A 46-year-old Caucasian male presented with a classic case of chronic myelogenous leukemia. However, he failed to respond to imatinib (Gleevec) in both traditional and dose-escalating regimens. After failure of nilotinib (Tasigna), mutational analysis sequencing of the kinase domain using nested polymerase chain reaction was performed. This study revealed the resistance-related T315I mutation. At the same time, the patient suddenly entered an accelerated phase of the disease, and continuation of either monotherapy or combination therapy with readily available tyrosine kinase inhibitors was felt to be ill-advised. Thus, the patient was treated with an alternate modality with good initial hematological response. Approximately 2 ½ years later, while hematologically stable, the patient developed a solitary, exquisitely painful ulceration, 7 cm × 5 cm, located on the mid-medial foreleg. There was never any evidence of venous insufficiency. The patient denied the possibility of a spider bite.
While the treatment of chronic myelogenous leukemia (CML) has been revolutionized by the advent of tyrosine kinase inhibitor therapy, there remain some cases that are resistant to this form of management. The T315I mutation generally confers resistance to imatinib and, most typically, to other related drugs.[1,2] Thus, the clinician may be forced to use either investigative agents, newer second-line drugs, or older medications, such as hydroxyurea. The latter may actually have a rather broad, albeit infrequent, role to play in modern medicine. Hydroxyurea may be beneficial in the treatment of psoriasis, sickle cell disease, essential polycythemia, polycythemia vera, ovarian carcinoma, selected cases of colorectal cancer, and squamous cell carcinoma of the head and neck. In fact, the agent’s ease of administration, impressively low toxicity, and relatively low cost make it an attractive drug to utilize in appropriate clinical situations. The inhibition of ribonucleotide reductase, and thus interference with DNA synthesis, may be critical for the anticancer effects of this drug; other mechanisms (such as direct inhibition of thymidine kinase and DNA polymerase), may also be operative.
Although it should be recognized that hydroxyurea can be toxic, it is still considered quite safe for therapeutic use. Safety can usually be achieved via adjustments in dosage and in frequency of administration. Some of the adverse events commonly associated with hydroxyurea are stomatitis (up to 20%), nail pigmentation, febrile reactions, and nonspecific maculopapular drug eruptions.[4-6] Despite the fact that hydroxyurea is contraindicated in pregnancy due to the drug being a known mutagen and teratogen in animals, inadvertent administration during human pregnancy has not been reported to cause significant problems.
A well-known side effect rather characteristic of hydroxyurea is the development of extremely painful cutaneous ulcerations. In two large retrospective studies, this phenomenon occurred in 3% of 993 patients and in 3.4% of 3,411 patients, respectively.[5,6] The majority of such lesions occur at or near the malleoli or on the pretibial area of the leg. There is a slight preponderance of women developing these ulcerations, and such lesions typically occur after several to many years of drug administration.[5,6,8,9] In some instances, reduction in drug dose, along with topical wound care, will result in lesion resolution. However, in the majority (50% to 75%) of patients, the drug must be permanently discontinued before healing can occur; under these circumstances, resolution requires an average of 4 to 5 months.[5,6,8,9] Nonetheless, even after drug cessation, split-thickness skin grafting may be required for complete re-epithelialization to occur.