Real-world evidence on treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with B-cell acute lymphoblastic leukemia.

Blinatumomab is efficacious in patients with B-cell acute lymphoblastic leukemia (B-ALL), yet limited real-world data exists in this context. This retrospective study provided real-world data on the treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with newly diagnosed (ND) and relapsed/refractory (R/R) B-ALL. Patients with B-ALL who received at least one dose of blinatumomab in frontline or R/R settings between August 2021 and June 2023 were included. The primary outcome was the treatment pattern of blinatumomab. Key secondary outcomes included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity, median event-free survival (EFS), and safety. The study included 96 patients with B-ALL; 53 (55.2%) patients were in the ND group and 43 (44.8%) patients were in the R/R group. The median treatment duration was one cycle (range: 1-5). Most patients underwent chemotherapies, allo-HSCT, or experimental CAR-T following blinatumomab. The ND patients using blinatumomab induction therapy achieved 100% CR/CRi rate; 87.2% achieved MRD negativity within two cycles of blinatumomab. In R/R re-induction patients, the CR/CRi rate was 50%; MRD negativity rate was 64.2%. In R/R patients using blinatumomab for consolidation, MRD negativity rate was 90.9%. The median EFS was not reached in both ND and R/R patients; 1-year EFS rate was 90.8% (95% CI: 67%, 97%) and 55.1% (95% CI: 30%, 74%), respectively. Grade ≥ 3 adverse events were observed in 12.5% patients. Blinatumomab was found to be effective with a tolerable safety profile in real world setting.

Olverembatinib combined with blinatumomab in treating T315I-mutated Philadelphia chromosome-positive acute lymphoblastic leukemia: two-case report.

ABL tyrosine kinase inhibitors (TKIs) act an irreplaceable role in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The treatment of these diseases has been revolutionized by the application of immunotherapeutic modalities. However, diseases with ABL kinase domain mutation T315I are resistant to the majority of TKIs, which is responsible for treatment failure. Olverembatinib is a third-generation TKI that has been approved for the treatment of T315I-mutated chronic myeloid leukemia (CML) in China; its usage in Ph+ ALL needs further exploration. Here, we present two cases with relapsed T315I mutation Ph+ ALL who received the combination regimen of blinatumomab and olverembatinib. This regimen, which has not been reported yet, was safe and effective as the patients achieved minimal residual disease (MRD) negative after 1 cycle of therapy. The management of these cases provides evidence of this new chemo-free regimen as an efficient approach for relapsed or refractory(R/R)Ph+ ALL.

Blinatumomab-induced macrophage activating syndrome (MAS) in adult with B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab as a single agent has demonstrated superiority over salvage chemotherapy in patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), with manageable safety and efficacy. Though known to have anticipated drug toxicities including cytokine release syndrome (CRS) and neurotoxicity, there is only one prior report of macrophage activating syndrome (MAS) due to blinatumomab. Case Presentation: We report the first case of blinatumomab-induced MAS in an adult. The patient presented with fever, cough, and weakness on the second cycle of blinatumomab. Complete blood count was notable for severe leukopenia, with comprehensive metabolic panel notable for elevated alkaline phosphatase, AST, ALT, LDH, and hyperferritinemia consistent with MAS. The patient was already in MRD-negative remission at presentation with MAS. She responded rapidly to withholding the drug and administration of both tocilizumab and dexamethasone. She was able to restart therapy with blinatumomab dosed at 9 mcg/day with no recurrence of symptoms. Though MAS is not an expected association with blinatumomab, the risk for CRS is. Secondary MAS in this case likely shares a mechanism with other hyperinflammatory conditions. Management includes holding the offending agent, like blinatumomab, and administering tocilizumab and dexamethasone. Future research will be needed to predict which patients are at highest risk to develop MAS after similar T-cell therapies.

Impact of minimal residual disease response and of status of disease on survival after blinatumomab in B-cell acute lymphoblastic leukemia: results from a real-life study.

Blinatumomab is a bispecific T-cell engager approved for relapsed/refractory and minimal residual disease positive B-cell Acute Lymphoblastic Leukemia. We conducted a retrospective study evaluating the outcome of Blinatumomab. The impact of clinical and treatment-related variables on cumulative incidence of relapse/progression (CIRP), event-free (EFS) and overall survival (OS) was analyzed. From January 2016 to December 2022 50 Ph'- (37) and Ph+ (13) B-ALL patients received Blinatumomab. The median age was 37. Indications to blinatumomab were relapsed/refractory B-ALL in 29 and MRD-positive in 21 patients. Blinatumomab was the 2nd and 3rd line in 40 and in 10 patients, respectively. Twenty patients were treated pre-transplantation, ten were treated for relapse after transplant, twenty were not eligible for transplant. Out of 29 patients treated for relapsed/refractory disease, 16 (55%) achieved complete response and 12 achieved MRD-negativity. Out of 21 patients treated for MRD, 16 (76%) achieved MRD-negativity. At a median follow-up of 46 months the median EFS and OS were 11.5 and 16.2 months. The CIRP was 50%. In univariate analysis age, disease-status (overt vs. minimal disease) at blinatumomab, bridging to transplant after blinatumomab and MRD-response resulted significant for EFS and OS. In multivariate analysis only disease-status and MRD-response retained significance both for EFS and OS. Disease-status and MRD-response resulted significant for EFS and OS also after censoring at HSCT. This retrospective study on B-ALL patients treated with blinatumomab confirms a superior outcome for MRD-responsive over MRD non-responsive patients. Survival depends also on the disease-status prior treatment.

Successful treatment of a B/T MPAL patient by chemo-free treatment with venetoclax, azacitidine, and blinatumomab.

B/T mixed phenotype acute leukemia (MPAL), which represents only 2-3% of all MPAL cases, is classified as a high-risk leukemia subtype. Adults diagnosed with B/T MPAL have a notably low 3-year survival rate, estimated at 20-40%. The rarity and undercharacterization of B/T MPAL present substantial challenges in identifying an optimal treatment protocol. This report aims to shed light on this issue by presenting a case in which a patient with a complex karyotype was treated using a combination of venetoclax, azacitidine, and blinatumomab. This novel, chemo-free regimen resulted in the patient achieving both hematologic and molecular complete remission, with no severe organ or hematological toxicity observed. Notably, the patient continued to maintain molecular remission for 1 year following the transplantation. Based on these findings, the combination of venetoclax, azacitidine, and blinatumomab could be considered a potential therapeutic approach for B/T MPAL patients, meriting further investigation.

Treatment of Relapsed Acute Lymphocytic Leukemia in Adult Patients.

OPINION STATEMENT: For adult patients diagnosed with relapsed B cell-ALL (B-ALL), there have been significant improvements in available treatment options following the FDA approval of novel cellular and immunotherapy approaches - blinatumomab, chimeric antigen receptor (CAR) T therapy, and inotuzumab. For the last several years, research has focused on gaining a better understanding of the effects of specific disease and patient characteristics on long-term outcomes with each of the FDA-approved agents. In combination with the better prevention and management of unique, treatment-specific toxicities, providers can now select the best available treatment option for each individual patient diagnosed with relapsed, adult B-ALL needing therapy. This has allowed more patients to proceed to consolidative hematopoietic stem cell transplant (HSCT), and long-term data has even brought into question the need for HSCT for long-term durable remission for all patients. However, with the adoption of blinatumomab, CAR T therapy, and inotuzumab in front-line treatment regimens, it remains unclear what effects this will have on patients with relapsed B-ALL following exposure to these novel cellular and immunotherapy therapies. Unlike B-ALL, similar advances have unfortunately not yet been realized in T cell-ALL (T-ALL). Currently, new therapeutic approaches are underway to utilize similar targeting strategies that have been successful in B-ALL - monoclonal antibodies, bispecific T-cell engagers (BiTE), and CAR T therapy. Like B-ALL, the only existing approved therapy for relapsed T-ALL, nelarabine, is now used in the upfront treatment setting potentially limiting its utility in relapsed disease. Over the next several years, the hope is for patients diagnosed with T-ALL to experience the drastic improvement in outcomes as has been seen for patients diagnosed with B-ALL over the last decade.

Pneumocystis jirovecii Pneumonia Secondary to Blinatumomab Therapy: A Case Report.

INTRODUCTION: With the increasing use of blinatumomab in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), including minimal residual disease (MRD)-positive cases, awareness of its adverse effects has gradually improved. Pneumocystis jirovecii pneumonia (PCP) associated with blinatumomab therapy is rare. CASE PRESENTATION: We present a case of PCP in a patient undergoing blinatumomab therapy. A 70-year-old female diagnosed with Philadelphia-like CRLF2 overexpression B-cell precursor ALL received blinatumomab as consolidation therapy after achieving complete remission with prior induction chemotherapy. On the second day of blinatumomab infusion, she developed intermittent low-grade fever, and chest computed tomography (CT) revealed subtle infiltrates and nodules. Despite empiric trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, she progressed to significant shortness of breath and type I respiratory failure, with increased lactate dehydrogenase and ß-D-glucan assays. Chest CT showed diffuse ground-glass opacities with scattered small nodules. The dry cough prompted next-generation sequencing of peripheral blood, which tested positive for pneumocystis jirovecii without evidence of other pathogens. Consequently, the patient was diagnosed with PCP. The first cycle of blinatumomab had to be discontinued, and therapeutic dosages of TMP-SMX and dexamethasone were administered, resulting in full recovery and stable condition during follow-ups. CONCLUSION: PCP is rare in B-cell precursor ALL patients receiving blinatumomab therapy but manifests with early onset and rapid disease progression. Despite prophylaxis, PCP infection cannot be ignored during blinatumomab therapy. Therefore, heightened attention is warranted when using blinatumomab therapy.

Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

BACKGROUND: A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsed/refractory (R/R) B-ALL. METHODS: Data from five trials of blinatumomab for R/R B-ALL were pooled for analyses. Patients were placed in one of three groups: group 1, ≥50% bBMBs; group 2, ≥25% to <50% bBMBs; group 3, ≥5% to <25% bBMBs. Response and survival outcomes were compared between groups. RESULTS: Data from 683 patients (166 pediatric, 517 adult) were analyzed. Collectively, patients in groups 2 and 3 had significantly higher odds of achieving a complete remission (CR) (odds ratio [OR], 3.50 [95% confidence interval (CI), 2.23-5.48] and 3.93 [95% CI, 2.50-6.18], respectively; p < .001) and minimal/measurable residual disease response (OR, 2.61 and 3.37, respectively; p < .001) when compared with group 1 (reference). Groups 2 and 3 had a 37% and 46% reduction in the risk of death (hazard ratio [HR], 0.63 and 0.54, respectively; p < .001) and a 41% and 43% reduction in the risk of an event (relapse or death) (HR, 0.59 and 0.57, respectively; p < .001) compared with group 1. No significant differences in response or survival outcomes were observed between groups 2 and 3. Seven of nine patients whose bBMB% was lowered to <50% with dexamethasone achieved CR with blinatumomab. CONCLUSION: Any bBMB% <50% was associated with improved efficacy following blinatumomab treatment for R/R B-ALL.

Moving away from chemotherapy in newly diagnosed Philadelphia chromosome-positive B-cell acute lymphoblastic leukaemia.

Chemotherapy-free regimens are reshaping the treatment landscape of Philadelphia chromosome-positive acute lymphoblastic leukaemia. The report by Xie et al. suggests that the combination of dasatinib and prednisone is effective as induction and early consolidation. Survival was improved in patients who subsequently underwent allogeneic stem cell transplantation. Commentary on: Xie et al. Dasatinib plus prednisone as induction and consolidation for adults with Ph-positive acute lymphoblastic leukaemia: A single-arm, multicentre, phase 2 trial. Br J Haematol 2023;202:1119-1126.

Blinatumomab differentially modulates peripheral blood and bone marrow immune cell repertoire: A Campus ALL study.

Blinatumomab is the first bi-specific T-cell engager approved for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (B-ALL). Despite remarkable clinical results, the effects of blinatumomab on the host immune cell repertoire are not fully elucidated. In the present study, we characterized the peripheral blood (PB) and, for the first time, the bone marrow (BM) immune cell repertoire upon blinatumomab treatment. Twenty-nine patients with B-ALL received blinatumomab according to clinical practice. Deep multiparametric flow cytometry was used to characterize lymphoid subsets during the first treatment cycle. Blinatumomab induced a transient redistribution of PB effector T-cell subsets and Treg cells with a persistent increase in cytotoxic NK cells, which was associated with a transient upregulation of immune checkpoint receptors on PB CD4 and CD8 T-cell subpopulations and of CD39 expression on suppressive Treg cells. Of note, BM immune T-cell subsets showed a broader post-treatment subversion, including the modulation of markers associated with a T-cell-exhausted phenotype. In conclusion, our study indicates that blinatumomab differentially modulates the PB and BM immune cell repertoire, which may have relevant clinical implications in the therapeutic setting.

Pretreatment blast-to-lymphocyte ratio as a prognostic marker for CD19/CD3-bispecific T cell-engaging antibodies (blinatumomab) treatment against relapsed or refractory B-precursor acute lymphoblastic leukemia.

Blinatumomab is an immunotherapy drug approved for the treatment of acute lymphoblastic leukemia. Since not all patients respond to blinatumomab, markers are needed to predict the efficacy of blinatumomab in individual patients. We hypothesized that the pre-treatment blast-to-lymphocyte ratio would predict blinatumomab efficacy. To examine this possibility, we conducted a post hoc analysis using data from the TOWER Clinical Trials (NCT02013167). Multivariate analysis showed that, along with the treatment groups, each of the following was independently correlated with superior progression-free survival: salvage-treatment phase, allogeneic stem cell transplantation, and pre-treatment ratio of bone marrow blasts-to-peripheral blood lymphocytes < 25.

Anti-CD19/CD8 bispecific T cell engager for the potential treatment of B cell malignancies.

The administration of blinatumomab was accompanied by several adverse effects, including activation of regulatory T-cells and cytokine storm. The objective of this study was to produce and evaluate a novel αCD8/CD19 BiTE (αCD8/CD19) with the potency to directly target CD8+T-cells. In-silico studies were utilized for determining proper folding, receptor binding, and structural stability of αCD8/CD19 protein. Western blotting and indirect surface staining were used to evaluate the size accuracy and binding potency of the purified protein. Functionality was assessed for granzyme B production, cytotoxicity, and proliferation. TheαCD8/CD19recombinant protein was produced in the CHO-K1 cell line with a final concentration of 1.94 mg/l. The αCD8/CD19 bound to CD8+and CD19+cell lines and induced significant granzyme B production, cytotoxic activity and proliferation potential in the presence of IL-2 and tumor target cells. The maximum CD8+T-cell biological activity was observed on the 10th day with 10:1 effector-to-target ratio.

Comparing the efficacy of salvage regimens for relapsed/refractory B-cell acute lymphoblastic leukaemia: a systematic review and network meta-analysis.

The complete remission (CR) rate and overall survival (OS) of relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) are not satisfactory. The available salvage regimens include standard chemotherapy, inotuzumab ozogamicin, blinatumomab and cluster of differentiation (CD)19 chimeric antigen receptor T cells (CAR T), and the NCCN guidelines recommend all of these therapies with no preference. Dual CD19/CD22 CAR T-cells have emerged as new treatments and have shown some efficacy, with high CR rates and preventing CD19-negative relapse. However, direct comparisons of the CR rate and long-term survival among the different salvage therapies are lacking. Databases including PubMed, Embase, Web of Science and Cochrane were searched from inception to January 31, 2022, for relevant studies. The outcomes of interest were complete remission/complete remission with incomplete haematologic recovery (CR/CRi) rates and 1-year overall survival (OS) rates. Odds ratios (ORs) were generated for binary outcomes, and the mean difference (MD) was generated for consecutive outcomes by network meta-analysis. CD19 CAR T-cells demonstrated a significantly better effect in improving the CR/CRi rate than blinatumomab (OR = 8.32, 95% CI: 1.18 to 58.44) and chemotherapy (OR = 16.4, 95% CI: 2.76 to 97.45). In terms of OS, CD19 CAR T-cells and dual CD19/CD22 CAR T-cells both had a higher 1-year OS rate than blinatumomab, inotuzumab ozogamicin and chemotherapy. There was no significant difference between CD19 CAR T-cells and dual CD19/CD22 CAR T-cells in terms of 1-year OS and CR/CRi rates. CD19 CAR T-cells are effective in inducing CR, and CD19 CAR T-cells and dual CD19/CD22 CAR T-cells show benefits for overall survival. More high-quality randomized controlled trials and longer follow-ups are needed to confirm and update the results of this analysis in the future.

Mini-hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia.

Relapsed or refractory pediatric patients with B-acute lymphoblastic leukemia (B-ALL) have high rates of toxicities and relapse, and novel therapy is needed. We present a case of a 5-year-old male child with high-risk B-ALL that was refractory to several re-induction regimens. He was put into minimal residual disease-negative remission after re-induction with chemotherapy plus overlapping rituximab, inotuzumab ozogamicin, and blinatumomab, termed mini-hyper-CVD (cyclophosphamide, vincristine, and dexamethasone) plus CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab). This regimen was well tolerated, and he received his transplant and engrafted with no significant infections, toxicities, or sinusoidal obstruction syndrome. This is the first reported use of a condensed sequential immunotherapy/chemotherapy regimen in a pediatric leukemia patient.

Transient and fully reversible changes in laboratory parameters and modifications of the cytokine profile during blinatumomab treatment in children with relapsed or refractory B-cell acute lymphoblastic leukemia.

We analyzed changes in laboratory parameters, including blood counts, liver enzymes, inflammation and coagulation markers, and cytokines, from 70 blinatumomab-treated pediatric patients (NCT01471782). Overall, trends were consistent in responders and nonresponders. Platelets and lymphocytes peaked on day (D) 10 in cycle 1 and returned to baseline on D42 and D29, respectively. Neutrophils peaked on D2 and returned to baseline on D42. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin peaked on D17, reversing to baseline on D29; total protein levels were constant. These findings indicate that blinatumomab-induced changes in laboratory parameters were transient, reversible, and not requiring treatment interruptions in responders and nonresponders.

Real-world treatment patterns of novel drugs in relapsed or refractory acute lymphoblastic leukemia patients in Japan.

Aim: To evaluate treatment patterns of novel therapies (inotuzumab ozogamicin (inotuzumab), blinatumomab, and tisagenlecleucel) in patients with acute lymphoblastic leukemia (ALL) in a Japanese real-world setting. Patients & Methods: Patients with ALL diagnoses from a Japanese claims database were examined. Results: We included 194 patients (97 patients were prescribed inotuzumab; 97 patients were prescribed blinatumomab; and no patient was prescribed tisagenlecleucel); 81.4% in the inotuzumab group and 78.4% in the blinatumomab group were prescribed chemotherapy prior to the initiation of those drugs. Most patients were prescribed subsequent treatment (60.8 and 58.8%, respectively). A small number of patients were prescribed sequential treatment of inotuzumab-to-blinatumomab or blinatumomab-to-inotuzumab (20.3 and 10.5%, respectively). Conclusion: This study revealed inotuzumab and blinatumomab treatment features in Japan.

In acute lymphoblastic leukemia (ALL), the increase in leukemic cells prevents the production of normal blood cells. As a result, people with ALL become more susceptible to anemia, fatigue, infections, fever, bruising and bleeding easily. ALL progresses rapidly without treatment. In recent years, new therapeutic drugs, including inotuzumab and blinatumomab, have become available; however, it remains unclear how they have been used in clinical practice. In this report, we assess how they are used in clinical practice using a large database to collect the clinical data of ALL patients. To see the treatment pattern, we found that most of the patients (81.4% of patients who received inotuzumab and 78.4% of those who received blinatumomab) had received chemotherapy before starting treatment with inotuzumab or blinatumomab. After patients ended treatment with inotuzumab or blinatumomab, 60.8% of patients who received inotuzumab and 58.8% of those who received blinatumomab received the next therapies, including chemotherapy. However, a small number of patients had received inotuzumab-to-blinatumomab or blinatumomab-to-inotuzumab (20.3 and 10.5%, respectively). These findings show the real-world treatment patterns of inotuzumab and blinatumomab; that is, both inotuzumab and blinatumomab are more likely to be prescribed to patients who might not have enough efficacy from prior chemotherapy or might have had to stop chemotherapy early due to side effects. Overall, there is clinical meaningful information from our findings of how inotuzumab and blinatumomab have been used for treatment of ALL and this information could improve the clinical practice of ALL in Japan.

A next generation mathematical model for the in vitro to clinical translation of T-cell engagers.

T-cell engager (TCE) molecules activate the immune system and direct it to kill tumor cells. The key mechanism of action of TCEs is to crosslink CD3 on T cells and tumor associated antigens (TAAs) on tumor cells. The formation of this trimolecular complex (i.e. trimer) mimics the immune synapse, leading to therapeutic-dependent T-cell activation and killing of tumor cells. Computational models supporting TCE development must predict trimer formation accurately. Here, we present a next-generation two-step binding mathematical model for TCEs to describe trimer formation. Specifically, we propose to model the second binding step with trans-avidity and as a two-dimensional (2D) process where the reactants are modeled as the cell-surface density. Compared to the 3D binding model where the reactants are described in terms of concentration, the 2D model predicts less sensitivity of trimer formation to varying cell densities, which better matches changes in EC50 from in vitro cytotoxicity assay data with varying E:T ratios. In addition, when translating in vitro cytotoxicity data to predict in vivo active clinical dose for blinatumomab, the choice of model leads to a notable difference in dose prediction. The dose predicted by the 2D model aligns better with the approved clinical dose and the prediction is robust under variations in the in vitro to in vivo translation assumptions. In conclusion, the 2D model with trans-avidity to describe trimer formation is an improved approach for TCEs and is likely to produce more accurate predictions to support TCE development.

SEM Observation of the Filter after Administration of Blinatumomab: A Possibility of Leakage during Home Administration Using a Portable Infusion Pump.

Blinatumomab (Blincyto® injection solution) is classified as a bispecific T-cell engaging (BiTE) antibody and is intended for the treatment of relapsed/refractory acute lymphoblastic leukemia. It requires continuous infusion to maintain therapeutic levels. Therefore, it is often administered at home. Monoclonal antibodies, which are administered intravenously, have the potential to leak depending on the nature of the administration devices. Therefore, we investigated device-associated causes of blinatumomab leakage. We observed no apparent changes to the filter and its materials after exposure to the injection solution and surfactant. From scanning electron microscopic images, precipitate on the surface of the filters was observed after physical stimulation of the injection solution. Therefore, physical stimulations should be avoided during the prolonged administration of blinatumomab. In conclusion, the findings of this study assist in the safe administration of antibodies using portable infusion pumps, taking into consideration the composition of drug excipients and the choice of filter type and structure.

Relapse/Refractory Paediatric B-ALL Case with CD19- Phenotype Switching Indicating the Importance of Appropriate Diagnostic Approach and Targeted Treatment Adjustment-Case Report.

The case reported presents a rare CD19- phenotype shift of an acute lymphoblastic leukaemia clone during relapse/refractory ALL in a paediatric patient. We explore possible reasons for the promotion of CD19-negative cell selection, including discrete mutations and anti-CD19 treatment, which is gaining importance as targeted therapies such as blinatumomab enter standard treatment protocols. A 9-year-old male patient was diagnosed with B lymphocyte acute lymphoblastic leukaemia. Initial standard genetic analysis did not show significant chromosomal aberrations, and the patient underwent chemotherapy in line with the intermediate-risk protocol. After initially achieving remission, the disease relapsed, and the patient required hematopoietic stem cell transplantation (HSCT). In-depth retrospective microarray analysis performed at this point revealed additional risk factors, particularly a loss of function TP53 V173L mutation. A second recurrence was diagnosed which prompted targeted treatment application (blinatumomab) and subsequent HSCT. The third leukemic relapse, diagnosed shortly after the second HSCT, limited treatment options to last-resort CAR T-cell therapy in Germany. Subsequent immunophenotyping revealed insufficient CD19 expression by ALL clones and disqualified the patient from treatment. The patient died in October 2019 from disease progression. The case highlights the importance of in-depth molecular diagnostics and monitoring of relapse/recurrent ALL cases to identify and manage risk factors during treatment.

[Safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia]. / 贝林妥欧单抗治疗儿童复发/éš¾æ²»æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— çš„å®‰å ¨æ€§åŠè¿‘æœŸç–—æ•ˆåˆ†æž.

OBJECTIVES: To study the safety and short-term effectiveness of blinatumomab in the treatment of childhood relapsed/refractory acute lymphoblastic leukemia (R/R-ALL). METHODS: Six children with R/R-ALL who received blinatumomab treatment from August 2021 to August 2022 were included as subjects, and a retrospective analysis was performed for their clinical data. RESULTS: Among the six children, there were three boys and three girls, with a median age of 10.5 (5.0-13.0) years at the time of inclusion. Of all six children, one had refractory ALL and did not achieve remission after several times of chemotherapy, and 5 relapsed for the first time, with a median time of 30 (9-60) months from diagnosis to relapse. Minimal residual disease (MRD) before treatment was 15.50% (0.08%-78.30%). Three children achieved complete remission after treatment, among whom two had negative conversion of MRD. Five children had cytokine release syndrome (CRS), among whom 3 had grade 1 CRS and 2 had grade 2 CRS. Four children were bridged to allogeneic hematopoietic stem cell transplantation, with a median interval of 50 (40-70) days from blinatumomab treatment to transplantation. The six children were followed up for a median time of 170 days, and the results showed an overall survival rate of 41.7% (95%CI: 5.6%-76.7%) and a median survival time of 126 (95%CI: 53-199) days. CONCLUSIONS: Blinatumomab has good short-term safety and effectiveness in the treatment of childhood R/R-ALL, and its long-term effectiveness needs to be confirmed by studies with a larger sample size.