Role of Allogeneic Hematopoietic Stem-Cell Transplant Following TKI-Blinatumomab Induction for Ph-Positive Acute Lymphoblastic Leukemia in Adults

Role of Allogeneic Hematopoietic Stem-Cell Transplant Following TKI-Blinatumomab Induction for Ph-Positive Acute Lymphoblastic Leukemia in Adults | 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 Research Article Role of Allogeneic Hematopoietic Stem-Cell Transplant Following TKI-Blinatumomab Induction for Ph-Positive Acute Lymphoblastic Leukemia in Adults Nolan Holley, Laxmi Upadhyay, Shanawar Waris, Adnan Saifuddin, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8799277/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 14 You are reading this latest preprint version Abstract Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has traditionally been treated with tyrosine kinase inhibitors (TKIs) and systemic chemotherapy, often followed by allogeneic hematopoietic stem cell transplant (HCT). More recently, chemotherapy-free induction regimens combining TKIs and blinatumomab have demonstrated efficacy with reduced risk for chemotherapy-related toxicity. However, the benefit of allogeneic HCT in this setting remains unclear. Objective: Compare relapse-free survival (RFS), overall survival (OS), and infection rates in adult patients with Ph-positive ALL treated with TKI and blinatumomab induction, stratified by allogeneic HCT status, using retrospective data. Study Design: We conducted a retrospective cohort study using the TriNetX global federated electronic health record database. Adult patients with Ph-positive ALL treated with TKI (dasatinib or ponatinib) and blinatumomab were stratified by receipt of allogeneic HCT (HCT+ vs HCT-). Propensity score matching (PSM) was applied to control for baseline demographics, comorbidities, medications, and laboratory values. Outcomes included RFS, OS, and infection rates. Results: A total of 242 patients were included, with 162 in the HCT- cohort and 80 in the HCT+ cohort. Following PSM, 56 patients remain in each cohort. There were no significant differences in RFS (HR 0.795; 95% CI: 0.283-2.239; p = 0.664) or OS (HR 0.734; 95% CI: 0.240-2.248; p = 0.587) between groups following PSM. However, HCT was associated with a significantly higher risk of infections, including bacterial, viral, and COVID-19 infections (all p < 0.01). These findings remained consistent after PSM. Conclusions: Among adults with Ph-positive ALL treated with TKI and blinatumomab, allogeneic HCT was not associated with improved RFS or OS but was linked to increased infection risk. These findings support a more selective approach to transplant following chemotherapy-free induction, particularly in patients with high baseline infection risk. Prospective studies incorporating measurable residual disease (MRD) status are warranted to further guide transplant decisions in this evolving therapeutic landscape. Ph-positive acute lymphoblastic leukemia allogeneic stem cell transplant tyrosine kinase inhibitors blinatumomab Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) is characterized by the reciprocal translocation of chromosomes 9 and 22 to form the BCR-ABL1 fusion gene, which drives leukemogenesis of lymphocytes. 1 Collectively, this constitutively activated tyrosine kinase leads to the reduction of apoptosis and uncontrolled cell proliferation. 2 While this translocation is associated with poorer prognosis when compared to Ph-negative ALL, it serves as a target for tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and ponatinib. 3 – 8 While the use of a TKI forms the background of management for Ph-positive ALL, induction management strategies continue to typically include systemic chemotherapy, which is associated with substantial toxicities. 9 – 12 To avoid these toxicities, a chemotherapy-free induction strategy has been introduced consisting of a TKI, glucocorticoids, and the CD3 and CD19 bispecific T-cell engager, blinatumomab. 4 , 13 This regimen has shown effectiveness in inducing durable, long-term hematologic and molecular responses in adult Ph-positive ALL. 4 The use of allogeneic HCT remains a critical component of consolidation therapy, despite differing evidence regarding mortality benefit, especially in the era of second-generation TKIs. 14 – 17 When choosing to use a combination of TKI and blinatumomab for Ph-positive ALL, clinicians balance many factors such as age and comorbidities. 18 Effective management and avoidance of chemotherapy-related toxicities collectively make an induction strategy of TKI and blinatumomab an optimal regimen for patients who are elderly, have limited functional status, and substantial comorbidities. 13 , 19 – 22 The use of allogeneic HCT for Ph-positive ALL is associated with the risk of infection and transplant-related mortality (TRM). Thus, for patients in which clinicians are actively aiming to reduce treatment-related complications, further investigation of the role of allogeneic HCT, specifically in the setting of TKI and blinatumomab induction, is needed. There has been a major paradigm shift toward the use of selective transplant following TKI and blinatumomab, with focus on disease specific factors including measurable residual disease and cytogenetic profiles. While these details are important at the individual patient level, most current real-world multinational datasets lack this level of granularity. However, they continue to provide unique perspectives and broad overviews into the real-world outcomes that can either support or refute developing trends and guidance in the field of malignant hematology. In this study, we aim to contribute to a growing body of literature by broadly comparing relapse-free survival (RFS), overall survival (OS), and infection rates between patient with Ph-positive ALL treated with TKI and blinatumomab who did or did not undergo allogeneic HCT, using real-world, multicenter retrospective electronic health record data. METHODS A retrospective cohort study was completed using the TriNetX global federated research database comprising real-world de-identified electronic health records from over 100 healthcare organizations. The network contains information from more than 150 million patients and gives comprehensive data regarding patients’ diagnoses, procedures, medications, laboratory studies, demographics, and outcomes. Given the aggregated de-identified data provided by this database, Institutional Review Board oversight was deemed unnecessary. Study Sample Patients with the diagnosis of Ph-positive ALL who underwent TKI (dasatinib or ponatinib) and blinatumomab were isolated. Additional inclusion criteria included adult patients who were aged 18 or older at the time of the index event, which was the diagnosis and treatment of ALL. Two cohorts were created from this sample based on allogeneic HCT status. Cohort 1 did not receive allogeneic HCT (HCT-), and cohort 2 did receive allogeneic HCT (HCT+). Each patient’s index event used for comparisons was defined as the diagnosis of Ph-positive ALL with administration of TKI and blinatumomab ( Fig. 1 ) . Propensity Score Matching To control for mediators and confounders, propensity score matching (PSM) was conducted on demographics, comorbid diagnoses, concurrent medication use, and laboratory values. Matching variables included current age, age at index event, sex, race, ethnicity, complete metabolic panel values, complete blood count with differential values, body mass index, left ventricular systolic function, type II diabetes mellitus (T2DM), chronic kidney disease (CKD), human immunodeficiency virus (HIV), antilipemic agents, diuretics, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Statistical Analysis A comparative statistical analysis using the TriNetX platform was used to perform Kaplan-Meier analysis for the determination of differences in RFS and OS. Cox proportional hazards models were conducted to assess the statistical contribution of variables to outcomes. Kaplan-Meier figures were created using RStudio. Logistical regression was used to determine statistical significance for discrete variables such as overall infection and subtype infections. RStudio was also used for the creation of a Forest plot for displaying these findings. RFS is defined as survival without the presence of relapse. Relapse is defined as evidence of disease by bone marrow biopsy; minimal residual disease via flow cytometry, polymerase chain reaction (PCR), or next generation sequencing; and quantitative PCR of BCR-ABL1. Overall survival is defined as death from any cause following the index event. RESULTS Patient Characteristics A total of 242 patients were included in the study, with 162 patients in the HCT- cohort and 80 patients in the HCT+ cohort. The mean age of the HCT- cohort was 60.7±15.2 and the mean age of the HCT+ cohort was 47.5±15.1. The HCT- cohort was 53% female and the HCT+ cohort was 45% female. Mean follow-up was 465 days and 606 days for HCT- and HCT+, respectively. The HCT- cohort was 62% White and 16% Hispanic. The HCT+ cohort was 60% White and 13% Hispanic. For the HCT- cohort, 22% had T2DM, 11% had CKD, and 0% had HIV whereas for the HCT+ cohort, 15% had T2DM, 13% had CKD, and 13% had HIV. Following PSM, which accounted for differences in each sample, including select medications and laboratory values, each cohort was reduced to 56 patients. The average age of the HCT- group was 52.4±15.66, with 45% females for a mean follow-up time of 501 days. For the HCT+ group, the average age after PSM was 50.25±14.8, with 48% females and a mean follow-up time of 611 days (Table 1) . Table 1. Baseline Characteristics of Cohorts. Patients with Ph-positive ALL who underwent TKI-blinatumomab induction were isolated from the TriNetX database. Key demographics, comorbidities, medications, laboratory studies, and follow-up times were isolated from both pre-PSM and post-PSM cohorts. Relapse-Free Survival, Overall Survival Prior to PSM, there were no significant differences in RFS (Hazard ratio [HR]: 0.909; 95% Confidence Interval [95% CI]: 0.458-1.802; Log-Rank Test p = 0.784) and OS (HR: 0.959; 95% CI: 0.461-1.993; Log-Rank Test p = 0.692) between HCT- and HCT+ groups. Following PSM, there remained no significant association between HCT status and RFS (HR: 0.795; 95% CI: 0.283-2.239; Log-Rank Test p = 0.664) and OS (HR: 0.734; 95% CI: 0.240-2.248; Log-Rank Test p = 0.587). (Figure 2) . Figure 2. Relapse-free survival and overall survival. Kaplan-Meier analysis was utilized to reveal no statistically significant differences in RFS (A) and OS (B) in HCT- and HCT+ prior to PSM, as well as following PSM (C and D, respectively). Infection Risk Infection-free survival was significantly more favorable in the HCT- group prior to PSM (HR: 0.491; 95% CI: 0.348-0.692; Log-Rank Test p < 0.001). Following PSM, HCT- status continued to be associated with improved infection-free survival (HR: 0.412; 95% CI: 0.251-0.676; Log-Rank Test p < 0.001) (Figure 3) . In infection subgroup analysis prior to PSM, viral infections were most common (26.4% vs 57.5% for HCT- and HCT+, respectively), with significantly less viral infections occurring in the HCT- group (Odds ratio [OR] = 0.27; 95% CI: 0.15, 0.47; p < 0.001). HCT- was also associated with significantly less bacterial (OR = 0.38; 95% CI: 0.21, 0.68; p = 0.001), fungal infections (OR = 0.20; 95% CI: 0.09, 0.41; p < 0.001), and COVID-19 infections (OR = 0.45; 95% CI 0.26, 0.78; p = 0.004). Following PSM, these associations remained most consistent, with HCT- being associated with less overall infections (OR = 0.24; 95% CI: 0.11, 0.55; p < 0.001), bacterial infections (OR = 0.34; 95% CI: 0.14, 0.80; p = 0.013), viral infections (OR = 0.17; 95% CI: 0.07, 0.38; p < 0.001), and COVID-19 infections (OR = 0.22; 95% CI: 0.10, 0.50; p < 0.001). However, after PSM, HCT- was no longer associated with decreased fungal infections (OR = 0.54; 95% CI: 0.22, 1.33; p = 0.177) (Figure 4) . Figure 3. Infection-free survival. Kaplan-Meier analysis was used for determination of differences in infection-free survival. HCT+ was associated with significantly less infection-free survival prior to PSM (A) (HR 0.491; 95% CI: 0.348-0.692; p < 0.001) and following PSM (B) (HR 0.412; 95% CI: 0.251-0.676; p < 0.001). Figure 4. Forest plot for risk of subgroups of infection. HCT- was associated with significantly less infections (p < 0.001), including bacterial (p = 0.001), fungal (p < 0.001), viral (p < 0.001), and COVID-19 infections (p = 0.004) prior to PSM. Following PSM, HCT- remained associated significantly less infections (p < 0.001), including bacterial (p = 0.013), viral (p < 0.001), and COVID-19 infections (p < 0.001) but not fungal infections (p = 0.177). DISCUSSION This real-world, retrospective cohort study found no significant differences in RFS or OS between patients with Ph-positive ALL treated with TKI and blinatumomab who either did or did not undergo allogeneic HCT. Importantly but unsurprisingly, we identified a significantly higher burden of infections, including bacterial, viral, fungal, and COVID-19 in the HCT cohort. These findings remained consistent after rigorous propensity score matching, apart from fungal infections, for which the association was no longer statistically significant. These results following PSM reinforce the internal validity of our analysis. The advent of a chemotherapy-free induction regimen combining a TKI with blinatumomab has transformed frontline therapy for adults with Ph-positive ALL. This approach avoids substantial toxicities associated with traditional induction chemotherapy while maintaining high response rates. 4 , 23 The GIMEMA LAL2116 D-ALBA trial established the efficacy of dasatinib followed by blinatumomab for Ph-positive ALL. In this trial, which included 63 patients, 23 eventually underwent allogeneic HCT. Transplant-related mortality (TRM) was reported to be 12.5% for patients in complete hematologic response (CHR) and 13.7% overall. A separate trial using ponatinib rather than dasatinib demonstrated even higher rates of complete molecular remission (CMR) in both newly diagnosed and relapsed/refractory populations. 23 , 24 Despite these successes in establishing TKI and blinatumomab as a legitimate chemotherapy-free induction strategy, neither trial was designed to rigorously assess the added benefit of allogeneic HCT in this context. Allogeneic HCT remains a mainstay of Ph-positive ALL management, typically offered as a curative intervention for hematologic malignancies such as ALL. However, it is associated with significant morbidity, most notably of which is infection. In our study, the significant infection burden among patients receiving transplant underscores the careful and diligent consideration when contemplating HCT following TKI-blinatumomab induction, particularly in patients where treatment toxicity is already a major concern. For many clinicians, the choice to utilize a chemotherapy-free induction regimen often reflects a broader preference for a more conservative and risk-averse management strategy. Our findings align with a growing body of literature questioning the necessity of allogeneic HCT in patients with Ph-positive ALL, especially in the setting of use of TKI and blinatumomab. Many studies focus on the need for HCT following achievement of a deep molecular response, with minimal emphasis on the preceding management strategy, which serves as an area this study aims to address through an alternative perspective. There is increasing recognition of CMR as a key positive prognostic indicator in Ph-positive ALL. In a study by Ghobadi et al., there was found to be no survival advantage from allogeneic HCT in patients who achieved CMR following induction therapy. 25 In contrast, a more recent analysis by Badar et al. found that for patients achieving CMR at three months, they experienced improved RFS and OS if they subsequently underwent allogeneic HCT. 16 These conflicting findings are an example highlighting the complexity of transplant decision-making and suggest the need for more research to assist clinicians in the era of selective transplantation. Mutational profiles are also influential on outcomes, particularly in the context of the use of TKI-blinatumomab induction. Although not addressed due to limitation in the design of this study, the presence of the IKZF1 , CDKN2A/2B , and PAX5 mutations in particular were associated with poor outcomes in this group and could potentially mediate the need for HCT if TKI-blinatumomab is used. 4 , 26 , 27 The strength of our study lies in the use of a large, multicenter electronic health record database encompassing over 100 healthcare systems, enhancing generalizability of these findings. Our use of propensity score matching helped account for key confounders and mediators, while subgroup analyses of infection risk provided additional insight into the morbidity profile of allogeneic HCT in this setting. However, this study has limitations. As a retrospective analysis that is reliant on clinician-coded data, it is subject to potential misclassification and documentation bias. Additionally, the reduction in sample size after propensity score matching limits statistical power and could increase the risk of Type II error. Our dataset lacked access to MRD data post-induction, which is a factor that has become increasingly important in guiding transplant decisions in clinical practice. Additionally, TriNetX database does not currently have the capability of accessing for poor-risk cytogenetics. In the clinical trial that introduced TKI and blinatumomab as a chemotherapy-free induction, IKZF1 , CDKN2A/2B , and PAX5 mutations were associated with poor outcomes and thus may necessitate transplant. 4 Future prospective or retrospective registry-based studies that incorporate MRD and depth of molecular response as well as mutational abnormalities are needed to more precisely define which patients benefit from allogeneic HCT in TKI and blinatumomab era. CONCLUSION In conclusion, our findings suggest that allogeneic HCT may not provide additional survival benefit for patients with Ph-positive ALL treated with TKI and blinatumomab but is associated with increased infectious complications. These data support current evidence advocating for a more selective approach to transplantation, potentially guided by molecular response, cytogenetics, and patient-specific risk factors. Abbreviations ALL Acute lymphoblastic leukemia Ph Philadelphia chromosome TKI Tyrosine kinase inhibitor HCT Hematopoietic stem cell transplant RFS Relapse-free survival OS Overall survival PSM Propensity score matching MRD Measurable residual disease Declarations Author Contributions: Conceptualization, S.S. and N.H.; methodology, N.H., S.S., S.W. and L.U.; software, N.H., A.S., A.G. and M.K.; validation, N.H., A.G., L.U. and S.S.; formal analysis, N.H., S.W., A.S., L.U., M.K., A.G. and S.S.; investigation, N.H., L.U. and S.S.; resources, N.H, L.U., S.W., A.S., M.K and S.S..; data curation, N.H., A.G. and S.S.; writing—original draft preparation, N.H., S.W. and A.S.; writing—review and editing, N.H., S.W., A.S, L.U., M.K., A.G. and S.S.; visualization, N.H., L.U. and S.S.; supervision, L.U. and S.S.; project administration, N.H. and S.S.; funding acquisition, S.S.. All authors have read and agreed to the published version of the manuscript. Funding: The APC was funded by the West Virginia University Department of Hematology and Oncology. Institutional Review Board Statement: Ethical review and approval were waived for this study due to the deidentified nature of this multinational large database retrospective cohort study Informed Consent Statement: Patient consent was waived due to the deidentified nature of this multinational large database retrospective cohort study. Data Availability Statement: Restrictions apply to the availability of these data. Data were obtained from the TriNetX global federated database and are available on https://trinetx.com/ with the permission of TriNetX via purchasing of access. Acknowledgments: During the preparation of this manuscript/study, the author(s) used BioRender for the purposes of design of the graphical abstract and figures. All figure content and designs are original, without the use of generative artificial intelligence. 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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-8799277","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":598587855,"identity":"763da78f-c58f-4382-acd1-9156e06668a8","order_by":0,"name":"Nolan Holley","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYFAC5gYgcYCBjx1IfWxACOPRwgjRwgZUwziTZC3MvMRoMWdvbPxcwHBHjo2Z+Zi07Y46eQaJHDMJhgrrxAYcWix7DjZLz2B4ZszGzJYmnXvmsGEDWMuZdJxaDG4kNkjzMBxObGPmMZPObTuQwCCdlibB2HYYn5bm3xAt/N+kLdvqoFr+4dXSBrOFTZqxjRmoJfmYBGMDHi1nDrZZ8xgcBvnF2LK37bBhm/zjwxYJx9KNcWo53nz4Nk/FYTl+9uaHN3621cnz8xxsvPGhxloWlxaoRjDJIgEi2UBEAl7lCMD8gUiFo2AUjIJRMMIAAHACUDqSfK1OAAAAAElFTkSuQmCC","orcid":"","institution":"West Virginia University","correspondingAuthor":true,"prefix":"","firstName":"Nolan","middleName":"","lastName":"Holley","suffix":""},{"id":598587856,"identity":"969aa85f-a4f1-4595-ba3b-a4444f4856ba","order_by":1,"name":"Laxmi Upadhyay","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Laxmi","middleName":"","lastName":"Upadhyay","suffix":""},{"id":598587857,"identity":"cc2a5efc-fbe8-4c38-9e30-51c876895514","order_by":2,"name":"Shanawar Waris","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Shanawar","middleName":"","lastName":"Waris","suffix":""},{"id":598587858,"identity":"405dff98-fb12-4453-a85f-2f80a08a4cee","order_by":3,"name":"Adnan Saifuddin","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Adnan","middleName":"","lastName":"Saifuddin","suffix":""},{"id":598587859,"identity":"ff87ca58-52dd-43ab-8271-a8dec9c77e47","order_by":4,"name":"Mahd Khan","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Mahd","middleName":"","lastName":"Khan","suffix":""},{"id":598587860,"identity":"0009d29c-504a-4281-b485-e4161b415341","order_by":5,"name":"Austin Goncz","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Austin","middleName":"","lastName":"Goncz","suffix":""},{"id":598587861,"identity":"cae8051f-2c15-46e3-8b76-e119d7270967","order_by":6,"name":"Salahuddin Safi","email":"","orcid":"","institution":"West Virginia University","correspondingAuthor":false,"prefix":"","firstName":"Salahuddin","middleName":"","lastName":"Safi","suffix":""}],"badges":[],"createdAt":"2026-02-05 16:23:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8799277/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8799277/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103779260,"identity":"413b41fb-517d-4f3e-9886-01ce2b1786ec","added_by":"auto","created_at":"2026-03-02 19:54:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":17737,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEstablishment of Cohorts.\u003c/strong\u003e A total of 78,779 adult patients with acute lymphoblastic leukemia were isolated. Initial inclusion criteria were use of blinatumomab with dasatinib or ponatinib and initial exclusion criteria were use of doxorubicin or vincristine. Patients were then separated based on receipt of allogenic HCT (HCT+ vs HCT-). Propensity score matching was used to neutralize confounding.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8799277/v1/c5cc59f0edd793094c72c701.jpg"},{"id":103779263,"identity":"68bafc97-c9ae-4a05-a80e-b98731c41df1","added_by":"auto","created_at":"2026-03-02 19:54:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":146139,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelapse-free survival and overall survival.\u003c/strong\u003e Kaplan-Meier analysis was utilized to reveal no statistically significant differences in RFS (A) and OS (B) in HCT- and HCT+ prior to PSM, as well as following PSM (C and D, respectively).\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8799277/v1/a4e974c6cc9f0ba6d9c5ad75.jpg"},{"id":103779261,"identity":"4e1ad301-dd6b-4a72-a5ac-6f6caf8aea0b","added_by":"auto","created_at":"2026-03-02 19:54:38","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":94360,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInfection-free survival.\u003c/strong\u003e Kaplan-Meier analysis was used for determination of differences in infection-free survival. HCT+ was associated with significantly less infection-free survival prior to PSM (A) (HR 0.491; 95% CI: 0.348-0.692; p \u0026lt; 0.001) and following PSM (B) (HR 0.412; 95% CI: 0.251-0.676; p \u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8799277/v1/668f6f014a809ce01a3725e0.jpg"},{"id":103779266,"identity":"84c45414-80f8-4ca7-ad72-6a136dea8813","added_by":"auto","created_at":"2026-03-02 19:54:39","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":22428,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plot for risk of subgroups of infection.\u003c/strong\u003e HCT- was associated with significantly less infections (p \u0026lt; 0.001), including bacterial (p = 0.001), fungal (p \u0026lt; 0.001), viral (p \u0026lt; 0.001), and COVID-19 infections (p = 0.004) prior to PSM. Following PSM, HCT- remained associated significantly less infections (p \u0026lt; 0.001), including bacterial (p = 0.013), viral (p \u0026lt; 0.001), and COVID-19 infections (p \u0026lt; 0.001) but not fungal infections (p = 0.177).\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8799277/v1/19d3490f84da224bec416f8d.jpg"},{"id":104407768,"identity":"529a9d58-9e59-4b93-a689-ad3631f4831d","added_by":"auto","created_at":"2026-03-11 12:39:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":968584,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8799277/v1/49253024-4ed7-4f01-b6e8-99144a7ffd15.pdf"},{"id":104400090,"identity":"fa54e3a3-8101-4f41-bbc3-c8de3ea1f208","added_by":"auto","created_at":"2026-03-11 12:08:49","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":595385,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8799277/v1/4ec98a0f7cdff81035a743f3.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Role of Allogeneic Hematopoietic Stem-Cell Transplant Following TKI-Blinatumomab Induction for Ph-Positive Acute Lymphoblastic Leukemia in Adults","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePhiladelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) is characterized by the reciprocal translocation of chromosomes 9 and 22 to form the BCR-ABL1 fusion gene, which drives leukemogenesis of lymphocytes.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Collectively, this constitutively activated tyrosine kinase leads to the reduction of apoptosis and uncontrolled cell proliferation.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e While this translocation is associated with poorer prognosis when compared to Ph-negative ALL, it serves as a target for tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and ponatinib.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e While the use of a TKI forms the background of management for Ph-positive ALL, induction management strategies continue to typically include systemic chemotherapy, which is associated with substantial toxicities.\u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e To avoid these toxicities, a chemotherapy-free induction strategy has been introduced consisting of a TKI, glucocorticoids, and the CD3 and CD19 bispecific T-cell engager, blinatumomab.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e This regimen has shown effectiveness in inducing durable, long-term hematologic and molecular responses in adult Ph-positive ALL.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The use of allogeneic HCT remains a critical component of consolidation therapy, despite differing evidence regarding mortality benefit, especially in the era of second-generation TKIs.\u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWhen choosing to use a combination of TKI and blinatumomab for Ph-positive ALL, clinicians balance many factors such as age and comorbidities.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Effective management and avoidance of chemotherapy-related toxicities collectively make an induction strategy of TKI and blinatumomab an optimal regimen for patients who are elderly, have limited functional status, and substantial comorbidities.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e The use of allogeneic HCT for Ph-positive ALL is associated with the risk of infection and transplant-related mortality (TRM). Thus, for patients in which clinicians are actively aiming to reduce treatment-related complications, further investigation of the role of allogeneic HCT, specifically in the setting of TKI and blinatumomab induction, is needed. There has been a major paradigm shift toward the use of selective transplant following TKI and blinatumomab, with focus on disease specific factors including measurable residual disease and cytogenetic profiles. While these details are important at the individual patient level, most current real-world multinational datasets lack this level of granularity. However, they continue to provide unique perspectives and broad overviews into the real-world outcomes that can either support or refute developing trends and guidance in the field of malignant hematology. In this study, we aim to contribute to a growing body of literature by broadly comparing relapse-free survival (RFS), overall survival (OS), and infection rates between patient with Ph-positive ALL treated with TKI and blinatumomab who did or did not undergo allogeneic HCT, using real-world, multicenter retrospective electronic health record data.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eA retrospective cohort study was completed using the TriNetX global federated research database comprising real-world de-identified electronic health records from over 100 healthcare organizations. The network contains information from more than 150\u0026nbsp;million patients and gives comprehensive data regarding patients\u0026rsquo; diagnoses, procedures, medications, laboratory studies, demographics, and outcomes. Given the aggregated de-identified data provided by this database, Institutional Review Board oversight was deemed unnecessary.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Sample\u003c/h2\u003e \u003cp\u003ePatients with the diagnosis of Ph-positive ALL who underwent TKI (dasatinib or ponatinib) and blinatumomab were isolated. Additional inclusion criteria included adult patients who were aged 18 or older at the time of the index event, which was the diagnosis and treatment of ALL. Two cohorts were created from this sample based on allogeneic HCT status. Cohort 1 did not receive allogeneic HCT (HCT-), and cohort 2 did receive allogeneic HCT (HCT+). Each patient\u0026rsquo;s index event used for comparisons was defined as the diagnosis of Ph-positive ALL with administration of TKI and blinatumomab \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePropensity Score Matching\u003c/h3\u003e\n\u003cp\u003eTo control for mediators and confounders, propensity score matching (PSM) was conducted on demographics, comorbid diagnoses, concurrent medication use, and laboratory values. Matching variables included current age, age at index event, sex, race, ethnicity, complete metabolic panel values, complete blood count with differential values, body mass index, left ventricular systolic function, type II diabetes mellitus (T2DM), chronic kidney disease (CKD), human immunodeficiency virus (HIV), antilipemic agents, diuretics, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose co-transporter 2 (SGLT2) inhibitors.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eA comparative statistical analysis using the TriNetX platform was used to perform Kaplan-Meier analysis for the determination of differences in RFS and OS. Cox proportional hazards models were conducted to assess the statistical contribution of variables to outcomes. Kaplan-Meier figures were created using RStudio. Logistical regression was used to determine statistical significance for discrete variables such as overall infection and subtype infections. RStudio was also used for the creation of a Forest plot for displaying these findings. RFS is defined as survival without the presence of relapse. Relapse is defined as evidence of disease by bone marrow biopsy; minimal residual disease via flow cytometry, polymerase chain reaction (PCR), or next generation sequencing; and quantitative PCR of BCR-ABL1. Overall survival is defined as death from any cause following the index event.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cem\u003ePatient Characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 242 patients were included in the study, with 162 patients in the HCT- cohort and 80 patients in the HCT+ cohort. The mean age of the HCT- cohort was 60.7\u0026plusmn;15.2 and the mean age of the HCT+ cohort was 47.5\u0026plusmn;15.1. The HCT- cohort was 53% female and the HCT+ cohort was 45% female. Mean follow-up was 465 \u003cs\u003edays\u003c/s\u003e and 606 days for HCT- and HCT+, respectively. The HCT- cohort was 62% White and 16% Hispanic. The HCT+ cohort was 60% White and 13% Hispanic. For the HCT- cohort, 22% had T2DM, 11% had CKD, and 0% had HIV whereas for the HCT+ cohort, 15% had T2DM, 13% had CKD, and 13% had HIV. Following PSM, which accounted for differences in each sample, including select medications and laboratory values, each cohort was reduced to 56 patients. The average age of the HCT- group was 52.4\u0026plusmn;15.66, with 45% females for a mean follow-up time of 501 days. For the HCT+ group, the average age after PSM was 50.25\u0026plusmn;14.8, with 48% females and a mean follow-up time of 611 days \u003cstrong\u003e(Table 1)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Baseline Characteristics of Cohorts.\u003c/strong\u003e Patients with Ph-positive ALL who underwent TKI-blinatumomab induction were isolated from the TriNetX database. Key demographics, comorbidities, medications, laboratory studies, and follow-up times were isolated from both pre-PSM and post-PSM cohorts.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cimg width=\"593\" height=\"342\" src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img177248100054.png\" alt=\"A black background with a black square AI-generated content may be incorrect.\"\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRelapse-Free Survival, Overall Survival\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePrior to PSM, there were no significant differences in RFS (Hazard ratio [HR]: 0.909; 95% Confidence Interval [95% CI]: 0.458-1.802; Log-Rank Test \u003cem\u003ep\u003c/em\u003e = 0.784) and OS (HR: 0.959; 95% CI: 0.461-1.993; Log-Rank Test \u003cem\u003ep\u003c/em\u003e = 0.692) between HCT- and HCT+ groups. Following PSM, there remained no significant association between HCT status and RFS (HR: 0.795; 95% CI: 0.283-2.239; Log-Rank Test \u003cem\u003ep\u003c/em\u003e = 0.664) and OS (HR: 0.734; 95% CI: 0.240-2.248; Log-Rank Test \u003cem\u003ep\u003c/em\u003e = 0.587). \u003cstrong\u003e(Figure 2)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2. Relapse-free survival and overall survival.\u003c/strong\u003e Kaplan-Meier analysis was utilized to reveal no statistically significant differences in RFS (A) and OS (B) in HCT- and HCT+ prior to PSM, as well as following PSM (C and D, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInfection Risk\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eInfection-free survival was significantly more favorable in the HCT- group prior to PSM (HR: 0.491; 95% CI: 0.348-0.692; Log-Rank Test p \u0026lt; 0.001). Following PSM, HCT- status continued to be associated with improved infection-free survival (HR: 0.412; 95% CI: 0.251-0.676; Log-Rank Test p \u0026lt; 0.001) \u003cstrong\u003e(Figure 3)\u003c/strong\u003e. In infection subgroup analysis prior to PSM, viral infections were most common (26.4% vs 57.5% for HCT- and HCT+, respectively), with significantly less viral infections occurring in the HCT- group (Odds ratio [OR] = 0.27; 95% CI: 0.15, 0.47; p \u0026lt; 0.001). HCT- was also associated with significantly less bacterial (OR = 0.38; 95% CI: 0.21, 0.68; p = 0.001), fungal infections (OR = 0.20; 95% CI: 0.09, 0.41; p \u0026lt; 0.001), and COVID-19 infections (OR = 0.45; 95% CI 0.26, 0.78; p = 0.004). Following PSM, these associations remained most consistent, with HCT- being associated with less overall infections (OR = 0.24; 95% CI: 0.11, 0.55; p \u0026lt; 0.001), bacterial infections (OR = 0.34; 95% CI: 0.14, 0.80; p = 0.013), viral infections (OR = 0.17; 95% CI: 0.07, 0.38; p \u0026lt; 0.001), and COVID-19 infections (OR = 0.22; 95% CI: 0.10, 0.50; p \u0026lt; 0.001). However, after PSM, HCT- was no longer associated with decreased fungal infections (OR = 0.54; 95% CI: 0.22, 1.33; p = 0.177) \u003cstrong\u003e(Figure 4)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3. Infection-free survival.\u003c/strong\u003e Kaplan-Meier analysis was used for determination of differences in infection-free survival. HCT+ was associated with significantly less infection-free survival prior to PSM (A) (HR 0.491; 95% CI: 0.348-0.692; p \u0026lt; 0.001) and following PSM (B) (HR 0.412; 95% CI: 0.251-0.676; p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4. Forest plot for risk of subgroups of infection.\u003c/strong\u003e HCT- was associated with significantly less infections (p \u0026lt; 0.001), including bacterial (p = 0.001), fungal (p \u0026lt; 0.001), viral (p \u0026lt; 0.001), and COVID-19 infections (p = 0.004) prior to PSM. Following PSM, HCT- remained associated significantly less infections (p \u0026lt; 0.001), including bacterial (p = 0.013), viral (p \u0026lt; 0.001), and COVID-19 infections (p \u0026lt; 0.001) but not fungal infections (p = 0.177).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis real-world, retrospective cohort study found no significant differences in RFS or OS between patients with Ph-positive ALL treated with TKI and blinatumomab who either did or did not undergo allogeneic HCT. Importantly but unsurprisingly, we identified a significantly higher burden of infections, including bacterial, viral, fungal, and COVID-19 in the HCT cohort. These findings remained consistent after rigorous propensity score matching, apart from fungal infections, for which the association was no longer statistically significant. These results following PSM reinforce the internal validity of our analysis.\u003c/p\u003e \u003cp\u003eThe advent of a chemotherapy-free induction regimen combining a TKI with blinatumomab has transformed frontline therapy for adults with Ph-positive ALL. This approach avoids substantial toxicities associated with traditional induction chemotherapy while maintaining high response rates.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e The GIMEMA LAL2116 D-ALBA trial established the efficacy of dasatinib followed by blinatumomab for Ph-positive ALL. In this trial, which included 63 patients, 23 eventually underwent allogeneic HCT. Transplant-related mortality (TRM) was reported to be 12.5% for patients in complete hematologic response (CHR) and 13.7% overall. A separate trial using ponatinib rather than dasatinib demonstrated even higher rates of complete molecular remission (CMR) in both newly diagnosed and relapsed/refractory populations.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Despite these successes in establishing TKI and blinatumomab as a legitimate chemotherapy-free induction strategy, neither trial was designed to rigorously assess the added benefit of allogeneic HCT in this context.\u003c/p\u003e \u003cp\u003eAllogeneic HCT remains a mainstay of Ph-positive ALL management, typically offered as a curative intervention for hematologic malignancies such as ALL. However, it is associated with significant morbidity, most notably of which is infection. In our study, the significant infection burden among patients receiving transplant underscores the careful and diligent consideration when contemplating HCT following TKI-blinatumomab induction, particularly in patients where treatment toxicity is already a major concern. For many clinicians, the choice to utilize a chemotherapy-free induction regimen often reflects a broader preference for a more conservative and risk-averse management strategy.\u003c/p\u003e \u003cp\u003eOur findings align with a growing body of literature questioning the necessity of allogeneic HCT in patients with Ph-positive ALL, especially in the setting of use of TKI and blinatumomab. Many studies focus on the need for HCT following achievement of a deep molecular response, with minimal emphasis on the preceding management strategy, which serves as an area this study aims to address through an alternative perspective. There is increasing recognition of CMR as a key positive prognostic indicator in Ph-positive ALL. In a study by Ghobadi et al., there was found to be no survival advantage from allogeneic HCT in patients who achieved CMR following induction therapy.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e In contrast, a more recent analysis by Badar et al. found that for patients achieving CMR at three months, they experienced improved RFS and OS if they subsequently underwent allogeneic HCT.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e These conflicting findings are an example highlighting the complexity of transplant decision-making and suggest the need for more research to assist clinicians in the era of selective transplantation. Mutational profiles are also influential on outcomes, particularly in the context of the use of TKI-blinatumomab induction. Although not addressed due to limitation in the design of this study, the presence of the \u003cem\u003eIKZF1\u003c/em\u003e, \u003cem\u003eCDKN2A/2B\u003c/em\u003e, and \u003cem\u003ePAX5\u003c/em\u003e mutations in particular were associated with poor outcomes in this group and could potentially mediate the need for HCT if TKI-blinatumomab is used.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe strength of our study lies in the use of a large, multicenter electronic health record database encompassing over 100 healthcare systems, enhancing generalizability of these findings. Our use of propensity score matching helped account for key confounders and mediators, while subgroup analyses of infection risk provided additional insight into the morbidity profile of allogeneic HCT in this setting.\u003c/p\u003e \u003cp\u003eHowever, this study has limitations. As a retrospective analysis that is reliant on clinician-coded data, it is subject to potential misclassification and documentation bias. Additionally, the reduction in sample size after propensity score matching limits statistical power and could increase the risk of Type II error. Our dataset lacked access to MRD data post-induction, which is a factor that has become increasingly important in guiding transplant decisions in clinical practice. Additionally, TriNetX database does not currently have the capability of accessing for poor-risk cytogenetics. In the clinical trial that introduced TKI and blinatumomab as a chemotherapy-free induction, \u003cem\u003eIKZF1\u003c/em\u003e, \u003cem\u003eCDKN2A/2B\u003c/em\u003e, and \u003cem\u003ePAX5\u003c/em\u003e mutations were associated with poor outcomes and thus may necessitate transplant.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Future prospective or retrospective registry-based studies that incorporate MRD and depth of molecular response as well as mutational abnormalities are needed to more precisely define which patients benefit from allogeneic HCT in TKI and blinatumomab era.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, our findings suggest that allogeneic HCT may not provide additional survival benefit for patients with Ph-positive ALL treated with TKI and blinatumomab but is associated with increased infectious complications. These data support current evidence advocating for a more selective approach to transplantation, potentially guided by molecular response, cytogenetics, and patient-specific risk factors.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALL\u0026nbsp; \u0026nbsp;\u0026nbsp;Acute lymphoblastic leukemia\u003c/p\u003e\n\u003cp\u003ePh\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Philadelphia chromosome\u003c/p\u003e\n\u003cp\u003eTKI\u0026nbsp; \u0026nbsp; \u0026nbsp;Tyrosine kinase inhibitor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHCT\u0026nbsp; \u0026nbsp;\u0026nbsp;Hematopoietic stem cell transplant\u003c/p\u003e\n\u003cp\u003eRFS\u0026nbsp; \u0026nbsp; \u0026nbsp;Relapse-free survival\u003c/p\u003e\n\u003cp\u003eOS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Overall survival\u003c/p\u003e\n\u003cp\u003ePSM\u0026nbsp; \u0026nbsp;\u0026nbsp;Propensity score matching\u003c/p\u003e\n\u003cp\u003eMRD \u0026nbsp; Measurable residual disease\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Conceptualization, S.S. and N.H.; methodology, N.H., S.S., S.W. and L.U.; software, N.H., A.S., A.G. and M.K.; validation, N.H., A.G., L.U. and S.S.; formal analysis, N.H., S.W., A.S., L.U., M.K., A.G. and S.S.; investigation, N.H., L.U. and S.S.; resources, N.H, L.U., S.W., A.S., M.K and S.S..; data curation, N.H., A.G. and S.S.; writing—original draft preparation, N.H., S.W. and A.S.; writing—review and editing, N.H., S.W., A.S, L.U., M.K., A.G. and S.S.; visualization, N.H., L.U. and S.S.; supervision, L.U. and S.S.; project administration, N.H. and S.S.; funding acquisition, S.S.. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The APC was funded by the West Virginia University Department of Hematology and Oncology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u003c/strong\u003e Ethical review and approval were waived for this study due to the deidentified nature of this multinational large database retrospective cohort study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u003c/strong\u003e Patient consent was waived due to the deidentified nature of this multinational large database retrospective cohort study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e Restrictions apply to the availability of these data. Data were obtained from the TriNetX global federated database and are available on https://trinetx.com/ with the permission of TriNetX via purchasing of access.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e During the preparation of this manuscript/study, the author(s) used BioRender for the purposes of design of the graphical abstract and figures. All figure content and designs are original, without the use of generative artificial intelligence. The authors have reviewed and edited the output and take full responsibility for the content of this publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEl Fakih R, Jabbour E, Ravandi F et al (2018) Current paradigms in the management of Philadelphia chromosome positive acute lymphoblastic leukemia in adults. 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Blood 134(Supplement1):2753. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2019-122017\u003c/span\u003e\u003cspan address=\"10.1182/blood-2019-122017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Ph-positive acute lymphoblastic leukemia, allogeneic stem cell transplant, tyrosine kinase inhibitors, blinatumomab","lastPublishedDoi":"10.21203/rs.3.rs-8799277/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8799277/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has traditionally been treated with tyrosine kinase inhibitors (TKIs) and systemic chemotherapy, often followed by allogeneic hematopoietic stem cell transplant (HCT). More recently, chemotherapy-free induction regimens combining TKIs and blinatumomab have demonstrated efficacy with reduced risk for chemotherapy-related toxicity. However, the benefit of allogeneic HCT in this setting remains unclear.\u003c/p\u003e\n\u003cp\u003eObjective: Compare relapse-free survival (RFS), overall survival (OS), and infection rates in adult patients with Ph-positive ALL treated with TKI and blinatumomab induction, stratified by allogeneic HCT status, using retrospective data.\u003c/p\u003e\n\u003cp\u003eStudy Design: We conducted a retrospective cohort study using the TriNetX global federated electronic health record database. Adult patients with Ph-positive ALL treated with TKI (dasatinib or ponatinib) and blinatumomab were stratified by receipt of allogeneic HCT (HCT+ vs HCT-). Propensity score matching (PSM) was applied to control for baseline demographics, comorbidities, medications, and laboratory values. Outcomes included RFS, OS, and infection rates.\u003c/p\u003e\n\u003cp\u003eResults: A total of 242 patients were included, with 162 in the HCT- cohort and 80 in the HCT+ cohort. Following PSM, 56 patients remain in each cohort. There were no significant differences in RFS (HR 0.795; 95% CI: 0.283-2.239; p = 0.664) or OS (HR 0.734; 95% CI: 0.240-2.248; p = 0.587) between groups following PSM. However, HCT was associated with a significantly higher risk of infections, including bacterial, viral, and COVID-19 infections (all p \u0026lt; 0.01). These findings remained consistent after PSM.\u003c/p\u003e\n\u003cp\u003eConclusions: Among adults with Ph-positive ALL treated with TKI and blinatumomab, allogeneic HCT was not associated with improved RFS or OS but was linked to increased infection risk. These findings support a more selective approach to transplant following chemotherapy-free induction, particularly in patients with high baseline infection risk. Prospective studies incorporating measurable residual disease (MRD) status are warranted to further guide transplant decisions in this evolving therapeutic landscape.\u003c/p\u003e","manuscriptTitle":"Role of Allogeneic Hematopoietic Stem-Cell Transplant Following TKI-Blinatumomab Induction for Ph-Positive Acute Lymphoblastic Leukemia in Adults","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-02 19:54:14","doi":"10.21203/rs.3.rs-8799277/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-30T08:11:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T15:00:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-22T17:44:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219625433447522298218117449316830680808","date":"2026-03-17T17:26:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"40485870211870946287199382340144814046","date":"2026-03-16T13:07:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-15T17:57:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148119486241065241377628626173711239871","date":"2026-03-15T17:34:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"171095619890998393197102246299091949086","date":"2026-03-02T14:17:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49985148624374333017260555684437410531","date":"2026-02-28T16:04:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294856039844037063850234128228468078551","date":"2026-02-25T14:44:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-23T13:33:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-22T13:32:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-22T13:31:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2026-02-05T16:12:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"45b78af8-b471-4c77-ac8a-cca115fc8a98","owner":[],"postedDate":"March 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T08:25:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-02 19:54:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8799277","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8799277","identity":"rs-8799277","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}