Treating CD33-Positive de novo Acute Myeloid Leukemia in Pediatric Patients: Focus on the Clinical Value of Gemtuzumab Ozogamicin

Abstract

Although survival in pediatric acute myeloid leukemia (AML) has increased considerably over the past decades, refractory disease and relapse rates remain high. Refractory and relapsed disease are difficult to treat, with overall survival rates less than 40–50%. Preventing relapse should, therefore, be one of the highest priorities. Current conventional chemotherapy regimens are hard to intensify due to associated toxic complications, hence more effective therapies that do not increase toxicity are needed. A promising targeted agent is the CD33-directed antibody–drug conjugate gemtuzumab ozogamicin (GO). Because CD33 is highly expressed on leukemic cells in the majority of AML patients, GO can be useful for a broad range of patients. Better relapse-free survival (RFS) after therapy including GO has been reported in several pediatric clinical trials; however, ambiguity about the clinical value of GO in newly diagnosed children remains. Treatment with GO in de novo AML patients aged ≥1 month, in combination with standard chemotherapy is approved in the United States, whereas in Europe, GO is only approved for newly diagnosed patients aged ≥15 years. In this review, we aimed to clarify the clinical value of GO for treatment of newly diagnosed pediatric AML patients. Based on current literature, GO seems to have additional value, in terms of RFS, and acceptable toxicity when used in addition to chemotherapy during initial treatment. Moreover, in KMT2A-rearranged patients, the clinical value of GO was even more evident. Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.

Keywords:

• antibody–drug conjugates
• calicheamicin
• immunotherapy
• single-nucleotide polymorphism
• tailored therapy

Abbreviations

ADC, Antibody–drug conjugate; ADE, Ara-C, daunorubicin, etoposide; AML, Acute myeloid leukemia; CIR, Cumulative incidence of relapse; COG, Children’s Oncology Group; CR, Complete remission; DA, Daunorubicin, cytarabine; DFS, Disease-free survival; EFS, Event-free survival; EMA, European Medicines Agency; FLAG-Ida, Fludarabine, cytarabine, and idarubicin; GO, Gemtuzumab ozogamicin; HSCT, Hematological stem cell transplantation; MA, Mitoxantrone, cytarabine; MACE, Amsacrine, cytarabine and etoposide; MRC, Medical Research Council; MRD, Measurable residual disease; NOPHO, Nordic Society of Paediatric Haematology and Oncology; NRCI, National Cancer Research Institute; OS, Overall survival; RCT, Randomized controlled trial; RFS, Relapse-free survival; RR, Relapse rate; R/R, Relapse and refractory disease; SNP, Single-nucleotide polymorphism; SWOG, Southwest Oncology Group; TRM, Treatment-related mortality; US FDA, United States Food and Drug Administration; VOD, Veno-occlusive disease.

Acknowledgments

Figure 1 in this review was created with Biorender.com (accessed October 2022).

Disclosure

Prof. Dr. C Michel Zwaan reports institutional funding to perform clinical trials from Pfizer, Jazz, Takeda, and AbbVie, outside the submitted work. The authors report no other conflicts of interest in this work.