Clinical utilization of blinatumomab in Chinese monocentric patients with relapsed or refractory B-cell acute lymphoblastic leukemia

Clinical utilization of blinatumomab in Chinese monocentric patients with relapsed or refractory B-cell acute lymphoblastic leukemia | 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 Article Clinical utilization of blinatumomab in Chinese monocentric patients with relapsed or refractory B-cell acute lymphoblastic leukemia Jingkui Zhu, Jixin Fan, Tiantian Xie, Haiqiu Zhao, Runqing Lu, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2309595/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Blinatumomab has promising applications in treating relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, there are few studies on using blinatumomab for treating R/R B-ALL patients in China. Therefore, we evaluated the efficacy and safety of blinatumomab among Chinese R/R B-ALL patients. Methods: In total, 39 R/R B-ALL patients who received blinatumomab between October 2021 and August 2022 were selected as the study subjects. The primary endpoints include overall response rate (ORR) and complete minimal residual disease (MRD) response. Secondary endpoints included overall survival (OS) and adverse events (AEs). Results : The ORR and OS for 19 patients with less than 5% bone marrow (BM) blasts were 63.2% and 11 months (7.3–14.7), respectively. The median OS for the 20 patients was unavailable, and 17 (or 85%) had a full MRD response. Twenty-seven patients (69.2%) reported having at least 1 AE. Hematologic toxicity and infections were the most common AEs. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed on nine patients who had been remission-free for a long time. In the first month, one patient (11.1%) developed thrombotic microangiopathy associated with HSCT (TA-TMA) following transplantation. Conclusion: In R/R B-ALL patients, blinatumomab is an effective option in China. Biological sciences/Cancer/Cancer therapy Biological sciences/Cancer/Haematological cancer Blinatumomab R/R B-ALL ORR complete MRD response AEs allo-HSCT Introduction 5-year overall survival (OS) rates for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) range from 10–50% 1–3 . Although the development of targeted medications like tyrosine kinase inhibitors has improved outcomes for some subsets of people with R/R B-ALL, allo-HSCT continues to be an exceptional treatment 4,5 . Multiple studies have linked MRD to response duration and cure rates in R/R B-ALL, making it an important prognostic marker 4,6 . The prognosis of patients who test negative for MRD prior to HSCT is consistently better than that of patients who test positive for MRD 7 . R/R B-ALL targets CD19 because this transmembrane protein is highly expressed on the surface of B-lymphocyte 8,9 . Blinatumomab, the bispecific T-cell engager, draws both CD3 + T cells and CD19 + B cells, leading to the B cell lysis 10 . It is approved for both adult and pediatric R/R B-ALL. According to a multicenter retrospective analysis on R/R B-ALL in children and adolescents, the complete response (CR) rate of blinatumomab was 39% among patients with ≥ 5% BM blasts, and the complete MRD response rate was 81% among CR cases with positive MRD, demonstrating good efficacy and safety 11 . Blinatumomab significantly improves the CR rate and increases OS in adult patients compared to chemotherapy, leading to prolonged survival 12,13 . However, most of the aforementioned studies were conducted in Europe or the United States. Few studies have been conducted on the current blinatumomab usage in Chinese patients. To evaluate whether blinatumomab was effective and safe among Chinese cases, this work summarized blinatumomab treatment outcomes among 39 R/R B-ALL cases. Materials And Methods Study population The retrospective analysis of this study enrolled 39 R/R B-ALL patients treated with blinatumomab at the First Affiliated Hospital of Zhengzhou University between October 2021 and August 2022. R/R B-ALL was diagnosed according to National Comprehensive Cancer Network (NCCN) guidelines 14 .The Ethics Committee of First Affiliated Hospital of Zhengzhou University approved the present study. Treatment According to the percentage of BM blasts, all cases were divided into two groups: those with less than 5% and those with more than 5% of BM blasts (but MRD positive). For those with more than or equal to 5% BM blasts, blinatumomab was administered at the following doses for four weeks: 5 µg/m 2 (maximum 9 µg/d) was given in week 1, and then 15 µg/m 2 (maximum 28 µg/d); while for those with less than 5% BM blasts, 15 µg/m 2 (maximum 28 µg/d) was administered over the course of four weeks. To avoid infusion responses, all patients received dexamethasone (5 mg/m 2 ) prior to treatment. The infusion was stopped if the following grade 3 neurological events associated with blinatumomab occurred: tumor lysis syndrome, cytokine release syndrome (CRS), or disseminated intravascular coagulation/coagulopathy. Assessments of safety and efficacy Treatment was concluded with bone marrow aspiration to assess the clinical effectiveness of this work. According to the NCCN guideline 14 , responses are divided into complete response (CR), CR with partial/incomplete hematologic recovery (CRh/CRi), progressive disease (PD), and relapse. Overall relative risk (ORR) = CR + CRh + Cri. Two methods, real-time PCR (RT-PCR) and flow cytometry (FCM) were used to determine MRD 15 . In the absence of visible blasts, the condition was considered a complete MRD response 1 . Every adverse event (AE) reported from the beginning of treatment through 30 days after the last injection was graded according to National Cancer Institute standards (version 4.03). Statistical Analysis Patients were followed till October 31, 2022. The primary endpoints were CR, CRh, CRi or complete MRD response, while secondary endpoints included AEs and OS (duration between treatment initiation and all-cause mortality). SPSS ver. 26.0 was used for the statistical analysis. Fisher's exact test was used to compare categorical variables between groups, expressed as frequency (percentages). The OS was evaluated by Kaplan-Meier (KM) approach. P < 0.05 (two-sided) stands for statistical significance. Results Patient basic features Thirty-nine people participated in the study and were treated with blinatumomab infusions (Table 1 ). Nineteen patients (48.7%) had ≥ 5% BM blasts, eighteen (46.2%) were aged 18 years or older, and twenty-five (64.1%) were male. Patients typically underwent between two to twenty chemotherapy cycles before beginning blinatumomab (median, 5). Thirteen patients (33.3%) were positive for Philadelphia chromosome (Ph) acute lymphoblastic leukemia. The most common alterations were IKZF1, TP53, NRAS, and KRAS mutations. Table 1 Baseline characteristics of the patient(N = 39) Characteristic No. (%) Sex Male 25 Female 17 Age, years < 18 21 ≥ 18 18 Bone marrow blasts, % < 5 20 ≥ 5 19 Median number of chemotherapies 5(2–20) Cytogenetic group Ph+ 5 Ph- 13 Gene mutation 3 IKZF1 7 TP53 3 NRAS 6 KRAS 4 Clinical Efficacy The ORR and OS were 63.2% and 11 (range 7.3–14.7) months among the nineteen patients with ≥ 5% BM blasts. Eight (42.1%) patients reached CR, three (15.8%) reached CRh, and one (5.3%) reached CRi. There was no significant difference in overall response rate (ORR) between males and females, younger and older patients, those with and without a positive or negative Ph, and those with a low or high percentage of BM blasts. The median OS was not unavailable for 20 patients with < 5% BM blasts, of whom 17 (85%) achieved a complete MRD response. There was no statistically significant difference when comparing males to females, under-18 to over-18, and Ph-positive vs. Ph-negative complete MRD response rates. Response to treatment in patients with various clinical characteristics are listed in Table 2 . Table 2 Response to treatment in patients with various clinical characteristics Patients with ≥ 5% BM blasts Patients with < 5% BM blasts All patients Patients with ORR(%) All patients Complete MRD response Sex Male 12 6(50) 13 12(92.3) Female 7 6(85.7) 7 5(71.4) Age, years < 18 10 5(50) 11 9(81.8) ≥ 18 9 7(77.8) 9 8(88.9) Cytogenetic group Ph+ 5 5(100) 7 6(85.7) Ph- 14 7(50) 13 11(64.7) BM blasts, % ≥ 50 11 7(63.6) / / < 50 8 5(62.5) / / BM: bone marrow; ORR: overall response rate; MRD: minimal residual disease; Ph: Philadelphia chromosome. Allo-hsct And Post-transplant-related Complications After receiving blinatumomab, nine individuals underwent allo-HSCT while in continuous remission. One (11.1%) of them had acute graft-versus-host disease (GVHD), and one (11.1%) experienced TA-TMA in the first month after the transplant. One patient (11.1%) acquired Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia on day 27 post-transplant. At day + 165 after the transplant, one (11.1%) patient experienced chronic GVHD. Recurrence And Survival As of October 31, 2022, two patients had relapsed: one while waiting for allo-HSCT and another after the transplant. Seven patients ultimately passed away at the hospital: four from sepsis, two from disease progression, and one from a cerebral hemorrhage. Aes In total, 27 patients (69.2%) reported having at least one AE. There were 14 (35.9%) and 8 (20.5%) patients who experienced AEs of grades 3 and 4, respectively. The most common adverse events (AEs) involve the blood and immune system. Only one patient had a severe case of CRS, whereas two others experienced mild neurological events (tremor). AEs experienced by patients are listed in Table 3 . Table 3 Summary of adverse events NO. (%) Any grade Grade 3 Grade 4 Any adverse event, n(%) 27 (69.2) 14 (35.9) 8 (20.5) Hematologic toxicity 10 (25.6) 6 (15.4) 3 (7.7) Neutropenia 8 (20.5) 3 (7.7) 2 (5.1) Anemia 3 (7.7) 2 (5.1) 0 (0) Thrombocytopenia 6 (15.4) 2 (5.1) 2 (5.1) Infection 15 (38.5) 9 (23.1) 6 (15.4) CRS 1 (2.6) 1 (2.6) 0 (0) Pyrexia 6 (15.4) 0 (0) 0 (0) Neurological events (tremor) 2 (5.1) 0 (0) 0 (0) CRS: cytokine release syndrome Discussion R/R B-ALL is associated with dismal prognostic outcomes, even though ALL survival has greatly improved in the past few decades. Blinatumomab, a bispecific T cell-engager antibody construct, has shown promising results and potential uses in treating R/R B-ALL 10 . Unfortunately, there is a lack of research on the current blinatumomab usage among Chinese patients. Therefore, we evaluated the efficacy and safety of blinatumomab in R/R B-ALL patients in China. In cases showing ≥ 5% BM blasts, 12 patients (63.2%) achieved CR/CRi/CRh, with 10 of those patients achieving a complete MRD response; 17 patients (85%) of those with < 5% BM blast had a complete MRD response. These response rates are consistent with those that have been previously reported 12,15−17 . Notably, there was no discernible difference in response rates between those with Ph + and those with Ph-ALL. This demonstrates that blinatumomab has the potential to reverse the poor prognosis of Ph + patients and provide them with the same level of effectiveness as Ph- patients. There was no correlation between T315I mutations and the therapeutic efficacy of blinatumomab in R/R Ph + ALL 18 . Couturier et al. analyzed twenty-six cases of R/R Ph + ALL treated with ponatinib and blinatumomab retrospectively 19 . They discovered that ponatinib, in combination with blinatumomab, could further improve the prognosis of these patients, as 25 (96.2%) of them achieved CR and 23 (88.5%) had a complete MRD response. Multiple studies have linked the tumor burden of patients to the effectiveness and median OS of blinatumomab 15,20,21 . Despite there being no statistically significant difference, patients in this trial with a higher percentage of baseline BM blasts (> 50%) had a poorer ORR and a shorter median OS. The only baseline factor that predicts how blinatumomab-treated individuals would fare is their tumor load 15 . We hypothesize that the tumor burden is a measure of leukemia aggressiveness and that patients with a high tumor burden have more aggressive leukemia 18 . This may shed light on why patients with high tumor burden have such a low response rate. Blinatumomab has significantly improved survival over chemotherapy in cases with a high tumor burden in the bone marrow 12 . However, patients who do not respond to blinatumomab still face a dismal prognosis; some research suggests that adding other antibodies, like inotuzumab ozogamicin, to the mix can improve prognosis 13,17,22 . To date, allo-HSCT is the only treatment available for R/R B-ALL. However, allo-HSCT lost much of its efficacy in cases with post-transplant relapse. It is a significant factor in graft failure. There is a strong association between pre-transplant MRD and recurrence 23,24 .Many patients are able to receive transplants thanks to blinatumomab's increased MRD-negative patient rate and decreased AE rate compared to chemotherapy 3 .In recent years, blinatumomab has been used to bridge R/R B-ALL cases to allo-HSCT after reaching CR. However, the transplant-related toxicities of blinatumomab after CR remain mainly unclear 25 . While longer follow-up is needed, in this study, the rates of post-transplant complications such as viral infection, acute/chronic GVHD, or EBV-related post-transplant lymphoproliferative disease were not increased in cases receiving allo-HSCT after blinatumomab treatment 25–28 . In veno-occlusive disease, the severe toxic effect among patients receiving inotuzumab ozogamicin, was not associated with blinatumomab treatment 26 . Blinatumomab activates internal cytotoxic T cells to kill blasts carrying the CD19 molecule. Therefore, those who undergo a blinatumomab bridge transplant may experience more immune-related complications 25 . In this study, nine individuals underwent allo-HSCT after receiving blinatumomab, and one (11.1%) experienced TA-TMA, which is contradictory to earlier studies, where they showed Chinese patients have a higher incidence of TA-TMA 29 . Further investigations are needed to determine if this medication increases TA-TMA risk in Chinese individuals. It would be fascinating to see further studies on how blinatumomab affects regulatory/cytotoxic T-cells, the duration of remission, and immune-related problems following allo-HSCT. These findings reveal a high incidence of AEs. Rates of grade 3 or higher hematologic toxicity and infection have been found in 23.1% and 38.5% of cases, respectively. Patients receiving blinatumomab experienced hematologic toxicity at a rate comparable to those previously reported 3 . This high infection rate may be due to people waiting too long to treat it. The patient experiences bone marrow suppression, impaired immunological function, and an increased risk of infection while receiving blinatumomab for an extended period that overlaps with subsequent antileukemic therapy. However, our investigation had the following drawbacks: firstly, the present unicentric, retrospective work had few samples, significant individual variation, and numerous confounders. Secondly, we only employed a single treatment cycle, and some patients had unsatisfactory responses; it is unclear whether more cycles or drug combinations would further enhance these patients' outcomes. Finally, more study is needed to determine whether blinatumomab enhances the likelihood of immune-related side effects following bridging allo-HSCT. Conclusion In conclusion, this study discovered the effectiveness of blinatumomab in treating R/R B-ALL Chinese patients, with infection and hematologic toxicity as the main AEs. These results, however, need to be further backed up by larger, randomized, controlled trials that will be conducted at multiple centers. Declarations Data availability statement All data generated or analyzed during this study are included in this published article. Ethics statement The study was approved by the ethics review board of the first Affiliated Hospital of Zhengzhou University in accordance with the Declaration of Helsinki. Written informed consent was obtained from all individual patients included in the study. Authors' contributions JKZ, JXF and TTX collected data and performed statistical analysis; JKZ, JXF wrote the manuscript; YPS, FH and RG were responsible for study design, manuscript revision, and final version approval. HQZ, RQL, YYZ, YML, XSX, DMW and ZXJ contributed patient data, reviewed this manuscript, and gave their final approval for submission. Funding The present study was funded by Natural Science Foundation of Henan Province (182300410301), Medical Science and Technology Research Project of Henan Province (SBGJ202102147, SBGJ202003036, 2018020118), Science and Technology Plan of Henan Province (182102310160), Project of Higher Education of Henan Province (18A320050). Acknowledgments We thank all the patients who participated in this study and their families. Competing interests The authors declare that they have no competing interests. References Kiyoi, H. et al. 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Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBAC9gYILQeh2IjQwnMAQhuTriWxgXgt7Icfv+apuJc+v/+MAcOHssMM/LMbCGjhSTOz5jlTnNvYcMaAcca5wwwSdw7g12IvwcNmzNuWkNvM2GPAzNt2mMFAIoGALVAt6WzMPAbMf4nUwvwYqCWBhw2ohZEoLUC/MM45k2A4g4et4GDPuXQeiRuEtABD7MObigR5+f7DGx/8KLOW459BQAsQsEnAWAdAZhBUDwTMH4hRNQpGwSgYBSMYAABrmjiRRNFt4gAAAABJRU5ErkJggg==","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Guo","suffix":""}],"badges":[],"createdAt":"2022-11-24 14:44:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2309595/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2309595/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":35688779,"identity":"c11ba97c-5cba-4b2f-8b76-9ac115252b3f","added_by":"auto","created_at":"2023-04-13 05:44:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":315003,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2309595/v1/f6b2321e-53d8-4ff9-b5f6-5050b2c0c47c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical utilization of blinatumomab in Chinese monocentric patients with relapsed or refractory B-cell acute lymphoblastic leukemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003e5-year overall survival (OS) rates for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) range from 10\u0026ndash;50%\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e. Although the development of targeted medications like tyrosine kinase inhibitors has improved outcomes for some subsets of people with R/R B-ALL, allo-HSCT continues to be an exceptional treatment \u003csup\u003e4,5\u003c/sup\u003e. Multiple studies have linked MRD to response duration and cure rates in R/R B-ALL, making it an important prognostic marker \u003csup\u003e4,6\u003c/sup\u003e. The prognosis of patients who test negative for MRD prior to HSCT is consistently better than that of patients who test positive for MRD \u003csup\u003e7\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eR/R B-ALL targets CD19 because this transmembrane protein is highly expressed on the surface of B-lymphocyte \u003csup\u003e8,9\u003c/sup\u003e. Blinatumomab, the bispecific T-cell engager, draws both CD3\u0026thinsp;+\u0026thinsp;T cells and CD19\u0026thinsp;+\u0026thinsp;B cells, leading to the B cell lysis \u003csup\u003e10\u003c/sup\u003e. It is approved for both adult and pediatric R/R B-ALL. According to a multicenter retrospective analysis on R/R B-ALL in children and adolescents, the complete response (CR) rate of blinatumomab was 39% among patients with \u003cb\u003e\u0026ge;\u003c/b\u003e\u0026thinsp;5% BM blasts, and the complete MRD response rate was 81% among CR cases with positive MRD, demonstrating good efficacy and safety \u003csup\u003e11\u003c/sup\u003e. Blinatumomab significantly improves the CR rate and increases OS in adult patients compared to chemotherapy, leading to prolonged survival\u003csup\u003e12,13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, most of the aforementioned studies were conducted in Europe or the United States. Few studies have been conducted on the current blinatumomab usage in Chinese patients. To evaluate whether blinatumomab was effective and safe among Chinese cases, this work summarized blinatumomab treatment outcomes among 39 R/R B-ALL cases.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThe retrospective analysis of this study enrolled 39 R/R B-ALL patients treated with blinatumomab at the First Affiliated Hospital of Zhengzhou University between October 2021 and August 2022. R/R B-ALL was diagnosed according to National Comprehensive Cancer Network (NCCN) guidelines \u003csup\u003e14\u003c/sup\u003e.The Ethics Committee of First Affiliated Hospital of Zhengzhou University approved the present study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003eAccording to the percentage of BM blasts, all cases were divided into two groups: those with less than 5% and those with more than 5% of BM blasts (but MRD positive). For those with more than or equal to 5% BM blasts, blinatumomab was administered at the following doses for four weeks: 5 \u0026micro;g/m\u003csup\u003e2\u003c/sup\u003e (maximum 9 \u0026micro;g/d) was given in week 1, and then 15 \u0026micro;g/m\u003csup\u003e2\u003c/sup\u003e (maximum 28 \u0026micro;g/d); while for those with less than 5% BM blasts, 15 \u0026micro;g/m\u003csup\u003e2\u003c/sup\u003e (maximum 28 \u0026micro;g/d) was administered over the course of four weeks. To avoid infusion responses, all patients received dexamethasone (5 mg/m\u003csup\u003e2\u003c/sup\u003e) prior to treatment. The infusion was stopped if the following grade 3 neurological events associated with blinatumomab occurred: tumor lysis syndrome, cytokine release syndrome (CRS), or disseminated intravascular coagulation/coagulopathy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAssessments of safety and efficacy\u003c/h2\u003e \u003cp\u003eTreatment was concluded with bone marrow aspiration to assess the clinical effectiveness of this work. According to the NCCN guideline \u003csup\u003e14\u003c/sup\u003e, responses are divided into complete response (CR), CR with partial/incomplete hematologic recovery (CRh/CRi), progressive disease (PD), and relapse. Overall relative risk (ORR)\u0026thinsp;=\u0026thinsp;CR\u0026thinsp;+\u0026thinsp;CRh\u0026thinsp;+\u0026thinsp;Cri. Two methods, real-time PCR (RT-PCR) and flow cytometry (FCM) were used to determine MRD \u003csup\u003e15\u003c/sup\u003e. In the absence of visible blasts, the condition was considered a complete MRD response \u003csup\u003e1\u003c/sup\u003e. Every adverse event (AE) reported from the beginning of treatment through 30 days after the last injection was graded according to National Cancer Institute standards (version 4.03).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePatients were followed till October 31, 2022. The primary endpoints were CR, CRh, CRi or complete MRD response, while secondary endpoints included AEs and OS (duration between treatment initiation and all-cause mortality). SPSS ver. 26.0 was used for the statistical analysis. Fisher's exact test was used to compare categorical variables between groups, expressed as frequency (percentages). The OS was evaluated by Kaplan-Meier (KM) approach. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (two-sided) stands for statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient basic features\u003c/h2\u003e \u003cp\u003eThirty-nine people participated in the study and were treated with blinatumomab infusions (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Nineteen patients (48.7%) had\u0026thinsp;\u0026ge;\u0026thinsp;5% BM blasts, eighteen (46.2%) were aged 18 years or older, and twenty-five (64.1%) were male. Patients typically underwent between two to twenty chemotherapy cycles before beginning blinatumomab (median, 5). Thirteen patients (33.3%) were positive for Philadelphia chromosome (Ph) acute lymphoblastic leukemia. The most common alterations were IKZF1, TP53, NRAS, and KRAS mutations.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the patient(N\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow blasts, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian number of chemotherapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(2\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytogenetic group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePh+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePh-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIKZF1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTP53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNRAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKRAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical Efficacy\u003c/h3\u003e\n\u003cp\u003eThe ORR and OS were 63.2% and 11 (range 7.3\u0026ndash;14.7) months among the nineteen patients with \u0026ge;\u0026thinsp;5% BM blasts. Eight (42.1%) patients reached CR, three (15.8%) reached CRh, and one (5.3%) reached CRi. There was no significant difference in overall response rate (ORR) between males and females, younger and older patients, those with and without a positive or negative Ph, and those with a low or high percentage of BM blasts.\u003c/p\u003e \u003cp\u003eThe median OS was not unavailable for 20 patients with \u0026lt;\u0026thinsp;5% BM blasts, of whom 17 (85%) achieved a complete MRD response. There was no statistically significant difference when comparing males to females, under-18 to over-18, and Ph-positive vs. Ph-negative complete MRD response rates. Response to treatment in patients with various clinical characteristics are listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResponse to treatment in patients with various clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with \u0026ge;\u0026thinsp;5% BM blasts\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatients with \u0026lt;\u0026thinsp;5% BM blasts\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatients with ORR(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComplete MRD response\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12(92.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(85.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(71.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9(81.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7(77.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8(88.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytogenetic group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePh+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6(85.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePh-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11(64.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBM blasts, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7(63.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eBM: bone marrow; ORR: overall response rate; MRD: minimal residual disease; Ph: Philadelphia chromosome.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eAllo-hsct And Post-transplant-related Complications\u003c/h3\u003e\n\u003cp\u003eAfter receiving blinatumomab, nine individuals underwent allo-HSCT while in continuous remission. One (11.1%) of them had acute graft-versus-host disease (GVHD), and one (11.1%) experienced TA-TMA in the first month after the transplant. One patient (11.1%) acquired Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia on day 27 post-transplant. At day\u0026thinsp;+\u0026thinsp;165 after the transplant, one (11.1%) patient experienced chronic GVHD.\u003c/p\u003e\n\u003ch3\u003eRecurrence And Survival\u003c/h3\u003e\n\u003cp\u003eAs of October 31, 2022, two patients had relapsed: one while waiting for allo-HSCT and another after the transplant. Seven patients ultimately passed away at the hospital: four from sepsis, two from disease progression, and one from a cerebral hemorrhage.\u003c/p\u003e\n\u003ch3\u003eAes\u003c/h3\u003e\n\u003cp\u003eIn total, 27 patients (69.2%) reported having at least one AE. There were 14 (35.9%) and 8 (20.5%) patients who experienced AEs of grades 3 and 4, respectively. The most common adverse events (AEs) involve the blood and immune system. Only one patient had a severe case of CRS, whereas two others experienced mild neurological events (tremor). AEs experienced by patients are listed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of adverse events\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eNO. (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny adverse event, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (69.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (35.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (20.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (20.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (15.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePyrexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological events (tremor)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCRS: cytokine release syndrome\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eR/R B-ALL is associated with dismal prognostic outcomes, even though ALL survival has greatly improved in the past few decades. Blinatumomab, a bispecific T cell-engager antibody construct, has shown promising results and potential uses in treating R/R B-ALL \u003csup\u003e10\u003c/sup\u003e. Unfortunately, there is a lack of research on the current blinatumomab usage among Chinese patients. Therefore, we evaluated the efficacy and safety of blinatumomab in R/R B-ALL patients in China.\u003c/p\u003e \u003cp\u003eIn cases showing\u0026thinsp;\u0026ge;\u0026thinsp;5% BM blasts, 12 patients (63.2%) achieved CR/CRi/CRh, with 10 of those patients achieving a complete MRD response; 17 patients (85%) of those with \u0026lt;\u0026thinsp;5% BM blast had a complete MRD response. These response rates are consistent with those that have been previously reported\u003csup\u003e12,15\u0026minus;17\u003c/sup\u003e. Notably, there was no discernible difference in response rates between those with Ph\u0026thinsp;+\u0026thinsp;and those with Ph-ALL. This demonstrates that blinatumomab has the potential to reverse the poor prognosis of Ph\u0026thinsp;+\u0026thinsp;patients and provide them with the same level of effectiveness as Ph- patients. There was no correlation between T315I mutations and the therapeutic efficacy of blinatumomab in R/R Ph\u0026thinsp;+\u0026thinsp;ALL \u003csup\u003e18\u003c/sup\u003e. Couturier et al. analyzed twenty-six cases of R/R Ph\u0026thinsp;+\u0026thinsp;ALL treated with ponatinib and blinatumomab retrospectively \u003csup\u003e19\u003c/sup\u003e. They discovered that ponatinib, in combination with blinatumomab, could further improve the prognosis of these patients, as 25 (96.2%) of them achieved CR and 23 (88.5%) had a complete MRD response.\u003c/p\u003e \u003cp\u003eMultiple studies have linked the tumor burden of patients to the effectiveness and median OS of blinatumomab \u003csup\u003e15,20,21\u003c/sup\u003e. Despite there being no statistically significant difference, patients in this trial with a higher percentage of baseline BM blasts (\u0026gt;\u0026thinsp;50%) had a poorer ORR and a shorter median OS. The only baseline factor that predicts how blinatumomab-treated individuals would fare is their tumor load \u003csup\u003e15\u003c/sup\u003e. We hypothesize that the tumor burden is a measure of leukemia aggressiveness and that patients with a high tumor burden have more aggressive leukemia \u003csup\u003e18\u003c/sup\u003e. This may shed light on why patients with high tumor burden have such a low response rate. Blinatumomab has significantly improved survival over chemotherapy in cases with a high tumor burden in the bone marrow \u003csup\u003e12\u003c/sup\u003e. However, patients who do not respond to blinatumomab still face a dismal prognosis; some research suggests that adding other antibodies, like inotuzumab ozogamicin, to the mix can improve prognosis \u003csup\u003e13,17,22\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo date, allo-HSCT is the only treatment available for R/R B-ALL. However, allo-HSCT lost much of its efficacy in cases with post-transplant relapse. It is a significant factor in graft failure. There is a strong association between pre-transplant MRD and recurrence \u003csup\u003e23,24\u003c/sup\u003e.Many patients are able to receive transplants thanks to blinatumomab's increased MRD-negative patient rate and decreased AE rate compared to chemotherapy \u003csup\u003e3\u003c/sup\u003e.In recent years, blinatumomab has been used to bridge R/R B-ALL cases to allo-HSCT after reaching CR. However, the transplant-related toxicities of blinatumomab after CR remain mainly unclear \u003csup\u003e25\u003c/sup\u003e. While longer follow-up is needed, in this study, the rates of post-transplant complications such as viral infection, acute/chronic GVHD, or EBV-related post-transplant lymphoproliferative disease were not increased in cases receiving allo-HSCT after blinatumomab treatment \u003csup\u003e25\u0026ndash;28\u003c/sup\u003e. In veno-occlusive disease, the severe toxic effect among patients receiving inotuzumab ozogamicin, was not associated with blinatumomab treatment \u003csup\u003e26\u003c/sup\u003e. Blinatumomab activates internal cytotoxic T cells to kill blasts carrying the CD19 molecule. Therefore, those who undergo a blinatumomab bridge transplant may experience more immune-related complications \u003csup\u003e25\u003c/sup\u003e. In this study, nine individuals underwent allo-HSCT after receiving blinatumomab, and one (11.1%) experienced TA-TMA, which is contradictory to earlier studies, where they showed Chinese patients have a higher incidence of TA-TMA \u003csup\u003e29\u003c/sup\u003e. Further investigations are needed to determine if this medication increases TA-TMA risk in Chinese individuals. It would be fascinating to see further studies on how blinatumomab affects regulatory/cytotoxic T-cells, the duration of remission, and immune-related problems following allo-HSCT.\u003c/p\u003e \u003cp\u003eThese findings reveal a high incidence of AEs. Rates of grade 3 or higher hematologic toxicity and infection have been found in 23.1% and 38.5% of cases, respectively. Patients receiving blinatumomab experienced hematologic toxicity at a rate comparable to those previously reported\u003csup\u003e3\u003c/sup\u003e. This high infection rate may be due to people waiting too long to treat it. The patient experiences bone marrow suppression, impaired immunological function, and an increased risk of infection while receiving blinatumomab for an extended period that overlaps with subsequent antileukemic therapy.\u003c/p\u003e \u003cp\u003eHowever, our investigation had the following drawbacks: firstly, the present unicentric, retrospective work had few samples, significant individual variation, and numerous confounders. Secondly, we only employed a single treatment cycle, and some patients had unsatisfactory responses; it is unclear whether more cycles or drug combinations would further enhance these patients' outcomes. Finally, more study is needed to determine whether blinatumomab enhances the likelihood of immune-related side effects following bridging allo-HSCT.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this study discovered the effectiveness of blinatumomab in treating R/R B-ALL Chinese patients, with infection and hematologic toxicity as the main AEs. These results, however, need to be further backed up by larger, randomized, controlled trials that will be conducted at multiple centers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics review board of the first Affiliated Hospital of Zhengzhou University\u0026nbsp;in accordance with the Declaration of Helsinki. Written informed consent was obtained from all individual patients included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJKZ, JXF and TTX collected data and performed statistical analysis;\u0026nbsp;JKZ, JXF wrote the manuscript; YPS, FH and RG were responsible for study design, manuscript revision, and final version approval. HQZ, RQL, YYZ, YML, XSX, DMW and ZXJ contributed patient data, reviewed this manuscript, and gave their final approval for submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study was funded by Natural Science Foundation of Henan Province (182300410301), Medical Science and Technology Research Project of Henan Province (SBGJ202102147, SBGJ202003036, 2018020118), Science and Technology Plan of Henan Province (182102310160), Project of Higher Education of Henan Province (18A320050).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients who participated in this study and their families.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKiyoi, H. \u003cem\u003eet al.\u003c/em\u003e Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia. \u003cem\u003eCancer Sci\u003c/em\u003e \u003cstrong\u003e111\u003c/strong\u003e, 1314\u0026ndash;1323, doi:10.1111/cas.14322 (2020).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003eParker, C. \u003cem\u003eet al.\u003c/em\u003e Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e376\u003c/strong\u003e, 2009\u0026ndash;2017, doi:10.1016/S0140-6736(10)62002-8 (2010).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003eBrown, P. 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R. \u003cem\u003eet al.\u003c/em\u003e Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. \u003cem\u003eHaematologica\u003c/em\u003e \u003cstrong\u003e101\u003c/strong\u003e, e465-e468 (2016).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003eYe, Y. \u003cem\u003eet al.\u003c/em\u003e Risk and prognostic factors of transplantation-associated thrombotic microangiopathy in allogeneic haematopoietic stem cell transplantation: a nested case control study. \u003cem\u003eHematol Oncol\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, 821\u0026ndash;827, doi:10.1002/hon.2310 (2017).\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Blinatumomab, R/R B-ALL, ORR, complete MRD response, AEs, allo-HSCT ","lastPublishedDoi":"10.21203/rs.3.rs-2309595/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2309595/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eBlinatumomab has promising applications in treating relapsed or refractory B-cell\u003cstrong\u003e \u003c/strong\u003eacute lymphoblastic leukemia (R/R B-ALL). However, there are few studies on using blinatumomab for treating R/R B-ALL patients in China. Therefore, we evaluated the efficacy and safety of blinatumomab among Chinese R/R B-ALL patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eIn total, 39 R/R B-ALL patients who received blinatumomab between October 2021 and August 2022 were selected as the study subjects. The primary endpoints include overall response rate (ORR)\u003cstrong\u003e \u003c/strong\u003eand complete minimal residual disease (MRD) response. Secondary endpoints included overall survival (OS) and adverse events\u003cstrong\u003e \u003c/strong\u003e(AEs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The ORR and OS for 19 patients with less than 5% bone marrow (BM) blasts were 63.2% and 11 months (7.3–14.7), respectively. The median OS for the 20 patients was unavailable, and 17 (or 85%) had a full MRD response. Twenty-seven patients (69.2%) reported having at least 1 AE. Hematologic toxicity and infections were the most common AEs. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed on nine patients who had been remission-free for a long time. In the first month, one patient (11.1%) developed thrombotic microangiopathy associated with HSCT (TA-TMA) following transplantation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn R/R B-ALL patients, blinatumomab is an effective option in China.\u003c/p\u003e","manuscriptTitle":"Clinical utilization of blinatumomab in Chinese monocentric patients with relapsed or refractory B-cell acute lymphoblastic leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-11-30 08:22:14","doi":"10.21203/rs.3.rs-2309595/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b988fbff-9f68-44cc-a115-ce84ecc25978","owner":[],"postedDate":"November 30th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":17256379,"name":"Biological sciences/Cancer/Cancer therapy"},{"id":17256380,"name":"Biological sciences/Cancer/Haematological cancer"}],"tags":[],"updatedAt":"2023-04-13T05:44:29+00:00","versionOfRecord":[],"versionCreatedAt":"2022-11-30 08:22:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2309595","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2309595","identity":"rs-2309595","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}