Immunotherapeutic approaches

The COG AAML00P2 (NCT00028899) study established the maximum tolerated dose (MTD) of gemtuzumab ozogamicin, when combined with mitoxantrone and high-dose cytarabine, as 3 mg/m2. The MTD of gemtuzumab ozogamicin, when combined with Capizzi II–based, high-dose cytarabine, was 2 mg/m2.[23]

The COG AAML00P2 (NCT00028899) study established the maximum tolerated dose (MTD) of gemtuzumab ozogamicin, when combined with mitoxantrone and high-dose cytarabine, as 3 mg/m2. The MTD of gemtuzumab ozogamicin, when combined with Capizzi II–based, high-dose cytarabine, was 2 mg/m2.[23]

These regimens produced an overall remission response rate of 45% (±15%), a 1-year event-free survival (EFS) rate of 38% (±14%), and a 1-year overall survival (OS) rate of 53% (±15%).

The COG AAML00P2 (NCT00028899) study established the maximum tolerated dose (MTD) of gemtuzumab ozogamicin, when combined with mitoxantrone and high-dose cytarabine, as 3 mg/m2. The MTD of gemtuzumab ozogamicin, when combined with Capizzi II–based, high-dose cytarabine, was 2 mg/m2.[23]

Sinusoidal occlusion syndrome was seen in one patient with a previous HSCT during the cycle containing gemtuzumab ozogamicin and in 4 of 28 patients during subsequent HSCT (grade 1 in two patients, grade 3 in 1 patient, and grade 4 in 1 patient), all of whom recovered.

The COG AAML00P2 (NCT00028899) study established the maximum tolerated dose (MTD) of gemtuzumab ozogamicin, when combined with mitoxantrone and high-dose cytarabine, as 3 mg/m2. The MTD of gemtuzumab ozogamicin, when combined with Capizzi II–based, high-dose cytarabine, was 2 mg/m2.[23]

This same MTD of gemtuzumab ozogamicin was found in the dose escalation portion of the UK MRC AML15 study in adults. In these patients, escalation beyond 3 mg/m2/dose, when given with a conventional intensive chemotherapy backbone, was not feasible because of hepatotoxicity and delayed hematopoietic recovery.[24] Gemtuzumab ozogamicin at 3 mg/m2/dose, when given with consecutive courses of intensive chemotherapy, was also not tolerated.

The Relapsed AML 2001/02 study was a single-arm trial for children (n = 30) who experienced a second relapse or had refractory AML after the cancer did not respond to a second induction regimen. Gemtuzumab ozogamicin as a single agent was dosed at 7.5 mg/dose (children younger than 3 years received 0.25 mg/kg) given every 14 days for two total doses.[25]

The Relapsed AML 2001/02 study was a single-arm trial for children (n = 30) who experienced a second relapse or had refractory AML after the cancer did not respond to a second induction regimen. Gemtuzumab ozogamicin as a single agent was dosed at 7.5 mg/dose (children younger than 3 years received 0.25 mg/kg) given every 14 days for two total doses.[25]

CR or CRp was seen in 37% of patients. Nine patients subsequently underwent HSCT, and three of these patients remained in continuous CR.

The Relapsed AML 2001/02 study was a single-arm trial for children (n = 30) who experienced a second relapse or had refractory AML after the cancer did not respond to a second induction regimen. Gemtuzumab ozogamicin as a single agent was dosed at 7.5 mg/dose (children younger than 3 years received 0.25 mg/kg) given every 14 days for two total doses.[25]

All patients received prophylactic defibrotide during HSCT without experiencing any sinusoidal occlusion syndrome.

The Relapsed AML 2001/02 study was a single-arm trial for children (n = 30) who experienced a second relapse or had refractory AML after the cancer did not respond to a second induction regimen. Gemtuzumab ozogamicin as a single agent was dosed at 7.5 mg/dose (children younger than 3 years received 0.25 mg/kg) given every 14 days for two total doses.[25]

In a prior study of children who received single-agent gemtuzumab ozogamicin, administered at 6 to 9 mg/m2 per dose, patients did not receive defibrotide prophylaxis during subsequent HSCT. These studies demonstrated an increased risk of sinusoidal occlusion syndrome, particularly for patients who underwent HSCT less than 3.5 months after the last dose of gemtuzumab ozogamicin.[26]

Two prospective studies from the Acute Leukemia French Association (ALFA) group examined fractionated gemtuzumab ozogamicin (3 mg/m2/dose on days 1, 4, and 7) in adults with relapsed AML.

Two prospective studies from the Acute Leukemia French Association (ALFA) group examined fractionated gemtuzumab ozogamicin (3 mg/m2/dose on days 1, 4, and 7) in adults with relapsed AML.

The MYLOFRANCE 1 trial evaluated single-agent fractionated dosing in 57 adults with AML in first relapse, which resulted in a CR rate of 26% and a CRp rate of 7%. No sinusoidal occlusion syndrome occurred during or in subsequent HSCT.[27]

Two prospective studies from the Acute Leukemia French Association (ALFA) group examined fractionated gemtuzumab ozogamicin (3 mg/m2/dose on days 1, 4, and 7) in adults with relapsed AML.

Subsequently, the MYLOFRANCE 2 trial was a phase I/II study (n = 20) that combined the same fractionated dose of gemtuzumab ozogamicin with a dose-finding backbone of daunomycin and cytarabine. Nine patients achieved CR and two patients achieved a CRp. The recommended phase II dose was found to be 60 mg/m2 per day for 3 days for daunomycin and 200 mg/m2 per day for 7 days for cytarabine. No sinusoidal occlusion syndrome was experienced.[28]

Two prospective studies from the Acute Leukemia French Association (ALFA) group examined fractionated gemtuzumab ozogamicin (3 mg/m2/dose on days 1, 4, and 7) in adults with relapsed AML.

Fractionated gemtuzumab ozogamicin dosing has been shown to be safe and effective in adults with de novo AML;[29] it is now being evaluated in the MyeChild01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.