Cumulative chemotherapy increases mafosfamide toxicity for normal progenitor cells in AML patients: rationale for cryopreserving adapted-dose purged marrow early in first complete remission.

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.