Abstract
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has led to unprecedented results to date in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), yet its clinical application in elderly patients with R/R DLBCL remains somewhat limited. In this study, a total of 31 R/R DLBCL patients older than 65 years of age were enrolled and received humanized anti-CD19 CAR T-cell therapy. Patients were stratified into a fit, unfit, or frail group according to the comprehensive geriatric assessment (CGA). The fit group had a higher objective response (OR) rate (ORR) and complete response (CR) rate than that of the unfit/frail group, but there was no difference in the part response (PR) rate between the groups. The unfit/frail group was more likely to experience AEs than the fit group. The peak proportion of anti-CD19 CAR T-cells in the fit group was significantly higher than that of the unfit/frail group. The CGA can be used to effectively predict the treatment response, adverse events, and long-term survival.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for 30–40% of cases, with the median age of onset being older than 65 years [Citation1]. Although the five-year survival rate for patients with DLBCL has risen to more than 60% with the application of standardized treatments and hematopoietic stem cell transplantation, nearly half of patients progress to relapsed/refractory (R/R) DLBCL. Patients with R/R DLBCL, especially elderly individuals, have a poor prognosis [Citation2,Citation3], so new treatments are needed to prolong survival and improve the prognosis of this population.
As a revolutionary immunotherapy therapy, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has achieved unprecedented results in hematological tumors [Citation4]. As CD19 is expressed on the surface of most B-cell malignant tumors but not on pluripotent bone marrow stem cells, CD19 has been used as a target for B-cell malignancies, including B-cell acute lymphoblastic leukemia, NHL, multiple myeloma, and chronic lymphocytic leukemia [Citation5]. Despite the wide application and high efficacy of anti-CD19 CAR T-cell therapy, reports of adverse events (AEs) such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS) have influenced its use [Citation6]. Especially in elderly patients, AEs associated with anti-CD19 CAR T-cell therapy might be more obvious.
Although anti-CD19 CAR T-cell therapy has been reported in the treatment of NHL, including R/R DLBCL, few studies to date have assessed the safety of anti-CD19 CAR T-cell therapy in elderly R/R DLBCL patients, and its clinical application in the elderly R/R DLBCL population is limited. In ZUMA-1 [Citation7] to R/R DLBCL patients who received CAR T-cell therapy, the CR rate in patients ≥65 years was higher than that of in patients <65 years (75% vs. 53%). Lin et al. [Citation8] reported 49 R/R DLBCL patients (24 patients >65 years, 25 patients <65 years) who received CAR T-cell therapy with a median follow-up of 179 days. The CR rate at 100 days was 51%, while the 6-month progression-free survival (PFS) and overall survival (OS) were 48% and 71%, respectively. Neither of the two studies carried out a comprehensive geriatric assessment (CGA) of fit, unfit, and frail groups of R/R DLBCL patients over 65 years of age and further analyzed the differences in efficacy and side effects in the three groups. The CGA is an effective system designed to evaluate the prognosis and improve the survival of elderly patients with cancer. The CGA system includes age, activities of daily living (ADL), instrumental ADL (IADL), and the Cumulative Illness Rating Score for Geriatrics (CIRS-G) [Citation9].
In this study, elderly R/R DLBCL patients were grouped according to their CGA results (fit vs. unfit/frail) before receiving humanized anti-CD19 CAR T-cell therapy. We then analyzed the efficacy and AEs of anti-CD19 CAR T-cell therapy and compared findings between these groups.
Methods
Clinical trial participants
From September 2018 to February 2020, we conducted a single-arm, single-center clinical study. A total of 31 patients older than 65 years of age with R/R DLBCL who met the R/R DLBCL standard defined by the World Health Organization were included [Citation10]. Our study inclusion criteria included R/R DLBCL patients, but those with primary central nervous system DLBCL were not included. All patients were enrolled in a clinical trial of humanized anti-CD19 CAR-modified T-cell therapy for R/R DLBCL (ChiCTR1800018059) and signed an informed consent form before enrollment. From the date of anti-CD19 CAR T-cell infusion, follow-up was carried out up to the cutoff date (31 March 2021) or the date of death.
For eligibility, patients had to be ≥18 years old, have a Karnofsky score ≥60, meet the WHO diagnostic criteria for R/R DLBCL, have measurable or evaluable lesions, and have well-functioning main tissues and organs: (1) liver function: ALT/AST <3 times the upper limit of normal (ULN) and bilirubin ≤34.2 μmol/L, (2) renal function: creatinine <220 μmol/L, (3) lung function: indoor oxygen saturation ≥95%, and (4) heart function: left ventricular ejection fraction (LVEF) ≥40%. The key exclusion criteria were as follows: females who were pregnant (positive urine/blood pregnancy test) or breastfeeding, patients with uncontrollable infectious diseases within 4 weeks before enrollment, patients with active hepatitis B/C, and patients with HIV infection.
Patient groups
Before the R/R DLBCL patients were enrolled in the anti-CD19 CAR T-cell therapy, CGA was performed on all the patients. Patients younger than 80 years of age with normal ADLs and IADLs scores, no grade 3 or 4 comorbidities, and less than five grade 2 comorbidities were classified into the fit group. Those older than 80 years of age with an ADLs score of five points, an IADLs score of six or seven points, no grade 3 or 4 comorbidities, and five to eight grade 2 comorbidities were included in the unfit group. Finally, patients older than 80 years of age or younger patients with any grade 3 or 4 comorbidities or more than eight grade 2 comorbidities or with higher scores on the ADLs/IADLs scales were included in the frail group ().
Table 1. Grouping criteria for comprehensive geriatric assessment system.
Anti-CD19 CAR T-cell therapy
Peripheral blood mononuclear cells of all the 31 R/R DLBCL patients were separated from peripheral venous blood. The lentivirus containing the humanized CD19 CAR gene construct was supplied by Shanghai Genbase Biotechnology (Shanghai, China). The CAR T-cells were composed of a humanized anti-CD19 antigen-binding region (scFv); CD8-α hinge; and a transmembrane domain, the 4-1BB-CD3ζ costimulatory-activation domain (). When the anti-CD19 CAR T-cells were harvested, their transduction efficiency was analyzed by flow cytometry.
Figure 1. Structure and infusion of humanized anti-CD19 CAR T-cells. (A) CAR T-cells were composed of a humanized anti-CD19 antigen-binding region (scFv), CD8-α hinge, and a transmembrane domain, the 4-1BB-CD3ζ costimulatory-activation domain. (B) Participants received a lymphodepletion therapy regimen (fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2) from four to two days before receiving anti-CD19 CAR T-cell therapy.
The participants received a lymphodepletion therapy regimen (fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2) from four to two days before receiving anti-CD19 CAR T-cell therapy. Then, on day 0, humanized anti-CD19 CAR T-cells were infused at a dose of 2 × 106/kg ().
Objectives and clinical response criteria
The primary study endpoint was the incidence of AEs. Secondary endpoints included the objective response (OR) rate (ORR), complete response (CR) rate, part response (PR) rate, OS, PFS, and CAR T-cell therapy duration. Patients were monitored with computed tomography or positron-emission tomography-computed tomography at month 3, month 6, month 12, and month 24 after anti-CD19 CAR T-cell infusion. Only stage IV R/R DLBCL patients received biopsies at month 3, month 6, month 12, and month 24 after anti-CD19 CAR T-cell infusion. Clinical response was assessed according to the Lugano Revised Criteria for Response Assessment for Malignant Lymphoma [Citation11], which considered CR, PR, stable disease (SD), progressive disease (PD), and relapse. Patients who obtained PR and SD received maintenance therapy with a BTK inhibitor or lenalidomide.
AEs observed after humanized anti-CD19 CAR T-cell infusion
We used the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.03) and Lee et al.’s [Citation12] modified criteria to assess AEs, including CRS. ICANS grade was evaluated in accordance with the American Society for Blood and Marrow Transplantation (ASBM) ICANS Consensus Grading for Adults [Citation13]. The interleukin (IL)-1β, IL-6, IL-2R, tumor necrosis factor-α (TNF-α), IL-8, IL-10, C-reactive protein (CRP), and ferritin levels in peripheral blood serum after humanized anti-CD19 CAR T-cell infusion were measured by quantitative immunofluorescence analysis.
Results
Patient characteristics
The median age of the 31 patients enrolled in our study was 73 years (range: 65–86 years). Seventeen (54.8%), 10 (32.3%), and four (12.9%) of these patients were categorized into the fit, unfit, and frail groups, respectively (). The patient characteristics of the total 31 R/R DLBCL patients before anti-CD19 CAR T-cell therapy are presented in . The median time from leukocyte apheresis to infusion was 14.4 days (range: 12–16 days). The median time from infusion to data cutoff was 16 months (range: 0.5–20 months).
Table 2. Baseline characteristics of the patients (n = 31).
Clinical responses
All 31 R/R DLBCL patients were followed up with to the cutoff date in our study. One to two months after anti-CD19 CAR T-cell infusion, we evaluated the efficacy in all patients. The best ORR was 77.4% (24/31). Among all 31 patients, 16 patients (51.6%) experienced a CR, eight patients (25.8%) experienced a PR, and seven patients (22.6%) attained SD ().
Figure 2. Feasibility assessments of humanized anti-CD19 CAR T-cells. (A) Treatment response and duration after beginning CAR T-cell infusion. (B) The Kaplan–Meier estimates of the PFS. The median PFS lengths of the two groups were 11.4 months and 7.0 months (p=.037). (C) The Kaplan–Meier estimates of the OS. The median overall survival lengths of the two groups were not reached and 11.0 months (p=.002).
Analysis based on the CGA system showed that the ORR, CR, and PR rates in the fit group were 88.2%, 58.8%, and 29.4%, respectively, while the ORR, CR, and PR rates of the unfit/frail group were 64.3%, 42.9%, and 21.4%, respectively. As such, the ORR and CR rates were higher in the fit group than in the unfit/frail group (p = .003 and p = .012), while there was no difference in the PR rate between these two groups (p = .182) (). Additionally, the fit group had a higher median PFS rate than the unfit/frail group (11.4 months vs. 7.0 months; p = .037) (). The median OS in the fit group (not reached) was better than that of the unfit/frail group (11.0 months) (p = .002) ().
Table 3. Clinical responses in CGA subgroup.
Among the 16 patients who obtained a CR, 13 patients (81.3%) maintained their CR for more than 12 months, but the other three patients experienced relapses at 12 months, 12 months, and 11 months, respectively, after CAR T-cell infusion ().
Safety and adverse effects
All patients experienced CAR T-cell treatment-related AEs (). The most common AEs of grade 3 or higher were leukopenia (35.5%), anemia (32.3%), and pyrexia (19.4%). CRS occurred in 16 patients (51.6%), with four patients (12.9%) experiencing grade 3 or higher CRS (including one patient in the fit group and three patients in the unfit/frail group). The median time of CRS after CAR T-cell infusion was 4.6 days (range: 3–7 days). In this study, ICANS of any grade occurred in five patients (16.1%) within one month after infusion, although only one patient (3.2%) experienced grade 3 ICANS in the unfit/frail group. The median time of ICANS onset was five days (range: 3–8 days), and the median duration of ICANS was seven days (range: 3–10 days).
Table 4. Adverse event associated with treatment, n (%).
A subgroup analysis of AEs showed that the unfit/frail group was more likely to experience CRS, hematological toxicity, cardiovascular events, increased aminotransferase levels, and increased creatinine levels than the fit group (p = .023, p = .017, p = .042, p = .016, and p = .026). There was no significant difference in other AEs between these two groups (). Varying degrees of infection were found in two patients in the fit group and five patients in the unfit/frail group; all seven of these patients were diagnosed with bacterial infection and cured by antibiotic treatment. During the follow-up period, no fungal or viral infections were observed. It is noteworthy that the two patients who died from heart failure and malignant arrhythmia were in the unfit/frail group.
Table 5. CGA subgroup analysis of adverse events, n (%).
Among the inflammatory mediators detected, IL-6, IL-10, and CRP levels were associated with CRS grade, while IL-1, IL-2R, TNF-α, IL-8, and ferritin levels were not associated with CRS grade. IL-6 and CRP levels were higher in the unfit/frail group. However, there was no difference in the other inflammatory factors between the two groups.
The expansion of humanized anti-CD19 CAR T-cells
Following humanized anti-CD19 CAR T-cell therapy, the proportions of anti-CD19 CAR T-cells in peripheral blood were observed at 0, 7, 14, 30, and 60 days following infusion (). The median expansion peaks of anti-CD19 CAR T-cells were 24.59%±9.39% in the fit group and 15.21%±5.30% in the unfit/frail group. The peak proportion of anti-CD19 CAR T-cells in the fit group was significantly higher than that in the unfit/frail group (p = .003) (). Next, we compared the peak proportions of anti-CD19 CAR T-cells in the two groups that had an OR and, similarly, found that it was higher in the fit group (n = 15) (29.12%±8.41%) than in the unfit/frail group (n = 9) (18.78%±2.57%) (p = .019) ().
Figure 3. The expansion of anti-CD19 CAR T-cells. (A) The proportions of anti-CD19 CAR T-cells changed within 60 days after infusion in the fit group (n = 17). (B) The proportions of anti-CD19 CAR T-cells changed within 60 days after infusion in the unfit/frail group (n = 14). (C) The peak proportion of anti-CD19 CAR T-cells in the fit group was significantly higher than that in the unfit/frail group (24.59%±9.39% vs. 15.21%±5.30%; p=.003). (D) The proportion of anti-CD19 CAR T-cells in patients with an ORR was higher in the fit group than in the unfit/frail group (29.12%±8.41%% vs. 18.78%±2.57%; p=.019).
Discussion
In our study, 31 patients with R/R DLBCL older than 65 years of age were treated with humanized CD19 CAR T-cells. Twenty-four patients (77.4%) obtained an ORR, 16 patients (51.6%) obtained a CR, and 13 patients (41.9%) maintained a CR for more than 12 months. In the SCHOLAR-1 study [Citation3], for patients ≥65 years of age, available treatments resulted in an ORR of only 19% and a one-year survival rate of 30% in the period before CART treatment. Therefore, for elderly patients with R/R DLBCL, CAR T-cell therapy could achieve satisfactory efficacy. Compared with other studies of elderly R/R DLBCL treated with CAR T-cell therapy, our results were similar to those in younger R/R DLBCL patients [Citation14–19]. Moreover, in older R/R DLBCL patients, the CR rate (51.6%) was similar to that in Lin et al.’s study (51%) [Citation8] and inferior to that in the ZUMA-1 study (75%) [Citation7]. The CGA grouping method showed that the ORR, CR, median PFS, and median OS in the fit group were higher than those in the unfit/frail group, suggesting that further stratification of DLBCL patients older than 65 years of age could help in the evaluation of treatment efficacy and more accurate prognosis prediction.
Compared with young patients, older patients tend to have multiple complications, a poorer physical condition, viscera function weakness, a multidrug regimen, and other problems. Although all the patients in our study experienced CD19 CAR T-cell treatment-related AEs, only two patients in the unfit/frail group developed irreversible cardiac insufficiency, including heart failure and malignant arrhythmia, after 10 and 12 days of infusion, respectively, before dying after aggressive treatment. The 51.5% CRS incidence rate and the 12.9% incidence rate of grade 3 or higher CRS were similar to those in the ZUMA-1 study [Citation7]. It should be noted that the incidence of ICANS was lower in our study than in the ZUMA-1 study [Citation7], which might be related to the adoption of humanized CAR and the addition of a CD8-α hinge in the CAR T-cell structure [Citation20]. With the application of glucocorticoids and tocilizumab [Citation13,Citation21,Citation22], CRS and ICANS are mostly reversible without clinical sequelae. Even with the extension of follow-up time, no new serious AEs were recorded.
Within one month after CAR T-cell infusion, a total of seven patients (22.6%) developed treatment-related infections, similar to previous studies [Citation23]. There was no increase in infection due to advanced age. Significantly, all seven patients had CRS of grade 2 or higher, which also verified the correlation between the severity of CRS and CAR T-cell treatment-associated infections. We define cardiovascular events as arrhythmias, heart failure, and cardiovascular death [Citation24]. The incidence of cardiovascular events (19.4%) in our study was higher than that in a previous study (12%) [Citation24], but most events were manageable. The incidence of cardiovascular death was within the acceptable range (6.5%) in our study.
On the other hand, the unfit/frail group had a poor general condition and limited organ reserve function. This may be why unfit/frail patients experienced more severe CRS and other AEs despite the smaller number of CAR T-cell infusions. When elderly patients did not respond to CAR T, the condition of the patients in the unfit/frail group rapidly worsened due to their poor general condition and limited organ reserve function. This may be the reason the two groups of patients had similar PFS curves but clearly separated OS curves. It is necessary to carry out relevant prospective studies among elderly DLBCL patients in the future assessing whether the CGA system could be used to evaluate and adjust the infusion dose of CAR T-cells to reduce AEs.
The analysis of peripheral blood inflammatory factors confirmed that the severity of CRS was correlated with the expression levels of IL-6, IL-10, and CRP in peripheral blood [Citation25–28]. The higher levels of IL-6 and CRP in the unfit/frail group may be related to the higher rate of AEs in this group.
We examined the proportions of anti-CA19 CAR T-cells in peripheral blood within two months after infusion. The median peak proportion of anti-CD19 CAR T-cells in the fit group exceeded that of the unfit/frail group and showed similar results in the two groups that obtained ORRs, which may be the reason why the fit group achieved a higher ORR and CR rate.
In conclusion, despite the limitations of a small sample size and short follow-up time, our results demonstrate positive efficacy and controlled side effects of humanized anti-CD19 CAR T-cell therapy in elderly patients. Elderly patients should not be excluded from receiving CAR T-cell therapy. The CGA system is used to stratify elderly patients with R/R DLBCL under CAR T-cell therapy to effectively predict their treatment response, adverse reactions, and long-term survival. In the future, we look forward to more prospective randomized controlled studies that will guide treatment through CGA stratification, and this will help develop a combination of CGA scales suitable for elderly R/R DLBCL patients and standardize them to help more effectively stratify patients and guide treatment.
Author contributions
Concept and design: DQ. Drafting or revised of the manuscript: ZH. Acquisition of data: LM, LQ, WJ, LCC, JYY, MJX, and LJY. Analysis and interpretation of data: LM and LQ. Writing, review, and/or revision of manuscript: all authors. Study supervision: DQ.
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Download PDF (235.2 KB)Acknowledgements
We thank the patients for their participation in our study.
Trial registration: The patients were enrolled in a clinical trial registered as ChiCTR1800018059.
Ethics approval and consent to participate: This study was approved by the Medical Ethics Committee of the Department of Hematology at Tianjin First Center Hospital (Tianjin, China) (approval no.: 2015002X and 2018N105KY). The patients provided written informed consent in accordance with the Declaration of Helsinki. The clinical trial in our study was registered at http://www.chictr.org.cn/index.aspx as ChiCTR1800018059.
Disclosure statement
The authors have no conflicts of interest to report.
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