marrow recovery) was 23% (n=7; 10–42) and the rate of overall response was 47% (n=14; 28–66). In the primary efficacy analysis set at DL2, the undetectable MRD rate was 63% (n=31; 48–77) in blood and 59% (n=29; 44–73) in marrow, with a 96% concordance of detectable MRD and undetectable MRD between blood and marrow. Median time to first response was 1·2 months (IQR 1·0–3·0) and median time to first complete response or remission (including with incomplete marrow recovery) was 3·0 months (1·2–3·3). Median duration of response was 35·3 months (11·0–not reached [NR]) and median duration of complete response or remission (including with incomplete marrow recovery) was NR (table 2, figure 2A). Median progression-free survival was 11·9 months (5·7–26·2; figure 2B); median overall survival was 30·3 months (11·2–NR; figure 2C).

Table 2:

Efficacy endpoints

	Full population		BTK inhibitor progression and venetoclax failure subset

	DL2 (n=87)	Total (n=96)	DL2 (n=49)	Total (n=53)

Primary endpoint^*
IRC-assessed rate of complete response or remission (including incomplete marrow recovery), % (95% CI)^†	18% (11–28)	18% (11–27)	18% (9–32)^‡	19% (9–32)
p value	··	··	0·0006	··
Key secondary efficacy endpoints
IRC-assessed overall response, % (95% CI)^†	47% (36–58)	48% (38–58)	43% (29–58)^§	43% (30–58)
p value	··	··	0·39	··
Undetectable MRD in blood
n	56	62	31	33
Rate, % (95% CI)^†	64% (53–74)	65% (54–74)	63% (48–77)	62% (48–75)
Undetectable MRD in marrow (exploratory endpoint)
n	51	57	29	31
Rate, % (95% CI)^†	59% (48–69)	59% (49–69)	59% (44–73)	59% (44–72)
Other secondary efficacy endpoints
Best overall response, n (%)
Complete response or remission (including incomplete marrow recovery)	16 (18%)	17 (18%)	9 (18%)	10 (19%)
Partial response or remission (including nodular partial response or remission)	25 (29%)	29 (30%)	12 (24%)	13 (25%)
Stable disease	34 (39%)	38 (40%)	21 (43%)	23 (43%)
Progressive disease	6 (7%)	6 (6%)	4 (8%)	4 (8%)
Not evaluable	6 (7%)	6 (6%)	3 (6%)	3 (6%)
Time to first response, months, median (IQR)	1·5 (1·0–3·1)	2·0 (1·0–3·1)	1·2 (1·0–3·0)	1·1 (1·0–3·0)
Time to first complete response or remission (including incomplete marrow recovery), months, median (IQR)	4·4 (3·0–7·5)	5·5 (3·0–8·8)	3·0 (1·2–3·3)	3·0 (1·2–6·0)
Duration of response
Months, median (95% CI)^¶	35·25 (19·78–NR)	35·25 (19·78–NR)	35·25 (11·01–NR)	35·25 (12·42–NR)
Probability at 12 months, % (95% CI)^¶	84·2 (68·2–92·6)	83·5 (68·5–91·8)	74·7 (49·4–88·6)	76·1 (51·6–89·3)
Probability at 18 months, % (95% CI)^¶	72·3 (54·4–84·1)	70·3 (53·5–82·0)	69·3 (44·0–84·9)	71·0 (46·4–85·8)
Duration of complete response or remission (including incomplete marrow recovery), months, median (95% CI)^¶	NR (12·22–NR)	NR	NR	NR
Progression-free survival
Number of events	87	96	49	53
Months, median (95% CI)^¶	17·97 (9·43–30·13)	17·87 (9·43–26·87)	11·93 (5·72–26·18)	11·93 (5·72–26·18)
Probability at 12 months, % (95% CI)^¶	57·0 (45·0–67·3)	56·6 (45·3–66·5)	46·8 (31·3–60·8)	46·6 (31·7–60·1)
Probability at 18 months, % (95% CI)^¶	47·6 (35·7–58·7)	46·9 (35·6–57·4)	41·7 (26·7–56·0)	41·8 (27·3–55·6)
Progression-free survival in patients with complete response or remission (including incomplete marrow recovery)
Number of events	16	17	9	10
Months, median (95% CI)^¶	NR (30·13–NR)	NR (30·13–NR)	NR	NR
Probability at 12 months, % (95% CI)^¶	100 (NR–NR)	100 (NR–NR)	100 (NR–NR)	100 (NR–NR)
Probability at 18 months, % (95% CI)^¶	100 (NR–NR)	100 (NR–NR)	100 (NR–NR)	100 (NR–NR)
Overall survival
Number of events	32	36	20	22
Months, median (95% CI)^¶	43·17 (26·87–NR)	43·17 (27·07–NR)	30·26 (11·24–NR)	30·26 (17·71–NR)
Probability at 12 months, % (95% CI)^¶	71·7 (60·5–80·2)	73·4 (63·0–81·4)	65·8 (49·6–77·8)	68·7 (53·4–79·9)
Probability at 18 months, % (95% CI)^¶	70·3 (59·0–79·1)	71·0 (60·3–79·3)	63·1 (46·9–75·7)	63·8 (48·1–75·8)

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BTK=Bruton tyrosine kinase. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. IRC=independent review committee. MRD=minimal residual disease. NR=not reached. CAR⁺=chimeric antigen receptor-positive.

The primary endpoint was in the BTK inhibitor progression and venetoclax failure subset at DL2 only.

^†

Two-sided 95% exact Clopper-Pearson CIs.

^‡

One-sided p value from binomial exact test (null hypothesis, ≤5%).

^§

One-sided p value from binomial exact test (null hypothesis, ≤40%); the p value would not be presented if the hypothesis for complete response or remission (including incomplete marrow recovery) was not rejected at the one-sided 2·5% significant level.

^¶

The Kaplan-Meier method was used to obtain two-sided 95% CIs.

Figure 2: — Kaplan-Meier curves are shown for duration of response by best overall response (A), progression-free survival by best overall response (B), overall survival by best overall response (C), and progression-free survival by MRD status in blood (D). Data are expressed as median (95% CI). CAR⁺=chimeric antigen receptor-positive. CR=complete response or remission. CRi=complete response or remission with incomplete marrow recovery. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. Liso-cel=lisocabtagene maraleucel. MRD=minimal residual disease. nPR=nodular partial response or remission. NR=not reached. PR=partial response or remission.

*Patients were not evaluable for MRD (eg, calibration failure).

In a post-hoc analysis of MRD-evaluable patients in the primary efficacy analysis set at DL2, all those with complete response or remission (including with incomplete marrow recovery) or partial response or remission (including nodular partial response or remission) reached undetectable MRD in both blood and marrow. 12 of 20 patients with stable disease reached undetectable MRD status in blood and ten of 20 reached undetectable MRD status in marrow (appendix p 24). For most patients, the clearance of chronic lymphocytic leukaemia cells in both compartments occurred by day 30 (appendix p 25). In exploratory analyses of undetectable MRD and progression-free survival, median progression-free survival was 26·2 months (95% CI 10·3–NR) in patients with undetectable MRD and 2·8 months (0·8–NR) in those with detectable MRD in blood (figure 2D). In a post-hoc analysis, median progression-free survival was 6·4 months (95% CI 3·7–12·0) in patients with stable disease and undetectable MRD and 2·8 months (1·9–NR) in patients with stable disease and detectable MRD.

In the full efficacy set at DL2 (n=87), efficacy outcomes per IRC were consistent with those in the primary efficacy analysis set at DL2 (table 2, appendix pp 42–45). Response rates in the intention-to-treat population were also similar to those in the efficacy analysis sets (appendix p 26).

In the full safety set (n=117), 108 (92%) patients experienced treatment-emergent adverse events of grade 3 or higher (table 3, appendix pp 27–29), most commonly cytopenias: neutropenia (71, 61%), anaemia (61, 52%), and thrombocytopenia (48, 41%). 51 deaths occurred on the study (appendix pp 30–31), of which eight occurred before and 43 occurred after CAR T-cell infusion. Three of the eight deaths before and 27 of 43 deaths (including six with Richter transformation) after CAR T-cell infusion were due to disease progression. Of the 16 deaths that occurred without progression after CAR T-cell infusion, five were due to adverse events (all within 90 days) and 11 were due to other reasons (all >90 days; COVID-19, n=6). Of the five deaths from adverse events, one was considered by the investigator to be related to liso-cel; this patient died at day 14 after liso-cel infusion due to macrophage activation syndrome-haemophagocytic lymphohistiocytosis. Among the four deaths from adverse events unrelated to liso-cel, one occurred at day 78 after liso-cel infusion due to respiratory failure in the context of the diagnosis of a grade 3 pneumonia on day 63; one occurred at day 19 due to multidrug-resistant Enterobacter cloacae sepsis; one occurred at day 14 due to Escherichia coli sepsis; and one patient had a history of neutropenia and hypogammaglobulinaemia before liso-cel infusion and died of grade 5 disseminated Aspergillus infection at day 58 after liso-cel infusion. Any-grade cytokine release syndrome was reported in 99 (85%) patients (table 4, appendix pp 32–33). Ten (9%) patients had grade 3 cytokine release syndrome and no grade 4 or 5 cytokine release syndrome occurred. Any-grade neurological events were reported in 53 (45%) patients. 21 (18%) patients had grade 3 neurological events and one (1%) patient had a grade 4 neurological event. No grade 5 neurological events occurred. Among the 21 patients with grade 3 neurological events (individual patients could have had more than one neurological event), nine had confusional state, seven had encephalopathy, four had agitation, three had aphasia, two had delirium, and two had somnolence; one patient each had grade 3 headache, restless leg syndrome, fatigue, muscular weakness, tremor, mental status change, and cognitive disorder. One patient had grade 4 encephalopathy and grade 4 somnolence. The most common treatment-emergent neurological adverse events regardless of attribution were headache (34, 29%), confusional state (31, 26%), and dizziness (29, 25%; appendix p 34). For cytokine release syndrome management, 78 (67%) patients received tocilizumab or corticosteroids or both. For neurological event management, 39 (33%) patients received tocilizumab or corticosteroids or both. Grade 3 or higher infections were reported in 20 (17%) patients. Prolonged cytopenias (grade ≥3 at day 30) were reported in 63 (54%) patients; of patients with prolonged cytopenia and laboratory results after day 30, 15 (100%) of 15 patients with anaemia, 36 (80%) of 45 patients with neutropenia, and 27 (73%) of 37 patients with thrombocytopenia had recovered to grade 2 or lower within 90 days after liso-cel infusion (appendix p 35). Of the nine patients who had ongoing neutropenia at day 90, three resolved to grade 2 or lower, and six had not resolved by the end of the study. One of the nine patients who had ongoing neutropenia at day 90 experienced grade 3 or higher infection; this patient, as noted earlier, had a history of neutropenia and hypogammaglobulinaemia before liso-cel infusion and died of grade 5 Aspergillus infection. Second primary malignancies were reported in 11 (9%) patients, none of which were considered related to liso-cel. Safety outcomes at DL2 and in the BTK inhibitor progression and venetoclax failure subset were consistent with those in the full population (appendix pp 27–35).

Table 3:

Treatment-emergent adverse events (safety set)

	Any grade	Grade 3	Grade 4	Grade 5

Any treatment-emergent adverse event	117 (100%)	18 (15%)	85 (73%)	5 (4%)^*
Cytokine release syndrome	99 (85%)	10 (9%)	0	0
Anaemia	78 (67%)	61 (52%)	0	0
Neutropenia	72 (62%)	11 (9%)	60 (51%)	0
Thrombocytopenia	58 (50%)	14 (12%)	34 (29%)	0
Fatigue	40 (34%)	7 (6%)	0	0
Nausea	39 (33%)	0	0	0
Diarrhoea	34 (29%)	1 (1%)	0	0
Headache	34 (29%)	1 (1%)	0	0
Leukopenia	34 (29%)	3 (3%)	28 (24%)	0
Hypokalaemia	32 (27%)	2 (2%)	0	0
Pyrexia	32 (27%)	1 (1%)	0	0
Confusional state	31 (26%)	11 (9%)	0	0
Hypocalcaemia	30 (26%)	5 (4%)	0	0
Constipation	29 (25%)	0	0	0
Decreased appetite	29 (25%)	4 (3%)	0	0
Dizziness	29 (25%)	0	0	0
Hypophosphataemia	28 (24%)	14 (12%)	2 (2%)	0
Tremor	28 (24%)	2 (2%)	0	0
Lymphopenia	24 (21%)	7 (6%)	16 (14%)	0
Hypomagnesaemia	24 (21%)	0	0	0
Decreased blood fibrinogen	23 (20%)	6 (5%)	0	0
Hyperglycaemia	23 (20%)	10 (9%)	2 (2%)	0

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Data are n (%). The table includes the most common treatment-emergent adverse events (≥20%) in the full population (n=117). Liso-cel=lisocabtagene maraleucel.

Four of the five deaths from adverse events were considered by investigators to be unrelated to liso-cel (respiratory failure, sepsis, Escherichia coli infection, and invasive aspergillosis; n=1 each) and one death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis)

Table 4:

Adverse events of special interest and management of cytokine release syndrome and neurological events (safety set)

	Full population (n=117)

Patients with cytokine release syndrome
Any grade	99 (85%)
Grade 1	43 (37%)
Grade 2	46 (39%)
Grade 3	10 (9%)
Grade 4	0
Grade 5	0
Time to cytokine release syndrome onset, days^*	4 (1–7)
Time to cytokine release syndrome resolution, days^*	6 (4–11)
Patients with neurological events ^†
Any grade	53 (45%)
Grade 1	13 (11%)
Grade 2	18 (15%)
Grade 3	21 (18%)
Grade 4	1 (1%)
Grade 5	0
Time to neurological event onset, days^*	7 (4–11)
Time to neurological event resolution, days^*	7 (4–16)
Tocilizumab and corticosteroid use for cytokine release syndrome
Doses of tocilizumab (n=76)	1 (1–2)
Tocilizumab only	41 (35%)
Corticosteroids only	2 (2%)
Both tocilizumab and corticosteroids	35 (30%)
Tocilizumab or corticosteroids or both	78 (67%)
Tocilizumab and corticosteroid use for neurological event
Doses of tocilizumab (n=8)	1 (1–1)
Tocilizumab only	0
Corticosteroids only	31 (26%)
Both tocilizumab and corticosteroids	8 (7%)
Tocilizumab or corticosteroids or both	39 (33%)
Other adverse events of special interest
Prolonged cytopenia^‡	63 (54%)
Grade ≥3 infections^§	20 (17%)
Hypogammaglobulinaemia^¶	18 (15%)
Tumour lysis syndrome	13 (11%)
Second primary malignancy^\|\|	11 (9%)
Macrophage activation syndrome^**	4 (3%)

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Data are n (%) or median (IQR). Liso-cel=lisocabtagene maraleucel.

Any event that stopped and started again within 7 days was considered a single episode; time to resolution was defined as the number of days from onset of the first event to when the last event of the first episode ended; patients with an unresolved episode were excluded.

^†

Neurological events were defined as investigator-identified neurological adverse events related to liso-cel.

^‡

Defined as grade ≥3 laboratory abnormalities of one or more of neutropenia, anaemia, or thrombocytopenia at day 30 after liso-cel infusion.

^§

Infection includes grade ≥3 treatment-emergent adverse events from the infections and infestations system organ class by adverse event high-level group term.

^¶

Based on adverse events only; adverse events from the 90-day treatment-emergent period, post-treatment-emergent period, and long-term follow-up were included; grade 3 hypogammaglobulinaemia occurred in three patients, with no grade 4 or 5 events during the study.

^||

Based on adverse events only; adverse events from the 90-day treatment-emergent period, post-treatment-emergent period, and long-term follow-up were included.

^**

Grade ≥3 macrophage activation syndrome events occurred in three patients (grade 3, n=1; grade 4, n=1; grade 5, n=1).

Six patients had a previous allogeneic haematopoietic stem-cell transplantation and one patient had an autologous transplantation. None of these patients developed graft-versus-host disease. Three of these patients developed grade 3 or higher infections and four patients developed prolonged cytopenia. No unusual safety signals were observed in patients who had previous allogeneic or autologous haematopoietic stem-cell transplantation.

In the cellular kinetic set (n=117), liso-cel exhibited rapid expansion with median time to maximum expansion of 14 days (IQR 10–15) after infusion (appendix p 36). Median maximum expansion was 76 622 copies per μg (IQR 29 568–182 265) and median area under the curve from 0 to 28 days after infusion was 663 910 day*copies per μg (IQR 204 380–1 741 815). Persistence of liso-cel transgene was detected up to 36 months after infusion (one of four evaluable patients at month 36; patient was in complete response or remission (including with incomplete marrow recovery); appendix p 46). CD19⁺ cell aplasia increased from 24 (21%) of 117 patients at baseline to 89 (85%) of 105 on day 30 after liso-cel infusion; the proportion of patients with CD19⁺ cell aplasia remained high up to month 24 (appendix p 37). In a post-hoc analysis, in both the full population and the BTK inhibitor progression and venetoclax failure subset, higher liso-cel expansion was observed in responders than in non-responders and in patients with undetectable MRD than in those without (appendix pp 38–39). Post-hoc analyses indicated that liso-cel expansion in patients with stable disease and undetectable MRD was generally similar to expansion in patients with complete response or remission (including with incomplete marrow recovery) or partial response or remission (including nodular partial response or remission), but it was higher than expansion in patients with stable disease and detectable MRD (figure 3). Liso-cel expansion coincided with a decrease in peripheral CD19⁺ cells in patients with stable disease and undetectable MRD, similar to those with undetectable MRD and complete response or remission (including with incomplete marrow recovery) or partial response or remission (including nodular partial response or remission). By contrast, patients with stable disease and detectable MRD or progressive disease had a lower expansion and did not clear CD19⁺ cells over time.

Figure 3: — Relationship between liso-cel cellular kinetic parameter AUC_(0–28d) and efficacy by response (A) and by best overall response and MRD status in blood (B). Total CD19⁺ cells versus liso-cel expansion in responders (C), patients with stable disease (D, E), and patients with progressive disease (F). In parts A and B, the cellular kinetic parameter AUC_(0–28d) values from individual patients are shown as circles, with the median of each subgroup shown by lines. Patients with unknown MRD status were excluded. Patients with progressive disease who also had detectable MRD are not shown because the sample size was small (n=2). AUC_(0–28d)=area under the curve from 0 to 28 days after infusion. CAR⁺=chimeric antigen receptor-positive. CR=complete response or remission. CRi=complete response or remission with incomplete marrow recovery. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. Liso-cel=lisocabtagene maraleucel. MRD=minimal residual disease. nPR=nodular partial response or remission. PR=partial response or remission. uMRD=undetectable minimal residual disease.

Discussion

Despite recent advances, outcomes remain dismal for patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after disease progression on previous BTK inhibitor and venetoclax failure.^4,7,10,11 Specifically, heavily pretreated patients with high-risk cytogenetic features have low complete response or remission rates (including with incomplete marrow recovery) of 0–5% and short median overall survival.^{4,7,8,10,11,18} Real-world evidence indicates progressively worse outcomes as treatment options become exhausted.⁹ In later lines of therapy, chronic lymphocytic leukaemia no longer appears to behave as an indolent or chronic disease.⁹ Safe and effective treatment options in this population are scarce.^5,19–22 In previous studies, CD19-directed CAR T-cell therapies showed promise as a potential treatment modality for relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma but were not investigated further.^4,23–26 T cells from patients with chronic lymphocytic leukaemia are known to be dysfunctional²⁷ and producing functional CAR T cells capable of both in vivo expansion and persistence can be challenging. We postulate that the manufacturing process could be an important contributing factor to the success of liso-cel to overcome these challenges compared with previous CAR T-cell studies in chronic lymphocytic leukaemia, specifically in enrichment of T cells and early removal of impurities during the manufacturing process. The liso-cel manufacturing process is designed to produce a consistent product of high purity and we previously demonstrated that liso-cel could be successfully produced across several CD19⁺ haematological malignancies, including chronic lymphocytic leukaemia.^13,28 Heterogeneity in donor starting material can affect CAR T-cell attributes such as phenotype and function. In addition, increased absolute lymphocyte counts in patients with chronic lymphocytic leukaemia correspond to reduced CD3⁺ cells and increased CD19⁺ cells in the leukapheresis starting material for CAR T-cell manufacturing. Separate manufacture and administration of CD8⁺ and CD4⁺ liso-cel CAR⁺ T-cell components at a defined composition are distinguishing features of liso-cel and might be important in relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma because patients can have a skewed CD8⁺-to-CD4⁺ ratio and reduced numbers of peripheral T cells.²⁶ Furthermore, the early selection of CD8⁺ and CD4⁺ T cells and removal of non-T-cell impurities before activation and transduction of the CAR T cells enables normalisation of process intermediates and increases the CD8⁺ and CD4⁺ CAR⁺ T-cell lineage purity. Additionally, this step enables removal of the high proportion of residual CD19⁺ cells observed in chronic lymphocytic leukaemia leukapheresis material before transduction, thereby reducing the risk of these cells inhibiting CAR T-cell expansion during manufacturing and helping to prevent transduction of CD19⁺ cells with CAR T-cell construct.^26,29 In TRANSCEND CLL 004, liso-cel was successfully manufactured for 96% of patients who underwent leukapheresis and most infused patients received close to the target dose, which was accompanied by high in vivo expansion. Enrolled patients were heavily pretreated; the majority had received previous BTK inhibitor and venetoclax, most had high-risk disease, and almost half had bulky disease, overall representing a population with a crucial unmet need. The study met its primary endpoint, with liso-cel achieving a rate of complete response or remission (including with incomplete marrow recovery) of 18% in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after BTK inhibitor progression and venetoclax failure. Responses were durable after a one-time infusion with liso-cel, with a median duration of response of 35·3 months overall and not reached in patients with complete response or remission (including with incomplete marrow recovery). Efficacy outcomes were similar in the full population (relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after progression on BTK inhibitor), showing a clinical benefit of liso-cel in this broader population.

Liso-cel generated complete response or remission (including with incomplete marrow recovery) and induced high undetectable MRD rates in both blood and marrow (>95% concordance). We also showed that undetectable MRD versus detectable MRD was associated with longer progression-free survival, irrespective of best overall response. Undetectable MRD was reached by day 30 post infusion in most patients. All MRD-evaluable patients with complete response or remission (including with incomplete marrow recovery) or partial response or remission (including nodular partial response or remission) reached undetectable MRD in both blood and marrow. About half of MRD-evaluable patients with stable disease reached undetectable MRD status in blood, marrow, or both. Among patients with stable disease, those who achieved undetectable MRD in blood had higher liso-cel expansion with longer median progression-free survival compared with those who had detectable MRD, suggesting that these patients derive clinical benefit from liso-cel even without meeting response criteria by iwCLL 2018.

Liso-cel was associated with higher incidences of cytokine release syndrome and neurological events than were reported for large B cell lymphoma,^30–32 which is consistent with other CAR T-cell studies in chronic lymphocytic leukaemia^4,23–26 and might be related to the underlying biology of the disease. One grade 4 neurological event, no grade 4 cytokine release syndrome, and no grade 5 cytokine release syndrome or neurological events were reported in this study; cytokine release syndrome and neurological events were manageable with tocilizumab, corticosteroid treatment, or both, with the majority receiving one dose of tocilizumab. Although prolonged cytopenias were reported in 63 (54%) patients, most recovered to grade 2 or lower within 3 months after liso-cel infusion. Grade 3 or higher infections occurred in 20 (17%) patients; the majority were manageable with standard treatments.

Liso-cel has the potential to fill a gap in the treatment landscape for patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma who have experienced disease progression on previous BTK inhibitor and venetoclax failure. Whereas most current and emerging therapies target BTK, BCL2, PI3K, or anti-CD20 with continuous treatment, liso-cel represents a new mechanism of action with a single dose of treatment. Even with investigational non-covalent BTK inhibitors, risk of mutations that cause resistance to these therapies are emerging. Moreover, unlike current therapies, liso-cel is a one-time infusion that does not require continuous treatment. In this patient population that has exhausted all standard therapies and has limited treatment options available, liso-cel has shown a positive benefit–risk profile.

This study is limited by the single-arm design. In addition, the study enrolled patients with heavily pretreated relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma whose disease had failed multiple previous lines of therapy, including BTK inhibitor and venetoclax. In this patient population, the dropout rate after leukapheresis was 15% (20 of 137 patients), despite a high manufacturing success rate of 96% (131 of 137) and optional bridging therapy for disease control during liso-cel manufacturing. Among the reasons for dropout were accelerated disease progression, which led to patient death or no longer meeting eligibility criteria. The follow-up period for duration of response and survival outcomes is still short, with more than 50% of responders ongoing and about 60% of efficacy-evaluable patients censored for overall survival. Longer follow-up will provide further insight into the durability of response and long-term survival benefits of liso-cel in relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, because single-dose treatment with a long treatment-free interval is an important benefit to patients. To further understand the potential association between CD19⁺ cell levels and disease relapse, additional investigation is needed, because the assay used in this study does not distinguish between malignant and normal CD19⁺ cells.

In summary, liso-cel induced durable complete response or remission in patients with difficult-to-treat relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients with BTK inhibitor progression and venetoclax failure, with a manageable safety profile. These results support a one-time infusion of liso-cel as a potential new treatment modality for relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma.

Supplementary Material

NIHMS2026426-supplement-1.docx^{(279.3KB, docx)}

Research in context.

Evidence before this study

We searched PubMed for clinical trials published from Nov 6, 1997, to Nov 6, 2017, using the terms “chimeric antigen receptor” and (“chronic lymphocytic leukemia” or “small lymphocytic lymphoma”) with no language restrictions. Our search identified clinical data from six small, single-centre studies and one case report on chimeric antigen receptor (CAR) T-cell therapies in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. These studies evaluated the feasibility of CAR T-cell therapies as a new treatment modality in chronic lymphocytic leukaemia or small lymphocytic lymphoma; however, in most cases, producing functional CAR T cells capable of both in vivo expansion and persistence was challenging. In addition, data were scarce for patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after disease progression on previous Bruton tyrosine kinase (BTK) inhibitor and venetoclax failure. At the time of TRANSCEND CLL 004 initiation, BTK inhibitor and venetoclax had shown efficacy in relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, but cases of relapse and refractoriness were also observed. Patients with BTK inhibitor progression and venetoclax failure represent a population with a new and rapidly growing unmet therapeutic need.

Added value of this study

TRANSCEND CLL 004 (NCT03331198) is the first multicentre clinical trial of CD19-directed CAR T-cell therapy for patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. This study is the first to report efficacy for CAR T-cell therapy in relapsed or refractory chronic lymphocytic leukaemia after progression on BTK inhibitor and venetoclax failure. Lisocabtagene maraleucel (liso-cel) was successfully manufactured for most patients and the majority received their intended target dose. This study demonstrated the feasibility of CAR T-cell therapy as a treatment option in relapsed or refractory chronic lymphocytic leukaemia. The depth and durability of the responses and manageable safety profile observed with a single dose of liso-cel in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after BTK inhibitor progression and venetoclax failure indicate that liso-cel is a potentially effective treatment for this population with a high unmet medical need.

Implications of all the available evidence

The TRANSCEND CLL 004 data indicate that a one-time infusion of liso-cel is a potential new treatment modality for patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma after BTK inhibitor progression and venetoclax failure, who have limited treatment options and a crucial unmet need.

Acknowledgments

We thank all study sites and patients for their participation in the study; Jason Wall (BMS) for assistance with minimal residual disease analyses; and Nanda Balasubramanian (BMS) for assistance with quantitative PCR data in cellular kinetic analyses. This study was funded by Juno Therapeutics, a BMS Company. Writing and editorial assistance were provided by Bu Reinen, Robert Schupp, and Lauren Connor (The Lockwood Group, Stamford, CT, USA), funded by BMS. BF was affiliated with the University of California San Francisco in San Francisco, CA, USA at the time of the study and is now affiliated with the Division of Hematology at Stanford University School of Medicine in Stanford, CA, USA.

Footnotes

Declaration of interests

TS discloses institutional support to conduct this study and manuscript writing support for this manuscript from Bristol Myers Squibb (BMS); fees for speakers’ bureaus from BMS, AstraZeneca, and BeiGene; participation on a data safety monitoring board for BeiGene; participation on an advisory board for AbbVie, BeiGene, BMS, Celgene, a BMS Company, AstraZeneca, and Gilead. DGM discloses institutional research funding from Kite, Juno Therapeutics, a BMS Company, Celgene, a BMS Company, Legend Biotech, and BMS; consulting fees from A2 Biotherapeutics, Navan Technologies, Chimeric Therapeutics, Genentech, BMS, ImmPACT Bio, Gilead Sciences, and Interius; rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics, a BMS Company; advisory boards for BMS, Caribou Biosciences, Celgene, a BMS Company, Genentech, Incyte, Janssen, Juno Therapeutics, a BMS Company, Mustang Bio, MorphoSys, Kite, Lilly, Novartis, and Umoja; and stock options from A2 Biotherapeutics and Navan Technologies. SSK discloses grants or contracts from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs; royalties or licences from Novartis, Humanigen, Mettaforge Therapeutics, Sendero, and Mustang Bio; participation on a scientific advisory board for Kite, Juno Therapeutics, a BMS Company, Novartis, Humanigen, Calibr, Torque, Capstan Therapeutics, Lentigen, LEAH Labs, and Luminary Therapeutics; participation on a data safety monitoring board for Humanigen; and research funding from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs. DMB discloses grants paid to their institution (Duke University) and the role of site principal investigator for clinical trials from AbbVie, ArQule/Merck, Ascentage, Acerta, BeiGene, Catapult, DTRM Biopharma, Genentech, Celgene, a BMS Company, Juno Therapeutics, a BMS Company, BMS, MEI Pharma, Newave, Novartis, and TG Therapeutics; consulting fees from Genentech, AbbVie, and Pharmacyclics; participation on a panel of the National Comprehensive Cancer Network for chronic lymphocytic leukaemia or small lymphocytic lymphoma and hairy cell leukaemia, a registry steering committee for informCLL (Pharmacyclics) and CORE (AbbVie), and an expert medical council for Chronic Lymphocytic Leukemia Society (unpaid), and being a leukaemia committee member and trial champion of S1925 for Alliance in Clinical Trials (unpaid); and writing support for abstracts or manuscripts from AbbVie, BeiGene, Pharmacyclics, and TG Therapeutics. KD discloses institutional research funding for this study from BMS; institutional grants or contracts from BMS, Kite/Gilead, and Genmab; consulting fees for participation on an advisory board for BMS; and honoraria for participation in American Society of Hematology Congress Connect. JS discloses consulting fees from AbbVie, AstraZeneca, BeiGene, BMS, Roche, Seattle Genetics, and TG Therapeutics; and research funding paid to their institution from Adaptive Biotechnologies, BeiGene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics. PAR discloses consulting fees from AbbVie, BMS, Janssen, Novartis, BeiGene, Kite/Gilead, Intellia Therapeutics, Sana Biotechnology, CVS Caremark, Genmab, Pharmacyclics, Takeda, Karyopharm Therapeutics, Nektar Therapeutics, Nurix Therapeutics, and ADC Therapeutics; honoraria from Kite/Gilead; and support for attending meetings or travel from Nektar Therapeutics. NNS discloses support for this manuscript from Juno Therapeutics, a BMS Company; research funding from Loxo@Lilly and Miltenyi Biotec; consulting fees from Loxo@Lilly and Miltenyi Biotec; participation on a data safety monitoring board for Incyte; participation on an advisory board for Epizyme, Janssen, Kite Pharma, Incyte, Seattle Genetics, Novartis, Juno Therapeutics, a BMS Company, TG Therapeutics, and Umoja Biopharma; travel support from Loxo@Lilly and Miltenyi Biotec; stock or stock options from Tundra Targeted Therapeutics; and is a scientific advisory board member and founder of Tundra Targeted Therapeutics. RN discloses consulting fees from Actinium Pharmaceuticals; consulting fees for participation on an advisory board for Incyte; and stock or stock options from Pfizer. BF discloses research funding from BMS; consulting fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, BMS, Genentech, Genmab, Loxo@Lilly, Pharmacyclics, and TG Therapeutics; honoraria from Curio Science and Medscape; support for attending meetings or travel from AbbVie and Loxo@Lilly; and participation on a guideline panel for chronic lymphocytic leukaemia and hairy cell leukaemia for the National Comprehensive Cancer Network (unpaid). DMS discloses grants or contracts from Celgene, a BMS Company, Novartis, AstraZeneca, Merck, MingSight Pharmaceuticals, and Newave; consulting fees from Lilly, Genentech, Pharmacyclics/Janssen, Karyopharm Therapeutics, BeiGene, Innate Pharma, AstraZeneca, AbbVie, CSL Behring, Celgene, a BMS Company, TG Therapeutics, and Innate Pharma; and research funding from Acerta Pharma, Gilead Sciences, Karyopharm Therapeutics, MingSight Pharmaceuticals, ArQule, Novartis, Verastem Oncology, and Juno Therapeutics, a BMS Company. SM discloses institutional funding from Juno Therapeutics, a BMS Company, BeiGene, Loxo@Lilly, AstraZeneca, and AbbVie; consulting fees from TG Therapeutics; honoraria from AstraZeneca, BeiGene, Janssen, Lilly, and Pharmacyclics; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, BeiGene, BMS, Genentech, and Janssen. TF discloses consulting fees from Seattle Genetics, BMS, Genmab, ADC Therapeutics, and AstraZeneca; speakers’ bureau fees from Seattle Genetics and Kite; travel expenses from Seattle Genetics and Takeda; honoraria from Seattle Genetics, Pharmacyclics/Janssen, AbbVie, BMS, Kite, Bayer, and Takeda; and research funding from BMS, Seattle Genetics, Portola Pharmaceuticals, Eisai, Kyowa Kirin, Amgen, Viracta Therapeutics, Cell Medica, Roche, Trillium Therapeutics, and Pfizer. SJS discloses consulting fees from Caribou Biosciences, Genentech/Roche, Genmab, Kite Pharma, Incyte, Legend Biotech, MorphoSys, Mustang Bio, Nordic Nanovector, and Novartis; honoraria from Novartis and Takeda; a patent for combination therapies of chimeric antigen receptor and programmed cell death protein-1 inhibitors licensed to Novartis; research funding from Merck and Genentech/Roche; and travel accommodations from Genentech/Roche and Novartis. SKP is an employee of BMS and a shareholder of BMS and Autolus. SAT, S-SO, EP, LP, and YC are employees and shareholders of BMS. WGW discloses travel expenses from AbbVie, Genentech, and Eli Lilly; and research funding from AbbVie, Acerta Pharma, BMS, Cyclacel Pharmaceuticals, Genentech, Gilead Sciences, GlaxoSmithKline, Loxo@Lilly, Novartis, and Oncternal Therapeutics. SRS declares no competing interests.

Data sharing

The BMS policy on data sharing can be found online.

References

1.O’Reilly A, Murphy J, Rawe S, Garvey M. Chronic lymphocytic leukemia: a review of front-line treatment options, with a focus on elderly CLL patients. Clin Lymphoma Myeloma Leuk 2018; 18: 249–56. [DOI] [PubMed] [Google Scholar]
2.Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med 2019; 380: 2095–103. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018; 378: 1107–20. [DOI] [PubMed] [Google Scholar]
4.Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol 2021; 14: 69. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Sharman JP, Coutre SE, Furman RR, et al. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol 2019; 37: 1391–402. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 2018; 132: 2446–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Sedlarikova L, Petrackova A, Papajik T, Turcsanyi P, Kriegova E. Resistance-associated mutations in chronic lymphocytic leukemia patients treated with novel agents. Front Oncol 2020; 10: 894. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv 2021; 5: 4054–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Mato AR, Hess LM, Chen Y, et al. Outcomes for patients with chronic lymphocytic leukemia (CLL) previously treated with both a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Clin Lymphoma Myeloma Leuk 2023; 23: 57–67. [DOI] [PubMed] [Google Scholar]
10.Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib. Blood 2016; 128: 637. [Google Scholar]
11.Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res 2020; 26: 3589–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018; 19: 65–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood 2022; 139: 1794–806. [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018; 131: 2745–60. [DOI] [PubMed] [Google Scholar]
15.Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124: 188–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Ogasawara K, Dodds M, Mack T, Lymp J, Dell’Aringa J, Smith J. Population cellular kinetics of lisocabtagene maraleucel, an autologous CD19-directed chimeric antigen receptor T-cell product, in patients with relapsed/refractory large B-cell lymphoma. Clin Pharmacokinet 2021; 60: 1621–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Ogasawara K, Lymp J, Mack T, et al. In vivo cellular expansion of lisocabtagene maraleucel and association with efficacy and safety in relapsed/refractory large B-cell lymphoma. Clin Pharmacol Ther 2022; 112: 81–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.AbbVie. VENCLEXTA (venetoclax) prescribing information. June, 2022. https://www.rxabbvie.com/pdf/venclexta.pdf (accessed Feb 23, 2023).
19.Gribben JG. Stem cell transplantation in chronic lymphocytic leukemia. Biol Blood Marrow Transplant 2009; 15 (1 suppl): 53–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet 2021; 397: 892–901. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Mato A, Nabhan C, Lamanna N, et al. The Connect CLL Registry: final analysis of 1494 patients with chronic lymphocytic leukemia across 199 US sites. Blood Adv 2020; 4: 1407–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Eyre TA, Hess LM, Sugihara T, et al. Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Leuk Lymphoma 2023; published online March 29. 10.1080/10428194.2023.2190436. [DOI] [PubMed] [Google Scholar]
23.Geyer MB, Rivière I, Sénéchal B, et al. Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight 2019; 5: e122627. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol 2017; 35: 3010–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Flinn IW, Jaeger U, Shah NN, et al. A first-in-human study of YTB323, a novel, autologous CD19-directed CAR-T cell therapy manufactured using the novel T-chargeTM platform, for the treatment of patients (pts) with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). Blood 2021; 138 (suppl 1): 740. [Google Scholar]
26.Heyman BM, Tzachanis D, Kipps TJ. Recent advances in CAR T-cell therapy for patients with chronic lymphocytic leukemia. Cancers (Basel) 2022; 14: 1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Peters FS, Strefford JC, Eldering E, Kater AP. T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective. Haematologica 2021; 106: 1234–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Teoh J, Brown LF. Developing lisocabtagene maraleucel chimeric antigen receptor T-cell manufacturing for improved process, product quality and consistency across CD19⁺ hematologic indications. Cytotherapy 2022; 24: 962–73. [DOI] [PubMed] [Google Scholar]
29.Ruella M, Xu J, Barrett DM, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med 2018; 24: 1499–503. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol 2022; 23: 1066–77. [DOI] [PubMed] [Google Scholar]
31.Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood 2023; 141: 1675–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020; 396: 839–52. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

NIHMS2026426-supplement-1.docx^{(279.3KB, docx)}

[R1] 1.O’Reilly A, Murphy J, Rawe S, Garvey M. Chronic lymphocytic leukemia: a review of front-line treatment options, with a focus on elderly CLL patients. Clin Lymphoma Myeloma Leuk 2018; 18: 249–56. [DOI] [PubMed] [Google Scholar]

[R2] 2.Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med 2019; 380: 2095–103. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018; 378: 1107–20. [DOI] [PubMed] [Google Scholar]

[R4] 4.Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol 2021; 14: 69. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Sharman JP, Coutre SE, Furman RR, et al. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol 2019; 37: 1391–402. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] 6.Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 2018; 132: 2446–55. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] 7.Sedlarikova L, Petrackova A, Papajik T, Turcsanyi P, Kriegova E. Resistance-associated mutations in chronic lymphocytic leukemia patients treated with novel agents. Front Oncol 2020; 10: 894. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] 8.Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv 2021; 5: 4054–58. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] 9.Mato AR, Hess LM, Chen Y, et al. Outcomes for patients with chronic lymphocytic leukemia (CLL) previously treated with both a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Clin Lymphoma Myeloma Leuk 2023; 23: 57–67. [DOI] [PubMed] [Google Scholar]

[R10] 10.Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib. Blood 2016; 128: 637. [Google Scholar]

[R11] 11.Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res 2020; 26: 3589–96. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] 12.Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018; 19: 65–75. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] 13.Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood 2022; 139: 1794–806. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R14] 14.Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018; 131: 2745–60. [DOI] [PubMed] [Google Scholar]

[R15] 15.Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124: 188–95. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] 16.Ogasawara K, Dodds M, Mack T, Lymp J, Dell’Aringa J, Smith J. Population cellular kinetics of lisocabtagene maraleucel, an autologous CD19-directed chimeric antigen receptor T-cell product, in patients with relapsed/refractory large B-cell lymphoma. Clin Pharmacokinet 2021; 60: 1621–33. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R17] 17.Ogasawara K, Lymp J, Mack T, et al. In vivo cellular expansion of lisocabtagene maraleucel and association with efficacy and safety in relapsed/refractory large B-cell lymphoma. Clin Pharmacol Ther 2022; 112: 81–89. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] 18.AbbVie. VENCLEXTA (venetoclax) prescribing information. June, 2022. https://www.rxabbvie.com/pdf/venclexta.pdf (accessed Feb 23, 2023).

[R19] 19.Gribben JG. Stem cell transplantation in chronic lymphocytic leukemia. Biol Blood Marrow Transplant 2009; 15 (1 suppl): 53–58. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] 20.Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet 2021; 397: 892–901. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R21] 21.Mato A, Nabhan C, Lamanna N, et al. The Connect CLL Registry: final analysis of 1494 patients with chronic lymphocytic leukemia across 199 US sites. Blood Adv 2020; 4: 1407–18. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R22] 22.Eyre TA, Hess LM, Sugihara T, et al. Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study. Leuk Lymphoma 2023; published online March 29. 10.1080/10428194.2023.2190436. [DOI] [PubMed] [Google Scholar]

[R23] 23.Geyer MB, Rivière I, Sénéchal B, et al. Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight 2019; 5: e122627. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R24] 24.Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol 2017; 35: 3010–20. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R25] 25.Flinn IW, Jaeger U, Shah NN, et al. A first-in-human study of YTB323, a novel, autologous CD19-directed CAR-T cell therapy manufactured using the novel T-chargeTM platform, for the treatment of patients (pts) with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). Blood 2021; 138 (suppl 1): 740. [Google Scholar]

[R26] 26.Heyman BM, Tzachanis D, Kipps TJ. Recent advances in CAR T-cell therapy for patients with chronic lymphocytic leukemia. Cancers (Basel) 2022; 14: 1715. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R27] 27.Peters FS, Strefford JC, Eldering E, Kater AP. T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective. Haematologica 2021; 106: 1234–43. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R28] 28.Teoh J, Brown LF. Developing lisocabtagene maraleucel chimeric antigen receptor T-cell manufacturing for improved process, product quality and consistency across CD19⁺ hematologic indications. Cytotherapy 2022; 24: 962–73. [DOI] [PubMed] [Google Scholar]

[R29] 29.Ruella M, Xu J, Barrett DM, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med 2018; 24: 1499–503. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] 30.Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol 2022; 23: 1066–77. [DOI] [PubMed] [Google Scholar]

[R31] 31.Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood 2023; 141: 1675–84. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] 32.Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020; 396: 839–52. [DOI] [PubMed] [Google Scholar]

PERMALINK

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study

Tanya Siddiqi

David G Maloney

Saad S Kenderian

Danielle M Brander

Kathleen Dorritie

Jacob Soumerai

Peter A Riedell

Nirav N Shah

Rajneesh Nath

Bita Fakhri

Deborah M Stephens

Shuo Ma

Tatyana Feldman

Scott R Solomon

Stephen J Schuster

Serena K Perna

Sherilyn A Tuazon

San-San Ou

Eniko Papp

Leanne Peiser

Yizhe Chen

William G Wierda

Abstract

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Methods

Study design and participants

Procedures

Outcomes

Statistical analysis

Role of the funding source

Results

Figure 1: Trial profile.

Table 1:

Table 2:

Figure 2: Kaplan-Meier curves in the primary efficacy analysis set at DL2.

Table 3:

Table 4:

Figure 3: Cellular kinetics and total CD19+ cells in the full population at DL2.

Discussion

Supplementary Material

Research in context.

Evidence before this study

Added value of this study

Implications of all the available evidence

Acknowledgments

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Figure 3: Cellular kinetics and total CD19⁺ cells in the full population at DL2.