Clinical Challenging Cases series: Novel Options for Refractory Cancer Therapy-induced Thrombocytopenia（r-CTIT）

Clinical Challenging Cases series: Novel Options for Refractory Cancer Therapy-induced Thrombocytopenia（r-CTIT） | 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 Clinical Challenging Cases series: Novel Options for Refractory Cancer Therapy-induced Thrombocytopenia（r-CTIT） Li-Li Hong, Qiang Wen, Hai-Li Zhou, Shou-Jun Wang, Kai-Li Chen, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3798488/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 Refractory cancer therapy-induced thrombocytopenia (r-CTIT) presents a life-threatening complication of tumor therapy, for which there is currently no established and effective long-term treatment. Methods Umbilical cord blood (UCB) is rich in hematopoietic stem cells with multi-lineage differentiation potential, while umbilical cord mesenchymal stem cells (UC-MSCs) have been shown to support megakaryocytopoiesis and regulate the bone marrow microenvironment. The components of cells have demonstrated great value in the treatment of hematopoietic failure diseases, especially in patients with r-CTIT.To investigate the impact of intravenous sequential infusion of UCB and UC-MSCs in patients with r-CTIT, we conducted a follow-up study. Results Among the 13 patients evaluated, the platelet response rate was 84.6% (11/13). Complete response (CR) was observed in 53.8% (7/13) of the patients, while partial response (PR) was seen in 84.6% (9/13) of the patients. The median time for platelet recovery in all patients was 53 days (range: 6-217 days). Our findings revealed that the infusion of UCB and UC-MSCs in r-CTIT patients has shown positive effects on erythroid and neutrophil levels, with an 84.6% erythroid response rate (11/13) and a 92.3% improvement in neutrophil count. Furthermore, no severe adverse reactions to the infusion were observed. Conclusions Based on our study, we can conclude that the sequential infusion of UCB and UC-MSCs can be a novel and promising therapeutic approach for r-CTIT patients. UCB (umbilical cord blood) UC-MSCs (umbilical cord mesenchymal stem cells) Refractory cancer therapy-induced thrombocytopenia (r-CTIT) Bone marrow microenvironment. Figures Figure 1 Figure 2 Figure 3 Introduction Cancer therapy-induced thrombocytopenia (CTIT) is a common complication following anti-tumor therapy resulting from radiotherapy, chemotherapy, monoclonal antibodies, and targeted therapy. The degree of CTIT can be influenced by various factors such as tumor type, type and dosage of anti-tumor drugs used. CTIT is defined as a platelet count of less than 100x10^9/L after anti-tumor therapy and is categorized into different grades based on the platelet count: grade 1 (75x10^9/L to less than 100x10^9/L), grade 2 (50x10^9/L to less than 75x10^9/L), grade 3 (25x10^9/L to less than 50x10^9/L), and grade 4 (less than 25x10^9/L)[ 1 ]. Among these, refractory cancer therapy-induced thrombocytopenia (r-CTIT), defined as a platelet count less than 20x10^9/L and unresponsive to two different kinds of platelet-promoting agents, is the most serious type. While the intensity of anti-tumor drugs is often associated with therapeutic efficacy, higher drug intensity can intensify thrombocytopenia, thereby increasing the risk of bleeding. As a result, r-CTIT can impede treatment progress and adversely affect long-term survival. Therapeutic strategies for CTIT typically involves platelet transfusion, recombinant human interleukin-11(rhIL-11), and thrombopoietin (TPO) replacement therapy to stimulate platelet production, which includes recombinant human thrombopoietin (rhTPO) and thrombopoietin receptor agonists (TPO-RA) such as romiplostim, eltrombopag, avatrombopag [ 2 – 4 ]. However, for patients with r-CTIT, these therapies have demonstrated poor clinical outcomes. Single platelet transfusion is not a long-term solution, and repeated transfusions can induce transfusion resistance [ 5 ]. Platelet-promoting agents can increase platelet production, but they are only effective for some patients and may be discontinued due to adverse reactions during treatment [ 6 ]. Studies have shown that anti-tumor therapies can damage various cells and hematopoietic cytokines in the bone marrow, leading to hematopoietic disorders. Moreover, with the increasing complexity and integration of cancer treatments, more patients are experiencing severe and persistent bone marrow suppression, resulting in severe thrombocytopenia and pancytopenia. The management strategies for such refractory patients are often limited, and without effective treatment, r-CTIT can be life-threatening. Our study have also revealed a decrease in erythroid and granulocyte levels among these patients. Platelets are derived from megakaryocytes. Thrombopoietin, as a major regulator factor in bone marrow, plays a crucial role in promoting the differentiation of hematopoietic stem and progenitor cells into platelets. Thrombocytopoiesis initiates with HSCs, which differentiate into megakaryocyte progenitors and eventually mature into platelets. Human umbilical cord blood (UCB) is abundant in relatively primitive hematopoietic stem and progenitor cells, making it an important source of stem cells. UCB has gained widespread attention for its potential to generate platelets due to several advantages, including its wide source, weak surface antigenicity, higher proliferation potential compared to bone marrow counterparts, greater compatibility for HLA match, and a comparatively lower risk for graft-vs-host disease (GVHD) [ 7 ]. The first successful UCB transplant using UCB as a source of hematopoietic cells was performed to treat a child with Fanconi anemia [ 8 ]. Nowadays, UCB is considered as an alternative source of HSCs for allogeneic HSC transplantation in the treatment of hematologic disorders and other genetic diseases. Matsunaga et al. has demonstrated the capacity of UCB-HSCs to generate clinically useful quantities of platelets [ 9 ]. MSCs possess the ability to differentiate into cellular components that support the hematopoietic microenvironment. Emerging studies indicate a growing therapeutic potential of MSCs for thrombocytopenia [ 10 , 11 ]. MSCs have been validated in cases of prolonged isolated thrombocytopenia following allogeneic hematopoietic stem cell transplantation [ 12 ]. UC-MSCs, which are easily accessible and have lower antigenicity, have been used for graft-versus-host disease. However, our study represents the first treatment attempt for r-CTIT patients. The application and study of stem cell transplantation technology in hematopoietic failure diseases also offer a new idea for treating r-CTIT. We propose a new method that utilizes UCB units as the source of hematopoietic stem, progenitor cells, and mesenchymal stem cells to provide a hematopoietic niche for producing functional platelets. In this study, we analyzed r-CTIT patients who received sequential infusions of UCB and UC-MSCs in order to provide an effective treatment strategy for these patients. Methods Patients and clinical data Patients diagnosed with various types of tumors have undergone conventional anti-tumor therapies, including chemotherapy, radiotherapy, monoclonal antibodies, and targeted therapy. In this study, we define r-CTIT as a condition where the platelet count remains below 20x109/L and is unresponsive to at least two different platelet-promoting agents. A total of 13 r-CTIT patients were screened at our center from May 1, 2020, to May 1, 2023. All patients are expected to be free of primary disease progression within 6 months. The treatment approach involved sequential infusions of UCB and UC-MSCs. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2019-X-031-02), in accordance with the Declaration of Helsinki. Treatment Procedure The occurrence time of r-CTIT was defined as the first instance of a platelet count below 20×109/L accompanied by treatment failure using two different platelet-promoting agents. The duration of CTIT was defined as the time elapsed from r-CTIT diagnosis to the initiation of infusion treatment. UCB units and UC-MSCs were obtained from Zhejiang Province UCB bank. HLA typing for patients and UCB units was performed at the UCB unit bank. UC-MSCs were infused with a single administration of 1.0×107 MSCs/kg body weight. R-CTIT patients received a sequential infusion treatment of UCB and UC-MSCs. The therapy regimen is as follows (Fig. 1 ): day 0 was defined as the date of r-CTIT diagnosis, where a single UCB unit was infused sequentially followed by weekly infusions of UC-MSCs for 2–3 weeks. Glucocorticoids were administered prior to transfusion to prevent infusion reactions. All patients received a subcutaneous injection of recombinant human granulocyte colony-stimulating factor (G-CSF) at a dose of 5 ~ 10 mg/kg/d until the neutrophil count reached 1.5×109/L. Thrombopoietin or other forms of TPO replacement therapy was continuously administered, or discontinued when the platelet count increased to 100×109/L. Efficacy Criteria and Safety The time of onset is defined as the duration from the initiation of treatment to the attainment of efficacy. The response evaluation encompasses complete response and partial response. Complete response (CR) is defined as a PLT count ≥ 50×109/L without PLT transfusion for 7 consecutive days. Partial response (PR) is defined as a PLT count of 20–50 ×109/L without PLT transfusion for 7 consecutive days. No response (NR) is defined as by a PLT count < 20×109/L or the need for PLT transfusion after 24 weeks of treatment. Adverse reactions were assessed in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 [ 1 ]. Statistical Analysis The statistical analysis was conducted using SPSS 28.0 software. The data were presented as mean ± standard deviation. Kaplan-Meier survival analysis was employed to assess overall survivals. P < 0.05 was considered to have a statistically significant difference. Results Patients , characteristics A total of 13 r-CTIT patients who underwent cell infusion therapy between May 1, 2020 and May 1, 2023 were included in this study. The clinical characteristics of these patients are summarized in Table 1 . The follow-up period ranged from 20 to 1053 days (median, 252 days). Among the enrolled patients, there were 12 females and 1 male, with ages ranging from 17 to76 years (median, 63 years). The distribution of primary malignancies was as follows: 1 endometrial cancer, 1 rectal cancer, 1 osteosarcoma, 6 ovarian malignancies, 3 breast cancers, and 1 primary myelofibrosis. Patients with non-hematologic malignancies exhibited stable disease. 10 patients had an ECOG score of 1 while 3 had a score of 2. 8 patients had concomitant infections, including 2 cases of pneumonia (1 severe), 2 cases of bloodstream infection, 1 case of abdominal infection, 2 cases of COVID-19 infection, and 1 case of gum infection. No patient had cytomegalovirus infection, but 3 patients were found to have Epstein-Barr viremia. 2 patients were complicated by deep vein thrombosis. All patients presented with varying degrees of bleeding, primarily manifested as skin, mucous membrane, and gingival bleeding. One patient suffered from multiple epidural hemorrhages that did not respond to regular platelet transfusion and required matching platelet transfusion. The anti-tumor treatment regimen comprised of radiotherapy, chemotherapy, monoclonal antibody drugs, and targeted therapy. Chemotherapy drugs administered included paclitaxel, pemetrexed, docetaxel, epirubicin, cisplatin, carboplatin, cyclophosphamide, adriamycin, and demethylation drugs. Monoclonal antibodies such as bevacizumab, trastuzumab, and pembrolizumab were also used. 4 patients received concurrent chemoradiotherapy. Platelet-promoting agents for CTIT consisted of interleukin-11 (IL-11), thrombopoietin (TPO) and thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag and avatrombopag. All patients were treated withTPO and TPO-RAs, while 7 also received intravenous gamma globulin and 5 were treated with IL-11. All patients were administered two different types of drugs, with 10 receiving more than three different drugs. 11 patients presented with an absolute neutrophil count below 1.0×109/L, with 6 cases below 0.5×109/L. The median hemoglobin level was 62 g/L (range: 35-95g/L) with 6 patients having levels below 60 g/L. The platelet counts of all patients were less than 20×109/L, with 11 patients below 10×109/L and 7 patients below 5×109/L; two patients did not respond to regular platelet transfusion. One patient experienced multiple epidural hemorrhages prior to therapy and only responded to genotype platelet transfusions. All patients had mild to moderate bleeding symptoms, including skin, oral cavity, nasal bleeding and so on. Before receiving treatment, bone marrow aspiration and biopsy were performed on R-CTIT patients. Among them, 5 patients showed hypoplasia or extremely hypoplasia of bone marrow, while 5 patients showed no presence of megakaryocytes in bone marrow. 1 patient exhibited an abnormal karyotype of 46, XX, t(3;7)(q26;q21)[ 17 ]/46, XX[ 3 ]. Additionally, 3 patients with non-hematologic malignancies presented myeloid gene mutations, including MPL mutation, ZRSR2 mutation, as well as CBL, DNMT3A, FLT3, IDH2, KDM6A, and NF1 mutations. The HLA typing, number of infused cells, and chimerism data for all UCB units are presented in Table 2 . The median count of CD34 + cells was 2.37×105/kg (range: 1.23 to 6.2 ×105/kg), while the median total nucleated cell (TNC) count was 7.72 ×107/kg (range: 3.5 to 9.33 ×107/kg). Chimerism detection was completed for two patients. Table 1 Baseline characteristics of the patients (n = 13) ID Gender/Age Tumor type/ Disease status ECOG Infection Complications Previous antitumor drugs Previous therapy Bone marrow Previous PLT count (10^9/L) Previous N count (10^9/L) Previous HB count (g/L) 1 F/54 Endometrial carcinoma / SD 1 no Mild or moderate bleeding • Paclitaxel; Cisplatin G;I;T;E;A Hypoplasia of marrow , with two megakaryocyte;nomroal karyotype;NGS: MPL mutation 3 0.7 76 2 M/72 Rectal cancer / SD 2 pneumonia Mild or moderate bleeding • Capecitabine ;oxaliplatin G;T;E Hypoplasia , without megakaryocytes; nomroal karyotype;ZRSR2 mutation 3 0.3 95 3 F/52 Ovarian cancer / SD 1 no Multiple epidural hemorrhages • Paclitaxel ;carboplatin G;T;E;A Hyperplastic;2 megakaryocytes; nomroal karyotype 2 0.7 59 4 F/67 Ovarian cancer / SD 1 no Mild or moderate bleeding • Paclitaxel; Cisplatin; • bevacizumab T;E;A Hyperplastic;without megakaryocytes; nomroal karyotype 8 0.9 49 5 F/17 Osteosarcoma / SD 2 Bloodstream infection Mild or moderate bleeding • Methotrexate, doxorubicin, and cisplatin; Recombinant human endostatin T;I;E;A Hyperplastic;2 megakaryocytes; nomroal karyotype 7 0.1 56 6 F/67 Ovarian cancer / SD 1 Abdominal infection Mild or moderate bleeding • Paclitaxel ;carboplatin; doxorubicin, G;T;E;A Hyperplastic;2 megakaryocytes; nomroal karyotype;Mutation: CBL、DNMT3A、FLT3、IDH2、KDM6A、NF1 7 0.5 62 7 F/62 Breast cancer / SD 2 Severe pneumonia Mild or moderate bleeding • Epirubicin; cyclophosphamide,;paclitaxel I;T;E Hypoplasia , without megakaryocytes; karyotype: 46,XX,t(3;7)(q26;q21) 1 0.1 35 8 F/63 Breast cancer / SD 1 COVID-19 Mild or moderate bleeding Epirubicin;cyclophosphamide,;paclitaxel I;E Hypoplasia , without megakaryocytes; normal karyotype 2 0.2 42 9 F/75 Ovarian cancer / SD 1 no Mild or moderate bleeding • Paclitaxel; Cisplatin; bevacizumab T Hyperplastic;2 megakaryocytes; nomroal karyotype 18 1.8 79 10 F/48 Breast cancer / SD 1 no Mild bleeding • Paclitaxel,;trastuzumab T;E Hypoplasia;without megakaryocytes,;nomroal karyotype; 14 0.7 90 11 F/50 Myelofibrosis / SD 1 Bloodstream infection Mild bleeding Homoharringtonine; G;I;T Extremely hypoplasia;without megakaryocytes,;nomroal karyotype; Mutation:JAK2,ASXL1 4 0.1 37 12 F/69 Ovarian cancer / SD 1 Gingival infection Mild or moderate bleeding • Paclitaxel; Carboplatin; • Adriamycin liposome; Bevacizumab; Niraparib G;I;T Hypoplasia;without megakaryocytes,;nomroal karyotype 3 1.6 78 13 F/76 Ovarian cancer / SD 1 COVID-19 Mild or moderate bleeding • Carboplatin; • Adriamycin liposome; G;I;T;E Hyperplastic;6megakaryocytes; nomroal karyotype 5 0.6 92 Table 2 Clinical data of UCB, UC-MSCs and chimerism. ID UCB HLA match TNC×10 7 /kg CD34 + ×10 5 /kg UC-MSCs (1×10 7 /kg, weekly) Chimerism % (d7, d14, d28) 1 7/10 6.3 6.2 8*3w NA 2 4/6 5.1 2.7 8*3w NA 3 6/10 5.2 3.12 7*3w NA 4 7/10 3.5 1.0 7*3w NA 5 6/10 4.2 1.23 5*3w NA 6 6/10 6.0 4.98 6*3w NA 7 6/10 8.5 5.44 6*3w NA 8 5/10 9.33 3.59 6*2w NA 9 7/10 5.3 1.06 6*2w NA 10 5/6 6.0 1.98 6*2w NA 11 7/10 8.04 3.45 6*2w 0.056; 1.833; 0.002 12 5/10 7.2 3.61 6*2w NA 13 8/10 9.14 2.37 5*3w 0.042; 0.05; 0.003 Abbreviation: UCB: umbilical cord blood; TNC: Total nucleated cells; UC-MSCs:umbilical cord mesenchymal stem cells NA: Not available. Hematopoietic Response The recovery time of blood cells was summarized in Table 3 , while the response was illustrated through a swimmer plot in Fig. 2 . The overall survival rate stood at 83.3%, as depicted in Fig. 3 . The median duration from r-CTIT diagnosis to treatment initiation was 147 days (range: 21–635 days). During follow-up, platelet response rate was 84.6% (11/13). 53.8% (7/13) patients achieved CR, while PR rate was 84.6% (9/13). The median time for platelet recovery in all patients was 53 days (range: 6-217 days). Erythroid response proportion was 84.6% (11/13), with a median response time of 35 days (range: 10–118 days). Neutrophil response rate was 92.3%(12/13), with a median granulocytic response time of 23 days (range: 6-150 days). During follow-up, only one patient with osteosarcoma passed away due to disease recurrence. Table 3 The blood cell recovery time. ID • Duration • of CTIT diagnosis to treatment initiation (d) Onset to start of treatment Duration time of PLT recovery to 20*10^9/L(d) Duration time of PLT recovery to 50*10^9/L(d) Duration time of PLT recovery to 100*10^9/L(d) • Duration time of HB ≥ 90×10^9/L or greater than 20% of the baseline level(d) Duration time of N recovery to 1.5*10^9/L(d) Effect evaluation Follow-up time Clinical outcomes 1 186 2020/6/12 217 243 482 56 28 CR 2023/5/1 Alive 2 37 2021/8/27 33 48 68 27 18 CR 2023/5/1 Alive 3 147 2021/9/9 54 61 233 52 13 CR 2023/5/1 Alive 4 217 2021/9/28 53 245 / 50 11 CR 2023/5/1 Alive 5 313 2021/4/15 138 / / 118 150 PR 2022/10/5 Death 6 391 2021/7/27 94 / / 35 23 PR 2023/5/1 Alive 7 635 2022/8/22 64 88 / 18 34 CR 2023/5/1 Alive 8 97 2023/2/15 48 / / 48 / PR 2023/5/1 Alive 9 390 2022/8/22 0 / / 10 / PR 2022/9/15 Alive 10 130 2022/11/24 20 29 34 11 7 CR 2023/5/1 Alive 11 38 2023/1/14 6 19 27 25 6 CR 2023/5/1 Alive 12 21 2023/2/9 0 / / / / NR 2023/5/1 Alive 13 125 2023/3/27 31 / / / 25 PR 2023/5/1 Alive Chimerism analysis revealed that one patient (through the analysis of short tandem repeat regions) had chimerism levels increasing from0.056% on day7 to 1.833% on day14, but decreasing again to 0.002% on day28. Another patient's chimerism level increased from 0.042% on day7 to 0.05% on day14, dropping down again to 0.003% one month after therapy. Safety None of the patients experienced graft-versus-host disease (GVHD). No severe adverse reactions was observed during the infusion process. Moreover, there were no reported cases of serious side effects or thrombotic events throughout the follow-up period. DISCUSSION The presence of r-CTIT hindered the treatment progress and adversely affected long-term survival. Unfortunately, there is currently no clearly effective treatment available to address this issue. Therefore, it is imperative to explore feasible and safe therapeutic methods. Through clinical observation, we have noted that r-CTIT patients often exhibit long-term thrombocytopenia characterized by a lack of megakaryocytes and persistent bone marrow hypoplasia, sometimes accompanied by erythropenia and neutropenia. Our study, presented here for the first time, indicates that UCB and UC-MSCs infusion for r-CTIT patients is feasible and safe. CTIT is a severe and fatal complication in cancer patients. In our study, the average age of the 13 patients was 63 years old, and they presented with poor physical status and serious complications after anti-tumor treatment. Epstein-Barr viremia was present in 3 patients, and 10 patients had received three types of platelet-promoting agents. Effective treatment strategies for these critically ill patients are lacking. The incidence and severity of CDIT vary among different patient populations and regimens. A recent study found among15,521 patients with solid tumors, the incidence of CTIT was 4% and 2%, developed grade 3 and grade 4 thrombocytopenia, respectively. Among 2537 patients with hematological malignancies, 16% developed grade 3 thrombocytopenia, and 12% had grade 4 [ 13 ]. Platinum and gemcitabine-based chemotherapy regimens were found to be most strongly associated with severe thrombocytopenia, with CTIT occurring in 82% of those receiving only carboplatin, and in 58%, 64%, and 59% of those receiving combination therapies with carboplatin, gemcitabine, or paclitaxel, respectively [ 14 ]. In our study, 9 patients had received platinum-based drugs as part of their chemotherapy regimen, resulting in 6 patients with severe neutropenia, 6 patients with severe anemia, and 11 patients with platelet counts less than 10×109/L. Additionally, 5 patients displayed acquired hematopoietic function failure, and 3 solid tumor patients had myeloid gene mutations. The CTIT mechanism is complex, as not all anti-tumor agents cause thrombocytopenia in the same way. For example, alkylating agents such as busulfan and carboplatin affect pluripotential stem cells [ 15 , 16 ], while cyclophosphamide acts on megakaryocyte progenitors [ 17 ]. Antibody-drug conjugates, on the other hand, inhibit megakaryocyte growth and differentiation [ 18 ]. All of those can reduce platelet production. Etoposide increases platelet destruction by reducing BCL-X (L) activity, leading to platelet apoptosis [ 19 ]. The impact of anti-tumor agents on various aspects of platelet formation contributes to a decrease in platelet count. Our study found that r-CTIT patients receiving various combinations of drugs experienced persistent thrombocytopenia, and even pancytopenia. We suspect that this is due to injuries at the early stages of HSC and progenitor cells involved in platelet formation. Therefore, we believe the underlying mechanism may be associated with hematopoietic stem cell injury and bone marrow microenvironment disorders. Anti-tumor therapy can impair various cells and cytokines, thereby reducing the self-renewal and proliferation ability of HSCs and destroying hematopoietic function of the bone marrow microenvironment [ 20 , 21 ]. HSCs have the potential to proliferate and differentiate into various types of mature blood cells. UCB, as an alternative source to bone marrow, offers several advantages including high proliferative potential, weak antigenicity, and a low incidence of GVHD [ 22 ]. Consequently, UCB has emerged as a promising therapy in various medical fields [ 23 , 24 ]. A clinical observation investigated that UCB infusion markedly improved chemotherapy-related myelosuppression. The underlying mechanism of UCB infusion is hypothesized to involve the production of large amounts of hematopoietic growth factors to activate stem cells and repair injured cells in the bone marrow [ 25 ]. UCB is also rich in HSCs, which theoretically have the ability to self-renew and differentiate into progenitor and mature cells. Therefore, UCB infusion has the capacity to reverse and restore hematopoiesis through producing functional blood cells. As an alternative stem cells source for hematopoietic stem cell transplantation (HSCT), one limiting factor of UCB lies in low number of cells per unit, which can result in delayed engraftment and immune reconstitution. HSCT is a process of replacing and reconstructing the hematopoietic system, in which the recipient receives HSC infusion. Prior to the infusion, the recipient typically undergoes conditioning regimens such as total body radiation therapy or a combination of cytotoxic drugs and immunosuppressive agents to ensure the successful engraftment of HSCs [ 26 ]. R-CTIT patients exhibit prolonged hypoplasia after exposure to radiation or cytotoxic drugs, resulting in structurally empty bone marrow and hematopoietic defects, similar to those seen in conditioning regimens for transplantation. Therefore, we hypothesized, whether UCB as a source of stem cell could rescue hematopoietic function obstacle. It is verified that UCB unit infusion without any immunosuppressive agents was safe. However, chimerism was detected in 2 patients at very low levels, and this gradually decreased after blood cell recovery. This suggests that UCB did not play a significant role in engraftment for reconstructing hematopoietic recovery. Transplanted UCB was eliminated by the host immune system and therefore did not permanently engraft in the recipient's bone marrow. However, recent studies have reported that UCB-derived megakaryocytes and progenitors can produce functional platelets. Xi et al explored the feasibility and safety of utilizing UCB-derived megakaryocytes and progenitors for the treatment of thrombocytopenia, especially in patients who received multiple rounds of high-dose radiotherapy and chemotherapy [ 27 ]. In future studies, it would be worthwhile to explore the components of UCB that could enhance platelet production. Chemoradiotherapy-induced hematopoietic damage is partially attributed to the loss of critical stromal and endothelial cell components within the hematopoietic niche, which provides structural and physiological support for hematopoiesis [ 28 ]. MSCs is an essential part of the bone marrow niche microenvironment and secrete a variety of chemokines and cytokines that facilitate the homing, proliferation, and differentiation of hematopoietic cells, thus playing a significant role in promoting hematopoietic recovery [ 29 ]. MSCs secrete numerous cytokines that act on HSCs and stromal cells, including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, stromal cell-derived factor, and vascular endothelial growth factor. Furthermore, studies have demonstrated that the infusion of mismatched allogeneic MSCs does not cause cell rejection, making it safe for clinical practice [ 30 ]. The first report describing the infusion of autologous MSCs during PBPC transplantation in advanced breast cancer patients prompted hematopoietic recovery, particularly in platelet counts [ 31 ]. More recently, MSCs have been reported to regulate megakaryocyte differentiation and contribute to platelet formation, indicating their potential in immunomodulation as well. BM-MSCs have been shown to increase platelet counts in mice with ITP by upregulating regulatory T cells and the secretion of cytokines (IL-10 and TGF-β1). Additionally, intravenous infusion of UC-MSCs has been reported to improve platelet counts in patients with chronic refractory immune thrombocytopenia [ 32 ]. Thrombocytopenia is categorized into primary and secondary forms, with the latter one potentially associated with infections such as COVID-19. With the widespread use of immune-targeted therapies, immune-related thrombocytopenia has become more prevalent. The immunomodulatory, engraftment-promoting, and reparative properties of MSCs have been extensively studied in preclinical models and clinical trials. In our study, the overall platelet response rate was 84.6%. The median time to platelet response was 53 days, with erythroid response occurring at a median of 35 days and granulocyte response at a median of 23 days. Importantly, no severe infusion reactions were reported during the infusion therapy, and no GVHD occurred throughout the observation period. It is worth noting that among the patients included in the study, 8 individuals had co-existing severe infections. Out of these, 7 patients achieved recovery, while unfortunately, one patient with osteosarcoma died due to disease recurrence. The bone marrow serves as an immune organ in the body, and its compromised function can lead to significant deficiencies in the ability to combat infections. Therefore, we hypothesize that sequential infusion of UCB combined with UC-MSCs may possess anti-infection potential and help alleviate myelosuppression symptoms. This effect could be attributed to the immunomodulatory properties of the infused cells. The observation indicated that infusion of UCB and UC-MSCs is beneficial for r-CTIT patients. We speculate that the following mechanisms may be involved: UCB's ability to provide temporary hematopoietic recovery, enhance cell survival in damaged cells, and promote megakaryocyte differentiation into platelets. UC-MSCs, acting as a hematopoietic niche, could promote immune and hematopoietic recovery while moderating inflammatory response. However, it remains unclear whether UCB and UC-MSCs directly improve hematopoiesis, thus further experiments are needed to confirm this. Conclusion In conclusion, our study presents a novel and salvage therapeutic approach for patients with life-threatening r-CTIT. The sequential infusion of UCB combined with UC-MSCs demonstrated significant efficacy, good safety, and no obvious side effects in r-CTIT patients. Prospective studies are warranted to further explore the underlying mechanisms of UCB and UC-MSCs in the treatment of r-CTIT. Declarations Date availability statement Ethics Statement The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University hospital Ethics committees(2019-X-031-02). The patients/ participants provided their written informed consent to participate in this study. Author contributions Haifeng, Zhuang designed the study. Lili, Hong and Qiang, Wen wrote the manuscript. Kaili, Chen and Yongjun, Wang analyzed the data. Jie, Mu; Haili, Zhou; Shoujun, Wang and Siyu, Shen collected the data. Acknowledgments We thank ZHEJIANG CORD BLOOD BANK in China for the kindly help. We thank the patients and the families. Competing interests The authors declare no competing interests. Funding information Zhejiang Provincial Medical and Health Science and Technology Project (2020KY196) ,the Foundation of Zhejiang Province Chinese Medicine Science and Technology Plans (2020ZA044) and Open Research Fund Program of Key Laboratory of Blood Safety Research of Zhejiang province(2023KF003). References Viera AF-MNSSA-SA. Using the Common Terminology Criteria for Adverse Events (CTCAE – Version 5.0) to Evaluate the Severity of Side Effects of Antineoplastic Treatments.2019. Kuter DJ. Treatment of chemotherapy-induced thrombocytopenia in patients with non-hematologic malignancies. Haematologica 2022; 107: 1243–1263. Al-Samkari H, Parnes AD, Goodarzi K et al. A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies. Haematologica 2021; 106: 1148–1157. Al-Samkari H. 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Three-Dimensional Culture of Umbilical Cord Mesenchymal Stem Cells Effectively Promotes Platelet Recovery in Immune Thrombocytopenia. Biol. Pharm. Bull 2020; Bull. 43,: 1052–1060. Zhang P, Zhang G, Liu X et al. Mesenchymal stem cells improve platelet counts in mice with immune thrombocytopenia. J Cell Biochem 2019; 120: 11274–11283. Zhu L, Liu J, Kong P et al. Analysis of the Efficacy and Safety of Avatrombopag Combined With MSCs for the Treatment of Thrombocytopenia After Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2022; 13: 910893. Shaw JL, Nielson CM, Park JK et al. The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies. Eur J Haematol 2021; 106: 662–672. Ten Berg MJ, van den Bemt Pm Fau - Shantakumar S, Shantakumar S Fau - Bennett D et al. Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: results from a retrospective hospital-based cohort study. Drug Saf. 2011; 34(12): 1151–1160. Meng A, Wang Y, Van Zant G, Zhou D. Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res 2003; 63: 5414–5419. Das B, Antoon R, Tsuchida R et al. Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth. Neoplasia 2008; 10: 1105–1119. Diaz-Montero CM, Wang Y, Shao L et al. The glutathione disulfide mimetic NOV-002 inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress. Free Radic Biol Med 2012; 52: 1560–1568. Rainone M, Kasparian S, Nguyen T et al. Thrombopoietin Receptor Agonists for Thrombocytopenia Secondary to HER2-Targeted Antibody Drug Conjugates. Oncologist 2023; 28: e843-e846. Josefsson EC, James C, Henley KJ et al. Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. J Exp Med 2011; 208: 2017–2031. Gao A, Zhang L, Zhong D. Chemotherapy-induced thrombocytopenia: literature review. Discov Oncol 2023; 14: 10. Shao L, Wang Y, Chang J et al. Hematopoietic stem cell senescence and cancer therapy-induced long-term bone marrow injury. Transl Cancer Res 2013; 2: 397–411. Li Lu R-NS, Hal E. Broxmeyera. Stem cells from bone marrow, umbilical cord blood and peripheral blood for clinical application: current status and future application. Critical Reviews in Oncology/Hematology 1996; 22: 61–78. Paton MCB, Wall DA, Elwood N et al. Safety of allogeneic umbilical cord blood infusions for the treatment of neurological conditions: a systematic review of clinical studies. Cytotherapy 2022; 24: 2–9. Ilic D, Miere C, Lazic E. Umbilical cord blood stem cells: clinical trials in non-hematological disorders. Br Med Bull 2012; 102: 43–57. Yao Y, Song Q, Chu Y et al. Infusion of allogeneic umbilical cord blood hematopoietic stem cells in patients with chemotherapy-related myelosuppression. Exp Ther Med 2014; 8: 1946–1950. Galgano L, Hutt D. HSCT: How Does It Work? In Kenyon M, Babic A (eds): The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT. Cham (CH): Springer Copyright 2018, EBMT and the Author(s). 2018; 23–36. Xi J, Zhu H, Liu D et al. Infusion of megakaryocytic progenitor products generated from cord blood hematopoietic stem/progenitor cells: results of the phase 1 study. PLoS One 2013; 8: e54941. Rafieemehr H, Maleki Behzad M, Azandeh S et al. Chemo/radiotherapy-Induced Bone Marrow Niche Alterations. Cancer Invest 2021; 39: 180–194. Geeta Rai DD, Khushbu Priya. New insights on stem cells modeling and treatment of human diseases. Frontiers in Bioscience 2020; 25,: 1568–1599. Zhou T, Yuan Z, Weng J et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol 2021; 14: 24. By Omer N. Koc¸, Stanton L. Gerson BWC, Stephanie M. Dyhouse, Stephen E. Haynesworth, Arnold I. Caplan, and Hillard M. Lazarus. Rapid Hematopoietic Recovery After Coinfusion of Autologous-Blood Stem Cells and Culture-Expanded Marrow Mesenchymal Stem Cells in Advanced Breast Cancer Patients Receiving High-Dose Chemotherapy. Journal of Clinical Oncology 2000; Vol 18, No 2 (January): 307–316. Wang X, Yin X, Sun W et al. Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: A two-year follow-up. Exp Ther Med 2017; 13: 2255–2258. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-3798488","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":263898651,"identity":"65dc8bb3-f601-48ba-92db-9124f233e733","order_by":0,"name":"Li-Li Hong","email":"","orcid":"","institution":"Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li-Li","middleName":"","lastName":"Hong","suffix":""},{"id":263898652,"identity":"79af5482-d8af-4f77-bccf-2f122895884c","order_by":1,"name":"Qiang Wen","email":"","orcid":"","institution":"Zhejiang Cancer 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University","correspondingAuthor":true,"prefix":"","firstName":"Hai-Feng","middleName":"","lastName":"Zhuang","suffix":""}],"badges":[],"createdAt":"2023-12-24 02:14:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3798488/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3798488/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49090332,"identity":"a625f2a8-2952-4ca3-a5bc-5b0a293e4374","added_by":"auto","created_at":"2024-01-03 01:43:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43738,"visible":true,"origin":"","legend":"\u003cp\u003eThe therapy regimen of sequentially infusion with UCB and UC-MSCs for R-CTIT patients.\u003c/p\u003e","description":"","filename":"Fig1.CTITProtocol.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3798488/v1/d1ed829d02e6365f0a544778.jpg"},{"id":49090334,"identity":"f5a321df-f9c8-432d-a431-6c01297ab24d","added_by":"auto","created_at":"2024-01-03 01:43:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":175256,"visible":true,"origin":"","legend":"\u003cp\u003eSwimmer plot for the response evaluable patients.\u003c/p\u003e","description":"","filename":"Fig2.SwimmerPlotforResponse.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3798488/v1/1de535d6014fb65224c658d8.jpg"},{"id":49090333,"identity":"946f2b95-d555-46aa-bacb-771feeea9750","added_by":"auto","created_at":"2024-01-03 01:43:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":64550,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival probability of the whole cohort.\u003c/p\u003e","description":"","filename":"Fig3.OS.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3798488/v1/2150b7f1de552817329538d2.jpg"},{"id":61820077,"identity":"a29a2aa4-ed64-4cff-ad77-2a20bd86b879","added_by":"auto","created_at":"2024-08-06 01:35:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":939759,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3798488/v1/ca110095-f673-4eca-98dc-8f79e3cebdb2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Challenging Cases series: Novel Options for Refractory Cancer Therapy-induced Thrombocytopenia（r-CTIT）","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCancer therapy-induced thrombocytopenia (CTIT) is a common complication following anti-tumor therapy resulting from radiotherapy, chemotherapy, monoclonal antibodies, and targeted therapy. The degree of CTIT can be influenced by various factors such as tumor type, type and dosage of anti-tumor drugs used. CTIT is defined as a platelet count of less than 100x10^9/L after anti-tumor therapy and is categorized into different grades based on the platelet count: grade 1 (75x10^9/L to less than 100x10^9/L), grade 2 (50x10^9/L to less than 75x10^9/L), grade 3 (25x10^9/L to less than 50x10^9/L), and grade 4 (less than 25x10^9/L)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Among these, refractory cancer therapy-induced thrombocytopenia (r-CTIT), defined as a platelet count less than 20x10^9/L and unresponsive to two different kinds of platelet-promoting agents, is the most serious type. While the intensity of anti-tumor drugs is often associated with therapeutic efficacy, higher drug intensity can intensify thrombocytopenia, thereby increasing the risk of bleeding. As a result, r-CTIT can impede treatment progress and adversely affect long-term survival.\u003c/p\u003e \u003cp\u003eTherapeutic strategies for CTIT typically involves platelet transfusion, recombinant human interleukin-11(rhIL-11), and thrombopoietin (TPO) replacement therapy to stimulate platelet production, which includes recombinant human thrombopoietin (rhTPO) and thrombopoietin receptor agonists (TPO-RA) such as romiplostim, eltrombopag, avatrombopag [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, for patients with r-CTIT, these therapies have demonstrated poor clinical outcomes. Single platelet transfusion is not a long-term solution, and repeated transfusions can induce transfusion resistance [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Platelet-promoting agents can increase platelet production, but they are only effective for some patients and may be discontinued due to adverse reactions during treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Studies have shown that anti-tumor therapies can damage various cells and hematopoietic cytokines in the bone marrow, leading to hematopoietic disorders. Moreover, with the increasing complexity and integration of cancer treatments, more patients are experiencing severe and persistent bone marrow suppression, resulting in severe thrombocytopenia and pancytopenia. The management strategies for such refractory patients are often limited, and without effective treatment, r-CTIT can be life-threatening. Our study have also revealed a decrease in erythroid and granulocyte levels among these patients.\u003c/p\u003e \u003cp\u003ePlatelets are derived from megakaryocytes. Thrombopoietin, as a major regulator factor in bone marrow, plays a crucial role in promoting the differentiation of hematopoietic stem and progenitor cells into platelets. Thrombocytopoiesis initiates with HSCs, which differentiate into megakaryocyte progenitors and eventually mature into platelets. Human umbilical cord blood (UCB) is abundant in relatively primitive hematopoietic stem and progenitor cells, making it an important source of stem cells. UCB has gained widespread attention for its potential to generate platelets due to several advantages, including its wide source, weak surface antigenicity, higher proliferation potential compared to bone marrow counterparts, greater compatibility for HLA match, and a comparatively lower risk for graft-vs-host disease (GVHD) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The first successful UCB transplant using UCB as a source of hematopoietic cells was performed to treat a child with Fanconi anemia [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Nowadays, UCB is considered as an alternative source of HSCs for allogeneic HSC transplantation in the treatment of hematologic disorders and other genetic diseases. Matsunaga et al. has demonstrated the capacity of UCB-HSCs to generate clinically useful quantities of platelets [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMSCs possess the ability to differentiate into cellular components that support the hematopoietic microenvironment. Emerging studies indicate a growing therapeutic potential of MSCs for thrombocytopenia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. MSCs have been validated in cases of prolonged isolated thrombocytopenia following allogeneic hematopoietic stem cell transplantation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. UC-MSCs, which are easily accessible and have lower antigenicity, have been used for graft-versus-host disease. However, our study represents the first treatment attempt for r-CTIT patients.\u003c/p\u003e \u003cp\u003eThe application and study of stem cell transplantation technology in hematopoietic failure diseases also offer a new idea for treating r-CTIT. We propose a new method that utilizes UCB units as the source of hematopoietic stem, progenitor cells, and mesenchymal stem cells to provide a hematopoietic niche for producing functional platelets. In this study, we analyzed r-CTIT patients who received sequential infusions of UCB and UC-MSCs in order to provide an effective treatment strategy for these patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients and clinical data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients diagnosed with various types of tumors have undergone conventional anti-tumor therapies, including chemotherapy, radiotherapy, monoclonal antibodies, and targeted therapy. In this study, we define r-CTIT as a condition where the platelet count remains below 20x109/L and is unresponsive to at least two different platelet-promoting agents. A total of 13 r-CTIT patients were screened at our center from May 1, 2020, to May 1, 2023. All patients are expected to be free of primary disease progression within 6 months. The treatment approach involved sequential infusions of UCB and UC-MSCs. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2019-X-031-02), in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003ch3\u003eTreatment Procedure\u003c/h3\u003e\n\u003cp\u003eThe occurrence time of r-CTIT was defined as the first instance of a platelet count below 20\u0026times;109/L accompanied by treatment failure using two different platelet-promoting agents. The duration of CTIT was defined as the time elapsed from r-CTIT diagnosis to the initiation of infusion treatment. UCB units and UC-MSCs were obtained from Zhejiang Province UCB bank. HLA typing for patients and UCB units was performed at the UCB unit bank. UC-MSCs were infused with a single administration of 1.0\u0026times;107 MSCs/kg body weight.\u003c/p\u003e\n\u003cp\u003eR-CTIT patients received a sequential infusion treatment of UCB and UC-MSCs. The therapy regimen is as follows (Fig. \u003cspan\u003e1\u003c/span\u003e): day 0 was defined as the date of r-CTIT diagnosis, where a single UCB unit was infused sequentially followed by weekly infusions of UC-MSCs for 2\u0026ndash;3 weeks. Glucocorticoids were administered prior to transfusion to prevent infusion reactions. All patients received a subcutaneous injection of recombinant human granulocyte colony-stimulating factor (G-CSF) at a dose of 5\u0026thinsp;~\u0026thinsp;10 mg/kg/d until the neutrophil count reached 1.5\u0026times;109/L. Thrombopoietin or other forms of TPO replacement therapy was continuously administered, or discontinued when the platelet count increased to 100\u0026times;109/L.\u003c/p\u003e\n\u003ch3\u003eEfficacy Criteria and Safety\u003c/h3\u003e\n\u003cp\u003eThe time of onset is defined as the duration from the initiation of treatment to the attainment of efficacy. The response evaluation encompasses complete response and partial response. Complete response (CR) is defined as a PLT count\u0026thinsp;\u0026ge;\u0026thinsp;50\u0026times;109/L without PLT transfusion for 7 consecutive days. Partial response (PR) is defined as a PLT count of 20\u0026ndash;50 \u0026times;109/L without PLT transfusion for 7 consecutive days. No response (NR) is defined as by a PLT count\u0026thinsp;\u0026lt;\u0026thinsp;20\u0026times;109/L or the need for PLT transfusion after 24 weeks of treatment. Adverse reactions were assessed in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 [\u003cspan\u003e1\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eThe statistical analysis was conducted using SPSS 28.0 software. The data were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Kaplan-Meier survival analysis was employed to assess overall survivals. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to have a statistically significant difference.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003csup\u003e,\u003c/sup\u003e\u003cstrong\u003echaracteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 13 r-CTIT patients who underwent cell infusion therapy between May 1, 2020 and May 1, 2023 were included in this study. The clinical characteristics of these patients are summarized in Table \u003cspan\u003e1\u003c/span\u003e. The follow-up period ranged from 20 to 1053 days (median, 252 days). Among the enrolled patients, there were 12 females and 1 male, with ages ranging from 17 to76 years (median, 63 years). The distribution of primary malignancies was as follows: 1 endometrial cancer, 1 rectal cancer, 1 osteosarcoma, 6 ovarian malignancies, 3 breast cancers, and 1 primary myelofibrosis. Patients with non-hematologic malignancies exhibited stable disease. 10 patients had an ECOG score of 1 while 3 had a score of 2. 8 patients had concomitant infections, including 2 cases of pneumonia (1 severe), 2 cases of bloodstream infection, 1 case of abdominal infection, 2 cases of COVID-19 infection, and 1 case of gum infection. No patient had cytomegalovirus infection, but 3 patients were found to have Epstein-Barr viremia. 2 patients were complicated by deep vein thrombosis. All patients presented with varying degrees of bleeding, primarily manifested as skin, mucous membrane, and gingival bleeding. One patient suffered from multiple epidural hemorrhages that did not respond to regular platelet transfusion and required matching platelet transfusion.\u003c/p\u003e\n\u003cp\u003eThe anti-tumor treatment regimen comprised of radiotherapy, chemotherapy, monoclonal antibody drugs, and targeted therapy. Chemotherapy drugs administered included paclitaxel, pemetrexed, docetaxel, epirubicin, cisplatin, carboplatin, cyclophosphamide, adriamycin, and demethylation drugs. Monoclonal antibodies such as bevacizumab, trastuzumab, and pembrolizumab were also used. 4 patients received concurrent chemoradiotherapy. Platelet-promoting agents for CTIT consisted of interleukin-11 (IL-11), thrombopoietin (TPO) and thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag and avatrombopag. All patients were treated withTPO and TPO-RAs, while 7 also received intravenous gamma globulin and 5 were treated with IL-11. All patients were administered two different types of drugs, with 10 receiving more than three different drugs.\u003c/p\u003e\n\u003cp\u003e11 patients presented with an absolute neutrophil count below 1.0\u0026times;109/L, with 6 cases below 0.5\u0026times;109/L. The median hemoglobin level was 62 g/L (range: 35-95g/L) with 6 patients having levels below 60 g/L. The platelet counts of all patients were less than 20\u0026times;109/L, with 11 patients below 10\u0026times;109/L and 7 patients below 5\u0026times;109/L; two patients did not respond to regular platelet transfusion. One patient experienced multiple epidural hemorrhages prior to therapy and only responded to genotype platelet transfusions. All patients had mild to moderate bleeding symptoms, including skin, oral cavity, nasal bleeding and so on.\u003c/p\u003e\n\u003cp\u003eBefore receiving treatment, bone marrow aspiration and biopsy were performed on R-CTIT patients. Among them, 5 patients showed hypoplasia or extremely hypoplasia of bone marrow, while 5 patients showed no presence of megakaryocytes in bone marrow. 1 patient exhibited an abnormal karyotype of 46, XX, t(3;7)(q26;q21)[\u003cspan\u003e17\u003c/span\u003e]/46, XX[\u003cspan\u003e3\u003c/span\u003e]. Additionally, 3 patients with non-hematologic malignancies presented myeloid gene mutations, including MPL mutation, ZRSR2 mutation, as well as CBL, DNMT3A, FLT3, IDH2, KDM6A, and NF1 mutations.\u003c/p\u003e\n\u003cp\u003eThe HLA typing, number of infused cells, and chimerism data for all UCB units are presented in Table\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e. The median count of CD34\u0026thinsp;+\u0026thinsp;cells was 2.37\u0026times;105/kg (range: 1.23 to 6.2 \u0026times;105/kg), while the median total nucleated cell (TNC) count was 7.72 \u0026times;107/kg (range: 3.5 to 9.33 \u0026times;107/kg). Chimerism detection was completed for two patients.\u003c/p\u003e\n\u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eBaseline characteristics of the patients (n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"12\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003eID\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eGender/Age\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eTumor type/\u003cbr\u003eDisease status\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eECOG\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eInfection\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eComplications\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePrevious antitumor drugs\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePrevious therapy\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eBone marrow\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePrevious\u003cbr\u003ePLT count (10^9/L)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePrevious\u003cbr\u003eN count (10^9/L)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePrevious\u003cbr\u003eHB count (g/L)\u003cbr\u003e\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/54\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eEndometrial carcinoma\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eno\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Paclitaxel; Cisplatin\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eG;I;T;E;A\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHypoplasia\u0026nbsp;of\u0026nbsp;marrow\u0026nbsp;,\u0026nbsp;with two\u0026nbsp;megakaryocyte;nomroal karyotype;NGS: MPL mutation\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e76\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eM/72\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eRectal cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003epneumonia\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Capecitabine ;oxaliplatin\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eG;T;E\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHypoplasia\u0026nbsp;,\u0026nbsp;without megakaryocytes; nomroal karyotype;ZRSR2 mutation\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e95\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/52\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eOvarian cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eno\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMultiple epidural hemorrhages\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Paclitaxel ;carboplatin\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eG;T;E;A\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHyperplastic;2 megakaryocytes; nomroal karyotype\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e59\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e4\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/67\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eOvarian cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eno\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Paclitaxel; Cisplatin;\u003cbr\u003e\u0026bull; bevacizumab\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eT;E;A\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHyperplastic;without megakaryocytes; nomroal karyotype\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e8\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e49\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/17\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eOsteosarcoma\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eBloodstream infection\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Methotrexate, doxorubicin, and cisplatin; Recombinant human endostatin\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eT;I;E;A\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHyperplastic;2 megakaryocytes; nomroal karyotype\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e56\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/67\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eOvarian cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAbdominal\u003cbr\u003einfection\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Paclitaxel ;carboplatin; doxorubicin,\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eG;T;E;A\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHyperplastic;2 megakaryocytes; nomroal karyotype;Mutation: CBL、DNMT3A、FLT3、IDH2、KDM6A、NF1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e62\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/62\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eBreast cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eSevere pneumonia\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Epirubicin; cyclophosphamide,;paclitaxel\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eI;T;E\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHypoplasia\u0026nbsp;,\u0026nbsp;without megakaryocytes; karyotype: 46,XX,t(3;7)(q26;q21)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e35\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e8\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/63\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eBreast cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCOVID-19\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eEpirubicin;cyclophosphamide,;paclitaxel\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eI;E\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHypoplasia\u0026nbsp;,\u0026nbsp;without megakaryocytes; normal karyotype\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e42\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/75\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eOvarian cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eno\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Paclitaxel; Cisplatin;\u003cbr\u003ebevacizumab\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eT\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHyperplastic;2 megakaryocytes; nomroal karyotype\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e18\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.8\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e79\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/48\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eBreast cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eno\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Paclitaxel,;trastuzumab\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eT;E\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHypoplasia;without megakaryocytes,;nomroal karyotype;\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e14\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e90\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e11\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/50\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMyelofibrosis\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eBloodstream infection\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHomoharringtonine;\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eG;I;T\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eExtremely hypoplasia;without megakaryocytes,;nomroal karyotype; Mutation:JAK2,ASXL1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e37\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e12\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/69\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eOvarian cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eGingival infection\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Paclitaxel; Carboplatin;\u003cbr\u003e\u0026bull; Adriamycin liposome;\u003cbr\u003eBevacizumab;\u003cbr\u003eNiraparib\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eG;I;T\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHypoplasia;without megakaryocytes,;nomroal karyotype\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e78\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e13\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eF/76\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eOvarian cancer\u003cbr\u003e/ SD\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCOVID-19\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eMild or moderate bleeding\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026bull; Carboplatin;\u003cbr\u003e\u0026bull; Adriamycin liposome;\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eG;I;T;E\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eHyperplastic;6megakaryocytes; nomroal karyotype\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e92\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eClinical data of UCB, UC-MSCs and chimerism.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003eID\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eUCB HLA match\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eTNC\u0026times;10\u003csup\u003e7\u003c/sup\u003e/kg\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eCD34\u003csup\u003e+\u003c/sup\u003e\u0026times;10\u003csup\u003e5\u003c/sup\u003e/kg\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eUC-MSCs\u003cbr\u003e(1\u0026times;10\u003csup\u003e7\u003c/sup\u003e/kg, weekly)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eChimerism %\u003cbr\u003e(d7, d14, d28)\u003cbr\u003e\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e7/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e6.3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e6.2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e8*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e4/6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2.7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e8*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3.12\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e7*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e4\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e7/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3.5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.0\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e7*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4.2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.23\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e6.0\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4.98\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e8.5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.44\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e8\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e9.33\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3.59\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6*2w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e7/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.06\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6*2w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5/6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e6.0\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.98\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6*2w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e11\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e7/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e8.04\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3.45\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6*2w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e0.056; 1.833; 0.002\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e12\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e7.2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e3.61\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6*2w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNA\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e13\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e8/10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e9.14\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2.37\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5*3w\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e0.042; 0.05; 0.003\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eAbbreviation: UCB: umbilical cord blood; TNC: Total nucleated cells; UC-MSCs:umbilical cord mesenchymal stem cells NA: Not available.\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eHematopoietic Response\u003c/h3\u003e\n\u003cp\u003eThe recovery time of blood cells was summarized in Table \u003cspan\u003e3\u003c/span\u003e, while the response was illustrated through a swimmer plot in Fig. \u003cspan\u003e2\u003c/span\u003e. The overall survival rate stood at 83.3%, as depicted in Fig. \u003cspan\u003e3\u003c/span\u003e. The median duration from r-CTIT diagnosis to treatment initiation was 147 days (range: 21\u0026ndash;635 days). During follow-up, platelet response rate was 84.6% (11/13). 53.8% (7/13) patients achieved CR, while PR rate was 84.6% (9/13). The median time for platelet recovery in all patients was 53 days (range: 6-217 days). Erythroid response proportion was 84.6% (11/13), with a median response time of 35 days (range: 10\u0026ndash;118 days). Neutrophil response rate was 92.3%(12/13), with a median granulocytic response time of 23 days (range: 6-150 days). During follow-up, only one patient with osteosarcoma passed away due to disease recurrence.\u003c/p\u003e\n\u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eThe blood cell recovery time.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"11\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003eID\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026bull; Duration\u003cbr\u003e\u0026bull; of CTIT diagnosis to treatment initiation\u003cbr\u003e(d)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eOnset to start of treatment\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eDuration time of PLT recovery to 20*10^9/L(d)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eDuration time of PLT recovery to 50*10^9/L(d)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eDuration time of PLT recovery to 100*10^9/L(d)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026bull; Duration time of HB\u0026thinsp;\u0026ge;\u0026thinsp;90\u0026times;10^9/L or greater than 20% of the baseline level(d)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eDuration time of N recovery to 1.5*10^9/L(d)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eEffect evaluation\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eFollow-up time\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eClinical\u003cbr\u003eoutcomes\u003cbr\u003e\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e186\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2020/6/12\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e217\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e243\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e482\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e56\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e28\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e2\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e37\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2021/8/27\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e33\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e48\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e68\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e27\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e18\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e147\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2021/9/9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e54\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e61\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e233\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e52\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e13\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e4\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e217\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2021/9/28\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e53\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e245\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e50\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e11\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e313\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2021/4/15\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e138\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e118\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e150\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003ePR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2022/10/5\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eDeath\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e391\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2021/7/27\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e94\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e35\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e23\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003ePR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e635\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2022/8/22\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e64\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e88\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e18\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e34\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e8\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e97\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/2/15\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e48\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e48\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003ePR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e390\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2022/8/22\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003ePR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2022/9/15\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e10\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e130\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2022/11/24\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e20\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e29\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e34\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e11\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e7\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e11\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e38\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/1/14\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e19\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e27\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e25\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eCR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e12\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e21\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/2/9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eNR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e13\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e125\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/3/27\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e31\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e/\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e25\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003ePR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2023/5/1\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003eAlive\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eChimerism analysis revealed that one patient (through the analysis of short tandem repeat regions) had chimerism levels increasing from0.056% on day7 to 1.833% on day14, but decreasing again to 0.002% on day28. Another patient\u0026apos;s chimerism level increased from 0.042% on day7 to 0.05% on day14, dropping down again to 0.003% one month after therapy.\u003c/p\u003e\n\u003ch3\u003eSafety\u003c/h3\u003e\n\u003cp\u003eNone of the patients experienced graft-versus-host disease (GVHD). No severe adverse reactions was observed during the infusion process. Moreover, there were no reported cases of serious side effects or thrombotic events throughout the follow-up period.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe presence of r-CTIT hindered the treatment progress and adversely affected long-term survival. Unfortunately, there is currently no clearly effective treatment available to address this issue. Therefore, it is imperative to explore feasible and safe therapeutic methods. Through clinical observation, we have noted that r-CTIT patients often exhibit long-term thrombocytopenia characterized by a lack of megakaryocytes and persistent bone marrow hypoplasia, sometimes accompanied by erythropenia and neutropenia. Our study, presented here for the first time, indicates that UCB and UC-MSCs infusion for r-CTIT patients is feasible and safe.\u003c/p\u003e\n\u003cp\u003eCTIT is a severe and fatal complication in cancer patients. In our study, the average age of the 13 patients was 63 years old, and they presented with poor physical status and serious complications after anti-tumor treatment. Epstein-Barr viremia was present in 3 patients, and 10 patients had received three types of platelet-promoting agents. Effective treatment strategies for these critically ill patients are lacking. The incidence and severity of CDIT vary among different patient populations and regimens. A recent study found among15,521 patients with solid tumors, the incidence of CTIT was 4% and 2%, developed grade 3 and grade 4 thrombocytopenia, respectively. Among 2537 patients with hematological malignancies, 16% developed grade 3 thrombocytopenia, and 12% had grade 4 [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. Platinum and gemcitabine-based chemotherapy regimens were found to be most strongly associated with severe thrombocytopenia, with CTIT occurring in 82% of those receiving only carboplatin, and in 58%, 64%, and 59% of those receiving combination therapies with carboplatin, gemcitabine, or paclitaxel, respectively [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our study, 9 patients had received platinum-based drugs as part of their chemotherapy regimen, resulting in 6 patients with severe neutropenia, 6 patients with severe anemia, and 11 patients with platelet counts less than 10\u0026times;109/L. Additionally, 5 patients displayed acquired hematopoietic function failure, and 3 solid tumor patients had myeloid gene mutations.\u003c/p\u003e\n\u003cp\u003eThe CTIT mechanism is complex, as not all anti-tumor agents cause thrombocytopenia in the same way. For example, alkylating agents such as busulfan and carboplatin affect pluripotential stem cells [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e], while cyclophosphamide acts on megakaryocyte progenitors [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Antibody-drug conjugates, on the other hand, inhibit megakaryocyte growth and differentiation [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. All of those can reduce platelet production. Etoposide increases platelet destruction by reducing BCL-X (L) activity, leading to platelet apoptosis [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. The impact of anti-tumor agents on various aspects of platelet formation contributes to a decrease in platelet count. Our study found that r-CTIT patients receiving various combinations of drugs experienced persistent thrombocytopenia, and even pancytopenia. We suspect that this is due to injuries at the early stages of HSC and progenitor cells involved in platelet formation. Therefore, we believe the underlying mechanism may be associated with hematopoietic stem cell injury and bone marrow microenvironment disorders.\u003c/p\u003e\n\u003cp\u003eAnti-tumor therapy can impair various cells and cytokines, thereby reducing the self-renewal and proliferation ability of HSCs and destroying hematopoietic function of the bone marrow microenvironment [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. HSCs have the potential to proliferate and differentiate into various types of mature blood cells.\u003c/p\u003e\n\u003cp\u003eUCB, as an alternative source to bone marrow, offers several advantages including high proliferative potential, weak antigenicity, and a low incidence of GVHD [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. Consequently, UCB has emerged as a promising therapy in various medical fields [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. A clinical observation investigated that UCB infusion markedly improved chemotherapy-related myelosuppression. The underlying mechanism of UCB infusion is hypothesized to involve the production of large amounts of hematopoietic growth factors to activate stem cells and repair injured cells in the bone marrow [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. UCB is also rich in HSCs, which theoretically have the ability to self-renew and differentiate into progenitor and mature cells. Therefore, UCB infusion has the capacity to reverse and restore hematopoiesis through producing functional blood cells. As an alternative stem cells source for hematopoietic stem cell transplantation (HSCT), one limiting factor of UCB lies in low number of cells per unit, which can result in delayed engraftment and immune reconstitution.\u003c/p\u003e\n\u003cp\u003eHSCT is a process of replacing and reconstructing the hematopoietic system, in which the recipient receives HSC infusion. Prior to the infusion, the recipient typically undergoes conditioning regimens such as total body radiation therapy or a combination of cytotoxic drugs and immunosuppressive agents to ensure the successful engraftment of HSCs [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. R-CTIT patients exhibit prolonged hypoplasia after exposure to radiation or cytotoxic drugs, resulting in structurally empty bone marrow and hematopoietic defects, similar to those seen in conditioning regimens for transplantation. Therefore, we hypothesized, whether UCB as a source of stem cell could rescue hematopoietic function obstacle. It is verified that UCB unit infusion without any immunosuppressive agents was safe. However, chimerism was detected in 2 patients at very low levels, and this gradually decreased after blood cell recovery. This suggests that UCB did not play a significant role in engraftment for reconstructing hematopoietic recovery. Transplanted UCB was eliminated by the host immune system and therefore did not permanently engraft in the recipient\u0026apos;s bone marrow. However, recent studies have reported that UCB-derived megakaryocytes and progenitors can produce functional platelets.\u003c/p\u003e\n\u003cp\u003eXi et al explored the feasibility and safety of utilizing UCB-derived megakaryocytes and progenitors for the treatment of thrombocytopenia, especially in patients who received multiple rounds of high-dose radiotherapy and chemotherapy [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. In future studies, it would be worthwhile to explore the components of UCB that could enhance platelet production.\u003c/p\u003e\n\u003cp\u003eChemoradiotherapy-induced hematopoietic damage is partially attributed to the loss of critical stromal and endothelial cell components within the hematopoietic niche, which provides structural and physiological support for hematopoiesis [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. MSCs is an essential part of the bone marrow niche microenvironment and secrete a variety of chemokines and cytokines that facilitate the homing, proliferation, and differentiation of hematopoietic cells, thus playing a significant role in promoting hematopoietic recovery [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. MSCs secrete numerous cytokines that act on HSCs and stromal cells, including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, stromal cell-derived factor, and vascular endothelial growth factor. Furthermore, studies have demonstrated that the infusion of mismatched allogeneic MSCs does not cause cell rejection, making it safe for clinical practice [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. The first report describing the infusion of autologous MSCs during PBPC transplantation in advanced breast cancer patients prompted hematopoietic recovery, particularly in platelet counts [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. More recently, MSCs have been reported to regulate megakaryocyte differentiation and contribute to platelet formation, indicating their potential in immunomodulation as well. BM-MSCs have been shown to increase platelet counts in mice with ITP by upregulating regulatory T cells and the secretion of cytokines (IL-10 and TGF-\u0026beta;1). Additionally, intravenous infusion of UC-MSCs has been reported to improve platelet counts in patients with chronic refractory immune thrombocytopenia [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]. Thrombocytopenia is categorized into primary and secondary forms, with the latter one potentially associated with infections such as COVID-19. With the widespread use of immune-targeted therapies, immune-related thrombocytopenia has become more prevalent. The immunomodulatory, engraftment-promoting, and reparative properties of MSCs have been extensively studied in preclinical models and clinical trials.\u003c/p\u003e\n\u003cp\u003eIn our study, the overall platelet response rate was 84.6%. The median time to platelet response was 53 days, with erythroid response occurring at a median of 35 days and granulocyte response at a median of 23 days. Importantly, no severe infusion reactions were reported during the infusion therapy, and no GVHD occurred throughout the observation period. It is worth noting that among the patients included in the study, 8 individuals had co-existing severe infections. Out of these, 7 patients achieved recovery, while unfortunately, one patient with osteosarcoma died due to disease recurrence. The bone marrow serves as an immune organ in the body, and its compromised function can lead to significant deficiencies in the ability to combat infections. Therefore, we hypothesize that sequential infusion of UCB combined with UC-MSCs may possess anti-infection potential and help alleviate myelosuppression symptoms. This effect could be attributed to the immunomodulatory properties of the infused cells.\u003c/p\u003e\n\u003cp\u003eThe observation indicated that infusion of UCB and UC-MSCs is beneficial for r-CTIT patients. We speculate that the following mechanisms may be involved: UCB\u0026apos;s ability to provide temporary hematopoietic recovery, enhance cell survival in damaged cells, and promote megakaryocyte differentiation into platelets. UC-MSCs, acting as a hematopoietic niche, could promote immune and hematopoietic recovery while moderating inflammatory response. However, it remains unclear whether UCB and UC-MSCs directly improve hematopoiesis, thus further experiments are needed to confirm this.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study presents a novel and salvage therapeutic approach for patients with life-threatening r-CTIT. The sequential infusion of UCB combined with UC-MSCs demonstrated significant efficacy, good safety, and no obvious side effects in r-CTIT patients. Prospective studies are warranted to further explore the underlying mechanisms of UCB and UC-MSCs in the treatment of r-CTIT.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDate availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University hospital Ethics committees(2019-X-031-02). The patients/ participants provided their written informed consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHaifeng, Zhuang designed the study. Lili, Hong and Qiang, Wen wrote the manuscript. Kaili, Chen and Yongjun, Wang analyzed the data. Jie, Mu; Haili, Zhou; Shoujun, Wang and Siyu, Shen collected the data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank ZHEJIANG CORD BLOOD BANK in China for the kindly help. We thank the patients and the families.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u0026nbsp;\u003c/strong\u003e Zhejiang Provincial Medical and Health Science and Technology Project (2020KY196) ,the Foundation of Zhejiang Province Chinese Medicine Science and Technology Plans (2020ZA044) and Open Research Fund Program of Key Laboratory of Blood Safety Research of Zhejiang province(2023KF003).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eViera AF-MNSSA-SA. 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Chemo/radiotherapy-Induced Bone Marrow Niche Alterations. Cancer Invest 2021; 39: 180\u0026ndash;194.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeeta Rai DD, Khushbu Priya. New insights on stem cells modeling and treatment of human diseases. Frontiers in Bioscience 2020; 25,: 1568\u0026ndash;1599.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou T, Yuan Z, Weng J et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol 2021; 14: 24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBy Omer N. Koc\u0026cedil;, Stanton L. Gerson BWC, Stephanie M. Dyhouse, Stephen E. Haynesworth, Arnold I. Caplan, and Hillard M. Lazarus. Rapid Hematopoietic Recovery After Coinfusion of Autologous-Blood Stem Cells and Culture-Expanded Marrow Mesenchymal Stem Cells in Advanced Breast Cancer Patients Receiving High-Dose Chemotherapy. Journal of Clinical Oncology 2000; Vol\u0026nbsp;18, No 2 (January): 307\u0026ndash;316.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Yin X, Sun W et al. Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: A two-year follow-up. Exp Ther Med 2017; 13: 2255\u0026ndash;2258.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"UCB (umbilical cord blood), UC-MSCs (umbilical cord mesenchymal stem cells), Refractory cancer therapy-induced thrombocytopenia (r-CTIT), Bone marrow microenvironment.","lastPublishedDoi":"10.21203/rs.3.rs-3798488/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3798488/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eRefractory cancer therapy-induced thrombocytopenia (r-CTIT) presents a life-threatening complication of tumor therapy, for which there is currently no established and effective long-term treatment.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eUmbilical cord blood (UCB) is rich in hematopoietic stem cells with multi-lineage differentiation potential, while umbilical cord mesenchymal stem cells (UC-MSCs) have been shown to support megakaryocytopoiesis and regulate the bone marrow microenvironment. The components of cells have demonstrated great value in the treatment of hematopoietic failure diseases, especially in patients with r-CTIT.To investigate the impact of intravenous sequential infusion of UCB and UC-MSCs in patients with r-CTIT, we conducted a follow-up study.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 13 patients evaluated, the platelet response rate was 84.6% (11/13). Complete response (CR) was observed in 53.8% (7/13) of the patients, while partial response (PR) was seen in 84.6% (9/13) of the patients. The median time for platelet recovery in all patients was 53 days (range: 6-217 days). Our findings revealed that the infusion of UCB and UC-MSCs in r-CTIT patients has shown positive effects on erythroid and neutrophil levels, with an 84.6% erythroid response rate (11/13) and a 92.3% improvement in neutrophil count. Furthermore, no severe adverse reactions to the infusion were observed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eBased on our study, we can conclude that the sequential infusion of UCB and UC-MSCs can be a novel and promising therapeutic approach for r-CTIT patients.\u003c/p\u003e","manuscriptTitle":"Clinical Challenging Cases series: Novel Options for Refractory Cancer Therapy-induced Thrombocytopenia（r-CTIT）","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 01:43:33","doi":"10.21203/rs.3.rs-3798488/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":"e3b03768-49a3-43cc-8343-8d1f1bfe7baa","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-07T03:25:31+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-03 01:43:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3798488","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3798488","identity":"rs-3798488","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}