Management of Asymptomatic Hyperleukocytosis Induced by Ibrutinib in a Patient with Chronic Lymphocytic Leukemia: A Case Study and Structured Follow-Up

Management of Asymptomatic Hyperleukocytosis Induced by Ibrutinib in a Patient with Chronic Lymphocytic Leukemia: A Case Study and Structured Follow-Up | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Management of Asymptomatic Hyperleukocytosis Induced by Ibrutinib in a Patient with Chronic Lymphocytic Leukemia: A Case Study and Structured Follow-Up H. A. Nati-Castillo, Isabella Lara-Puello, Andres David Sastre-Martínez, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9132281/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The use of irreversible bruton tyrosine kinase inhibitors (iBTK) represented a change in the history of cancer management, thanks to higher response and maintenance rates. However, these new medications bring with them adverse effects, even putting patients' lives at risk. Case presentation : This report describes a patient with chronic lymphocytic leukemia (CLL) treated with ibrutinib who developed persistent, asymptomatic hyperleukocytosis with a maximum leukocyte count of 593.66×10⁹/L, over a two-month period. The leukocyte count gradually normalized without intervention. Conclusions The absence of established guidelines for managing such cases poses diagnostic and monitoring challenges. This case underscores the utility of expectant management and emphasizes the need for stricter leukocyte monitoring to better characterize the duration and evolution of this phenomenon. Given the limited data on hyperleukocytosis in iBTK-treated patients, further case reports are essential, not only in CLL but also in other malignancies treated with iBTKs. BTK inhibitor Hyperleukocytosis Ibrutinib chronic lymphocytic leukemia Figures Figure 1 Figure 2 Introduction Irreversible Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, acalabrutinib, zanubrutinib, and others, have become increasingly central to the treatment of various hematologic malignancies, including lymphomas and leukemias [ 1 – 4 ] These inhibitors have also shown promise in treating solid tumors like breast, ovarian, colorectal, and prostate cancers. Among leukemias, chronic lymphocytic leukemia (CLL) is particularly prevalent in Western populations, accounting for approximately 11% of all hematologic malignancies. CLL exhibits a highly variable clinical course, ranging from indolent to aggressive forms, often requiring novel therapeutic approaches [ 5 ]. Ibrutinib, the first BTKi approved by the US Food and Drug Administration (FDA) in 2013 and by the European Medicines Agency (EMA), has revolutionized CLL treatment. Clinical trials have demonstrated significant improvements in overall survival and progression-free survival for CLL patients treated with ibrutinib [ 6 ]. As a first generation BTKi, ibrutinib differs from newer agents in this class, particularly in its adverse effect profile, which has become more apparent with widespread use [ 7 ]. Ibrutinib's side effects include cardiovascular complications such as atrial fibrillation, ventricular arrhythmias, conduction disorders, heart failure, hypertension, and bleeding [ 8 ]. Other systemic adverse effects encompass arthralgia, dermatologic reactions (e.g., rashes, petechiae, hematomas), and increased susceptibility to infections, including Pneumocystis jiroveci pneumonia, fungal infections, and reactivation of hepatitis B. Gastrointestinal issues such as diarrhea and pneumonitis have also been reported [ 9 – 11 ]. A less frequently discussed but clinically significant phenomenon associated with BTKi therapy is hyperleukocytosis. This hematologic effect occurs when ibrutinib promotes the rapid migration of lymphocytes from lymphoid tissues into the bloodstream, leading to a transient increase in white blood cell counts. While often asymptomatic, extreme hyperleukocytosis can pose serious risks, necessitating careful monitoring and management [ 12 ]. We present a case of a patient with CLL who developed marked hyperleukocytosis following the initiation of ibrutinib with asymptomatic course. Case presentation A 65-year-old male with a 10-year history of well-controlled hypertension (managed with Valsartan 80 mg orally every 12 hours) was diagnosed with CLL in 2019. His CLL was classified as Binet stage A and Rai stage 1, with normal TP53 and unmutated IgHV. After four years of stable disease, the patient presented with new constitutional symptoms over three months, including a 5% unintentional weight loss, night sweats, and progressive lymphadenopathy, primarily in the axillary region, along with an increase in total leukocyte count (WBC). Given the clinical progression and laboratory findings, including a total leukocyte count of 320.30 x 10⁹/L with lymphocytosis of 297.22 x 10⁹/L, hemoglobin (Hb) of 8.3 g/dL, and platelets at 100.0 x 10⁹/L, the patient met the criteria for initiating treatment with a Bruton tyrosine kinase inhibitor (BTKi). Ibrutinib was started at a dose of 420 mg per day (Fig. 1). **INSERT FIGURE 1** Figure 1. Timeline of Evolution and Follow-Up of Cell Count in Patients with CLL Before and After Ibrutinib Administration. Within 24 hours of starting ibrutinib, the patient's leukocyte count increased significantly to 496.07 x 10⁹/L, with lymphocytes rising to 487.8 x 10⁹/L. Concurrently, hemoglobin levels decreased to 7.4 g/dL, and platelets dropped to 69.0 x 10⁹/L. During the first week of treatment, the patient developed purpuric-type lesions in the right popliteal area, characterized by a palpable, stony, non-mobile mass measuring approximately 5x5 cm in the right calf region and another mass measuring 2x1 cm in the lower back (Fig. 2). **INSERT FIGURE 2** Figure 2. Patient’s Purpuric Lesions. A) Two erythematous-purpuric macules are visible in the popliteal fossa, with diffuse borders and a smooth surface. The lower macule measures approximately 2x2 cm and coalesces with the upper macule, which measures 1x1 cm in diameter. B) Multiple coalescent purpuric macules with some petechiae on the surface are present in the right calf region, varying in size. Ultrasound confirmed the presence of oval, heterogeneous focal areas, predominantly echogenic with hypoechoic regions, consistent with hematomas associated with diffuse edema of the subcutaneous cellular tissue in the posteromedial region of the thigh. These were treated with a topical anti-inflammatory agent. Complete resolution of these manifestations was achieved four weeks after initiating treatment, although hemoglobin levels remained persistently low, without any associated bleeding. A ferrokinetic profile revealed low serum iron levels of 20.2 mg/dL and ferritin of 110 ng/mL. Consequently, the patient was treated with a single dose of intravenous iron carboxymaltose (1000 mg) while continuing the ibrutinib regimen. The patient's hematological profile was monitored weekly for six weeks, then biweekly, followed by a three-week interval, and finally monthly check-ups. During weeks 2 and 3, a gradual decrease in leukocyte levels was observed, accompanied by a corresponding increase in hemoglobin, reflecting the correction of iron deficiency, as well as an improvement in platelet levels (Fig. 1). A peripheral blood smear performed during week 2 revealed a predominance of mature lymphocytes, Gumprecht shadows, macrocytosis, and anisocytosis, ruling out other causes of leukocytosis. Despite the progressive decrease in leukocyte and lymphocyte levels, the patient’s leukocyte count peaked at 593.66 x 10⁹/L, with lymphocytes reaching 582.49 x 10⁹/L after five weeks of treatment. These elevated levels persisted for two weeks without any associated symptoms or clinical manifestations. From week 7 onward, the leukocyte count began to gradually decrease during subsequent periodic controls (Fig. 1). Notably, the patient remained asymptomatic throughout the entire process, requiring no additional management. The BTKi therapy was never suspended, and as the patient’s cell lines stabilized, he remained clinically stable. Monthly follow-up visits have been planned to continue monitoring his condition. Discussion The introduction of tyrosine kinase inhibitors has revolutionized the management of oncological pathologies that previously had limited treatment options, often confined to observational approaches by physicians. With this advancement, our understanding of the real-life safety profiles and potential adverse effects of these drugs has expanded, including the phenomenon of hyperleukocytosis. Hyperleukocytosis is defined as a leukocyte count exceeding 100.00 x 10⁹/L in patients diagnosed with hematological neoplasms, identified through blood counts in the absence of clinical symptoms [ 13 ]. This condition differs from leukostasis, a clinical diagnosis where hyperleukocytosis is accompanied by symptoms such as headache, blurred vision, confusion, dyspnea, hypoxemia, and tachypnea—symptoms indicative of multiorgan involvement due to leukocyte aggregation [ 14 ]. In our patient, we encountered an atypical scenario. Despite exceeding a leukocyte count of 590.0 x 10⁹/L, the patient remained asymptomatic, aside from a self-limiting local hematoma that resolved after one month. This case generated significant interest within the medical team, especially considering the scarcity of literature on similar cases. Previous reports have documented fatal outcomes in patients with leukocytosis of similar magnitude and the same disease, as noted by Ibrahim et al. described an 81-year-old woman with a leukocyte count of 500.8 x 10⁹/L three weeks after initiating ibrutinib, who developed lumbar pain followed by right pleural effusion consistent with chylothorax, ultimately resulting in multisystem organ failure and death shortly after leukapheresis [ 15 ]. Similar symptomatic effects have been reported in CLL cases without ibrutinib. For instance, Cukierman et al. described a 73-year-old woman with newly diagnosed CLL who experienced extreme hyperleukocytosis of 2000 x 10⁹/L, leading to thrombosis of the common femoral vein, which resolved following leukapheresis [ 16 ]. In our patient, the leukocyte elevation induced by ibrutinib occurred almost immediately, as observed in a correlative analysis of a phase II study conducted in 2014. Significant increases in leukocyte count were noted within four hours of treatment initiation, mirroring the pattern seen in our patient, who showed a substantial increase in leukocytes within 24 hours of starting ibrutinib [ 13 ], The study further reported that 46% of patients exhibited significant leukocyte elevations by day two, and 78% by the fourth week. Our patient reached peak leukocyte levels in the fifth week. Interestingly, the greatest increases were typically associated with patients having an IGHV mutation, which our patient did not possess. Nonetheless, our patient's absolute lymphocyte count (ALC) reached 582.49 x 10⁹/L, far surpassing the highest ALC recorded in the study, which was 475.00 x 10⁹/L. In phase III studies, hyperleukocytosis was reported as a rare event, occurring in only 1% of BTKi users. However, these studies were limited in their ability to provide detailed observations and personalized follow-up, as was done in our case. We implemented a tailored weekly monitoring scheme using blood counts, gradually extending the intervals to two, three, and four weeks as the patient's condition stabilized, a novel approach that proved successful. Management of hyperleukocytosis in patients on BTKi therapy depends on whether the patient is symptomatic or asymptomatic. Options range from temporarily suspending ibrutinib and adopting a watchful waiting approach, to using concomitant therapy with rituximab to mitigate lymphocytosis, or in extreme cases, employing leukapheresis. The success rates of these interventions vary and are often based on isolated case reports [ 16 , 17 ]. In our patient, the high leukocyte counts initially caused concern, but the absence of symptoms justified a conservative management approach. We achieved a successful outcome through vigilant monitoring under a structured weekly scheme, with stabilization of leukocyte levels by 18 weeks, without the need to discontinue ibrutinib. This case expands the therapeutic understanding of ibrutinib, demonstrating its effects with prolonged follow-up and underscoring the importance of individualized patient management. Furthermore, it highlights the significance of documenting such cases in regions like South America, where data on these phenomena are scarce, thus contributing valuable insights to the global medical community. Conclusions This case underscores the critical importance of vigilant follow-up and individualized management for patients with CLL, particularly when dealing with BTKi (ibrutinib)-associated hyperleukocytosis. The structured follow-up strategy employed in this case, characterized by regular blood count monitoring, proved effective in managing this rare but potentially concerning side effect. The findings suggest that with careful observation and a personalized approach, ibrutinib can be safely continued in patients who develop hyperleukocytosis, without compromising treatment efficacy or patient safety. Declarations Informed consent: Written informed consent was obtained from the patient for publication of the details of his medical case. The participant has consented to the submission of the case report to the journal. Conflicts of Interest: The authors declare no conflicts of interest. Funding: This research received no external funding. Author Contribution HANC, ILP, MAO, and RGG contributed to the conceptualization of the study. Methodology was developed by HANC, MAI, and JSIC. Resources were provided by HANC, ILP, MAO, and RGG. Software was managed by HANC, ILP, MAO, and JSST. Validation was carried out by JSIC. Formal analysis was performed by HANC, ILP, ADSM, MAO, RGG, JSST, and JSIC. Visualization was conducted by HANC, MAI, and JSIC. The original draft of the manuscript was written by HANC, ILP, ADSM, MAO, RGG, and JSIC. Review and editing of the manuscript were performed by JSST, MAI, and JSIC. All authors have read and agreed to the published version of the manuscript. Acknowledgments: None. Data availability: Data are available on reasonable request from the authors. References Zhang Q, Wen C, Zhao L, Wang YA (2023) Comprehensive Review of Small-Molecule Inhibitors Targeting Bruton Tyrosine Kinase: Synthetic Approaches and Clinical Applications. Molecules 28:8037. 10.3390/molecules28248037 Yin S, Zheng X, Zhang W, Zhao H, Zhang R, Li W, Chen F (2024) Efficacy and Safety of New-Generation Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Systematic Review and Meta-Analysis. Ann Hematol 103:2231–2244. 10.1007/s00277-023-05486-x Wen T, Wang J, Shi Y, Qian H, Liu P (2021) Inhibitors Targeting Bruton’s Tyrosine Kinase in Cancers: Drug Development Advances. Leukemia 35:312–332. 10.1038/s41375-020-01072-6 Hatashima A, Karami M, Shadman M (2022) Approved and Emerging Bruton’s Tyrosine Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia. Expert Opin Pharmacother 23:1545–1557. 10.1080/14656566.2022.2113384 Zhou H, Hu P, Yan X, Zhang Y, Shi W (2020) Ibrutinib in Chronic Lymphocytic Leukemia: Clinical Applications, Drug Resistance, and Prospects. Onco Targets Ther 13:4877–4892. 10.2147/OTT.S249586 Timofeeva N, Gandhi V (2021) Ibrutinib Combinations in CLL Therapy: Scientific Rationale and Clinical Results. Blood Cancer J 11. 10.1038/s41408-021-00467-7 Coombs CC (2024) Frontline Therapy of CLL-Changing Treatment Paradigms. Curr Hematol Malig Rep 19:65–74. 10.1007/s11899-024-00726-x Baratta SJ, Miroli A, Cabarcos JP, Bezares RF, Baratta SJ, Miroli A, Cabarcos JP, Bezares RF (2022) Inhibidores de Bruton Tirosina Quinasa. ¿Qué Necesita Saber El Oncohematólogo y El Cardiólogo? Med (Buenos Aires) 82:914–926 Paydas S (2019) Management of Adverse Effects/Toxicity of Ibrutinib. Crit Rev Oncol Hematol 136:56–63. 10.1016/j.critrevonc.2019.02.001 Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, Howlett C, Skarbnik A, Cheson BD, Zent C et al (2018) Toxicities and Outcomes of 616 Ibrutinib-Treated Patients in the United States: A Real-World Analysis. Haematologica 103 , 874–879. 10.3324/haematol.2017.182907 Estupiñán HY, Berglöf A, Zain R, Smith CIE (2021) Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Front Cell Dev Biol 9:630942. 10.3389/fcell.2021.630942 Deeks ED, Ibrutinib (2017) A Review in Chronic Lymphocytic Leukaemia. Drugs 77:225–236. 10.1007/s40265-017-0695-3 Herman SEM, Niemann CU, Farooqui M, Jones J, Mustafa RZ, Lipsky A, Saba N, Martyr S, Soto S, Valdez J et al (2014) Ibrutinib-Induced Lymphocytosis in Patients with Chronic Lymphocytic Leukemia: Correlative Analyses from a Phase II Study. Leukemia 28:2188–2196. 10.1038/leu.2014.122 Giammarco S, Chiusolo P, Piccirillo N, Di Giovanni A, Metafuni E, Laurenti L, Sica S, Pagano L (2017) Hyperleukocytosis and Leukostasis: Management of a Medical Emergency. Expert Rev Hematol 10:147–154. 10.1080/17474086.2017.1270754 Ibrahim S, Seshan N, Berges P, Hussain N, DeFraia C, Zuhoski A, Hussain K (2019) Ibrutinib-Induced Hyperleukocytosis and Leukostasis in a Patient with Chronic Lymphocytic Leukemia. CHEST 156 , A2149–A2150. 10.1016/j.chest.2019.08.2091 Cukierman T, Gatt ME, Libster D, Goldschmidt N, Matzner Y (2002) Chronic Lymphocytic Leukemia Presenting with Extreme Hyperleukocytosis and Thrombosis of the Common Femoral Vein. Leuk Lymphoma 43:1865–1868. 10.1080/1042819021000006367 Barrientos JC, Burger JA, Byrd JC, Hillmen P, Zhou C, Ninomoto J, James DF, Kipps TJ (2019) Characterizing the Kinetics of Lymphocytosis in Patients with Chronic Lymphocytic Leukemia Treated with Single-Agent Ibrutinib. Leuk Lymphoma 60:1000–1005. 10.1080/10428194.2018.1512710 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9132281","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":614711656,"identity":"2c985c7b-575e-4cdc-85d4-1f7a2649d13d","order_by":0,"name":"H. A. 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A) Two erythematous-purpuric macules are visible in the popliteal fossa, with diffuse borders and a smooth surface. The lower macule measures approximately 2x2 cm and coalesces with the upper macule, which measures 1x1 cm in diameter. B) Multiple coalescent purpuric macules with some petechiae on the surface are present in the right calf region, varying in size.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9132281/v1/e2f2aaa5d3c924d4fb6185a8.jpg"},{"id":107106753,"identity":"d36a4af6-fabf-4cb0-9297-fa8d1a53bca0","added_by":"auto","created_at":"2026-04-16 21:24:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1291927,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9132281/v1/724e68c8-0960-4e93-8c95-9e13e64a30b7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Management of Asymptomatic Hyperleukocytosis Induced by Ibrutinib in a Patient with Chronic Lymphocytic Leukemia: A Case Study and Structured Follow-Up","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIrreversible Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, acalabrutinib, zanubrutinib, and others, have become increasingly central to the treatment of various hematologic malignancies, including lymphomas and leukemias [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] These inhibitors have also shown promise in treating solid tumors like breast, ovarian, colorectal, and prostate cancers. Among leukemias, chronic lymphocytic leukemia (CLL) is particularly prevalent in Western populations, accounting for approximately 11% of all hematologic malignancies. CLL exhibits a highly variable clinical course, ranging from indolent to aggressive forms, often requiring novel therapeutic approaches [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIbrutinib, the first BTKi approved by the US Food and Drug Administration (FDA) in 2013 and by the European Medicines Agency (EMA), has revolutionized CLL treatment. Clinical trials have demonstrated significant improvements in overall survival and progression-free survival for CLL patients treated with ibrutinib [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. As a first generation BTKi, ibrutinib differs from newer agents in this class, particularly in its adverse effect profile, which has become more apparent with widespread use [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIbrutinib's side effects include cardiovascular complications such as atrial fibrillation, ventricular arrhythmias, conduction disorders, heart failure, hypertension, and bleeding [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Other systemic adverse effects encompass arthralgia, dermatologic reactions (e.g., rashes, petechiae, hematomas), and increased susceptibility to infections, including \u003cem\u003ePneumocystis jiroveci\u003c/em\u003e pneumonia, fungal infections, and reactivation of hepatitis B. Gastrointestinal issues such as diarrhea and pneumonitis have also been reported [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA less frequently discussed but clinically significant phenomenon associated with BTKi therapy is hyperleukocytosis. This hematologic effect occurs when ibrutinib promotes the rapid migration of lymphocytes from lymphoid tissues into the bloodstream, leading to a transient increase in white blood cell counts. While often asymptomatic, extreme hyperleukocytosis can pose serious risks, necessitating careful monitoring and management [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe present a case of a patient with CLL who developed marked hyperleukocytosis following the initiation of ibrutinib with asymptomatic course.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 65-year-old male with a 10-year history of well-controlled hypertension (managed with Valsartan 80 mg orally every 12 hours) was diagnosed with CLL in 2019. His CLL was classified as Binet stage A and Rai stage 1, with normal TP53 and unmutated IgHV. After four years of stable disease, the patient presented with new constitutional symptoms over three months, including a 5% unintentional weight loss, night sweats, and progressive lymphadenopathy, primarily in the axillary region, along with an increase in total leukocyte count (WBC).\u003c/p\u003e \u003cp\u003eGiven the clinical progression and laboratory findings, including a total leukocyte count of 320.30 x 10⁹/L with lymphocytosis of 297.22 x 10⁹/L, hemoglobin (Hb) of 8.3 g/dL, and platelets at 100.0 x 10⁹/L, the patient met the criteria for initiating treatment with a Bruton tyrosine kinase inhibitor (BTKi). Ibrutinib was started at a dose of 420 mg per day (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e**INSERT FIGURE 1**\u003c/h2\u003e \u003cp\u003e \u003cb\u003eFigure 1.\u003c/b\u003e Timeline of Evolution and Follow-Up of Cell Count in Patients with CLL Before and After Ibrutinib Administration.\u003c/p\u003e \u003cp\u003eWithin 24 hours of starting ibrutinib, the patient's leukocyte count increased significantly to 496.07 x 10⁹/L, with lymphocytes rising to 487.8 x 10⁹/L. Concurrently, hemoglobin levels decreased to 7.4 g/dL, and platelets dropped to 69.0 x 10⁹/L. During the first week of treatment, the patient developed purpuric-type lesions in the right popliteal area, characterized by a palpable, stony, non-mobile mass measuring approximately 5x5 cm in the right calf region and another mass measuring 2x1 cm in the lower back (Fig.\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e**INSERT FIGURE 2**\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003eFigure 2.\u003c/b\u003e Patient\u0026rsquo;s Purpuric Lesions. A) Two erythematous-purpuric macules are visible in the popliteal fossa, with diffuse borders and a smooth surface. The lower macule measures approximately 2x2 cm and coalesces with the upper macule, which measures 1x1 cm in diameter. B) Multiple coalescent purpuric macules with some petechiae on the surface are present in the right calf region, varying in size.\u003c/p\u003e \u003cp\u003eUltrasound confirmed the presence of oval, heterogeneous focal areas, predominantly echogenic with hypoechoic regions, consistent with hematomas associated with diffuse edema of the subcutaneous cellular tissue in the posteromedial region of the thigh. These were treated with a topical anti-inflammatory agent.\u003c/p\u003e \u003cp\u003eComplete resolution of these manifestations was achieved four weeks after initiating treatment, although hemoglobin levels remained persistently low, without any associated bleeding. A ferrokinetic profile revealed low serum iron levels of 20.2 mg/dL and ferritin of 110 ng/mL. Consequently, the patient was treated with a single dose of intravenous iron carboxymaltose (1000 mg) while continuing the ibrutinib regimen.\u003c/p\u003e \u003cp\u003eThe patient's hematological profile was monitored weekly for six weeks, then biweekly, followed by a three-week interval, and finally monthly check-ups. During weeks 2 and 3, a gradual decrease in leukocyte levels was observed, accompanied by a corresponding increase in hemoglobin, reflecting the correction of iron deficiency, as well as an improvement in platelet levels (Fig.\u0026nbsp;1). A peripheral blood smear performed during week 2 revealed a predominance of mature lymphocytes, Gumprecht shadows, macrocytosis, and anisocytosis, ruling out other causes of leukocytosis.\u003c/p\u003e \u003cp\u003eDespite the progressive decrease in leukocyte and lymphocyte levels, the patient\u0026rsquo;s leukocyte count peaked at 593.66 x 10⁹/L, with lymphocytes reaching 582.49 x 10⁹/L after five weeks of treatment. These elevated levels persisted for two weeks without any associated symptoms or clinical manifestations. From week 7 onward, the leukocyte count began to gradually decrease during subsequent periodic controls (Fig.\u0026nbsp;1). Notably, the patient remained asymptomatic throughout the entire process, requiring no additional management. The BTKi therapy was never suspended, and as the patient\u0026rsquo;s cell lines stabilized, he remained clinically stable. Monthly follow-up visits have been planned to continue monitoring his condition.\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eThe introduction of tyrosine kinase inhibitors has revolutionized the management of oncological pathologies that previously had limited treatment options, often confined to observational approaches by physicians. With this advancement, our understanding of the real-life safety profiles and potential adverse effects of these drugs has expanded, including the phenomenon of hyperleukocytosis. Hyperleukocytosis is defined as a leukocyte count exceeding 100.00 x 10⁹/L in patients diagnosed with hematological neoplasms, identified through blood counts in the absence of clinical symptoms [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This condition differs from leukostasis, a clinical diagnosis where hyperleukocytosis is accompanied by symptoms such as headache, blurred vision, confusion, dyspnea, hypoxemia, and tachypnea\u0026mdash;symptoms indicative of multiorgan involvement due to leukocyte aggregation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our patient, we encountered an atypical scenario. Despite exceeding a leukocyte count of 590.0 x 10⁹/L, the patient remained asymptomatic, aside from a self-limiting local hematoma that resolved after one month. This case generated significant interest within the medical team, especially considering the scarcity of literature on similar cases. Previous reports have documented fatal outcomes in patients with leukocytosis of similar magnitude and the same disease, as noted by Ibrahim et al. described an 81-year-old woman with a leukocyte count of 500.8 x 10⁹/L three weeks after initiating ibrutinib, who developed lumbar pain followed by right pleural effusion consistent with chylothorax, ultimately resulting in multisystem organ failure and death shortly after leukapheresis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSimilar symptomatic effects have been reported in CLL cases without ibrutinib. For instance, Cukierman et al. described a 73-year-old woman with newly diagnosed CLL who experienced extreme hyperleukocytosis of 2000 x 10⁹/L, leading to thrombosis of the common femoral vein, which resolved following leukapheresis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our patient, the leukocyte elevation induced by ibrutinib occurred almost immediately, as observed in a correlative analysis of a phase II study conducted in 2014. Significant increases in leukocyte count were noted within four hours of treatment initiation, mirroring the pattern seen in our patient, who showed a substantial increase in leukocytes within 24 hours of starting ibrutinib [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], The study further reported that 46% of patients exhibited significant leukocyte elevations by day two, and 78% by the fourth week. Our patient reached peak leukocyte levels in the fifth week. Interestingly, the greatest increases were typically associated with patients having an IGHV mutation, which our patient did not possess. Nonetheless, our patient's absolute lymphocyte count (ALC) reached 582.49 x 10⁹/L, far surpassing the highest ALC recorded in the study, which was 475.00 x 10⁹/L.\u003c/p\u003e \u003cp\u003eIn phase III studies, hyperleukocytosis was reported as a rare event, occurring in only 1% of BTKi users. However, these studies were limited in their ability to provide detailed observations and personalized follow-up, as was done in our case. We implemented a tailored weekly monitoring scheme using blood counts, gradually extending the intervals to two, three, and four weeks as the patient's condition stabilized, a novel approach that proved successful.\u003c/p\u003e \u003cp\u003eManagement of hyperleukocytosis in patients on BTKi therapy depends on whether the patient is symptomatic or asymptomatic. Options range from temporarily suspending ibrutinib and adopting a watchful waiting approach, to using concomitant therapy with rituximab to mitigate lymphocytosis, or in extreme cases, employing leukapheresis. The success rates of these interventions vary and are often based on isolated case reports [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our patient, the high leukocyte counts initially caused concern, but the absence of symptoms justified a conservative management approach. We achieved a successful outcome through vigilant monitoring under a structured weekly scheme, with stabilization of leukocyte levels by 18 weeks, without the need to discontinue ibrutinib. This case expands the therapeutic understanding of ibrutinib, demonstrating its effects with prolonged follow-up and underscoring the importance of individualized patient management. Furthermore, it highlights the significance of documenting such cases in regions like South America, where data on these phenomena are scarce, thus contributing valuable insights to the global medical community.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case underscores the critical importance of vigilant follow-up and individualized management for patients with CLL, particularly when dealing with BTKi (ibrutinib)-associated hyperleukocytosis. The structured follow-up strategy employed in this case, characterized by regular blood count monitoring, proved effective in managing this rare but potentially concerning side effect. The findings suggest that with careful observation and a personalized approach, ibrutinib can be safely continued in patients who develop hyperleukocytosis, without compromising treatment efficacy or patient safety.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eInformed consent:\u003c/h2\u003e \u003cp\u003eWritten informed consent was obtained from the patient for publication of the details of his medical case. The participant has consented to the submission of the case report to the journal.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research received no external funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHANC, ILP, MAO, and RGG contributed to the conceptualization of the study. Methodology was developed by HANC, MAI, and JSIC. Resources were provided by HANC, ILP, MAO, and RGG. Software was managed by HANC, ILP, MAO, and JSST. Validation was carried out by JSIC. Formal analysis was performed by HANC, ILP, ADSM, MAO, RGG, JSST, and JSIC. Visualization was conducted by HANC, MAI, and JSIC. The original draft of the manuscript was written by HANC, ILP, ADSM, MAO, RGG, and JSIC. Review and editing of the manuscript were performed by JSST, MAI, and JSIC. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData availability:\u003c/h2\u003e \u003cp\u003eData are available on reasonable request from the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhang Q, Wen C, Zhao L, Wang YA (2023) Comprehensive Review of Small-Molecule Inhibitors Targeting Bruton Tyrosine Kinase: Synthetic Approaches and Clinical Applications. 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Leuk Lymphoma 43:1865\u0026ndash;1868. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/1042819021000006367\u003c/span\u003e\u003cspan address=\"10.1080/1042819021000006367\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarrientos JC, Burger JA, Byrd JC, Hillmen P, Zhou C, Ninomoto J, James DF, Kipps TJ (2019) Characterizing the Kinetics of Lymphocytosis in Patients with Chronic Lymphocytic Leukemia Treated with Single-Agent Ibrutinib. Leuk Lymphoma 60:1000\u0026ndash;1005. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/10428194.2018.1512710\u003c/span\u003e\u003cspan address=\"10.1080/10428194.2018.1512710\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"BTK inhibitor, Hyperleukocytosis, Ibrutinib, chronic lymphocytic leukemia","lastPublishedDoi":"10.21203/rs.3.rs-9132281/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9132281/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe use of irreversible bruton tyrosine kinase inhibitors (iBTK) represented a change in the history of cancer management, thanks to higher response and maintenance rates. However, these new medications bring with them adverse effects, even putting patients' lives at risk.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e: This report describes a patient with chronic lymphocytic leukemia (CLL) treated with ibrutinib who developed persistent, asymptomatic hyperleukocytosis with a maximum leukocyte count of 593.66×10⁹/L, over a two-month period. The leukocyte count gradually normalized without intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe absence of established guidelines for managing such cases poses diagnostic and monitoring challenges. This case underscores the utility of expectant management and emphasizes the need for stricter leukocyte monitoring to better characterize the duration and evolution of this phenomenon. Given the limited data on hyperleukocytosis in iBTK-treated patients, further case reports are essential, not only in CLL but also in other malignancies treated with iBTKs.\u003c/p\u003e","manuscriptTitle":"Management of Asymptomatic Hyperleukocytosis Induced by Ibrutinib in a Patient with Chronic Lymphocytic Leukemia: A Case Study and Structured Follow-Up","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-02 07:05:28","doi":"10.21203/rs.3.rs-9132281/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73be0834-3124-4102-af00-375971b3f682","owner":[],"postedDate":"April 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-16T21:24:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-02 07:05:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9132281","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9132281","identity":"rs-9132281","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}