Mylotarg (gemtuzumab ozogamicin)

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

Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

P2, N=146, Recruiting, Technische Universität Dresden | Not yet recruiting --> Recruiting

P2, N=20, Active, not recruiting, Shaare Zedek Medical Center | Recruiting --> Active, not recruiting | Trial completion date: Mar 2027 --> Sep 2028 | Trial primary completion date: Mar 2024 --> Sep 2028

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.

P2, N=75, Completed, University of Nebraska | Active, not recruiting --> Completed | Trial primary completion date: Oct 2024 --> Mar 2024

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

From gemtuzumab ozogamicin to trastuzumab emtansine (T-DM1), and now to third-generation agents such as trastuzumab deruxtecan (DS-8201) and disitamab vedotin (RC48), improvements have been made in target selectivity, potency, linker stability, and reduced off-target effects. ADCs represent a promising frontier in precision cancer treatment, with continued research enhancing their potential in breast cancer and beyond. This review provides a comprehensive exploration of ADCs' evolution in breast cancer therapy, offering a molecular perspective to inform clinical practice and update colleagues on this dynamic field.

Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor)...To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions.

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.

In Japan, 4 drugs are approved as ADCs for leukemia and lymphoma: gemtuzumab ozogamicin(GO)consists of an anti-CD33 monoclonal antibody bound to calicheamicin via a linker, approved for relapsed/refractory acute myeloid leukemia. Brentuximab vedotin (BV)has anti-CD30 antibodies bound to MMAE via a linker and is approved for CD30-positive Hodgkin's lymphoma, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma...Inotuzumab ozogamicin(IO)has an anti-CD22 antibody bound to calicheamicin via a linker, approved for relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia...Polatuzumab vedotin(PV)has an anti-CD79b monoclonal antibody bounds to MMAE via a linker, approved for diffuse large B-cell lymphoma(DLBCL). In DLBCL patients with an international prognostic index score(IPI score)of 2 or higher, the combination of PV plus rituximab, cyclophosphamide, doxorubicin, and prednisone(PV+R-CHP)extended PFS at 2 years compared with R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which has long been the standard of care. As shown, ADCs exhibit high therapeutic efficacy in leukemia and lymphoma treatment, but many aspects of their resistance mechanisms remain unclear and require further research.

P2, N=70, Recruiting, St. Jude Children's Research Hospital | Trial primary completion date: Mar 2025 --> Dec 2026

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=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=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.

FLT3 inhibitors, gemtuzumab ozogamicin, and CPX-351 have been shown to improve outcomes for specific subsets of patients. Venetoclax (VEN) with a hypomethylating agent (HMA) is the standard-of-care frontline regimen for most older patients, except perhaps for those with an IDH1 mutation where ivosidenib with azacitidine may also be considered...This article focuses on recent updates and ongoing challenges in the management of AML, with a particular focus on the ongoing challenge of secondary AML and considerations regarding the selection of initial therapy in younger patients. An overview of common side effects and toxicities associated with targeted therapies is also presented here, along with recommended strategies to mitigate these risks.

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