Antibody-drug conjugate therapy (gemtuzumab ozogamicin)

The Children's Oncology Group (COG) completed two trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[3,4]

The Children's Oncology Group (COG) completed two trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[3,4]

With the use of gemtuzumab ozogamicin during induction cycle 1, dosed at 3 mg/m2 on day 6, the randomized trial identified an improvement in EFS but not in OS; this was likely impacted by postremission toxicity mortality. Patients had a reduction in postremission relapse overall and specifically in the following distinct subsets of patients:[4]

The Children's Oncology Group (COG) completed two trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[3,4] › With the use of gemtuzumab ozogamicin during induction cycle 1, dosed at 3 mg/m2 on day 6, the randomized trial identified an improvement in EFS but not in OS; this was likely impacted by postremission toxicity mortality. Patients had a reduction in postremission relapse overall and specifically in the following distinct subsets of patients:[4]

Patients with low-risk cytogenetics.

The Children's Oncology Group (COG) completed two trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[3,4] › With the use of gemtuzumab ozogamicin during induction cycle 1, dosed at 3 mg/m2 on day 6, the randomized trial identified an improvement in EFS but not in OS; this was likely impacted by postremission toxicity mortality. Patients had a reduction in postremission relapse overall and specifically in the following distinct subsets of patients:[4]

Patients with KMT2A-rearranged AML, both overall and in the context of high-risk and non–high-risk fusions. These patients had improvement in outcome from treatment with gemtuzumab.[20]

The Children's Oncology Group (COG) completed two trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[3,4] › With the use of gemtuzumab ozogamicin during induction cycle 1, dosed at 3 mg/m2 on day 6, the randomized trial identified an improvement in EFS but not in OS; this was likely impacted by postremission toxicity mortality. Patients had a reduction in postremission relapse overall and specifically in the following distinct subsets of patients:[4]

Patients with high-risk high-allelic ratio (>0.4) FLT3 internal tandem duplication (ITD) AML who then received a hematopoietic stem cell transplant (HSCT) from any donor.[21]

The Children's Oncology Group (COG) completed two trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[3,4]

The efficacy and safety of gemtuzumab ozogamicin in children, which included infants as young as 1 month,[22] were established in these trials.

A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin in adults with AML observed the following:[23] Fractionated gemtuzumab ozogamicin dosing (3 mg/m2 per dose on days 1, 4, and 7; maximum dose, 5 mg), which has been shown to be safe and effective in adult patients with de novo AML, is an alternative option to single-dose administration during induction.[24] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the MyeChild 01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.

A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin in adults with AML observed the following:[23] Fractionated gemtuzumab ozogamicin dosing (3 mg/m2 per dose on days 1, 4, and 7; maximum dose, 5 mg), which has been shown to be safe and effective in adult patients with de novo AML, is an alternative option to single-dose administration during induction.[24] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the MyeChild 01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.

The greatest OS benefit was for patients with low-risk cytogenetics (t(8;21)(q22;q22) and inv(16)(p13;q22)/t(16;16)(p13;q22)).

A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin in adults with AML observed the following:[23] Fractionated gemtuzumab ozogamicin dosing (3 mg/m2 per dose on days 1, 4, and 7; maximum dose, 5 mg), which has been shown to be safe and effective in adult patients with de novo AML, is an alternative option to single-dose administration during induction.[24] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the MyeChild 01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.

Adult patients with AML and intermediate-risk cytogenetics who received gemtuzumab ozogamicin had a significant but more modest improvement in OS.

A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin in adults with AML observed the following:[23] Fractionated gemtuzumab ozogamicin dosing (3 mg/m2 per dose on days 1, 4, and 7; maximum dose, 5 mg), which has been shown to be safe and effective in adult patients with de novo AML, is an alternative option to single-dose administration during induction.[24] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the MyeChild 01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.

There was no evidence of benefit for patients with adverse cytogenetics.

A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin in adults with AML observed the following:[23] Fractionated gemtuzumab ozogamicin dosing (3 mg/m2 per dose on days 1, 4, and 7; maximum dose, 5 mg), which has been shown to be safe and effective in adult patients with de novo AML, is an alternative option to single-dose administration during induction.[24] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the MyeChild 01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.

The evidence for a benefit in patients with FLT3 ITD variants was mixed; the French ALFA-0701 (NCT00927498) trial showed a trend toward a benefit, whereas the five-trial meta-analysis study did not find a benefit.[23,24] These trials did not examine the outcomes specifically for the combination of gemtuzumab ozogamicin followed by HSCT, as was reported by the COG.[21]

The expression intensity of CD33 on leukemic cells appeared to predict which patients benefited from gemtuzumab ozogamicin on the COG AAML0531 clinical trial.[20][Level of evidence B1]

The expression intensity of CD33 on leukemic cells appeared to predict which patients benefited from gemtuzumab ozogamicin on the COG AAML0531 clinical trial.[20][Level of evidence B1]

Patients whose CD33 intensity fell into the highest three population quartiles benefited from treatment with gemtuzumab ozogamicin (i.e., improved relapse risk, DFS, and EFS), whereas those in the lowest quartile had no reduction in relapse risk, EFS, or OS.

The expression intensity of CD33 on leukemic cells appeared to predict which patients benefited from gemtuzumab ozogamicin on the COG AAML0531 clinical trial.[20][Level of evidence B1]

This impact was seen for low-, intermediate-, and high-risk patients.

In a retrospective analysis of the ALFA-0701 (NCT00927498) trial of older adults, higher CD33 expression corresponded with greater benefit from treatment with gemtuzumab ozogamicin.[25]

The CD33 receptor on AML cells exhibited architectural variability (polymorphism) that resulted in 51% of patients expressing the single nucleotide polymorphism (SNP) rs12459419 (designated CC). The alteration of this SNP resulted in a CD33 isoform lacking the CD33 IgV domain to which gemtuzumab ozogamicin binds and that is used in diagnostic immunophenotyping.[26]

The CD33 receptor on AML cells exhibited architectural variability (polymorphism) that resulted in 51% of patients expressing the single nucleotide polymorphism (SNP) rs12459419 (designated CC). The alteration of this SNP resulted in a CD33 isoform lacking the CD33 IgV domain to which gemtuzumab ozogamicin binds and that is used in diagnostic immunophenotyping.[26]

The patients with this SNP had a significant reduction in relapse with the use of gemtuzumab ozogamicin, compared with patients who were not treated with this drug (26% vs. 49%; P < .001).

The CD33 receptor on AML cells exhibited architectural variability (polymorphism) that resulted in 51% of patients expressing the single nucleotide polymorphism (SNP) rs12459419 (designated CC). The alteration of this SNP resulted in a CD33 isoform lacking the CD33 IgV domain to which gemtuzumab ozogamicin binds and that is used in diagnostic immunophenotyping.[26]

For patients with either a one or two allele C>T variant (CT and TT phenotypes, respectively) at this SNP, there was no reduction in relapse when adding gemtuzumab ozogamicin therapy (5-year cumulative incidence of relapse, 39% vs. 40%; P = .85).