978P - Correlation of pharmacokinetics of 6MP and its metabolites with haematological toxicity: Step towards development of pharmacokinetics based model f...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Leukaemia
Pharmacology
Presenter Manju Sengar
Citation Annals of Oncology (2014) 25 (suppl_4): iv327-iv339. 10.1093/annonc/mdu339
Authors M. Sengar1, V. Gota2, S. Rath2, H. Jain1, H. Menon3, U. Dangi1, M. Gurjar2, K. Jadhav1
  • 1Medical Oncology, Tata Memorial Hospital Centre, 400012 - Mumbai/IN
  • 2Clinical Pharmacology, Tata Memorial Centre, 40012 - Mumbai/IN
  • 3Medical Oncology, Tata Memorial Hospital, 40012 - Mumbai/IN

Abstract

Aim

Dosing of 6MP has remained empirical in acute lymphoblastic leukemia (ALL) with leucocyte count and thiopurine methyl transferase (TPMT) being the main determinants. However, TPMT alone cannot predict for marked inter-individual differences. In our experience, adult ALL patients tolerate standard 6- MP doses poorly, resulting in frequent dose interruptions or subtherapeutic doses. To address this issue we are conducting a study to develop pharmacokinetic model (PK) for optimal 6 MP dosing. Herein we report the preliminary data for correlationof PK parameters of 6 MP and its metabolites with toxicity (dose interruptions and dose reduction).

Methods

Adult ALL patients (18 years or more) who were receiving 6 MP during interim maintenance (IM)or maintenance (M) phase of MCP841 protocol were enrolled after informed consent. Plasma samples were collected on day 1 for measuring 6-mercaptopurine levels using HPLC. TPMT activity was calculated by measuring 6-mMP (6-methylmercaptopurine) and 6-methyl thioguanine nucleotides (6-mTGN) levels in erythrocytes on day 1.Levels for 6-mMP and 6-TGN were also measured in erythrocytes using HPLC on day 8 and day 22 of the IM and on day 1 of M phase upto 6 months post enrollment. Statistical analysis was performed with receiver operating characteristic curve to assess the discrimination potential of level of 6-mp, 6-mMP (day 8 and day 22), 6-TGN (day 8 and day 22), 6-mMP and 6-mTGN levels (day 1-IM) for toxicity. Mean AUC has been compared for the above parameters using Mann-Whitney test. Binomial logistic regression was performed to assess correlation of various covariates with the toxicity.

Results

29 patients (males-24, females-5) with median age of 28 years (range,16-50) were enrolled.14 patients experienced dose interruptions (median-1, range1-2)) and 10 required dose reduction due to grade 4 cytopenias. OnDay 22 levels, a concentration of 0.315 ug/ml for 6-mMP (AUC = 0.73, p = 0.2) and 0.17 ug/ml for 6-TGN (AUC = 0.92,p value =0.01)in erythrocytes could successfully discriminate between patients who suffered from toxicity. Day 8 levels were not discriminatory. Hemoglobin (p= 0.05) and TPMT activity (p = 0.08) were found to be significant covariates for toxicity.

Conclusions

Preliminary data does suggest the value of PK variables on 6 MP toxicity.

Disclosure

All authors have declared no conflicts of interest.