A phase I/II study of CY and topotecan in patients with high-risk malignancies undergoing autologous hematopoietic cell transplantation: the St Jude long-term follow-up

• Published in: Bone marrow transplantation (Basingstoke) Vol. 47; no. 11; pp. 1448 - 1454
• Main Authors: KASOW, K. A, STEWART, C. F, HALE, G. A, BARFIELD, R. C, WRIGHT, N. L, LI, C, SRIVASTAVA, D. K, LEUNG, W, HORWITZ, E. M, BOWMAN, L. C, HANDGRETINGER, R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.11.2012
• Subjects: Adolescent; Age; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Autografts; Biological and medical sciences; Bone marrow; Bone marrow transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Brain tumors; Cancer; Care and treatment; Child; Child, Preschool; Children; Combined Modality Therapy; Cyclophosphamide; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Dosage; Dosage and administration; Fatalities; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Hemopoiesis; Hepatotoxicity; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes (neutrophilic); Lymphoma; Malignancy; Medical sciences; Neoplasms - drug therapy; Neoplasms - surgery; Neuroblastoma; Neurology; Platelets; Retina; Retinoblastoma; Risk; Risk Factors; Risk groups; Sarcoma; Stem cell transplantation; Survival Rate; Topoisomerase I Inhibitors - administration & dosage; Topoisomerase I Inhibitors - adverse effects; Topotecan; Topotecan - administration & dosage; Topotecan - adverse effects; Toxicity; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation, Autologous; Tumors of the nervous system. Phacomatoses; Veno-occlusive disease; Antineoplastic agent; High risk; Stem cell; Hematopoietic cell; Homograft; Neuroblastoma; Isomerases; Lymphoproliferative syndrome; Phase II trial; Autologous hematopoietic stem cell transplantation; Bone marrow; Graft; Topoisomerase I inhibitor; Camptothecin derivatives; Human; Nervous system diseases; Hematology; Sarcoma; Enzyme; DNA topoisomerase; Enzyme inhibitor; Topotecan; Malignant hemopathy; Malignant tumor; Lymphoid neoplasm; Long term; Lymphoma; autologous BMT; Treatment; Follow up study; CY; Phase I trial; Autonomic neuropathy; Cancer; High malignancy
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/bmt.2012.51

Fifty-eight consecutive children with high-risk malignancies were treated with CY, and targeted topotecan followed by autologous hematopoietic cell transplantation (AHCT) in a phase I/II Institutional Review Board-approved study. Twelve participants enrolled in phase I; 5 received dose level 1 of topotecan 3 mg/m(2) per day, with subsequent doses targeted to total systemic exposure of 100±20 ng h/mL and CY 750 mg/m(2) per day. Seven participants received dose level 2. CY dose escalation to 1 g/m(2) per day was considered excessively toxic; one died from irreversible veno-occlusive disease and two experienced reversible hepatotoxicity. These adverse events halted further dose escalation. A total of 46 participants were enrolled in phase II; results are on the 51 participants who received therapy at dose level 1, the maximum tolerated dose. Diagnoses included neuroblastoma (26), sarcoma (9), lymphoma (8), brain tumors (5), Wilms (2) and retinoblastoma (1). Twenty participants (39.3%) were in CR1 at enrollment; median age was 5.1 years. Most common non-hematological grade III-IV toxicity was gastrointestinal (n=37). Neutrophil and platelet engraftment occurred at a median of 15 and 24 days, respectively. Twenty-six (51%) participants remain alive at a median of 6.4 years after AHCT. CY 3.75 g/m(2), and targeted topotecan followed by AHCT are feasible and produce acceptable toxicity in children with high-risk malignancies.