Sensitivity of Primary Clonogenic Blasts from Acute Lymphoblastic Leukemia Patients to an Activated Cyclophosphamide, viz., Mafosfamide

Abstract

Primary cyclophosphamide-naive clonogenic blasts from 32 patients with newly diagnosed acute lymphoblastic leukemia (ALL) were tested for their in vitro sensitivity to an “activated” cyclophosphamide, viz., mafosf amide, using leukemic progenitor cell (LPC) colony assays. Marked interpatient variation in the responses of LPC from newly diagnosed patients to ma-fosfamide prompted assessment of mafosfamide sensitivity in relation to more frequently measured parameters of newly diagnosed ALL. Only immunophenotype and sex showed a significant association with the intrinsic mafosfamide sensitivity of LPC. LPC from T-lineage ALL patients were more resistant to mafosfamide than LPC from B-lineage ALL patients, as reflected by 1.8-fold and 4.3-fold higher mean SF₁₀ and SF₂₀ (surviving fractions of ALL LPC at 10 and 20 μM mafosfamide, respectively) values. LPC from male patients were more resistant to mafosfamide than LPC from female patients, as reflected by 1.9-fold and 4.8-fold higher mean SF₂₀ and SF₂₀ values. In comparison to T-lineage ALL patients, a significantly greater fraction of B-lineage ALL patients had mafosfamide-sensitive LPC with SF₁₀ values of <0.25 (61% vs 11%, P = 0.01). Notably, all four cases exhibiting resistance to mafosfamide, i.e., SF₂₀ ± 0.5, were males with T-lineage ALL. In order to exclude the influence of sex as a confounding factor in the observed immunophenotype-mafosfamide sensitivity association, we also compared the mafosfamide sensitivities of LPC from male patients only. The means of SF₁₀, and SF₂₀ values of LPC from male T-lineage ALL patients were 1.5- and 3.2-fold higher than those of LPC from male B-lineage ALL patients (P < 0.1). Thus, in the male patient subgroup, the immunophenotype-mafosfamide sensitivity association remained significant.

Key Words:

• Primary clonogenic blasts
• leukemia
• ALL cyclophosphamide
• mafosfamide