Altered oxidative product formation in neutrophils of patients recovering from therapy for acute leukemia.

During chemotherapy for acute leukemias, severe neutropenia allows acquisition of life-threatening infections that are difficult to clear with antibiotics alone. With return of myelopoiesis, even severe infections often improve dramatically. We have sequentially examined oxidative metabolic responses of polymorphonuclear leukocytes (PMNL) from 30 patients with acute leukemias before induction chemotherapy and after recovery of myelopoiesis (circulat-ing PMNL >500/µL). Maximal oxidative metabolic responses were quantitated by flow cytometric analysis of H202-dependent oxidation of intracellular 2’,7’-dichloro-fluorescin (DCFH) in individual PMNL after stimulation with phorbol myristate acetate (PMA). Resting PMNL oxidized a mean of 6.8 attomoles (amol) DCFH/cell/15 min, with no difference between normal or patients’ PMNL. PMA-stimu-lated normal PMNL oxidized 183 ± 35 amol/cell (mean ± SD, n = 120). In patients’ PMNL obtained before chemotherapy, the mean DCFH oxidation was not significantly different from controls (216 ± 78 amol/cell). However, 11 of 22 samples revealed populations of granulocytes with increased (primed) oxidative responses; seven of these 11 patients had proven or suspected infection at presentation. At recovery from chemotherapy-induced neutropenia, PMNL from 19 of 21 patients possessed one or more significant subpopulations with primed oxidation in response to PMA. In these 19 patients, 61% ± 8% of PMNL comprised primed populations that oxidized 503 ± 46 amol/cell. Oxidative activity was most pronounced in patients with proven or clinically suspected infections (with 41% ± 9% of PMNL oxidizing 615 ± 79 amol/cell). However, oxidative responses to PMA were also significantly increased in recovery PMNL from ten patients without clinical or laboratory evidence of active infection (79% ± 11% of PMNL primed to oxidize 402 ± 29 amol/ cell). The peak responses of the primed subpopulations were short-lived and generally lasted three days or less, although oxidative responses remained elevated above normal for a week or more. All of the patients with increased PMNL responsiveness survived their hospitalization. In contrast, PMNL from four patients had a significant population (18% to 82% of cells) with reduced responsiveness. Two of these four patients (with 71% and 75% subnormal cells) died during this induction attempt; the third died during a second induction attempt; only one survived to discharge. The clinical significance of these phenomena is yet to be determined. The results support the clinical observation that recovery after therapy for acute leukemia suggests the presence of granulocytes with potent functional activity. Priming apparently may occur in the absence of overt infection, possibly because of stimulatory substances released during the period of prolonged neutropenia. Only a small number of patients were observed with the opposite phenomenon of hypoactive PMNL; however, the high mortality in this group suggests that the normal response (and/or the ability to prime PMNL following neutropenia) may be important to the eventual clinical outcome.