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.
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.
Authors: Clet Niyikiza; Sharyn D Baker; David E Seitz; Jackie M Walling; Katrina Nelson; James J Rusthoven; Sally P Stabler; Paolo Paoletti; A Hilary Calvert; Robert H Allen Journal: Mol Cancer Ther Date: 2002-05 Impact factor: 6.261
Authors: C O Rodriguez; W Plunkett; M T Paff; M Du; B Nowak; P Ramakrishna; M J Keating; V Gandhi Journal: J Chromatogr B Biomed Sci Appl Date: 2000-08-18
Authors: David S Miller; John A Blessing; Carolyn N Krasner; Robert S Mannel; Parviz Hanjani; Michael L Pearl; Steven E Waggoner; Cecelia H Boardman Journal: J Clin Oncol Date: 2009-03-30 Impact factor: 44.544
Authors: V J Chen; J R Bewley; S L Andis; R M Schultz; P W Iversen; C Shih; L G Mendelsohn; D E Seitz; J L Tonkinson Journal: Br J Cancer Date: 1998 Impact factor: 7.640