CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin
Abstract
:Simple Summary
Abstract
1. CD33 Expression in Normal Myelopoiesis
2. CD33 Expression in Acute Myeloid Leukemia
3. Gemtuzumab Ozogamicin (GO) and Mechanism of Action
4. GO and Clinical Studies
Study | Treatment (Induction) | Patients | Median Age (Years) | ORR (CR + CRi) | OS | PFS/EFS | Early Mortality | Relapse | Comment | Reference |
---|---|---|---|---|---|---|---|---|---|---|
AAML0531 | ADE (10 + 3 + 5) +/− GO 3 mg/m2 D + 6 | 1022 | 9.7 (0–30) | 88% v 85%; | 3 years: (69.4% v 65.4%; p = 0.39) | EFS (3 yrs): 53.1% v 46.9%; p = 0.04 | 6.6% v 4.1%; p = 0.09 | 3 yrs: 32.8% v 41.3%; p = 0.006 | In pediatric patients, low doses of GO did not increase OS. EFS was improved with fewer relapses but slightly increased toxicity. | [59] |
SWOG S0106 | DA (dauno 45 mg/m2) + GO 6 mg/m2 D4 vs. DA (dauno 60 mg/m2) | 595 | 47(18–60) | (69% v 70% p = 0.59 +76% v 74% p = 0.36 | 5 years: 46% v 50% p = 0.85 | RFS (5 yrs) 43% v 42%; p = 0.4 | 5% v 1% p = 0.0062 | 5 yrs: 43% v 42%; p = 0.4 | GO failed to show improvement in CR rate, DFS, or OS. Toxicity was significantly higher. | [42] |
ALFA-0701 | DA + GO 3 mg/m2 D 1,4,7 vs. DA | 271 | 62.2 | CR: 70.4% v 69.9%; CRp: 11.1% v 3.7% | Median 27.5 v 21.8 moths p = 0.16 | Median EFS 17.3 v 9.5 months p = 0.0002. No advantage in EFS with GO for poor cytogenetic risk | 6% v 4% | Median RFS 28.0 v 11.4 months | Fractionation of doses of the GO allows safe delivery of a much higher cumulative dose and improves outcomes. | [49,50] |
MRC AML15 | DA or FLAG-Ida +/− GO 3 mg/m2 D + 1 | 1113 | 49 (0–71) | CR: 82% v 83% p = 0.8; CRi: 3% v 4% p = 0.4 | 5 years: 43% v 41% p = 0.3 OS improved with GO for good risk cytogenetics | RFS (5 yrs) 39% v 35%; p = 0.09 | 11% v 10% | 5-YRS 46% v 50% p = 0.12 | A single low dose of GO associated with different induction schemes in young patients produced similar outcomes. However, a survival benefit for patients with favorable cytogenetics was evident. | [43] |
NCRI AML16 | DA (3 + 10) or DClofarabine +/−GO 3 mg/m2 D + 1 | 1115 | 67 (51–84) | CR: 62% v 58% p = 0.14; CRi: 9% v 10% p = 0.3 | 3 years: (25% v 20%; p = 0.05) | RFS (3 yrs) 21% v 16%; p = 0.04 | 9% v 8% | 3-YRS 68% v 76% p = 0.007 | Single low dose of GO in older pts. significantly reduced relapse risk, and improved OS with acceptable toxicity | [44] |
NCRI AML17 | ADE or DA + GO 3 mg/m2 v 6 mg/m2 | 788 | 50 (0–81) | CR: 82% v 76% p = 0.003; CRi: 7% v 10% p = 0.17 | 4 years: (50% v 47%; p = 0.3) | RFS (4 yrs) 44% v 38%; p = 0.3 | 3% v 7%; p = 0.02 | 4-YRS 46% v 54% p = 0.15 | Single low dose of GO had similar disease-free and overall survival, but less toxicity with respect to intermediate dose. | [52] |
GOELAMS AML 2006 IR | DA +/− GO 6 mg/m2 | 238 | 50 (18–60) | 91.6% v 86.5% (p = NS) | 3 years: 53% v 46% | EFS (3 yrs) 51% v 33% | 10% v 4.5% (p = NS) | / | In patients with intermediate cytogenetics AML, GO failed to improve OS | [45,46] |
EORTC-GIMEMA AML-17 | MICE +/− GO 6 mg/m2 D 1, 15 | 472 | 67 (60–75) | CR: 39% v 41%; CRp: 9% v 8% | 2.5 years:16% v 21.7% p = 0.07 | EFS (1 yr) 18% | 17% v 12% | / | Combining two upfront doses of GO 6 mg/m2 with sequential chemotherapy does not benefit older patients with AML, is too toxic for those >70 years. | [56] |
EORTC-GIMEMA AML-19 | GO (6 mg/m2 on D1 and 3 mg/m2 on D8) vs. BSC | 237 | 77 (62–88) | CR: 8.1% CRi: 16.2% | 1 year: 24.3% v 9.7% | Median DFS was 5.3 months | 7% | / | Older patients treated in first line with GO showed significantly improved OS in all subgroups, with comparable toxicity than BSC. | [57] |
5. GO and Current Indications
6. In Vitro Relationship between CD33 Expression and GO Efficacy
7. In Vivo Relationship between CD33 Expression and GO Efficacy
8. Prognostic Impact of Cytogenetic Alterations and Molecular Profile on GO Efficacy
9. Relationship between CD33 Single Nucleotide Polymorphisms and GO Efficacy
10. GO Resistance
11. GO as Maintenance Therapy in AML
12. CD33 Bispecific Antibodies and CAR-T CD33
13. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Predictors of response to GO |
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Uncertain predictive role on response to GO |
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Unfavorable predictors of response to GO |
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Resistance mechanisms to GO |
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Most important GO-related adverse events in ALFA-0701 study [49,50] |
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CD33 bispecific antibodies in clinical trials |
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Molica, M.; Perrone, S.; Mazzone, C.; Niscola, P.; Cesini, L.; Abruzzese, E.; de Fabritiis, P. CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin. Cancers 2021, 13, 3214. https://doi.org/10.3390/cancers13133214
Molica M, Perrone S, Mazzone C, Niscola P, Cesini L, Abruzzese E, de Fabritiis P. CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin. Cancers. 2021; 13(13):3214. https://doi.org/10.3390/cancers13133214
Chicago/Turabian StyleMolica, Matteo, Salvatore Perrone, Carla Mazzone, Pasquale Niscola, Laura Cesini, Elisabetta Abruzzese, and Paolo de Fabritiis. 2021. "CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin" Cancers 13, no. 13: 3214. https://doi.org/10.3390/cancers13133214