Gemtuzumab ozogamicin plus cytarabine in elderly patients with relapsed or refractory acute myeloid leukaemia

Gemtuzumab ozogamicin (GO) is a humanized IgG4 anti-CD33 monoclonal antibody conjugated to a cytotoxic calicheamicin derivative. This drug is approved for the treatment of patients with CD33-positive acute myeloid leukaemia (AML) in first relapse who are 60 years of age or older and who are not candidates for other cytotoxic chemotherapy. However, the clinical benefit of GO monotherapy in this setting remains modest, with a complete remission (CR) rate of about 15% and a median overall survival (OS) rarely exceeding 5 months (Pagano et al, 2007; Stasi et al, 2008). Therefore, several studies have evaluated the efficacy of GO in combination with cytotoxic chemotherapy in order to improve the outcome of patients with refractory/relapsed AML (Pagano et al, 2007; Stasi et al, 2008). We report here our experience concerning the activity and the safety of a combination of GO and cytarabine in intravenous continuous perfusion (IVCP) in patients over 60 years of age with relapsed/refractory AML. The study included all the patients treated at the Centre Antoine-Lacassagne (Nice, France) between January 2005 and June 2007 with GO plus cytarabine and who matched the following criteria: de novo or secondary acute myeloid leukaemia (sAML, except for acute promyelocytic leukemia); primary refractory or relapsed AML and age ≥60 years. Such patients were required to have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and no severe hepatic or renal dysfunction. CR was defined as (i) absence of blasts in the peripheral blood, (ii) normal marrow with <5% blasts, (iii) neutrophil count >1 × 109/l and (iv) platelet count >100 × 109/l, for more than 1 month. Patients who met these criteria but still had 6–25% marrow blasts were considered to have a partial remission as long as the blast count had decreased by at least 50%. Patients with all CR criteria, but with persistent thrombocytopenia, were defined as CRp. The overall remission rate (ORR) was the sum of CR, CRp and PR rates. OS was defined as the interval from the start of therapy to the time of death or the last follow-up. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria version 3.0 (NCI-CTC 3.0). A total of 14 patients (eight males, six females) were included in this study. The median age was 70 years (range, 61–78 years). Seven patients had de novo AML and seven patients had sAML. Nine patients had intermediate- and five poor-risk cytogenetics. Patients had received a median of one previous line (range, one to three lines) of therapy. The ECOG PS was 0 in 10 patients, 1 in four patients and 2 in three patients. All patients received GO (6 mg/m2, day 1 and 4mg/m2, day 8 as a 2-h i.v. infusion) and cytarabine (100 mg/m2/24 h, days 1–7 in IVCP). The ORR was 28% and included two CR, one CRp and one PR. One CR patient received GO 3 mg/m2 every 3 months as ‘maintenance’ therapy and relapsed at day 170. The second CR received a course of mitoxantrone (10 mg/m2 mitoxantrone i.v. day 1) combined with cytarabine (200 mg/m2/24 h s.c. days 1–5) every 3 weeks for a total of five courses as consolidation therapy and relapsed at day 276. The CRp and the PR patients did not receive any further treatment. The CRp patient died from veno-occlusive disease (VOD) at day 87, whereas the PR patient was still in remission 301 d after the treatment. The median OS was 4·6 months. Treatment-related death occurred in four patients (28%): two from septic shock, one from VOD and one from an intracerebral haemorrhage. All patients presented febrile neutropenia. Four patients had recovery of their absolute neutrophil count to >5 × 109/l and of the platelet count to 50 000 × 109/l in a median of 22 and 25 d from the start of treatment respectively. Four patients (28%) had grade 3 or 4 non-haematological toxic events that included: cholestasis (21%), hyperbilirubinemia (21%), liver cytolysis (21%) and metabolic acidosis (14%). Piccaluga et al (2004) claimed that the association of GO and cytarabine in IVCP was effective in elderly patients with an acceptable hepatic toxicity profile. Their study included both untreated (n = 5) and relapsed patients (n = 4) and the median age was 63 years (range 50–71 years). The CR rate was 55%. There was no toxic death and no case of VOD. We have showed here by studying a more homogenous population which have included only elderly patients (≥60 years) with relapsed/refractory disease that this regimen is associated with a CR + CRp rate of 21%, similar to that observed with other combination regimens used in the same setting. However, the toxicity, characterized by an unacceptable rate of death, related to the treatment and a high incidence of liver injury, including one case of fatal VOD, was more pronounced than that reported by Piccaluga et al (2004). Of importance, our study population was characterized by a more advanced age and by a more aggressive disease because all the patients were treated in a relapsed/refractory setting. Interestingly, a review of safety reports for GO have shown that the VOD incidence was relatively low (3%) at doses of GO ≤6 mg/m2 if administered as monotherapy or in combination with non-hepatotoxic agents (McKoy et al, 2007). Moreover, an elegant in vitro study demonstrated that, by combining GO with low-dose cytarabine, the dose of GO could be reduced 10-fold to produce the same effects (Morris et al, 2006). This findings strongly suggest that low-dose GO in combination with low-dose cytarabine may be an effective chemotherapy regimen for elderly AML patients with an expected better safety profile than that of the regimen used in our study. The ongoing UK AML 16 Trial, which evaluates a regimen combining low-dose cytarabine (20 mg/12 h, days 1–10) and low dose GO (5 mg, day 1) in patients not considered fit for intensive treatment, will better define the clinical benefit resulting from such a strategy (http://www.download.bham.ac.uk/bctu/AML16/Trial/AML16%20Protocol%20V5%20May%202006.pdf).