Summary
Background
The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.
Methods
This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16–70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10−3 and had exhausted standard treatment options were enrolled in the study, which comprised a dose-escalation phase of up to three UCART19 doses followed by a safety expansion phase. Patients underwent lymphodepletion with fludarabine (30 mg/m2 per day intravenously for 3 days) and cyclophosphamide (500 mg/m2 per day intravenously for 3 days) with or without alemtuzumab (1 mg/kg or 40 mg or 60 mg over 5 days) and received UCART19 doses of 6 × 106, 6–8 × 107, or 1·8–2·4 × 108 total CAR T cells intravenously, followed by safety evaluation and disease response assessments. The primary endpoint was incidence and severity of adverse events. Secondary endpoints were the overall response rate, duration of response, relapse-free survival, progression-free survival, and overall survival. This trial is registered with ClinicalTrials.gov (NCT02746952) and is complete.
Findings
Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8–24·8). Median age was 37 years (IQR 28–45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8–24·8), overall response rate was 48% (95% CI 28–69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2–2·8), and overall survival was 13·4 months (95% CI 4·8–23·0).
Interpretation
UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia.
Funding
Servier.
Introduction
Relapsed or refractory B-cell acute lymphoblastic leukaemia in adults has a dismal prognosis, with 3-year overall survival of 4–15% after salvage treatment.1 CD19-directed therapies, such as blinatumomab, are approved for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia, leading to 6-month event-free survival of 31% and a median overall survival of 7·7 months.2 Tisagenlecleucel, an autologous CD19-targeted chimeric antigen receptor (CAR) T-cell product, with an 81% response rate and 50% event-free survival at 12 months,3 is now approved for the treatment of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia.4
The results of CAR T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia, however, have not been as impressive, with increased toxicity and inferior outcomes.5–8 Brexucabtagene autoleucel, an autologous anti-CD19 CAR T-cell product, was approved by the US Food and Drug Administration in 2021 for use in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia on the basis of results from the ZUMA-3 trial.9 Rapidly proliferative disease, high costs of the product, and manufacturing failure have further limited the use of autologous CAR T-cell therapy in the setting of adult B-cell acute lymphoblastic leukaemia.
Off-the-shelf allogeneic CAR T cells generated from healthy donors can overcome some of these limitations due to their immediate availability. However, these products require strategies to minimise the development of graft-versus-host disease (GVHD) and rejection of non-HLA-matched products following recipient immune reconstitution.10 UCART19 uses mRNA encoding transcription activator-like effector nucleases (TALEN) to disrupt the TRAC gene to minimise the risk of GVHD and the CD52 gene to confer resistance to alemtuzumab, used during lymphodepletion to improve UCART19 persistence in the host.10
The CALM trial is a first-in-human dose-finding study investigating the safety, antileukaemic activity, and cellular kinetics of UCART19 administered to adults with relapsed or refractory B-cell acute lymphoblastic leukaemia.11 Preliminary results for the first 14 patients enrolled in this trial, and for seven paediatric patients enrolled in the PALL trial, have been previously reported.11 Here, we present the final results of the CALM trial.
Methods
Study design and participants
This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan (appendix p 5) to evaluate the safety of UCART19 in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. The trial had two parts: a dose-escalation phase to evaluate the safety of increasing UCART19 doses and establish the maximum tolerated dose and recommended dose and an expansion phase to confirm the safety of the recommended dose.
To be eligible for the study, patients had to have relapsed or refractory B-cell acute lymphoblastic leukaemia, be aged 16–70 years with either more than 5% CD19-positive leukaemic blasts in bone marrow or a minimal residual disease level of at least 1 × 10−3, assessed either by flow cytometry or quantitative PCR (qPCR), and to have exhausted other standard treatment options. Other eligibility criteria included ECOG performance status less than 2, estimated life expectancy of at least 12 weeks, adequate organ function, use of appropriate contraception to prevent pregnancy for up to 12 months after UCART19 administration, availability of a suitable allogeneic haematopoietic stem-cell transplantation (HSCT) donor, and ability to provide written informed consent. Exclusion criteria included CD19-negative B-cell acute lymphoblastic leukaemia, Burkitt or mixed lineage leukaemia, extra-medullary disease (except CNS-1, CNS-2, or isolated skin involvement), disease progression after cytoreduction, inability to receive alemtuzumab, active CNS disease, previous gene or cell therapy, clinically significant neurological dysfunction, previous antileukaemic therapies or investigational products within five half-lives before UCART19 administration, radioimmunotherapy within the past 8 weeks before inclusion, allogeneic HSCT within the past 3 months or donor lymphocyte infusions within the past 6 weeks, use of an anti-CD20 antibody within the past 3 months, presence of anti-HLA antibodies against UCART19, active acute or chronic GVHD, use of corticosteroids at a dose of more than 1 mg/kg within 5 days before UCART19 administration, clinically significant cardiac dysfunction, active infections, presence of another malignancy within the past 2 years, surgery within the past 3 months, HIV or human T-cell lymphotropic virus type 1 positivity, and contraindication to lymphodepletion drugs (appendix pp 126–128). All laboratory tests to confirm eligibility were performed by the recruiting sites with no requirement for central confirmation.
The trial was sponsored by Servier and performed in accordance with the principles of the Declaration of Helsinki. The protocol was approved by local or central independent ethics committees or institutional review boards and regulatory bodies according to each country’s requirements. Written informed consent was obtained from all patients before initiating any treatment. The study protocol is provided in the appendix (pp 30–246).
Procedures
Patients with more than 50% bone marrow blasts or greater than 15 × 106 peripheral blasts per µL or elevated lactate dehydrogenase suggesting rapidly proliferative disease were allowed to receive cytoreduction chemotherapy before study inclusion. Lymphodepletion consisted of fludarabine 30 mg/m2 per day intravenously for 3 days (day −7 to day −5) and cyclophosphamide 500 mg/m2 per day intravenously for 3 days (day −4 to day −2) with or without alemtuzumab 1 mg/kg or 40 mg or 60 mg over 5 days (day −7 to day −3), before UCART19 intravenous infusion (appendix p 14).
UCART19 was manufactured from healthy donor peripheral blood mononuclear cells by lentiviral transduction of the CAR construct (as described in detail previously11). TALEN mRNA targeting the TRAC and CD52 genes was electroporated into the cells to simultaneously disrupt expression of T-cell receptor (TCR)αβ and CD52. Batches from six different donors were used for the trial and manufactured in advance of patient enrolment. A batch from one other donor was used for the redosing of a patient. Allocation of donor batches was done randomly, except at redosing when a different donor to the first infusion was chosen where possible. Characteristics of the final infused product are described in the appendix (pp 15–17).
Three UCART19 doses were evaluated in the dose-escalation phase: 6 × 106 (dose level 1), 6 – 8 × 107 (dose level 2), and 1·8–2·4 × 108 (dose level 3) total CAR T cells, as per modified toxicity probability interval design (appendix pp 166–167), and overseen by an independent data and safety monitoring board. Dose escalation was determined by the frequency and severity of dose-limiting toxicities at each dose level. A dose-limiting toxicity was defined as an adverse event or abnormal laboratory value observed in the first 28 days following UCART19 administration considered to be related to UCART19 and meeting the following criteria: cytokine release syndrome grade 4 or higher, acute GVHD grade 2 or higher requiring high-dose steroids, tumour lysis syndrome grade 4 or higher, non-haematological toxicity grade 3 or higher, or neurological toxicity grade 3 or higher not resolving within 7 days. A patient was considered non-evaluable for dose-limiting toxicity assessment if more than 120% of the assigned dose was received, unless no dose-limiting toxicity was observed; or if less than 80% of the assigned dose was received or the patient did not complete the safety evaluation at day 28, unless a dose-limiting toxicity was observed. Non-evaluable patients were replaced (appendix p 118). The starting UCART19 cell dose of 6 × 106 cells (equivalent to 1 × 105 cells per kg for 60 kg average bodyweight) was chosen at a ten-fold lower dose than the commonly used dose of 1 × 106 CAR T cells per kg shown to be safe and efficacious for other autologous CAR T-cell products. Skipping of doses was not permitted. The minimum interval between UCART19 dosing and commencement of lymphodepletion of the next patient was set at 28 days for dose level 1 and for the first patient of a new dose level during the dose escalation phase. Predefined study stopping criteria included occurrence of any death within 28 days following UCART19 infusion, two or more cytokine release syndrome grade 4 or higher events or a cytokine release syndrome grade 3 event that did not resolve within 14 days, or two or more neurotoxicity events grade 4 or higher. The data and safety monitoring board was responsible for assessing safety data at the end of each dose level and to make recommendations on the next dose level to be tested, to stop the study if stopping criteria were met, or to suggest modifications to the lymphodepletion regimen if appropriate.
Following cell infusion, patients were monitored for toxicity related to lymphodepletion or UCART19 for up to 12 months. Disease response was assessed locally by bone marrow biopsy and blood count 28 days and 84 days after UCART19 infusion (appendix p 6) on the basis of the National Comprehensive Cancer Network guidelines (appendix p 207). A second administration of UCART19 was considered if patients had a suboptimal disease response (minimal residual disease-positive at day 28) or no response, an early CD19-positive relapse, or poor persistence of UCART19 (undetectable concentrations in blood beyond day 14) while still meeting all other eligibility criteria.
Patients who had a complete response or complete response with incomplete haematological recovery were considered for allogeneic HSCT, at the investigator’s discretion. Institutional antimicrobial prophylaxis guidelines were followed throughout the study. Enrolled patients could discontinue from the study if they withdrew consent or upon availability of a therapeutic alternative based on investigator’s judgement.
Outcomes
The primary objective of the study was to evaluate the safety of UCART19 in relapsed or refractory B-cell acute lymphoblastic leukaemia and to determine the maximum tolerated dose and the recommended dose. The primary outcome measure was adverse events, graded mostly according to the Common Terminology Criteria for Adverse Events, version 5.0. Cytokine release syndrome was graded according to the approach outlined by Lee and colleagues,12 GVHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium,13 and tumour lysis syndrome according to the criteria by Hochberg and Cairo.14
Secondary objectives were to assess the antileukaemic activity of UCART19 as measured by the overall response rate, duration of response, relapse-free survival, progression-free survival, and overall survival. Overall response rate was defined as the percentage of patients with a complete response or complete response with incomplete haematological recovery as best response. Duration of response was calculated among the responders from the time of first complete response or complete response with incomplete haematological recovery after UCART19 infusion until the date of progression or death, whichever occurred first. Relapse-free survival was calculated among the responders from the date of first complete response or complete response with incomplete haematological recovery after UCART19 infusion until the date of relapse or death due to any cause, whichever occurs first. Progression-free survival was calculated from the date of UCART19 administration until the date of progression or death, whichever occurs first. Overall survival was calculated from the date of the first UCART19 administration until death due to any cause.
Prespecified exploratory objectives included assessing the proportion of patients who underwent subsequent allogeneic HSCT and the proportion who were redosed with UCART19; analysing the expansion kinetics, phenotype, trafficking, and persistence of UCART19 cells and the pharmacokinetic profile of alemtuzumab; assessing the host immune response to lymphodepletion and UCART19 treatment; measuring cytokine concentrations; and identifying gene expression signatures that correlate with UCART19 expansion, persistence, and antileukaemic activity. The present report describes some results of the exploratory objectives. Additional results are described in a separate publication (in press15).
Statistical analysis
The incidence of adverse events and activity outcomes were assessed for all patients who received UCART19. Time-dependent parameters were estimated using Kaplan-Meier curves and reported as median and 95% CI or IQR. Two-sided Fisher’s exact tests were used in comparisons of categorical variables (exploratory analyses).
Owing to the use of a modified toxicity probability interval design, the exact sample size could not be prespecified. The proposed dose allocation method was designed to improve upon dose-finding decision rules based on a bayesian model, by instead obtaining a set of decision rules based on toxicity posterior intervals. Each dose level was designed to have a minimum of three evaluable patients, with two to four additional patients included at the same dose if applicable and at least six patients planned to be treated at the maximum tolerated dose. The maximum number of evaluable patients for the dose-escalation phase was predicted to be 18.
Statistical analyses were performed using SAS software, version 9.2. For further details of the statistical plan see appendix pp 166–173 and pp 247–317.
This study is registered with ClinicalTrials.gov, NCT02746952.
Role of the funding source
The funder of the study was involved in the study design, data collection, data analysis, and data interpretation, and provided medical writing support.
Results
Between Aug 1, 2016, and June 30, 2020, 35 patients were screened and 25 were enrolled and treated with UCART19 (figure 1). The data cutoff date was Oct 26, 2020. Seven patients were excluded, because they did not meet the eligibility criteria; two had non-quantifiable minimal residual disease, one had liver dysfunction, one had ongoing fever and bilirubin concentration above threshold limit, one had not exhausted all alternative treatment options, one had active cytomegalovirus viraemia, and one had CD19-negative disease. Additionally, one patient was not included owing to temporary hold of the study and two patients owing to the COVID-19 pandemic. None of the enrolled patients had access to an autologous CAR T-cell product, either licensed or through a clinical trial, during the time period of the study. Median age was 37 years (IQR 28–45), and patients had received a median of four previous lines of therapy (IQR 3–5), including inotuzumab ozogamicin in eight (32%) patients and blinatumomab in 12 (48%; table 1). 18 (72%) patients had undergone previous allogeneic HSCT. 13 (52%) patients had cytoreduction treatment before lymphodepletion (appendix pp 18–19). 22 (88%) patients received fludarabine, cyclophosphamide, and alemtuzumab for lymphodepletion, and three (12%) received only fludarabine and cyclophosphamide due to investigator’s concern about increased risk of viral infections with alemtuzumab. Of the 22 patients who received alemtuzumab, the dose was 1 mg/kg in ten patients, 40 mg in seven patients, 60 mg in four patients, and 54 mg in one patient (during the expansion phase, alemtuzumab was given at the incorrect dose in two patients in whom the intended dose was 60 mg: one received alemtuzumab 40 mg and the other alemtuzumab 54 mg). Median time between enrolment and UCART19 infusion was 9 days (IQR 8–13). The median blast percentage in bone marrow before lymphodepletion was 33% (12–69).
Figure 1: Study profile.
*Alemtuzumab doses were as follows: 1 mg/kg (n=10), 40 mg total flat dose (n=7), 60 mg (n=4), and 54 mg (n=1). During the expansion phase, alemtuzumab was given at the incorrect dose in two patients (intended dose 60 mg): one received alemtuzumab 40 mg and the other alemtuzumab 54 mg. †At dose level 2, six patients were enrolled in the safety expansion part and the other six were enrolled in the dose-escalation part.
Table 1:
Baseline characteristics
| Dose level 1 (n=6) | Dose level 2 (n=12) | Dose level 3 (n=7) | All (n=25) | |
|---|---|---|---|---|
| Age, years | ||||
| Median (IQR) | 23 (20–28) | 40 (35–49) | 39 (37–60) | 37 (28–45) |
| Range | 18–42 | 22–62 | 22–64 | 18–64 |
| Sex | ||||
| Male | 4 (67%) | 5 (42%) | 5 (71%) | 14 (56%) |
| Female | 2 (33%) | 7 (58%) | 2 (29%) | 11 (44%) |
| Race | ||||
| White | 4 (67%) | 8 (67%) | 5 (71%) | 17 (68%) |
| Black or African-American | 1 (17%) | 1 (8%) | 0 | 2 (8%) |
| Asian | 0 | 2 (17%) | 0 | 2 (8%) |
| Other | 1 (17%) | 1 (8%) | 2 (29%) | 4 (16%) |
| Number of previous lines of therapy | ||||
| 1 | 1 (17%) | 0 | 0 | 1 (4%) |
| 2 | 0 | 0 | 2 (29%) | 2 (8%) |
| 3 | 1 (17%) | 3 (25%) | 2 (29%) | 6 (24%) |
| ≥4 | 4 (67%) | 9 (75%) | 3 (43%) | 16 (64%) |
| Median (IQR) | 4 (3–4) | 4 (4–5) | 3 (2–5) | 4 (3–5) |
| Range | 1–5 | 3–6 | 2–6 | 1–6 |
| Previous allogeneic stem-cell transplantation | 5 (83%) | 8 (67%) | 5 (71%) | 18 (72%) |
| High cytogenetic risk* | 1 (17%) | 5 (42%) | 1 (14%) | 7 (28%) |
| Cytoreduction treatment | 3 (50%) | 7 (58%) | 3 (43%) | 13 (52%) |
| Cellularity† | ||||
| Hypocellular | 4 (67%) | 3 (33%) | 5 (71%) | 12 (55%) |
| Hypercellular | 1 (17%) | 4 (44%) | 1 (14%) | 6 (27%) |
| Percentage of blasts before Lymphodepletion | ||||
| <5% | 2 (33%) | 1 (8%) | 0 | 3 (12%) |
| 5–25% | 2 (33%) | 1 (8%) | 4 (57%) | 7 (28%) |
| 26–50% | 1 (17%) | 3 (25%) | 1 (14%) | 5 (20%) |
| >50% | 1 (17%) | 7 (58%) | 2 (29%) | 10 (40%) |
| Median (IQR) | 17% (4–43) | 61% (33–84) | 20% (12–56) | 33% (12–69) |
| Range | 1–95% | 0–96% | 8–94% | 0–96% |
| Percentage of blasts before or at first UCART19 infusion‡ | ||||
| <5% | 3 (60%) | 4 (36%) | 2 (29%) | 9 (39%) |
| 5–25% | 0 | 2 (18%) | 2 (29%) | 4 (17%) |
| 26–50% | 0 | 2 (18%) | 0 | 2 (9%) |
| >50% | 2 (40%) | 3 (27%) | 3 (43%) | 8 (35%) |
| Median (IQR) | 3% (3–69) | 18% (4–98) | 10% (2–66) | 10% (3–74) |
| Range | 3–100% | 0–100% | 0–80% | 0–100% |
Data are n (%), unless otherwise specified.
BCR-ABL translocation (n=4), hypodiploidy (n=1), TCF3-PBX1 (n=1), and mixed-lineage leukaemia rearrangement (n=1).0
Data unavailable for three patients in dose level 2, so n=9 in dose level 2 and n=22 in overall cohort for this parameter.
Last analysable value before or at the first UCART19 treatment infusion date. Where bone marrow aspirate data for blasts were unavailable, bone marrow trephine biopsy is included. n=5 in dose level 1, n=11 in dose level 2, n=7 in dose level 3, and n=23 in overall cohort.
During dose escalation, six patients were treated with UCART19 at dose level 1, six at dose level 2, and seven at dose level 3. Dose level 3 was considered to be the maximum tolerated dose but the recommended dose was determined to be dose level 2 based on a combination of a similar safety profile across dose levels, UCART19 expansion kinetics, and antileukaemic activity. A further six patients received 6–8 × 107 cells during the expansion phase.
All patients developed adverse events related to lymphodepletion or UCART19, or both (appendix pp 20–21), including 21 (84%) patients with an adverse event of grade 3 or higher (table 2 and appendix p 7). Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias.
Table 2:
Adverse events of special interest related to lymphodepletion or UCART19 and occurring after the first UCART19 infusion in the full analysis set (n=25)
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 | |
|---|---|---|---|---|---|
| Cytokine release syndrome* | 4 (16%) | 10 (40%) | 4 (16%) | 2 (8%) | 0 |
| Neurological events | 6 (24%) | 0 | 0 | 1 (4%) | 0 |
| Acute cutaneous graft-versus-host disease | 2 (8%) | 0 | 0 | 0 | 0 |
| Infections | 1 (4%) | 4 (16%) | 3 (12%) | 2 (8%) | 2 (8%) |
| Prolonged grade 4 cytopenia | NA | NA | NA | 4 (16%) | 0 |
| B-cell aplasia | 1 (4%) | 2 (8%) | 0 | 0 | 0 |
| Tumour lysis syndrome | 0 | 0 | 2 (8%) | 0 | 0 |
Data are n (%). NA=not applicable.
Includes preferred terms for both cytokine release syndrome and haemophagocytic lymphohistiocytosis.
20 (80%) patients developed cytokine release syndrome of any grade and six (24%) developed grade 3 or higher cytokine release syndrome, including three who also met the criteria for haemophagocytic lymphohistiocytosis16 (grade 3 [n=2] and grade 4 [n=1]). Median time to onset of cytokine release syndrome was 7·5 days (IQR 5–8) after UCART19 infusion and median duration was 6 days (4–10). Cytokine release syndrome treatment consisted of tocilizumab in 13 (65%) patients, steroids in four (20%), and anakinra in two (10%). Of the 20 patients who had cytokine release syndrome, eight (40%) required admission to the intensive care unit and two (10%) received inotropic support (appendix pp 24–25).
Seven (28%) patients developed neurological events, which were grade 1 in six (24%) patients and grade 4 in one (4%) who had concurrent grade 3 cytokine release syndrome. Median time to onset of a neurological event was 10 days (IQR 9–23) after UCART19 infusion, and median duration was 5 days (IQR 3–6).
Grade 3 or higher cytopenia (neutropenia or thrombocytopenia; appendix p 26) not resolved by day 28 occurred in ten (40%) patients and by day 42 in eight (32%). Four (16%) patients had prolonged cytopenia, defined as grade 4 neutropenia or thrombocytopenia occurring in the absence of more than 5% bone marrow blasts and persisting beyond day 42 from UCART19 infusion (table 2).
Severe infections (grade ≥3) occurred in seven (28%) patients; three (12%) developed grade 3 or higher viral infections, including cytomegalovirus and adenovirus (appendix p 27).
Two (8%) patients developed grade 1 acute cutaneous GVHD clinically, both of whom had skin biopsies, with histological confirmation in one. No gastrointestinal or hepatic GVHD was observed.
14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. Two of the deaths associated with infections occurred after the subsequent allogeneic HSCT (appendix pp 22–23).
After a median of follow-up of 12·8 months (IQR 2·8–24·8), 12 (48%; 95% CI 28–69), of 25 patients had a complete response or complete response with incomplete haematological recovery as best overall response after the first UCART19 infusion, with nine (75%) of 12 responders becoming minimal residual disease-negative (figure 2). Clinical responses were reported at all doses: four (67%) of six patients had an overall response at dose level 1, five (42%) of 12 at dose level 2, and three (43%) of seven at dose level 3. All of the 12 responders had received lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (12 [55%] of 22 patients who received this lymphodepletion regimen). Median duration of response among the 12 responders was 7·4 months (95% CI 1·8 to not calculable). Nine (75%) of these patients underwent subsequent allogeneic HSCT at a median of 1·71 months (IQR 1·45–2·07) after UCART19 infusion.
Figure 2: Clinical course of individual patients after UCART19 infusion—full analysis set (n=25).
Numbers on the y-axis are trial numbers of the patients. Trial numbers were assigned according to the order in which the patients were screened for eligibility during the enrolment phase (eg, 00009 refers to the 9th patient screened). Patient 00031 had refractory disease and was redosed immediately after first disease assessment.
Pre-evaluation refers to the period between day 0 and day 28. The arrows at the end of the bars indicate patients in ongoing long-term follow-up. HSCT=haematopoietic stem-cell transplantation. *Patients redosed with UCART19 in compassionate use.
Response rates were higher in patients with lower tumour burden (bone marrow blasts ≤50% of nucleated cells) before lymphodepletion (p=0·041) and in those who had received fewer than four previous lines of therapy (p=0·041; appendix pp 10–11). Lactate dehydrogenase concentrations were higher in non-responders than responders, but the difference was not statistically significant (appendix p 12). Response rates were not significantly different between patients who received previous cytoreduction and those who did not (appendix p 28). The change in bone marrow blast percentage with lymphodepletion was not significantly different between responders and non-responders (p=0·23; appendix p 29). No association was noted between tumour burden and severity of cytokine release syndrome (data not shown).
Median progression-free survival was 2·1 months (95% CI 1·2–2·8) and median overall survival was 13·4 months (95% CI 4·8–23·0; figure 3). Median relapse-free survival was the same as duration of response (ie, 7·4 months [95% CI 1·8 to not calculable]). At 6 months, overall survival was 61% (95% CI 38–77), relapse-free survival among responders was 55% (95% CI 23–78), and progression-free survival was 29% (95% CI 13–48). 11 patients were alive at the time of database lock, including five with ongoing response after a single UCART19 infusion and one after a second UCART19 infusion, and all after allogeneic HSCT. The remaining patients had refractory or progressive disease (figure 2). None of the patients were reported to have relapsed with CD19-negative disease.
Figure 3: Patient survival—full analysis set (n=25).
(A) Overall survival. (B) Progression-free survival. (C) Relapse-free survival. Overall survival and progression-free survival are shown in all patients (n=25) and in the subgroup who received lymphodepletion with FCA (n=22).
All 12 patients who had a response received FCA; hence, panel C (relapse-free survival) has only one curve. Vertical lines on the curves represent censored participants. FCA=fludarabine, cyclophosphamide, and alemtuzumab.
14 (56%) patients showed UCART19 expansion, with peak blood concentrations occurring at a median of 14 days (range 10–27). UCART19 persisted in blood for a median of 28 days (range 10–82; appendix pp 8–9). Persistence of UCART19 was defined from the day of infusion until the last day showing a quantifiable amount of transgene observed in blood, the lower limit of quantification of the qPCR assay being 10 copies per µg of genomic DNA. We were unable to evaluate B-cell aplasia as a marker of UCART19 persistence as all patients who responded to UCART19 proceeded to subsequent allogeneic HSCT. Four patients underwent allogeneic HSCT from day 42, while still having detectable UCART19 concentrations, with conditioning that ablated residual UCART19. All patients demonstrating UCART19 expansion received lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab, and no expansion was observed in the three patients treated with only fludarabine and cyclophosphamide.
Persistence of UCART19 by qPCR in blood beyond day 42 was observed in five patients, including one who still had quantifiable cells at day 82. No relationship between UCART19 cell dose or batch and cell expansion was observed (appendix pp 8–9). Host T-lymphocyte counts, but not natural killer cell counts, were negatively associated with UCART19 expansion (data not shown). All batches were found to have a proportion of cells with t(1;14) translocation (appendix p 15–17), an expected consequence of CD52 and TRAC gene editing, but none of these cells showed any proliferative advantage in exvivo assays or in patients treated with UCART19.
Five (20%) patients received a second infusion of UCART19 (at the same dose as the first infusion) 36–99 days following the first infusion, either for early disease progression (n=2) or suboptimal response (n=3). Lymphodepletion before the second infusion was done with fludarabine and cyclophosphamide only (n=1) or with fludarabine, cyclophosphamide, and alemtuzumab, using alemtuzumab at 1 mg/kg (n=3) or 60 mg (n=1). Three (60%) of the five patients were redosed with a batch from a different donor.
Among the five patients who received a second infusion of UCART19, two of three evaluable patients showed UCART19 expansion, had complete response or complete response with incomplete haematological recovery as the best overall response, and underwent subsequent allogeneic HSCT. Of the two non-evaluable patients (treated on a compassionate basis), one had a complete response and the other had progressive disease as per investigator’s assessment. One of two responders relapsed 10 months after the second infusion and the other still had a response 6 months after infusion. Two patients developed grade 1 cytokine release syndrome and one patient developed prolonged cytopenia following UCART19 redosing.
Discussion
This first completed study of an allogeneic genome-edited anti-CD19 CAR T-cell product in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia showed predictable safety with UCART19 and a response rate of 48% among a patient cohort with high tumour burden and rapidly proliferative disease (60% had >25% blasts before lymphodepletion and 52% required cytoreduction), many of whom had no alternative treatment options. Our results substantiate preliminary results with UCART19 in the first 14 adult patients from this trial.11
The spectrum of adverse events observed with UCART19 was similar to that seen with autologous CAR T-cell products,3,8,9 the most frequent being cytokine release syndrome and anaemia, with mostly mild neurotoxicity and minimal GVHD. Most patients who showed UCART19 expansion developed cytokine release syndrome, and although 40% of patients required transfer to the intensive care unit, only a minority required organ support with inotropes, dialysis, or ventilation. Standard methods of treating cytokine release syndrome with tocilizumab and steroids were generally effective. Of note, more aggressive and earlier management of cytokine release syndrome has now become standard compared with when the trial first started. Neurological events were mostly mild, with only one patient having grade 4 neurotoxicity in association with cytokine release syndrome. Concern that residual infused TCRαβ-positive cells would expand and cause transfusion-associated GVHD was not observed; only two patients developed grade 1 GVHD, with no expansion of donor TCRαβ-positive cells seen in blood or bone marrow.
Cytopenias are common adverse events that have been observed following all classes of CAR T-cell therapy.17 Prolonged (>30 days) severe cytopenias have been reported in 30% of tisagenlecleucel and axicabtagene ciloleucel recipients.17 In our study, prolonged grade 4 cytopenia (>42 days) occurred in 16% of patients. Prolonged cytopenia did not appear to be dose dependent and might be associated with disease status, previous therapies, and the use of the myelosuppressive drug alemtuzumab in the lymphodepletion regimen.14,17 In anticipation of myelosuppression, allogeneic HSCT donors were identified before treatment, so that patients who reached complete response would be candidates for subsequent rescue by allogeneic HSCT also in the event of prolonged cytopenia.
Infectious complications, particularly cytomegalovirus and adenovirus infections and Epstein-Barr virus reactivation, were observed, and were a consequence of the alemtuzumab-containing lymphodepletion regimen. To mitigate infection risk, patients routinely received prophylactic antimicrobials, were closely monitored with weekly viral PCR testing, and were managed with pre-emptive antiviral treatment. Nevertheless, five patients died as a result of infectious complications, two following subsequent allogeneic HSCT.
Alemtuzumab was omitted in three patients who were at high risk of viral infections, but no UCART19 expansion was detected in these patients. To reduce the incidence of severe viral infections, the alemtuzumab dose was reduced during the dose-escalation phase from 1 mg/kg to a 40 mg flat dose, but the dose was subsequently increased to 60 mg in the dose-expansion phase to improve antileukaemic activity. Based on our experience, alemtuzumab appears to be required for UCART19 expansion, with a dose of 60 mg or higher associated with the best results.11
It is encouraging that 48% of the entire cohort, and 55% of those who received lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab, had a complete response or complete response with incomplete haematological recovery. The response rate was highest at the lowest UCART19 dose level (67% at dose level 1 vs 42% at dose level 2 vs 43% at dose level 3). Notably, the treatment approach was most homogeneous at dose level 1, with all patients treated at the same site, where they received an identical lymphodepletion dosing schedule (fludarabine, cyclophosphamide, and alemtuzumab, with alemtuzumab dosed at 1 mg/kg) and UCART19 from the same batch. It is conceivable that the lower alemtuzumab dose (40 mg) used at subsequent dose levels might have contributed to the reduced antileukaemic activity in these groups by increasing the risk of earlier host immune recovery and graft rejection (appendix p 13).
UCART19 expansion was observed at every dose level, with the highest peak level seen at dose level 2, but with no apparent association between cell dose and expansion or persistence beyond day 28. However, persistence of UCART19 in blood beyond day 42 was evident in only five of 14 patients. Early recovery of host T lymphocyte counts suggested a T-cell mediated rejection of UCART19. Data were either insufficient or unavailable to evaluate the potential contributory role of donor-specific anti-HLA antibodies or anti-UCART19 antibodies in limiting UCART19 persistence. Duration of B-cell aplasia could not reliably be used as a surrogate marker of UCART19 functional persistence, as patients that responded proceeded to have allogeneic HSCT with consequent elimination of UCART19 cells by the conditioning regimen.
Dose level 2 was chosen as the recommended dose, because it had similar safety profile to dose levels 1 and 3, it resulted in increased UCART19 expansion and persistence in individuals receiving lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab compared with dose levels 1 and 3, and it had antileukaemic activity in patients who were older or who had more aggressive disease (on the basis of adverse cytogenetic risk and higher tumour burden).
Redosing with UCART19 proved to be feasible and was associated with antileukaemic activity, as shown by UCART19 expansion and response in three of five patients who received a second infusion. The optimal redosing strategy, whether to use UCART19 from the same or a different donor or batch, the timing after the first infusion, and the type of lymphodepletion required have yet to be determined. However, redosing could overcome the limited persistence of UCART19 and deepen and prolong the response of some patients.
Allogeneic HSCT, either as consolidation or to treat prolonged cytopenia, was not part of the study protocol. Nevertheless, allogeneic HSCT was performed in the majority of UCART19-treated patients who had a complete response or complete response with incomplete haematological recovery. The results of this study suggest that UCART19 is active as a bridge to allogeneic HSCT; however, given the limited persistence, further strategies to improve the persistence of UCART19 are being investigated and, if successful, could eventually reduce the need for subsequent HSCT.
The limitations of the study included the variation in alemtuzumab dose between dose levels 1, 2, and 3, the use of a flat dose of UCART19 despite considerable variation in patient weight within each dose level, and the differences in donor batches used for the trial, making it difficult to determine the optimal dose level.
Differences in patient characteristics, trial designs, and reported outcomes make it difficult to directly compare the results of UCART19 with autologous anti-CD19 CAR T-cell products. Most of the patients enrolled in the CALM trial were unable to access an autologous CAR T-cell product through a clinical trial either because of profound lymphopenia, rapid kinetics of disease progression, lack of available apheresis or manufacturing slots, or indeed the absence of any suitable CAR T-cell trials at the time. Importantly, no patient was unable to be infused with UCART19 after enrolment because of disease progression. Published studies have reported complete response or complete response with incomplete haematological recovery rates at 28 days after infusion with autologous anti-CD19 CAR T-cell products in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia as 69% (95% CI 51–83%) with CTL019,18 85% (62·1–96·7%) with AUTO-1,19 71% (57–82%) with KTE-X19,20 and 83% (70–92%) with the MSKCC 19–28z CAR.8 The 2-year event-free survival for CTL019 was 31% (95% CI 15–49) overall but 49·5% (21–73) in the high-dose fractionated infusion cohort compared with 48% (23·1–69·7) in the ALLCAR19 study with AUTO-1. Median relapse-free survival after KTE-X19 was 11·6 months (95% CI 2·7–15) in the ZUMA-3 trial and median event-free survival was 6·1 months (5·0–11·5) in the MSKCC study. A further study using a 19-4-1BBz CAR reported a complete response rate of 85% and a median event-free survival of 7·6 months (95% CI not provided) in responders.6
This phase 1, first-in-human, dose-finding clinical study of UCART19, the first genome-edited, off-the-shelf, allogeneic CAR T-cell product, in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia demonstrated the safety and feasibility of using allogeneic CAR T cells in patients for whom autologous CAR T cells might not be an option, and represents a substantial step forward in CAR T-cell development.
Supplementary Material
Research in context.
Evidence before this study
A PubMed search was carried out using search terms “allogeneic CAR” or “allogeneic chimeric antigen receptor” or “off the shelf CAR” AND “acute lymphoblastic leukaemia” for all articles published from database inception to June 1, 2021, with no language restrictions. The only other clinical studies of allogeneic CAR T cells in B-cell acute lymphoblastic leukaemia identified were case reports or series involving HLA-matched or haploidentical donor-derived CD19 CAR T cells following allogeneic stem-cell transplantation. Several other genome-edited CAR T-cell products are being evaluated in ongoing clinical trials of haematological malignancies and solid tumours.
Added value of this study
This study demonstrates for the first time the feasibility of using an off-the-shelf CAR T-cell product to treat adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The safety profile of UCART19 was shown, with the TCRαβ genome editing approach successfully preventing any clinically significant graft-versus-host disease. High response rates to UCART19 were seen, similar to response rates seen with autologous CAR T cells. No clear dose correlation between infused cell dose and response was observed. The study also highlighted issues relating to limited persistence of UCART19 and the increased risk of viral infections resulting from the more intense lymphodepletion regimen.
Implications of all the available evidence
The successful use of genome-edited CAR T cells in the CALM trial supports the use of such a strategy for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia when access to an autologous CAR T-cell product is unavailable or when disease progression is too rapid. It opens up the possibility of other cancers being treated in a similar way with universal off-the-shelf CAR T-cell products.
Acknowledgments
UCART19 is exclusively licensed to Servier from Cellectis and uses Cellectis’ technologies, and is being co-developed by Servier and Allogene Therapeutics. Servier funded the clinical study. Servier and Allogene Therapeutics reviewed and edited the manuscript, and had a role in the decision to submit the manuscript for publication. In addition, Servier helped design the study and collect and analyse the data. Springer Healthcare Communications edited the manuscript before submission. This medical editing assistance was funded by Servier. We would like to thank the patients and their families, and members of the data and safety monitoring board.
Footnotes
Declaration of interests
RB received research funding from Servier and Allogene and has participated in advisory boards for Kite/Gilead, Novartis, Celgene/Bristol-Myers Squibb, Cellectis, and Enara Bio. NJ reports grants and personal fees from Servier during the conduct of the study; grants, personal fees, and non-financial support from Pharmacyclics, AstraZeneca, Genentech, Verastem, Pfizer, AbbVie, ADC Therapeutics, Precision Biosciences, and Adaptive Biotechnologies; personal fees and non-financial support from Janssen; and grants and non-financial support from Bristol-Myers Squib, Celgene, Seattle Genetics, Incyte, and Cellectis, outside the submitted work. MVM is an inventor on patents related to adoptive cell therapies held by Massachusetts General Hospital and the University of Pennysylvania (some of which are licensed to Novartis), holds equity in TCR2 and Century Therapeutics, and has served as a consultant for multiple companies involved in cell therapies. NB, CG, and AJ received research funding from Servier. DY reports grants and non-financial support from Servier during the conduct of the study, and non-financial support from Amgen and personal fees from Pfizer, outside the submitted work. MK reports grants and other from AbbVie, F. Hoffman La-Roche, Stemline Therapeutics, Forty-Seven, and Genentech; grants from Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, Astra Zeneca, Rafael Pharmaceutical, and Sanofi; and honoraria from Reata Pharmaceutical and Janssen outside the submitted work. MK also has a patent US 7,795,305 B2 “CDDO-compounds and combination therapies thereof” with royalties paid to Reata Pharm, a patent “Combination therapy with a mutant IDH1 inhibitor and a BCL-2” licensed to Eli Lilly, and a patent 62/993,166 “Combination of a MCL-1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof” pending to Novartis. MJF has advisory roles with Kite/Gilead, Novartis, Celgene/Bristol-Myers Squibb, Arcellx, and Iovance, and recieves trial support from Kite/Gilead and Novartis. TT reports personal fees from Merck Sharp & Dohme; grants and personal fees from Kyowa Kirin; personal fees from Takeda, Pfizer, and Bristol-Myers Squibb; grants from Chugai, Sanofi, Astellas, Teijin Pharma, Fuji Pharma, Nippon Shinyaku, Japan Society for the Promotion of Science KAKENHI (17H04206), and The Center of Innovation Program from Japan Science and Technology Agency; non-financial support from Janssen; and grants, personal fees, and non-financial support from Novartis, outside the submitted work. KK reports grants and personal fees from AbbVie, Chugai, Eisai, Janssen, Novartis, Daiichi Sankyo, Takeda, and Kyowa-Kirin, and personal fees from AstraZeneca, Celgene, Ono, MSD, Mundi, Dainippon-Sumitomo, and Bristol-Myers Squibb, outside the submitted work. FBo, FBi, IM, SD, MA-C, MP, and SF are employees of Servier. SB and AG-B were previous employees of Servier. EB reports personal fees from Novartis, Astellas, Alexion, Jazz Pharmaceuticals, and Gilead outside the submitted work. MM reports grants and personal fees from Sanofi and Jazz Pharmaceuticals; personal fees from Janssen, Celgene, Bristol-Myers Squibb, Takeda, and Amgen; and grants from Roche, outside the submitted work.
Data sharing
The data from this study will be made available upon reasonable request from a qualified medical or scientific professional for the specific purpose laid out in that request and may include deidentified individual participant data. The data for this request will be available after a data access agreement has been signed. All requests should be made to FBi (florence.binlich@servier.com).
Contributor Information
Reuben Benjamin, Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London, UK; Rayne Institute, School of Cancer and Pharmaceutical Sciences, Kings College London, London, UK.
Nitin Jain, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Marcela V Maus, Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA.
Nicolas Boissel, Department of Haematology, Saint-Louis Hospital, Paris, France.
Charlotte Graham, Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London, UK.
Agnieszka Jozwik, Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London, UK.
Deborah Yallop, Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London, UK.
Marina Konopleva, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Matthew J Frigault, Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA.
Takanori Teshima, Department of Haematology, Hokkaido University Hospital, Sapporo, Japan.
Koji Kato, Department of Haematology, Kyushu University Hospital, Fukuoka, Japan.
Floriane Boucaud, Institut de Recherches Internationales Servier, Suresnes, France.
Svetlana Balandraud, Institut de Recherches Internationales Servier, Suresnes, France.
Athos Gianella-Borradori, Institut de Recherches Internationales Servier, Suresnes, France.
Florence Binlich, Institut de Recherches Internationales Servier, Suresnes, France.
Ibtissam Marchiq, Institut de Recherches Servier, Croissy-sur-Seine, France.
Sandra Dupouy, Institut de Recherches Internationales Servier, Suresnes, France.
Maria Almena-Carrasco, Institut de Recherches Internationales Servier, Suresnes, France.
Matthieu Pannaux, Institut de Recherches Internationales Servier, Suresnes, France.
Sylvain Fouliard, Institut de Recherches Internationales Servier, Suresnes, France.
Eolia Brissot, Department of Haematology, Saint-Antoine Hospital, Paris, France.
Mohamad Mohty, Department of Haematology, Saint-Antoine Hospital, Paris, France.
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