A Phase I, Dose Escalation Study of Clofarabine in Combination with Fractionated Gemtuzumab Ozogamicin in Relapsed and Refractory Acute Myeloid Leukemia (AML).

There is no standard therapy for relapsed or refractory AML. The few agents with activity in this setting often have overlapping toxicities that restrict their use in combination. Clofarabine (CLO) is an adenine-containing nucleoside analog with activity in AML that can cause reversible myelosuppression and hepatotoxicity. Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody conjugated to a calicheamicin derivative, and is approved for relapsed AML. It is associated with hepatic sinusoidal obstructive syndrome (SOS), but a fractionated dosing schedule appears to mitigate this risk (Taksin AL et al. Leukemia2007). The primary objective of this study was to determine maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of CLO when combined with fractionated GO in patients ≦ 60 years of age with relapsed and/or refractory AML.

Eligibility criteria: AML refractory to ≥ 2 induction regimens, or relapsed within 1 year of cytarabine-containing therapy; age 18-60 years; adequate hepatic and renal function; and candidacy for allogeneic transplant. Induction therapy was: CLO 20 mg/m²/day (cohort 1) or 30 mg/m²/day (cohort 2) days 1-5, with GO 3 mg/m²/day days 1, 4 and 7. Patients in CR could receive 1-2 consolidation cycles with single agent CLO days 1-5 at the same dose as induction. A novel dose assignment strategy was used. Initial escalation occurred with 3 patients per cohort until 1 patient developed a DLT. Additional patients were assigned to the current dose cohort if the proportion experiencing a DLT at that dose was between 0.18 and 0.34. Otherwise, the dose was increased or decreased depending on DLT proportion. Toxicity was graded by Common Terminology Criteria for Adverse Events. DLT was defined as persistent grade 3-4 thrombocytopenia or neutropenia at day 42 without evidence of AML; grade 3 non-hematologic toxicity for ≥ 14 days; or any duration grade 4 non-hematologic toxicity. MTD was estimated as the dose with observed DLT rate closest to 0.26. Response was assessed using International Working Group Criteria, at the sooner of day 42 or recovery to absolute neutrophils ≥1.5 × 10⁹/L and platelets ≥ 100 × 10⁹/L.

Ten patients were treated in cohort 1, and 4 patients in cohort 2. Median age was 39 years (range 21-54). Median duration of prior remission in relapsed patients was 4 months (range 1-8). Three patients had primary refractory AML, and 4 were refractory to salvage therapy for relapse. Five patients (36%) had favorable, 2 (14%) intermediate and 7 (50%) unfavorable cytogenetics. One patient relapsed after autologous transplant, and 2 relapsed with extramedullary disease. Among cohort 1, 3/10 patients experienced DLT: 1 with prolonged grade 4 thrombocytopenia, 1 with SOS, and 1 with rhabdomyolysis. One patient in dose cohort 1 died with residual leukemia prior to day 42. Among cohort 2, 2/4 patients experienced a DLT, 1 with prolonged grade 4 thrombocytopenia, and 1 with grade 4 aspartate aminotransferase (AST) elevation. Transient grade 3 elevations of AST and alanine aminotransferase (ALT) occurred in 3 patients in cohort 1 and 1 patient in cohort 2, while transient grade 3 hyperbilirubinemia occurred in 1 patient in cohort 2. Of 6 patients who developed grade 3-4 hepatotoxicity, 5 (83%) had history of ≥ grade 2 liver injury. Of 8 patients without grade 3-4 hepatoxicity, 2 (25%) had history of ≥ grade 2 liver injury. Four patients underwent allogeneic transplant, with fatal SOS developing in 1 patient in cohort 1 who underwent a second ablative total-body-irradiation-based transplant. Responses (4/13 evaluable for response) occurred only in relapsed patients (table). Responding patients had median durations of grade 3-4 neutropenia and thrombocytopenia of 33.5 days (range 23-66), and 33.5 days (28-70), respectively.

The MTD of CLO in combination with fractionated GO is 20 mg/m²/day for 5 days. Responses have been observed in relapsed AML patients with high risk features. Hepatoxicity appears associated with prior liver injury. Further enrollment continues to confirm the MTD and explore response rate.

Foster:Genzyme Corporation: Consultancy, Research Funding. Off Label Use: Use of clofarabine in acute myeloid leukemia Use of gemtuzumab ozogamicin in acute myeloid leukemia in patients under the age of 60 years. Voorhees:Celgene Corporation: Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Speakers Bureau. Richards:Cephalon, Inc.: Speakers Bureau. Shea:Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.