Autologous bone marrow transplantation for acute leukemia using transplant chemopurified with metabolite of oxazaphosphorines (ASTA Z 7557, INN mafosfamide)

Abstract

The contamination of autologous marrow with clonogenic tumor cells has been the main argument against ABMT in acute leukemia. In a preclinical study we evaluated an active cyclophosphamide derivative named "ASTA Z 7557". We observed that the toxic effect of this drug on CFU-GM growth was dependent on nucleated cell concentration as well as on red blood cell contamination. The potency of the drug was in close relationship with the incubation temperature. The growth of leukemic CFU was inhibited with an ASTA Z dose higher than 30 micrograms/ml. In our system, beyond 40 micrograms/ml more than 95% of committed stem cells are destroyed. Fifteen patients had autotransplant because of AML for 10 patients and because of ALL for 5 patients (4 patients were grafted in relapse and 11 patients in remission). We demonstrated that the marrow take was possible although the inoculum is CFU-GM depleted. Five of the 10 AML patients are alive and remain disease-free at 45+, 65+, 190+, 345+ and 570+ days from ABMT without any maintenance treatment. Four of the 5 ALL patients are alive, three of them in complete remission (40+, 110+, 250+ days). The number of patients reported in this clinical study was relatively small and more cases should be evaluated to be conclusive. Nevertheless the feasibility of chemopurified ABMT was demonstrated.

Purging of G-CSF-mobilized peripheral autografts in acute leukemia with mafosfamide and amifostine to protect normal progenitor cells

“…For PBPC, reports of relapse after PBPCT suggest that mobilized leukemic progenitor cells can contribute to relapse in a similar way to bone marrow. 13,14 Several groups have demonstrated the clinical feasibility of mafosfamide-purged ABMT with good clinical results. 13,15,16 Gorin 2,3 and Laporte et al 17 have shown in a series of 125 patients receiving mafosfamide-purged autografts that high CD34 + counts before purging correlates with a low transplant-related mortality and aggressive purging correlates with a low risk of relapse.…”

“…13,14 Several groups have demonstrated the clinical feasibility of mafosfamide-purged ABMT with good clinical results. 13,15,16 Gorin 2,3 and Laporte et al 17 have shown in a series of 125 patients receiving mafosfamide-purged autografts that high CD34 + counts before purging correlates with a low transplant-related mortality and aggressive purging correlates with a low risk of relapse. It was further shown that the best results in vivo are achieved when the number of CD34 + cells in the graft is very high and the graft is then purged as aggressively as possible.…”

“…Since red cells also influence mafosfamide toxicity, 13 the suspension was adjusted to a hematocrit of 5%.…”

Phase-I study of mafosfamide-cyclohexylamine (ASTA-Z-7557, NSC 345 842) and limited phase-I data on mafosfamide-lysine

“…In its present form mafosfamide is of little clinical interest for iv administration but may be useful for treating harvested bone marrow in an attempt to purge it of tumor cells (5). It may also be of use for regional or topical therapies.…”

History and Development of Autologous Stem Cell Transplantation for Acute Myeloid Leukemia

“…These studies clearly established that tumor cells may be eliminated from normal marrow suspensions without completely destroying the pluripotent stem cells. Several teams throughout the world, in the United States [31], France [32], including our team in Paris [33][34][35][36], Germany [37] and Italy started programs of ABMT with high dose cyclophosphamide and TBI (single dose at 10 Gy or fractionated at 12 Gy) using marrow purged in vitro with either 4HC in the United States, or mafosfamide (a related compound) in Europe. Most teams treated the marrow with fixed doses of mafosfamide while we adjusted the dose to what we considered to be the maximum tolerated dose defined as sparing 5% residual CFU-GM [33,35,36].…”