Acquired DNA mutations associated with in vivo hydroxyurea exposure

Hydroxyurea (HU) is an effective therapeutic agent for patients with myelop roliferative disorders (MPDs) or sickle cell disease (SCD). Short-term HU t oxicities primarily include transient myelosuppression, but long-term HU ri sks have not been defined. The mutagenic and carcinogenic potential of HU i s not established, although HU has been associated with an increased risk o f leukemia in some patients with MPD. In this study, 2 assays were used to quantitate acquired somatic DNA mutations in peripheral blood mononuclear c ells (PBMCs) after in vivo HU exposure. The HPRT assay measures hypoxanthin e phosphoribosyl transferase (hprt) mutations, while the VDJ assay identifi es "illegitimate" T-cell receptor V gamma-J beta interlocus recombination e vents. PBMCs were analyzed from patients with MPD, adults and children with SCD, and normal controls. MPD patients with prolonged HU exposure had numb ers of DNA mutations equivalent to patients with low HU exposure or control s. Similarly, adults with SCD had equivalent numbers of DNA mutations regar dless of HU exposure, children with SCD and 30-month HU exposure had equiva lent hprt(-) mutations but significantly more VDJ mutations (1.82 +/- 1.20 events per mu g DNA) than children with 7-month HU exposure (1.58 +/- 0.87 events) or no HU exposure (1.06 +/- 0.45 events), P = .04 by analysis of va riance. Taken together, these data suggest that the mutagenic and carcinoge nic potential of in vivo HU therapy is low. Although increased numbers of i llegitimate VDJ recombination events do not directly portend leukemia, youn g patients with SCD acid HU exposure should be monitored serially for incre ases in DNA mutations. (Blood. 2000; 95:3589-3593) (C) 2000 by The American Society of Hematology.