High dose cytarabine plus gemtuzumab ozogamicin for patients with relapsed or refractory acute myeloid leukemia: Cancer and Leukemia Group B study 19902

Abstract

Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate, was combined with high dose cytarabine (HiDAC; cytarabine 3 g/m² over 3 h daily for 5 days) for adults with relapsed or refractory AML. HiDAC plus GO 9 mg/m² on day 7 and 4.5 mg/m² on day 14 was not tolerated, but HiDAC followed by GO 9 mg/m² on day 7 was safe: 12/37 (32%) patients with relapsed AML achieved complete remission. Median overall survival was 8.9 months. No grade 4 hepatic veno-occlusive disease was observed. This regimen merits further study, both in this setting and as a remission consolidation therapy.

Introduction

Therapy for acute myeloid leukemia (AML) in adults remains disappointing. Approximately one-third of adults between the ages of 18–60 years can expect long-term disease-free survival (DFS) with anthracycline plus cytarabine chemotherapy for remission induction, followed by consolidation with intensive chemotherapy or hematopoietic stem cell transplantation (HCT) [1]. The situation for older adults is worse; even among those who are treated aggressively, only 5–10% will be long-term survivors [2]. While rarely cured solely by additional chemotherapy, patients with relapsed AML can sometimes be rendered into a minimal disease state following reinduction therapy [3]. Such patients can often proceed to a curative HCT either from an allogeneic [4] or autologous [5], [6] source.

The optimal therapy for patients with relapsed or refractory AML in unclear. High dose cytarabine (HiDAC), either alone [7] or in combination with other agents [8] is commonly used. However, increasingly routine use of this therapy during induction [9] and especially during post-remission treatment [10] makes subsequent success less likely. Other agents used to treat patients with relapsed AML include gemtuzumab ozogamicin (GO) [11] etoposide/mitoxantrone [12], novel nucleoside analogs cladribine [13] or fludarabine [14] and non-cytotoxic agents such as flavopiridol [15] or sirolimus [16]. The wide variation in remission rates (10–50%) after these therapies reflects intrinsic differences among these agents and combinations as well as host factors, such as age, the amount of prior of therapy, and most importantly, the length of the disease-free interval preceding the relapse [17].

The most recently approved agent for the treatment of relapsed AML in adults is GO [18], [19], [20]. GO is a humanized monoclonal antibody directed against the CD33 antigen, expressed on blast cells from 80% to 90% of patients with AML. The antibody is conjugated to the toxin calicheamicin. When this molecule binds to a CD33-expressing cell, internalization occurs and the calicheamicin toxin is liberated in the acidic microsomal environment. When released, calicheamicin induces double strand DNA breaks and cell death. Pivotal studies were performed in 142 patients with relapsed AML whose first complete remission (CR1) lasted for at least 3 months and generally more than 6 months [18], [19], [20]. A 30% CR rate was reported, although half of these responders had incomplete platelet recovery to <100,000/μl (CRp). These data led to approval by the FDA for patients over age 60 with relapsed AML whose blasts expressed CD33. Major side effects were limited to infusion-related toxicities, reversible hepatic toxicity, and prolonged myelosuppression. Subsequent studies have described severe hepatotoxicity when GO was given alone or in combination with chemotherapy [21], or if an allogeneic HCT was done within 3 months after exposure [22]. GO has been investigated alone or in combination as frontline therapy in patients with AML [23], [24] including large randomized (MRC-15 [25] and SWOG 0106 [26]) trials, and/or as a post-remission strategy (ECOG 1900 [27] and SWOG 0106 trials). The MRC 15 trials used GO at 3 mg/m² on day 1 of induction and consolidation chemotherapy and the SWOG 0106 trial used 6 mg/m² on day 4 of induction therapy and then 5 mg/m² for 3-month doses during maintenance.

The clinical trial reported here combined GO and HiDAC. These two drugs have different mechanism of actions and toxicities. We hypothesized that GO could be given safely immediately after cytarabine because it does not cause mucositis and that initial cytoreduction with HiDAC would yield a low number of residual target cells, thus allowing more concentrated binding of the anti-CD33 monoclonal antibody. Our study determined a tolerable dose of GO that could be given following a standard 5-day regimen of HiDAC. We originally hoped to employ a novel schedule wherein two doses of GO were given 7 days apart in contrast to the standard 14-day interval, but this did not prove to be feasible. We now report the Phase I component of the trial as well as the results obtained in 37 patients with relapsed AML who were treated at the recommended Phase II doses (RPTD) of cytarabine at 3 gm/m² per day for 5 days plus GO at 9 mg/m² on day 7.