A phase 1 study of the antibody‐drug conjugate brentuximab vedotin with re‐induction chemotherapy in patients with CD30‐expressing relapsed/refractory acute myeloid leukemia

Abstract

Background Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody‐drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re‐induction chemotherapy for patients with CD30‐expressing R/R AML. Methods Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. Results There were no dose‐limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease‐free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. Conclusions The combination of BV with MEC was found to be safe in patients with CD30‐expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). Lay summary The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Cohort Study

“…AE were assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [30]. In accordance with the guidelines for administration of LEN, the dose of LEN was reduced or treatment interrupted when any AE of grade 3 or higher severity or any unacceptable drug-related AE of grade 2 severity occurred.…”

Antibody–Drug Conjugates for the Treatment of Acute Pediatric Leukemia

“…After licensing in Hodgkin lymphoma and anaplastic large cell lymphoma, brentuximab was studied in other CD30 expressing hematologic malignancies. In a phase I study in adults with AML, brentuximab was combined with re-induction chemotherapy in CD30 expressing relapsed AML [76]. The composite response rate was 36% with a median disease-free survival of 6.8 months [76].…”

Natural killer cell-based immunotherapy for acute myeloid leukemia

“…Preclinical studies investigating the efficacy of novel Fc-optimized antibodies targeting various potential antigens such as CD133, CD33, CD157 and IL-1 receptor accessory protein (IL1RAP) as well as new regimens of antibodies combined with NK cell transfer exhibited promising results and these strategies can be valuable to be conducted in future clinical trials [130][131][132][133][134][135][136]. Antibody-drug conjugates (ADCs) and antibody-radio conjugates are promising strategies to enhance the antibody potency as well, and they yield superior clinical impacts on AML patients [137][138][139][140][141]. Gemtuzumab ozogamicin (GO), the combination of anti-CD33 antibody with anti-neoplastic agent calicheamicin, is currently the only ADC approved by the Food and Drug Administration (FDA) for the treatment of newly diagnosed and R/R CD33 + AML [142][143][144].…”