Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity from Pemetrexed Therapy 1 Clet Niyikiza, 2 Sharyn D. Baker, David E. Seitz, Jackie M. Walling, Katrina Nelson, James J. Rusthoven, Sally P. Stabler, Paolo Paoletti, A. Hilary Calvert, and Robert H. Allen Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285 [C. N., K. N., J. J. R., P. P.]; Cancer Treatment and Research Center (CTRC), University of Texas, San Antonio, Texas 78229 [S. D. B.]; Indiana University School of Medicine, Indianapolis, Indiana 46202 [D. E. S.]; Lilly Research Laboratories, Tularik Inc, South San Francisco, California 94080 [J. M. W.]; University of Colorado Health Sciences Center, Denver, Colorado 80220 [S. P. S., R. H. A.]; and University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom NE4 6BE [A. H. C.] Abstract The purpose of this study was to identify predictive factors for severe toxicity caused by antifolate- chemotherapy using pemetrexed (ALIMTA, LY231514), as a model. Data on potential predictive factors for severe toxicity from pemetrexed were collected from 246 patients treated between 1995 and 1999. Multivariate stepwise regression methods were used to identify markers predictive of severe toxicity. Using a multiple logistic regression model allowed us to quantify the relative risk of developing toxicities and to generate a validated clinical hypothesis on ways to improve the safety profile of pemetrexed. Pretreatment total plasma homocysteine (tHcy) levels significantly predict severe thrombocytopenia and neutropenia with or without associated grade 3/4 diarrhea, mucositis, or infection. Pretreatment methylmalonic acid (MMA) levels significantly and independently predict grade 3/4 diarrhea and mucositis; however, these toxicities are still predicted by tHcy alone. Patients with elevated baseline levels of tHcy alone, or of both tHcy and MMA, were found to have a high risk of severe toxicity that led us to postulate that reducing tHcy would result in a reduction of severe toxicity with no harm to efficacy. This study points out for the first time the importance of pretreatment tHcy levels in predicting severe toxicity associated with an antifolate and sets the stage for a prospective clinical intervention to protect patients from pemetrexed-induced severe toxicity and possibly improve the drug’s efficacy. Antifolates as a class have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. Although infrequent, a combination of such toxicities can carry a high risk of mortality. This phenomenon had been unpredictable until now. Our work shows that by measuring tHcy, one can identify patients that are at risk of toxicity before treatment. Most importantly, decreasing homocysteine levels via vitamin supplementation leads to a better safety profile of pemetrexed and possibly to an improved efficacy. Introduction In 1998, it was estimated that 90% of new anticancer agents designed in laboratories around the world never make it into routine clinical use (1). Three main reasons were put forth for this sobering statistic: (a) high toxicity seen with new agents that carry serious safety concerns; (b) lack of efficacy of these agents; and (c) a disconnect between the work of preclinical bench scientists and bedside clinicians that often reflected a failure to ensure that clinical trial designs for new agents were based on the best-known mechanism of action of the agent. Because most anticancer agents have a narrow therapeu- tic window, optimizing the chance that a treatment succeeds without causing undue harm to the patient is of paramount importance. Accurate information about both the new drug and the patient becomes critical. Interruption of development of a new drug or limitation of its effectiveness or wide use occurs when either severe toxicity or lack of efficacy is noted. It is not unusual that, when a new agent shows toxicity with limited antitumor activity, little effort is made to persistently look for ways to circumvent the toxicity with the possibility of improving efficacy. Toxicity or lack of efficacy could be re- lated to a patient’s individual clinical, demographic, or ge- netic profile. Ideally, the goal is to devise a simple, optimal dosing strategy for a new agent that incorporates what is known about its mechanism of action and about the patient characteristics. This paradigm is the subject of the present study. We discuss how, after serious safety concerns arose, predictive factors for severe toxicity associated with pem- etrexed were identified, and how these factors led to the formulation of a clinical intervention to modulate the toxicity of this antifolate/anticancer agent while improving its effi- cacy. The results of this prospective clinical intervention are the subject of a separate upcoming publication. 3 Antifolates represent one of the most extensively investi- gated classes of antineoplastic agents, with aminopterin ini- tially demonstrating clinical activity more than 50 years ago (2). Methotrexate was developed shortly thereafter and, to- day, is a standard component of chemotherapeutic regimens effective for malignancies such as lymphoma, breast cancer, and head and neck cancer (3– 6). The cytotoxic activity and subsequent effectiveness of antifolates can be associated Received 3/1/02; revised 3/25/02; accepted 3/28/02. 1 Supported by Eli Lilly and Company. 2 To whom requests for reprints should be addressed, at Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. 3 J. Rusthoven, C. Niyikiza, P. Bunn, et al. Reducing toxicity from pem- etrexed therapy with folic acid and vitamin B 12 supplementation, submit- ted for publication. 545 Vol. 1, 545–552, May 2002 Molecular Cancer Therapeutics on December 2, 2021. © 2002 American Association for Cancer Research. mct.aacrjournals.org Downloaded from