A phase I trial of high-dose clofarabine, etoposide, and cyclophosphamide and autologous peripheral blood stem cell transplantation in patients with primary refractory and relapsed and refractory non-Hodgkin lymphoma.
Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m(2)/day on days -6 to -2 in successive cohorts, in combination with etoposide 60 mg/kg (day -8), and cyclophosphamide 100 mg/kg (day -6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32-67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m(2)/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = 1) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CR(U)), and 2 patients achieved a partial response, for an overall response rate of 94%. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63% (95% confidence interval [CI]: 43%-91%) and 68% (95% CI: 49%-96%), respectively. We recommend clofarabine 70 mg/m(2)/day × 5 days as a phase II dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Shivani
S
Srivastava
David
D
Jones
Lisa L
LL
Wood
Jennifer E
JE
Schwartz
Robert P
RP
Nelson
Rafat
R
Abonour
Angie
A
Secrest
Elizabeth
E
Cox
Jay
J
Baute
Cheryl
C
Sullivan
Kathleen
K
Kane
Michael J
MJ
Robertson
Sherif S
SS
Farag
D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000009:adverse effects; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D000077866:Clofarabine; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D000069585:Filgrastim; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006402:Hematologic Diseases / Q000139:chemically induced; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000601:surgery / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011994:Recombinant Proteins; D012008:Recurrence; D016879:Salvage Therapy; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D000077866:Clofarabine; D003520:Cyclophosphamide; D000069585:Filgrastim