Site Links

Reference

About this site

Section Links

Clinical Trials/Protocols for the Treatment of Childhood ALL

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.

Should We Enter a Clinical Trial?

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.

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.

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.

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 combined

COG has 4 tracks of clinical trials, SR ALL, HR ALL, infant ALL, and T-cell ALL. Each child is tracked at initial diagnosis according to age/WBC/phenotype to one of the 4 trials. Within each trial are different arms, either randomized or specified according to how the child's ALL responds to treatment. (2005)

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

COG 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

COG infant ALL: less than 1 year is classified separately and goes to a specific protocol

COG T-cell: has its own protocol in COG, COG 00P2, this trial incorporated ara G 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.

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 (2005), if they find a certain level of MRD after 28 days of induction therapy, the child is put on a more aggressive arm of the protocol.

response to treatment: RER and SER

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 get less aggressive treatment. If a patient is not in remission after 4 weeks of induction treatment, they are 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 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), 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:

ALL clinical trials

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.

Interesting article on ALL treatment

2005: MedScape has an article that talks about current ALL treatment. It's written for the lay person and discusses MRD, new drugs (ara G and clofarabine), and new tactics. This article may not stay online forever (a pre-apology for a potential broken link) and you need to be registered (free) with MedScape to view the article.

Acute Leukemia: Don't Throw Out the Old Therapies, Yet

New Drugs for ALL

A couple new drugs have been approved for ALL treatment, ara G (nelarabine, mainly for T-cell) and Clofarabine (Evoltra, made by Bioenvision, Inc; for relapsed ALL) (both on Sea to Ara C). Your best bet for finding new treatments will be to contact the COG, or search cancer.gov for clinical trials in phase I or II.

Articles on drugs in the pipeline:

Fodosine TM (BioCryst; also called forodesine hydrochloride or BCX-1777 or Immucillin-H) is "a transition-state analog inhibitor of the target enzyme purine nucleoside phosphorylase (PNP)" [from the BioCryst web site]. This means is that it is designed to stop PNP; note that ara G was also designed to inhibit PNP. PubMed abstract of August 2005 article in Blood. In Oct 2005, this drug was given orphan drug status for T-cell ALL (among other leukemias) and is in phase II trials. Fodosine, PNP Inhibitor, on the BioCryst web site Dec 2006.

Annamycin, a novel liposomal drug from the anthracycline family with potentially reduced cardiotoxicity, a patented liposomal formulation, and the potential to circumvent multi-drug resistance in ALL (from Callisto Pharmaceuticals, Inc.). 6/24/2005 -- Callisto Pharmaceuticals, Inc. announced today that the Office of Orphan Products Development of the United States Food and Drug Administration (FDA) has granted orphan drug designation to the company's drug candidate Annamycin for the treatment of acute lymphoblastic leukemia (relapsed). 12/05 -- clinical trial launched.

Tipifarnib (ZarnestraTM), a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. T-cell ALL potential

Dasatinib for Ph+ ALL.

Possible new tactics:

St. Judes: Genetic trick used to kill leukemia cells, "Natural killer (NK) immune system cells can be genetically modified to brandish a powerful “on” switch that prompts them to aggressively attack and kill leukemic cells, according to St. Jude researchers."

Acute Lymphoblastic Leukemia: Time for T. The indolocarbazole derivative CEP-701 selectively and potently kills cells derived from several childhood acute lymphoblastic leukemias (ALL) that overexpress the FLT3 gene, researchers report. (Other treatments listed in article; from ASH 2004 meeting. On MedScape.)

Evaluation of dendritic cells loaded with apoptotic cancer cells or expressing tumour mRNA as potential cancer vaccines against leukemia. Silvija Jarnjak-Jankovic, Rolf D Pettersen, Stein Sæbøe-Larssen, Finn Wesenberg and Gustav Gaudernack. BMC Cancer 2005, 5:20 Published 18 February 2005.

Targeting FLT3 in primary MLL-gene–rearranged infant acute lymphoblastic leukemia. Ronald W. Stam et. al. Blood, 1 October 2005, Vol. 106, No. 7, pp. 2484-2490. Abstract. FT3 might turn out to be a good target for targetted chemotherapy: "leukemic cells from infants with MLL were significantly more sensitive to the Fms-like tyrosine kinase 3 (FLT3) inhibitor PKC412 (N-benzoyl staurosporine) than noninfant ALL cells".

Oral Aminopterin for relapsed ALL. Aminopterin was used decades ago in ALL treatment but was replaced by methotrexate. Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia. Peter D. Cole et al., Clinical Cancer Research Vol. 11, 8089-8096, November 15, 2005.

Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. Haematologica. 2005 Dec;90(12):1701-3.

Rapamycin, a drug used to prevent rejection in transplant recipients, could show anti-leukemia activity in steroid-resistant cells, as indicated by gene expression connectivity maps. (Dana Farber) Presented at the Dec 2005 ASH meeting. Abstract.

Nilotinib. Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50. Abstract.

Dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). Abstract.

Researchers Uncover Clues That May Lead To Better Therapies For Children With T-Cell Acute Lymphocytic Leukemia. "Researchers' discovery of clues to the cause of T-cell acute lymphoblastic leukemia (T-ALL) could lead to the development of new targeted therapies for this extremely difficult disease. The researchers, led by Michelle Kelliher, PhD, of the University of Massachusetts Medical School, will report on their findings in the November issue of the journal Molecular and Cellular Biology. The researchers report that abnormal expression of one gene - Notch 1 - activates another gene - c-myc - which is a known cause of leukemia and lymphoma. Recent studies have shown that a majority of T-ALL cases carry mutations that abnormally activate the Notch 1 gene." Online article.

Antileukemic and Cytogenetic Activity by Triple Administration of Three Modified Steroidal Derivatives of Nitrogen Mustards. M.A. Fousteris, et al., Chemotherapy, Chemotherapy. 2007;53(2):118-26. Abstract.

Epratuzumab, a humanized monoclonal antibody against CD22. Used in phase II trials by COG. Abstract.

ABT-737 (Abbott Laboratories) acts by inhibiting the Bcl-2 family of proteins (these are expressed in ALL) and inhibit the mechanisms responsible for destroying ALL cells. When used in combination with common drugs administered in ALL therapy, ABT-737 has the ability to enhance the combined toxicity of these drugs against the leukaemia cells with minimal effects on the normal cells of the body. Abstract. (Not yet used in human trials, 2007.)

DMAPT (dimethylamino-parthenolide). The naturally-occurring compound, parthenolide (PTL), is found in feverfew or bachelor's button (daisies). PTL can induce the death of human leukemia stem ce, lls without killing normal cells. DMAPT is an analog of the naturally-occurring compound with an increased water solubility that shows the same anti-leukemia stem cell action in animal studies. Human trials (in England) are planned for AML and ALL patients. (2007) Link to Blood abstract. Link to lay article. Another lay article. Yet another lay article.

NOTCH 1: Oncogene and Achilles' Heel in T-ALL. A good article on possible new ways to treat T-cell ALL on the St. Judes Cure For Kids website. Free registration is required.

Immunomodulation against leukemias and lymphomas: A realistic future treatment? S. Mittal et al., Feb. 2008, Critical Reviews in Oncology/Hematology.

Stem cells for leukemia found. "The new research, published in the journal Science, shows that pre-cancerous stem cells arise from an abnormal fusion of two genes during the mother’s pregnancy to create a hybrid protein ‘TEL-AML1’. This genetic mistake can set in motion a series of events that cause the cells to become leukaemic." Lay article. Journal article: "Initiating and Cancer-Propagating Cells in TEL-AML1-Associated Childhood Leukemia." Dengli Hong et al, Science 18 January 2008: Vol. 319. no. 5861, pp. 336 - 339. Abstract. Another lay article from BBC news.

Flavopiridol displays preclinical activity in acute lymphoblastic leukemia. Flavopiridol (FP; Alvocidib) is an agent that affects the expression of cell cycle regulatory proteins. This article shows that FP kills ALL cell lines in culture. The research was funded by STOP cancer. (Ped Blood and Cancer, 2008)

T-cell ALL: "Not The Protein, But Its Location In The Cell, Determines The Onset Of Leukemia". Lay article. Journal article. "...the researchers want to further investigate the therapeutic possibilities of compounds that render binding between the complex and NUP214-ABL1 impossible. This study also indicates that the location of proteins can play an important role in other forms of cancer/leukemia as well." (Kinase activation and transformation by NUP214-ABL1 is dependent on the context of the nuclear pore. De Keersmaecker K et al. Mol Cell. 2008 Jul 11;31(1):134-42.

1/09 Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia. Charles G. Mullighan et al. NEJM published online January 7, 2009. Abstract. Full text available free online. NCI news release. This comes out of the targeted therapies intiative from NCI. target.cancer.gov Might lead to therapies targeted to the IKAROS gene.

Phase I trial for children/adolescents with refractory ALL. CAT-8015 proves promising in a child who failed 3rd remission. Trial information. CAT-8015 is an anti-CD22 immunotoxin (see this NIH page for more information).

Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Roman Crazzolara et al., Blood First Edition Paper, prepublished online February 4, 2009. Abstract. Rapamycin (mTOR) inhibitor, RAD001 (Everolimus). Encouraging results.

"These data indicate silvestrol has efficacy against B-cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias." The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. David M. Lucas et al., Blood First Edition Paper, prepublished online February 3, 2009. Abstract.

Helleborus niger, a plant extract, shows promise in killing leukemia cells in culture. 2009 Pediatric Blood and Cancer article abstract.

A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. T Ikezoe et al, Leukemia advance online publication 7 May 2009.

Blinatumomab, developed by Micromet. Lay article. PubMed abstract. June 2009: "Micromet announced that its antibody blinatumomab showed a high response rate in a phase 2 clinical study of acute lymphoblastic leukemia patients with minimal residual disease. Blinatumomab is a therapeutic antibody that activates a patient's T cells to seek out and destroy cancer cells."

T-cell ALL: Researchers found a "key protein receptor embedded on the outer surface of leukemic cells is responsible for infiltrating the brain and spinal cord." 2009. Lay article, article in Nature.

Bacterial proteins as potential drugs in the treatment of leukemia. Formerly used only for solid tumors, Azurin and Laz (bacterial proteins) have shown anticancer effects in leukemia cell lines. The authors recently identified another protein, Pa-CARD, from Pseudomonas aeruginosa that . . . demonstrates cytotoxic activity against leukemia cells. Jennifer Kwan et al., Abtsract. Published in Leukemia Research, 2009.

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.

contact webmaster/ped-onc home/last updated 9/09