A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma
Jennifer R. Brown,
Bradley Messmer,
Lillian Werner,
Matthew S. Davids,
Evgeny Mikler,
Jeffrey G. Supko,
David C. Fisher,
Ann S. LaCasce,
Philippe Armand,
Eric Jacobsen,
Virginia Dalton,
Bethany Tesar,
Stacey M. Fernandes,
Sean McDonough,
Jerome Ritz,
Laura Rassenti,
Thomas J. Kipps,
Donna Neuberg,
Arnold S. Freedman
Affiliations
Jennifer R. Brown
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Bradley Messmer
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Lillian Werner
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Matthew S. Davids
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Evgeny Mikler
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Jeffrey G. Supko
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
David C. Fisher
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Ann S. LaCasce
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Philippe Armand
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Eric Jacobsen
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Virginia Dalton
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Bethany Tesar
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Stacey M. Fernandes
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Sean McDonough
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Jerome Ritz
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Laura Rassenti
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Thomas J. Kipps
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Donna Neuberg
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Arnold S. Freedman
Department of Medical Oncology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Moores Cancer Center, UC San Diego, LaJolla, CA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m2 and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80% of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab, and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance. We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).
