Pharmacokinetic analysis of crushed venetoclax tablets combined with azacitizine for recurrent pediatric acute myeloid leukemia (AML)

Pharmacokinetic analysis of crushed venetoclax tablets combined with azacitizine for recurrent pediatric acute myeloid leukemia (AML) | 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 Pharmacokinetic analysis of crushed venetoclax tablets combined with azacitizine for recurrent pediatric acute myeloid leukemia (AML) Motohiro Matsui, Takeo Yasu, Atsushi Makimoto, Yuki Yuza This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4212887/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Dec, 2024 Read the published version in Cancer Chemotherapy and Pharmacology → Version 1 posted 9 You are reading this latest preprint version Abstract Background: The efficacy of a combination therapy consisting of venetoclax (VEN) and azacytidine (AZA) for newly diagnosed acute myeloid leukemia (AML) has been confirmed in elderly patients. However, the clinical data on VEN for pediatric AML are limited. A combination therapy consisting of crushed VEN tablets and AZA (VEN/AZA) was administered to two children with recurrent AML. The pharmacokinetics of VEN were then analysed. Case Presentation: [Patient 1] A 1-year-old, male patient who experienced an AML relapse following an allogeneic hematopoietic stem cell transplantation received three courses of VEN/AZA. At the initial dosage of VEN (8 mg/kg), the minimum plasma concentration (C min ) was only 0.44 μg/ml, which was far less than the optimal C min of 1.2 μg/ml. Subsequent dose-escalation to 10 mg/kg only achieved C min 0.42 μg/ml. [Patient 2] A 3-year-old, female patient in whom infantile acute lymphoblastic leukemia was originally diagnosed experienced a recurrence in the form of AML after lineage-switching. Three courses of VEN/AZA were administered with the same therapeutic drug monitoring as in Case 1. The C min of VEN was 0.15 μg/ml at 8 mg/kg. Afterwards, voliconazole 16 mg/kg/day was begun for a concomitant fungal infection together with VEN 2 mg/kg. This combination finally achieved C min 1.14 μg/ml probably through CYP3A4 inhibition by voriconazole. In terms of safety, only grade 4 hematological adverse events were observed in both patients. In terms of efficacy, patient 1 and patient 2 achieved stable disease status for two months and six months, respectively. Conclusion: Pediatric patients barely attain an effective plasma concentration of VEN when crushed tablets are used at the same dosage as in adults. Venetoclax pediatric pharmacokinetic analyses AML INTRODUCTION Venetoclax (VEN) is an tablet formulation of a selective B-cell lymphoma-2 (BCL-2) protein inhibitor and is used to treat acute myeloid leukemia (AML) in adult patients, including the elderly. In older patients who are deemed unfit for cytotoxic chemotherapy, a combination therapy consisting of VEN and a hypomethylating agent, such as decitabine or azacitidine, led to a 70% rate of complete remission with (CR) or without (CR-i) count recovery. 1 However, the preclinical and clinical data on VEN for pediatric AML are still limited. A recent, monocentric study reported that when a combination of VEN with azacytidine (VEN/AZA) was administered to eight, pediatric patients with AML, six patients had an objective response, including three with CR with negative minimal residual disease (MRD). 2 A pediatric phase 1 study demonstrated that a combination of VEN with high-dosage cytarabine with or without idarubicin was safe and effective as a treatment for relapsed/refractory AML 3 . However, the optimal VEN dosage in the combination therapy with AZA has not yet been determined, and no pediatric formulation of this regimen has been established. We herein discuss two, pediatric patients with recurrent AML to whom the VEN/AZA combination therapy was administered due to the lack of other, promising salvage therapy. Crushed VEN tablets were administered to each patient, and the plasma concentration of the drug was measured for therapeutic drug monitoring and pharmacokinetic assessment. The clinical safety and efficacy of VEN/AZA were simultaneously evaluated. Material and Methods Ethics approval The present, pharmacokinetic study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of Tokyo Metropolitan Children’s Medical Center (TMCMC) (protocol code: 2023b-48). The off-label use of VEN/AZA was approved by the ethics committee of TMCMC. Informed consent was obtained from the patients’ parents in accordance with local, institutional guidelines. Pharmacokinetic analysis The protocol for the pharmacokinetic analysis of VEN in pediatric patients with relapsed AML was previously established at TMCMC. Because the VEN tablets were too large for infantile patients, they were crushed by the Pharmacy Department to enable oral administration. Blood samples were collected before and six hours after VEN administration, and the minimum (C min ) and maximum plasma concentrations (C max ) were measured. The VEN concentration in the patients’ plasma was measured using high-performance liquid chromatography–ultraviolet 4 . Treatment regimen VEN/AZA was administered in 28-day cycles with AZA 75 mg/m 2 /day given intravenously on days 1–7 of each cycle. VEN was weight-adjusted to an adult-equivalent dose of 800 mg and administered orally once daily from day 1 through 28. The VEN dosage was gradually escalated on days 1–3 of cycle 1 to minimize the risk of tumor lysis syndrome before being increased to the target dosage. The response criteria to VEN/AZA therapy were assessed as follows: morphologic CR was defined as bone marrow blasts < 5% with recovery of the complete blood count; CR with an incomplete blood count (CR-i) was defined as bone marrow blasts < 5% with incomplete recovery of at least one cell lineage; morphologic leukemia-free state (MLFS) was defined as bone marrow blasts < 5% with no hematological recovery. Patient background Patient 1 received the diagnosis of AML M6 with a complex karyotype. He experienced a relapse during consolidation therapy, which was then bridged with FLAG-GO (fludarabine/cytarabine/G-CSF/ gemtuzumab ozogamicin) to cord blood transplantation (CBT). He experienced a relapse on day 62 after the CBT and began VEN/AZA to control the recurrence. Patient 2 presented at 5 months of life with pancytopenia and received the diagnosis of infantile acute lymphoblastic leukemia (KMT2A-rearranged). She experienced a relapse while receiving maintenance lymphoid therapy per protocol Interfant 99 5 . She received the ALL-REZ BFM 2002 protocol 6 followed by an unrelated bone marrow transplantation. She experienced a relapse on day 150 post-BMT and received bridging therapy with vincristine, prednisolone, and L -asparaginase (VPL) to chimeric antigen receptor (CAR)-T cell therapy with tisagenlecleucel. One month after the CAR-T infusion, AML consistent with the lineage switch was diagnosed, and VEN/AZA was begun to control the disease. Results Patients’ treatment course Patient 1 received three cycles of VEN/AZA. He failed to achieve complete remission (CR) after the first cycle and received two, additional cycles as palliative chemotherapy. The patient’s body weight was 10.8 kg. He received VEN 80 mg (8 mg/kg) daily in the first course. Due to the low C min of VEN in the first course (Table 1), the dosage was increased to 15 mg/kg/day in second and third courses. He did not receive any additional drugs during any of the courses that might inhibit cytochrome P450 3A (CYP3A). When he failed to respond to the third course of VEN/AZA, cytarabine 100 mg/m 2 /day was administered for five days. After two cycles of cytarabine, he died of refractory AML. Patient 2 received five cycles of VEN/AZA. She had a body weight of 10 kg and received VEN 80 mg (8 mg/kg) for five days in the first course. The patient did not receive any additional drugs during the first course that might inhibit CYP3A. She failed to achieve CR after the first cycle and therefore received four more cycles of VEN/AZA as palliative chemotherapy. After two cycles of VEN/AZA, aspergillus pneumonia developed. Voriconazole was begun, and VEN was temporarily discontinued. During the third to fourth cycle, voliconazole 16 mg/kg/day was administered concurrently with VEN 2 mg/kg. When the patient failed to respond to a fifth course of VEN/AZA, VEN plus low-dose cytarabine (75 mg/m 2 /dose i.v. push) was begun. After one course of this treatment, she died of refractory AML. Pharmacological results Table 1 sumarizes the results of the pharmacokinetic analysis. Patient 1 received a maintenance dosage of crushed VEN tablets 8 mg/kg and achieved a mean steady-state C min of 0.44 μg/ml (range: 0.32-0.44 μg/ml) in the first course. The low mean C min in the first course prompted an increase in the maintenance dosage to 15 mg/kg. The mean steady-state C min in the second and third course was 0.42 (range 0.42-0.48 μg/ml) and 0.46 μg/ml (range: 0.44-0.48 μg/ml), respectively, and the mean C max in the third course was 2.24 (range: 2.10-2.38 μg/ml) μg/ml. In patient 2, at a maintenance dosage of crushed VEN tablets 8 mg/kg in the first course, the mean steady-state C min and C max was 0.15 (range: 0.15-0.35 μg/ml) and 0.86 μg/ml (range: 0.82-1.98 μg/ml), respectively. After initiating treatment for the fungal infection with voriconazole and reducing the maintenance dosage to 2 mg/kg, the mean C min and C max in the third course was 1.14 (range: 0.86-1.16 μg/ml) and 1.98 μg/ml (range: 1.19-2.26 μg/ml), respectively. Safety and efficacy evaluation After one VEN/AZA cycle, Patient 1’s marrow revealed refractory disease. He maintained stable disease for two months. After one VEN/AZA cycle, Patient 2’s marrow revealed MLFS with bone marrow blasts < 5% by morphology in the absence of complete blood count recovery. A second marrow biopsy two weeks later demonstrated refractory disease. She maintained stable disease status for six months with three cycles of VEN/AZA. The two patients in this study received in total eight cycles of VEN/AZA. There were no grade 5 adverse events. Cytopenia and infectious complications were the most common, adverse events. Febrile neutropenia occurred in six cycles in five patients. Bacteremia occurred in two cycles in the two patients. The cause of infection was Enterococcus faecium in each patient. One patient experienced a central venous catheter-related infection and aspergillus pneumonia. Discussion To the best of our knowledge, the present case report is the first to demonstrate the pharmacokinetics and safety of crushed VEN tablets combined with AZA in pediatric patients with relapsed AML. Neither of our patients achieved an optimal plasma VEN concentration with the standard VEN dosage for adults, and the optimal plasma level of VEN was able to be achieved only when the drug was combined with voriconazole. This finding suggested that increasing the plasma VEN concentration may be difficult in pediatric patients at least using the current formulation, which requires modifying the tablet formulation by crushing. Although a previous study reported that crushed VEN tablets increased the blood level of venetoclax in adult patients 8 , the plasma VEN concentration in our patients remained low despite sufficient dosing with crushed tablets (8–15 mg/kg/day). A pediatric phase I study found that a maximum dosage of VEN (tablet) 360 mg/m 2 combined with cytarabine 1000 mg/m 2 /dose with or without idarubicin 12mg/m 2 was able to achieve an optimal concentration (about 2.0 µg/mL) 3 . Aanzai et al. reported that the C min of whole VEN tablets was approximately twice that of crushed tablets in older patients 8 . These findings suggested that the bioavailability of VEN in young children may be low especially when crushed tablets are used. An appropriate pharmaceutical formulation of VEN must therefore be developed to evaluate the bioavailability and pharmacokinetics of VEN in young children. In the present case report, an elevated serum VEN concentration was able to be achieved in Patient 2 when voriconazole was co-administered. Voriconazole inhibits cytochrome P450 3A4 (CYP3A4) to varying degrees. Because CYP3A4 is the enzyme primarily responsible for the metabolism of VEN, the addition of voriconazole resulted in elevating the plasma VEN concentration. However, increased exposure to VEN can increase the risk of toxicity. In Patient 2, after initiating treatment for the fungal infection with voriconazole and reducing the maintenance VEN dosage to 2 mg/kg, the mean C min rose ten-fold. Patient 1 was unable to achieve the optimal plasma level of VEN despite dose-escalation. A previous study found that the coadministration of moderate and strong CYP3A inhibitors, severe hepatic impairment, and food were the main factors impacting VEN PK 9 . None of these factors differed between the first and third course. During the first course in Patient 1, the VEN concentration was elevated for unknown reasons. In the present study, VEN/AZA was generally clinically ineffective and able to maintain stable disease status only for two to six months. Amanda et al. reported that six of eight pediatric patients who received VEN/AZA, two for high-grade MDS and four for AML, had a morphologic response. Few studies have addressed the issue of maintaining VEN/AZA efficacy in cases of relapsed AML. Low plasma VEN may explain the treatment’s lack of efficacy in the present study. Thus, a well-designed, dose-finding study is warranted to determine the optimal VEN dosage in a combination therapy with AZA for pediatric patients, especially if crushed tablets are to be used. In terms of the safety, both patients had grade 4 hematological adverse events before the start of VEN therapy which were attributable to an underlying disease. In previous reports, hematological AEs were the most common toxicities observed. 10 , 11 . Since patients with cytopenia were included in these analyses, many of the hematological symptoms had their onset before the initiation of VEN and were attributable to an underlying disease. In the present study VEN/AZA was adminsitered as a palliative chemotherapy; thus, determining whether the cause of the cytopenia was VEN or an underlying bone marrow dysfunction was not possible. Conclusion The present study was unable to determine the optimal AZA dosage or the safety and efficacy profiles of the regimen in pediatric patients. Moreover, the standard adult VEN dosage was insufficent to attain a therapeutic serum concentration of the drug. Thus, a dose-finding study is warranted to address these issues. An appropriate pharmaceutical formulation of VEN should also be developed for use in the pediatric patient population. Abbreviations AML Acute myeloid leukemia C min Minimum concentration VEN/AZA Venetoclax and azacytidine BCL-2 B-cell lymphoma-2 CR Complete remission CR-i Complete remission without count recovery MRD Minimal residual disease C max Maximum plasma concentration CBT Cord blood transplantation FLAG-GO Fludarabine/cytarabine/G-CSF/ gemtuzumab ozogamicin VPL Vincristine, prednisolone, and L-asparaginase CAR-T Chimeric antigen receptor -T cell CYP3A Cytochrome P450 3A CR-i CR with incomplete count recovery MLFS Morphologic leukemia-free state Statements and declarations Author Contribution Matsui M: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Visualization; Writing-original draft. Yasu T: Pharmacokinetic analysis, review, and editing.Makimoto A: Writing, review, and editing. Yuza Y: Writing, review, and editing.All the authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. The authors state explicitly that there are no conflicts of interest in connection with this article. Acknowledgement We thank Mr. James Robert Valera for his assistance with editing this manuscript. References DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19(2):216–228 Winters AC, Maloney KW, Treece AL, Gore L, Franklin AK (2020) Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. Pediatr Blood Cancer 67(10):e28398 Karol SE, Alexander TB, Budhraja A, Pounds SB, Canavera K, Wang L, Wolf J, Klco JM, Mead PE, Das Gupta S, Kim SY, Salem AH, Palenski T, Lacayo NJ, Pui CH, Opferman JT, Rubnitz JE (2020) Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol 21:551–560 Yasu T, Gando Y, Nomura Y, Kosugi N, Kobayashi M (2022 Apr) Determination of Venetoclax Concentration in Plasma Using High-Performance Liquid Chromatography. J Chromatogr Sci 5:bmac027 Mann G, Attarbaschi A, Schrappe M, De Lorenzo P, Peters C, Hann I, De Rossi G, Felice M, Lausen B, Leblanc T, Szczepanski T, Ferster A, Janka-Schaub G, Rubnitz J, Silverman LB, Stary J, Campbell M, Li CK, Suppiah R, Biondi A, Vora A, Valsecchi MG, Pieters R (2010) Interfant-99 Study Group. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood 116(15):2644–2650 Bader P, Kreyenberg H, Henze GH, Eckert C, Reising M, Willasch A, Barth A, Borkhardt A, Peters C, Handgretinger R, Sykora KW, Holter W, Kabisch H, Klingebiel T, von Stackelberg A, ALL-REZ BFM Study Group (2009) Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol 27(3):377–384 AbbVie Inc (2021) VENCLEXTA® prescribing information. https://www.rxabbvie.com/pdf/venclexta.pdf . Accessed 2022 Apr 5 Anzai M, Yasu T, Gando Y, Shirota M, Kobayashi M (2022) Increased blood levels of venetoclax due to intake of crushed venetoclax tablets. Ann Hematol 101(9):2097–2098 Gong JQX, Suleiman AA, Menon R, Deng R, Mensing S, Salem AH (2023 Apr) Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials. J Clin Pharmacol 13. 10.1002/jcph.2248 DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS et al (2019) Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133(1):7–17 Maiti A, DiNardo CD, Rausch CR, Pemmaraju N, Garcia-Manero G, Ohanian M et al (2019) Ten-day decitabine with venetoclax (DEC10-VEN) in acute myeloid leukemia: updated results of a phase II trial. Blood 134(Suppl 1):2637–2637 Table Table 1. Results of pharmacokinetic analysis Cycle VEN dosage (mg/kg) Concurrent medication CYP3A4 inhibitor Cmin (μg/ml) Cmax (μg/ml) Duration of disease control Patient 1 1 8 Aza None 0.44 NE 2 months 2 15 Aza None 0.42 NE 3 15 Aza None 0.46 2.24 Patient 2 1 8 Aza None 0.15 0.86 6 months 3 2 Aza VCZ 1.14 1.98 AZA, azacytidine; VCZ, voliconazole; VEN, venetcrax, NE, not examined Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 07 Dec, 2024 Read the published version in Cancer Chemotherapy and Pharmacology → Version 1 posted Editorial decision: Revision requested 12 Jun, 2024 Reviews received at journal 21 May, 2024 Reviews received at journal 20 May, 2024 Reviewers agreed at journal 30 Apr, 2024 Reviewers agreed at journal 29 Apr, 2024 Reviewers invited by journal 29 Apr, 2024 Submission checks completed at journal 03 Apr, 2024 Editor assigned by journal 03 Apr, 2024 First submitted to journal 03 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-4212887","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":287322717,"identity":"21455ea7-633e-41a5-aa90-1b8eaeb8a5a8","order_by":0,"name":"Motohiro Matsui","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYJACZgYDOFtCjoGBhwGC8WiAaWFsAGox5iFOCwNcC0NiD37lDAy67f0HHxcU3JNjEDv8/OHPNov0/WJnjz1gkLmDU4vZmcPMxjMMio0ZpNMMm3nbJHJ7pPPSDRh4nuHWciOZTZrHICGxQTrBsJkRrCXHTIKB5zAxWtI/Nv5sk0jnIUFLjmED0GEJhLWcOWxsDNQC9EtO4WyecxKGPbdzzA0S8PnleOPDxzx/EuQYpNM3fPxRVifPPjvH7MHHHtwhBgf2BxBsNmDsHMClEDtgY2D4QaKWUTAKRsEoGM4AACmzS4q2OUpFAAAAAElFTkSuQmCC","orcid":"","institution":"Tokyo Metropolitan Children’s Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Motohiro","middleName":"","lastName":"Matsui","suffix":""},{"id":287322718,"identity":"d1b16888-59c1-4bc6-b6cf-5c6ff2a5242c","order_by":1,"name":"Takeo Yasu","email":"","orcid":"","institution":"Meiji Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Takeo","middleName":"","lastName":"Yasu","suffix":""},{"id":287322719,"identity":"35dccf89-2405-4ec6-8aed-267322104cf9","order_by":2,"name":"Atsushi Makimoto","email":"","orcid":"","institution":"Tokyo Metropolitan Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Makimoto","suffix":""},{"id":287322720,"identity":"43ae44da-d44c-4644-b869-1ee02cabc5c6","order_by":3,"name":"Yuki Yuza","email":"","orcid":"","institution":"Tokyo Metropolitan Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Yuza","suffix":""}],"badges":[],"createdAt":"2024-04-03 12:52:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4212887/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4212887/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00280-024-04730-z","type":"published","date":"2024-12-07T15:58:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70964946,"identity":"3c0b6589-23af-4a4d-93d7-8b4ac4ee9478","added_by":"auto","created_at":"2024-12-09 16:17:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":320557,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4212887/v1/1504a563-47a5-48a7-93ef-cda8fbf8eeec.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacokinetic analysis of crushed venetoclax tablets combined with azacitizine for recurrent pediatric acute myeloid leukemia (AML)","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eVenetoclax (VEN) is an tablet formulation of a selective B-cell lymphoma-2 (BCL-2) protein inhibitor and is used to treat acute myeloid leukemia (AML) in adult patients, including the elderly. In older patients who are deemed unfit for cytotoxic chemotherapy, a combination therapy consisting of VEN and a hypomethylating agent, such as decitabine or azacitidine, led to a 70% rate of complete remission with (CR) or without (CR-i) count recovery.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e However, the preclinical and clinical data on VEN for pediatric AML are still limited.\u003c/p\u003e \u003cp\u003eA recent, monocentric study reported that when a combination of VEN with azacytidine (VEN/AZA) was administered to eight, pediatric patients with AML, six patients had an objective response, including three with CR with negative minimal residual disease (MRD).\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e A pediatric phase 1 study demonstrated that a combination of VEN with high-dosage cytarabine with or without idarubicin was safe and effective as a treatment for relapsed/refractory AML\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. However, the optimal VEN dosage in the combination therapy with AZA has not yet been determined, and no pediatric formulation of this regimen has been established.\u003c/p\u003e \u003cp\u003eWe herein discuss two, pediatric patients with recurrent AML to whom the VEN/AZA combination therapy was administered due to the lack of other, promising salvage therapy. Crushed VEN tablets were administered to each patient, and the plasma concentration of the drug was measured for therapeutic drug monitoring and pharmacokinetic assessment. The clinical safety and efficacy of VEN/AZA were simultaneously evaluated.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eThe present, pharmacokinetic study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of Tokyo Metropolitan Children\u0026rsquo;s Medical Center (TMCMC) (protocol code: 2023b-48). The off-label use of VEN/AZA was approved by the ethics committee of TMCMC. Informed consent was obtained from the patients\u0026rsquo; parents in accordance with local, institutional guidelines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetic analysis\u003c/h2\u003e \u003cp\u003eThe protocol for the pharmacokinetic analysis of VEN in pediatric patients with relapsed AML was previously established at TMCMC. Because the VEN tablets were too large for infantile patients, they were crushed by the Pharmacy Department to enable oral administration. Blood samples were collected before and six hours after VEN administration, and the minimum (C\u003csub\u003emin\u003c/sub\u003e) and maximum plasma concentrations (C\u003csub\u003emax\u003c/sub\u003e) were measured. The VEN concentration in the patients\u0026rsquo; plasma was measured using high-performance liquid chromatography\u0026ndash;ultraviolet\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatment regimen\u003c/h2\u003e \u003cp\u003eVEN/AZA was administered in 28-day cycles with AZA 75 mg/m\u003csup\u003e2\u003c/sup\u003e/day given intravenously on days 1\u0026ndash;7 of each cycle. VEN was weight-adjusted to an adult-equivalent dose of 800 mg and administered orally once daily from day 1 through 28. The VEN dosage was gradually escalated on days 1\u0026ndash;3 of cycle 1 to minimize the risk of tumor lysis syndrome before being increased to the target dosage.\u003c/p\u003e \u003cp\u003eThe response criteria to VEN/AZA therapy were assessed as follows: morphologic CR was defined as bone marrow blasts\u0026thinsp;\u0026lt;\u0026thinsp;5% with recovery of the complete blood count; CR with an incomplete blood count (CR-i) was defined as bone marrow blasts\u0026thinsp;\u0026lt;\u0026thinsp;5% with incomplete recovery of at least one cell lineage; morphologic leukemia-free state (MLFS) was defined as bone marrow blasts\u0026thinsp;\u0026lt;\u0026thinsp;5% with no hematological recovery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatient background\u003c/h2\u003e \u003cp\u003ePatient 1 received the diagnosis of AML M6 with a complex karyotype. He experienced a relapse during consolidation therapy, which was then bridged with FLAG-GO (fludarabine/cytarabine/G-CSF/ gemtuzumab ozogamicin) to cord blood transplantation (CBT). He experienced a relapse on day 62 after the CBT and began VEN/AZA to control the recurrence.\u003c/p\u003e \u003cp\u003ePatient 2 presented at 5 months of life with pancytopenia and received the diagnosis of infantile acute lymphoblastic leukemia (KMT2A-rearranged). She experienced a relapse while receiving maintenance lymphoid therapy per protocol Interfant 99\u003csup\u003e5\u003c/sup\u003e. She received the ALL-REZ BFM 2002 protocol\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e followed by an unrelated bone marrow transplantation. She experienced a relapse on day 150 post-BMT and received bridging therapy with vincristine, prednisolone, and L -asparaginase (VPL) to chimeric antigen receptor (CAR)-T cell therapy with tisagenlecleucel. One month after the CAR-T infusion, AML consistent with the lineage switch was diagnosed, and VEN/AZA was begun to control the disease.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatients’ treatment course\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Patient 1 received three cycles of VEN/AZA. He failed to achieve complete remission (CR) after the first cycle and received two, additional cycles as palliative chemotherapy. The patient’s body weight was 10.8 kg. He received VEN 80 mg (8 mg/kg) daily in the first course. Due to the low C\u003csub\u003emin\u003c/sub\u003e of VEN in the first course (Table 1), the dosage was increased to 15 mg/kg/day in second and third courses. He did not receive any additional drugs during any of the courses that might inhibit cytochrome P450 3A (CYP3A). When he failed to respond to the third course of VEN/AZA, cytarabine 100 mg/m\u003csup\u003e2\u003c/sup\u003e/day was administered for five days. After two cycles of cytarabine, he died of refractory AML.\u003c/p\u003e\n\u003cp\u003ePatient 2 received five cycles of VEN/AZA. She had a body weight of 10 kg and received VEN 80 mg (8 mg/kg) for five days in the first course. The patient did not receive any additional drugs during the first course that might inhibit CYP3A. She failed to achieve CR after the first cycle and therefore received four more cycles of VEN/AZA as palliative chemotherapy. After two cycles of VEN/AZA, aspergillus pneumonia developed. Voriconazole was begun, and VEN was temporarily discontinued. During the third to fourth cycle, voliconazole\u0026nbsp;16 mg/kg/day was administered concurrently with VEN 2 mg/kg. When the patient failed to respond to a fifth course of VEN/AZA, VEN plus low-dose cytarabine (75 mg/m\u003csup\u003e2\u003c/sup\u003e/dose i.v. push) was begun. After one course of this treatment, she died of refractory AML.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePharmacological results\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 sumarizes the results of the pharmacokinetic analysis. Patient 1 received a maintenance dosage of crushed VEN tablets 8 mg/kg and achieved a mean steady-state C\u003csub\u003emin\u003c/sub\u003e of 0.44 μg/ml (range: 0.32-0.44 μg/ml) in the first course. The low mean C\u003csub\u003emin\u003c/sub\u003e in the first course prompted an increase in the maintenance dosage to 15 mg/kg. The mean steady-state C\u003csub\u003emin\u003c/sub\u003ein the second and third course was 0.42 (range 0.42-0.48 μg/ml) and 0.46 μg/ml (range: 0.44-0.48 μg/ml), respectively, and the mean C\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ein the third course was 2.24 (range: 2.10-2.38 μg/ml) μg/ml.\u003c/p\u003e\n\u003cp\u003eIn patient 2, at a maintenance dosage of crushed VEN tablets 8 mg/kg in the first course, the mean steady-state C\u003csub\u003emin\u003c/sub\u003e and C\u003csub\u003emax\u0026nbsp;\u003c/sub\u003ewas 0.15 (range: 0.15-0.35 μg/ml) and 0.86 μg/ml (range: 0.82-1.98 μg/ml), respectively. After initiating treatment for the fungal infection with voriconazole and reducing the maintenance dosage to 2 mg/kg, the mean C\u003csub\u003emin\u003c/sub\u003e and C\u003csub\u003emax\u003c/sub\u003e in the third course was 1.14 (range: 0.86-1.16 μg/ml) and 1.98 μg/ml (range: 1.19-2.26 μg/ml), respectively.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSafety and efficacy evaluation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;After one VEN/AZA cycle, Patient 1’s marrow revealed refractory disease. He maintained stable disease for two months. After one VEN/AZA cycle, Patient 2’s marrow revealed MLFS with bone marrow blasts \u0026lt; 5% by morphology in the absence of complete blood count recovery. A second marrow biopsy two weeks later demonstrated refractory disease. She maintained stable disease status for six months with three cycles of VEN/AZA.\u003c/p\u003e\n\u003cp\u003eThe two patients in this study received in total eight cycles of VEN/AZA. There were no grade 5 adverse events. Cytopenia and infectious complications were the most common, adverse events. Febrile neutropenia occurred in six cycles in five patients. Bacteremia occurred in two cycles in the two patients. The cause of infection was \u003cem\u003eEnterococcus faecium\u003c/em\u003e in each patient. One patient experienced a central venous catheter-related infection and aspergillus pneumonia.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, the present case report is the first to demonstrate the pharmacokinetics and safety of crushed VEN tablets combined with AZA in pediatric patients with relapsed AML. Neither of our patients achieved an optimal plasma VEN concentration with the standard VEN dosage for adults, and the optimal plasma level of VEN was able to be achieved only when the drug was combined with voriconazole. This finding suggested that increasing the plasma VEN concentration may be difficult in pediatric patients at least using the current formulation, which requires modifying the tablet formulation by crushing.\u003c/p\u003e \u003cp\u003eAlthough a previous study reported that crushed VEN tablets increased the blood level of venetoclax in adult patients\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, the plasma VEN concentration in our patients remained low despite sufficient dosing with crushed tablets (8\u0026ndash;15 mg/kg/day). A pediatric phase I study found that a maximum dosage of VEN (tablet) 360 mg/m\u003csup\u003e2\u003c/sup\u003e combined with cytarabine 1000 mg/m\u003csup\u003e2\u003c/sup\u003e/dose with or without idarubicin 12mg/m\u003csup\u003e2\u003c/sup\u003e was able to achieve an optimal concentration (about 2.0 \u0026micro;g/mL)\u003csup\u003e3\u003c/sup\u003e. Aanzai et al. reported that the C\u003csub\u003emin\u003c/sub\u003e of whole VEN tablets was approximately twice that of crushed tablets in older patients\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. These findings suggested that the bioavailability of VEN in young children may be low especially when crushed tablets are used. An appropriate pharmaceutical formulation of VEN must therefore be developed to evaluate the bioavailability and pharmacokinetics of VEN in young children.\u003c/p\u003e \u003cp\u003eIn the present case report, an elevated serum VEN concentration was able to be achieved in Patient 2 when voriconazole was co-administered. Voriconazole inhibits cytochrome P450 3A4 (CYP3A4) to varying degrees. Because CYP3A4 is the enzyme primarily responsible for the metabolism of VEN, the addition of voriconazole resulted in elevating the plasma VEN concentration. However, increased exposure to VEN can increase the risk of toxicity. In Patient 2, after initiating treatment for the fungal infection with voriconazole and reducing the maintenance VEN dosage to 2 mg/kg, the mean C\u003csub\u003emin\u003c/sub\u003e rose ten-fold.\u003c/p\u003e \u003cp\u003ePatient 1 was unable to achieve the optimal plasma level of VEN despite dose-escalation. A previous study found that the coadministration of moderate and strong CYP3A inhibitors, severe hepatic impairment, and food were the main factors impacting VEN PK\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. None of these factors differed between the first and third course. During the first course in Patient 1, the VEN concentration was elevated for unknown reasons.\u003c/p\u003e \u003cp\u003eIn the present study, VEN/AZA was generally clinically ineffective and able to maintain stable disease status only for two to six months. Amanda et al. reported that six of eight pediatric patients who received VEN/AZA, two for high-grade MDS and four for AML, had a morphologic response. Few studies have addressed the issue of maintaining VEN/AZA efficacy in cases of relapsed AML. Low plasma VEN may explain the treatment\u0026rsquo;s lack of efficacy in the present study. Thus, a well-designed, dose-finding study is warranted to determine the optimal VEN dosage in a combination therapy with AZA for pediatric patients, especially if crushed tablets are to be used.\u003c/p\u003e \u003cp\u003eIn terms of the safety, both patients had grade 4 hematological adverse events before the start of VEN therapy which were attributable to an underlying disease. In previous reports, hematological AEs were the most common toxicities observed.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e ,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Since patients with cytopenia were included in these analyses, many of the hematological symptoms had their onset before the initiation of VEN and were attributable to an underlying disease. In the present study VEN/AZA was adminsitered as a palliative chemotherapy; thus, determining whether the cause of the cytopenia was VEN or an underlying bone marrow dysfunction was not possible.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study was unable to determine the optimal AZA dosage or the safety and efficacy profiles of the regimen in pediatric patients. Moreover, the standard adult VEN dosage was insufficent to attain a therapeutic serum concentration of the drug. Thus, a dose-finding study is warranted to address these issues. An appropriate pharmaceutical formulation of VEN should also be developed for use in the pediatric patient population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eAML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eAcute myeloid leukemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eMinimum concentration\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eVEN/AZA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eVenetoclax and azacytidine\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eBCL-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eB-cell lymphoma-2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eComplete remission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eCR-i\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eComplete remission\u0026nbsp;without count recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eMRD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eMinimal residual disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eMaximum plasma concentration\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eCBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eCord blood transplantation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eFLAG-GO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eFludarabine/cytarabine/G-CSF/\u0026nbsp;gemtuzumab ozogamicin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eVPL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eVincristine, prednisolone, and L-asparaginase\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eCAR-T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eChimeric antigen receptor -T cell\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eCYP3A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eCytochrome P450 3A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eCR-i\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eCR with incomplete count recovery\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.991181657848324%\" valign=\"top\"\u003e\n \u003cp\u003eMLFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"85.00881834215167%\" valign=\"top\"\u003e\n \u003cp\u003eMorphologic leukemia-free state\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Statements and declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMatsui M: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Visualization; Writing-original draft. Yasu T: Pharmacokinetic analysis, review, and editing.Makimoto A: Writing, review, and editing. Yuza Y: Writing, review, and editing.All the authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003cp\u003eThe authors state explicitly that there are no conflicts of interest in connection with this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Mr. James Robert Valera for his assistance with editing this manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19(2):216\u0026ndash;228\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWinters AC, Maloney KW, Treece AL, Gore L, Franklin AK (2020) Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. Pediatr Blood Cancer 67(10):e28398\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarol SE, Alexander TB, Budhraja A, Pounds SB, Canavera K, Wang L, Wolf J, Klco JM, Mead PE, Das Gupta S, Kim SY, Salem AH, Palenski T, Lacayo NJ, Pui CH, Opferman JT, Rubnitz JE (2020) Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. 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Blood 116(15):2644\u0026ndash;2650\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBader P, Kreyenberg H, Henze GH, Eckert C, Reising M, Willasch A, Barth A, Borkhardt A, Peters C, Handgretinger R, Sykora KW, Holter W, Kabisch H, Klingebiel T, von Stackelberg A, ALL-REZ BFM Study Group (2009) Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol 27(3):377\u0026ndash;384\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbbVie Inc (2021) VENCLEXTA\u0026reg; prescribing information. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.rxabbvie.com/pdf/venclexta.pdf\u003c/span\u003e\u003cspan address=\"https://www.rxabbvie.com/pdf/venclexta.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 2022 Apr 5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnzai M, Yasu T, Gando Y, Shirota M, Kobayashi M (2022) Increased blood levels of venetoclax due to intake of crushed venetoclax tablets. Ann Hematol 101(9):2097\u0026ndash;2098\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGong JQX, Suleiman AA, Menon R, Deng R, Mensing S, Salem AH (2023 Apr) Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials. J Clin Pharmacol 13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jcph.2248\u003c/span\u003e\u003cspan address=\"10.1002/jcph.2248\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS et al (2019) Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133(1):7\u0026ndash;17\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaiti A, DiNardo CD, Rausch CR, Pemmaraju N, Garcia-Manero G, Ohanian M et al (2019) Ten-day decitabine with venetoclax (DEC10-VEN) in acute myeloid leukemia: updated results of a phase II trial. Blood 134(Suppl 1):2637\u0026ndash;2637\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1. Results of pharmacokinetic analysis\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"623\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.003215434083602%\" valign=\"top\"\u003e\n \u003cp\u003eCycle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.057877813504824%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;VEN dosage\u003c/p\u003e\n \u003cp\u003e(mg/kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.112540192926046%\" valign=\"top\"\u003e\n \u003cp\u003eConcurrent\u003c/p\u003e\n \u003cp\u003emedication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.95176848874598%\" valign=\"top\"\u003e\n \u003cp\u003eCYP3A4 inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.128617363344052%\" valign=\"top\"\u003e\n \u003cp\u003eCmin\u003c/p\u003e\n \u003cp\u003e(\u0026mu;g/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.57556270096463%\" valign=\"top\"\u003e\n \u003cp\u003eCmax\u003c/p\u003e\n \u003cp\u003e(\u0026mu;g/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.82636655948553%\" valign=\"top\"\u003e\n \u003cp\u003eDuration of disease control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.82636655948553%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.344051446945338%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003ePatient 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.003215434083602%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.057877813504824%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.112540192926046%\" valign=\"top\"\u003e\n \u003cp\u003eAza\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.95176848874598%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.128617363344052%\" valign=\"top\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.57556270096463%\" valign=\"top\"\u003e\n \u003cp\u003eNE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.82636655948553%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e2 months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.362030905077262%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.556291390728475%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.750551876379692%\" valign=\"top\"\u003e\n \u003cp\u003eAza\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.52980132450331%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.907284768211921%\" valign=\"top\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003eNE\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.362030905077262%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.556291390728475%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.750551876379692%\" valign=\"top\"\u003e\n \u003cp\u003eAza\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.52980132450331%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.907284768211921%\" valign=\"top\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e2.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.344051446945338%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePatient 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.003215434083602%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.057877813504824%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.112540192926046%\" valign=\"top\"\u003e\n \u003cp\u003eAza\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.95176848874598%\" valign=\"top\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.128617363344052%\" valign=\"top\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.57556270096463%\" valign=\"top\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.82636655948553%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.362030905077262%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.556291390728475%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.750551876379692%\" valign=\"top\"\u003e\n \u003cp\u003eAza\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.52980132450331%\" valign=\"top\"\u003e\n \u003cp\u003eVCZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.907284768211921%\" valign=\"top\"\u003e\n \u003cp\u003e1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.894039735099337%\" valign=\"top\"\u003e\n \u003cp\u003e1.98\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\u003eAZA, azacytidine; VCZ, voliconazole; VEN, venetcrax, NE, not examined\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-chemotherapy-and-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccap","sideBox":"Learn more about [Cancer Chemotherapy and Pharmacology](http://link.springer.com/journal/280)","snPcode":"280","submissionUrl":"https://submission.nature.com/new-submission/280/3","title":"Cancer Chemotherapy and Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Venetoclax, pediatric, pharmacokinetic analyses, AML","lastPublishedDoi":"10.21203/rs.3.rs-4212887/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4212887/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe efficacy of a combination therapy consisting of venetoclax (VEN) and azacytidine (AZA) for newly diagnosed acute myeloid leukemia (AML) has been confirmed in elderly patients. However, the clinical data on VEN for pediatric AML are limited. A combination therapy consisting of crushed VEN tablets and AZA (VEN/AZA) was administered to two children with recurrent AML. The pharmacokinetics of VEN were then analysed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003e [Patient 1] A 1-year-old, male patient who experienced an AML relapse following an allogeneic hematopoietic stem cell transplantation received three courses of VEN/AZA. At the initial dosage of VEN (8 mg/kg), the minimum plasma concentration (C\u003csub\u003emin\u003c/sub\u003e) was only 0.44 μg/ml, which was far less than the optimal C\u003csub\u003emin\u003c/sub\u003e of 1.2 μg/ml. Subsequent dose-escalation to 10 mg/kg only achieved C\u003csub\u003emin \u003c/sub\u003e0.42 μg/ml.\u0026nbsp; [Patient 2] A 3-year-old, female patient in whom infantile acute lymphoblastic leukemia was originally diagnosed experienced a recurrence in the form of AML after lineage-switching. Three courses of VEN/AZA were administered with the same therapeutic drug monitoring as in Case 1. The C\u003csub\u003emin \u003c/sub\u003eof VEN was 0.15 μg/ml at 8 mg/kg. Afterwards, voliconazole 16 mg/kg/day was begun for a concomitant fungal infection together with VEN 2 mg/kg. This combination finally achieved C\u003csub\u003emin\u003c/sub\u003e 1.14 μg/ml probably through CYP3A4 inhibition by voriconazole. In terms of safety, only grade 4 hematological adverse events were observed in both patients. In terms of efficacy, patient 1 and patient 2 achieved stable disease status for two months and six months, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003ePediatric patients barely attain an effective plasma concentration of VEN when crushed tablets are used at the same dosage as in adults.\u003c/p\u003e","manuscriptTitle":"Pharmacokinetic analysis of crushed venetoclax tablets combined with azacitizine for recurrent pediatric acute myeloid leukemia (AML)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-09 08:42:03","doi":"10.21203/rs.3.rs-4212887/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-13T01:33:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-21T18:43:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-21T02:50:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"53834794298780516014518676565513076294","date":"2024-04-30T14:32:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"32707194914034479702754204688582422625","date":"2024-04-30T03:19:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-30T02:44:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-04T03:30:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-04T03:30:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Chemotherapy and Pharmacology","date":"2024-04-03T12:51:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-chemotherapy-and-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccap","sideBox":"Learn more about [Cancer Chemotherapy and Pharmacology](http://link.springer.com/journal/280)","snPcode":"280","submissionUrl":"https://submission.nature.com/new-submission/280/3","title":"Cancer Chemotherapy and Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4b53a39d-dcd6-436f-9ba0-54d345d0c1fb","owner":[],"postedDate":"April 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T16:08:05+00:00","versionOfRecord":{"articleIdentity":"rs-4212887","link":"https://doi.org/10.1007/s00280-024-04730-z","journal":{"identity":"cancer-chemotherapy-and-pharmacology","isVorOnly":false,"title":"Cancer Chemotherapy and Pharmacology"},"publishedOn":"2024-12-07 15:58:12","publishedOnDateReadable":"December 7th, 2024"},"versionCreatedAt":"2024-04-09 08:42:03","video":"","vorDoi":"10.1007/s00280-024-04730-z","vorDoiUrl":"https://doi.org/10.1007/s00280-024-04730-z","workflowStages":[]},"version":"v1","identity":"rs-4212887","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4212887","identity":"rs-4212887","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}