Blinatumomab Therapy Research Articles

The characterization and the impact of CSF pleocytosis during blinatumomab therapy for adult acute lymphoblastic leukemia

Reactive pleocytosis in the CSF has been observed with blinatumomab but has not been well-described. We performed a retrospective study of 88 patients who received intrathecal chemotherapy (IT) while on blinatumomab with CSF analyzed to determine if pleocytosis had an impact efficacy and safety. Blinatumomab was used for relapsed/refractory 62.5%, MRD-positive 31.8%, and consolidation in MRD-negative 5.7%. The incidence of pleocytosis in CSF was 51% and was more frequent after day 15 (55.8% vs. 18.2%, p = 0.025). Pleocytosis did not impact CR, clearance of MRD positivity, PFS and OS rates. Lower incidence of non-CNS extramedullary relapse was seen (3.7% vs. 30.8%, p = 0.011) with pleocytosis in CSF. Analysis of CSF by flow cytometry showed median CD4:CD8 ratio of 1.34. In conclusion, CSF pleocytosis is prevalent with blinatumomab but only demonstrated lower rates of non-CNS extramedullary relapse but no impact on CNS relapse or neurotoxicity.

Blinatumomab Therapy for Low Level Minimal Residual Disease Detected By Next-Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia

Blinatumomab Therapy for Low Level Minimal Residual Disease Detected By Next-Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia

Short-Term Efficacy and Safety of Blinatumomab in Early Postinduction Intensification Therapy for Pediatric B-Cell Acute Lymphoblastic Leukemia

Background: Multidrug chemotherapy is the main treatment for children with B-cell acute lymphoblastic leukemia (B-ALL), which has been associated with multiple long-term complications and high rates of treatment non-completion due to toxicities. Recently, blinatumomab has proven to be effective and well-tolerated in the treatment of relapsed or refractory pediatric B-ALL. However, there is still a lack of reports about the real-world application of blinatumomab in pediatric B-ALL who achieved first complete remission (CR). O bjectives: To assess the short-term efficacy and safety of blinatumomab in early postinduction intensification therapy for children with B-ALL who had achieved first complete remission in a real-world setting. M ethods: A single-center retrospective analysis was performed to collect data on pediatric B-ALL patients (pts) who received blinatumomab monotherapy during early postinduction intensification therapy. All pts had undergone China Children's Leukemia Group (CCLG)-2018 induction chemotherapy until achieving CR. Blinatumomab treatment was initiated after obtaining consent from patients and caregivers, following detailed counseling about the potential risks and benefits. Efficacy was assessed based on minimal residual disease (MRD) negativity (<0.01%) using multiparameter flow cytometry (MFC). Adverse events (AEs) were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. R esult: From September 2022 to July 2023, A total of 11 pts were included in this study due to chemotherapy intolerance: median age was 3 years (range, 1 to 11 years) with 54.5% (n=6) being male. Before blinatumomab therapy, MRD was detected in four pts with values of 0.024%, 0.037%, 10%, and 0.09%, respectively.The remaining pts tested negative for MRD. After one cycle of blinatumomab therapy, all MRDpos pts showed a decline in MRD, and 75% achieved undetectable MRD. The median follow-up time was 3 months. A total of 28 AEs were reported, with 75% classified as grade 1-2 and the remaining 25% as grade 3-4. The most frequently reported AEs were grade 1-2 fever (90.9%), observed within 7 days of treatment. Grade 3-4 hematological AEs included decreased white blood cell count and decreased neutrophil count. Additionally, four cases of infection, two cases of transient rash and one case of grade 2 diarrhea were observed. No pts experienced immune effector cell-associated neurotoxicity syndrome (ICANS), grade 3-4 cytokine release syndrome (CRS) or unexpected serious adverse events (SAEs). Furthermore, none of the AEs resulted in treatment delay, dose reduction or discontinuation. All pts experiencing treatment-associated toxicities recovered and proceeded to consolidation therapy. C onclusion: The use of blinatumomab in early intensification demonstrated promising short-term efficacy and a manageable safety profile in pediatric B-ALL pts. However, further confirmation of these results requires larger, randomized clinical trials.

Short-Term Blinatumomab As a Bridge Therapy for Hematopoietic Stem Cell Transplantation in B-Cell Acute Lymphoblastic Leukemia with Low Leukemia Burden

Introduction The influence of pre-transplant leukemic load on relapse and long-term survival is well-documented among patients with B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab, a bispecific T cell engager, has shown promising results as an effective treatment for relapsed B-ALL. However, the dosage (28μg/day) and duration (28 days of continuous infusion) of blinatumomab have been predominantly determined in a relapsed leukemia context. Therefore, in the minimal residual disease (MRD) scenario, the standard dosing may exceed the required amount, potentially leading to increased toxicity, delays in transitioning to the scheduled transplant, and superfluous economic expenditure. Methods We enrolled B-ALL patients with ≤10% MRD who were slated for allogeneic hematopoietic stem cell transplantation (ASCT). MRD was quantified via multi-parameter flow cytometry or polymerase chain reaction (PCR) for the target gene. Blinatumomab therapy began at 8 μg/day, gradually escalating to 28 μg/day over only 5-10 days. Bone marrow cells were harvested post-blinatumomab therapy. Upon acquiring MRD negativity, patients proceeded to the transplantation protocol. All patients underwent myeloablative conditioning with chidamide, fludarabine, cytarabine, and busulfan. Peripheral stem-cell grafts were harvested from HLA-matched sibling donors (MSD), matched unrelated donors (MUD), or haploidentical donors (HID). Post-transplantation acute GVHD prophylaxis consisted of cyclophosphamide and cyclosporine. For HID transplant recipients, mycophenolate mofetil was added from day +5 to day +35. Follow-up examinations were scheduled at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results Our study cohort comprised 20 patients (13 females, 7 males), median age 35.5 years (range 15-58). Patient and disease characteristics are summarized in Table 1. During the blinatumomab therapy, 8 patients (40%) experienced grade 1 cytokine release syndrome (CRS), and 1 patient (5%) experienced grade 2 CRS, with no instances of grade 3 or higher CRS observed. All patients achieved complete remission (CR) and MRD clearance evaluated by flow cytometry following blinatumomab treatment. Eleven patients were diagnosed with Philadelphia chromosome-positive ALL, and 5 of them didn't achieve MRD clearance evaluated by PCR. Allo-SCT was conducted following blinatumomab at a median interval of 5.5 days (range 1-29) using MSD in 4 patients, MUD in 2 patients, and HID in 14 patients. The median time to neutrophil and platelet engraftment was 12 days (range 9-17) and 13 days (range 9-28), respectively. The median follow-up duration was 10.2 months (range 2-21.7). By day +30 post-ASCT, all patients achieved CR and MRD clearance with full donor chimerism. Acute GVHD (aGVHD) (grades II-IV) and (grades III-IV) incidences were recorded at 10.0% and 5.3% respectively (Figure 1A). One fatality occurred due to COVID-19-associated pulmonary aspergillosis 7.2 months post-transplantation. Among the 18 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) was 44.4%, with no instances of severe cGVHD observed (Figure 1B). No patient relapsed at the last follow-up on July 31, 2023. The estimated 1-year progression-free survival (PFS) and overall survival (OS) both stood at 90% (Figure 1C). Conclusion Short-term blinatumomab as a bridging therapy for adult patients with low-burden B-ALL transitioning to ASCT demonstrates comparable efficacy to standard dosing regarding disease control and survival outcomes.

Liver failure after treatment with inotuzumab and polychemotherapy including PEG-asparaginase in a patient with relapsed Philadelphia chromosome–negative acute lymphoblastic leukemia

We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient died from complications of a drug-induced acute liver failure after a salvage therapy combining inotuzumab ozogamicin (InO)-based induction followed by consolidation with high dose MTX and pegaspargase based on the GMALL protocol for older ALL patients. After a diagnosis of the extramedullary relapse in the form of a retro vesical chloroma, the patient received an individualized multi-agent chemotherapy based on induction chemotherapy for older patients in combination with InO. After four administrations of InO, in combination with vincristine, dexamethasone, cytarabine, and cyclophosphamide, CT-imaging showed a reduction in volume of the chloroma and response to therapy. Consolidation with high-dose methotrexate and pegaspargase was administered. The patient developed toxic liver damage manifested by hyperbilirubinemia and progressive hepatic encephalopathy. The diagnostic criteria for VOD were met, and therapy with defibrotide was initiated. Liver biopsy revealed no histological signs of VOD but instead steatohepatitis indicative of drug-induced toxicity. The patient ultimately died of hemorrhagic shock through postinterventional hemorrhage after liver biopsy. In conclusion, although InO shows promising results in the therapy of r/r ALL with and without additional chemotherapy, the combination with MTX and pegaspargase in an intensively pretreated patient with relapse after HCST may impart an increased risk for liver-related toxicity. Special caution is required when assessing fitness for further liver toxic regimens. A key takeaway is also the reminder that InO can cause liver damage not only in the form of VOD but also through direct hepatocellular toxicity.

Treatment response of a two-dose regimen of dose-adjusted inotuzumab ozogamicin in relapsed/refractory B-cell acute lymphoblastic leukemia

Objective: To observe the treatment response of a two-dose regimen of inotuzumab ozogamicin (inotuzumab), a monoclonal antibody targeting CD22, for patients with heavily treated relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), including those failed or relapsed after chimeric antigen receptor (CAR) -T-cell therapy. Methods: Pediatric and adult patients who received two doses of inotuzumab and who were evaluated after inotuzumab treatment were included. Antibody infusions were performed between March 2020 and September 2022. All patients expressed CD22 antigen as detected by flow cytometry (>80% leukemic cells displaying CD22) before treatment. For adults, the maximum dosage per administration was 1 mg (with a total of two administrations). For children, the maximum dosage per administration was 0.85 mg/m(2) (no more than 1 mg/dose; total of two administrations). The total dosage administered to each patient was less than the standard dosage of 1.8 mg/m(2). Results: Twenty-one patients with R/R B-ALL were included, including five children (<18 years old) and sixteen adults. Seventeen patients presented with 5.0% -99.0% leukemic blasts in the bone marrow/peripheral blood or with extramedullary disease, and four patients were minimal residual disease (MRD) -positive. Fourteen patients underwent both CD19 and CD22 CAR-T-cell therapy, four underwent CD19 CAR-T-cell therapy, and three underwent blinatumomab therapy. Eleven patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). After inotuzumab treatment, 14 of 21 patients (66.7% ) achieved a complete response (CR, one was MRD-positive CR), and all four MRD-positive patients turned MRD-negative. Four of six patients who failed recent CD22 CAR-T-cell therapy achieved a CR after subsequent inotuzumab treatment. Seven patients (33.3% ) demonstrated no response. Grade 1-3 hepatotoxicity occurred in five patients (23.8% ), one child with no response experienced hepatic veno-occlusive disease (HVOD) during salvage transplantation and recovered completely. Conclusion: For patients with heavily treated R/R B-ALL, including those who had undergone allo-HSCT and CD19/CD22 CAR-T-cell therapy, the two-dose regimen of inotuzumab resulted in a CR rate of 66.7%, and the frequency of hepatotoxicity and HVOD was low.

Blinatumomab Therapy Is Associated with Favorable Outcomes after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with B Cell Acute Lymphoblastic Leukemia

Blinatumomab, a bispecific T cell engager that binds CD19 in leukemic cells and CD3 in cytotoxic T cells and leads to leukemic blast lysis, is often used in pediatric patients with relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) prior to allogeneic hematopoietic cell transplantation (allo-HCT). Concerns about the potential risk of blinatumomab-related immune-mediated toxicities after allo-HCT have not been adequately addressed. These include graft-versus-host disease (GVHD), delayed engraftment, and graft failure or rejection. Pediatric-specific data reporting post-HCT outcomes of patients treated with blinatumomab are scarce and limited to small cohorts. We sought to investigate the clinical outcomes of pediatric patients with R/R B-ALL who received blinatumomab therapy pre-HCT, focusing on overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM), as well as the incidence of immune-mediated post-HCT complications including GVHD, delayed neutrophil or platelet engraftment, graft failure, and graft rejection. We also investigated blinatumomab's effects on B cell reconstitution based on achievement of i.v. immunoglobulin (IVIG) independence post-HCT. This single-center, retrospective study included patients with B-ALL receiving blinatumomab therapy before undergoing allo-HCT, with transplantation performed between 2016 and 2021 at our institution. Patients receiving blinatumomab for relapse after allo-HCT were excluded. Patients receiving chemotherapy alone before allo-HCT during the same period composed the control group. Seventy-two patients were included, 31 of whom received blinatumomab before allo-HCT. Survival estimates were obtained using the Kaplan-Meier method, and the log-rank test was used to analyze differences between groups. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and continuous variables were compared using the Wilcoxon rank-sum test. Cumulative incidences were estimated using the competing risks method, and Gray's test was used to analyze differences between groups. A Cox proportional hazards regression model was used for univariate and multivariable analyses for OS. Landmark analysis was performed at the set time points of 30 days and 100 days post-allo-HCT. Most patients in the study cohort had high-risk relapsed B-ALL. Blinatumomab therapy induced minimal residual disease (MRD)-negative remissions in all patients, whereas 5 patients (12.2%) receiving chemotherapy alone had persistent MRD pre-allo-HCT. Time from the start of therapy to the date of allo-HCT was shorter for patients who received blinatumomab compared with those who received chemotherapy (P < .0001). Blinatumomab therapy was associated with greater LFS compared to chemotherapy alone (P = .049), but when limited to 1 year, LFS was not significantly different from control (P = .066). There appeared to be higher OS, lower CIR, and lower NRM in patients receiving blinatumomab compared to the control group; however, the differences were not significant. None of the variables assessed in multivariable analysis was associated with differences in OS. When compared to the controls, blinatumomab therapy did not result in a higher incidence of acute or chronic GVHD, delayed neutrophil or platelet engraftment, or graft failure or rejection. The time to IVIG infusion independence post-allo-HCT was similar in the 2 groups. This study supports the use of blinatumomab salvage therapy for R/R B-ALL before allo-HCT given its efficacy in inducing MRD-negative remissions and optimizing LFS, as well as its lack of association with an increased incidence of post-allo-HCT adverse immune-mediated toxicities. Larger, prospective studies are needed to confirm these findings and to investigate blinatumomab's effects in long-term post-allo-HCT events.

In-Depth Immune Profiling in Children with BCP-ALL within the AIEOP-BFM ALL 2017 Study

The international multicenter frontline therapy trial AIEOP-BFM ALL 2017 prospectively randomizes CD19-targeting T-cell engager blinatumomab (BLN) against standard of care (SOC) to improve outcomes in pediatric patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) stratified for high (HR) and medium (MR) risks of relapse. In HR arm BLN is given earlier, directly after intensified HR therapy block, while in the MR arm, it is given towards the end of chemotherapy, before maintenance. The immune composition prior to BLN might thus differ between both treatment groups (HR vs MR) which may impact BLN-mediated anti-leukemic activity. Within the Germany-wide immune monitoring program accompanying the AIEOP-BFM ALL 2017 trial we addressed this question and studied a total of 1056 longitudinal peripheral blood samples collected between 11/2018 and 05/2022 from 381 BCP-ALL pts. Samples were prospectively analyzed with multicolor flow cytometry to study immune cell composition (Panel 1) at the time of BLN application (d0) and under ongoing immunotherapy within first 24h (d1), at day 14 (d14), at the end of the cycle I (d28) and end of cycle 2 (day28_II), if applicable (Figure 1A). In-depth T-cell profiling was performed in the BLN arm, utilizing 4 additional 12-color panels concentrated on markers associated with T-cell functionality (measured with standardized cytometer settings). Data were analyzed using classical 2D-manual gating strategies (&amp;gt; 2000 variables) and completed with R-based machine learning algorithms; namely partial Least-Squares Discriminant Analysis (PLS-DA), a multivariate dimensionality-reduction tool for identifying HR- and MR-defining immune signatures and PhenoGraph algorithm for unsupervised T-cell cluster detection. T-cell receptor excision circles (TRECs) and TR-repertoire analysis were also performed among paired samples of 117 BLN-treated pts. Baseline immune composition differed notably between HR and MR pts directly prior to BLN therapy, as shown by PLS-DA analysis on manually gated immune subsets. HR pts showed higher neutrophil counts and lower lymphocyte and monocyte counts compared to MR pts. Interestingly, MR pts had higher levels of B- and T-cells, which are crucial for BLN-mediated T-cell activation. HR pts displayed an elevated CD4+/CD8+ ratio, shifted naïve/memory T-cell phenotypes and increased proportions of immunosuppressive T-regulatory cells. These results suggest that more intensive therapy protocols directly prior to BLN influence the immune composition towards compromised states in the HR arm, potentially affecting BLN-mediated T-cell leukemia control. BLN effectively depleted CD19+ cells in 221 out of 224 pts. We observed significantly stronger T-cell activation/expansion in MR pts compared to HR pts under BLN therapy. This expansion that was primarily attributed to naïve CD8+ T-cell populations, resulting from clonal T-cell proliferation independent of thymic contribution, as supported by TREC and TR-repertoire analysis. The PhenoGraph clustering also identified this expanding naïve CD8+ T-cell populations, surprisingly marked by loss of adhesion molecule DNAM1 (panel 1), normally involved in NK and T-cell mediated cytotoxicity and by gaining the expression of TIM-3 (panel 3), an inhibitory molecule usually co-expressed with PD1 on exhausted T-cells with memory phenotypes. In this setting however, TIM3 was not co-expressed with PD1 (Figure 1B) and its expression was correlated with the B-cell levels at baseline and was strongest in MR pts under BLN therapy. Our data suggest an until now undescribed association between DNAM1 and TIM3 with BLN-mediated T-cell activation, hinting that they may serve as a measure of T-cell activation strength or an early T-cell exhaustion marker. In conclusion our study provides clinically relevant insights in how chemotherapy prior BLN might affect the patients´ immune system, possibly influencing the BLN anti-leukemic activity, and helps to determine the optimal place of immunotherapy with BLN in multimodal treatment schedules. Here, we report until know undescribed effect of BLN on T-cell compartment. Upcoming clinical data, which will be correlated with obtained immune profiles will answer the open question regarding the clinical relevance of these findings, and shed light into the mechanisms determining response to BLN, for its maximum benefit in childhood ALL.

A Real-World Evidence on Effectiveness and Safety of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia

Introduction Blinatumomab, a bispecific T-cell antibody, has emerged as a novel therapy with a promising efficacy and tolerable safety in patients with B-cell acute lymphoblastic leukemia (B-ALL). However, there is a paucity of data on blinatumomab for patients with newly diagnosed and relapsed/refractory (R/R) B-ALL in frontline and relapsed settings outside the clinical trials. This study aimed to describe the treatment patterns, effectiveness and safety of blinatumomab in Chinese patients with B-ALL. Methods In this retrospective observational study, data of patients with B-ALL who received at least one dose of blinatumomab in frontline or relapsed settings between August 2021 and June 2023 were collected from electronic medical data of the Department of Haematology of the First Affiliated Hospital of Soochow, China. The primary endpoint of the study was the treatment pattern of blinatumomab therapy, including median treatment cycles. Secondary endpoints included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity (i.e., complete MRD remission, defined as MRD &amp;lt;0.01%), median event-free survival (EFS) and 1-year EFS rate, median overall survival (OS) and 1-year OS rate, duration of response (DOR) and adverse events (AEs). Results In total, 96 patients with B-ALL (53 males and 43 females) were included. Of these, 53 received frontline treatment (blinatumomab used for first line remission induction: n=6; first line consolidation: n=39; first line induction or consolidation unknown: n=8), and 43 were R/R patients (blinatumomab for remission re-induction: n=28; R/R consolidation: n=14; R/R re-induction or consolidation unknown: n=1). The median age was 34 years (range: 11-67). Among R/R patients, 18 (18.8%), 12 (12.5%) and 13 (13.5%) had received 2, 3, and ≥3 previous lines of treatments, respectively. Sixteen patients were refractory to the last treatment. Among patients using blinatumomab for consolidation, MRD status at the start of therapy was positive in 29 (30.2%), and negative in 23 (24.0%) patients. Most of the patients (66.7%) received 1 cycle of blinatumomab followed by 2 (20.8%), 3 (7.3%), 4 (4.2%), and 5 (1.0%) cycles of the drug. The median treatment cycle was 1 (range: 1-5) with a median follow-up of 205 days (range: 15-652). In frontline treatment, all those using blinatumomab for remission induction and first line unknown status achieved CR with the CR/CRi rate of 100% (14/14) after blinatumomab. In patients with evaluable MRD (n=47) in the frontline setting, 87.2% (n=41) achieved MRD negativity within the 2 cycles of blinatumomab. In the following cycles, 3 more patients achieved MRD remission with overall complete MRD remission rate of 93.6% (44/47). In R/R re-induction patients, the CR/CRi rate was 50% (14/28) after blinatumomab treatment. Complete MRD remission rate in R/R patients who achieved CR within 2 cycles of blinatumomab was 73% (19/26). Median EFS was not reached (NR) in both frontline and R/R patients and the 1-year EFS rate was 90.8% (95% CI: 67% - 97%) and 55.1% (95% CI: 30% - 74%), respectively (Figure 1). Stratification of EFS by CR status at blinatumomab initiation showed 1-year EFS rate of 93.8% and 100% in first line consolidation and remission induction patients, respectively, whereas, R/R consolidation and re-induction patients showed 1-year EFS rate of 66.8% and 59.3%, respectively. None of the frontline treated patients died until the last follow-up time. In R/R patients the median OS was not reached and the 1-year OS rate was 70.9% (95% CI: 50% - 84%). OS stratified by CR status in R/R patients showed 1-year OS of 87.5% in consolidation and 69.9% in re-induction patients. Median DOR was NR in both frontline and relapsed settings. Seven (7.3%), and 3 (3.1%) patients reported any grade, and grade ≥3 cytokine release syndrome, respectively. Immune effector cell-associated neurotoxicity syndrome was reported by 1 patient (grade ≥3). Infection of any grade and grade ≥3 was reported by 6 (6.2%) and 4 (4.2%) patients, respectively. Increase in liver enzymes and neutropenia were observed in 1 patient (grade ≥3) each. Conclusion This study showed that using blinatumomab for remission induction and consolidation with one to five cycles was effective in the treatment of patients with B-ALL in the frontline as well as relapsed settings and had a tolerable safety profile.

Blinatumomab Therapy for Low Level Minimal Residual Disease Detected By Next-Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia

Introduction: Blinatumomab, a bi-specific T-cell engager, has shown clinical benefit in patients with relapsed-refractory and hematologic complete remission with minimal residual disease (MRD)-positive Acute Lymphoblastic Leukemia (ALL). The BLAST trial (Gökbuget N et al., Blood. 2018) demonstrated improved overall survival (OS) and disease-free survival (DFS) in patients with MRD-positive disease (≥0.1%) who achieved MRD response with Blinatumomab. We sought to evaluate the utility of Blinatumomab in low levels of MRD (&amp;lt;0.1%) using clonoSEQ with a sensitivity of (0.0001%). Methods: Adult (18+) B- ALL patients that underwent treatment for B-cell ALL at Norris Comprehensive Cancer Center (NCCC) between 2016 and 2022 who had residual disease tracked using the Next Generation Sequencing (NGS)-based clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) were included. Patients who received Blinatumomab for MRD positivity were included only if they had a tracked clonoSEQ sequence within one month before starting treatment. Patients who didn't receive Blinatumomab were included if they had an MRD-positive clonoSEQ report. Those who were relapse/refractory when found to be MRD positive were excluded. Cumulative incidence of relapse (CIR) was evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome. At the same time, OS and DFS were analyzed using Cox proportional hazards model. The start time was set to the date of the MRD report, and patients were censored until the last follow-up. Confounder-adjusted KM curves were calculated using direct standardization. Results: 47 patients were included with a median age at diagnosis of 45 years (range: 21-70). Most were Hispanic (N = 33, 70.2%), and the median follow-up time was 12 months. The 3-year OS, DFS, and CIR were 95.4% (95% CI 89.3-100%), 75.1% (95% CI 60.4-93.5%), and 20.3% (95% CI 7.2-38.0%). Twenty-six patients were treated with Blinatumomab (median two cycles, range 1-9), with most (N= 14, 53.8%) having low levels of MRD (&amp;lt;0.1%). Fourteen patients (53.8%) achieved MRD negativity with a median time to MRD negativity of 3.1 months. There were no relapses or death in patients who achieved MRD negativity in the treated group. However, non-responders with Blinatumomab had one death and two relapses. All patients continued Maintenance therapy after receiving Blinatumomab and did not proceed with the transplant. The patients who received Blinatumomab were more likely to be MRD positive on multiparameter flow cytometry (MFC) (60.0% vs. 28.6%, P = 0.042) but had a similar distribution of patient age, treatment type, and receipt of transplant. Additionally, there was a trend toward increased median percent residual cells on clonoSEQ (0.018% vs. 0.003% P =0.244) and flow (0.02% vs 0% P =0.066) in the Blinatumomab treatment group. On univariate analysis, significant predictors of CIR and DFS were flow percent (DFS: HR = 1.54; 95% CI 1.07-2.23; P = 0.019; CIR: HR = 1.83; 95% CI 1.38-2.41; P&amp;lt;0.001) and clonoSEQ residual cell count(DFS: HR = 1.58; 95% CI 1.04-2.41; P = 0.031, CIR: HR = 1.88; 95% CI 1.18-2.97 P=0.008). When controlling for the number of residual cells on close, patients who received Blinatumomab had significantly better CIR(HR = 0.11; 95% CI 0.02-0.69; P = 0.019) and a trend towards improved DFS(HR = 0.21; 95% CI 0.04-1.28; P = 0.092), but no difference in OS. On subgroup analysis of the 31 patients with low levels of MRD (&amp;lt;0.1%), there was no improvement in DFS for patients who were treated with Blinatumomab (HR = 0.41; 95% CI 0.04-3.91; P = 0.44). Of those with low levels of MRD, only two relapsed, and both did not receive Blinatumomab. Conclusions: In B cell ALL, Blinatumomab may offer a CIR benefit to patients with low levels of MRD as detected on clonoSEQ.

Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy

Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias1–4 remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch. Genomic monitoring of primary leukemias and recurrences may predict therapy resistance, especially regarding anti-CD19 treatment.

Blinatumomab as salvage therapy in patients with relapsed/refractory B-ALL who have failed/progressed after anti-CD19-CAR T therapy

Background Anti-CD19 chimeric antigen receptors (CARs) T-cell therapy has been shown to have excellent efficacy in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). But many patients are refractory to anti-CD19-CAR T-cell therapy or relapse again. Methods Five patients with R/R B-ALL did not respond to anti-CD19-CAR T-cell therapy or had a disease progression again after CAR-T cell therapy. They received a salvage therapy of Blinatumomab. The clinical response, CD19 expression on ALL cells, the proportion of CD3+ T cells, level of cytokine levels of interleukin-6 (IL-6), hematological toxicity, grade of cytokine release syndrome (CRS), and immune effector cell-associated neurotoxic syndrome (ICANS) were observed in salvage therapy of Blinatumomab. Results Four patients obtained CR/CRi, even in patients without high expression of CD19 in B-ALL cells, while the other patient received NR after Blinatumomab therapy. The CD19 expression on ALL cells, the proportion of CD3+ T cells, and CD3+CD8+ T cells were deficient in Pt 5, who obtained PR in Blinatumomab therapy. One patient (Pt 3) was diagnosed with grade 0 hematological toxicity. The other four patients were diagnosed with grades 2–3 of hematological toxicity. The CRS was grade 0/one patient, grade 1/three, and grade 2/one. The ICANS was grade 0/four patients, grade 1/one. Rhizopus microsporus pneumonia and cryptococcal encephalopathy in two patients were controlled during Blinatumomab therapy. Conclusions Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in R/R B-ALL patients without high expression of CD19 in B-ALL cells, patients with CNS leukemia or co-infection. Key messages Some R/R B-ALL patients did not respond to anti-CD19 CAR T-cell therapy or had a disease progression again. Effective and safe salvage therapy for such patients remains to be explored. Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in patients without high expression of CD19 in B-ALL cells. Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in patients with CNS leukemia or co-infection.

Multiparameter flow cytometry and ClonoSEQ correlation to evaluate precursor B-lymphoblastic leukemia measurable residual disease.

Measurable residual disease (MRD) detection for precursor B-lymphoblastic leukemia (B-ALL) has become the standard of care. However, the testing methodology has not been standardized. We aim to correlate COG multiparameter flow cytometry (MFC) and ClonoSEQ techniques to assess the test characteristics, to study abnormal immunophenotype for B-ALL MRD, and to observe B-ALL clonal evolution and the impact of blinatumomab therapy on MFC testing. MFC and molecular reports were retrieved from electronic medical records and data was reviewed. Included in this study were 74 bone marrow samples collected from 31 B-ALL patients at our institution between January 2021 and March 2022. COG MFC and ClonoSEQ results were concordant in 59/74 samples (80%) with positive concordant results in 12 samples (16%) and negative concordant results in 47 samples (64%). Discordant results were seen in 15/74 samples (20%), with 14 samples (19%) showing ClonoSEQ + /MFC- results and only 1 sample (1%) showing MFC + /ClonoSEQ- result. ClonoSEQ + /MFC- cases had MRD values ranging from 1 to 1400 cells/million nucleated cells with 86% of cases showing MRD values of < 100 cells/million nucleated cells. Newly identified dominant sequences were detected using ClonoSEQ in 2/31 patients (6%) during follow-up. All 14 bone marrow samples from 8 patients, who had gone through blinatumomab immunotherapy, were MRD negative by MFC, but 3 cases were MRD positive by ClonoSEQ. Our results show strong correlation between COG MFC and ClonoSEQ (r = 0.96), and both methods are complementary. Clonal evolution may occur, and blinatumomab immunotherapy may impact MFC B-ALL MRD evaluation.

Blinatumomab therapy for B cell acute lymphoblastic leukemia accompanied by persistent or relapsed low-level MRD prior to hematopoietic stem cell transplantation in Chinese children: a case series

BackgroundBlinatumomab could be successfully used to reduce minimal residual disease (MRD) prior to hematopoietic stem cell transplantation (HSCT) in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL), but sound evidence is lacking in China.Case presentationThis retrospective study assessed the application of blinatumomab in B-ALL accompanied by persistent or relapsed low-level MRD before HSCT from April 2019 to July 2021. Two cases (Cases 1 and 2) initially achieved remission with MRD < 0.01% upon conventional therapy but had MRD relapse with MRD ≥ 0.01% but < 1% during maintenance treatment. Case 3 had no response to routine treatment, with high MRD (9.88% and 1.23% at days 19 and 46, respectively). Nevertheless, all patients had undetectable MRD. Cases 2 and 3 had undetectable fusion gene following blinatumomab therapy. By bone marrow monitoring (bone marrow morphology, bone marrow MRD and fusion gene) post-HSCT, the patients were persistently negative until May 15, 2022. No patient had serious adverse events before or during blinatumomab treatment.ConclusionsBlinatumomab therapy showed a good performance for three pediatric cases with detectable but low MRD before HSCT in China. However, further prospective studies with large sample sizes are still needed for further clarification.

The role of blinatumomab in the treatment of B-cell relapses of acute lymphoblastic leukemia in children: own experience

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Despite remarkable improvements in the treatment of pediatric acute lymphoblastic leukemia over last years, relapse still carries a poor prognosis with considerable morbidity and mortality. New immunotherapeutic approaches will change the way we treated our patients and the results we had. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory B-cell lymphoblastic leukemia. The use of Blinatumomab in relapsed B-cell ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. The therapy results for patients in the high risk group remain far from optimal due to refractoriness to chemotherapy, death from infectious complications, as well as acute chemotherapy toxicity. This article demonstrates the results of our experience of using Blinatumomab in children with the high-risk group relapsed B-cell ALL treated according to the ALL-REZ 2016 protocol. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The efficacy and toxicity of innovational blocks with the use of fludarabine and clofarabine with subsequent Blinatumomab infusion are shown. And we present the efficacy of autologous CD3+ lymphocytes infusion once a week during the continuous blinatumomab therapy. Also we demonstrate the results of using Blinatumomab for the treatment of patients with refractory to the first line therapy relapsed B-lymphoblastic leukemia and patients with a second relapse of B-cell ALL. The first line therapy in these patients was carried out according to the ALL-REZ 2014 protocol. Our results show an improved reduction in minimal residual disease in patients with refractory relapsed B-cell ALL as well as an increased event free survival in children with the high-risk group relapsed B-cell ALL.

Pneumocystis jiroveci Pneumonia secondary to tyrosine kinase inhibitor with blinatumomab therapy: A case report.

Pneumocystis jiroveci Pneumonia (PCP) is a common cause of opportunistic lung infection and is associated with high mortality in immunocompromised patients. Few reports describe pneumocystis jiroveci as a causative agent of tyrosine kinase inhibitor or blinatumomab related infections. Case presentation A 64-year-old man with philadelphia chromosome positive acute lymphoblastic leukemia (ALL) presented to the intensive care unit with intermittent high fever and shortness of breath. Three cycles of tyrosine kinase inhibitor (TKI) with blinatumomab therapy were given in recent 4months. Next-generation sequencing of bronchoalveolar lavage fluid and peripheral blood showed pneumocystis jiroveci. After trimethoprim- sulfamethoxazole treatment and subsequent mechanical ventilation, the infection was controlled successfully. Due to susceptibility and early onset of PCP in ALL patients received TKI combined with blinatumomab therapy, so we should be alert to PCP when pulmonary infection occurred.

Haematopoietic Progenitor Cell Mobilisation Following Blinatumomab Therapy

Background: Our institution routinely performs autologous back-up haematopoietic progenitor cell (HPC) harvest prior to unrelated donor transplantation, particularly in the post-pandemic era, or in other circumstances if there is risk of graft failure. This practice is influenced by our relative geographical isolation and significant challenges in obtaining emergency allogeneic products. As the treatment landscape for paediatric acute lymphoblastic leukaemia (ALL) has expanded to incorporate immunotherapy, many patients proceeding to transplant receive the bispecific T-cell engager blinatumomab. Little is known about HPC mobilisation outcomes in patients following blinatumomab therapy. Here we report our experience with HPC mobilisation for autologous back-up harvest in paediatric patients with ALL treated with blinatumomab. Methods: We reviewed HPC mobilisation attempts in patients with ALL at The Children's Hospital at Westmead, Sydney, Australia from 1 January 2012 to 30 June 2022. Patients were analysed in two groups: those mobilised following blinatumomab and those mobilised following chemotherapy or from steady state. Patients were mobilised according to our institutional practice. Following chemotherapy or blinatumomab, granulocyte-colony stimulating factor (G-CSF) was given subcutaneously at a dose of 5 µg/kg/day after chemotherapy, or 10 µg/kg/day after blinatumomab or from steady state haematopoiesis. Records were assessed retrospectively for demographics, mobilisation strategy, G-CSF days, apheresis days, final HPC yield in CD34+ cells/kg, transplant characteristics, and outcomes. Successful mobilisation was defined as proceeding to apheresis and successful harvest at the patient level by achieving an HPC yield of at least 2 x 106 CD34+ cells/kg. Results: Over the 10.5 year (y) study period, 30 patients with ALL underwent 34 HPC mobilisation attempts for the purpose of autologous back-up HPC harvest prior to allogeneic transplant; 7 (23%) after blinatumomab and 23 (77%) after chemotherapy. Mobilisation and apheresis characteristics of the two groups are summarised in Table 1. There were no differences in age, weight, gender, disease status or prior exposure to radiotherapy between the blinatumomab and chemotherapy groups. Successful mobilisation was less likely in the blinatumomab group with 5/8 (63%) proceeding to apheresis vs 24/26 (92%) in the chemotherapy group, P=.037. In 29 successful mobilisations, the blinatumomab group had a lower median number of days of G-CSF (6 (range 5-7) vs 11 (3-24), P=.006), and greater utilisation of plerixafor (2/5 (40%) vs 0/24 (0%), P=.001). On day 1 of apheresis, the blinatumomab group had a lower median CD34+ count x 106/L (27 (20-32) vs 57 (13-636), P=.021) and a higher median white cell count x 109/L (37.4 (24.5-79) vs 15.6 (1.3-63.5), P=.015). Although the median total HPC yield of CD34+ cells x 106/kg was significantly lower in the blinatumomab group (2.2 (2-4.7) vs 5.6 (1.4-35.2), P=.033), there was no difference in the proportion of patients achieving the collection target of 2 x 106 CD34+ cells/kg (5/5 (100%) vs 21/23 (91%), P=.494). With a median follow up of 1.6y for the blinatumomab group and 7y for the chemotherapy group, there was no difference in 2y relapse-free (83% vs 57%, P=.310) or overall (83% vs 67%, P=.5903) survival between the groups. Of 28 patients who proceeded to transplant, 3 (11%) required autologous HPC reinfusion for secondary graft failure, 2/3 after 9/10 matched unrelated donor transplants without serotherapy, and all from the chemotherapy group. Neutrophil engraftment for these 3 patients occurred at a median of 13 days (range 11 - 14). One patient died 35 days after salvage reinfusion without achieving platelet engraftment. The 2 surviving patients achieved platelet engraftment at 18 and 29 days post reinfusion and remain alive in continuous complete remission more than 3y following HPC re-infusion. Conclusions: HPC mobilisation for autologous back-up harvest is feasible for ALL patients following blinatumomab. However, these patients are at risk of failed mobilisation and may benefit from pre-emptive strategies such as the use of plerixafor to optimise mobilisation success. Our relatively high rate of salvage reinfusion of autologous HPCs in ALL patients underlines the utility of universal back-up harvests for patients undergoing unrelated donor transplant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dermatologic Adverse Events in Acute Lymphocytic Leukemia Patients Treated with Bispecific T-Cell Engager Blinatumomab

Blinatumomab is a novel FDA-approved bi-specific T-cell engager (BiTE) that significantly improves survival (vs standard chemotherapy) in adults with relapsed or refractory Philadelphia chromosome positive or negative B-cell precursor ALL (B-ALL) and is associated with high rates of clearing persistent measurable residual disease. Though the best known adverse effects associated with blinatumomab include cytokine release syndrome and neurologic toxicity, dermatologic adverse events (DAE) have also been reported in 16% of patients in clinical trials (FDA, 2018). In this study, we aimed to assess the incidence of DAEs in B-ALL patients treated with blinatumomab and characterize their associated clinical and histopathologic features. We conducted a retrospective analysis of B-ALL patients treated with blinatumomab monotherapy at Memorial Sloan Kettering Cancer Center from 1/1/2012 - 10/1/2021 (N=45). Seven patients experienced a total of nine DAEs (15.6%). Median number of blinatumomab cycles at time of DAE onset was one (range cycles 1-3). Median time to DAE onset following blinatumomab induction was 40 days (range 5-115 days). The most common DAEs were rashes (N=4); types included eczema, folliculitis, papular dermatitis, and panniculitis. Other DAEs (N=5) included new onset psoriasis, seborrheic dermatitis, acne, facial erythema, and nail dystrophy. All DAEs were grade 1, many DAEs did not require treatment, and no DAEs warranted interruption or discontinuation of blinatumomab. Four of the 7 patients with DAEs developed CRS at any point during blinatumomab therapy (ASTCT consensus grade 1, N=3; grade 2, N=1). Six of 7 patients with DAE achieved undetectable minimal residual disease (MRD) in the course of blinatumomab therapy or maintained MRD negativity. This is the most comprehensive study to report incidence and clinico-morphologic patterns of DAEs associated with blinatumomab monotherapy. Blinatumomab DAEs may be more common in patients who experience CRS; this finding may support that DAEs are the result of increased circulating cytokines secondary to effective immune activation by blinatumomab. DAEs are mild and we recommend that patients with severe rash during blinatumomab infusion are carefully evaluated for other etiologies of rash.

Safety and Pharmacokinetics of Subcutaneous Blinatumomab (SC blinatumomab) for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL); Results from a Phase 1b Study

Background: Blinatumomab, a BiTE® (bispecific T cell engager) immuno-oncology therapy, which redirects CD3+ T cells to engage and lyse CD19+ target cells, has demonstrated efficacy and a tolerable safety profile in patients (pts) with R/R B-ALL when administered as a 28-day continuous intravenous infusion (cIV). SC blinatumomab can simplify treatment administration, improve pt convenience, and reduce cost. Here, we present the dose-escalation results of a multicenter, single-arm, open-label, phase 1b study (NCT04521231) to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SC blinatumomab in adults with R/R B-ALL. Methods: In this ongoing trial, 4 cohorts of up to 6 pts each were planned. Pts in each cohort received 2‒5 cycles of SC blinatumomab. Each cycle included a 26-day treatment period and a 1-week treatment-free interval. Pts in cohorts 1, 2, 3, and 4 received 40, 120, 250, or 500 µg of SC blinatumomab once daily, respectively, from days 1 to 7. This was followed by a thrice-weekly regimen of 250 µg SC blinatumomab for cohorts 1 and 2 and 500 and 1000 µg of SC blinatumomab for cohorts 3 and 4, respectively, from days 8 to 26 of cycle 1, and from days 1 to 26 for all subsequent cycles. Bone marrow (BM) evaluation was performed on day 27 of each cycle and additionally on day 12 of cycle 1 in cohorts 3 and 4. Results: Twenty pts were enrolled at the data cut-off of June 20, 2022 (6 in cohort 1, 3 in cohort 2, 5 in cohort 3, and 6 in cohort 4). Median age was 58 years (range, 19‒83). Ten pts (50%) were aged >55 years. The number of prior therapies ranged from 2 to 4. All pts had an Eastern Cooperative Oncology Group score of 0-1 at enrollment. Six pts were refractory to frontline or salvage therapy, 9 pts relapsed after chemotherapy, 3 pts relapsed after prior hematopoietic stem cell transplantation (HSCT), 1 pt relapsed after prior HSCT and anti-CD19 chimeric antigen receptor T cell therapy, and 1 pt relapsed after 2 prior HSCTs and blinatumomab therapy where initial residual disease was cleared with cIV blinatumomab enabling first HSCT. The median number of cycles of SC blinatumomab received was 1 (range, 1‒5). Seven pts received 1 cycle, 1 pt received 2, 1 pt received 4 and 2 pts received 5. Six pts ended treatment during cycle 1 and in 3 pts cycle 1 is ongoing. Median bone marrow blast count at the start of the study was 77% (range, 6‒100%). No dose-limiting toxicities were reported in any cohort. Seventeen pts had grade ≥3 treatment-emergent adverse events (TEAEs; Table). Six pts (30.0%) had neurotoxicity (NT) at any grade and 4 pts (20%) had NT at grade 3. Sixteen pts (80.0%) had cytokine release syndrome (CRS) at any grade and 2 pts (10.0%) had CRS at grade 3 (cohort 4; each event resolved within 48 h and subsequent cycle 1 dose was restarted). There was no incidence of NT or CRS at grade ≥4. Six pts ended treatment due to TEAEs, of which 4 pts were from cohort 1 (n=1, grade 5 herpes encephalitis unrelated to blinatumomab; n=1, injection site reaction in cycle 2 in pt with no response; n=1, hyperleukocytosis due to disease progression; n=1, face swelling due to progression of extramedullary disease) and 2 pts were from cohort 3 (n=1, grade 2 CRS, grade 3 liver enzyme elevation, and grade 3 NT [dysarthria and disorientation]; n=1, disease non-response). Preliminary PK results through cohort 3 (cohort 4 ongoing) showed that observed exposures (average concentrations at steady state [SS]) of SC blinatumomab were consistent with the efficacious exposures (SS concentration) of the approved regimen of cIV blinatumomab. The PD profile demonstrated that peripheral T cell redistribution and activation (CD3+ and CD8+ CD69+ T cells), transient cytokine elevation (IL-6, IL-10, IFN-γ), and CD19+ B cell depletion were consistent with the historical PD profile for cIV blinatumomab. Nine of 14 pts (64.3%) in cohorts 1‒3 (cohort 4 ongoing; 3 of 6 [50%], 2 of 3 [66%], 4 of 5 [80%] in cohorts 1, 2, and 3, respectively) achieved complete response with full or partial hematologic recovery within 2 cycles of SC blinatumomab without the presence of measurable residual disease (MRD<10-4). Conclusion: In this ongoing phase 1b dose-escalation study, SC blinatumomab demonstrated an acceptable safety profile and anti-leukemia activity in heavily pretreated pts with R/R B-ALL. PK exposures and PD profiles were consistent with those reported for the cIV regimen of blinatumomab, supporting the use of SC dosing of blinatumomab in this pt population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Single Cycle of Blinatumomab Followed By High-Dose Chemotherapy in the Induction Therapy for Ph-Negative Acute Lymphoblastic Leukemia in Adults. Primary Endpoint Analysis of the Blina-Cell Trial

Background: Blinatumomab induces a high proportion of complete molecular responses in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and ALL with persistent or recurrent measurable residual disease (MRD) after initial therapy. However, responses are generally short if they are not followed by allogeneic stem cell transplantation (HSCT). We infer that blinatumomab needs to be incorporated sequentially into the early phase of treatment to enhance rates of MRD negativity, lower the need of HSCT and improve survival. Methods: Induction therapy in the Blina-CELL Phase 2 trial (NCT04554485) consisted of run-in phase (dexamethasone 10 mg/m2 days 1-7, cyclophosphamide 200 mg/m2 days 3-5, vincristine 2 mg day 6, and daunorubicin 45 mg/m2 days 6-7), first induction phase (blinatumomab 9 µg/day days 12-19 and 28 µg/day days 20-40), and second induction phase (dexamethasone 10 mg/m2 days 50-54, vindesine 3 mg/m2 day 50, methotrexate 1.5 g/m2 day 50, etoposide 250 mg/m2 days 53-54, and cytarabine 2x 2 g/m2 day 54). Consolidation chemotherapy was identical to the GMALL 07/2003 protocol. Intensive intrathecal prophylaxis was given in both induction and consolidation phases. The primary endpoint was MRD evaluated by quantification of IG/TR rearrangements at week 11 (at the end of induction II). The minimum sensitivity and quantitative range of all assays was 10e-4. Results: Twenty-nine patients started this treatment between May 2019 and March 2022. One patient terminated the study after 3 days of blinatumomab infusion due to elevated liver function tests, one was considered a screening failure due to the missing MRD target. Twenty-seven patients were evaluable. Median age was 41 years (range, 19-65). Median white blood cell count (WBC) at diagnosis was 6.2 x 109/L (range, 0.6-67.7). Twenty-five patients (93%) achieved complete remission (CR) at the end of induction I, 2 (7%) were refractory (both had BCR::ABL1-like phenotype). No patient died during the induction phase. Of the 25 patients in CR, 13 (52%) had complete molecular response (CMR) at day 40 (upon termination of blinatumomab infusion), 11 (44%) had positive non-quantifiable MRD and one (4%) patient had quantifiable MRD >10e-4. Primary endpoint assessment at week 11 showed 20 (80%) patients in CMR, 3 (12%) with positive non-quantifiable MRD and 2 (8%) with MRD ≥10e-4. Four (16%) patients underwent HSCT due to MRD failure or reappearance, all were pre-treated with a further 1-2 cycles of blinatumomab. Three of them (75%) entered HSCT in CMR. One patient was transplanted in CMR for high-risk features (proB, KMT2A rearrangement). The follow-up period is still ongoing. With 18 months of median follow, the overall and relapse-free survival in the study is 18.2 and 15.9 months, respectively. The most frequent grade 3-4 adverse events of blinatumomab therapy were: febrile neutropenia (15%), elevated ALT/AST (11%), soft tissue infection (7%) and low fibrinogen (7%). Only one case of grade 3 cytokine release syndrome was documented. No neurotoxicity events were observed during the induction phase of treatment. Conclusion: Remission induction strategy combining one cycle of blinatumomab with one cycle of high-dose chemotherapy provides a high molecular response rate (CMR or non-quantifiable MRD) of 92%. This approach translates into a low transplant rate due to a high MRD response and has a favourable safety profile. Longer follow-up is needed to evaluate survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal