title: Phase 1 dose-escalation trial of clofarabine followed by escalating dose of fractionated cyclophosphamide in adults with relapsed or refractory acute leukaemias.
abstract: The prognosis of patients with relapsed and refractory acute leukaemia (RRAL) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia (AML), 12 acute lymphoblastic leukaemia (ALL)] in this Phase 1 dose-escalation trial of daily-infused clofarabine (CLO) followed by cyclophosphamide (CY) for four consecutive days (CLO-CYx4). The median age was 48·5 years. The median number of prior regimens was 2 (range 1-5), and 6/40 patients (15%) had prior allogeneic haematopoietic stem cell transplant. 28/40 patients (70%) had adverse genetic features. 6/40 patients (15%) died within 60 d of induction (two infections, four progressive disease). The average time to neutrophil recovery (absolute neutrophil count ≥0·5 × 10(9) /l was 34 d, (range, 17-78). The overall response rate (ORR) was 33% (13/40), with seven complete remissions (18%), four complete remissions with incomplete recovery of blood counts (10%), and two partial remissions (5%). ORR was 25% (7/28), and 50% (6/12), for AML and ALL respectively. Notably, the clinical responses were independent of dose level. 7/17 patients (41%) exhibited CLO-mediated enhancement of CY-induced DNA, which was associated with, but not necessary for, improved clinical outcomes. In summary, the CLO-CYx4 regimen was well tolerated and had activity in patients with RRAL, especially relapsed ALL. Therefore, CLO-CYx4 can be considered a salvage therapy for adults with RRALs, and warrants further investigations.
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Amer M
authors.initials: AM
authors.lastname: Zeidan
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Ricklis
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Hetty E
authors.initials: HE
authors.lastname: Carraway
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Hyun D
authors.initials: HD
authors.lastname: Yun
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Greer
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Showel
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Gladstone
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.affiliation: Division of Hematologic Malignancies, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000077866:Clofarabine; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine; D003520:Cyclophosphamide