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.

All patients were refractory to hypomethylating agents and venetoclax. The MTD of DLI in combination with GO for relapsed/refractory AML patients is 2x10 8 CD3+ cells/kg. Treatment in an older relapsed/refractory population was well tolerated. Patients reliably developed fevers post DLI with Grade1 or 2 CRS.

Our real-world single-institute experience in patients with EM AML suggests that GO combined with chemotherapy in the upfront setting results in promising outcomes with high overall response rates (CR 50%, PR 13%) by RECIST criteria, durable remissions, and prolonged overall survival in largely favorable and intermediate risk AML. However, despite high partial response rates (4% CR, 50% PR) following GO-based therapy in R/R EM AML, survival was less than 2 months likely due to the high proportion of patients in this cohort with poor risk disease. Further investigations and larger studies are warranted to establish the optimal use of GO in EM AML.

This study presents an innovative approach with the potential to predict GO responders versus non-responders in AML. A single phenotypic biomarker overcomes the need to determine CD33 expression levels in each patient or to assess the presence of specific polymorphic variants, as well as additional molecular biomarkers. Patient Micro Avatars present a compelling alternative to comprehensively identify patients who are most likely to benefit from GO treatment.

Background: While the standard regimen for AML has been intense chemotherapy followed by stem-cell transplantation (SCT), addition of immunotherapeutics such as gemtuzumab ozogamicin (GO) to this has shown to improve outcomes in multiple clinical trials... While P67. 6-bound-CD33-FL internalized as expected in AML cell lines expressing CD33-FL only (Fig. 1A), we show for the first time that HL2541-bound-CD33-D2 also internalizes upon antibody binding in cell lines expressing CD33-D2 isoform only (Fig.

Recent findings have altered the landscape of pediatric AML therapy with exciting immediate and long-term implications. Ongoing studies may soon define this as standard as well. After many years in which few new therapies have become available for children with AML, recent and upcoming advances may soon dramatically alter the therapeutic landscape.

P1, N=13, Terminated, Jonsson Comprehensive Cancer Center | Trial completion date: Jul 2025 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Oct 2023; slow accrual

P2, N=50, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

GO was administered in combination with daunorubicin and cytarabine (3+7, N = 30; or 2+5, N = 1) at standard dose on days 1, 4, 7 of induction, and on day 1 of consolidation for up to two cycles...Table 1. Patients’ characteristics.

Gemtuzumab Ozogamicin (GO), a monoclonal antibody targeting CD33, linked to calicheamicin, is approved in combination with daunorubicin and cytarabine (3+7) for the treatment of patients with previously untreated, de novo CD33-positive non promyelocytic AML...Figura 1. Overall survival of the whole population (34 cases) from the diagnosis.

P2, N=50, Recruiting, Centre Antoine Lacassagne | Not yet recruiting --> Recruiting

Since 2017, we have seen eleven novel Food & Drug Administration (FDA)-approved medications for AML, all of which extend beyond the classical cytarabine-based cytostatic chemotherapy...However, despite these translational efforts, we currently have no immune-based therapies for AML on the market, with the exception of gemtuzumab ozogamicin. In this focused review, we discuss molecular target validation and the most relevant clinical updates for immune-based experimental therapeutics including anti-CD47 monoclonal antibodies, CAR-T therapies, and bispecific T cell engagers. We highlight barriers to the clinical translation of these therapies in AML, and we propose solutions to optimize the manufacturing and delivery of the most novel immune-based therapies in the pipeline.

In this trial, pts were assigned to intensive chemotherapy plus all-trans retinoic acid with or without gemtuzumab ozogamicin; none of the pts received midostaurin. Our study provides comprehensive data on the genomic landscape and its clinical impact in pts with NPM1mut AML fit for intensive chemotherapy. The co-mutational pattern clearly differs between younger and older NPM1mut AML pts. Using this large dataset allowed the identification of secondary and tertiary gene-gene interactions with significant impact on outcome.

Midostaurin was added for FLT3mut leukemia since 2018...Gemtuzumab ozogamicin and maintenance with FLT3 inhibitors or CC486 could be added... A database search yielded 90 patients with NPM1 AML who were treated according the abovementioned protocol between 5/2015 and 11/2022 and achieved remission, with a median follow-up of 872 days (range 103-2751). Forty-seven patients were to receive consolidation cycles without transplantation in CR1, based on the aforementioned criteria. All but one patient (death from sepsis) completed treatment cycles.

Introduction: The approval of venetoclax (VEN)-based frontline therapy for acute myeloid leukemia (AML) in November 2018 marks a new era of AML care...Among patients who were tested and qualified, no difference was observed in the use of gemtuzumab ozogamicin, CPX-351, FLT3 inhibitors or IDH1/2 inhibitors across race/ethnicity... In this large, real-world dataset, we demonstrate OS improvements in the era of modern AML care, particularly among patients >70 years though their outcomes remain inferior to younger patients. Intriguingly, the largest OS improvement was observed in NHB, where the OS disparity between NHB and NHW in Pre era appears to have been mitigated. Hispanics have not experienced similar OS improvement in modern AML care.

The MyeChild 01 international phase III trial (NCT02724163) in children with de novo AML allocated patients up to 3 doses of gemtuzumab ozogamicin (GO 3mg/m2/dose) during the first course of induction chemotherapy (mitoxantrone 12 mg/m2/dose x4; cytarabine 100 mg/m2/dose x20). Two intensive courses of induction chemotherapy, including GO and mitoxantrone in course 1 and FLA-Ida in course 2, consolidated with allogeneic HSCT, appears to be an effective approach for most HR patients. 2 year estimated outcomes for HR patients compare favourably to recent trials of GO in pediatric AML, with particularly encouraging data for patients with KMT2A-r and FLT3-ITD.

Two hundred and one (90%) received an anthracycline-based IT, the others received gemtuzumab ozogamicin as part of a clinical protocol research. CVE occurred in 33% of patients during IT and were severe. The major adverse role of onset of infection for CVE occurrence after IT could overcome the prognostic value of mutations usually associated with CV risk in the healthy population (i.e. TET2, DNMT3A, ASXL1, ...).

The CD33 scFv was derived from Gemtuzumab ozogamicin (clone: hP67.6)... We developed multiple CD33 and TIM3 dual CAR T cells using both "AND" and "OR" gating strategies in this study. Our findings revealed that dual CAR T cells provided higher avidity and cytotoxicity compared to single targeting CAR T cells against dual antigen expressing target cells in vitro. Importantly, only the split CAR T constructs demonstrated specific killing of CD33+TIM3+ cell lines and primary AML cells while sparing HSPCs.

However, targeting CD33 e.g. with the antibody-drug conjugate (ADC) gemtuzumab ozogamicin often leads to prolonged cytopenia due to suppression of normal myelopoiesis...Similar to HSPCs devoid of CD33 these engineered cells could enable tumor-selective immunotherapy using ADCs or CAR T cells but with preserved CD33 expression and function. Furthermore, since base editing is suitable for multiplexing, they may in the future be multiplexed to protect CD33 and other targets for combination immunotherapy.