No Advantages of Fractionated Versus Single Dose(s) of Gemtuzumab Ozogamicin (GO) As Part of the Midam Salvage Regimen in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients

Background: Gemtuzumab Ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody linked to calicheamicin. It was developed to treat relapsed CD33+ AML patients, first at the dose of 9 mg/m² administered twice at day +1 and +14, than combined with chemotherapy but with reduced dose to lower toxicity. In 2008, we reported a 63% (50% of complete remission (CR) + 13% of CR with incomplete platelets recovery (CRp), platelets <100 Giga/L)) overall response rate (ORR) using the MIDAM salvage regimen combining Mitoxantrone 12 mg/m²/day on days 1 through 3, Ara-C 1 g/m² every 12 hours on days 1 through 5 and a single dose of GO at 9 mg/m² (Chevallier et al , JCO, 2008). Besides thrombocytopenia, liver toxicity, especially sinusoidal obstructive syndrome (SOS), remains a matter of concern when considering GO administration. The use of fractionated GO doses (3 mg/m² day +1 +4 and +7) was developed by Castaigne et al., first in the setting of relapsed/refractory AML patients both in monotherapy or with chemotherapy, then in the first-line setting, showing excellent efficacy and safety profile. However, currently, there is no data allowing to asserting that fractionated doses of GO are safer or more efficient than the use of single GO dose administration. Results reported bellow indicates no difference between fractionated vs single GO dose(s) as part of the MIDAM regimen.

Materials and Method: This was a single center retrospective study including all CD33+ relapsed/refractory AML patients who received the MIDAM regimen, from 2008 to March 2015. Between 2008 and July 2012, all patients received GO as a single dose at 9 mg/m² day +4 (s-MIDAM group) and after until March 2015 it was decided to fractionate the GO dose according to Castaigne'schedule at 3 mg/m²/day day +1 +4 and +7 (fra-MIDAM group). All patients were treated as part of a compassionate use program as GO is not available in France for routine use. The main objective was to compare the incidence of SOS and related-deaths between both groups (s-MIDAM vs fra-MIDAM). Secondary objectives were to compare ORR (CR+CRp), median time of neutrophils and platelets (>20 Giga/L, >50 Giga/L, >100 Giga/L) recovery and overall survival (OS).

Results: 33 patients were included in the study, 15 in the fra-MIDAM group and 18 in the s-MIDAM group. Characteristics of patients were similar between the former and the latter in terms of age (median: 55 vs 52 years, p=NS), gender (male: 60% vs 66%, p=NS), cytogenetics risk (favorable 33% vs 28%, intermediate 60% vs 39%, high: 7% vs 33%, p=NS) or median CD33+ expression (99% vs 99.5%, p=NS).There were more refractory patients in the s-MIDAM group (39% vs 7%, p=0.04) but more patients for whom adapted lower dose of Ara-C (4 g/m² instead of 10 g/m² total dose, for one patient) or mitoxantrone (3 patients did not received any, and 1 received 2 days instead of 3 days) were prescribed in the fra-MIDAM group (27% vs 0%, p=0.04). Also, 20% and 28% of patients received a reduced dose of GO (6 mg/m², administered in 2 fractionated dose (3 mg/m² twice) or a single dose) in the fra-MIDAM and the s-MIDAM groups, respectively (p=NS).

ORR was similar between both groups (fra-MIDAM: 53% vs s-MIDAM: 61%, p=NS) as well as the CR rate (33% vs 39%, p=NS) or the CRp rate (20% vs 22%, p=NS). Median time to neutrophils and platelets (>20 Giga/L, >50 Giga/L and >100 Giga/L) recovery were also similar (fra-MIDAM: 29 days vs s-MIDAM: 26 days, p=0.25; 24 vs 26 days, p=NS; 27 vs 34 days, p=0.13 and 38 vs 36.5 days, p=NS). Among patients in response, 40% vs 67% were allotransplanted after the fra-MIDAM and the s-MIDAM regimens, respectively, (p=NS). With a median follow-up of 139 days and 782 days for the fra-MIDAM and the s-MIDAM groups, respectively, median OS was 7.2 months for the former and 10.2 months for the latter (p=NS). Sixty percent of patients died in the fra-MIDAM group vs 72% in the s-MIDAM group (p=NS), with no significant differences in terms of causes of death. Regarding our primary objective, 2 and 3 cases developed SOS after the fra-MIDAM and the s-MIDAM regimen, respectively, and these 5 patients died of SOS.

Conclusion: Use of fractionated GO doses compared to single GO dose as part of the MIDAM salvage regimen for relapsed/refractory AML patients showed no advantages in terms of outcomes or lower toxicity, especially regarding incidence of SOS or death due to SOS. Both schedules are equivalent and can be used.