Disproportionality Analysis of Tumour Lysis Syndrome (TLS) Associated with Bruton's Tyrosine Kinase Inhibitor (BTKi) using Food and Drug Administration Adverse Events Reporting System (FAERS) Database

doi:10.21203/rs.3.rs-1849066/v1

Download PDF

Research Article

Disproportionality Analysis of Tumour Lysis Syndrome (TLS) Associated with Bruton's Tyrosine Kinase Inhibitor (BTKi) using Food and Drug Administration Adverse Events Reporting System (FAERS) Database

https://doi.org/10.21203/rs.3.rs-1849066/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Bruton's tyrosine kinase inhibitors (BTKis) are used for treating B-cell leukaemia and lymphomas like chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenström macroglobulinemia. Tumour lysis syndrome (TLS) is an adverse event associated with this class, the prevalence of which is not well studied in an actual context.

Objective: This study aims to detect the possible safety signal of BTKis-associated with TLS through disproportionality analysis in the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Patients and Methods: A case/non-case retrospective disproportionality analysis was performed in a publicly available FAERS database using OpenVigil 2.1 (2014Q1-2021Q3). The preferred term defined by MedDRA v24 used for the study was "tumour lysis syndrome" and the drugs included in the analysis were acalabrutinib, ibrutinib, and zanubrutinib. Reporting odds ratio (ROR) was used as the analysis data mining algorithm.

Results: 2852 cases of TLS were identified from FAERS database, of which 121 (4.2%) reports were associated with BTKis. Ibrutinib accounted for 103 (85.1%), acalabrutinib for 15 (12.4%), and zanubrutinib for 3 (2.5%) cases of TLS reports associated with BTKis. Positive signal strength was obtained for ibrutinib [ROR 13.5 (95%CI: 11.1-16.4), acalabrutinib [ROR 42.8 (25.7-71.3), and zanubrutinib [ROR 72.4 (23-227.5)] associated TLS. On gender stratification, acalabrutinib and ibrutinib were found to have a higher value (ROR of 1.7 times) for females than males.

Conclusion: Our analysis of spontaneous reporting data identified signals for TLS with acalabrutinib, ibrutinib, and zanubrutinib. More research with a superior epidemiological study design of a defined population is required to validate these findings.

Bruton’s tyrosine kinase inhibitor

tumour lysis syndrome

acalabrutinib

ibrutinib

zanubrutinib

disproportionality analysis

FAERS.

The study aimed to identify the potential safety signals of Bruton's tyrosine kinase inhibitors (BTKis) associated with the occurrence of tumour lysis syndrome (TLS) using the Food and Drug Administration Adverse Event Reporting System (FAERS) database.
We identified 2852 cases of TLS from FAERS database, of which 121 (4.2%) reports were associated with BTKis.
The BTKis, ibrutinib, acalabrutinib and zanubrutinib accounted for 103 (85.1%), 15 (12.4%), and 3 (2.5%) cases of TLS reports respectively.

Bruton's tyrosine kinase (BTK) is a crucial mediator in B-cell antigen receptor and cytokine receptor pathway. The activation of this pathway is essential for B-cell trafficking, chemotaxis, and adhesion and is induced by BTK's activity through the signalling of B-cell surface receptors. Acalabrutinib, ibrutinib, and zanubrutinib are approved BTK inhibitors (BTKis), while evobrutinib, tolebrutinib, fenebrutinib, pirtobrutinib, spebrutinib and tirabrutinib are still under clinical trials. They inhibit BTK by creating a covalent bond with a cysteine residue in the enzyme's active site, thus preventing it from performing its function. Mantle cell lymphoma (MCL), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma, and Waldenström's macroglobulinemia are the main indications for these drugs [1–3].

Tumour lysis syndrome (TLS) is a life-threatening cancer chemotherapy-related oncologic emergency in which massive malignant cells die and break down rapidly, releasing vast amounts of potassium, nucleic acids, cytokines, and phosphate into the systemic circulation either spontaneously or in response to therapy. Hyperkalaemia, hyperphosphatemia, hyperuricemia, and secondary hypocalcaemia are all caused by the rapid release of these intracellular components. These metabolic abnormalities can lead to significant morbidity, putting patients at risk of severe clinical consequences, including cardiac arrhythmias, acute kidney injury, fluid overload, pulmonary oedema, seizures, and even death [4, 5]. TLS may also be a severe complication of cancers such as acute lymphocytic leukaemia, Burkitt's leukaemia (BL), advanced BL, acute myeloid leukaemia (AML), and advanced diffuse large B-cell lymphoma (DLBCL) [6].

Only a few studies have addressed the safety profile of BTKis, focusing on cardiovascular-related adverse events, pericarditis, skin cancer, and progressive multifocal leukoencephalopathy [7–14] and the majority of which are based on ibrutinib. Among the BTKis, ibrutinib has the potential to cause TLS [15]. However, it has not been reported for acalabrutinib and zanubrutinib. This study aims to assess the potential signal between BTKis and TLS adverse events through disproportionality analysis in the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

2.1 Data source

The case/non-case retrospective disproportionality analysis was performed in a publicly available FAERS database, part of the MedWatch public-access database that allows healthcare professionals, consumers, patients, and pharmaceutical companies to record adverse events worldwide [16]. Our study was based on all reports of TLS associated with BTKis received by the Food and Drug Administration from year 2014Q1 to 2021Q3.

2.2 Study procedure

Data mining, extraction, and filtration were carried out by using the OpenVigil 2.1-MedDRA-v24, which is a web-based tool for pharmacovigilance data analysis from national and international sources [17]. The disproportionality was measured using reporting odds ratios (ROR). OpenVigil operate with clean data, by removing the majority of duplicates and reports with incomplete information [18, 19]. We retrieved reports of TLS reported in connection with BTKis, namely acalabrutinib, ibrutinib, and zanubrutinib. Other BTKis under clinical trials were excluded from the further investigation because of no reports of TLS. Various filters such as age, gender, indication, region, and outcomes were used to narrow down the data further.

2.3 Statistical analysis

The reports of patients with BTKis and TLS were summarized using descriptive analysis. The frequentist algorithm, ROR was used to calculate the statistical signal strength of the association between TLS and BTKis [20]. ROR is a standard disproportionality approach for detecting whether a specific adverse event (AE) is recorded more frequently than expected with a particular drug, allowing researchers to investigate the possibility of a disproportionate link between the two. A higher ROR value indicates greater disproportionality, which means that a drug is more likely to cause a specific AE than all other drugs [21]. The age stratification was performed by dividing the study population into 3 groups: 0–18 years, 19–64 years, and > 65 years. The threshold for a positive signal was considered as ROR-1.96SE > 1 with a minimum of 3 reports [22–24].

A total of 2852 cases of TLS were identified from the FAERS database, of which 121 (4.2%) reports were associated with BTKis.

3.1 Ibrutinib associated TLS

Among the total reports of BTKis associated with TLS, 103 reports (85.1%) were identified from the FAERS database for ibrutinib, and the ROR was found to be 13.5 (95% CI: 11.1–16.4). On performing age and gender stratification, it was found that the age group of 19–64 years (n = 17) had the highest signal strength of ROR 19.23 (1.9 times to the other age groups), and the female gender had a higher signal strength of ROR 14.29 (1.7 times than males), as given in table 1. However, the other 46 cases for age and 27 cases for gender is not specified. The most common indication for ibrutinib was CLL [n = 66 (64%)]. The indication and region reported are given in Table 2. Hospitalization due to the adverse event was recorded in 51 (49.5%) reports. The event's outcomes are summarized in Table 2.

3.2 Acalabrutinib associated TLS

Among the total reports of BTKis associated TLS, 15 reports (12.4%) were identified for acalabrutinib, and the ROR was found to be 42.8 (25.7–71.3). On performing age and gender stratification, it was found that the geriatric population (65–100 years) [n = 7] had the highest signal strength (ROR 35.04), and the female gender had a higher signal strength of ROR of 48.81 (1.7 times than males), as given in table 1. However, the other 8 cases for age and 3 cases for gender is not specified. The most common indication for acalabrutinib was CLL [n = 12 (80%)]. The indication and region reported are given in Table 2. Due to the adverse event, hospitalization was recorded in 9 (60%) reports. The event's outcomes are summarized in Table 2.

3.3 Zanubrutinib associated TLS

Among the total reports of BTKis associated TLS, 3 reports (2.5%) were identified for zanubrutinib, and the ROR was found to be 72.4 (23-227.5). The most common indication for zanubrutinib was CLL [n = 3 (100%)]. The indication and region reported are given in Table 2. Hospitalization due to the adverse event was recorded in 3 (100%) of reports. The event’s outcomes are summarized in Table 2.

BTKis have emerged as potential therapeutic option for haematological malignancies [25]. However, the incidence of TLS, which is a haematooncologic emergency due to a rapid breakdown of malignant cells usually induced by this cytotoxic therapy, is not well studied. The TLS is characterized by hyperphosphatemia, hyperuricemia, hyperkalaemia, metabolic acidosis, and hypocalcaemia. It is caused by cancer cells breaking down quickly and releasing intracellular components like nucleic acids, cytokines, potassium, and phosphate into the bloodstream. However, in quickly proliferating high-grade hematologic malignancies such as BL, AML, and anaplastic large T-cell or DLBCL, it may be spontaneous [25]. Several factors increase the risk of TLS, including the type of cancer, the nature and intensity of anticancer therapy, and the occurrence of pre-existing diseases such as renal insufficiency [26]. Thus, TLS can result in acute renal failure, heart arrhythmogenicity, CNS toxicity, and ultimately death [6].

Our study mainly focuses on the possible signal of BTKis (ibrutinib, acalabrutinib, zanubrutinib) and TLS. Regulatory agencies and pharmaceutical companies utilize this method to identify AEs that newly marketed medications may cause. Though this technique may reveal a probable drug-AE link, it does not establish any causal relationship, which can only be established by randomized controlled trials that aid in the discovery of potential AE mechanisms.

A total of 2852 cases of TLS were identified from the FAERS database, of which 4.2% reports were associated with BTKis. Zanubrutinib was observed to have the highest signal strength for TLS, while the greatest number of reported cases of TLS were with ibrutinib. No cases of zanubrutinib and acalabrutinib associated TLS has been reported in the literature and clinical trial data and this is the first study to do so. The incidence of TLS is rare and only few cases describing ibrutinib-induced TLS have been published [27–30] and not often reported in clinical trials [31].

Age stratification of study population revealed that TLS cases were prominent in geriatric population for acalabrutinib and ibrutinib, whereas zanubrutinib had no cases. Some publications have suggested that the average age of people when they are diagnosed with CLL and MCL is around 60–70 years [32, 33]. Age may be a risk factor since diminished heart and vascular stature, impaired renal function, and complicated concurrent medication use may all lead to numerous clinical adverse outcomes in elderly persons and could be one of the causes for higher signal strength when compared to other age groups, while the underlying rationale for the same is unknown [34]. On gender stratification, females were found to have more signal strength than males for ibrutinib and acalabrutinib, whereas zanubrutinib reported no cases, indicating that female patients are more susceptible and vulnerable than male patients.

The consequences of this syndrome as per this study was 63 hospitalizations, 40 deaths and 17 life-threatening events. Also, a total of 76 other serious medical events were reported. Therefore, treatment with ibrutinib, acalabrutinib and zanubrutinib must be used with caution and under close supervision.

Our findings may have certain limitations because of the nature of the FAERS data. This study may help in establishing a probable drug-AE link but does not establish any causal relationship which can only be established by large, superior, well-designed epidemiological studies that may aid in determining the incidence, risk factors and prevention of these AEs. It is a spontaneous reporting system with a notoriety bias, weber effect and missing data [35].

Our study explored the association of BTKis with TLS using FAERS database. It revealed a significant link between BTKis and TLS, implying that the drugs with higher signal strength must be closely monitored. Assessment and characterization of BTKis associated TLS are becoming increasingly important as the use of BTKis in oncology is expanding. This research aims to notify healthcare professionals on the possibility of TLS with BTKis and the need for meticulous monitoring and follow up of these patients.

Disclosures and declarations

Funding: No additional funding was received for this work.

Conflicts of Interest/Competing Interests: The authors have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval: Not applicable.

Consent to Participate: Not applicable.

Consent for Publication: Not applicable.

Availability of Data and Material: Not applicable.

Acknowledgements: The authors gratefully thank Ms. Aarushi Kheterpal, and Mr. Ashwin Dhas, Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India, for their contribution in data extraction.

Authors contributions: V.S. and M.R. conceptualized this study. Z., A.S., L.L., and G.K., retrieved and analysed the data. Z., A.S., L.L and LT drafted the original manuscript. G.N., N.H., L.T., V.S., and M.R. critically reviewed and edited the manuscript. All authors read and approved the final manuscript.

Imbruvica (Ibrutinib) [package insert]. Horsham, PA USA: Janssen Biotech, Inc; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210563s000lbl.pdf. Accessed 22 Mar 2022.
Calquence (Acalabrutinib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf. Accessed 22 Mar 2022.
Brukinsa (zanubrutinib) [package insert]. San Mateo, CA: BeiGene USA, Inc; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213217s000lbl.pdf. Accessed 22 Mar 2022.
Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149(4):578–586. https://doi.org/10.1111/j.1365-2141.2010.08143.x.
Abu-Alfa AK, Younes A. Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and management. Am J Kidney Dis. 2010;55(5 Supp l3):S1-13;quizS14-9. https://doi.org/10.1053/j.ajkd.2009.10.056.
Mirrakhimov AE, Ali AM, Khan M, Barbaryan A. Tumor Lysis Syndrome in Solid Tumors: An up to Date Review of the Literature. Rare Tumors. 2014;6(2):5389. https://doi.org/10.4081/rt.2014.5389.
Salem JE, Manouchehri A, Bretagne M, Lebrun-Vignes B, Groarke JD, Johnson DB, Yang T, Reddy NM, Funck-Brentano C, Brown JR, Roden DM, Moslehi JJ. Cardiovascular Toxicities Associated With Ibrutinib. J Am Coll Cardiol. 2019;74(13):1667–1678. https://doi.org/10.1016/j.jacc.2019.07.056.
Xiao L, Salem JE, Clauss S, Hanley A, Bapat A, Hulsmans M, Iwamoto Y, Wojtkiewicz G, Cetinbas M, Schloss MJ, Tedeschi J, Lebrun-Vignes B, Lundby A, Sadreyev RI, Moslehi J, Nahrendorf M, Ellinor PT, Milan DJ. Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase. Circ J. 2020;142(25):2443–2455. https://doi.org/10.1161/CIRCULATIONAHA.120.049210.
Allouchery M, Tomowiak C, Lombard T, Pérault-Pochat MC, Salvo F. Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database. Front Pharmacol. 2021;12:769315. https://doi.org/10.3389/fphar.2021.769315.
Ye JZ, Hansen FB, Mills RW, Lundby A. Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability. JACC CardioOncol. 2021;3(1):88–97. https://doi.org/10.1016/j.jaccao.2021.01.009.
Cheng C, Woronow D, Nayernama A, Wroblewski T, Jones SC. Ibrutinib-associated ventricular arrhythmia in the FDA Adverse Event Reporting System. Leuk Lymphoma. 2018;59(12):3016–3017. https://doi.org/10.1080/10428194.2018.1457149.
Grewal US, Thotamgari SR, Sheth AR, Gaddam SJ, Ahmad J, Beedupalli K, Dominic P. Cardiovascular complications associated with novel agents in the chronic lymphocytic leukemia armamentarium: A pharmacovigilance analysis. Int J Cardiol. 2021;344:186–189. https://doi.org/10.1016/j.ijcard.2021.10.011.
Sun X, Ma Z, Guo Q, Zhao Z, Liu L. Ibrutinib-related skin cancer: A pharmacovigilance study from the Food and Drug Administration Adverse Event Reporting System. Eur J Cancer. 2022;160:277–278. https://doi.org/10.1016/j.ejca.2021.10.034.
Raisch DW, Rafi JA, Chen C, Bennett CL. Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA's adverse event reporting system. Expert Opin Drug Saf. 2016;15(8):1003–11. https://doi.org/10.1080/14740338.2016.1198775.
Titus-Rains KS, Brown JN, Hammond JM. Ibrutinib-associated tumor lysis syndrome in chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma: A case series and review of the literature. J Oncol Pharm Pract. 2018;24(7):544–549. https://doi.org/10.1177/1078155217718617.
Questions and Answers on FDA’s Adverse Event Reporting. System (FAERS) | FDA. https://www.fda.gov/drugs/surveillance/questions-and-answers-fdas-adverse-event-reporting-system-faers. Accessed 01 April 2022.
Böhm R, Bulin C, Waetzig V, Cascorbi I, Klein HJ, Herdegen T. Pharmacovigilance-based drug repurposing: The search for inverse signals via OpenVigil identifies putative drugs against viral respiratory infections. Br J Clin Pharmacol. 2021;87(11):4421–4431. https://doi.org/10.1111/bcp.14868.
Böhm R, Höcker J, Cascorbi I, Herdegen T. OpenVigil–free eyeballs on AERS pharmacovigilance data. Nat Biotechnol. 2012;30(2):137–8. https://doi.org/10.1038/nbt.2113.
Böhm R, von Hehn L, Herdegen T, Klein HJ, Bruhn O, Petri H, Höcker J. OpenVigil. FDA - Inspection of U.S. American Adverse Drug Events Pharmacovigilance Data and Novel Clinical Applications. PLoS ONE. 2016;11(6):e0157753. https://doi.org/10.1371/journal.pone.0157753.
Sanagawa A, Hotta Y, Kondo M, Nishikawa R, Tohkin M, Kimura K. Tumor lysis syndrome associated with bortezomib: A post-hoc analysis after signal detection using the US Food and Drug Administration Adverse Event Reporting System. Anticancer Drugs. 2020;31(2):183–189. https://doi.org/10.1097/cad.0000000000000862.
Huang J, Jia Y, Sun S, Meng L. Adverse event profiles of dipeptidyl peptidase-4 inhibitors: data mining of the public version of the FDA adverse event reporting system. BMC Pharmacol Toxicol. 2020;21(1):68. https://doi.org/10.1186/s40360-020-00447-w.
Zorych I, Madigan D, Ryan P, Bate A. Disproportionality methods for pharmacovigilance in longitudinal observational databases. Stat Methods Med Res. 2013;22(1):39–56. https://doi.org/10.1177/0962280211403602.
Van Puijenbroek EP, Bate A, Leufkens HG, Lindquist M, Orre R, Egberts AC. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf. 2002;11(1):3–10. https://doi.org/10.1002/pds.668.
Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001;10(6):483–6. https://doi.org/10.1002/pds.677.
Matuszkiewicz-Rowinska J, Malyszko J. Prevention and Treatment of Tumor Lysis Syndromein the Era of Onco-Nephrology Progress. Kidney Blood Press Res. 2020;45(5):645–660. https://doi.org/10.1159/000509934.
Tazi I, Nafl H, Elhoudzi J, Mahmal L, Harif M. Management of pediatric tumor lysis syndrome. Arab J Nephrol Transplant. 2011;4(3):147–54. https://doi.org/10.4314/ajnt.v4i3.71027.
Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. https://doi.org/10.1056/NEJMoa1215637.
Kaur V, Mehta P, Johnsurd J, Govindarajan R. Ibrutinib-associated tumor lysis syndrome in a patient with chronic lymphocytic leukemia. Blood. 2014;124(23):3503–5. https://doi.org/10.1182/blood-2014-08-591875.
Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Zhang L, Baher L, Cheng M, Lee D, Beaupre DM, Rule S. Long-term follow-up of MCL patients treated with single-agent ibrutinib:updated safety and efficacy results. Blood. 2015;126(6):739–45. https://doi.org/10.1182/blood-2015-03-635326.
Kaur V, Swami A. Ibrutinib-associated tumor lysis syndrome in a patient with mantle cell lymphoma: A case report. J Oncol Pharm Pract. 2017;23(3):235–239. https://doi.org/10.1177/1078155216637218.
O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, Grant B, Richards DA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Izumi R, Hamdy A, Chang BY, Graef T, Clow F, Buggy JJ, James DF, Byrd JC. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58. https://doi.org/10.1016/s1470-2045(13)70513-8.
The American Cancer Society medical and editorial content team. Key statistics for chronic lymphocytic leukemia. American Cancer Society. 2022. http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed 30 April 2022.
Lynch DT, Koya S, Acharya U. Mantle Cell Lymphoma. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
Wang L, Li X, Zhao B, Mei D, Jiang J, Duan J. Immune Checkpoint Inhibitor-Associated Tumor Lysis Syndrome: A Real-World Pharmacovigilance Study. Front Pharmacol. 2021;12:679207. https://doi.org/10.3389/fphar.2021.679207.
Neha R, Subeesh V, Beulah E, Gouri N, Maheswari E. Existence of Notoriety Bias in FDA Adverse Event Reporting System Database and Its Impact on Signal Strength. Hosp Pharm. 2021;56(3):152–158. https://doi.org/10.1177/0018578719882323.

Table 1- Disproportionality analysis of BTKis associated TLS

Variables	Ibrutinib		Acalabrutinib		Zanubrutinib
	DE	ROR (CI 95%)	DE	ROR (CI 95%)	DE	ROR (CI 95%)
Signal Strength
	103	13.486 (11.1-16.4)	15	42.806 (25.7-71.3)	3	72.407 (23.05-227.49)
Age
Median age (IQR)	71 (65.5-74)		71 (67-72)		NA
0-18	-	-	-	-	-	-
19-64	17	19.225 (11.88-31.11)	-	-	-	-
65-100	40	9.952 (7.24-13.68)	7	35.042 (16.54-74.22)	-	-
Gender
Male	55	8.235 (6.29-10.79)	9	28.857 (14.92-55.82)	-	-
Female	21	14.291 (9.26-22.05)	3	48.811 (15.64-152.39)	-	-

DE: Case reports, ROR: Reporting odds ratio, CI: Confidence interval, IQR: Inter-quartile range, NA: Not applicable.

Table 2- Indication, region, and outcome

	Ibrutinib	Acalabrutinib	Zanubrutinib
Indication (Top 3)	Indication/N (%)
1	CLL/66 (64)	CLL/12 (80)	CLL/3 (100)
2	MCL/17 (16.5)	MCL/1 (6.7)
3	CLLR/3 (3)	CLLR/1 (6.7)
Region (Top 2)	Region/N (%)
1	North America/59 (57.3)	Europe/9 (60)	Asia/2 (66.7)
2	Europe/27 (26.2)	North America/6 (40)	North America/1 (33.3)
Outcome	N (%)
Death	39 (37.9)	1 (6.7)	-
Hospitalization- Initial or prolonged	51 (49.5)	9 (60)	3 (100)
Life-threatening	14 (13.6)	2 (13.3)	1 (33.3)
Disability	2 (1.9)	-	-
Required intervention to prevent permanent damage	-	-	-
Congenital anomaly	-	-	-
Other	66 (64)	10 (66.7)	-

N: Number of reports, CLL: Chronic lymphocytic leukaemia, CLLR: Chronic lymphocytic leukaemia refractory, MCL: Mantle cell lymphoma.

Download PDF

Version 1

posted

You are reading this latest preprint version

Disproportionality Analysis of Tumour Lysis Syndrome (TLS) Associated with Bruton's Tyrosine Kinase Inhibitor (BTKi) using Food and Drug Administration Adverse Events Reporting System (FAERS) Database

Status:

Version 1

Abstract

Key Points

1. Introduction

2. Methods

2.1 Data source

2.2 Study procedure

2.3 Statistical analysis

3. Results

3.1 Ibrutinib associated TLS

3.2 Acalabrutinib associated TLS

3.3 Zanubrutinib associated TLS

4. Discussion

5. Conclusion

Declarations

References

Tables

Status:

Version 1