title: Cumulative chemotherapy increases mafosfamide toxicity for normal progenitor cells in AML patients: rationale for cryopreserving adapted-dose purged marrow early in first complete remission.
abstract: To evaluate whether conditions for adapted dose mafosfamide (mafo) purging vary with accumulating chemotherapy, we studied the sensitivity of bone marrow CFU-GM in a total of 30 patients at different stages of treatment. We determined the dose of 95% CFU-GM growth-inhibition by mafo (ID95) in 23 patients with acute myeloid leukemia (AML) and 7 patients with lymphoid malignancies in first or second complete remission (CR). Sixteen AML patients were studied in early first CR prior to intensive consolidation with high-dose cytarabine (HDAC) and had a median ID95 of 130 (range 90-190) micrograms mafo/ml; the median ID95 in 3 of 7 AML-CR1 and 4 of 7 AML-CR2 patients who previously had HDAC therapy was 75 (range 55-110) micrograms/ml whereas a control group of 7 patients with lymphoid malignancies in CR1 showed a median ID95 of 100 (range 80-160) micrograms/ml. In AML the difference between patients in CR1 prior to HDAC and patients in CR1 after HDAC late consolidation or in CR2 was highly significant (p = 0.0006). We conclude that accumulating chemotherapy pre-treatment, in particular HDAC intensive consolidation, increases mafo toxicity for non-leukemic bone marrow CFU-GM and conversely decreases the mafo concentration applicable for adjusted-dose purging to eliminate residual leukemic cells. Hence mafo purging appears to be more efficient when done in early CR1 compared with later stages of disease.
authors.affiliation: Department of Hematology, Johann Wolfgang Goethe-University Frankfurt/Main, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Bruecher
authors.forename: R
authors.initials: R
authors.lastname: Claudé
authors.forename: D
authors.initials: D
authors.lastname: Hoelzer
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D016465:Bone Marrow Purging; D015925:Cryopreservation; D003520:Cyclophosphamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D003561:Cytarabine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D003561:Cytarabine; C048341:mafosfamide; D003520:Cyclophosphamide