Resolving Myelosuppression with Modafinil in the Treatment of Metastatic Pheochromocytoma and Paraganglioma: A Single Case Study

Resolving Myelosuppression with Modafinil in the Treatment of Metastatic Pheochromocytoma and Paraganglioma: A Single Case Study | 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 Short Report Resolving Myelosuppression with Modafinil in the Treatment of Metastatic Pheochromocytoma and Paraganglioma: A Single Case Study Emirhan Harbi, Aytug Altundag, Erhan Yarar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7135896/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 Temozolomide (TMZ) is an effective treatment option for patients with metastatic Pheochromocytoma and Paraganglioma (mPPGL), but it carries a risk of severe myelosuppression. In this single case study, a 19-year-old male patient receiving TMZ and Sunitinib (SUN) combination therapy developed severe thrombocytopenia and neutropenia after the first dose of the second cycle of TMZ. Following the initiation of Modafinil treatment without traditional supportive treatments, a rapid and significant improvement in platelet and neutrophil levels was observed. The patient remained asymptomatic during this period, and did not require blood product transfusions. In the next cycle, the combination of TMZ and Modafinil was administered, with the addition of Vincristine (VCR). The patient remained asymptomatic throughout the cycle, and platelet counts did not decrease during the combination of Modafinil and TMZ. This suggests that modafinil may increase thrombopoietin (TPO) production by suppressing proinflammatory cytokines such as TNF-α and IL-6. This case is noteworthy as it is the first reported case in the literature of modafinil improving chemotherapy-induced myelosuppression. The findings suggest that modafinil may be a potential agent for reducing hematological toxicities. However, since this observation is based on a single case, more comprehensive preclinical and clinical studies are needed to confirm its effect. Myelosuppression modafinil temozolomide sunitinib vincristine pheochromocytoma and paraganglioma Introduction Pheochromocytoma and paraganglioma (PPGL) is a rare and metastasizing neuroendocrine tumor (NET) that requires multidisciplinary treatment [1,2]. Temozolomide (TMZ), an alkylating agent, has shown promising results, especially in PPGL patients with SDHB mutations [3]. However, the clinical use of TMZ may be limited by hematologic side effects such as bone marrow suppression. One of the most common hematologic toxicities during TMZ treatment is thrombocytopenia and neutropenia. In studies in patients with glial tumors, the rate of TMZ-induced severe thrombocytopenia such as grade 3 or 4 is around 15-20%, and similar levels of neutropenia have been observed. Such cytopenias may often require interventions such as dose reduction, treatment interruption, or platelet transfusion support. Supportive approaches are usually used in the management of TMZ-induced myelosuppression. These include dose adjustments, growth factor support (e.g. G-CSF for neutropenia) and transfusion of blood products such as platelet suspensions for thrombocytopenia and erythrocyte suspensions for anemia. However, persistent or recurrent cytopenias despite such support can be a dangerous clinical problem, especially in intensive or long-term protocols. Therefore, the search for new strategies that can preserve hematopoietic function during chemotherapy is of great importance and remains an unmet need. Modafinil is a non-amphetamine derivative known for its wakefulness-enhancing effect and is approved for conditions such as narcolepsy or shift work sleep disorder [4–6]. It is pharmacologically different from classical psychostimulants [7–9]. In addition to its clinical use in areas other than sleep regulation, it is also used off-label in conditions such as fatigue and cognitive impairment [6,10,11]. There are some preliminary studies suggesting that modafinil has regulatory effects on the immune system and inflammation [12–15]. In a study in mouse xenograft models, modafinil treatment was shown to suppress proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels [16]. On the other hand, some studies have also reported immune system activating effects of modafinil [12,17]. These contrasting findings suggest that modafinil may have context-dependent effects on the immune system. This may have potential effects on hematopoiesis and platelet production. In this single case study, a 19-year-old man with metastatic PPGL developed severe myelosuppression (leukopenia, thrombocytopenia, and neutropenia) due to the combination of TMZ and Sunitinib (SUN). Following the initiation of modafinil, a rapid and safe stabilization of platelet and neutrophil counts was observed without any additional treatment. The patient remained asymptomatic during this period and did not require any blood product supplementation. For the first time in the literature, it has been shown that modafinil may have a corrective effect on chemotherapy-induced myelosuppression. As a possible mechanism, modafinil may increase thrombopoietin (TPO) production from the liver by suppressing proinflammatory cytokines such as TNF-α and IL-6 [18–20]. History of myelosuppression and treatments The patient is receiving a combination of the DNA alkylating agent TMZ and the multi-kinase inhibitor SUN in 28-day cycles for the treatment of PPGL. The patient takes SUN 50 mg/day for the first 14 days, and TMZ 200 mg/m2 for 5 days after SUN is finished, followed by a 9-day break and then a repeat cycle. The first cycle ended asymptomatically and comfortably. However, in the 2 nd cycle, Platelet (PLT) levels, which were good during 14 days of SUN, unexpectedly decreased 15 hours after the first day's dosage of TMZ, and thrombocytopenia developed. Some haemogram blood values before and after TMZ are shown in Table 1. And also, some simple biochemical parameters are shown in Table 2. Table 1 : Haemogram before and after TMZ/SUN for 2 nd cycle. Day PLT (10³/μL) (150 – 400) WBC (10³/μL) (4.5 – 11) ANC (10³/μL) (2.5 – 7) HGB (g/dL) (14 – 18) MPV (fL) (7.4 – 10.4) Day 10 for SUN 145 6.29 2.65 15.1 8.8 Day 15 (15h after TMZ) 38 3.2 1.28 14.5 11.5 Day 16 40 3.41 0.92 12.8 10.4 Day 17 43 2.24 0.5 13.2 10.4 Day 18 56 2.41 0.52 12.8 8.9 Day 19 69 2 0.49 12.6 9.5 Day 20 127 2.36 1.0 13.3 9.2 Day 28 248 3.67 1.72 14.4 7.9 Table 1: Haemogram before and after TMZ/SUN for 2 nd cycle. Table 2 : Simple biochemical parameters before and after TMZ/SUN for 2 nd cycle. Day Creatinine (mg/dl) K/Na (mmol/L) ALT/AST (U/L) Urea (mg/dL) Day 10 for SUN 0.69 4.3/140 22/17 15 Day 15 (15h after TMZ) 0.94 4.1/139 23/20 16 Day 16 0.63 3.9/139 32/29 12 Day 17 - - - - Day 18 - - - - Day 19 0.62 4.1/139 31/28 8 Day 20 - - - - Day 28 0.57 4.2/140 18/20 24 Table 2: Simple biochemical parameters before and after TMZ/SUN for 2 nd cycle. Single case clinical trial: Blood Values in Combination of TMZ with Modafinil In Cycle 3, the patient received a single 100 mg/day SUN treatment for the first 7 days and biochemistry and haemogram were monitored daily. There were no symptomatic abnormalities, but 50 mg/day SUN was continued for the other 7 days. On day 15, TMZ 200 mg/m 2 and Modafinil 400 mg/day were started. Interestingly, PLT and other haemogram values started to increase instead of decreasing. 200 mg/m 2 TMZ was administered for 4 days, 200 mg TMZ and 1 mg/1ml Vincristine was administered on the 4 th day. During this 5-day addition of TMZ and Vincristine (VCR), the patient was treated with Modafinil 400 to 600 mg every day. The patient survived the 3 rd cycle without any toxicity. Haemogram and simple biochemistry values during this period are shown in Table 3, And also, some simple biochemical parameters are shown in Table 4. Table 3 : Haemogram before and after TMZ/SUN and VCR with Modafinil 3 rd cycle Day PLT (10³/μL) (150 – 400) WBC (10³/μL) (4.5 – 11) ANC (10³/μL) (2.5 – 7) HGB (g/dL) (14 – 18) MPV (fL) (7.4 – 10.4) Day 14 for SUN 228 4.9 2.27 13.7 8.5 Day 15 (15h after TMZ) 250 8.08 4.17 14.5 8.2 Day 16 238 5.95 3.38 14.7 8.0 Day 17 249 5.45 3.17 14.2 8.7 Day 18 (TMZ and VCR) 261 3.81 3.18 13.7 8.1 Day 19 242 4.1 3.0 12.8 8.3 Table 3: Haemogram before and after TMZ/SUN and VCR with Modafinil for cycle 3 rd cycle. Table 4 : Simple biochemical parameters before and after TMZ/SUN and VCR with Modafinil for 3 rd cycle Day Creatinine (mg/dl) K/Na (mmol/L) ALT/AST/ (U/L) Urea (mg/dL) Day 14 for SUN 0.69 4.2/139 25/16 15 Day 15 (15h after TMZ) 0.65 4.1/139 60/44 13 Day 16 0.63 4.2/139 83/52 18 Day 17 0.65 4.0/137 69/32 45.6 Day 18 (TMZ and VCR) 0.59 4.6/138 49/26 32 Day 19 0.62 4.4/140 40/20 36 Table 4: Simple biochemical parameters before and after TMZ/SUN and VCR with Modafinil for cycle 3 rd . On day 17, the urea value, which rises and then falls, is due to dehydration. Discussion PPGLs are tumors characterized by catecholaminergic crises. Especially this case is a case of a noradrenergic PPGL characterized by elevated normetanephrine (NMN). Modafinil may not have triggered the catecholaminergic crisis because of the current maximum dose of alpha-blockade used by this patient, but modafinil is not safe for PPGL patients. This is because modafinil can cause false positive diagnoses by raising 3-methoxytyramine (3-MT), a metabolite of dopamine, in plasma [ 21 ]. 3-MT elevation can be interpreted in connection with metastatic processes of Head and Neck PGL (HNPGL) or PPGL, and 3-MT elevation is more common in PPGLs, especially in SDHD-related PPGLs [ 22 ]. TMZ-induced myelosuppression is known to be a serious dose-limiting side effect, especially in malignancies requiring long-term treatment. In such cases, supportive strategies such as dose reduction, treatment interruption or blood product transfusions are usually applied. However, in cases where these supportive strategies may be inadequate, alternative or complementary treatment approaches are needed. In the present case, modafinil significantly improved platelet and neutrophil counts, suggesting that it may have a positive effect on hematopoietic function. Possible mechanisms may include modafinil increasing TPO production in the liver and suppressing the inflammatory response. TPO is one of the major factors that directly stimulate megakaryocyte differentiation and platelet production. Our findings in this study are the first to report the treatment of TMZ-induced myelosuppression with modafinil. Furthermore, modafinil did not induce any catecholaminergic crisis in this patient. In the next cycle, 400 to 600 mg/day of Modafinil was added to 200 mg/m 2 of TMZ, and 1 mg/1 ml of VCR was administered on the 4th day of the 5-day cycle. No symptoms were observed. The patient tolerated the maximum dose of TMZ for 5 days while taking Modafinil. Platelet counts did not decrease with the combination of Modafinil and TMZ, neutrophil and leukocyte counts did not drop to dangerous levels, and the patient remained asymptomatic throughout treatment. Another important finding was that Modafinil prevented TMZ-related fatigue in this mPPGL patient. This is the first case reported in the literature that modafinil may improve chemotherapy-induced myelosuppression. However, these findings cannot be generalized on the basis of a single case. Prospective and controlled studies with larger patient series are needed to clarify the effects of modafinil on hematologic toxicities. However, xenograft trials need to be conducted before human studies. Because this is a single case, it does not have any generalizable meaning, and by addressing the role of Modafinil on myelosuppression; it opens a research topic for researchers in this field. Future comprehensive xenograft model studies may further elucidate the relationship between modafinil and TPO. Results During the second cycle of mPPGL treatment, the patient developed significant myelosuppression approximately 15 hours after TMZ administration; platelet count decreased from 145x10³/µL to 38 x10³/µL, and neutrophil count decreased from 2.65x10³/µL to 1.28x10³/µL. The neutrophil count further decreased to 0.49 x10³/µL in the following days, and platelet levels remained low. Following the initiation of modafinil therapy without conventional supportive treatments (transfusion, G-CSF, etc.), a rapid and significant improvement in hematological parameters was observed. The platelet count increased to 127x10³/µL on day 20 and 248x10³/µL on day 28, while the neutrophil count reached 1.72x10³/µL. During this period, the patient remained asymptomatic; no complications such as infection, fever, or bleeding were observed, and no blood product transfusion was required. Then, in the third cycle, the combination of TMZ and Modafinil was initiated, and TMZ + VCR was administered on the 4th day; during this process, the platelet counts never fell below 228x10³/µL, and other hematological values remained stable. Biochemical parameters remained stable throughout treatment, except for an acute increase in urea due to dehydration. Modafinil also prevented TMZ-related fatigue. These findings suggest that modafinil may have a regulatory effect on chemotherapy-induced myelosuppression; however, as this is a single case, further preclinical and clinical studies are needed. Conclusion In this study in a single patient with mPPGL, maximum dose TMZ-induced myelosuppression was quickly and safely treated with Modafinil. This was followed by a combination of TMZ and Modafinil in the next cycle, with no symptoms, no myelosuppression, and stable blood values. These findings provide the first evidence to evaluate the role of Modafinil in myelosuppression in preclinical and clinical trials. Declarations Ethical Approval and Consent to participate The Patient in the article has given signed consent to the conduct and publication of this study. Human Ethics The patient provided written and signed informed consent for participation and publication. Consent for publication The patient is aware that this study will be published and has given consent. Availability of supporting data All relevant data are included within the article. Additional information is available from the corresponding author upon reasonable request. Funding This study received no funding. Competing interests The authors declare no competing interests. Authors' contributions E.H. managed the case and prepared the manuscript. E.Y. and A.A. assisted in managing the case and contributed to the interpretation of the data and the critical revision of the manuscript. All authors read and approved the final manuscript. Acknowledgements The authors thank the patient and his family for their cooperation and consent. References Harbi E, Aschner M. Nuclear medicine and perspective thoughts in the diagnosis and treatment of pheochromocytoma and paraganglioma. J Neuroendocrinol. 2025. Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas. Endocr Pathol. 2022;33:90–114. Hadoux J, Favier J, Scoazec J, Leboulleux S, Al Ghuzlan A, Caramella C, et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 2014;135:2711–20. Schwartz J. Modafinil in the treatment of excessive sleepiness. Drug Des Devel Ther. 2008;71. Minzenberg MJ, Carter CS. Modafinil: A Review of Neurochemical Actions and Effects on Cognition. Neuropsychopharmacology. 2008;33:1477–502. Karl Greenblatt, Ninos Adams. Modafinil. StatPearls [Internet]; 2023. Schmitt KC, Reith MEA. The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors. PLoS One. 2011;6:e25790. Hersey M, Tanda G. Modafinil, an atypical CNS stimulant? 2024. p. 287–326. Mereu M, Chun LE, Prisinzano TE, Newman AH, Katz JL, Tanda G. The unique psychostimulant profile of (±)‐modafinil: investigation of behavioral and neurochemical effects in mice. European Journal of Neuroscience. 2017;45:167–74. Mereu M, Bonci A, Newman AH, Tanda G. The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. Psychopharmacology (Berl). 2013;229:415–34. Kamal M-AM, Essam RM, Abdelkader NF, Zaki HF. Modafinil Ameliorated Fibromyalgia Syndrome in Rats by Modulating Mast Cells and Microglia Activation Through Dopamine/Substance P/MRGPRX/Histamine and PI3K/p-Akt/NF-κB Signaling Pathways. Journal of Neuroimmune Pharmacology. 2025;20:38. Zager A. Modulating the immune response with the wake-promoting drug modafinil: A potential therapeutic approach for inflammatory disorders. Brain Behav Immun. 2020;88:878–86. Amini MJ, Seighali N, Arabazadeh Bahri R, Ala M, Mohammad Jafari R, Dehpour AR. Repurposing of modafinil as an anti-inflammatory drug: a systematic review of experimental studies. Naunyn Schmiedebergs Arch Pharmacol. 2025; Zager A, Brandão WN, Margatho RO, Cruz DSG, Peron JP, Tufik S, et al. Increased interferon-mediated immunity following in vitro and in vivo Modafinil treatment on peripheral immune cells. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:297–305. Dejban P, Rahimi N, Takzare N, Dehpour AR. Biochemical and histopathological evidence for the beneficial effects of modafinil on the rat model of inflammatory bowel disease: involvement of nitric oxide pathway. Pharmacological Reports. 2020;72:135–46. Ghorbanzadeh H, Mohebkhodaei P, Nematizadeh M, Rahimi N, Rafeiean M, Ghasemi M, et al. Analgesic and anti-inflammatory effects of modafinil in a mouse model of neuropathic pain: A role for nitrergic and serotonergic pathways. Neurol Res. 2022;44:390–402. Moradi F, Eslami F, Rahimi N, Koohfar A, Shayan M, Maadani M, et al. Modafinil exerts anticonvulsive effects against lithium-pilocarpine-induced status epilepticus in rats: A role for tumor necrosis factor-α and nitric oxide signaling. Epilepsy & Behavior. 2022;130:108649. Kurokawa T, Ohkohchi N. Platelets in liver disease, cancer and regeneration. World J Gastroenterol. 2017;23:3228. Cardier JE. Effects of Megakaryocyte Growth and Development Factor (Thrombopoietin) on Liver Endothelial Cells in Vitro. Microvasc Res. 1999;58:108–13. Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, et al. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther. 2025;10:63. Rao D, Peitzsch M, Prejbisz A, Hanus K, Fassnacht M, Beuschlein F, et al. Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma. Eur J Endocrinol. 2017;177:103–13. Antonio K, Valdez MMN, Mercado-Asis L, Taïeb D, Pacak K. Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options. Gland Surg. 2020;9:105–23. 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-7135896","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":487741303,"identity":"a92654d4-5d42-45e5-b75c-16b743f0533b","order_by":0,"name":"Emirhan Harbi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYFACxgZmIJnAwMDDcEDCwAYk0niAeC0WBWlgEQJaGBjgWhgqPhwGi+DVwi92uO1zQc2dPP7ZZw8euGFw3m5t+2GgLTU20bi0SM5ObJ4949izYolzeQkHZxjcTt52JhGo5VhabgMOLQa3E5uZedgOJzac4TE4LAHUYnYAqIWx4TBOLfZgLf8OJ84HafljcC7Z7PxD/FoMpIFaeNsOJ24AagEG8gE7sxsEbJEA2cLbdzhx4xm+BKCW5ASzG0BbEvD4hX92+mNmnm+HE+ed4T38QeKPnb3Z+fSHDz7U2ODUggESwSoTiFUOAvakKB4Fo2AUjIKRAQAVvGoFDHrRGgAAAABJRU5ErkJggg==","orcid":"","institution":"Honorary Member, Turkish Society of Nuclear Medicine (TSNM)","correspondingAuthor":true,"prefix":"","firstName":"Emirhan","middleName":"","lastName":"Harbi","suffix":""},{"id":487741304,"identity":"e7caf26d-5017-4e19-995c-08783d57c78d","order_by":1,"name":"Aytug Altundag","email":"","orcid":"","institution":"Biruni University","correspondingAuthor":false,"prefix":"","firstName":"Aytug","middleName":"","lastName":"Altundag","suffix":""},{"id":487741305,"identity":"e9879410-052f-41f7-b606-1b2a11ee1d4e","order_by":2,"name":"Erhan Yarar","email":"","orcid":"","institution":"Emeritus Member, The International Cannabinoid Research Society (ICRS)","correspondingAuthor":false,"prefix":"","firstName":"Erhan","middleName":"","lastName":"Yarar","suffix":""}],"badges":[],"createdAt":"2025-07-16 05:08:27","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7135896/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7135896/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87291953,"identity":"9b3e84ac-92c5-4cf0-9886-b3a125a77bfe","added_by":"auto","created_at":"2025-07-22 11:38:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":760741,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7135896/v1/c57f4ddb-e02a-4390-9065-223ab27c2c03.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Resolving Myelosuppression with Modafinil in the Treatment of Metastatic Pheochromocytoma and Paraganglioma: A Single Case Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePheochromocytoma and paraganglioma (PPGL) is a rare and metastasizing neuroendocrine tumor (NET) that requires multidisciplinary treatment [1,2]. Temozolomide (TMZ), an alkylating agent, has shown promising results, especially in PPGL patients with SDHB mutations [3]. However, the clinical use of TMZ may be limited by hematologic side effects such as bone marrow suppression. One of the most common hematologic toxicities during TMZ treatment is thrombocytopenia and neutropenia. In studies in patients with glial tumors, the rate of TMZ-induced severe thrombocytopenia such as grade 3 or 4 is around 15-20%, and similar levels of neutropenia have been observed. Such cytopenias may often require interventions such as dose reduction, treatment interruption, or platelet transfusion support.\u003c/p\u003e\n\u003cp\u003eSupportive approaches are usually used in the management of TMZ-induced myelosuppression. These include dose adjustments, growth factor support (e.g. G-CSF for neutropenia) and transfusion of blood products such as platelet suspensions for thrombocytopenia and erythrocyte suspensions for anemia. However, persistent or recurrent cytopenias despite such support can be a dangerous clinical problem, especially in intensive or long-term protocols. Therefore, the search for new strategies that can preserve hematopoietic function during chemotherapy is of great importance and remains an unmet need.\u003c/p\u003e\n\u003cp\u003eModafinil is a non-amphetamine derivative known for its wakefulness-enhancing effect and is approved for conditions such as narcolepsy or shift work sleep disorder [4\u0026ndash;6]. It is pharmacologically different from classical psychostimulants [7\u0026ndash;9]. In addition to its clinical use in areas other than sleep regulation, it is also used off-label in conditions such as fatigue and cognitive impairment [6,10,11]. There are some preliminary studies suggesting that modafinil has regulatory effects on the immune system and inflammation [12\u0026ndash;15]. In a study in mouse xenograft models, modafinil treatment was shown to suppress proinflammatory cytokines tumor necrosis factor-\u0026alpha; (TNF-\u0026alpha;) and interleukin 6 (IL-6) levels [16]. On the other hand, some studies have also reported immune system activating effects of modafinil [12,17]. These contrasting findings suggest that modafinil may have context-dependent effects on the immune system. This may have potential effects on hematopoiesis and platelet production.\u003c/p\u003e\n\u003cp\u003eIn this single case study, a 19-year-old man with metastatic PPGL developed severe myelosuppression (leukopenia, thrombocytopenia, and neutropenia) due to the combination of TMZ and Sunitinib (SUN). Following the initiation of modafinil, a rapid and safe stabilization of platelet and neutrophil counts was observed without any additional treatment. The patient remained asymptomatic during this period and did not require any blood product supplementation. For the first time in the literature, it has been shown that modafinil may have a corrective effect on chemotherapy-induced myelosuppression. As a possible mechanism, modafinil may increase thrombopoietin (TPO) production from the liver by suppressing proinflammatory cytokines such as TNF-\u0026alpha; and IL-6 [18\u0026ndash;20].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHistory of myelosuppression and treatments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient is receiving a combination of the DNA alkylating agent TMZ and the multi-kinase inhibitor SUN in 28-day cycles for the treatment of PPGL. The patient takes SUN 50 mg/day for the first 14 days, and TMZ 200 mg/m2 for 5 days after SUN is finished, followed by a 9-day break and then a repeat cycle.\u003c/p\u003e\n\u003cp\u003eThe first cycle ended asymptomatically and comfortably. However, in the 2\u003csup\u003end\u003c/sup\u003e cycle, Platelet (PLT) levels, which were good during 14 days of SUN, unexpectedly decreased 15 hours after the first day\u0026apos;s dosage of TMZ, and thrombocytopenia developed. Some haemogram blood values before and after TMZ are shown in Table 1. And also, some simple biochemical parameters are shown in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e\u003cstrong\u003e: Haemogram before and after TMZ/SUN for 2\u003csup\u003end\u0026nbsp;\u003c/sup\u003ecycle.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" width=\"747\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePLT (10\u0026sup3;/\u0026mu;L) (150 \u0026ndash; 400)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWBC (10\u0026sup3;/\u0026mu;L) (4.5 \u0026ndash; 11)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eANC (10\u0026sup3;/\u0026mu;L)\u0026nbsp;\u003cbr\u003e\u0026nbsp;(2.5 \u0026ndash; 7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHGB \u0026nbsp;(g/dL) (14 \u0026ndash; 18)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMPV (fL)\u0026nbsp;\u003cbr\u003e\u0026nbsp;(7.4 \u0026ndash; 10.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 10 for SUN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e6.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e2.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e15.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 15 (15h after TMZ)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e11.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e3.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e12.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e2.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e13.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e2.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e12.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e12.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e248\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e3.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e1.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e14.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Haemogram before and after TMZ/SUN for 2\u003csup\u003end\u003c/sup\u003e cycle.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e\u003cstrong\u003e: Simple biochemical parameters before and after TMZ/SUN for 2\u003csup\u003end\u003c/sup\u003e cycle.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" width=\"652\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDay\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCreatinine (mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eK/Na (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eALT/AST (U/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eUrea (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 10 for SUN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.3/140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22/17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 15 (15h after TMZ)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.1/139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23/20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.9/139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.1/139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31/28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDay 20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.2/140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18/20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003eSimple biochemical parameters before and after TMZ/SUN for 2\u003csup\u003end\u003c/sup\u003e cycle.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSingle case clinical trial: Blood Values in Combination of TMZ with Modafinil\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn Cycle 3, the patient received a single 100 mg/day SUN treatment for the first 7 days and biochemistry and haemogram were monitored daily. There were no symptomatic abnormalities, but 50 mg/day SUN was continued for the other 7 days. On day 15, TMZ 200 mg/m\u003csup\u003e2\u003c/sup\u003e and Modafinil 400 mg/day were started. Interestingly, PLT and other haemogram values started to increase instead of decreasing. 200 mg/m\u003csup\u003e2\u003c/sup\u003e TMZ was administered for 4 days, 200 mg TMZ and 1 mg/1ml Vincristine was administered on the 4\u003csup\u003eth\u003c/sup\u003e day. During this 5-day addition of TMZ and Vincristine (VCR), the patient was treated with Modafinil 400 to 600 mg every day. The patient survived the 3\u003csup\u003erd\u003c/sup\u003e cycle without any toxicity. Haemogram and simple biochemistry values during this period are shown in Table 3, And also, some simple biochemical parameters are shown in Table 4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e\u003cstrong\u003e: Haemogram before and after TMZ/SUN\u003c/strong\u003e and \u003cstrong\u003eVCR with Modafinil 3\u003csup\u003erd\u003c/sup\u003e cycle\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" width=\"747\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePLT (10\u0026sup3;/\u0026mu;L) (150 \u0026ndash; 400)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWBC (10\u0026sup3;/\u0026mu;L) (4.5 \u0026ndash; 11)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eANC (10\u0026sup3;/\u0026mu;L)\u0026nbsp;\u003cbr\u003e\u0026nbsp;(2.5 \u0026ndash; 7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHGB \u0026nbsp;(g/dL) (14 \u0026ndash; 18)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMPV (fL)\u0026nbsp;\u003cbr\u003e\u0026nbsp;(7.4 \u0026ndash; 10.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 14 for SUN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e2.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e13.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 15 (15h after TMZ)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e8.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e4.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e5.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e3.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e14.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e249\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e5.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e3.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e14.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 18 (TMZ and VCR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e261\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e3.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e3.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e13.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 167px;\"\u003e\n \u003cp\u003eDay 19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e12.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e8.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3:\u003c/strong\u003e Haemogram before and after TMZ/SUN and VCR with Modafinil for cycle 3\u003csup\u003erd\u003c/sup\u003e cycle.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4\u003c/strong\u003e\u003cstrong\u003e: Simple biochemical parameters before and after TMZ/SUN and VCR with Modafinil for 3\u003csup\u003erd\u003c/sup\u003e cycle\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" width=\"709\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 205px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCreatinine (mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eK/Na (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALT/AST/ (U/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrea (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 205px;\"\u003e\n \u003cp\u003eDay 14 for SUN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.2/139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e25/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 205px;\"\u003e\n \u003cp\u003eDay 15 (15h after TMZ)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.1/139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e60/44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 205px;\"\u003e\n \u003cp\u003eDay 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.2/139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e83/52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 205px;\"\u003e\n \u003cp\u003eDay 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.0/137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e69/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e45.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 205px;\"\u003e\n \u003cp\u003eDay 18 (TMZ and VCR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.6/138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e49/26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 205px;\"\u003e\n \u003cp\u003eDay 19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.4/140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e40/20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Simple biochemical parameters before and after\u003c/strong\u003e \u003cstrong\u003eTMZ/SUN and VCR with Modafinil for cycle 3\u003csup\u003erd\u003c/sup\u003e. On\u003c/strong\u003e day 17, the urea value, which rises and then falls, is due to dehydration.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePPGLs are tumors characterized by catecholaminergic crises. Especially this case is a case of a noradrenergic PPGL characterized by elevated normetanephrine (NMN). Modafinil may not have triggered the catecholaminergic crisis because of the current maximum dose of alpha-blockade used by this patient, but modafinil is not safe for PPGL patients. This is because modafinil can cause false positive diagnoses by raising 3-methoxytyramine (3-MT), a metabolite of dopamine, in plasma [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. 3-MT elevation can be interpreted in connection with metastatic processes of Head and Neck PGL (HNPGL) or PPGL, and 3-MT elevation is more common in PPGLs, especially in SDHD-related PPGLs [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTMZ-induced myelosuppression is known to be a serious dose-limiting side effect, especially in malignancies requiring long-term treatment. In such cases, supportive strategies such as dose reduction, treatment interruption or blood product transfusions are usually applied. However, in cases where these supportive strategies may be inadequate, alternative or complementary treatment approaches are needed. In the present case, modafinil significantly improved platelet and neutrophil counts, suggesting that it may have a positive effect on hematopoietic function. Possible mechanisms may include modafinil increasing TPO production in the liver and suppressing the inflammatory response. TPO is one of the major factors that directly stimulate megakaryocyte differentiation and platelet production.\u003c/p\u003e\u003cp\u003eOur findings in this study are the first to report the treatment of TMZ-induced myelosuppression with modafinil. Furthermore, modafinil did not induce any catecholaminergic crisis in this patient. In the next cycle, 400 to 600 mg/day of Modafinil was added to 200 mg/m\u003csup\u003e2\u003c/sup\u003e of TMZ, and 1 mg/1 ml of VCR was administered on the 4th day of the 5-day cycle. No symptoms were observed. The patient tolerated the maximum dose of TMZ for 5 days while taking Modafinil. Platelet counts did not decrease with the combination of Modafinil and TMZ, neutrophil and leukocyte counts did not drop to dangerous levels, and the patient remained asymptomatic throughout treatment. Another important finding was that Modafinil prevented TMZ-related fatigue in this mPPGL patient.\u003c/p\u003e\u003cp\u003eThis is the first case reported in the literature that modafinil may improve chemotherapy-induced myelosuppression. However, these findings cannot be generalized on the basis of a single case. Prospective and controlled studies with larger patient series are needed to clarify the effects of modafinil on hematologic toxicities. However, xenograft trials need to be conducted before human studies. Because this is a single case, it does not have any generalizable meaning, and by addressing the role of Modafinil on myelosuppression; it opens a research topic for researchers in this field. Future comprehensive xenograft model studies may further elucidate the relationship between modafinil and TPO.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the second cycle of mPPGL treatment, the patient developed significant myelosuppression approximately 15 hours after TMZ administration; platelet count decreased from 145x10\u0026sup3;/\u0026micro;L to 38 x10\u0026sup3;/\u0026micro;L, and neutrophil count decreased from 2.65x10\u0026sup3;/\u0026micro;L to 1.28x10\u0026sup3;/\u0026micro;L. The neutrophil count further decreased to 0.49 x10\u0026sup3;/\u0026micro;L in the following days, and platelet levels remained low. Following the initiation of modafinil therapy without conventional supportive treatments (transfusion, G-CSF, etc.), a rapid and significant improvement in hematological parameters was observed. The platelet count increased to 127x10\u0026sup3;/\u0026micro;L on day 20 and 248x10\u0026sup3;/\u0026micro;L on day 28, while the neutrophil count reached 1.72x10\u0026sup3;/\u0026micro;L. During this period, the patient remained asymptomatic; no complications such as infection, fever, or bleeding were observed, and no blood product transfusion was required. Then, in the third cycle, the combination of TMZ and Modafinil was initiated, and TMZ\u0026thinsp;+\u0026thinsp;VCR was administered on the 4th day; during this process, the platelet counts never fell below 228x10\u0026sup3;/\u0026micro;L, and other hematological values remained stable. Biochemical parameters remained stable throughout treatment, except for an acute increase in urea due to dehydration. Modafinil also prevented TMZ-related fatigue. These findings suggest that modafinil may have a regulatory effect on chemotherapy-induced myelosuppression; however, as this is a single case, further preclinical and clinical studies are needed.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study in a single patient with mPPGL, maximum dose TMZ-induced myelosuppression was quickly and safely treated with Modafinil. This was followed by a combination of TMZ and Modafinil in the next cycle, with no symptoms, no myelosuppression, and stable blood values. These findings provide the first evidence to evaluate the role of Modafinil in myelosuppression in preclinical and clinical trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical Approval and Consent to participate\u003c/h2\u003e\n\u003cp\u003eThe Patient in the article has given signed consent to the conduct and publication of this study.\u003c/p\u003e\n\u003ch2\u003eHuman Ethics\u003c/h2\u003e\n\u003cp\u003eThe patient provided written and signed informed consent for participation and publication.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eThe patient is aware that this study will be published and has given consent.\u003c/p\u003e\n\u003ch2\u003eAvailability of supporting data\u003c/h2\u003e\n\u003cp\u003eAll relevant data are included within the article. Additional information is available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study received no funding.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026apos; contributions\u003c/h2\u003e\n\u003cp\u003eE.H. managed the case and prepared the manuscript. E.Y. and A.A. assisted in managing the case and contributed to the interpretation of the data and the critical revision of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThe authors thank the patient and his family for their cooperation and consent.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHarbi E, Aschner M. Nuclear medicine and perspective thoughts in the diagnosis and treatment of pheochromocytoma and paraganglioma. J Neuroendocrinol. 2025. \u003c/li\u003e\n\u003cli\u003eMete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas. Endocr Pathol. 2022;33:90\u0026ndash;114. \u003c/li\u003e\n\u003cli\u003eHadoux J, Favier J, Scoazec J, Leboulleux S, Al Ghuzlan A, Caramella C, et al. \u003cem\u003eSDHB\u003c/em\u003e mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 2014;135:2711\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eSchwartz J. Modafinil in the treatment of excessive sleepiness. Drug Des Devel Ther. 2008;71. \u003c/li\u003e\n\u003cli\u003eMinzenberg MJ, Carter CS. Modafinil: A Review of Neurochemical Actions and Effects on Cognition. Neuropsychopharmacology. 2008;33:1477\u0026ndash;502. \u003c/li\u003e\n\u003cli\u003eKarl Greenblatt, Ninos Adams. Modafinil. StatPearls [Internet]; 2023. \u003c/li\u003e\n\u003cli\u003eSchmitt KC, Reith MEA. The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors. PLoS One. 2011;6:e25790. \u003c/li\u003e\n\u003cli\u003eHersey M, Tanda G. Modafinil, an atypical CNS stimulant? 2024. p. 287\u0026ndash;326. \u003c/li\u003e\n\u003cli\u003eMereu M, Chun LE, Prisinzano TE, Newman AH, Katz JL, Tanda G. The unique psychostimulant profile of (\u0026plusmn;)‐modafinil: investigation of behavioral and neurochemical effects in mice. European Journal of Neuroscience. 2017;45:167\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eMereu M, Bonci A, Newman AH, Tanda G. The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. Psychopharmacology (Berl). 2013;229:415\u0026ndash;34. \u003c/li\u003e\n\u003cli\u003eKamal M-AM, Essam RM, Abdelkader NF, Zaki HF. Modafinil Ameliorated Fibromyalgia Syndrome in Rats by Modulating Mast Cells and Microglia Activation Through Dopamine/Substance P/MRGPRX/Histamine and PI3K/p-Akt/NF-\u0026kappa;B Signaling Pathways. Journal of Neuroimmune Pharmacology. 2025;20:38. \u003c/li\u003e\n\u003cli\u003eZager A. Modulating the immune response with the wake-promoting drug modafinil: A potential therapeutic approach for inflammatory disorders. Brain Behav Immun. 2020;88:878\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eAmini MJ, Seighali N, Arabazadeh Bahri R, Ala M, Mohammad Jafari R, Dehpour AR. Repurposing of modafinil as an anti-inflammatory drug: a systematic review of experimental studies. Naunyn Schmiedebergs Arch Pharmacol. 2025; \u003c/li\u003e\n\u003cli\u003eZager A, Brand\u0026atilde;o WN, Margatho RO, Cruz DSG, Peron JP, Tufik S, et al. Increased interferon-mediated immunity following in vitro and in vivo Modafinil treatment on peripheral immune cells. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:297\u0026ndash;305. \u003c/li\u003e\n\u003cli\u003eDejban P, Rahimi N, Takzare N, Dehpour AR. Biochemical and histopathological evidence for the beneficial effects of modafinil on the rat model of inflammatory bowel disease: involvement of nitric oxide pathway. Pharmacological Reports. 2020;72:135\u0026ndash;46. \u003c/li\u003e\n\u003cli\u003eGhorbanzadeh H, Mohebkhodaei P, Nematizadeh M, Rahimi N, Rafeiean M, Ghasemi M, et al. Analgesic and anti-inflammatory effects of modafinil in a mouse model of neuropathic pain: A role for nitrergic and serotonergic pathways. Neurol Res. 2022;44:390\u0026ndash;402. \u003c/li\u003e\n\u003cli\u003eMoradi F, Eslami F, Rahimi N, Koohfar A, Shayan M, Maadani M, et al. Modafinil exerts anticonvulsive effects against lithium-pilocarpine-induced status epilepticus in rats: A role for tumor necrosis factor-\u0026alpha; and nitric oxide signaling. Epilepsy \u0026amp; Behavior. 2022;130:108649. \u003c/li\u003e\n\u003cli\u003eKurokawa T, Ohkohchi N. Platelets in liver disease, cancer and regeneration. World J Gastroenterol. 2017;23:3228. \u003c/li\u003e\n\u003cli\u003eCardier JE. Effects of Megakaryocyte Growth and Development Factor (Thrombopoietin) on Liver Endothelial Cells in Vitro. Microvasc Res. 1999;58:108\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eMa X, Huang T, Chen X, Li Q, Liao M, Fu L, et al. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther. 2025;10:63. \u003c/li\u003e\n\u003cli\u003eRao D, Peitzsch M, Prejbisz A, Hanus K, Fassnacht M, Beuschlein F, et al. Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma. Eur J Endocrinol. 2017;177:103\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eAntonio K, Valdez MMN, Mercado-Asis L, Ta\u0026iuml;eb D, Pacak K. Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options. Gland Surg. 2020;9:105\u0026ndash;23. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"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":"Myelosuppression, modafinil, temozolomide, sunitinib, vincristine, pheochromocytoma and paraganglioma","lastPublishedDoi":"10.21203/rs.3.rs-7135896/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7135896/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTemozolomide (TMZ) is an effective treatment option for patients with metastatic Pheochromocytoma and Paraganglioma (mPPGL), but it carries a risk of severe myelosuppression. In this single case study, a 19-year-old male patient receiving TMZ and Sunitinib (SUN) combination therapy developed severe thrombocytopenia and neutropenia after the first dose of the second cycle of TMZ. Following the initiation of Modafinil treatment without traditional supportive treatments, a rapid and significant improvement in platelet and neutrophil levels was observed. The patient remained asymptomatic during this period, and did not require blood product transfusions. In the next cycle, the combination of TMZ and Modafinil was administered, with the addition of Vincristine (VCR). The patient remained asymptomatic throughout the cycle, and platelet counts did not decrease during the combination of Modafinil and TMZ. \u0026nbsp;This suggests that modafinil may increase thrombopoietin (TPO) production by suppressing proinflammatory cytokines such as TNF-α and IL-6. This case is noteworthy as it is the first reported case in the literature of modafinil improving chemotherapy-induced myelosuppression. The findings suggest that modafinil may be a potential agent for reducing hematological toxicities. However, since this observation is based on a single case, more comprehensive preclinical and clinical studies are needed to confirm its effect.\u003c/p\u003e","manuscriptTitle":"Resolving Myelosuppression with Modafinil in the Treatment of Metastatic Pheochromocytoma and Paraganglioma: A Single Case Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-22 11:30:46","doi":"10.21203/rs.3.rs-7135896/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":"98e5264a-2286-40bf-815f-af66472f8e3d","owner":[],"postedDate":"July 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-22T11:30:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-22 11:30:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7135896","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7135896","identity":"rs-7135896","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}