Therapeutic drug monitoring of imatinib – how far are we in the leukemia setting?

Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and replaced hematopoietic stem cell transplantation (hSCT) as the key treatment option for these patients. More recently, the so-called Philadelphia chromosome-like (Ph-like) ALL has similarly benefitted from TKIs. However, many patients shift from the first generation TKI, imatinib, due to treatment-related toxicities or lack of treatment efficacy. A more personalized approach to TKI treatment could counteract these challenges and potentially be more cost-effective. Therapeutic drug monitoring (TDM) has led to higher response rates and less treatment-related toxicity in adult CML but is rarely used in ALL or in childhood CML. This review summarizes different antileukemic treatment indications for TKIs with focus on imatinib and its pharmacokinetic/-dynamic properties as well as opportunities and pitfalls of TDM for imatinib treatment in relation to pharmacogenetics and co-medication for pediatric and adult Ph+/Ph-like leukemias. TDM of imatinib adds value to standard monitoring of ABL-class leukemia by uncovering non-adherence and potentially mitigating adverse effects. Clinically implementable pharmacokinetic/-dynamic models adjusted for relevant pharmacogenetics could improve individual dosing. Prospective trials of TDM-based treatments, including both children and adults, are needed.</p

Clinical characteristics and registry-validated extended pedigrees of germline <i>TP53</i> mutation carriers in Denmark

<div><p>Introduction</p><p><i>TP53</i> mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.</p><p>Methods</p><p>We performed a nation-wide exploration of <i>TP53</i> mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.</p><p>Results</p><p>We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three <i>de novo</i> germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1–54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer <i>TP53</i> mutation carriers than the 300–1,100 expected based on estimated background population frequencies.</p><p>Conclusion</p><p>Germline <i>TP53</i> mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.</p></div

Clinical characteristics and registry-validated extended pedigrees of germline <i>TP53</i> mutation carriers in Denmark - Fig 1

<p>(A) Pedigrees of three Danish families harboring germline <i>TP53</i> mutations. (B) NM_000546 isoform of the <i>TP53</i> gene protein product showing the mutations found in this study (upper track) and all published mutations from the IARC database (lower track). In the upper track, 5 novel germline mutations described in this study are expanded. In the lower track, mutations from 9 loci in the IARC database are expanded, corresponding to the 9 non-novel mutation sites described in this study. 14 IARC mutations were left out as they were either complex (13) or not classified (1). Variant colors: blue, missense, orange, nonsense, purple, splice region, red, frameshift, green, silent, grey, protein deletion.</p

Clinical and mutational data of families with 36 confirmed or <i>obligate</i> germline <i>TP53</i> mutations carriers.

<p>Clinical and mutational data of families with 36 confirmed or <i>obligate</i> germline <i>TP53</i> mutations carriers.</p

IARC database characteristics of germline <i>TP53</i> mutations observed in both IARC and in this study (families with more than 10 confirmed carriers in the IARC database are in bold).

<p>IARC database characteristics of germline <i>TP53</i> mutations observed in both IARC and in this study (families with more than 10 confirmed carriers in the IARC database are in bold).</p

Datasheet1_Physician-defined severe toxicities occurring during and after cancer treatment: Modified consensus definitions and clinical applicability in the evaluation of cancer treatment.docx

Overall survival after cancer is increasing for the majority of cancer types, but survivors can be burdened lifelong by treatment-related severe toxicities. Integration of long-term toxicities in treatment evaluation is not least important for children and young adults with cancers with high survival probability. We present modified consensus definitions of 21 previously published physician-defined Severe Toxicities (STs), each reflecting the most serious long-term treatment-related toxicities and representing an unacceptable price for cure. Applying the Severe Toxicity (ST) concept to real-world data required careful adjustments of the original consensus definitions, translating them into standardized endpoints for evaluating treatment-related outcomes to ensure that (1) the STs can be classified uniformly and prospectively across different cohorts, and (2) the ST definitions allow for valid statistical analyses. The current paper presents the resulting modified consensus definitions of the 21 STs proposed to be included in outcome reporting of cancer treatment.</p

Additional file 1: of DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia

Methods description, figures, and tables can be found at the Clinical Epigenetics webpage. (DOCX 282 kb