Phase 1 dose-escalation trial of clofarabine followed by escalating dose of fractionated cyclophosphamide in adults with relapsed or refractory acute leukaemias

• Published in: British journal of haematology Vol. 158; no. 2; pp. 198 - 207
• Main Authors: Zeidan, Amer M., Ricklis, Rebecca M., Carraway, Hetty E., Yun, Hyun D., Greer, Jacqueline M., Smith, B. Douglas, Levis, Mark J., McDevitt, Michael A., Pratz, Keith W., Showel, Margaret M., Gladstone, Douglas E., Gore, Steven D., Karp, Judith E.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.07.2012; Blackwell
• Subjects: Acute lymphatic leukemia; acute lymphoblastic leukaemia; Acute lymphoblastic leukemia; acute myeloid leukaemia; Acute myeloid leukemia; Adenine Nucleotides - administration & dosage; Adenine Nucleotides - adverse effects; Adenine Nucleotides - therapeutic use; Adult; Age; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Arabinonucleosides - administration & dosage; Arabinonucleosides - adverse effects; Arabinonucleosides - therapeutic use; Biological and medical sciences; Blood; Clinical trials; Clofarabine; Cyclophosphamide; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Cyclophosphamide - therapeutic use; Deoxyribonucleic acid; DNA; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatalities; Female; Hematologic and hematopoietic diseases; Hematology; Hematopoietic stem cells; Humans; Infection; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes (neutrophilic); Male; Medical sciences; Middle Aged; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Prognosis; Prospective Studies; Recurrence; refractory leukaemia; Remission; Remission Induction; Salvage; Salvage Therapy - methods; Treatment Outcome; Young Adult; Antineoplastic agent; Acute myelogenous leukemia; Relapse; Increasing dose; acute myeloid leukaemia; Lymphoproliferative syndrome; acute lymphoblastic leukaemia; Nucleoside analog; Adult; Acute lymphocytic leukemia; refractory leukaemia; Human; Treatment resistance; Hematology; Acute leukemia; Malignant hemopathy; Clofarabine; Fractionated dose; Alkylating agent; Oxazaphosphinane derivatives; Cyclophosphamide; Antimetabolic; Nitrogen mustard; Phase I trial; Cancer
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2012.09142.x

Summary 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 × 109/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.