Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology.

Schmiegelow, Kjeld; Schrøder, Henrik Daa; Gustafsson, G; Kristinsson, Jakob; Glomstein, Anders; Salmi, Toivo T.; Wranne, L

doi:10.1200/jco.1995.13.2.345

Cited by 134 publications

(93 citation statements)

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“…Once the model is identified for a cancer, predictions could be made (as exemplified in this paper) on an individual basis for incoming patients. As mentioned early, the clinically related studies by Lillyman and Lennard 13 and Schmiegelow et al 22 and the in vitro work of Bo¨kkerink et al 3 hint at the positive relationship between metabolite levels, the corresponding death rates, and the resulting probability of cure. By modeling this system, the appropriate durations of treatment or treatment adjustments can be made quantitatively for individual patients.…”

Section: Discussionmentioning

confidence: 93%

“…As an example, an extended period (up to 2 years) of maintenance chemotherapy has been shown to be necessary for prolonged remission of childhood acute lymphoblastic leukemia. 13 High drug metabolite levels are associated with a decreased risk of relapse 22 and increased cytotoxicity in vitro. 3 To assist with the design of the optimal treatment strategies, mathematical models have been used to estimate cancer cell populations and the response to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

et al. 2007

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Abstract-The objective of chemotherapy is to eradicate all cancerous cells. However, due to the stochastic behavior of cells, the elimination of all cancerous cells must be discussed probabilistically. We hypothesize, and demonstrate in the results, that the mean and standard deviation of a cancer cell population, derived through the probabilistic interpretation of population balance equations, are sufficient to estimate the likelihood of cancer eradication. Our analysis of a binary cell division model reveals that an expected cancer population that is six standard deviations less than one cell provides a good estimate for the treatment durations that nearly ensures treatment successes. This approximation is evaluated and tested on two other physiologically likely scenarios: variable patient response to chemotherapy and the presence of a dormant population. We find that early identification of individual patient susceptibility to the chemotherapeutic agent is extremely important to all patients as treatment adjustments for non-responders greatly enhances their likelihood of cure while responders need not be subjected to needlessly harsh treatments. Presence of a dormant population increases both the required treatment duration and population variability, but the same estimation method holds. This work is a step toward using stochastic models for a quantitative evaluation of chemotherapy.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

et al. 2007

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“…It is likely that improved identification of unfavourable chromosomal aberrations, 18 differences in drug sensitivity, 19 pharmacological profiles 8 and PCR and/or flowcytometry monitoring of residual disease (ie treatment response) 20,21 may identify those patients who should be upgraded to treatment intensification or even allogeneic stem cell transplantation in first remission. Effective therapy other than BMT is still lacking for patients with WBC Ͼ200 × 10 9 /l, high-risk chromosomal aberrations, and for some of the infants.…”

Section: Discussionmentioning

confidence: 99%

“…Patients in the latter group were recommended to have their dose of oral 6-Mp and/or Mtx increased until the erythrocyte levels of 6-Mp and Mtx metabolites reached a certain level or their white cell count fell below 1.5 × 10 9 /l. 8 …”

Section: Treatmentmentioning

confidence: 99%

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Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation

et al. 2000

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In this population-based material from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2860 children below 15 years of age were diagnosed with acute lymphoblastic leukemia (ALL) from July 1981 to June 1998. The annual incidence was 3.9/100 000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification with multidrug chemotherapy, including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. The overall event-free survival (EFS) at 5 years has increased from 56.5 ± 1.7% in the early 1980s to 77.6 ± 1.4% during the 1990s. The main improvements were seen in children with non-high risk leukemia. In high-risk patients, progress has been moderate, especially in children with high WBC (у100 × 10 9 /l) at diagnosis. During the last time period (January 1992-June 1998), only 10% of the patients have received cranial irradiation in first remission, while 90% of the patients have received pulses of high dose methotrexate (5-8 g/m 2 ) isolated or combined with high-dose cytosine arabinoside (total dose 12 g/m 2 ) plus multiple intrathecal injections of methotrexate as CNS-targeted treatment, not translating into increased cumulative incidence of CNS relapse. Leukemia (2000) 14, 2267-2275.

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Systemic Exposure to Thiopurines and Risk of Relapse in Children With Acute Lymphoblastic Leukemia

et al. 2015

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Importance Variability in prescribed 6-mercaptopurine and lack of adherence to 6-mercaptopurine could result in intra-individual variability in systemic exposure to 6-mercaptopurine (measured as erythrocyte thioguanine nucleotide levels) in children with acute lymphoblastic leukemia. The impact of intra-individual variability in systemic exposure to 6-mercaptopurine on relapse risk is unknown. Objective To determine impact of high intra-individual variability in 6-mercaptopurine systemic exposure on relapse risk in children with acute lymphoblastic leukemia. Design Prospective longitudinal design; daily adherence monitoring, 6-mercaptopurine dose-intensity and erythrocyte thioguanine nucleotide levels (pmol/8*10^8 erythrocytes) measured for 6 consecutive months per patient; cohort followed for a median of 6.7 years from diagnosis. Setting Children’s Oncology Group study (COG-AALL03N1); 94 participating institutions; ambulatory care setting. Participants Participants included 742 children meeting the following eligibility criteria: diagnosis of acute lymphoblastic leukemia at ≤21 years; in first continuous remission at study entry; receiving self/parent/caregiver-administered oral 6-mercaptopurine during maintenance. Median age at diagnosis: 5 years; 68% were male; 43% with NCI-based high-risk disease. Main Outcome Measures Adherence measured electronically using Medication Event Monitoring System that recorded date/time of each 6-mercaptopurine bottle opening; adherence rate defined as ratio of days of 6-mercaptopurine bottle opened to days when 6-mercaptopurine prescribed. 6-mercaptopurine doses actually prescribed were divided by planned protocol doses (75mg/m2/day) to compute average monthly dose-intensity. Electronically-monitored adherence (68,716 person-days), 6-mercaptopurine dose-intensity (120,439 person-days) and monthly erythrocyte thioguanine nucleotide levels (n=3,944 measurements) contributed to the analysis. Using intra-individual coefficients of variation (CV %), patients were classified as having stable (CV % <85th percentile) vs. varying (CV % ≥85th percentile) indices. Results Adjusting for clinical prognosticators, patients with 6-mercaptopurine non-adherence (mean adherence rate <95%) were at a 2.7 fold increased risk of relapse (95% confidence interval [CI], 1.3 to 5.6, p=0.01). Among adherers, high intra-individual variability in thioguanine nucleotide levels contributes to increased relapse risk (HR=4.4, 95% CI, 1.2 to 15.7, p=0.02). Furthermore, adherers with varying thioguanine nucleotide levels had varying 6-mercaptopurine dose-intensity (OR=4.5, p=0.006) and 6-mercaptopurine drug interruptions (OR=10.2, p=0.003). Conclusions and Relevance These findings emphasize the need to maximize 6-mercaptopurine adherence and maintain steady thiopurine exposure to minimize relapse in children with acute lymphoblastic leukemia.

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Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology.

Abstract: The pharmacokinetics of MTX and 6MP may have significant influence on the risk of relapse. The value of dose adjustments by E-MTX and E-6TGN remains to be determined.

Cited by 134 publications

References 28 publications

Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation

Systemic Exposure to Thiopurines and Risk of Relapse in Children With Acute Lymphoblastic Leukemia

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