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.
- 1978-1984: In 1978, chromosome number of leukemia cells was determined. Eventually the chromosome number was found to have prognostic significance in childhood ALL. Chromosome number is the "ploidy" of leukemia cells; hyperdiploidy was associated with a good prognosis. In 1981, the Philadelphia chromosome was first described in adult ALL. In 1984, researchers at St. Jude identified the first two phenotype-specific chromosomal translocations in childhood ALL, (t(1;19)(q23;p13.3) and t(11;14)(p13;q13). Specific chromosomal translocations were determined to be associated with a worse prognosis.
- 1984-88: The St. Jude Total Therapy XI protocol became the first childhood ALL treatment plan in which chromosomal translocations or hyperdiploidy were used to direct the patients to a high- or low-risk protocol. (Low-risk had less aggressive therapy.)
- 2000-2007: ETV6- RUNX1 fusion (also known as TEL-AML1) directs patients to less-aggressive therapy. MRD (minimum residual disease) assays are developed to measure very low levels of disease in bone marrow samples, and if MRD is found after week 6 of treatment, treatment is intensified. MRD in patients with Ph+ containing the BCR-ABL1 fusion directs them to stem cell transplants (and more recently imatinib treatment - which targets ABL tyrosine kinase).
- During this same time period, COG protocols similar concept-driven protocols as the St. Jude protocols. Childhood ALL claims a greater than 85% cure.
- 2007-present: Dasatinib (which targets ABL tyrosine kinase) is used to treat Ph-chromosome containing the BCR-ABL1 fusion. Pre-B ALL with the t(1;19) chromosomal translocation, now known as the TCF3-PBX1 fusion, show an increased risk of CNS relapse. St. Jude begins to assign patients with this marker to intensive intrathecal chemotherapy.
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.
- IKZF1 alteration is a hallmark of two high-risk ALL subtypes: Philadelphia chromosome (BCR-ABL1)-positive ALL and a new subtype termed "BCR-ABL1-like" ALL.
- "Among genetic abnormalities identified in BCR-ABL1-like cases, EBF1-PDGFB or NUP214-ABL1 fusions responded to ABL tyrosine kinase inhibitors (which also inhibit PDGFB), and BCR-JAK2 or mutated IL7R responded to a JAK2 inhibitor in preclinical studies." (Direct quote from Evanset al article, and this article is cited: Roberts, K.G. et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22, 153–166, 2012. This article in turn is discussed on my New Treatments page.)
- The CRLF2 rearrangement is present in about 8% of childhood ALL cases, many of which are Down syndrome patients. About half the patients with CRLF2 rearrangements have mutations in JAK1 or JAK2, leading to a COG phase I trial for ruxolitinib, a JAK inhibitor.
- In early T-cell ALL (precursor T-cell), researchers can now describe a sub-type similar to myeloid leukemia, suggesting "epigenetic therapy".
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."