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

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

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

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.

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.

Thus, our results suggest that the addition of GO to induction regimens does not negatively impact PBSC mobilization in favorable-risk AML patients. To our best knowledge, this is the first study comparing the stem cell mobilization potential in favorable-risk AML patients treated with vs. without GO.

P1, N=18, Recruiting, Uma Borate | Suspended --> Recruiting

The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.

P2, N=36, Recruiting, University of Washington | Trial primary completion date: Mar 2023 --> Dec 2024

P1, N=35, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting

P1, N=18, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Dec 2024 --> Nov 2025

P1, N=22, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=18, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Not available.

P1, N=18, Suspended, Uma Borate | Recruiting --> Suspended

P1, N=35, Not yet recruiting, Bristol-Myers Squibb

P1, N=18, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2027 --> May 2025 | Trial primary completion date: Feb 2027 --> May 2025

P1, N=18, Recruiting, M.D. Anderson Cancer Center | Trial completion date: May 2024 --> Feb 2027 | Trial primary completion date: May 2024 --> Feb 2027

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

Among reported cases, patients undergoing TPE and those receiving steroids had improved outcomes. Practitioners should be aware of this rare drug side-effect and the potential utility of TPE for these patients.

EMI at diagnosis is an independent adverse prognostic risk factor for pediatric AML, and GO treatment potentially improves survival for patients with EMI at diagnosis.

P2, N=16, Active, not recruiting, Robert Redner, MD | Completed --> Active, not recruiting | Trial completion date: Feb 2023 --> Dec 2028

P2, N=89, Recruiting, Associazione Italiana Ematologia Oncologia Pediatrica | Trial completion date: Oct 2024 --> Oct 2027 | Trial primary completion date: Oct 2022 --> Oct 2025

Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

P2, N=39, Recruiting, University of Maryland, Baltimore | Trial completion date: Feb 2025 --> Feb 2027 | Trial primary completion date: Jan 2024 --> Jun 2026

P2, N=133, Active, not recruiting, National Cancer Institute (NCI)

While previous CD33-targeting antibody-drug conjugates (ADCs) like gemtuzumab ozogamicin (GO, Mylotarg) have shown efficacy in AML treatment, they have suffered from toxicity and narrow therapeutic window...The development of GLK-33 addresses the limitations of previous ADCs, offering a wider therapeutic window, improved tolerability, and activity against drug-resistant leukemia cells. These findings encourage further exploration of GLK-33 in AML through clinical trials.

P1, N=25, Recruiting, Roswell Park Cancer Institute | Active, not recruiting --> Recruiting

P3, N=1400, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P1, N=18, Recruiting, Uma Borate | Trial primary completion date: Jan 2024 --> Jan 2025

P=N/A, N=165, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1, N=36, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting | Phase classification: P1a/1b --> P1

The drug's mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity.

Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.

Sinusoidal obstruction syndrome occurred in two children. The use of GO in severely pretreated children, including those under 15 years of age, with previous failure of AML treatment is a feasible and effective bridging therapy to allo-HSCT with an acceptable toxicity profile.

P2, N=270, Recruiting, M.D. Anderson Cancer Center | N=200 --> 270

P3, N=98, Recruiting, LLS PedAL Initiative, LLC

P1, N=18, Active, not recruiting, John Quigley | Recruiting --> Active, not recruiting

Trem-cel (formerly VOR33) is manufactured from CD34+ cells isolated from matched-donor apheresis and modified by CRISPR/Cas9 gene-editing to remove CD33, with the goal of protecting normal hematopoietic cells from post-HCT CD33-directed therapies...Donors undergo mobilization with G-CSF and plerixafor prior to apheresis and manufacturing of trem-cel... Initial results demonstrate trem-cel has rapid primary neutrophil engraftment similar to non-edited CD34-selected grafts (Luznik et al 2022, JCO 40:356-368) and a high CD33 editing efficiency leading to a majority of myeloid cells lacking CD33 expression and supporting the biologic dispensability of CD33. The exposure at 0.5mg/m2 GO dose corresponded to higher doses of GO in AML patients, possibly due to reduction of the CD33 hematopoietic antigen sink. Minimal cytopenias have been observed thus far after treatment with GO, supporting the hypothesis that CD33 deletion can protect donor cells from CD33-targeted therapies.

This raises the possibility of false positives for PCT in the context of GO-induced infusion reactions, underscoring the need for cautious interpretation of PCT values for infection differentiation in patients undergoing regimens that include GO. Further research with larger patient cohorts is warranted to validate these findings and improve our understanding of the implications of PCT measurements in this clinical setting.

The use of deeply characterized AML patient primary samples within the AML VitroScreen ® platform allowed for high throughput drug testing, which represents the ideal clinical translational setting in preclinical research. The use of this innovative system for patient selection and drug screening will support the development of new and tailored therapeutic strategies for patients with primary or recurrent AML, leading to improved patient outcomes.