Leukemia & Down syndrome


Leukemia & Down syndrome

Kids with DS are 20 to 30 times more likely to develop leukemia than kids without DS. 1 in 100 kids with DS will develop leukemia. These children have unique reactions and needs. The purpose of this forum will be to discuss those issues.

Members: 15
Latest Activity: Dec 2, 2009

Discussion Forum

DS & Methotrexate

Started by Nicki Harris. Last reply by Nicki Harris Nov 29, 2009. 5 Replies

Chemo doses

Started by Nicki Harris. Last reply by Nicki Harris Apr 9, 2009. 8 Replies

Please tell your story...

Started by Nicki Harris. Last reply by Lynnette Seeley Nov 18, 2008. 2 Replies

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Comment by Linda M. Scott on December 2, 2009 at 12:34pm

absolutely no problem - I can talk off the hind leg of a donkey, and absolutely love working in cancer research, so it's nice to be able to contribute in some small way!

Even for we scientists, there's never enough time to keep up with the literature, and I worry that you may become bogged down by all the jargon we use in our research. Don't soldier on through it if you start getting a head-ache ;) Maybe I can translate some of the geek-speak...

all the best,

Comment by Jeannie Dallahi on December 2, 2009 at 11:58am
Thank you so much for sharing so much with us - I love to learn all of this but never have enough time to properly investigate and read all that I would like to read . I so appreciate your time and effort to share and teach us about your research. I'm hoping to read through your reports in the coming week, and again, thank you so much! Jeannie
Comment by Jeannie Dallahi on December 2, 2009 at 11:56am
I'm sorry to hear how much Elizabeth is struggling with the treatment and its side effects - I can't imagine how scary a blood clot in the brain must have been. I know that it is much harder for older children than the younger ones. Is she able to walk at all? It must be so difficult. Does she get home programming for school or go to school? It sounds like we are at a very similar point in treatment - Amina has about 8 months to go in this final phase, which is referred to as "Continuation" in our protocol. Her 3 week cycles inlcude: IV Vincristine once every 3 weeks, IV Methotrexate weekly, Oral Dexamethasone twice daily for 5 days during Week 1, Oral 6MP daily for 14 days - weeks 1&2, and she recently had her 6th LP (Hydrocortisone, Methotrexate, Cytarabine) @ every 9 weeks, so she only has 1 or 2 more LP's at every 18 weeks. She is also on Bactrim prophylactically 6 doses per week. We have been fortunate in that overall, she has tolerated the chemo well, although Induction was very difficult with 2 potentially serious blood infections and a mass on her lung (resulting from one of the infections) that required a lobectomy/thoracotomy - they removed the lower right lobe of her lung with the mass. She has had 3 PICC lines and this is her 3rd Port - and this port she's had nearly a year so here's hoping it will stay through July!!! She also had some skin issues early on, and now her asthma has gotten increasingly worse so she is on a daily controller (Flovent) and a nebulizer when her asthma is acting up - the comprised lung may have something to do with this problem although it could just be the steroids. The Orthopaedic doctor made me feel better yesterday when he said that her Osteopenia is not too bad given how long she has been on chemo and he would expect to see it at this stage. He said she does not have the foot drop from Vincristine, so the limp is most likely from an injury she sustained a few weeks ago but is healing - he x-rayed her foot, tibia, femur, and hips to be sure nothing else is going on - all checked out fine - and we follow up in a few weeks to check to be sure the limping has improved. As for school, Amina is repeating her 4 year old preschool this year instead of going on to Kindergarten, since she stayed home the entire year last year and received services at home. She returned to her preschool classroom this fall, but missed frequently, and several weeks ago when the flu started to hit hard around here, we pulled her out and are back to home programming with the school until March or April, when flu season is over, and then she will go back to her classroom. She also goes to private speech and physical therapy once a week. Does your daughter have friends who come to see her? Does she have siblings? I find that to be one of the hardest things - Amina's brothers are 12 and 14 and love to play with her, but she never sees kids her own age, with the exception of her cousin who she adores but only sees about once or twice a month. I can't wait till next fall when she can get back to her activities, classes, soccer and all that stuff. Anyway, I appreciate the support and I will keep your daughter in my thoughts and prayers and wish you and your family the best. Jeannie
Comment by Linda M. Scott on December 1, 2009 at 12:12pm

not sure what was going on with my phone last night - could not post a response to your emails, so will try again now using my office computer... Will address various posts from you busy ladies in the order they were posted :)

Nicki: I mentioned in an earlier post that ALL investigators at St. Jude's (who are arguably the most successful group studying the molecular genetics of pediatric ALL) also looked for JAK mutations in a group of 187 patients they had identified as high-risk; this group included nine DS-ALL kids. Twenty were found to have a JAK mutation (mostly in the JAK2 gene, but also some cases with mutations in the JAK1 gene) - 18 non-DS kids and 2 DS kids. So about 1 in 10 high-risk non-DS ALL patients has a JAK2 mutation, or about 3% of all non-DS ALL cases.

Jeannie: research is underway looking at the genetic mutations in pediatric ALL, irrespective of JAK2 mutation status. Cancer cells generally do not carry only one mutation, but have a wide number of different mutations, and this is part of what makes it difficult for investigators to sort out what is really going on, and to develop better drugs. For example, patients with a JAK2 mutation may also have mutations in genes called IKZF1 (or ikaros), CRLF2 and CDKN2A/B. People with different combinations of these mutations may have different disease courses, and investigators are hoping to use this sort of information in the future to figure out which patients have a relatively mild form of ALL, and which have a form that needs more aggressive clinical intervention.

For most cancers, we do not yet know what is the "initiating" mutation, the one that starts the whole process of turning a normal cell into a malignant one. In Down Syndrome, you have a different scenario, as the additional copy of chromosome 21 could be considered the "initiating" mutation. But even then, we don't understand how having an extra copy of this chromosome affects cancer rates, and there are a lot of questions to be answered. One that intrigues a lot of scientists of course is why do these kiddies have a 10- to 20-fold increased risk of developing leukemia? And perhaps something that you may not know that I find fascinating is that children with DS are significantly less likely to get other solid tumors throughout their lifetime.

The initiating mutation is not usually enough to change a healthy cell to a cancerous cell, but it starts off a number of other events that over time may lead to a cancerous cell and then development of a tumor. One common phenomenon is that it makes more "daughter cells" - copies of itself that also carry the initiating mutation. In general, once you have the initiating mutation in a cell (with different initiating mutations for different types of cancer, and perhaps there are multiple potential initiating mutations for ALL), a whole bunch of other mutations will occur (for reasons that we are only starting to understand). You can think of the development of a cancer cell as a mini-form of accelerated evolution: mutations can be either neutral or have a "positive" or "negative" effect on that cell. If its negative, the cell that carries it will die - if this happens almost straight after an initiating mutation, then a tumor may never appear, but if it happens later, there will be many other daughter cells that don't get this second (negative) mutation, and they will carry on growing. If a mutation is neutral, the cell will neither die or prosper, but continue to grow with this mutation inside it. If the mutation is "positive", it will provide some kind of advantage over the other daughter cells that don't have it, and it will eventually out-compete these. Sometimes the positive advantage may be that cells with a particular mutation (say X) may be able to withstand chemotherapeutic drugs better than those without X. So when the patient is first exposed to a drug, there may be a good response as the X-negative cells start to die. But the X-positive cells (which may be less than 1% of the total) will survive and continue to grow, so that over time they replace in number the lost X-negative cells. This is what can happen with remission (almost all cells dying) and relapse (some cells re-emerging). This is what makes treatment for these horrid diseases so difficult.

Until 2007, we did not have any idea of the mutations that were occurring in DS-ALL. Scientists had had more success with DS-associated acute megakaryoblastic leukemia (AMkL), the other type of leukemia that DS kids tend to get - they have a 500-fold increased chance of getting this than non-DS children (where it is extremely rare). John Crispino, who is at the University of Chicago, identified a mutation (in a gene called GATA1) that develops in all DS kids that have a blood problem called transient myeloproliferative disorder (TMPD). About 20% of DS children are born with this (the mutation occurs during fetal life), and they have high numbers of platelets in their blood. These are the cells that normally form a blood clot or a scab where there is a wound that cause bleeding. Interestingly, the high platelet counts and the TMPD go away (without any treatment) in the first few months after birth, and most children have no lasting problems. But a tenth of children that had TMPD will develop AMkL, and these cells are clearly descendants from those present in the earlier TMPD, as they carry the GATA1 mutation. Presumably they have developed other mutations (which scientists are busy looking for) that cause a pre-leukemic GATA1-mutated cell to transform into a nastier variety.

The good news is that DS kids with AMkL respond well to chemotherapy.

Does that make any sense? Or am I still using too much scientist's jargon?! :) I will write something in a day or two about the research being done about predictors of who will develop leukemia - this is something that I've been studying here in Texas, and that my colleagues at St. Jude's and others in London have been looking at. In summary, some interesting findings, but nothing earth-shattering that could (as yet) make a real impact in people's lives.

Jeanne: I will look into databases etc, as that is a very good question, and one for which I have no answer. It may be a week or two before I get back to you on this, as I have a conference to attend at the end of this week, and then some grant and publishing deadlines to meet. At least I have my Christmas shopping done... the mailing deadline to the Southern hemisphere is today, so I have to use November as my gift-buying month!

Nicki: Love this photo of your daughter also. I'm sorry to hear that she has had such a nasty time with treatment
Comment by Nicki Harris on December 1, 2009 at 8:36am
She's not done well with the treatment, Jeanie. She's been in a wheelchair sine the second month of treatment. She's had horrible problems with the chemo. We've almost lost her twice. She's in LTM with 10 months to go. Her chemo is: 35% nightly 6mp, 10% oral MTX, 100% prednisone, 100% of IT MTX- standard risk number due to neurotoxicity and talking about stopping them. The peg-asparaginase gave her a brain clot on her brain so those stopped after after receiving two. I'm nervous about the reduced doses and missed doses but I try to tell myself that her body doesn't need it to stay cancer free... that her body accepts just what it needs to keep that cancer at bay.. but I kinda don't believe it. I need to put up a current picture of Elizabeth. She's actually 15 years old. I just love this picture of her. Has Amina's doc reduced the vincristine since she's showing osteopenia. Her limp may be developing drop foot. Elizabeth's is severe. You're right to get her to an ortho soon. Take care, Nicki
Comment by Jeannie Dallahi on December 1, 2009 at 8:01am
I was wondering if there is an international or national database to register on for research studies of any kind, but also related to DS/Leukemia. Amina is on Clinical Trial for Standard Risk patients, but as far as I know, she is not involved in research related to DS and I would be happy to have her experience contribute to research and future progress. Jeannie
Comment by Jeannie Dallahi on December 1, 2009 at 7:58am
Hi! Thank you for this interesting discussion. Treatment with minimal side effects would be so incredible! We just discovered that Amina's bones are osteopenic, and she has started to limp - we have an appointment today with her Orthopaedist to discuss it in greater depth, but I am so concerned about her bone health due to the Dex & Methotrexate, and because she has had 3 courses of Prednisilone for asthma in addition to the Dex. Her asthma has also gotten much worse the longer she has been in treatment. Anyway, what great hope to think there may be treatment with fewer complications some day. As for the research, I was wondering about the other 80% who did not have the JAK2 gene mutation...aside from the connection to DS and ALL, are there any other predictors that an individual may get Leukemia? I know there is so much research out there that I want to read, but just can't find the time! Finally, Nicki - how is your daughter doing with her treatment and development? Thanks again for this discussion! Jeannie
Comment by Nicki Harris on December 1, 2009 at 12:30am
Thanks for posting this, Linda. Did they check kids with leukemia without DS to see if any of them had the gene mutation, and if so, what % of that group had it?
Thanks again for your participation. We really appreciate you! Nicki
Comment by Linda M. Scott on November 30, 2009 at 8:33pm
Hi everyone

I found the news article listed below, which describes the work I did in collaboration with Shai Izraeli, and thought it may be of interest. The original link is http://www.sawfnews.com/Health/59060.aspx

"July 28, 2009, (Sawf News) - A new JAK2 inhibitor drug offers "potential hope" to children who suffer from leukemia. The first experiences with these non-chemotherapy based treatments show very few side effects.

Each year, approximately 4,500 children in America are diagnosed with leukemia, according to the Leukemia and Lymphoma Society. A potentially deadly cancer of the blood, it is the most common cancer in children.

"Modern medicine can cure eight out of 10 cases of childhood leukemia, so parents can still be hopeful when they hear a diagnosis," says Dr. Shai Izraeli of Tel Aviv University's Sackler School of Medicine and Sheba Medical Center. "Our research gives hope and life to the 20% who might not make it as well as those who may experience a relapse."

The first researchers to discover a mutation of the JAK2 protein in patients with Down syndrome, the Tel Aviv University team suspected that this protein might also be linked to other disorders and diseases ? and they were right. Based on the successful results of this research a drug that is already in clinical trials for a blood disease common in adults may be relevant for acute childhood leukemia. If initial trials go well, the drug could fast-track through approvals and could be available for treating children with leukemia in only a few years.

The recent findings are based on Dr. Izraeli's original discovery of the JAK2 in Down syndrome, published recently in the prestigious medical journal The Lancet.

Finding a model in children with Down syndrome

According to Dr. Izraeli, a similar mutation of the JAK2 in Down syndrome and leukemia causes Polycythemia Vera, a disease common in adults that leads to the overproduction of blood. This discovery of a similar mutation in a subset of pediatric leukemia cases may provide a path to new life-saving medication options.

Dr. Izraeli first discovered JAK2 mutations in children who initially suffered from Down syndrome and subsequently developed leukemia (a child with Down syndrome is 20 to 30 times more likely to develop leukemia during childhood than a child without it). Dr. Izraeli was then inspired to screen for gene mutations that could result in increased proliferation of cells. In collaboration with the iBFM Study Group, a European childhood leukemia consortium, 90 cases of Down syndrome leukemia from all over Europe were studied. A JAK2 mutation was found in 20% of these cases.

The discovery represents a unique biological phenomenon. "This is perhaps the first example of two very similar ? but different ? mutations that apparently do the same thing in a cellular protein. But they're associated with two completely different disorders, one that causes polycythemia in adults and the other that causes leukemia in children," says Dr. Izraeli.

"Those children at the highest risk for leukemia may be treated with inhibitors of JAK2," he says. "And because of the existence of polycythemia in adults, there are already drugs to fight polycythemia entering into trials as we speak. We will know in just a few years what these drugs are capable of."

An alternative to chemotherapy

Dr. Izraeli says the discovery offers "potential hope" to children who suffer from leukemia. "JAK2 inhibitors are not based on chemotherapy. The first experiences with these treatments show very few side effects. All that researchers need to do is to expand these clinical trials to children and adults with high-risk leukemia ? and that can happen relatively quickly," says Dr. Izraeli.

Dr. Izraeli explains that typical chemotherapies for leukemia also have a high "toxicity cost." Children with leukemia are treated with 10 to 12 different chemotherapies over a period of two to three years. Some of them have long-term and irreversible damage, such as neurological, heart, bone problems and sterility. Researchers looking for viable alternatives may turn to Dr. Izraeli's research as a promising avenue for success.
Comment by Linda M. Scott on November 29, 2009 at 1:55pm
Hi again, Nicki

JAK2 is located on chromosome 9 (on the shorter arm, so chr 9p).

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Discussion Forum

DS & Methotrexate

Started by Nicki Harris. Last reply by Nicki Harris Nov 29, 2009. 5 Replies

Chemo doses

Started by Nicki Harris. Last reply by Nicki Harris Apr 9, 2009. 8 Replies

Please tell your story...

Started by Nicki Harris. Last reply by Lynnette Seeley Nov 18, 2008. 2 Replies


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