Doris K Hansen,1 Omar Alexis Castaneda Puglianini,1 Ariel Grajales-Cruz,1 Saurabh P Nagar,2 Sabyasachi Ghosh,2 Victoria Alegria,2 Kevin C De Braganca,2 Tamar Lengil,3 Mukta Sharma,3 Helen Pai,3 Matthew Perciavalle,4 Jessica Maitland,5 Bruno Emond,6 Todd Bixby,2 Zaina P Qureshi,2 Murali Janakiram7

1H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Johnson & Johnson, Horsham, PA, USA; 3Johnson & Johnson, Raritan, NJ, USA; 4Legend Biotech USA Inc, Somerset, NJ, USA; 5Analysis Group ULC, Toronto, ON, Canada; 6Analysis Group ULC, Montreal, QC, Canada; 7City of Hope, Duarte, CA, USA

Correspondence: Doris K Hansen, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA, Email [email protected]

Purpose: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory multiple myeloma (RRMM) approved after 1 prior line of therapy (LOT). Non-immune effector cell-associated neurotoxicity syndrome (ICANS) neurologic events (NEs) may occur following infusion. This real-world study evaluated non-ICANS NE onset and management among patients with RRMM treated with cilta-cel.
Patients and Methods: Electronic medical records from Loopback Analytics (02/2022– 05/2025) were used, supplemented with physician notes. Adults treated with cilta-cel after 1– 3 and ≥ 4 prior LOT were included (N=171). New-onset non-ICANS NEs included cranial nerve palsy (CNP), parkinsonism, and Guillain-Barré syndrome. Clinical outcomes among these patients were described.
Results: Among 171 patients, 73 had 1– 3 prior LOT and 98 had ≥ 4 prior LOT. Among patients with 1– 3 prior LOT (median follow-up: 6.1 months), CNP occurred in 4 patients, while no parkinsonism or Guillain-Barré syndrome were observed. Following CNP onset, symptoms improved among 3 patients. Among patients with ≥ 4 prior LOT (median follow-up: 17.4 months), CNP occurred in 3 patients, while parkinsonism and Guillain-Barré syndrome each occurred in 1 patient. All patients with CNP had symptom improvement and the patient with Guillain-Barré syndrome had symptom resolution. Median peak ALC (103 cells/μL) was higher in patients with versus without non-ICANS NEs (1– 3 prior LOT: 7.60 vs 2.12; ≥ 4 prior LOT: 11.64 vs 1.96). All patients with events had at least a partial response to cilta-cel and remained alive at the end of follow-up.
Conclusion: This real-world cohort showed low incidence of CNP, parkinsonism, and Guillain-Barré syndrome following cilta-cel. Elevated post-infusion ALC warrants further investigation into its role as a biomarker to inform monitoring and management strategies, consistent with prior reports. Most patients with CNP reported improvement, the patient with Guillain-Barré syndrome reported resolution, all patients with available response assessments responded to cilta-cel, and no deaths were reported. An infographic titled Real-World Incidence and Management of Non-ICANS Neurologic Events Following Ciltacabtagene Autoleucel in Multiple Myeloma. Subtitle: Retrospective EMR cohort study evaluating the incidence, clinical characteristics, management and outcomes of non-ICANS NEs following cilta-cel in patients with MM treated after 1– 3 prior LOT or 4 prior LOT. Left section, RESULTS and PATIENT CHARACTERISTICS with a patient icon group: 171 patients with MM treated with cilta-cel after 1– 3 prior LOT (n equals 73) or 4 prior LOT (n equals 98). BASELINE DEMOGRAPHICS table: No. of patients 73 and 98; Median age 65 y and 64 y; Female 46.6 percent and 37.8 percent. CLINICAL CHARACTERISTICS: High-risk cytogenetic abnormalities 55.8 percent and 63.3 percent; Median follow-up 6.1 months and 17.4 months. Middle section, a left-to-right timeline with markers: Day 0 Cilta-cel infusion; Day 11 Median Peak ALC; Days 18– 105 Onset of non-ICANS NEs. Below the timeline, a bar chart labeled MEDIAN PEAK ALC (10 superscript 3 cells per microliter). For 1– 3 prior LOT: 7.60 for patients who developed non-ICANS NEs and 2.12 for patients who did not develop non-ICANS NEs. For 4 prior LOT: 11.64 for patients who developed non-ICANS NEs and 1.96 for patients who did not develop non-ICANS NEs. Right-middle section, RATE AND TIME OF ONSET OF NON-ICANS NEs with two columns (1– 3 prior LOT and 4 prior LOT): Cranial nerve palsy (Onset days 18– 37) 5.5 percent (n equals 4) and 3.1 percent (n equals 3). Parkinsonism (Onset day 46) 0.0 percent and 1.0 percent (n equals 1). Guillain–Barré syndrome (Onset day 105) 0.0 percent and 1.0 percent (n equals 1). Right section, MANAGEMENT STRATEGIES with treatment icons and a list under MANAGED WITH: Cyclophosphamide; Dexamethasone or Prednisone; Intravenous immunoglobulin; Plasma cell exchange; Valacyclovir. Far-right section, OUTCOMES with a target icon and donut charts under IMPROVEMENT IN CRANIAL NERVE PALSY: 1– 3 prior LOT 75 percent; 4 prior LOT 100 percent. Notes: All with available response assessments responded to cilta-cel. In the 1 patient with Guillain–Barré syndrome, symptom resolution occurred. 1 patient experienced disease progression. No deaths were reported. Bottom callout with a lightbulb icon: The incidence of non-ICANS NEs was low following cilta-cel, both in patients with 1– 3 and 4 prior LOT. Elevated post-infusion ALC warrants further investigation into its role as a biomarker to inform monitoring and management strategies. Most patients reported an improvement in cranial nerve palsy and symptoms resolved in the 1 patient with Guillain–Barré syndrome. All evaluable patients responded to cilta-cel and no deaths were reported.Infographic on low non-ICANS neurologic event rates, timing, management and outcomes after cilta-cel.

Keywords: absolute lymphocyte count, CAR-T, cranial nerve palsy, Guillain-Barré syndrome, management strategy, parkinsonism

Introduction

Multiple myeloma (MM) is a hematologic cancer characterized by malignant plasma cells in the bone marrow,1 with most patients eventually relapsing (ie, disease progression after an initial response) or having refractory disease (ie, unresponsiveness or disease progression during treatment; RRMM).2 Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy initially approved by the United States (US) Food and Drug Administration (FDA) in 2022 for adults with RRMM after ≥4 prior lines of therapy (LOT).3–5 The CARTITUDE-1 trial demonstrated deep and durable responses in heavily pretreated patients,6–8 and CARTITUDE-4 showed improved progression-free and overall survival in earlier lines,9,10 supporting expanded approval in 2024 among lenalidomide-refractory patients after ≥1 prior LOT.11

Following CAR-T infusion, immune effector cell–associated neurotoxicity syndrome (ICANS) may occur, which has been well characterized, with guidelines for monitoring and management.12 Additional non-ICANS neurologic events (NEs) such as cranial nerve palsy (CNP), parkinsonism, and Guillain-Barré syndrome may also occur, but with low incidence observed across CARTITUDE-1 and CARTITUDE-4 trials.11,13,14

Real-world studies have reported a low incidence of non-ICANS NEs,15,16 but gaps remain in their characterization, management, and subsequent clinical outcomes in broader populations. This study sought to evaluate the real-world incidence of non-ICANS NEs among patients treated with cilta-cel after 1–3 prior LOT and ≥4 prior LOT, and to describe clinical characteristics, management, and outcomes among patients with non-ICANS NEs.

Materials and Methods Data Source

De-identified electronic medical records (EMR) from Loopback Analytics, supplemented with physician chart notes, were used to identify patients receiving cilta-cel between 02/28/2022 (initial FDA approval date) and 05/31/2025. Loopback Analytics captures data from >90 academic and community health system partners across 40 US states. The database includes patient demographics and clinical characteristics, treatments, biomarkers, and events (eg, response, adverse events, survival status). To our knowledge, data captured commercial use of cilta-cel (CARVYKTI®), with dose, timing, and route of administration consistent with US label.17 The study was considered exempt research under 45 CFR § 46.104(d)(4) as it involved only secondary use of data de-identified in compliance with the Health Insurance Portability and Accountability Act, specifically, 45 CFR § 164.514.

Study Design

In this retrospective cohort study of adults with RRMM treated with cilta-cel, the index date was the date of cilta-cel infusion on or after 02/28/2022. The baseline period spanned 12 months preceding infusion, and the follow-up period from infusion to the earliest of death, end of data availability, or last medical encounter. Clinical characteristics were derived from physician notes.

Study Population

Adults with MM (≥2 diagnoses on distinct dates, ≥1 prior to infusion) who received cilta-cel after 1–3 or ≥4 prior LOT and had ≥12 months between the first medical encounter and infusion were included (Figure 1). To account for potential missing claims due to left-censoring and out-of-network care, patients who received cilta-cel before 04/05/2024 (FDA approval date for earlier-line use) were included in the ≥4 prior LOT cohort. For infusions on or after 04/05/2024, patients were classified into cohorts using the number of prior LOT observed (1–3 or ≥4 prior LOT). Cohorts aligned with the CARTITUDE-4 (1–3 prior LOT) and CARTITUDE-1 (≥4 prior LOT) contexts.

Figure 1 Patient selection criteria.

Abbreviations: ALC, absolute lymphocyte count; CAR-T, chimeric antigen receptor T-cell; cilta-cel: ciltacabtagene autoleucel; LOT, line of therapy; MM, multiple myeloma; NE, neurologic event.

The study excluded patients with (1) no lymphodepleting chemotherapy (≥1 record for cyclophosphamide, fludarabine, or bendamustine 14 days preceding or 30 days post-infusion), (2) a diagnosis of amyloidosis preceding infusion, (3) baseline NE diagnosis, (4) no absolute lymphocyte count (ALC) laboratory test 30 days preceding and following infusion, and (5) participation in any clinical trial during the cilta-cel LOT (Tables S1-S2).

Study Outcomes and Statistical Analysis

Descriptive outcomes included incidence of non-ICANS NEs (ie, ≥2 diagnoses of the same condition on distinct days within 30 days of each other, verified using manual chart review [Table S1]), pre-lymphodepletion ALC (x 103 cells/µL; closest to cilta-cel infusion), post-infusion peak ALC, management of non-ICANS NEs, cilta-cel response (based on best response recorded), and survival.

Results Baseline Characteristics

Overall, 171 patients treated with cilta-cel met the study selection criteria (1–3 prior LOT: 73 [42.7%], ≥4 prior LOT: 98 [57.3%]).

In patients with 1–3 prior LOT, the median age was 65 years; 46.6% were female, 67.1% were White, 46.6% had Medicare insurance, and 57.1% received cilta-cel in an inpatient setting. The median Quan-CCI was 2.0, 6.0% had an Eastern Cooperative Oncology Group (ECOG) score ≥2, 33.3% had extramedullary disease, and 55.8% had high-risk cytogenetic abnormalities (Tables 1–2).

Table 1 Baseline Demographic Characteristics

Table 2 Baseline Clinical Characteristics

In patients with ≥4 prior LOT, the median age was 64 years; 37.8% were female, 70.4% were White, 52.0% had Medicare insurance, and 72.4% received cilta-cel in an inpatient setting. The median Quan-CCI was 2.0, 1.0% had an ECOG score ≥2, 19.4% had extramedullary disease, and 63.3% had high-risk cytogenetic abnormalities (Tables 1–2).

Non-ICANS NE Incidence

Among patients with 1–3 prior LOT, over a median (interquartile range [IQR]) follow-up of 6.1 (3.4–9.2) months, CNP occurred in 4 (5.5%) patients, of whom 3 were female; no parkinsonism nor Guillain-Barré syndrome were observed (Table 3). Among patients who developed non-ICANS NEs, the median (IQR) post-infusion peak ALC (7.60 [1.80–14.82] x 103 cells/µL), occurring at a median of 11 days post-infusion, was numerically higher than those without non-ICANS NEs (2.12 [1.10–4.62] x 103 cells/µL, Figure 2).

Table 3 Incidence of Non-ICANS NEs

Figure 2 Post-infusion peak ALC.

Abbreviations: ALC, absolute lymphocyte count; ICANS, immune effector cell–associated neurotoxicity syndrome; LOT, line of therapy; NE, neurologic event.

Among patients with ≥4 prior LOT, over a median (IQR) follow-up of 17.4 (12.5–22.8) months, CNP occurred in 3 (3.1%) patients, of whom 1 was female, while parkinsonism and Guillain-Barré syndrome each occurred in 1 (1.0%) patient, who were male and female, respectively (Table 3). Among patients who developed non-ICANS NEs, the median (IQR) post-infusion peak ALC (11.64 [8.52–20.69] x 103 cells/µL), occurring at a median of 11.5 days post-infusion, was numerically higher than those without non-ICANS NEs (1.96 [1.24–3.56] x 103 cells/µL; Figure 2).

Patient characteristics stratified by the development of non-ICANS NEs are presented in Tables S3-S4.

Post-Infusion Disease Course

Among 4 patients with 1–3 prior LOT with CNP, the median (IQR) pre-infusion ALC and post-infusion peak ALC were 0.10 [0.06–0.65] x 103 cells/µL and 7.60 [1.80–14.82] x 103 cells/µL (median day 11), respectively. CNP onset ranged from 21 to 31 days post-infusion. Management strategies comprised prednisone alone (2 patients) or prednisone in combination with valacyclovir (1 patient). Subsequently, 75.0% had symptom improvement within 3 to 15 days of CNP onset; symptom improvement was not recorded for the remaining patient. Among the 3 patients with a response assessment, all patients achieved at least partial response to cilta-cel between days 31 and 52. All 4 patients remained alive and progression-free at the end of follow-up (Figure 3)

Figure 3 Post-infusion disease course (1–3 prior LOT) – CNP.

Abbreviations: ALC, absolute lymphocyte count; cilta-cel, ciltacabtagene autoleucel; CNP, cranial nerve palsy; CR, complete response; ECOG, Eastern Cooperative Oncology Group; F, female; FU, follow-up; LOT, line of therapy; M, male; N/A, not available; PR, partial response; Pt, patient; y.o., years old

.

Among 3 patients with ≥4 prior LOT with CNP, the median (IQR) pre-infusion ALC and post-infusion peak ALC were 0.08 [0.04–0.11] x 103 cells/µL and 8.77 [8.27–26.87] x 103 cells/µL (median day 11), respectively. CNP onset ranged from 18 to 37 days post-infusion and management consisted of prednisone (all 3 patients), with 1 patient also receiving dexamethasone, valacyclovir, and intravenous immunoglobulin (IVIG). All patients showed symptom improvement within 4 to 18 days of CNP onset. All patients had at least partial response to cilta-cel between days 28 and 40 post-infusion and remained alive and progression-free at the end of follow-up (Figure 4).

Figure 4 Post-infusion disease course (≥4 prior LOT)a.

Abbreviations: ALC, absolute lymphocyte count; cilta-cel, ciltacabtagene autoleucel; CNP, cranial nerve palsy; CR, complete response; ECOG, Eastern Cooperative Oncology Group; F, female; FU, follow-up; IVIG, intravenous immunoglobulin; LOT, line of therapy; M, male; PR, partial response; Pt, patient; y.o., years old.

Note: a One patient with CNP also had Guillain-Barré syndrome.

For the patient with parkinsonism, pre-infusion ALC was 0.60 x 103 cells/µL and peak ALC post-infusion was 14.50 x 103 cells/µL (day 15). Parkinsonism occurred 46 days post-infusion and was managed with cyclophosphamide; symptom improvement or resolution was not reported. The patient achieved complete response to cilta-cel on day 54, progressed on day 412 post-infusion, and remained alive at the end of follow-up (Figure 4).

For the patient with Guillain-Barré syndrome (who also had CNP), pre-infusion ALC was 0.04 x 103 cells/µL and peak ALC post-infusion was 8.77 x 103 cells/µL on day 10. Guillain-Barré syndrome occurred 105 days post-infusion and was managed with IVIG and plasma cell exchange. Symptoms resolved 91 days following onset. The patient achieved complete response to cilta-cel on day 28 post-infusion and remained alive and progression-free at the end of follow-up (Figure 4).

Discussion

In this real-world EMR-based study among patients with RRMM receiving cilta-cel, low incidence of non-ICANS NEs (CNP, parkinsonism, Guillain-Barré syndrome) was observed. Patients with non-ICANS NEs had numerically higher post-infusion peak ALC than those without events, suggesting ALC may be a biomarker for patients at risk for non-ICANS NEs. Following therapeutic management, most patients with CNP showed symptom improvement or resolution and the patient with Guillain-Barré syndrome had symptom resolution. Among those with response assessments, all patients had at least partial response to cilta-cel. One patient experienced disease progression, and no deaths were observed.

In the CARTITUDE-4 (1–3 prior LOT) and CARTITUDE-1 (≥4 prior LOT) trials, CNP occurred in 9% and 3% of patients and parkinsonism in <1% and 6%, with no Guillain-Barré syndrome (one death reported after Guillain-Barré syndrome in another ongoing clinical study).11 Incidence of these non-ICANS NEs was slightly higher than those observed in the current study, which may be due in part to shifts in real-world practice, including increasing use of bridging therapies preceding CAR-T infusion.18 Nevertheless, observed incidence rates align with prior real-world studies, including those conducted in US academic medical centers and using registry data,15,16,19 which reported rates of 3–6% for CNP and 2–4% for parkinsonism among heavily-pretreated patients with RRMM. The current study additionally demonstrates low rates of Guillain-Barré syndrome in clinical practice, with no cases among patients with 1–3 prior LOT.

In this study, post-infusion peak ALC was numerically higher for patients with non-ICANS NEs than those without, corroborating recent reports in patients receiving BCMA-directed CAR-T therapies.16,20,21 Lim et al reported a median (IQR) peak ALC among patients without non-ICANS NEs of 1.82 (0.97–4.05) x 103 cells/µL, significantly lower than 5.33 (3.36–10.94) x 103 cells/µL and 11.1 (7.83–15.3) x 103 cells/µL for those with CNP and parkinsonism.16 They also found a significant correlation between ALC and CAR-positive (CAR+) T-cell counts in initial weeks following infusion (R=0.98),16 which aligns with prior findings linking expansion of CAR+ T-cells to increased risk of non-ICANS NEs.20–22 Therefore, ALC may serve as a clinically measurable surrogate for CAR+ T-cell expansion to identify at-risk patients and guide management strategies. Recent studies also emphasize using effective bridging therapies and prophylactic dexamethasone to reduce the risk of non-ICANS NEs among patients receiving CAR-T therapy.21,23,24

The low incidence of non-ICANS NEs in this study reinforces cilta-cel’s benefit-risk profile. Nonetheless, awareness of non-ICANS NEs associated with CAR-T therapies is necessary to guide monitoring and management.25,26 CNP was managed with systemic corticosteroids with or without valacyclovir or IVIG, parkinsonism with cyclophosphamide, and Guillain-Barré syndrome with IVIG and plasma cell exchange. While these management practices are consistent with recommendations in the cilta-cel label and guidelines,11,13 other strategies (eg, intrathecal chemotherapy) were not captured. As observed in other real-world studies and case series, approaches should vary by individual circumstances or institutional guidelines.14–16,27,28 Most patients with CNP in this study showed improvement in symptoms after treatment and all responded to cilta-cel, consistent with prior reports.16

Interpretation of these findings should be considered with limitations. Although physician notes may document care received outside their facilities, some services may not be fully captured, potentially underestimating events. Misclassification of non-ICANS NEs may have occurred due to coding inaccuracies and variations in documentation. Finally, daily ALC was not available for all patients which could lead to imprecision in peak measurements. Patients without ALC tests or with baseline NEs were excluded, and the relatively small sample size may limit generalizability to the broader RRMM population.

Conclusion

In this cohort of patients with RRMM receiving cilta-cel, the incidence of non-ICANS NEs (CNP, parkinsonism, Guillain-Barré syndrome) was low following cilta-cel infusion with individualized management, both in patients with 1–3 and ≥4 prior LOT. Elevated post-infusion ALC warrants further investigation into its role as a biomarker to inform monitoring and management, consistent with prior reports. Most patients with CNP showed symptom improvement and the patient with Guillain-Barré syndrome showed symptom resolution. Furthermore, all patients with available assessments responded to cilta-cel, and no deaths were reported. These results support the favorable benefit-risk profile of cilta-cel.

Abbreviations

ALC, Absolute lymphocyte count; BCMA, B-cell maturation antigen; CAR-T, Chimeric antigen receptor T-cell; CNP, Cranial nerve palsy; ECOG, Eastern Cooperative Oncology Group; EMR, Electronic medical records; FDA, Food and Drug Administration; HIPAA, Health Insurance Portability and Accountability Act; ICANS, Immune effector cell-associated neurotoxicity syndrome; IQR, Interquartile range; IVIG, Intravenous immunoglobulin; LOT, Line of therapy; MM, Multiple myeloma; NE, Neurologic event; Quan-CCI, Quan-Charlson Comorbidity Index; RRMM, Relapsed or refractory multiple myeloma; US, United States.

Data Sharing Statement

The data that support the findings of this study are available from Loopback Analytics. Restrictions apply to the availability of these data, which were used under license for this study. The data are available through requests made directly to Loopback Analytics, subject to their respective requirements for access.

Ethics Statement

This study was considered exempt from review by an institutional review board as it involved only the secondary use of data that were de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA). This research study was conducted in accordance with the principles stated in the Declaration of Helsinki.

Acknowledgments

Editorial assistance was provided by Flora Chik, PhD, MWC, Fanny Jiang, MSc, and Gordon Wong, BIE, and analytical support was provided by Alvi Rahman, PhD, Vicky Wei, MS, and Alessio Palladino, BEng, all employees of Analysis Group ULC, a consulting company that has provided paid consulting services to Johnson & Johnson. Part of the material in this manuscript was presented at the 67th American Society of Hematology Annual Meeting held December 6-9, 2025, in Orlando, FL, USA, as a poster presentation. The poster’s abstract was published in ‘Annual Meeting Abstracts: 67th American Society of Hematology Annual Meeting’ in Blood: [Real-world incidence and management of non-icans neurologic events following ciltacabtagene autoleucel in multiple myeloma | Blood | American Society of Hematology].

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was funded by Johnson & Johnson and Legend Biotech USA Inc. The study sponsors were involved in several aspects of the research, including the study design, interpretation of data, and editorial support.

Disclosure

DKH reports consultancy with AstraZeneca, Bristol Myers Squibb, Genentech, Johnson & Johnson, Karyopharm, Kite Pharma, Legend Biotech, and Pfizer and research funding from Adaptive Biotechnologies, Bristol Myers Squibb, Johnson & Johnson, Karyopharm, and Kite Pharma/Gilead Sciences. DKH is also supported by the NCI (R01CA281756-01A1) and the Pentecost Family Myeloma Research Center, received travel support from Janssen, BMS, Legend Biotech and advisory board for BMS, Janssen, AstraZeneca, Legend Biotech. OACP reports consultancy with Bristol Myers Squibb, Johnson & Johnson, and Legend Biotech and honoraria from Bristol Myers Squibb, and Legend Biotech. AGC reports consultancy with Amgen, GSK, Sanofi, Bristol Myers Squibb, Johnson & Johnson, Legend Biotech, Pfizer, Regeneron and Cellectar and research funding from Johnson & Johnson. SPN, SG, VA, KCD, TL, MS, HP, TB, and ZPQ are employees and stockholders of Johnson & Johnson. MP is an employee of Legend Biotech and owns stock options in Legend Biotech. JM and BE are employees of Analysis Group ULC, a consulting company that has provided paid consulting services to Johnson & Johnson. BE also reports payments made to his institution from Pfizer, Xenon, and AbbVie. MJ reports research funding from Legend Biotech, Bristol Myers Squibb, Fate Therapeutics, and Johnson & Johnson and honoraria from Legend Biotech, and Johnson & Johnson. The authors report no other conflicts of interest in this work.

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