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Clinical Trials/Protocols for the Treatment of Childhood ALL

Note: This section has health/medical information. It was not written by a health care professional. The medical references are:

Most children diagnosed with ALL enroll in a clinical trial or follow a standard treatment protocol (that itself is designed by past clinical trials). Historically, childhood ALL was the first childhood cancer to be treated systematically with chemotherapy and radiation in clinical trials; today, childhood ALL patients still enter clinical trials more often than do adult cancer patients. An excellent history of ALL treatment is available online: The Cure of Childhood Leukemia. Because of the success of past clinical trials, and because of the parents who enrolled their children in them, today most children with ALL are cured.

Most ALL clinical trials in North America are offered by the COG (Children's Oncology Group). Before there was COG, there was CCG (Children's Cancer Group) and POG (Pediatric Oncology Group); these two groups merged into COG in 1999. As of 2005, many children still follow CCG or POG trials that were designed about the time of the merger, and those trials still have the POG or CCG designation; the newest COG trials are designated "AALL". The majority of children's hospitals offer COG trials; St Judes and Dana Farber are notable exceptions in that they write their own slightly different trials.

You will probably be offered the choice to enroll in a randomized clinical trial or to follow the standard treatment for your child's type of ALL. That is always a difficult decision. Even after a parent has enrolled their child in a trial or has agreed to a particular protocol, they do have the right to change the treatment plan. If you research your child's cancer and find that you are not comfortable with the treatment plan, you should discuss this with the health care team and/or with oncologists at other hospitals. Please see the childhood cancer clinical trial page on this site for general information on clinical trials.

Should you enter your child in a clinical trial?

Parents new to ALL are usually asked by their child's oncologist to either enter an investigative study or use the current "best" protocol. It's a hard decision to make, especially without any knowledge of ALL treatment. If you decide to go with the investigative study, your child might get more chemo than necessary, or he/she might not get enough chemo. Maybe the investigative protocol will be better than standard treatment, maybe not. How can you sign an "informed consent" form in such a situation? In the past ALL trials, this decision had to be made within 72 hours; today parents get about a month to make the decision.

Parents of children diagnosed with leukemia discussed this topic and allowed their comments to be posted on the Web page below. We hope it helps other parents.

Prognosis Factors

At the initial diagnosis, certain characteristics of your child's ALL determine whether it is low- or high-risk. Lower risk ALL is treated with less aggressive treatment than is higher risk. Less aggressive means less chemotherapy and fewer different chemotherapy agents.

Prognosis factors determine the treatment plan for your child's ALL. Some prognosis factors are known right away, some are found out as your child's disease is treated and the response to treatment is monitored.

Please: Do not panic if you find a "less favorable" in the details of your child's cancer. It's just that, less favorable, it is not a prediction of failure. It is, however, likely to mean that your child will undergo a more intense treatment. The outcome is likely to be the same: event free survival. More on this in the author's essay.

Prognostic factors change over time. In the 1990s, age, type of leukemia (phenotype), and white blood cell counts at diagnosis were the major determining factors. By the late 2000s, certain cytogenetic factors (molecular characteristics of the ALL) and response to treatment as measured by MRD (Minimum Residual Disease, the number of leukemia cells that can be detected) became the prognostic factors of interest.

age

Younger age is considered a good prognosis factor, except for under 1 year of age, which is considered unfavorable. Currently, an age of 1-9 is required to be considered standard risk, while ages 10-30 is higher risk. (NCI risk designation.)

WBC, or white blood count, at diagnosis

High WBC at diagnosis is considered unfavorable. WBC must be less than 50,000/microliter to be considered standard risk. (NCI risk designation.)

phenotype

B-precursor is considered standard risk, while T-cell leukemia is put on a separate protocol (a protocol that is somewhat more aggressive but also incorporates certain tactics/drugs that have been shown particularly effective in treating T-cell ALL). Please see the ALL cell type page on this site to learn how they classify ALL.

age/WBC/phenotype/treatment response combined

COG has different tracks of clinical trials, LR ALL, SR ALL, HR ALL, infant ALL, VHR, and T-cell ALL. As of 2011, Ph+ patients go to a separate trial. Within each trial are different arms, either randomized or specified according to how the child's ALL responds to treatment. (2011)

NCI standard risk ALL, or SR ALL: B-precursor and WBC less than 50,000/microliter and age 1-9 years

NCI higher risk ALL, or HR ALL: B-precursor and WBC greater than or equal to 50,000/microliter or age greater or equal to 10 years

AR and LR and VHR patients are determined first according to the NCR SR and HR values, and then according to response to treatment and certain genetic factors of the ALL. These values cannot be determined at day one of diagnosis, so patients begin induction and wait for the results to come in.

A patient who is NCI HR can never be a LR patient, even if they respond well to treatment (e.g., MRD zero at day 29) and do not have any known negative genetics features.

COG infant ALL: less than 1 year is classified separately and goes to a specific protocol, COG-AALL0631 (2011).

COG T-cell: has its own protocol in COG, COG 0434, this trial incorporated Nelarabine and radiation; also see Treatment of T-Cell Leukemia (May 2003), a slide and transcript presentation.

CNS disease

CNS disease means that at diagnosis there are detectable leukemia cells in the cerebral spinal fluid, usually defined as more than 5 white blood cells per microliter. SR or HR ALL patients get additional spinal fluid treatment, dexamethasone, and radiation.

CNS disease will direct patients to a higher risk classification.

MRD, or Minimal Residual Disease

MRD is covered in a separate section on this web site: MRD in ALL. Briefly, it means that the tests for leukemia cells they have today are more sensitive than the old tests, and therefore they can now detect very low levels of leukemia in the patients. Currently in COG trials (2011), if they find a certain level of MRD after 28 days of induction therapy, the child is put on a more or less aggressive arm of the protocol. The critical value is 0.01% in a bone marrow sample, measured at day 29.

response to treatment: RER and SER

These definitions were used in the older COG trials (1990s-early 2000s). RER stands for rapid early responder and SER stands for slow early responder. RER basically means in remission by day 15, with remission defined in the old-fashioned way as less than 5% blasts in the bone marrow and the new-fashioned way as MRD negative by day 29. SER means it takes longer to get into remission. RER patients would get less aggressive treatment. If a patient is not in remission after 4 weeks of induction treatment, they would be put on a very aggressive protocol.

testicular disease

Boys with testicular disease are directed to more aggressive arms of protocols and/or are given radiation.

trisomies of 4, 10 and 17 or the ETV6-RUNX1 (or TEL-AML1) translocation

These are favorable cytogenetics and are necessary for the very lowest risk ALL protocol (and only if they qualify for that trial by age/WBC/phenotype).

MLL rearrangements, the BCR-ABL fusion transcript, t(9;22)(q34;q11) (PH+), or less than 44 chromosomes (hypodyploid)

These are unfavorable cytogenetics. In the case of MLL, if the child is a RER, he or she will be directed to an aggressive arm of the protocol; the t(9;22) or hypodiploid factors cause them to be directed to a different, more aggressive protocol. Hyperdiploid is a favorable prognostic factor.

gender

Males are considered higher risk than females, and are given the same treatment plans except that the maintenance treatment for males lasts up to a year longer.

Basic design of ALL clinical trials

"Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen." Thus reads the NCI on the cancer.gov ALL treatment page. Treatment includes systemic chemotherapy and treatment of the CNS (central nervous system); these are covered in the ped-onc medical procedures section.

A clinical trial is an investigative study, and that sounds a little scary at first. But it's not really a big chance you are taking with your child's life, as long as it is a phase III trial. Phase III trials are essentially attempts to fine-tune the current standard protocol.

Below is a very brief description of the design of ALL clinical trials. Please follow the following link to read the details of current and past clinical trials for ALL:

Induction generally lasts 4 weeks and includes 3 or 4 chemotherapy agents. Induction should get most children into remission.

Consolidation directly follows induction and is an intensification of treatment and can last 4-7 weeks.

Interim maintenance lasts about 8 weeks. Maintenance is a less-intense phase of treatment.

Delayed intensification is similar to induction/consolidation treatment. Some protocols have one delayed intensification, some have two with an interim maintenance between them.

Maintenance therapy begins after the last delayed intensification and continues until the total duration of therapy is 2-3 years.

If a child fails to go into remission by the end of induction, they are moved to a very aggressive protocol, that can include bone marrow transplant. Relapsed ALL is treated on trials designed specifically for relapsed ALL.

Special Topic: 6MP and TPMT

Some children are very sensitive to 6MP or 6-mercaptopurine, one of the drugs used throughout treatment for ALL. TPMT (thiopurine methyltranserase) is the enzyme that metabolizes 6MP (and 6TG) and some people have forms of this enzyme that do not work very well. The lower the TPMT activity, the greater is the exposure of the child to active 6MP, in other words, if your has a low TPMT activity, he/she is not able to break down the 6MP and thus it hangs around and keeps killing cells including their blood cells that fight infection. The symptoms of this are that the ANC plummets after the first dose of 6MP, possible to extremely low levels, resulting in serious infections.

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). Your child can be tested for TPMT deficiency; the test costs a little money and hopefully her oncologist will order the test.

An article on TPMT appeared in the Fall 2003 Candlelighters quarterly journal.

New Drugs/Treatment Strategies for ALL

What is in the pipeline for new treatments for ALL? I began in 2002 a collection of new drugs or new strategies for the treatment of childhood ALL. The list became so long that I moved it to another website (the website that I author for the ALL-kids email list, www.all-kids.org). Also see the targeted therapies and genetic alterations/TARGET articles I wrote:

General Disclaimer

These pages are intended for informational purposes only and are not intended to render medical advice. The information provided on Ped Onc Resource Center should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you suspect your child has a health problem, you should consult your health care provider.

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