Mylotarg (gemtuzumab ozogamicin)

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

P1/2, N=24, Recruiting, Vor Biopharma | N=18 --> 24 | Trial completion date: Sep 2025 --> Jan 2027 | Trial primary completion date: Dec 2023 --> Feb 2025

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.

Significance Statement Several in vitro and in vivo stability studies of ABBV-011, a calicheamicin-based ADC, identified circulating metabolites and catabolites and suggested that disulfide cleavage may be a key liability for the conjugated linker-payload. These observations may be relevant to other disulfide-linked ADCs, such as Mylotarg and Besponsa, both of which have reported similar half-lives that possibly indicate instability.

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 is partially supported by Astellas Pharma Global Development, Inc. The study population will include patients with AML with dual FLT3 and IDH1/IDH2 mutations R/R to initial intensive induction therapy, or for patients treated with low intensity therapy, the patient must be refractory to treatment with a single agent hypomethylating agent (HMA) or low dose cytarabine (LDAC) (at least two cycles) or an HMA/LDAC in combination with venetoclax (at least one cycle) or another standard of care therapy (e. g. gemtuzumab ozogamicin, glasdegib/LDAC). Patients with a history of autologous or allogeneic stem cell transplant for AML are permitted to participate in the study.

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

The patient started cytoreductive therapy with hydroxyurea but after recovery from the SARS COV2 infection, presented cutaneous nodularities, jet vomiting, eyelid ptosis and decreased visual acuity...She started induction chemotherapy 3+7 regimen plus anti-CD33 gemtuzumab-ozogamicin therapy and medicated lumbar punctures with cytarabine...The patient was started to pretransplantation work up but unfortunately a cytomegalic infection complicated by acute heart failure led to the death of the patient. In conclusion, this case report points out some effects of Gilteritinib: the potential utility of FLT3 inhibitors in relapsed AML patients, the safe administration, the efficacy of gilteritinib monotherapy also as a bridge to transplantation, the ability to clearance blast percentage in a short period of time.

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.

CD33 is a preferential target for AML CAR T cell therapy as it is expressed on the majority (>80%) of AML blasts and because prior clinical experience with gemtuzumab ozogamicin (GO; tradename: MylotargTM) has demonstrated the safety and efficacy of targeting CD33...Patients will receive lymphodepletion on days -5 to -2 with fludarabine (total 120 mg/m2) and cyclophosphamide (total 1000 mg/m2) followed by infusion of VCAR33 on Day 0...*NCT number pending. Clinical trial information submitted to CT.gov on July 19, 2023.

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.