Inhibition of cfu-gm growth by idarubicinol containing plasma samples obtained from poor prognosis lymphoma patients treated with 3-days infusion idarubicin

We have treated 14 patients with poor prognosis HD or NHL in a phase l-ll trial of high dose idarubicin and melphalan, with idarubicin dose-escalation. In order to verify the optimal timing of hematopoietic progenitors (HP) transplant, we studied the hematotoxic potential of idarubicinol (IDOL). We first performed cytotoxicity tests on clonogeneic cells derived from human umbilical cord blood. We then evaluated the myelotoxic effect of plasma samples drawn from patients on the day of transplant and on the subsequent two days. IDOL concentrations were measured in plasma by HPLC The median ID70 for CFU-GM was 130 ng/ml (range 80-170) after 1h and 12 ng/ml (range 7-17) after 24 h exposure to IDOL. CFU-GM performed after exposure to plasma samples showed a median growth inhibition of only 20% (range 0-43) on the day of transplantation when the median IDOL level was 11.15 ng/ml (range 3.3-17.4). On day +2 there was a marked reduction of plasma samples cytotoxicity with a median colony inhibition of 11% (range 0-32) and a median IDOL level of 6.9 ng/ml (range 3.2-114). The reduced in vitro toxicity of plasma samples compared to what expected from the dose-response curves, was not related to a protective effect of albumin on HP: the pattern of IDOL myelotoxicity was similar incubating HP in presence or in absence of human serum albumin. All patients achieved a rapid and sustained hematopoietic recovery with a median time to 1x10 WBC/I and 10x109 PLT/I of 13 days (range 10-17) and 13.5 days (range 11-19) respectively. These data suggest a discrepancy between in vitro and in vivo chemosensitivity of HP possibly explainable by the presence of circulating growth factors or HP interaction with the stromal environment in the in vivo condition.