Adverse events reported to the U.S. Food and Drug Administration Adverse Event Reporting System for tisagenlecleucel
Abstract
The U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell therapy, tisagenlecleucel, in August 2017. We sought to describe adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS) for tisagenlecleucel in the post-marketing period. We searched FAERS reports to identify U.S. patients treated with tisagenlecleucel between August 30, 2017-August 31, 2019. We reviewed individual reports, calculated AE frequencies and reporting rates (RRs), and used Empirical Bayesian Geometric Mean methods to identify disproportionate reporting. We identified 646 de-duplicated reports with a median age at AE of 18 (interquartile range: 11–56) years. The overall RR was 81.0%, and more than 95% of reports described a serious outcome. Cytokine release syndrome (CRS) was the most frequently reported AE (51.1%) with a RR of 41.4%; neurotoxicity was reported less frequently (21.2%), with a RR of 17.2%. Most disproportionately reported AEs were listed on the package insert or confounded by indication. We identified 13 subsequent neoplasms (SPN), the majority occurring within 6 months of tisagenlecleucel administration, and none reporting evidence of insertional mutagenesis. A total of 165 reports (26%) described a death outcome; most deaths occurred >30 days after treatment. The majority of deaths (64%) were due to progression of the underlying lymphoid neoplasm, and few (<5%) were attributed to CRS or neurotoxicity. We did not identify new safety concerns reported for tisagenlecleucel in the post-marketing period. Reporting rates for CRS and neurotoxicity were lower than identified in the prelicensure clinical trials.
1 INTRODUCTION
On August 30, 2017, the U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy.1 Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals Corporation) is a CD19-directed genetically modified immunotherapy that is comprised of genetically modified autologous T-cells using a lentiviral vector to encode an anti-CD19 chimeric antigen receptor.2 Administered as a single infusion, the initial indication was treatment of B-cell precursor acute lymphoblastic leukemia (ALL) refractory to treatment or in second or later relapse among individuals up to 25 years of age. On May 1, 2018, the indication expanded to treatment of adults with relapsed/refractory (r/r) large B-cell lymphoma (including diffuse large B-cell lymphoma [DLBCL] not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma) after two or more lines of systemic therapy. Because of the increased risk for cytokine release syndrome (CRS) and neurotoxicity identified in the pre-licensure clinical trials, tisagenlecleucel is available through a Risk Evaluation and Mitigation Strategy (REMS) program to ensure that the benefits of treatment outweigh the risks.3-5 As part of the REMS program, all cases of CRS and neurotoxicity must be reported either directly to FDA through the FDA Adverse Event Reporting System (FAERS)6 or to the sponsor (directly or indirectly through the Center for International Blood and Marrow Transplant Research [CIBMTR]), who submits these reports to FDA. The U.S. Product Information (USPI) includes a boxed warning5 regarding risks of CRS and neurotoxicity and a Warnings and Precautions section for hypersensitivity reactions, serious infections, prolonged cytopenias, hypogammaglobulinemia, effects on ability to drive and use machines, and second malignancies.2 Because of the potential risk of lentivirus vector integration and transformation of transduced host cells to result in a neoplastic process, FDA required a post-marketing study to assess long-term safety, including development of subsequent primary neoplasms (SPN).7
We sought to describe adverse events (AEs) submitted to FAERS for U.S. patients treated in the 2 years following initial tisagenlecleucel approval. We also aimed to describe the primary underlying cause of death among deceased patients, and the spectrum of SPNs diagnosed following treatment with tisagenlecleucel.
2 METHODS
2.1 Data sources
2.1.1 FAERS database
A spontaneous passive surveillance system, FAERS collects information on AEs, medication errors, and product quality matters associated with drugs and biologic products (excluding vaccines) as submitted by health care providers, pharmaceutical companies, and consumers.8 Drugs and biologics may be included as suspect agents, but may not be causally associated with the AE. Expedited (15-day) reports for serious and unexpected (unlabeled) events are required to be submitted by industry to FDA within 15 days of receipt. Non-expedited reports for serious and labeled events or non-serious reports are submitted by industry to FDA on a periodic basis, and direct reports are those submitted directly to FDA by health care providers and consumers. A report is classified as serious if an AE resulted in death, life-threatening illness, hospitalization or prolongation of existing hospitalization, permanent disability, or birth defect.9
Information collected in FAERS reports includes patient demographics, medical history, concomitant medications, description and outcome of the AE, reporting source, and country of submission.5 The FDA Adverse Event Reporting System codes AEs according to the international Medical Dictionary for Regulatory Activities (MedDRA)10, 11 using a tiered system of five categories that ranges from the broadest category (System Organ Class [SOC]) to more granular categories, including Preferred Term (PT). A PT describes signs or symptoms, diagnoses, indication for treatment, laboratory tests, procedures, and aspects of medical, social, or family history. A single FAERS report is assigned one or more PTs, and each PT is assigned a primary SOC, as defined within the MedDRA hierarchy.10 In contrast to the PTs “cytokine release syndrome” and “neurotoxicity,” which have been available in the MedDRA dictionary for more than a decade, the PT “immune effector cell-associated neurotoxicity (ICANS)” only became available in the first quarter of 2020. Thus, in a secondary analysis, we assessed the PTs included within the SOCs of nervous system and psychiatric disorders as a surrogate of ICANs. However, while some nonspecific signs and symptoms (e.g., headache, tremor, hallucinations, weakness) and entities with other plausible etiologies (eg, intracranial hemorrhage) are excluded from ICANs,12 we included all PTs within this surrogate category.
2.2 Statistical analyses
We conducted descriptive analyses overall and in two subpopulations: (1) children, adolescents, young adults (C-AYA), reflecting age ≤25 years and a diagnosis of ALL, and (2) adults, reflecting age >25 years and a diagnosis of large B-cell lymphoma, hereafter referred to as DLBCL. We retrieved information on age and indication for treatment from the specified data field and the text of the report.
2.2.1 Descriptive analyses
We searched for U.S. reports submitted to FAERS with tisagenlecleucel included as a suspect agent between August 30, 2017 and date of dataset download (November 13, 2020). We limited reports to those with a tisagenlecleucel treatment date between August 30, 2017 and August 31, 2019. For patients who received more than one tisagenlecleucel infusion, we considered the date of first infusion. To reflect the use in clinical practice, we excluded reports for patients treated through interventional clinical trials or compassionate use programs. For reports without date of administration, we used dates and time frames specified in unstructured fields, to identify cases likely treated within the period of interest. Through individual case review, we identified and excluded duplicate reports. We calculated frequencies and percentages for categorical variables and medians and interquartile ranges (IQR) for continuous variables using SAS version 9.4 (Cary, North Carolina, US).
2.2.2 Reporting rates
Novartis Pharmaceuticals Corporation provided information on the number of tisagenlecleucel doses supplied to treating facilities during the period of interest. Distribution data was provided according to patient age group and diagnosis (ALL, DLBCL). We calculated reporting rates by dividing the number of reports, overall and for selected AEs, by the number of doses distributed.
2.2.3 Data mining (disproportionality analyses)
We conducted Empirical Bayesian data mining analyses, with reports limited to those initially received between August 30, 2017 through August 31, 2019 (follow-up through November 13, 2020) to identify tisagenlecleucel-event pairs reported more frequently than expected compared to all other drug/biologic-event pairs reported to FAERS.13-15 We conducted overall and subgroup analyses by age (≤25 and >25 years) and adjusted for age group (<2, 2–4, 5–12, 13–16, 17–29, 30–45, 46–64, 65–75, 76–85, >85 years, and unknown age), sex, and calendar year in which the report was received.
Using the Multi-Item Gamma Poisson Shrinker algorithm in the Oracle Empirica™ Signal System, we estimated Empirical Bayes Geometric Mean (EBGM) and the 5th and 95th percentiles of the posterior distribution (EB05, EB95), which are interpreted as the lower and upper 95% confidence limit, respectively.14 The EBGM values reflect the relative reporting rates (after Bayesian smoothing) for the drug–event pairs studied.16 An EB05 ≥ 2.0 is used by FDA as a criterion for considering a potential signal, because this threshold suggests a high probability of the drug/biologic-event pair occurring at least twice as often as expected under the assumption that drug/biologic-events are randomly paired.14 However, an elevated data mining statistic should not be interpreted as evidence of a causal association between a drug/biologic product and an AE, but as a potential signal to be evaluated further in well-designed studies using other databases.14, 17
Data mining analyses relied on the most recent follow-up report for a given case and a de-duplication case-matching algorithm that is applied to all FAERS reports.18 Given that the same analysis parameters applied to tisagenlecleucel reports had to be applied to all other FAERS reports, data mining analyses were based on report receipt date (treatment dates were not considered) and subgroup analyses were based solely on age (≤25 and >25 years). Therefore, the number of reports in the descriptive analyses differed from those available for data mining analyses.
2.3 Case review
We reviewed individual FAERS reports with a death outcome, and those describing SPNs or AEs not included on the USPI.
2.3.1 Deaths
Two clinicians (GMD, CJ), independently reviewed all death reports to determine the cause of death, as stated on the report, and time from treatment to death. A third clinician (MTN) resolved the discrepant assignments (<5%). We considered the SOC of “neoplasms, benign, malignant, and unspecified” in two categories: (1) disease progression – included deaths due to the primary lymphoid neoplasm and those with multiple contributing causes and progression of underlying lymphoid neoplasm (given that progression of disease was often the principal underlying cause of death), and (2) SPN – included deaths related to an SPN diagnosed following treatment with tisagenlecleucel.
2.3.2 Subsequent primary neoplasms (SPNs)
We identified reports of SPN using the PT “second primary neoplasm” and PTs included in the neoplasms SOC that did not describe events specific to the indication for therapy. We separately reviewed reports with an AE related to lymphoma among individuals ≤25 years and leukemia among individuals >25 years of age to determine if reports described a primary neoplasm or SPN. When available, we collected data for patient demographics, cancer risk factors, site and type of SPN, time from first cancer diagnosis to tisagenlecleucel infusion and from treatment to SPN diagnosis, and treatments prior to tisagenlecleucel.
2.4 Ethics
This FAERS safety review did not require institutional review board approval because it met the Department of Health and Human Services regulations exemption from the Office for Protection from Research Risks.19
3 RESULTS
We assessed 646 tisagenlecleucel reports submitted to FAERS for patients treated between August 30, 2017 and August 31, 2019. The overall AE reporting rate was 81.0% and was higher among C-AYA (87.0%) than adults (62.7%). More than 95% of reports described a serious outcome, and 25.5% described a death outcome (C-AYA 25.2%; adults 27.9%).
The median age at AE was 18 (interquartile range [IQR]: 11–56) years, with C-AYAs and adults accounting for 65.3% of reports (98.8% treated for ALL) and 29.4% of reports (95.9% treated for DLBCL), respectively (Table 1). Males accounted for slightly more than half of reports, overall and among both treatment groups. The FDA received 63.2% of initial reports in 2019, the majority (71.9%) authored by physicians and other health professionals, and with at least half of reports including information updates (median report versions = 2).
| All reports (No. = 646) | Treatment group | |||||
|---|---|---|---|---|---|---|
| C-AYA (No. = 421) | Adult (No. = 197) | |||||
| Median age (IQR Q1-Q3), yearsa | 18 (11–56) | 13 (9–18) | 64 (58–71) | |||
| Median completeness scoreb (IQR Q1-Q3), % | 50 (50–90) | 100 (50–100) | 50 (50–50) | |||
| Median no. report versionsc (IQR Q1-Q3) | 2 (1–4) | 3 (1–5) | 3 (1–4) | |||
| Characteristic | No. | % | No. | % | No. | % |
|---|---|---|---|---|---|---|
| Sex | ||||||
| Males | 331 | 51.2 | 223 | 53.0 | 99 | 50.3 |
| Females | 234 | 36.2 | 153 | 36.3 | 75 | 38.1 |
| Not specified | 81 | 12.5 | 45 | 10.7 | 23 | 11.7 |
| Age, yearsa | ||||||
| <10 | 110 | 17.0 | 110 | 26.1 | ~ | ~ |
| 10–17 | 151 | 23.4 | 151 | 35.9 | ~ | ~ |
| 18–25 | 107 | 16.6 | 107 | 25.4 | ~ | ~ |
| 26–49 | 23 | 3.6 | ~ | ~ | 23 | 11.7 |
| 50–64 | 67 | 10.4 | ~ | ~ | 67 | 34.0 |
| 65–74 | 59 | 9.1 | ~ | ~ | 59 | 30.0 |
| ≥75 | 22 | 3.4 | ~ | ~ | 22 | 11.2 |
| Not specified | 107 | 16.6 | 53 | 12.6 | 26 | 13.2 |
| Indication for tisagenlecleuceld | ||||||
| ALL | 422 | 65.3 | 416 | 98.8 | 6 | 3.1 |
| DLBCL | 190 | 29.4 | 1 | 0.2 | 189 | 95.9 |
| Other specified | 5 | 0.8 | 3 | 0.7 | 2 | 1.0 |
| Not specified | 29 | 4.5 | 1 | 0.2 | ~ | ~ |
| Received at FDA (calendar year) | ||||||
| 2017e | 7 | 1.1 | 6 | 1.4 | ~ | ~ |
| 2018 | 138 | 21.4 | 109 | 25.9 | 17 | 8.6 |
| 2019 | 408 | 63.2 | 249 | 59.1 | 145 | 73.6 |
| 2020e | 93 | 14.4 | 57 | 13.5 | 35 | 17.8 |
| Reporter qualifications | ||||||
| Physician | 360 | 55.7 | 234 | 55.6 | 118 | 59.9 |
| Health professionalf | 169 | 16.2 | 120 | 28.5 | 39 | 19.8 |
| Consumer | 116 | 18.0 | 66 | 15.7 | 40 | 20.3 |
| Other specified | 1 | 0.2 | 1 | 0.2 | ~ | ~ |
| Type of report | ||||||
| Expedited, 15 day | 235 | 36.4 | 169 | 40.1 | 56 | 28.4 |
| Not expedited | 375 | 58.1 | 229 | 54.4 | 128 | 65.0 |
| Direct | 36 | 5.6 | 23 | 5.5 | 13 | 6.6 |
| Seriousnessg | ||||||
| Serious | 615 | 95.2 | 403 | 95.7 | 193 | 98.0 |
| Nonserious | 31 | 4.8 | 18 | 4.3 | 4 | 2.0 |
| Outcomeh | ||||||
| Death | 165 | 25.5 | 106 | 25.2 | 55 | 27.9 |
| Nonfatal, hospitalization | 95 | 14.7 | 69 | 16.4 | 2 | 12.7 |
| Nonfatal, life-threatening (without hospitalization specified) | 27 | 4.2 | 18 | 4.3 | 9 | 4.6 |
| Nonfatal, other (without hospitalization or life-threatening specified) | 328 | 50.8 | 210 | 49.9 | 104 | 52.8 |
| Not specified | 31 | 4.8 | 18 | 4.3 | 4 | 2.0 |
- Abbreviations: ALL, B-cell acute lymphocytic leukemia; C-AYA, children, adolescents, and young adults; DLBCL, diffuse large B-cell lymphoma; FDA, Food and Drug Administration; IQR, interquartile range; Q1, 25th percentile; Q3, 75th percentile.
- a Age indicated on FAERS reports generally reflects age at time of adverse event. Quantitative measures are limited to reports with age specified (eg., excludes reports indicating “infant,” “pediatric,” or “adult” patient). Treatment groups incorporated numeric and descriptive information (e.g., infant, pediatric) on age to categorize patients into the C-AYA or adult groups. Reports without age-related information were excluded from the treatment group analysis.
- b The completeness score is derived from 10 clinically relevant data elements (time-to-onset, indication, outcome, sex, age, dose, country, primary reporter, report type, narrative) available on reports and whether they are recorded in a usable way. If data in an element is either missing or is not meaningful a penalty is imposed. When information is present or meaningful, the penalty is zero. The formula to calculate the completeness score is: (1-P1)*(1-P2)…(1-P10) where P denotes a predetermined penalty for each of the 10 information elements.
- c The initial report submitted is the first version of the report. Any reports subsequently submitted with updated information are consecutively numbered beginning with version 2 (eg., the initial report is version 1, the first update is version 2, the second update is version 3).
- d Other specified indication for tisagenlecleucel included Burkitt lymphoma (n = 2; 1 C-AYA and 1 adult), primary mediastinal B-cell lymphoma (n = 1, C-AYA), lymphoma (n = 1, C-AYA), myeloma (n = 1, adult).
- e Partial year.
- f Health professional includes health professional, nurse, nurse practitioner, physician assistant, pharmacist.
- g Serious reports are those with an outcome that is defined as an important medical event based upon appropriate medical judgment that may jeopardize the patient or participant and may require medical or surgical intervention to prevent one of the other specified outcomes. Serious outcomes are defined in the Code of Federal Regulations (ie, death, hospitalization, life-threatening, disability, congenital anomaly, required intervention, or other serious outcome). Reports that do not meet these criteria are considered nonserious.
- h The outcome is specified by the individual submitting the FAERS report. Reporters may select more than one outcome. Outcomes were arranged in a hierarchical fashion for purposes of tabular presentation. No additional information is available for the outcome of “other.”
The most frequently reported PT was CRS (n = 330; 51.1%), with an overall reporting rate of 41.4%, reflecting a higher rate among C-AYA (RR = 45.7%) than adults (RR = 32.3%; Table 2). In contrast, the overall reporting rate for the PT neurotoxicity was 17.2% (n = 137), with the rate among C-AYA (RR = 20.9%) nearly twice that of adults (RR = 10.8%). Of the total CRS reports, 31.8% (n = 105) included a PT of neurotoxicity (Table S1, Appendix S1). In contrast, 76.6% of all reports with a PT of neurotoxicity included a PT of CRS (n = 105). Among the PTs in the combined SOC category of nervous system and psychiatric disorders (n = 187), 71.7% of reports included a PT of CRS (n = 134). After excluding headache (25.1%) and tremor (13.9%), the PTs most closely aligned with ICANs included neurotoxicity (73.3%), depressed level of consciousness (25.7%), aphasia (12.3%), confusional state (11.2%), and hemiparesis (10.7%).
| Total | Treatment group | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| C-AYA | Adult | |||||||||||
| No. reports | % | Ranka | RR (%) | No. reports | % | Ranka | RR (%) | No. reports | % | Ranka | RR (%) | |
| Total reportsc | 646 | 100 | ∼ | 81.0 | 421 | 100 | ∼ | 87.0 | 197 | 100 | ∼ | 62.7 |
| Preferred term | ||||||||||||
| Cytokine release syndrome | 330 | 51.1 | 1 | 41.4 | 221 | 52.5 | 1 | 45.7 | 101 | 51.3 | 1 | 32.2 |
| Pyrexia | 284 | 44.0 | 2 | 35.6 | 199 | 47.3 | 2 | 41.1 | 82 | 41.6 | 4 | 26.1 |
| Hemoglobin decreased | 219 | 33.9 | 3 | 27.4 | 127 | 30.2 | 6 | 26.2 | 92 | 46.7 | 2 | 29.3 |
| Lymphocyte count decreased | 216 | 33.4 | 4 | 27.1 | 134 | 31.8 | 4 | 27.7 | 82 | 41.6 | 4 | 26.1 |
| Hematocrit decreased | 208 | 32.2 | 5 | 26.1 | 122 | 29.0 | 7 | 25.2 | 86 | 43.7 | 3 | 27.4 |
| White blood cell count decreased | 205 | 31.7 | 6 | 25.7 | 133 | 31.6 | 5 | 27.5 | 72 | 36.5 | 5 | 22.9 |
| Hypogammaglobulinemia | 192 | 29.7 | 7 | 24.1 | 140 | 33.3 | 3 | 28.9 | 52 | 26.4 | 7 | 16.6 |
| Neutrophil count decreased | 173 | 26.8 | 8 | 21.7 | 122 | 29.0 | 7 | 25.2 | 51 | 25.9 | 8 | 16.2 |
| Platelet count decreased | 171 | 26.5 | 9 | 21.4 | 103 | 24.5 | 8 | 21.3 | 68 | 34.5 | 6 | 21.7 |
| Malignant neoplasm progressionb | 166 | 25.7 | 10 | 20.8 | 98 | 23.3 | 10 | 20.2 | 68 | 34.5 | 6 | 21.7 |
| Neurotoxicity | 137 | 21.2 | 11 | 17.2 | 101 | 24.0 | 9 | 20.9 | 34 | 17.3 | 10 | 10.8 |
| Hypotension | 115 | 17.8 | 12 | 14.4 | 85 | 20.2 | 11 | 17.6 | 30 | 15.2 | 12 | 9.6 |
| Cytopenia | 96 | 14.9 | 13 | 12.0 | 74 | 17.6 | 13 | 15.3 | 22 | 11.2 | 13 | 7.0 |
| Acute lymphocytic leukemia recurrentb | 85 | 13.2 | 14 | 10.7 | 84 | 20.0 | 12 | 17.4 | * | * | * | * |
| Hypoxia | 74 | 11.5 | 15 | 9.3 | 53 | 12.6 | 16 | 11.0 | * | * | * | * |
| B-cell type acute leukemiab | * | * | * | * | 63 | 15.0 | 14 | 13.0 | * | * | * | * |
| Treatment failure | * | * | * | * | 58 | 13.8 | 15 | 12.0 | * | * | * | * |
| Neutropenia | * | * | * | * | 45 | 10.7 | 17 | 9.3 | * | * | * | * |
| Diffuse large B-cell lymphomab | * | * | * | * | * | * | * | * | 47 | 23.9 | 9 | 15.0 |
| Diffuse large B-cell lymphoma recurrentb | * | * | * | * | * | * | * | * | 32 | 16.2 | 11 | 10.2 |
- Note: ~, not applicable; *, PT not reported for ≥10% of reports.
- Abbreviations: C-AYA, children, adolescents, young adults; PT, Preferred Term; SOC, System Organ Class; RR, reporting rate.
- a Ties in rank are represented by duplicate rank number. For example, two PTs with a rank of 5 are both assigned a rank of “5.”
- b PT is confounded by indication for therapy.
- c Treatment groups incorporated numeric and descriptive information (e.g., infant, pediatric) on age to categorize patients into the C-AYA or adult groups. Reports without age-related information were excluded from the treatment group analysis.
Cytopenias were among the 10 most frequently reported PTs, overall and in both subgroups. Whereas pyrexia and hypogammaglobulinemia were the next most frequently reported PTs among C-AYA, hemoglobin and/or hematocrit decreased were the next most commonly reported AEs among adults. Hemoglobin, hematocrit, and platelet count decreased were the only PTs with similar or higher reporting rates among adults than C-AYA. Notably, infections were not among the most commonly reported AEs. The PTs included within the SOC of infections and infestations are detailed in Table S2, Appendix S1.
3.1 Data mining (disproportionality analysis)
We found numerous tisagenlecleucel-AE pairs reported more than twice the expected when compared to all other drug/biologic-AE pairs reported to FAERS, including PTs reflecting cytopenias, CRS, infections, laboratory abnormalities, bleeding events, and neurotoxicity (Table 3). Overall, except for acidosis, serum ferritin increased, and C-reactive protein (CRP) increased, all other disproportionately reported PTs were listed on the USPI. Acidosis reflected a secondary phenomenon with the primary or underlying process representing a labeled triggering event (e.g., sepsis). Serum ferritin and/or CRP largely reflected an increase in these markers shortly after administration of tisagenlecleucel. Most patients had simultaneous increases in ferritin and CRP in conjunction with CRS, with or without neurotoxicity.
| SOC | PT | Total | Age group | |||||
|---|---|---|---|---|---|---|---|---|
| ≤25 Years | >25 Years | PT labeled? | ||||||
| No. | EBGM (EB05, EB95) | No. | EBGM (EB05, EB95) | No. | EBGM (EB05, EB95) | |||
| Blood and lymphatic system disorders | Febrile neutropenia | 37 | 40.8 (30.9, 53.2) | 33 | 46.7 (34.5, 61.9) | * | * (*) | Yes |
| Coagulopathy | 16 | 57.6 (37.3, 85.8) | 13 | 67.0 (40.9, 104.5) | * | * (*) | Yes | |
| Lymphopenia | 13 | 106.8 (65.7, 166.1) | 13 | 175.4 (107.9, 272.7) | * | * (*) | Yes | |
| Disseminated intravascular coagulation | 12 | 93.3 (56.2, 147.6) | 9 | 80.6 (44.0, 137.4) | * | * (*) | Yes | |
| Neutropenia | 11 | 5.5 (3.3, 8.9) | 6 | 5.3 (2.5, 10.2) | * | * (*) | Yes | |
| Pancytopenia | 10 | 14.3 (6.1, 31.7) | 7 | 16.1 (7.5, 33.9) | * | * (*) | Yes | |
| B-cell aplasia | 8 | 298.6 (158.4, 522.9) | 4 | 150.4 (56.7, 336.9) | * | * (*) | Yes | |
| Thrombocytopenia | 6 | 4.4 (2.1, 8.3) | * | * (*) | * | * (*) | Yes | |
| Cytopenia | 4 | 8.1 (2.4, 45.9) | * | * (*) | * | * (*) | Yes | |
| Leukopenia | * | * (*) | 3 | 15.1 (3.7, 61.7) | * | * (*) | Yes | |
| Hypofibrinogenemia | * | * (*) | 2 | 13.1 (2.1, 89.2) | * | * (*) | Yes | |
| Cardiac disorders | Tachycardia | 17 | 10.5 (6.5, 17.8) | 13 | 12.4 (7.5, 19.7) | * | * (*) | Yes |
| Left ventricular dysfunction | 6 | 77.0 (36.0, 148.4) | 6 | 100.8 (46.9, 194.0) | * | * (*) | Yes | |
| Eye disorders | Conjunctival hemorrhage | * | * (*) | 2 | 29.4 (3.0, 185.7) | * | * (*) | Yesb |
| Gastrointestinal disorders | Abdominal compartment syndrome | 3 | 33.7 (2.6, 181.6) | 3 | 69.1 (10.7, 211.0) | * | * (*) | Yes |
| Gastrointestinal hemorrhage | * | * (*) | 3 | 7.5 (2.4, 21.0) | * | * (*) | Yesb | |
| Pancreatitis | * | * (*) | 3 | 6.4 (2.0, 16.7) | * | * (*) | No | |
| General disorders and administration site conditions | Pyrexia | 79 | 15.6 (12.7, 19.1) | 46 | 12.6 (9.8, 16.0) | 17 | 21.8 (13.1, 33.0) | Yes |
| Disease progression | 15 | 13.7 (7.4, 25.0) | 10 | 31.6 (15.7, 56.4) | * | * (*) | CBI/E | |
| Multiple organ dysfunction syndrome | 13 | 25.4 (12.7, 41.5) | 8 | 15.5 (7.7, 30.4) | * | * (*) | Yes | |
| Therapy non-responder | 9 | 6.3 (3.5, 10.9) | 6 | 11.7 (5.3, 24.4) | * | * (*) | CBI/E | |
| Chills | * | * (*) | 5 | 8.3 (3.6, 17.5) | * | * (*) | Yes | |
| Hepatobiliary disorders | Hepatic function abnormal | * | * (*) | 3 | 15.5 (3.8, 63.5) | * | * (*) | Yes |
| Immune system disorders | Cytokine release syndrome | 134 | 412.4 (356.9, 474.4) | 68 | 290.4 (236.8, 353.2) | 28 | 449.9 (325.6, 609.1) | Yes |
| Hypogammaglobulinemia | 6 | 91.8 (43.4, 176.0) | 6 | 121.6 (57.2, 232.9) | * | * (*) | Yes | |
| Hemophagocytic lymphohistiocytosis | 5 | 10.4 (3.2, 44.1) | 4 | 13.9 (4.7, 41.7) | * | * (*) | Yes | |
| Cytokine storm | 3 | 120.3 (7.4, 368.1) | 2 | 47.5 (3.9, 261.2) | * | * (*) | Yes | |
| Infections and infestations | Sepsis | 9 | 5.7 (3.2, 9.8) | 6 | 10.6 (4.9, 21.6) | * | * (*) | Yes |
| Candida infection | 6 | 17.2 (4.5, 52.0) | 4 | 29.6 (7.6, 87.8) | * | * (*) | Yes | |
| Staphylococcal infection | 6 | 4.9 (2.4, 9.4) | 4 | 7.4 (2.8, 17.0) | * | * (*) | Yes | |
| Device related infection | 5 | 8.9 (3.0, 37.6) | 5 | 24.5 (8.1, 64.0) | * | * (*) | Yes | |
| Clostridium difficile infection | 5 | 4.5 (2.0, 9.0) | 3 | 9.4 (2.8, 30.4) | * | * (*) | Yes | |
| Bacteremia | 4 | 5.3 (2.0, 17.4) | * | * (*) | * | * (*) | Yes | |
| Viral upper respiratory tract infection | 4 | 14.2 (2.8, 73.0) | * | * (*) | * | * (*) | Yes | |
| Pneumonia fungal | 3 | 20.8 (2.2, 142.3) | * | * (*) | * | * (*) | Yes | |
| Septic shock | * | * (*) | 3 | 6.4 (2.0, 16.8) | Yes | |||
| Injury, poisoing, and procedural complications | Subdural hematoma | * | * (*) | 2 | 23.0 (2.7, 153.5) | * | * | Yesb |
| Investigations | Neutrophil count decreased | 20 | 55.2 (37.5, 78.9) | 17 | 72.7 (47.6, 107.2) | * | * (*) | Yes |
| White blood cell count decreased | 17 | 14.8 (8.2, 25.3) | 16 | 54.3 (34.7, 81.4) | * | * (*) | Yes | |
| Platelet count decreased | 17 | 15.3 (8.4, 25.9) | 13 | 39.8 (22.8, 63.9) | * | * (*) | Yes | |
| Serum ferritin increased | 8 | 79.1 (41.9, 138.6) | 5 | 58.4 (18.9, 128.5) | * | * (*) | No | |
| Lymphocyte count decreased | 6 | 15.1 (4.3, 48.1) | 5 | 34.6 (10.6, 84.8) | * | * (*) | Yes | |
| C-reactive protein increased | 5 | 63.7 (22.7, 138.3) | 4 | 83.1 (24.1, 196.4) | * | * (*) | No | |
| Blood fibrinogen decreased | 5 | 174.5 (76.2, 354.5) | 5 | 177.6 (77.4, 361.3) | * | * (*) | Yes | |
| International normalized ratio increased | 4 | 5.3 (2.0, 16.4) | 3 | 14.1 (3.6, 56.6) | * | * (*) | Yes | |
| Aspartate aminotransferase increased | * | * (*) | 4 | 5.6 (2.2, 12.4) | * | * (*) | Yes | |
| Blood creatinine increased | * | * (*) | 4 | 10.6 (3.8, 27.8) | * | * (*) | Yes | |
| Inflammatory marker increased | * | * (*) | 3 | 38.4 (6.4, 137.6) | * | * (*) | No | |
| Blood pressure decreased | * | * (*) | 3 | 8.3 (2.6, 24.8) | * | * (*) | Yes | |
| Blood pressure diastolic decreased | * | * (*) | 2 | 37.7 (3.4, 222.2) | * | * (*) | Yes | |
| Blood uric acid increased | * | * (*) | 2 | 24.6 (2.8, 162.2) | * | * (*) | Yes | |
| Metabolism and nutrition disorders | Fluid overload | 10 | 43.1 (24.2, 71.8) | 8 | 82.9 (43.3, 146.0) | * | * (*) | Yes |
| Acidosis | 7 | 55.1 (26.9, 102.0) | 6 | 52.3 (19.7, 106.8) | * | * (*) | No | |
| Tumor lysis syndrome | 6 | 60.0 (26.8, 118.1) | 6 | 92.6 (42.5, 178.8) | * | * (*) | Yes | |
| Hypokalemia | 5 | 5.1 (2.3, 10.9) | 4 | 9.3 (3.5, 22.9) | * | * (*) | Yes | |
| Hyperphosphatemia | 4 | 92.2 (29.2, 220.7) | 4 | 112.2 (39.4, 255.9) | * | * (*) | Yes | |
| Hyperuricemia | * | * (*) | 2 | 29.6 (3.0, 186.8) | * | * (*) | Yes | |
| Decreased appetite | * | * (*) | 7 | 4.8 (2.4, 8.8) | * | * (*) | Yes | |
| Musculoskeletal and connective tissue disorders | Myalgia | * | * (*) | 5 | 8.1 (3.5, 17.1) | * | * (*) | Yes |
| Neoplasms benign, malignant and unspecified | Malignant neoplasm progression | 34 | 47.7 (35.6, 62.8) | 13 | 77.3 (47.4, 120.4) | 10 | 48.5 (27.6, 80.2) | CBI/E |
| Acute lymphocytic leukemia recurrent | 28 | 245.9 (178.0, 332.9) | 19 | 181.1 (121.8, 261.2) | * | * (*) | CBI/E | |
| Diffuse large B-cell lymphoma | 17 | 302.7 (198.7, 445.7) | * | * (*) | 12 | 418.4 (251.9, 662.2) | CBI/E | |
| Acute lymphocytic leukemia | 10 | 141.6 (80.9, 234.0) | 7 | 110.4 (55.4, 201.5) | * | * (*) | CBI/E | |
| B-cell type acute leukemia | 4 | 155.1 (59.2, 348.2) | 2 | 30.6 (3.1, 191.5) | * | * (*) | CBI/E | |
| Diffuse large B-cell lymphoma recurrent | 4 | 195.7 (75.6, 435.4) | * | * (*) | * | * (*) | CBI/E | |
| Leukemia recurrent | 3 | 58.4 (3.4, 239.8) | * | * (*) | * | * (*) | CBI/E | |
| Nervous system disorders | Neurotoxicity | 22 | 59.0 (40.9, 83.0) | 13 | 44.5 (25.9, 70.6) | 6 | 78.6 (37.1, 150.7) | Yes |
| Encephalopathy | 20 | 71.2 (48.4, 101.8) | 15 | 78.2 (49.8, 118.1) | 4 | 28.7 (3.4, 101.4) | Yes | |
| Status epilepticus | 6 | 7.2 (3.2, 21.3) | * | * (*) | * | * (*) | Yes | |
| Hemorrhage intracranial | * | * (*) | 3 | 24.0 (4.8, 96.0) | * | * (*) | Yesb | |
| Cerebral hemorrhage | * | * (*) | 3 | 14.5 (3.7, 58.8) | * | * (*) | Yesb | |
| Facial paralysis | * | * (*) | 3 | 15.7 (3.8, 64.5) | * | * (*) | Yes | |
| Immune effector cell-associated neurotoxicity syndrome | * | * (*) | 2 | 54.2 (4.2, 286.0) | * | * (*) | Yes | |
| Intraventricular hemorrhage | * | * (*) | 2 | 12.9 (2.1, 87.6) | * | * (*) | Yesb | |
| Central nervous system hemorrhage | * | * (*) | 2 | 47.4 (3.9, 260.7) | * | * (*) | Yes | |
| Product issues | Out of specification test results | 3 | 185.6 (50.5, 508.6) | * | * (*) | * | * (*) | Product |
| Psychiatric disorders | Confusional state | 10 | 4.3 (2.5, 7.0) | 6 | 6.7 (3.2, 12.9) | * | * (*) | Yes |
| Delirium | 6 | 7.6 (3.2, 23.8) | * | * (*) | * | * (*) | Yes | |
| Disorientation | 5 | 5.1 (2.3, 10.6) | 3 | 8.5 (2.6, 25.5) | * | * (*) | Yes | |
| Renal and urinary disorders | Acute kidney injury | 21 | 4.7 (3.2, 6.6) | 17 | 18.3 (11.6, 28.1) | * | * (*) | Yes |
| Respiratory, thoracic and mediastinal disorders | Hypoxia | 20 | 33.8 (22.9, 48.3) | 16 | 39.1 (24.1, 59.6) | * | * (*) | Yes |
| Respiratory failure | 12 | 8.3 (4.9, 14.7) | 8 | 10.2 (5.3, 18.4) | * | * (*) | Yes | |
| Respiratory distress | * | * (*) | 4 | 6.0 (2.3, 13.5) | * | * (*) | Yes | |
| Pulmonary edema | * | * (*) | 3 | 7.5 (2.3, 20.9) | * | * (*) | Yes | |
| Vascular disorders | Hypotension | 46 | 18.9 (14.2, 24.3) | 36 | 27.4 (20.2, 36.4) | 7 | 5.9 (2.9, 12.3) | Yes |
| Capillary leak syndrome | 5 | 111.8 (48.4, 228.9) | 4 | 97.2 (31.7, 225.0) | * | * (*) | Yes | |
| Hypertension | * | * (*) | 8 | 10.3 (5.4, 18.5) | * | * (*) | Yes | |
| Hemodynamic instability | * | * (*) | 3 | 21.9 (4.6, 88.7) | * | * (*) | Yes | |
- Note: *, PT associated with EB05 <2.0 or not reported for the specified category.
- Abbreviations: CBI/E, confounded by indication for use/effectiveness; EBGM, empirical Bayes Geometric Mean; EB05, lower bound of EBGM 90% confidence interval; EB95, upper bound of EBGM 90% confidence interval; PT, Preferred Term; SOC, System Organ Class.
- a PTs reported disproportionately are those associated with an EB05 >2.0.
- b Term is considered related to the labeled adverse event term “bleeding episodes.”
Among individuals ≤25 years, we identified disproportionate reporting for pancreatitis (n = 3), an unlabeled event. The three patients, two females and one male (age range 6–13 years), had received tisagenlecleucel for treatment of r/r ALL. Two patients had a history of pancreatitis, received asparaginase 100 and 192 days prior to tisagenlecleucel, and developed pancreatitis 12 and 15 days following tisagenlecleucel. The third report provided no details about pancreatitis or possible risk factors. The remaining PTs reported disproportionately represented labeled events, were considered related to labeled events, or were confounded by indication for treatment.
3.2 SPNs
We identified 13 reported SPNs among individuals treated with tisagenlecleucel, eight (61.5%) among survivors of ALL and five (38.5%) among survivors of DLBCL (Table 4). The reported SPNs among C-AYA were all hematopoietic neoplasms, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In contrast, SPNs among adults were varied and primarily comprised of solid tumors. Among the 12 cases with specified time to SPN, all were reported within 1 year of treatment with tisagenlecleucel, and eight (66.7%) were reported within 6 months of treatment. None of the reports described testing for or evidence of insertional mutagenesis.
| Treatment group and case # | Age reported on FAERS report (years) | Sex | Time from lymphoid neoplasm diagnosis to tisagenlecleucel | Subsequent neoplasm | Tisagenlecleucel administration year | Time from tisagenlecleucel to SPN (months) | Potential risk factors for subsequent neoplasm, including treatments received for first neoplasm (includes lymphodepleting agents, if specified) |
|---|---|---|---|---|---|---|---|
| C-AYA | |||||||
| 1 | Infant | Male | Not specified | AML | Not specified | Not specified | None specified |
| 2 | 0.8 | Female | Not specified | AML | 2019 | <1 | None specified |
| 3 | 9 | Female | 8.8 years | AML | 2019 | 10.3 | MLL rearrangement; blinatumomab, inotuzumab |
| 4 | 13 | Female | 3.8 years | MDS/MPN | 2017 | 8.7 | Allogeneic HSCT, fludarabine, cyclophosphamide |
| 5 | 15 | Female | 8.6 months | AML | 2018 | <1 | MLL rearrangenment; intrathecal chemotherapy, blinatumomab, inotuzumab, cyclophosphamide, fludarabine |
| 6 | 15 | Female | NOS | AML | 2018 | <1 | None specified |
| 7 | 19 | Female | NOS | MDS | 2019 | 6.5 | MLL rearrangement; Li-Fraumeni syndrome |
| 8 | 25 | Male | 5 months | AML | 2017 | 2.4 | MLL rearrangement; hydroxyurea, cytarabine (systemic and intrathecal), ponatinib, rituximab, inotuzumab, cyclophosphamide, vincristine, doxorubicin, fludarabine |
| Adults | |||||||
| 9 | 59 | Male | 1.0 year | ALL | 2018 | 6.0 | Rituximab, cyclophosphamide, doxorubicin, vincristine, cytarabine, carboplatin, cisplatin, lenalidomide, gemcitabine, oxaliplatin, etoposide, fludarabine, ifosfamide; radiation therapy |
| 10 | 62 | Male | 4.1 years | MDS | 2019 | 4.4 | Rituximab, cyclophosphamide, doxorubicin, vincristine, gemcitabine, cisplatin, ibrutinib, autologous HSCT |
| 11 | 68 | Female | 4.2 years | Intrahepatic cholangiocarcinoma | 2018 | 3.9 | Partial gastrectomy (indication not specified), radiation therapy, rituximab, carboplatin, cyclophosphamide, doxorubicin, etoposide, fludarabine, vincristine |
| 12 | 69 | Male | NOS | Squamous cell carcinoma bladder | 2019 | 7.7 | Rituximab, cytarabine, gemcitabine, cyclophoaphamide, fludarabine. Notably, DLBCL was abutting the bladder |
| 13 | 71 | Male | 7.7 years | Basal cell carcinoma skin | 2018 | 3.9 | Prior autologous HSCT, rituximab, tositumomab-I131, lenalidomide, fludarabine, cyclophosphamide |
- Abbreviations: ALL, B-cell acute lymphocytic leukemia; AML, acute myeloid leukemia; C-AYA, children, adolescents, young adults; DLBCL, diffuse large B-cell lymphoma; FAERS, Food and Drug Adminstration Adverse Event Reporting System; HSCT, hematopoietic stem cell transplant; MDS, myelodysplastic syndrome; MLL, mixed lineage leukemia; MPN, myeloproliferative neoplasm; NOS, not otherwise specified; SPN, subsequent malignant neoplasm.
3.3 Deaths
There were a total of 165 deaths reported. Among those with specified age (n = 158), the median age was 18 (IQR: 11–58) years (Table 5). The median age among the C-AYA and adult groups was 13 (IQR: 7–18) and 65 (IQR: 58–72) years, respectively. More than 50% of deaths were reported among males, overall and in both treatment groups. The median time to death was 110 days (based on 103 reports with pertinent information), overall and for both subgroups, with 19.4% (n = 20) of deaths occurring within 30 days of treatment. Most reports without a date of death described deaths more than 90 days after receipt of tisagenlecleucel (e.g., based on date last known alive). Underlying cause of death was rarely attributed solely to CRS (n = 1) or neurotoxicity (n = 1). While some reports did not specify cause of death (6.7%), the majority of deaths (64.2%) were attributed to disease progression, overall and in both treatment groups, with infection (9.7%) comprising the next most frequent cause of death.
| All reports | Treatment group | |||||
|---|---|---|---|---|---|---|
| C-AYA | Adult | |||||
| Median age in years (IQR Q1-Q3), No. | 18 (11–58), n = 158 | 13 (7–18), n = 103 | 65 (58–72), n = 55 | |||
| Median specified days to death (IQR Q1-Q3), No. | 110 (42–222), n = 103 | 110 (38–235), n = 68 | 110 (44–156), n = 35 | |||
| No. reports with days to death not specified as a discrete numbera | 49 | 29 | 19 | |||
| <30 or >29 days | 2 | ∼ | 2 | |||
| >30 to >74 days | 8 | 6 | 2 | |||
| >90 to >163 days | 15 | 8 | 7 | |||
| >180 to >289 days | 13 | 7 | 5 | |||
| >365 days | 11 | 8 | 3 | |||
| Characteristic | No. reports | % | No. reports | % | No. reports | % |
|---|---|---|---|---|---|---|
| Total | 165 | 100 | 106 | 100 | 55 | 100 |
| Sex | ||||||
| Males | 90 | 54.6 | 58 | 54.7 | 31 | 56.4 |
| Females | 70 | 42.4 | 46 | 43.4 | 24 | 43.6 |
| Not specified | 5 | 3.0 | 2 | 1.9 | ∼ | ∼ |
| Underlying cause of death by SOC | ||||||
| Neoplasms benign, malignant, and unspecified | ||||||
| Disease progressionb | 106 | 64.2 | 58 | 54.7 | 47 | 85.5 |
| Second primary neoplasmb | 4 | 2.4 | 3 | 2.8 | 1 | 1.8 |
| Infection and infestionsc | 16 | 9.7 | 12 | 11.3 | 4 | 7.3 |
| Respiratory disorders | 7 | 4.2 | 7 | 6.6 | ∼ | ∼ |
| Multifactoriald | 5 | 3.0 | 4 | 3.8 | ∼ | ∼ |
| Immune system disorders | 4 | 2.4 | 4 | 3.8 | ∼ | ∼ |
| Vascular disorders | 4 | 2.4 | 4 | 3.8 | ∼ | ∼ |
| General disorders and administration site conditions | 4 | 2.4 | 3 | 2.8 | 1 | 1.8 |
| Other specifiede | 4 | 2.4 | 3 | 2.8 | 1 | 1.8 |
| Not specifiedf | 11 | 6.7 | 8 | 7.6 | 1 | 1.8 |
- Abbreviations: ∼, not applicable due to no reports; IQR, interquartile range; Q1, 25th percentile; Q3, 75th percentile; SOC, System Organ Class.
- a Categories are based on non-structured data retrieved through review of individual reports. If a patient was known to be alive at a specified time point and died at an unspecified time thereafter, time to death was noted to be “>” (greater than) the time last known alive. For this reason, these categories have gaps in time and are not mutually exclusive.
- b Category is based on PT included within the SOC, Neoplasms benign, malignant and unspecified.
- c Infections included: bacterial (n = 6), fungal (n = 2), multiple organisms (n = 2), influenza (n = 1), protozoal infection (n = 1), and organism not specified (n = 4).
- d Unable to assign a single SOC for underlying cause of death.
- e SOCs associated with single deaths: Injury, poisoning, and procedural complications; Hepatobiliary disorders; Cardiac disorders; Nervous system disorders.
- f Category does not represent an SOC.
4 DISCUSSION
We comprehensively describe the largest post-marketing case series of patients treated with tisagenlecleucel in the U.S. by leveraging FAERS data on AE frequencies, reporting rates, and disproportionate reporting, overall and according to age or treatment subgroups. We found that the reported AEs were consistent with those identified in the prelicensure clinical trials and described in the USPI.20-23 Despite the reporting requirement for all cases of CRS and neurotoxicity in the REMS program and allowing an extended time period for reporting (more than 1 year), we describe lower reporting rates for CRS and neurotoxicity than those identified in the prelicensure clinical trials.
Our safety findings compliment and extend those of the recent CIBMTR-based post-marketing study of tisagenlecleucel-treated patients in the U.S. and Canada.24 While a larger post-marketing study has been conducted in VigiBase, the assessment was limited to cardiac events.25 Other large, FAERS-based CAR-T studies have undertaken combined assessments of tisagenleclecucel and axicabtagene ciloleucel.26-28 While both CAR-T products target CD19, they have distinct costimulatory domains, vector transduction, and preservation methods, with limitations of product comparisons previously noted.29, 30
In the tisagenlecleucel pivotal clinical trials, CRS was the most common nonhematologic AE, reported in 77% of the 75 ELIANA trial participants with ALL and 58% of the 111 JULIET participants with DLBCL.22, 23 Although CRS was reported disproportionately to FAERS, overall and among both treatment groups, we noted lower reporting frequencies and reporting rates than in the clinical trials. Our findings align more with those of the CIBMTR study, where CRS was reported in 54.9% and 45.2% of ALL and DLBCL patients, respectively, although our reporting rates suggest an even lower occurrence. While differences from prelicensure clinical trials might be attributed to underreporting of AEs associated with passive surveillance systems – including FAERS – the required reporting of CRS through the REMS program for patients of all ages should have minimized this effect. Changes in the case definition of CRS over time might have also played a role. The higher occurrence of CRS among younger patients in our dataset parallels the pattern in ELIANA relative to JULIET, and in CIBMTR, however, direct comparisons are limited due to the uncontrolled nature of our analyses.
In the pivotal clinical trials, neurologic events occurring within 8 weeks of tisagenlecleucel infusion were noted in 40% of ALL and 21% of DLBCL patients.22, 23 Due to variable reporting of symptom onset and severity in FAERS reports, we did not calculate time to these events nor limit AEs to those occurring within a specified timeframe or by grade. However, despite differences in inclusion criteria and AE definitions between studies and over time, our results for all grades of neurotoxicity parallel those reported to the CIBMTR for ALL (27.1%) and lymphoma (18.1%). In ELIANA, the most common neurologic events of any grade were encephalopathy, confusional state, delirium, tremor, agitation, and somnolence, whereas in JULIET, they were headache and dizziness. While neurotoxicity and encephalopathy, overall and among both age groups, were reported more than twice expected compared to all other drug/biologic-AE reports in FAERS, a broader spectrum of nervous system and psychiatric disorders were reported among patients ≤25 years of age. In the clinical trials, the majority of neurologic events in ALL patients occurred concurrently with or shortly after CRS resolution,22 and in DLBCL, the majority of patients with grade ≥3 neurologic events had concurrent CRS.23 Without regard for timing or grade, we found that more than 70% of all reports with an AE included within the SOCs of nervous system/psychiatric disorders included a diagnosis of CRS, suggesting that the events may have occurred during the same episode of care for which the report was submitted.
Patients with r/r lymphoid neoplasms are at increased risk of infection from prior chemotherapy (including lymphodepleting therapy administered prior to tisagenlecleucel), hypogammaglobulinemia, immunodeficiency from their lymphoid neoplasm, and possibly tisagenlecleucel.31 In ELIANA and JULIET, infection of any grade within 8 weeks of tisagenlecleucel infusion occurred among 43% of ALL patients and among 34% of DLBCL; 39% of DLBCL patients developed infection more than 8 weeks after tisagenlecleucel.22, 23 Studies of other CAR-T cell products have described infection in approximately 30%-42% of an older ALL population within 28–30 days of CAR-T infusion and nearly 18% of patients with NHL.32, 33 Comparisons between studies is limited due to differences in patient characteristics, CAR-T products, time period of study, prophylactic antimicrobial therapy use, and other treatments. Infections, which are included in the Warnings and Precautions section of the USPI, were not among the most frequently reported AEs in FAERS, although this could be influenced by infection-related AEs being spread across multiple PTs (e.g., various types of infection) resulting in an apparent low frequency of overall infections. Furthermore, prolonged cytopenias, an identified potential risk following tisagenlecleucel, could further contribute to the infection risk. However, infections were disproportionately reported, overall and in the C-AYA group and accounted for approximately 10% of deaths.
We identified a few unlabeled events disproportionately reported, including increased inflammatory markers, serum ferritin, and C-reactive protein. While these nonspecific laboratory findings reflect an underlying inflammatory phenomenon, they represent secondary events, with several potentially inciting events, including CAR-T cell administration, infections, and neoplasms,34 all of these being labeled events. Similarly, acidosis reflects a secondary AE with labeled triggering events (e.g., sepsis). Pancreatitis, an unlabeled AE, was reported disproportionately in FAERS only among the C-AYA population. Asparaginase is a mainstay of therapy in ALL, but not DLBCL, and pancreatitis is a well-recognized potential AE for asparaginase.35-38 Of the two assessable FAERS reports of pancreatitis, both described prior history of pancreatitis and exposure to asparaginase, thereby confounding any potential association with tisagenlecleucel.
Compared to the general population, 6-month survivors of childhood B-ALL in the U.S. have nearly a 70-fold significantly increased risk of developing therapy-related MDS/AML.39 While chemotherapy is an important risk factor in MDS/AML, genetic syndromes and specific gene rearrangements in ALL (e.g., KMT2A, CRLF2) associated with lineage switch leukemias may also play a role.40-42 Our ALL patients who developed MDS/AML were heavily pre-treated with cytotoxic chemotherapy and also exhibited genetic risks, including MLL-rearrangements and Li-Fraumeni syndrome. While a variety of SPNs have been reported following DLBCL, risks of most subsequent solid tumors are not significantly increased among DLBCL survivors compared to the general population.43 Our finding of a diverse spectrum of singular SPNs among adults and short time to tumor development following tisagenlecleucel make a causal association unlikely.
We report few deaths occurring within 30 days of treatment, with the majority of all deaths related to underlying disease progression, with a much smaller fraction attributed to infection. The ELIANA trial reported 19 deaths (25.3%), with 17 occurring more than 30 days after infusion and the majority (n = 12) related to B-ALL relapse/progression.22 In JULIET, three out of 111 patients (2.7%) died within 30 days of receiving tisagenlecleucel from progression of lymphoma; no deaths were attributed to tisagenlecleucel.23 Post-marketing data with variable follow-up time continue to support few early deaths, few deaths attributed to acute treatment complications, and the majority of deaths related to lymphoid neoplasm progression.
A strength of our post-marketing assessment is the inclusion of a large number of tisagenlecleucel-treated patients. Although it is reassuring that most AEs identified in our study are consistent with the USPI, the majority of patients in our study were heavily treated for their lymphoid neoplasm prior to receiving tisagenlecleucel, and disentangling effects of prior therapies and pre-existing comorbidities, limited our causality assessments. Limitations of our study include its reliance on passive surveillance, which is associated with variable report quality, underreporting, duplicate reporting, and a predilection for reporting serious events and those occurring in close proximity to product administration.44, 45 In addition, reports are coded according to the information provided in the FAERS report; therefore, depending on the detail included, this will in turn influence the frequency of PTs. A PT associated with a low frequency could be attributed to rare occurrence, underreporting, or could be reflected in another closely associated PT with a different frequency (e.g., hemoglobin decreased, hematocrit decreased, anemia). Despite our efforts to exclude duplicate reports, those with limited information or non-distinguishing characteristics were difficult to de-duplicate and were maintained in the study. Furthermore, reports without treatment dates or anchoring temporal events were not excluded from study and may have resulted in overestimation of the reporting rates. The required reporting of CRS and neurotoxicity through the REMS program likely minimized underreporting of AEs (at least those associated with CRS and neurotoxicity) as has the sponsor's reporting mechanism through the CIBMTR. However, the generally lower reporting rates for most AEs among adults than C-AYA, raise the possibility that there may be differential reporting by age group. This finding could reflect stimulated reporting associated with use of the first marketed CAR-T cell product and the initial product indication limited to individuals ≤25 years of age.
In summary, our review of tisagenlecleucel reports submitted to FAERS did not identify new safety concerns. The frequencies of CRS and neurotoxicity we report, lower than those from the pre-licensure clinical trials, generally align with those reported from the CIBMTR registry, notwithstanding some differences in the study populations. FDA will continue to monitor the tisagenlecleucel safety profile across its life cycle.
ACKNOWLEDGMENTS
The authors thank Novartis Pharmaceuticals Corporation for providing distribution data for tisagenlecleucel and for review of a previous version of this manuscript; Lindsay M. Morton for helpful discussions; and Meghna Alimchandani and Larissa Lapteva for insightful comments on a previous version of this manuscript. Disclaimer: The opinions and information in this article are those of the authors, and do not represent the views and/or policies of the U.S. Food and Drug Administration.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
Graça M. Dores and Silvia Perez-Vilar conceived the study; all authors contributed to the design of the study; Graça M. Dores performed the statistical analyses; Graça M. Dores and Silvia Perez-Vilar drafted the manuscript; all authors analyzed the data, critically reviewed the manuscript for important intellectual content, and revised the manuscript.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are openly available through: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-latest-quarterly-data-files
