A phase I study of pemetrexed in patients with relapsed or refractory acute leukemia.

PURPOSE: To investigate the toxicity profile, activity, pharmacokinetics, and pharmacodynamics of pemetrexed in leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute leukemia were eligible. A phase I 3+3 design was implemented. Pemetrexed was infused intravenously (IV) over 25 min with vitamin supplementation. Courses were repeated every 3 to 4 weeks according to toxicity and efficacy. The starting dose of 900 mg/m² was escalated by approximately 33% until the dose-limiting toxicity (DLT) was determined. RESULTS: Twenty patients with acute myeloid (AML) or lymphocytic (ALL) leukemia received therapy. The main non-hematologic adverse event was liver dysfunction at several dose levels, including 2 DLTs at 3,600 mg/m². One patient with ALL (3,600 mg/m² dose level) achieved a partial response. Pemetrexed pharmacokinetics were linear with escalated dosing. Elevated plasma deoxyuridine was observed in a subset of patients following pemetrexed infusion, but was not correlated with dose levels. Changes in the nucleotide pools of circulating mononuclear cells were observed, but were variable. CONCLUSIONS: The recommended phase II dose of pemetrexed for future leukemia studies is 2,700 mg/m(2) IV over 25 min every 3 to 4 weeks with vitamin supplementation. Deoxyuridine levels did not increase with increasing pemetrexed dose, suggesting pemetrexed inhibition of thymidylate synthase (TS) may be saturated by the 900 mg/m² dose level. However, no firm conclusion can be made regarding TS saturation in tumor cells. While tolerable, pemetrexed monotherapy had limited activity in this highly refractory population. Exploration of pemetrexed in combination with other active agents in leukemia is a reasonable future endeavor.

Causes of death at autopsy in an inpatient hospice program.

BACKGROUND: Although postmortem examination has been reported in a variety of settings and diseases, the medical literature only makes sparse mention of postmortem findings regarding the manner of death in terminally ill patients receiving palliative care. We sought to identify causes of death in an inpatient hospice program as determined by autopsy. METHODS: A retrospective chart review of all deaths from January 1998 through June 2000 of the inpatient hospice unit at Audie L. Murphy Veterans Affairs Hospital in San Antonio, Texas, was conducted. Autopsies were routinely offered to survivors of all deceased patients during this period. Basic demographic and clinical characteristics were collected for all patients, and pathologic reports were reviewed. RESULTS: Forty-eight autopsies were conducted out of 260 deaths in the unit (18%). Patients who had autopsies were similar to nonautopsied patients in age, gender, length of stay, presence of cancer and whether this cancer was treated or not. Nonhispanic white patients were more likely to receive an autopsy and African American patients were less likely to receive one (p = 0.027). Most deaths were directly or indirectly related to the primary diagnosis. Pneumonia was present in 79% of all patients (n = 38), and appeared to be the major cause of death in 44% of patients (n = 21). Other deaths were determined to be due to cancer's direct effects, sepsis, ischemic heart disease, hepatic or renal failure, obstructive uropathy, subdural hemorrhage, pulmonary embolism, hypercalcemia and endocarditis. CONCLUSION: Pneumonia is the most frequent cause of death in patients in this inpatient hospice program.