The review highlights the challenges encountered in translating these promising approaches into clinical practice, including the setbacks faced by early DLL3-targeted therapies like Rovalpituzumab Tesirine (Rova-T)...The integration of cutting-edge technologies and interdisciplinary collaboration is proposed as a path forward to optimize DLL3-targeted therapies and improve outcomes for SCLC patients. This comprehensive overview provides insights into the current state and future directions of DLL3-targeted therapies, underscoring their potential to revolutionize SCLC treatment paradigms.

P1, N=18, Active, not recruiting, Uma Borate | Recruiting --> Active, not recruiting | Trial completion date: Jan 2025 --> Dec 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

P1/2, N=218, Active, not recruiting, AbbVie | Trial completion date: Dec 2024 --> Apr 2026 | Trial primary completion date: Dec 2024 --> Apr 2026

P1, N=260, Active, not recruiting, ADC Therapeutics S.A. | Recruiting --> Active, not recruiting

P1/2, N=179, Active, not recruiting, AbbVie | Trial completion date: Dec 2025 --> Dec 2026

Here we report the case of a child with DS who was diagnosed with a second relapse of BCP-ALL and has maintained complete remission through regular single-agent InO therapy. Single-agent maintenance using InO can be a good option to avoid subsequent relapse in patients with relapsed or refractory BCP-ALL who cannot proceed to allo-HCT and require less-toxic treatments.

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.

P1, N=28, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

It is unclear whether the addition of GO to cytarabine and anthracycline chemotherapy (7+3) improves clinical outcomes compared with other conventional regimens for AML. An improvement in OS was seen for patients who received GO and those treated with HD anthracycline, which was better explained by differences in patient performance status and comorbidities. Patients who received GO did not show increased toxicity.

P=N/A, N=1, Active, not recruiting, Pfizer | Not yet recruiting --> Active, not recruiting

P1, N=278, Active, not recruiting, MacroGenics | Recruiting --> Active, not recruiting | Trial completion date: Mar 2026 --> Jun 2025

Notably, a reduction in CD4 + T cells, predominantly contributing to treatment-related T-cell reduction, was only observed in patients undergoing Bendamustine-based regimens...Overall, FL patients demonstrated compromised T-cell immunity, with a lower CD4 + T cell count at diagnosis correlating with treatment response and early progression. Therefore, monitoring CD4 + T cells at diagnosis might reflect immune status and aid in stratifying FL patients.

P2/3, N=210, Recruiting, University of Birmingham | Active, not recruiting --> Recruiting

P3, N=414, Recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Trial primary completion date: Apr 2024 --> Apr 2025

"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."

We recently demonstrated that INO can be added safely to a non-myeloablative conditioning of bendamustine, fludarabine, and rituximab in patients with indolent lymphoid malignancies who required an allogeneic hematopoietic transplantation (HCT) (Am J Hematol 2024)...Patients who received transplants from MUDs received an additional dose of methotrexate 5 mg/m2 on day +11 and 1 mg/kg of rabbit anti-thymocyte globulin IV on days -1 and -2 before HCT...The patient who was in CR2 at transplant had Ph+ ALL and was maintained on ponatinib after HCT. Key prior therapies in ALL patients included blinatumomab (n=5) and INO (n=5)...The survival outcomes are encouraging and need to be validated in a larger number of patients. Currently, post-transplant cyclophosphamide has been implemented to lessen the risk of GVHD.

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.

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.

P1, N=24, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Apr 2025 --> Jun 2024 | Trial primary completion date: Apr 2025 --> May 2024

ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target.

Case presentation: Herein, we present the case of a 23-month-old girl with high-risk B-ALL who experienced very early isolated medullary relapse; following the failure of conventional chemotherapy according to the ALL-IC REL 2016 protocol, she went on to receive the bispecific T-cell engager (BiTE) blinatumomab and subsequently, due to refractory disease, the combination of fludarabine, cytarabine, and the proteasome inhibitor bortezomib without achieving remission. The minimal residual disease (MRD) was 0.08% on day 28, and InO was continued, thus achieving MRD negativity; the patient successfully underwent an allogeneic stem cell transplantation from a matched family donor. Our case highlights the efficacy and safety of InO as a salvage treatment in the setting of relapsed B-ALL refractory not only to conventional chemotherapy but also to novel treatments, such as blinatumomab and bortezomib.

Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.

P2, N=10, Terminated, M.D. Anderson Cancer Center | N=78 --> 10 | Trial completion date: Dec 2036 --> Oct 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2035 --> Oct 2024; PI Request. Slow accrual and lack of clinical interest

Patients who received bendamustine required more platelet transfusions (p = 0.02)...Conditioning with BEAM and BeEAM regimens is associated with comparable post-transplant outcomes. The toxicity of these regimens is comparable; however, BEAM is associated with a higher risk of pneumonia, while BeEAM is associated with a higher risk of mucositis.

P1, N=12, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows potent in vitro activity among established cell lines and a new cohort of patient-derived organoids as well as robust in vivo anti-tumor responses in cell line-derived and patient-derived xenografts...This works identifies DLK1 as a novel immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC. Our data support targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms in an active first-in-human phase I clinical trial ( NCT06041516 ).

P2, N=192, Active, not recruiting, MacroGenics | Trial primary completion date: Feb 2025 --> Jul 2024

P2, N=78, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P=N/A, N=421, Completed, Pfizer | Active, not recruiting --> Completed | N=200 --> 421

In this study, we have shown the cytotoxicity of BDM alone and in combination with novel agents including the histone deacetylase (HDAC) inhibitor tucidinostat, the enhancer of zeste homolog 1/2 (EZH1/2) dual inhibitor valemetostat, and the Bcl2 family inhibitor ABT-737. Our present results suggest that the combination of tucidinostat and BDM could additively prolong the survival of patients with R/R progressive ATL. The efficacy and safety of this combination are thus worthy of investigation in clinical settings.

P=N/A, N=1, Not yet recruiting, Pfizer | N=29 --> 1 | Initiation date: Jul 2024 --> Dec 2024

P1, N=12, Not yet recruiting, University of Utah

P2, N=270, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

P2, N=192, Active, not recruiting, MacroGenics | N=382 --> 192 | Trial completion date: May 2027 --> Feb 2025 | Trial primary completion date: May 2027 --> Feb 2025

She was treated with modified Ph-negative EWALL induction (Vincristine, Idarubicin, dexamethasone) and achieved a complete remission. However, she subsequently experienced an early relapse and was refractory to targeted therapy with blinatumomab. After treatment with inotuzumab ozogamicin, she achieved a second complete remission...It demonstrates that patients with ostensibly favourable prognostic factors may experience poor response rates to traditional chemotherapy as well as targeted salvage agents. It also illustrates the challenges of treating B-ALL in the elderly population.

Here, we investigated ABT-737 and Purvalanol A as a potential drug pairing for pediatric AML and described the development of CD33-targeted polymeric nanoparticles (NPs) to enable their simultaneous targeted codelivery. Moreover, conjugation to gemtuzumab resulted in improved NP binding and internalization in CD33-positive cells. Finally, CD33-targeted dual-loaded NPs showed enhanced cytotoxicity to CD33-positive AML cells via CD33-mediated targeted drug delivery.

She was successfully treated with the urgent insertion of a transjugular intrahepatic portosystemic shunt (TIPS), defibrotide, and high-dose corticosteroids. This case of successful treatment for very severe SOS supports a combination strategy involving the immediate mechanical reduction of portal hypertension through TIPS and drug-mediated inhibition of microvascular thrombosis. Furthermore, this case shows the need for an improved prevention strategy, including the identification of additional risk factors and biomarkers.

P2, N=100, Recruiting, Juan P. Alderuccio, MD | N=39 --> 100 | Trial completion date: Aug 2027 --> Aug 2030 | Trial primary completion date: Aug 2024 --> Aug 2027

P2, N=49, Recruiting, Fondazione Italiana Linfomi - ETS | Trial completion date: Feb 2027 --> Apr 2029 | Trial primary completion date: Feb 2025 --> Apr 2026

The CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin (GO), is commonly added to intensive chemotherapy (IC) in CBF-AML...Induction treatment regimens were categorized as IC alone, IC with GO, or IC with KIT inhibitor (dasatinib or midostaurin)...Patients treated with IC with KIT inhibitor experienced a significantly improved 3-year EFS of 85% compared to those with IC with or without GO (p = 0.04). We find in our study that there is no survival benefit in patients treated with IC with the addition of GO; improved EFS was seen in patients with CBF-AML treated with IC plus KIT inhibitors, consistent with outcomes noted in prospective studies utilizing this approach.

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