Predictive markers for haematological toxicity of pemetrexed

Our plain-English summary of Predictive markers for haematological toxicity of pemetrexed, by S.C. Kao, V.H. Phan, S.J. Clarke (Current Drug Targets, 2010).

The study

• Authors: S.C. Kao, V.H. Phan, S.J. Clarke
• Journal: Current Drug Targets
• Published: 2010;11(1):48-57
• Type of article: Review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pemetrexed is a multi-targeted anti metabolite that inhibits several key folate-dependent enzymes in the thymidine and purine biosynthetic pathways, including thymidylate synthase. It is currently approved for use in patients with non-small cell lung cancer and malignant mesothelioma. The sporadic and unpredictable occurrence of haematological toxicities of pemetrexed leading to potentially life threatening complications during the early developmental phase, prompted urgent need to identify potential predictive factors for haematological toxicities from pemetrexed. There is a well established association between elevated plasma homocysteine concentration, which is indicative of impaired functional folate status, and increased risk of haematological toxicity from pemetrexed. The decrease in incidence of toxicity after vitamin supplementation confirms the importance of functional folate status as a predictor for haematological toxicity. We review other factors that have a documented impact on haematological toxicity, including pemetrexed schedule, and pharmacokinetic parameters that are indicative of the extent of drug exposure. Further potential factors are explored in this review, such as the genotype of the pemetrexed metabolising enzymes and varying incidences of polymorphism of these genotypes in different ethnic groups that may account for the ethnic differences in neutropenic response to pemetrexed.

In plain English

This article was a review, not a new study. The authors reviewed research on what predicts blood-related (haematological) side effects, such as low white blood cell and platelet counts, from pemetrexed. Pemetrexed is a chemotherapy drug approved for non-small cell lung cancer and, with cisplatin, for malignant pleural mesothelioma. The article did not study asbestos exposure. In one reviewed study of 246 patients, high blood homocysteine before treatment, a sign of poor folate status, independently predicted severe drops in neutrophil and platelet counts. After routine folic acid and vitamin B12 supplements were introduced, the drug-related death rate across pemetrexed trials fell from 4.1% to 1.4%. In a phase III mesothelioma trial of pemetrexed with cisplatin, grade 3/4 neutropenia occurred in 41.4% of non-supplemented or partially supplemented patients and in 23.3% of fully supplemented patients. Reviewed studies linked toxicity to the amount of drug in the blood, the dosing schedule and, in a pooled analysis, older age. The authors concluded that high homocysteine signalled high risk and that supplementation improved safety. They said genetic, ethnic and other factors need further prospective study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published clinical, pharmacokinetic, laboratory and animal studies on predictors of haematological toxicity of pemetrexed
• Who was studied: No new patients were studied. The reviewed studies included phase I, II and III trials of pemetrexed in cancer patients (including malignant pleural mesothelioma and non-small cell lung cancer), pooled analyses, mouse experiments and cell studies.
• Exposure: The chemotherapy drug pemetrexed, at different doses and schedules, with and without folic acid and vitamin B12 supplementation. Pemetrexed was approved for non-small cell lung cancer (alone or with cisplatin) and for malignant pleural mesothelioma in combination with cisplatin. The article does not address asbestos or any fiber exposure.
• Main results:
  • In a reviewed study of 246 patients not given vitamin supplements (Niyikiza), elevated pre-treatment plasma homocysteine independently predicted severe thrombocytopenia and neutropenia.
  • Across all pemetrexed clinical studies, the drug-related death rate fell from 4.1% to 1.4% after routine vitamin supplementation was introduced.
  • In a reviewed phase III trial of pemetrexed plus cisplatin in malignant pleural mesothelioma, grade 3/4 neutropenia occurred in 41.4% of non-supplemented or partially supplemented patients and in 23.3% of fully supplemented patients (p=0.011).
  • In a reviewed phase II mesothelioma study (43 supplemented, 21 non-supplemented patients), supplemented patients completed a median of 6 cycles of therapy and non-supplemented patients a median of 2.
  • In phase I trials, myelotoxicity depended on the dosing schedule: the maximum tolerated dose was a total of 20 mg/m2 on the daily-for-5-days schedule and 600 mg/m2 on the single dose every 3 weeks schedule.
  • In a reviewed phase I study using the 3-weekly schedule, haematological toxicities correlated with drug exposure (dose, peak plasma concentration and AUC).
  • In a pooled analysis of 764 patients from 3 phase III trials, grade 4 toxicity occurred in 25.8% of elderly patients and 17.0% of younger patients (p=0.005).
  • A reviewed population model study noted that Japanese patients had a smaller neutropenic response to pemetrexed than Western patients.
• The authors' conclusion: The authors concluded that patients with elevated baseline homocysteine, alone or with elevated methylmalonic acid, had a high risk of severe haematological toxicity whatever their vitamin supplementation status, and that vitamin supplementation lowers homocysteine and improves the safety of pemetrexed. They also concluded that drug exposure and dosing schedule appear to predict toxicity, and that genetic and ethnic factors require further prospective study.
• Limitations the authors state:
  • The authors stated that age, performance status, baseline neutrophil count and tumour biomarkers as predictors need further validation in large prospective trials.
  • The authors noted that the population model used in the Latz studies was based on plasma drug levels and did not account for the drug's processing inside cells (polyglutamation).
  • The authors noted that clinical data linking thymidylate synthase variants or expression to pemetrexed toxicity are very limited.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Malignant Mesothelioma.

Related studies

• Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations — A. Corrigan, J.L. Walker, et al. (2014)
• Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma — D.E. Lustgarten, C. Deshpande, et al. (2013)
• Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy — G. Toyokawa, M. Takenoyama, et al. (2014)
• "One marker does not fit all": additional translational and validation studies are needed to identify faithful predictors of pemetrexed activity in mesothelioma — E. Giovannetti, G.J. Peters, et al. (2013)
• The current state of pemetrexed in ovarian cancer — R.E. Miller, S. Banerjee (2013)
• Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors — A.R. Hanauske, V. Chen, et al. (2001)

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