ALL-kids

Childhood ALL Treatment as a Paradigm for Genomic Medicine Implementation (2013)

I was impressed with the wealth of information in this short article by researchers at St. Jude, so I wrote this summary so that I would remember the important points.

Article: A Health-Care System Perspective on Implementing Genomic Medicine: Pediatric Acute Lymphoblastic Leukemia as a Paradigm. Evans WE, Crews KR, Pui CH, Clin Pharmacol Ther, epub 2013 Jan 17.

The development of treatment for childhood ALL is an example of the power of participation in clinical trials. Countless parents have taken a big breath, and signed their child onto a clinical trial, often within hours of finding out that their child has cancer. This participation has resulted in one of the great success stories of cancer treatment: currently the cure rate for childhood ALL is close to 90%. The majority of US children with ALL receive contemporary therapy according to frontline studies at St. Jude or the Children's Oncology Group (COG).

This article is authored by researchers at St. Jude Children's Research Hospital, Memphis, Tennessee, USA, who began to use genomics to individualize the treatment of childhood ALL in the 1980s. The authors use the treatment of ALL to illustrate the process of translating genomics into diagnostics that guide treatment decisions, showing the great potential this holds for improving the outcome of human diseases. The protocols used are concept-driven, and are not compromised by short-term medical economics.

Milestones

Pharmacokinetics/pharmacokynamics

Not every patient's body responds the same to each chemotherapy drug. In other words, some patients are more or less sensitive to a particular drug. This is called "Pharmacokinetics and pharmacokynamics". How a patient will react to a drug can be determined by genetic testing before that drug is ever given to them.

In childhood ALL, the pharmacokinetics/pharmacokynamics of two drugs have been studied: 6-mercaptopurine (MP) and methotrexate (MTX). (Other drugs are also briefly discussed.) Codeine metabolism to morphine has been studied.

Mercaptopurine: The treatment team determines the patient's thiopurine methyltransferase genotype (TPMT; see my discussion on the ped-onc website). For some genotypes, a very small dose of MP causes the patient to become neutropenic. One in 300 individuals cannot break down 6MP at all because of their TPMT; 10% of the population can break it down a little (and will require only 50% 6MP dosing for the rest of the protocol). Guidelines are written for using TPMT status for dosing 6MP. Only St. Jude protocols test all patients before dosing with MP.

Methotrexate: St. Jude uses higher doses of MTX in T-cell patients and pre-B ALL with the TCF3-PBX1 fusion, and lower doses in patients with hyperdiploid ALL who "avidly accumulate MTX-polyglutamates in their leukemia cells." They have identified identified germline polymorphisms in SLCO1B1 that significantly influence MTX clearance.

Other drugs: Holleman et al found "de novo sensitivity of ALL cells to prednisolone, vincristine, asparaginase, or doxorubicin is related to the expression of 20–40 genes (per drug) in ALL cells, and that their expression pattern is drug specific and predictive of treatment outcome." (Holleman, A. et al. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N. Engl. J. Med. 351, 533–542, 2004). Another quote from this current article (Evans et al): "Moreover, multidrug cross-resistance (two or more drugs) was related to the expression of a different set of genes and identified patients at the highest risk of relapse." They are working on strategies for overcoming resistance by targeting one or more of these genes.

Codeine: In 2007, researchers at St. Jude began routinely testing for cytochrome P450 2D6 (CYP2D6). This is a polymorphic gene involved in codeine metabolism. Poor metabolizers are at high risk for NOT responding to codeine. Other patients are rapid metabolizers and are at risk for toxicity with codeine doses considered normal for the general population.

High resolution genome-wide analyses

I made an attempt at describing these analyses in my lay article on genetic profiling.

Currently, researchers use tests for gene expression, DNA copy-number alterations, and perform whole-genome sequencing on samples of leukemia cells of childhood ALL patients. They are finding both subsets of ALL with good or bad prognosis, and/or subsets that can be targeted by the new flood of targeted therapeutics on the market.

Of importance:

Here are two direct quotes from the last paragraphs of the article:

"Therefore, what was once considered a single disease, "ALL", is now known to comprise numerous subtypes when defined at the genetic level. Of note, every major treatment center for childhood ALL now uses these somatic DNA alterations in ALL cells as diagnostics to determine the treatment regimen for a child with ALL."

"As implementation of genomics into routine clinical practice progresses, results must be both available statically in the medical record and provided actively as alerts to clinicians at the point of care. To this end, we have instituted both passive clinical decision support such as result interpretations in our electronic health record, and active rules and alerts that alert clinicians only when a high-priority genotype and a prescription for a high-risk medication are both present."