title: Correlation of occult clonogenic leukemia drug sensitivity with relapse after autologous bone marrow transplantation.
abstract: Despite initial complete remission rates exceeding 70%, the majority of patients with acute myeloid leukemia (AML) and adults with acute lymphocytic leukemia (ALL) eventually relapse. Improving the therapeutic results in acute leukemia requires detecting, and understanding the biology of, the minimal residual leukemia remaining after therapy and responsible for relapse. To investigate the biologic relevance of an in vitro assay for clonogenic leukemia (leukemia colony-forming units [CFU-L]) as a measure of minimal residual leukemia, we studied 58 consecutive patients with acute leukemia in complete remission undergoing autologous bone marrow transplantation (BMT) with cyclophosphamide-based therapy. CFU-L were cultured from the pretransplant remission marrows in 45 of 58 patients: 35 of 43 patients with AML and 10 of 15 with ALL. Clonal rearrangements, identical to the patients' overt leukemia when available, were detected in the occult CFU-L from four of the eight patients with ALL in whom adequate DNA for analysis could be obtained from the CFU-L. None of the uncultured pretransplant remission marrows from the 15 ALL patients showed clonal gene rearrangements. We also determined the in vitro sensitivity of the occult CFU-L to 4-hydroperoxycyclophosphamide (4HC), and correlated these results with the outcome of the patients. The sensitivity of the occult CFU-L to 4HC was the only factor that predicted relapse following BMT. The actuarial probability of relapse was 18% in the 23 patients whose CFU-L were sensitive to 4HC compared with 77% in the 22 patients whose CFU-L were resistant (P less than .001). The only factor that influenced the CFU-L sensitivity to 4HC was the type of leukemia. The CFU-L from the AML patients were more sensitive to 4HC than the CFU-L from the ALL patients (P = .001). Occult CFU-L genetically and functionally represent occult leukemia. Therefore, the CFU-L assay should provide a means for studying the biology of minimal residual leukemia and improving the therapeutic results in patients with acute leukemia.
authors.affiliation: Bone Marrow Transplantation Program, Johns Hopkins Oncology Center, Baltimore, MD.
authors.forename: C B
authors.initials: CB
authors.lastname: Miller
authors.forename: B A
authors.initials: BA
authors.lastname: Zehnbauer
authors.forename: S
authors.initials: S
authors.lastname: Piantadosi
authors.forename: S D
authors.initials: SD
authors.lastname: Rowley
authors.forename: R J
authors.initials: RJ
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation; D002648:Child; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014410:Tumor Stem Cell Assay
chemical_list: D003520:Cyclophosphamide; C011272:perfosfamide