P2, N=20, Recruiting, First Affiliated Hospital of Zhejiang University

P1, N=41, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Jun 2025

P1/2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Feb 2025 --> Dec 2025 | Trial primary completion date: Feb 2025 --> Jun 2025

P1/2, N=20, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P1/2, N=40, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P3, N=134, Active, not recruiting, Zenas BioPharma (USA), LLC | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2026 --> Jun 2026

P2, N=20, Recruiting, Northside Hospital, Inc. | Trial completion date: Aug 2025 --> Dec 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P1, N=90, Recruiting, Nkarta, Inc.

Starting from the initiation of blinatumomab treatment, with a median follow-up of 12 months, all patients remained in complete remission. Our study was the first to demonstrate that blinatumomab could further eradicate ddPCR MRD after patients achieve MFC-MRD undetectable status in B-ALL patients.

P1, N=24, Recruiting, Cullinan Therapeutics Inc. | Not yet recruiting --> Recruiting

Incorporation of blinatumomab and/or inotuzumab in CR1 may mitigate the negative prognostic significance of MRD, however it is unclear if intensity of standard post-remission therapy can be safely reduced without compromising outcomes...We designed a phase I clinical trial to determine safety and tolerability of UCD19 CAR-T cell therapy for adults with B-ALL in MRD+ CR1 who are at high risk for relapse.Methods : Eligible patients include adults (≥18yo) with B-ALL in CR1 after induction therapy, with MRD positivity by either flow cytometry or NGS (Clonoseq)...Longer follow-up is needed to determine if remissions remain durable, and to determine the relationship between functional persistence (as measured by B-cell aplasia) and remission durability. Enrollment is ongoing at DL2.

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2025 --> Jan 2027 | Trial primary completion date: Jan 2025 --> Jan 2027

P3, N=488, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Mar 2025

P2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P1, N=20, Not yet recruiting, Takeda | Initiation date: Nov 2024 --> May 2025

Blinatumomab, a CD19/CD3 bispecific T-cell engager; inotuzumab ozogamicin (INO), a CD22 antibody drug conjugate; and chimeric-antigen receptor (CAR) T-cell constructs are novel immune-therapeutic options for treatment of acute lymphoblastic leukemia (ALL). Herein, we discuss strategies to address the unique adverse effects of blinatumomab and ways to optimize its administration and integration into the treatment backbone of B-ALL. We outline our approach to combining and sequencing blinatumomab with other immunotherapies, such as INO and CD19 CAR T-cells, and provide recommendations for the management of toxicities and dose-optimization of blinatumomab therapy in clinical practice.

In further investigations of this issue, we show here that the pharmacological inhibition of MYC in various lymphoma and multiple myeloma cell lines, as well as patient-derived primary tumor cells, enhances their susceptibility to NK cell-mediated cytotoxicity induced by conventional antibodies targeting CD20 (rituximab) and CD38 (daratumumab), as well as T cell-mediated cytotoxicity induced by the CD19-targeting bispecific T-cell engager blinatumomab. In conclusion, MYC overexpressing tumor cells mitigated the efficacy of therapeutic antibodies through several non-overlapping mechanisms. Given the challenges associated with direct MYC inhibition due to toxicity, successful modulation of MYC-mediated immune evasion mechanisms may improve the outcome of immunotherapeutic approaches in B-cell malignancies.

P2, N=240, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1, N=231, Recruiting, AstraZeneca | N=116 --> 231

ALL with CREBBP gene mutation is more common in girls and has a low induction remission rate and a high recurrence rate, and it is often accompanied by other types of gene mutations and abnormal karyotypes. Most children with recurrence can achieve long-term survival after immunotherapy or hematopoietic stem cell transplantation.

P1/2, N=120, Recruiting, AstraZeneca | Trial completion date: Feb 2027 --> Jun 2027 | Trial primary completion date: Jan 2026 --> Jun 2026

P2, N=30, Recruiting, The First Affiliated Hospital of Soochow University | Not yet recruiting --> Recruiting

P1/2, N=54, Completed, Incyte Corporation | Active, not recruiting --> Completed

P2, N=37, Recruiting, David Bond, MD | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=54, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting | Trial completion date: Nov 2027 --> Jul 2027 | Trial primary completion date: Nov 2027 --> Jul 2027

P4, N=80, Not yet recruiting, The Third Affiliated Hospital, Sun Yat-sen University; The Third Affiliated Hospital, Sun Yat-sen University

P1, N=48, Recruiting, Century Therapeutics, Inc. | N=30 --> 48

"Introduction : Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL)...No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel...Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative."

Blinatumomab was not used during consolidation therapy in the reported patients. Its incorporation in the routine therapy of newly diagnosed patients may increase the proportion of patients receiving AHCT in a MRD negative state and further improve outcomes in this historically poor risk patient population.

Stem cell products with this T cell content will readily engraft into patients who have received lymphodepleting conditioning, yet despite this, we observed no unwanted engraftment, graft-versus-host disease, cytokine release syndrome after infusion of donor T cells, or enhanced toxicity of the blinatumomab. By demonstrating safety of infusion of large doses of unmodified donor lymphocytes, this study paves the way for future clinical trials of combinations of bispecific T cell engagers with allogeneic effector cells ('BiTEs plus cells').

Because of the above, further research is needed to explore whether using upfront immunotherapy like inotuzumab ozogamicin or blinatumomab in the upfront setting, as well as administering allogeneic transplant early in the treatment course of muTP53-ALL would decrease the risk of relapse and improve long-term survival. Although muTP53 ALL achieved a higher MRD-FC negative response compared to wtTP53 ALL, this did not translate into long-term survival in the muTP53 ALL. Whether using NGS for B-cell and T-cell receptors as a method for MRD testing, like clonoSEQ®, would provide a better prognostic tool is currently unknown.

Samples derived from cases from both the experimental and the control arm, based respectively on ponatinib followed by blinatumomab and on a combination of imatinib and conventional chemotherapy. While some groups reported a higher predictive prognostic power of IG/TR monitoring, our findings do not confirm these data, also in view of the very low rate of relapses so far observed. Nevertheless, a double-hit strategy may be informative for MRD monitoring and possibly for the distinction between typical/lymphoid Ph+ ALL vs multilineage/CML-like Ph+ ALL.

Method : This study involved adult patients aged 19 or older with B-ALL, treated with modified hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and allogeneic hematopoietic stem cell transplant (allogeneic-HSCT) at Catholic Hematology Hospital from May 2022 to June 2024...Poor MRD response was defined as > 0.1%, and complete MRD response as < 0.001%, and poor MRD responders were treated with MRD-directed therapy using blinatumomab or next-generation tyrosine kinase inhibitors...Conclusion : Our data suggested all MRD detection methods showed acceptable power and good concordance rates, but the detection power was different between Ph-positive and Ph-negative ALL. We also suggested MRD-directed therapeutic strategies might predict the significant time point of MRD for the prediction of survival outcomes.

Non-responders to blinatumomab have poor outcomes (2-year RFS : 25%) but may be salvaged by ASCT. The relatively low rate of NGS MRD negativity with blinatumomab monotherapy (31% in Ph- B-ALL) highlights the need for combination therapies in B-ALL.

Median prior lines of therapy was 3 (range 2–12), 18 (38%) pts received prior lenalidomide–based therapy, 7 (15%) pts received prior chimeric antigen receptor T-cell therapy (CAR-T), and 4 (9%) received prior CD20 TCE therapy. The exposure-response analysis supports the target dose of 7.2 mg. Further studies of AZD0486 are planned as monotherapy and in combination regimens.

Frontline therapy was hyper-CVAD-based ± immunotherapy (e.g. inotuzumab ozogamicin and/or blinatumomab) in 43% (n=69), mini-hyper-CVD-based ± immunotherapy in 28% (n=45), and chemotherapy-free in 29% (n=47, all of whom were Ph+). Importantly, no relapses were observed in pts with HR cytogenetic/molecular features who achieved early NGS MRD negativity, suggesting that early MRD dynamics should be included in ALL risk stratification systems. Pts with HR Ph- ALL who achieve deep MRD negativity within the first 6 months of frontline therapy do not appear to benefit from allogeneic SCT.

Ten (77%) pts received blinatumomab as part of initial therapy...Among pts who completed the DLT period (n=11), 7 (64%) experienced transient grade (G) 1 cytokine release syndrome (CRS) that resolved with tocilizumab +/- corticosteroid...CAR T cells had a robust expansion in the blood and CSF despite the low antigen setting. We have observed preliminary durable remissions and pts maintained function and cognition on day 100 post CAR-T.

P2, N=300, Suspended, National Cancer Institute (NCI) | N=550 --> 300

This report presents two pediatric ALL cases (one Ph+ and one Ph-like) with minimal residual disease negativity established by multicolor flow cytometry but persistent transcript detection by quantitative PCR (qPCR) even after second-line treatment with tyrosine kinase inhibitors combined with blinatumomab immunotherapy. Using droplet digital PCR, BCR::ABL1 or TPM3::PDGFRB transcripts were identified in CD19+ cells as well as in non-CD19+ cells, suggesting the presence of a Ph+ or Ph-like ALL-M subtype originating from hematopoietic stem cells. This report provides information for better characterization, diagnosis, and treatment of these ALL subtypes.

P1, N=209, Recruiting, BioRay Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting | Phase classification: P1/2 --> P1

P=N/A, N=30, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P1, N=33, Recruiting, Imugene Limited | N=52 --> 33 | Trial completion date: Sep 2025 --> May 2029 | Trial primary completion date: Sep 2024 --> Jun 2027