APL, Information and SupportInspired by Anita’s Journey through Acute Promyelocytic Leukemia

picked this up from: http://www.sciencedaily.com/releases/2008/05/080512105726.htm

I thought this article was interesting as it offers an explanation as to why Arsenic may be so effective for APL.   Understanding why Arsenic is so helpful with APL may eventually lead to more effective treatment methods for other cancers!

ScienceDaily (May 12, 2008) — In both leukemia and solid tumors, there exists among the multitude of warrior cancer cells a small subgroup that work undercover, patiently lying in wait to launch their attacks. Known as either cancer initiating cells (CICs) or leukemia initiating cells (LICs), these stealth populations are impervious to conventional chemotherapy and undaunted by targeted cancer therapies. When a leukemia patient relapses following a period of remission, it is the LICs that bear responsibility for the disease’s reemergence.

The secret to the survival abilities of these cells has been unclear. But in a paradoxical discovery, a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that a tumor suppressor protein known as PML appears to be the factor that enables LICs to maintain their quiescence — the inert state that protects them from being destroyed by cancer therapies — and suggests that inhibition of PML is a promising target for new therapeutics.

Their findings, which appear in the advance on-line issue of the journal Nature on May 12, additionally demonstrate that PML can be degraded with an arsenic-based agent used in traditional Chinese medicine. Importantly, when combined with chemotherapy, the arsenic-based therapy — already proven safe and non-toxic in clinical trials — can successfully treat chronic myeloid leukemia.

“Leukemia initiating cells share many properties of normal hematopoetic stem cells,” explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Genetics Program in BIDMC’s Cancer Center and Professor of Medicine and of Pathology at Harvard Medical School. “They are pluripotent, they readily replicate and they can indefinitely remain in a dormant state of quiescence.”

Consequently, while the majority of leukemic cells are vulnerable to any cancer therapies — including chemotherapy and targeted cancer treatments — that destroy cells during active DNA replication, LICs, with their unique quiescent properties, resemble an automobile with an endless supply of fuel and a sturdy set of brakes: They sit quietly idling in place, waiting to reinitiate malignancy after a period of remission.

Pandolfi’s laboratory has been working to develop new therapeutic approaches to target LICs and thereby treat chronic myeloid leukemia (CML), one of the most extensively investigated of stem cell disorders. CML is typically treated with the targeted therapy imatinib (Gleevec), a tyrosine kinase inhibitor.

“Gleevec does dramatically improve prognosis of CML patients,” notes Pandolfi. “But, unfortunately, Gleevec is not curative in most cases. Because it targets only dividing cells, the pool of quiescent LICs are able to remain intact.” As a result, when Gleevec therapy is discontinued, the cancer almost inevitably relapses.

The investigators set out to analyze expression of PML, a tumor suppressor protein that controls fundamental processes such as apoptosis, cellular proliferation and senescence. PML is commonly associated with acute promyelocytic leukemia (APL), in which it leads to the formation of a fusion protein that blocks cell differentiation.

After ascertaining that PML was highly expressed in the LICs of a CML mouse model, Pandolfi’s team also determined that PML is highly expressed in blasts from CML patients and that low PML levels corresponded with patients’ increased response to therapy and overall survival rates.

“We then analyzed LIC function in the absence of PML and revealed that PML has an indispensable role in maintaining LIC quiescence,” he adds. “As a result, PML-deficient LICs grow exhausted over time, becoming incapable of generating CML in the transplanted animals.”

Lastly, the investigators examined the impact of As2O3, an arsenic-based therapy that targets PML for degradation and is currently used for the treatment of acute promyelocytic leukemia. As predicted, inhibition of PML by As2O3 successfully disrupted LICs, increasing the efficacy of the anti-cancer therapy by sensitizing the LICs to pro-apoptopic stimuli.

“It’s actually a very simple concept,” says Pandolfi. “Ninety percent of existing cancer treatments are antiproliferative agents — they target the pool of proliferative cells, leaving behind the dormant LICs.

“But in determining that PML serves to guard the LICs that have been left behind, we also discovered that if we knock out PML [through pharmacologic means], the LICs will lose their braking abilities and run out of gas, thereby commiting the fatal error of proliferation — and exposing themselves to the deadly effects of cancer therapies.”
Pandolfi’s laboratory is now trying to determine whether PML exerts a similar role in the stem cells of other tissues, as well as in the cancer initiating cells of solid tumors.
“If this turn out to be the case,” he adds, “the transient use of As2O3 may represent a more global strategy to target CICs in other forms of cancer.”

This study was supported by grants from the National Institutes of Health.
Study coauthors include BIDMC Cancer Genetics investigators Keisuke Ito (first author), Rosa Bernardi, and Alessandro Morotti; Sahoko Matsuoka and Yasuo Ikeda of Keio University School of Medicine, Tokyo, Japan; Giuseppe Saglio of the University of Turin, Turin, Italy; Julie Teruya-Feldstein of Memorial Sloan-Kettering Cancer Center, New York, NY; and Jacalyn Rosenblatt and David Avigan of BIDMC’s Division of Hematology and Oncology.

http://www.sciencedaily.com/releases/2008/05/080512105726.htm Adapted from materials provided by Beth Israel Deaconess Medical Center.

Beth Israel Deaconess Medical Center (2008, May 12). Arsenic-based Therapy Shown To Help Eradicate Leukemia-initiating Cells. ScienceDaily. Retrieved May 12, 2008, from http://www.sciencedaily.com­ /releases/2008/05/080512105726.htm

First a very short Anita update; Anita is doing great!! She is 8 months post transplant and while her treatment wasn’t easy, we are fortunate to be where we are now in terms of her health.

Anita just had a clear PCR test result come in today – this was most welcome news. The test result means that there is no detectable trace of cancer in Anita’s blood right now.

You are never quite out of the woods with leukemia – it can always come back but a negative PCR test means that you are probably in a very high state of remission.

This post is going to wander a bit from the specific topic of APL. That’s OK though because there are many aspects of APL that are similar to any life threatening disease.

From time to time I am going to grab posts from the LLS forums that may be of interest to the APL community. There is a tremendous amount of helpful information on the LLS discussion forums, but like any busy forum, only the most current stuff is readily visible and older posts just get buried and lost over time.

So here we go – I am going to spotlight a lengthy thread about my hero “Zach Man” Zach is a 25 yr old guy that is seriously fighting for his life right now. He is fighting a very aggressive form of AML that isn’t giving an inch of slack or respite. Throughout the early part of the post, Zach is rolling with the punches, dealing with his treatments as well as can be expected. Pay special attention to his post on 03-13-2008 04:19 PM though. Zach is 25 yrs old and seems ready to give up the fight and “head home.”

Please read Zach’s post and I want you to think about what it would be like to have a brother, spouse, or any loved one in his position. It happened to me – it could happen to you too.

I want to stress that I deeply respect any decision Zach might make in terms of giving up the fight or carrying on…

So here’s the post… (note that I’m pasting only part of the post here ). Zach’s CaringBridge page is here too: http://www.caringbridge.org/visit/zachmc

How can you help Zach?

I encourage you to wish him well, but the unfortunate fact is that we can’t do much for Zach. The good news is that he is being treated by one of the best cancer treatment centers in the world – MD Anderson in Houston TX.

Cancer can’t always be successfully treated for individuals, but through collective effort we can make progress, slowly moving toward better treatments and more successful outcomes that will give individual patients a better chance of survival in the years to come.

Please take the time to learn more about cancer and how you can make a difference. There are many great resources to reach out to.

Here are a few for you to consider:

• www.leukemia.org
• www.livestrong.org
• www.acs.org
• http://www.marrow.org/

There are countless ways we can all help.

Remember when you support health related causes you are really giving to the entire world. Improvements in cancer treatments eventually reach many areas of the world, indeed reaching some areas better than others (yet another problem).

Chris

At the 43rd annual meeting of the American Society of Clinical Oncology, held last month (June) in Chicago, researchers presented findings from trials evaluating the safety and efficacy of new potential front line treatments for cancer. The use of Arsenic Trioxide as part of front line treatment for APL was discussed.

The Arsenic Trioxide related presentation

…The first study revealed that adding arsenic trioxide to standard therapy significantly increased overall survival among adults with newly diagnosed acute promyelocytic leukemia (APL). Arsenic trioxide has been used in traditional Chinese medicine for years, and it is currently prescribed as second-line treatment for patients with APL who do not respond to the standard therapy of combined all—trans retinoic acid and chemotherapy. About 70% of patients taking standard therapy experience a complete response, and 35% to 45% of patients are disease free at 5 years. …

In this randomized phase 3 trial of more than 500 patients, overall survival at 3 years of follow-up was 86% in the arsenic trioxide group vs 77% in the standard treatment group, and event-free survival was 77% and 59%, respectively. Cardiac irregularities and blood-related adverse effects such as low blood counts were not significantly different in the two groups, but infections and headaches were higher in the arsenic trioxide group (43%) than in the standard therapy group (28%).

“Addition of arsenic trioxide is associated with very little additional toxicity, and relapse was very uncommon in patients who received [the drug]: 5 out of 202 patients,” said lead author Bayard Powell, MD, of Wake Forest University Baptist Medical Center, in Winston-Salem, NC. “Arsenic trioxide should be incorporated into the therapy of patients with untreated APL,” he concluded.

Other countries, especially China have been using Arsenic in their front line APL treatments for some time. The US seems to be playing catch up on this one. At the same time, it is Arsenic after all (poison) so I can understand that the US has been slow to use Arsenic as an agent for treating new cases of APL.

Sure, Arsenic is poison but then so is water in a high enough dose. Have you ever heard the comment that its the dose that determines whether a compound is a medicine or a poison?

APL Treatments continue to improve, but there is more work to be done

When Anita was initially diagnosed with APL in 2002 her oncologist commented that APL is one of the less deadly types of leukemia. He was right of course but at the same time APL is certainly no walk in the park. I guess you could say that it is one of the best of the worst if that is saying much at all.

Take careful note of the statement that appears in the exerpt from the JAMA article: “35-40% of patients treated with standard therapy are disease free at 5 yrs”. My take on that sentence is that most patients do in fact relapse within a 5 yr period. Of course this is still better than other types of leukemia where many Dr’s will tell you that relapse after initial non-transplant based treatment is a virtual certainty.

My point here is that there is still much to be done in terms of improving the treatment for APL.

Oh — my other point…!! If you were recently diagnosed with APL and you are starting treatment, please ask your Dr. whether it would make sense to include Arsenic in your initial treatment.

Here is the link to the new JAMA article – http://jama.ama-assn.org/cgi/content/full/298/4/391

Sorry – but it looks like you will have to be a JAMA subscriber to see the article. I would be happy to email a copy to you if you email me with that request.

Anita’s Experience with Arsenic Trioxide

This site has a few postings about Anita’s specific experience with her Arsenic treatment. Overall her treatment with Arsenic was uneventful but effective.

In fact, Anita’s Arsenic treatment didn’t cause her to lose her hair or experience any of the nasty side effects that are normally associated with traditional chemotherapy.

I keep dwelling on Anita’s positive experience with Arsenic partly because I remember researching Arsenic for APL when Anita was to start her treatment. Of course most of the articles I found were plenty scary, some talking about sudden death during treatment and other serious problems.

Some of these APLBLOG posts seem to be coming up near the top of many of my test Google searches now – so maybe the “next person” that searches for APL Arsenic etc will see something more positive and practical than I did when I first searched on the subject. I ended up being quite scared for Anita after initially reading about Arsenic.

Arsenic can indeed be dangerous but as doctors have become more skilled at admininstering it (especially including close monitoring of electrolyte levels such as Potassium and Magnesium) the danger has become more managable. Some of the problems you might read about with Arsenic relate to issues that were more common when doctors were less skilled at managing its potential side effects.

(by the way – that picture is what Arsenic looks like in one of its natural forms)

Feedback on this blog post

There has been some interesting feedback on the Leukemia and Lymphoma Society bulletin boards. With respect to the individuals involved we’d like to summarize some of the points.

• Hi Chris,
  Thanks for the information. I too, have been doing a lot of reading about Ars.Tri. I was dx 5-06, rem. 6-06, 2 consol., and started ATRA maint.(90mg daily, 7 days on,7 days off)in 10-06. Originally my oncologist was only going to put me on it for a year. But now he wants me to continue until 10-08. Do you think I should broach the subject of adding Ars.Tri. at this time? I would value your input/opinion.with sincere thanks,
  - Beth
• I was fortunate to be one of the research study participants a little less than 5 years ago. I’m glad to see that Arsenic Trioxide is soon to be rolling out for all to receive as part of the frontline treatment for APL. I think it is as close to a “miracle” drug that there is.
  - mbatdorf
• I can’t offer any specific advice for you. The more I learn about all this the less apt I am to try and suggest much of anything specific to any specific individual.There are just too many variables that I don’t have knowledge or visibility on – even for my wife’s own treatment! I can tell you that I would have plenty of questions about Arsenic if I were in your shoes.

  I guess if you were to get Arsenic now it would be as an additional consolidation therapy as I suspect you are already in a good remission. Have you had a few negative PCR tests since achieving remission?

  There is nothing to suggest that you will certainly relapse although I think the “35-40% remain disease free at 5 yrs” comment should get everyone’s attention. Honestly that number scares me and I have seen plenty of similar numbers in other places over the years.

  Five years ago I remember hearing that Anita had a 70-80% chance of not relapsing in the first 5 yrs, with even less chance of relapse thereafter. She did not receive Arsenic and those were the “numbers” that were quoted for the Retinoic Acid/Chemo route she was offered and accepted in 2002. Arsenic was experimental as front-line treatment at that time so I am not trying to suggest that we should have been offered access to it 5 yrs ago.

  Of course she did relapse (exactly at 5 yrs!!!) and now the relapse stats for treatment that did not include arsenic seem to be reversed at least according to this JAMA article quoted in the original post.

  I also do not regard arsenic, or any drug for that matter as a miracle drug. There are risks with Arsenic and questions remain, like whether it could pre-dispose you to future different types of cancers years in the future.

  So back to my original comment that APL is rare. Why did I mention that? Here’s why…

  I think you are going to run into trouble getting your ONC to do any sort of “custom job” for you – i.e. adding Arsenic later in your treatment.

  Your probably going to get thinking like “Your in remission now – why mess with that?”. A 30 day course of Arsenic that includes much of any hospitlization will probably cost around 50k too (fyi). Your insurance might even balk about paying for it since you are already in remission etc.

  APL is so rate that any specific oncologist you are likely to speak with has treated only a handful of cases over his or her career. Of course there are all kinds of rare cancers that oncologists deal with every day – but the point still holds APL is rare. Oh – and Docs that are experienced with APL and Arsenic are rarer still!

  Ok – so what to do?

  I would try to get a few second opinions – perhaps including an opinion from one of the docs that was involved with the JAMA study.

  Basically I would try to develop a concensus between a few Docs – including some that are very familar with Arsenic in the APL context.

  You don’t want this crap to come back if you can avoid it. In your shoes, I would be interested in anything that might significantly help prevent its return.

  Anita’s auto transplant is going pretty much as planned but it is difficult, painful and not without its own risks. I wish she could have avoided the need for her transplant.

  -Chris

• One has to look more deeply into that JAMA article (I wasn’t willing to buy it, but I believe I saw the study a week or two ago). The event free survival numbers refer to, I think, protocols that used daunarubicin and/or ATRA. Idarubicin (used more commonly now, and a “newer” less heart toxic chemo) has been more effective with APL, and the PETHEMA APL99 protocol (which I was on) had a relapse rate under 1-3% for people who were low-intermediate risk and had achieved remission. I know these data were accurate as of 4 years, and how it has been almost eight years, and I emailed one of the APL “gurus” who has worked with Dr. Miguel Sanz (who ran the PETHEMA study) and he indicated that the numbers, as far as he knows, have persisted — i.e. the relapse rate 8 years later, is still under 1-3% for low to intermediate risk patients. This protocol used Ida+ATRA for induction, and IDA+ATRA, Mitoxantrone+ATRA, and IDA+ATRA for consolidation with two years of Atra/6MP/Methotrexate.

  I just finished maintenance. It is a long road with APL, and you need to be your own advocate. With APL there’s good news and bad news: good news is it is highly treatable and curable; bad news is that there are many ways to treat it, so choosing a course is mind-numbing. I DO think (based on my reading, for I’m not a doc) that therapy using Arsenic (which I did NOT have) is proving to be highly beneficial and efficacious.
  -pen65000

• The JAMA article mentions “35-40% are disease free at 5 years”. This sounds like another way of saying that 60-65% of APL patients relapse within 5 yrs at least when Arsenic is not used as part of initial treatment.I will try to ask Anita’s onc what “disease free” means in this context.Survival would be a different statistic altogether and would be higher.

  Maybe the 70-80% survival at 5 yrs from initial diagnosis could still be correct – it just that many (60-65%?) of those survivors might have relapsed during the 5 yr period, possibly needing more treatments, transplants etc.

  All these stats are tricky.

  -Chris

• quote:

  ---

  Maybe the 70-80% survival at 5 yrs from initial diagnosis could still be correct – it just that many (60-65%?) of those survivors might have relapsed during the 5 yr period, possibly needing more treatments, transplants etc.
  

  ---

  Though I haven’t really read this study to say whether that’s the case here, what you’ve noted is not necessarily an unspoken but a quietly spoken and unfortunate “read between the lines” fact in all AML treatment when discussing survival. Terms like “disease free survival” and “event free survival” and “relapse free survival” are additionally usually contextual, and can change the simple interpretation of statistics.

  I would be exceedingly encouraged by the fact that “event free survival” was so high, however. Especially after earlier concerns about treatment-related mortality and genotoxicity. (Issues that generally figure much more prominently into adoption of treatments here than in some places.)

  (And it reads to me as though the JAMA article is initially citing general statistics first when discussing 5-year disease free rates, and then the new study’s own statistics separately in discussing 3-year rates.)

  I have read a couple of very interesting new abstracts on an ATO and parthenolide combination, and on ATO’s ability to tamp down leukemic stem cells in APL.

  - MichaelM

• I think the LLS should have a good FAQ that explains all of these terms – disease free survival, relapse free survival, event free survival, treatment related mortality, overall survival, etc.
  Looking back to 2002, I believe we were quoted a 5 yr overall survival number of 70-80%. Our doc was not suggesting that there was only a 20-30% chance of relapse. Then again, if we had been told that there was a 60-65% chance that the leukemia would come back I don’t know what we would have done with that information. And yes, these numbers from the JAMA article apply to people that did not receive arsenic as part of their up front treatment.

  When Anita was first diagnosed our first concern was for her to survive (obviously) so we were not thinking about the nuances of how to interpret stats we were quoted.

  It is very hard to decide exactly how much of this information I even want to know when its my own family that is suffering. The question of what to do with any bit of information we are provided – i.e. is it actionable in some way – comes up at every turn.

  Better understanding DFS vs OS does seem important though as it could possibly help some people choose between more or less aggressive treatments up front. Of course more aggressive treatments might promise lesser relapse rates but provide possibly worse OS within a defined period of time (i.e. 5 yrs).

  In retrospect, I think we sort of ended up looking at Anita’s 2002 APL diagnosis through rose colored glasses, not realizing that the relapse rate was as high as it apparently is.

  Would we have done anything different with a better understanding of the survival numbers? Probably not.

  Some of this might speak to the importance of getting multiple opinions and consultations when you are diagnosed. Misunderstandings and partial understandings of relevant facts might tend to get flushed out a litle better when you start talking to multiple experts.

  -Chris

• There are some predictors about relapse, namely the patient’s white count at presentation. If the patient presents with a WBC of over 10,000, the patient is considered “high risk” for relapse. I forget what makes up “low” and “moderate” risk because I fall into the “high” risk category, and that was all I needed to know. In the studies I read (none of which included arsenic in the consolidation phase), all or almost all of the high risk patients relapsed. To counter that risk, my onc put me on an arsenic trioxide protocol. He believes that the arsenic essentially eliminates the high risk category. Additionally, in my protocol the daily 6MP in maintenance is only prescribed to high risk patients.

  My heart really does go out to you. I can tell how much you care about your wife and how hard you are working to help her beat this disease. When Anita was diagnosed the first time, you made the best decisions based on the information you and the medical community had at the time. Don’t second-guess the decisions you made in the past.

  -Diane

• Disease free survival (DFS) generally means just that – the length of survival from the original disease (not secondary) following a specific treatment during which no sign of disease was present. Though there is some wiggle room in defining what “reappearance of disease” means (which should be defined in each study), broadly speaking DFS ends when the disease reappears.Relapse free survival is similar, with the primary end point being relapse of disease and/or time of last follow-up. I’ve often seen it include death from any cause. (If you’re in remission but die in a car wreck, you were still in remission at the time of death.) Sometimes RFS is defined in the same way as DFS.Event free survival generally means the time during which there is no reappearance of disease (relapse), no death resulting from the disease _or_ the specific treatment in that trial, and no significant complications resulting from that specific treatment. As with DFS, the details of what constitutes disease reappearance and “significant” complications is something that should be defined in each trial.

  Some of this is a bit different from cancer to cancer as well, and again you can find variation for any of these from trial to trial, but they’re much more specific than simple OS.
  -MichaelM
  

  Full bulletin board post
  

Anita is at day +6 of her Auto transplant.   Her white count is at 200 for the second day in a row and is probably still heading down further for at least another few days.  If we are lucky she will start making white cells sometime soon, maybe by the end of the week.   She has no immune system now with so few white cells circulating in her blood.

You can think of white cells as the troops that protect your body from just about anything that shouldn’t be “in there.”   The normal range for white blood cells is between 4500-7000 – compared to Anita’s present level of 200.
Unfortunately, most chemotherapy drugs are not smart enough to distinguish good and necessary cells from cancer cells.   Without being able to tell the difference between good and bad cells, most chemotherapy wipes out your immune system right along with the cancer.
Fortunately, the immune system has tremendous recuperative power and can usually rebuild itself even after being almost completely wiped out.   We are waiting day by day right now for Anita’s immune system to pick itself up off the floor and start rebuilding itself essentially from scratch.

Some of you are already familiar with the type of stem cell transplant that Anita had – an autologous transplant.   Here is the basic idea again…

1.  Dr’s obtain stem cells from your blood system.  Think of the stem cells sort of like the “seeds” that will be used to grow the immune system back later on.   The stem cell are normally gathered by filtering your blood through a complicated machine, then saving the special cells that have been filtered out into a deep freeze.
2.   You are given extremely strong chemotherapy and sometimes radiation.  Your Dr’s seek to destroy all of your bone marrow with the chemo and the radiation.

3.  Your immune system is wiped out, poisoned really.   It is so thoroughly destroyed that you would die without the next step.   After completing the strong chemo you rest for a few days so most all trace of the very strong (poisonous) chemotherapeutic drugs can leave your body.
4.  Dr’s re-infuse the stem cells that were gathered back in step one.   You receive the cells back just like any other medicine that you might receive through an IV.

5.  The re-infused stem cells somehow know what to do – they find their way back inside your bones and “setup shop” making new immune system cells – platelets, red blood cells, white cells – everything you need.   You can think of the marrow as the soil that the stem cell seeds grow in.

6.  Slowly – over the course of at least a month, your immune system rebuilds to a healthy level – hopefully without the cancer.  During this rebuilding process you are at risk for serious infection and other complications.   Your Dr’s are smart and experienced and they know how to fight most infections but there is certainly some risk of serious complication until your body can rebuild and re-develop its immune system defenses.

Anita is at Day +6 at step 6 as outlined above.   Day 0 was is shown at step 4.

For the most part, Anita is doing OK.   Strong chemotherapy like this is tough to get through.   She has had a variety of painful and uncomfortable side effects from her treatment regimen but nothing that is really outside the norm given the circumstances.   All told, I am thankful that things are on track for her and seem to be going as expected at least for now.

Anita’s white cell count has been decreasing quickly over the past few days. It dipped below 500 today and will likely be close to zero within a few days.

It is completely expected to see Anita’s white count dropping now. She finished her chemotherapy about a week ago so the drop in her counts is essentially right on schedule.

Her counts should start rising within a week or so as her re-infused stem cells get back to work re-creating Anita’s immune system.

Lots of scary “potential stuff” comes along with low blood counts. Dr’s refer to low white blood cell counts as neutropenia.

I have been spending weekdays at City of Hope then coming down to San Diego on the weekends. The end of the weekend is nearing now, so I am leaving in a few minutes for the City of Hope (about a 2.5 hour drive).

Hopefully Anita won’t develop any infections while her white count is bottomed out. This week will be a little bit dangerous for her but at the same time her Dr’s are well prepared for any troublesome bugs that might try to take hold.

Right now, Anita is very tired and doesn’t leave her room each day. Her spirits are good and despite all the discomfort and pain she just refuses to complain about much of anything.
One of Anita’s Dr’s told me a while ago that her counts would probably recover faster after this transplant than they did five years ago after she underwent traditional chemotherapy.

Immune system stem cells are amazing – those little cells that were re-infused back into Anita after her strong chemo are basically “seeds” that will grow back into a re-formed immune system for Anita. You can think of the marrow, which is especially found in the long and large bones of the body as the “soil” that the stem cell seeds will grow from.

What puts the “stem” in Stem Cell?

Blood system stem cells are pluripotent which means that as they grow and divide the cells that they produce can grow up into all the types of cells that make up everything in your blood.

Think of a flower, it starts with a stem then rises from there to leaves, flowers, and whatever else – same idea.

** Please join with me in fighting APL and other cancers. Ways you can help:
- Remember Cancer related charities as part of your charitable giving.
- Pray for Anita and all other people suffering from life threatening disease.

- Donate Blood and register as a potential bone marrow donor. Every time you donate blood it saves a life – I have seen the impact of life saving donated blood coursing into Anita many times.

** Lastly, please check out a few of these videos from the City of Hope website,

Walk of Hope

and,

A few Patient Stories from City of Hope

especially check out: The Marshall Cotta Story and “Meeting my Lifesaver” from the above link.

Anita is at day +1 for her autologous stem cell transplant today. This means that the stem cells she donated for herself about a month ago were re-infused into her body yesterday.

The infusion went well with no special complications. Anita was watched very carefully during the stem cell infusion – the staff here at City of Hope is excellent and you can see the care and precision in all their work.
The strong 6 day chemotherapy regimen that she received to prepare for her transplant ended at day -2 (three days ago). Sorry to back into some of the timing here.
Anita received a strong myoablative (destroys your bone marrow) drug called Busulfan for 5 days. The received an infusion of Busulfan every 6 hours for the 5 days – total of 20 infusions.

For all the troublesome online talk I have seen about Busulfan, it didn’t seem to bother her much at least while she was receiving it. The drug on day 6 was another matter – Etoposide.

The Etoposide was a tough one. It had a strong almost turpentine like smell and I could tell Anita was somewhat disoriented while she was receiving it and for about one day after it was infused. Her Dr warned us that Etoposide would not be pleasant. The disorientation likely came from the Etoposide itself and all the drugs Anita was given to offset and protect her from its side effects – a real cocktail when its all mixed together.
Chemotherapy drugs are often given in combination, sort of acting as a 1-2 punch to kill cancer cells. Think of – if this one doesn’t get them – this other one will sort of thing.

Chemo can be tough – that probably isn’t news to you. Here’s a simple tip that helped Anita though one of the least pleasant aspects of chemo – Nausea…

Nausea is one of the main side effects of chemo. Ok – you know that… throwing up, can’t see straight etc. The idea of Nausea actually terrifies some people and there are plenty of cases where people have refused treatment from fear of “getting it.” Anita actually gets double vision at times when the nausea is active. It’s just a miserable deal all around when nausea has you in its grips.

Dr’s are really good at fighting nausea -its an old enemy. Every time Anita has ever received chemo she received certain pre-medications, like Zofran, to try and keep the nausea at bay. Usually Zofran works pretty well – especially for a few hours after it is given. The trouble for Anita always comes in the hours and days after receiving the chemo – after the Zofran wears off.

So here’s the deal. Dr’s will often give you more Zofran or any number of other anti-nausea meds if you ask for them. Problem though – you are tired and disoriented. Will you think to ask for anti-nausea meds early enough? Probably not. Another point is that all anti-nausea meds are preventative in nature, they won’t do much of anything for you once nausea sets in. Nausea will go away on its own, at least for a period of time after much vomiting and suffering.

Right after Anita’s chemo finished this time, I recognized a pattern where her nausea would start and Anita would fail to ask for anti-nausea meds soon enough to prevent the nausea from taking hold. There was one evening when the nausea took hold and kept Anita up very sick all night. It turned into a difficult and scary night for her.

So what worked for Anita’s nausea?

One of Anita’s clever Dr’s here at City of Hope came in the morning. She could see that Anita had been suffering and she “got her number” right away. She said something like: “Your not asking for your meds soon enough. I know what to do about that.” Her Dr promptly modified Anita’s anti-nausea meds order so that she automatically gets anti-nausea meds every 6 hours now – and she started Anita on a once a day anti-nausea pill called eMend at the same time.

There is a little bit of a trap here. Believe me – after a tough chemo regimen you may not have the awareness and ability to reliably ask for anti-nausea meds soon enough to prevent nausea from taking hold.

So if you are having a real tough time with nausea ask your Dr to consider putting you on an automatic schedule for anti-nausea meds. The meds may make you a little bit sleepy but believe me – being a bit sleepy and “napping alot” is a fine alternative to very unpleasant and aggressive nausea.

Dr’s do have alot of lattitude in giving anti-nausea meds – they are Dr’s after all – they need that lattitude. At the same time, some of the guidelines and procedures they work under are at least partially designed to save costs. Think about it – they won’t throw expensive anti-nausea drugs at someone that doesn’t need them and if you don’t ask for them you could end up with alot of extra suffering.

So just remember the idea of getting on an automatic anti-nausea schedule med – see what your Dr thinks of the idea if you have a tough time with nausea in your treatment.

Anita’s automatic anti-nausea med schedule helped Anita a great deal.

Chris

The point of this post is this new article – feel free to skip all my discussion and go right to the article.
My post which appears below, tries to provide some context for this (hopefully very helpful) new research.

Let’s start by reciting a basic problem. Here it is: Like many cancer cells, the internal mechanisms (i.e. the things that are broken inside) that make APL cells cancerous are not fully known. Through a series of tests combined by a visual review by experienced eyes, cancer cells can be accurately identified but scientists don’t usually know what made the cell cancerous in the first place.

Here’s the problem. If it’s tough to fully describe and understand your enemy (APL Cells) – you can bet it will tough to fight “them.”

Know your Enemy

It’s a basic tenet of warfare to know who you are fighting. In fact, the most troublesome adversaries are very secretive and difficult to understand. Enemies that hide, don’t reveal their inner nature – etc. Sound familar?

Ask yourself, how can we form an accurate and effective attack without understanding an enemy? Also ask yourself – how effective are generalized attacks against a very specific enemy? What are some of the drawbacks of generalized attacks on a specific enemy? Traditional chemo is a generalized attack in terms of this analogy – compare it to carpet bombing.

The APL Healthies

Let’s return to a subject that highlights the partially unknown nature of APL cells – I call it the problem of the “APL Healthies.” This problem highlights some of ways that the detailed nature of APL cancer calls and many other types of leukemia cells remain poorly understood. The new article I linked in the first sentence of this post might hopefully be a step toward resolving some of these unknowns at least for APL.

We spoke previously about the fact that cells that display the primary genetic markers that are used to identify the presence of Acute Promyelocytic Leukemia (t:15:17) are sometimes detected in apparently healthy individuals that will likely never develop full blown APL. There is a nice outside article located here on the whole subject of detecting leukemia associated cell markings in healthy individuals.

In fact, a few years ago, Quina et al. (2001) tried to create APL cells by exposing healthy human stem cells to radiation. The investigators ran into a little problem though – they found that there were about the same number of cells showing the t15:17 trait in their pre-radiation samples vs the post radiation samples. This sort of observation has actually been made for a variety of leukemias – certainly not just for APL.

I am always watching for APL related articles that will help me better understand the conflict of finding APL cells in so-called “healthies.”

Basically the RXR article discusses an additional genetic trait that must be present in a cell that carries the traditional t15:17 marker before it can become cancerous. Could RXR be missing from the cells that are often found in the healthies?

Another thought is that if RXR really does play a critical role in the development of fulminant APL then it could possibly be used as a specific target for a specially designed highly APL specific drug (think less debilitating chemo and fewer dangerous transplants). Could the RXR marker be an important element of the overall APL enemy (know your enemy)?

How can Dr’s detect something that they can’t fully describe? Experienced eyes and more than one type of test…

** Think of a silly example… even though I don’t know all the details regarding a 1967 Mustang, I do know one when I see one. There are certain visual cues that I look for – like the shape of the front grill for example. A PCR test is kind of like that – it looks for a very specific attribute, but perhaps not all attributes that are required to uniquely distinguish a type of cancer.

Scientists do more than just “look at the front grill” then they look for APL…

Researchers and Dr’s often use an assay called a PCR Test to determine if a specific type of cancer is detectable. PCR Tests can “see” cells that match a specific genetic pattern (i.e. watch for front grill) and they can even report the approximate concentration of those cells, often relative to a healthy cell type that should be present at a known concentration.

Some very important treatment decisions can be heavily influenced by specific PCR results. In Anita’s case, a specific PCR result that failed to find any remaining evidence of APL cells showing the t15:17 transcript helped determine the type of stem cell transplant (autologous) that would be best for her treatment.

Still though – when each of these PCR tests would come in for Anita, I would always ask myself – What does that test result really mean? What is the PCR test really seeing? What does the result mean, especially if that darn PCR test will sometimes be positive for a “healthy”?!!

As I have read more about PCR testing and leukemia in general, I understand better why actually looking at sampled bone marrow cells under a microscope is the gold standard for diagnosing and tracking the progress of any leukemia.

Rather than just looking for a very specific trait, like a PCR test does, an expert pathologist applies his considerable expertise, actually looking at specific cells taken from a bone marrow aspirate sample. The pathologist employs his or her experience to carefully identify any cells that appear to be abnormal – often providing comments that can provide the foundation for an entire treatment regimen.

There are plenty of pictures of what APL cells (scroll down to the M3, acute promyelocytic leukemia (APL) pics) and many other types of leukemia cells actually “look like” under the microscope. Again, this is a manifold subject, with numerous “exceptions to the rule” and some troublesome scenarios where certain types of leukemia cells very very closely resemble other types of leukemia, making it difficult to properly diagnose some types tumor types.

So if you were diagnosed with APL, or any leukemia, you can bet your Dr’s aren’t just relying on a PCR test – they look at many factors that are very carefully aligned and checked before any diagnosis or overall treatment plan is established.

New Attribute of Leukemic APL Cells has been Recognized- RXR
It has been recognized for a long time that APL cells almost always show the translocation of chromosome 15 and 17 PML/RARA, but again let’s return to the fact that cells showing this same t15:17 translocation are sometimes found in healthy individuals (let’s call them “healthies”).

My previous post that discussed Healthies and APL Cells discussed a two major possibilities on this. First, perhaps the natural immune systems in the healthies, have a special way of keeping the APL cells in check, or second, perhaps there are additional heretofore unknown genetic defect exists in fulminant (cancerous) APL cells – maybe even some combination of both of these ideas are true.

I decided to revisit the idea of the APL Healthies when I read the RXR article recently. The article describes the characterization of an additional defect that must be present in t15:17 cells before they can become leukemic (cancerous). Could this be the additional trait that must be present, before active APL can develop?

Generally, as the overall puzzle of how APL develops, becomes active, and potentially relapses, science can better develop more specific drugs to treat it. Indeed, APL is already unique because there are already two highly specific and very effective drugs to treat it (arsenic and retinoic acid). Both of these drugs are highly active against APL but unfortunately, they cannot be regarded as a cure because they don’t fully protect against relapses and resistance can develop to them over time. These drugs also both seem to need support from traditional (difficult to tolerate) chemotherapy to be most effective.

Simply put, there is more work to be done.

I am hopeful that this RXR research will be another “brick in the wall” toward treatments that hold more promise toward a real cure for APL.
One question I am left with after reading the article is whether the RXR structures are found in healthies as a trait in the t15:17 cells that sometimes carry? Is RXR an attribute that is only found in patients that have already or soon will develop full blown APL?

How’s Anita?

Here is a very short update on Anita.

Anita was admitted to the City of Hope about 10 days ago. She is at day zero of her transplant today. In fact, she received her own stem cells back about an hour ago and the process was uneventful. Anita’s nurse and two cell processing technicians stayed with Anita throughout the 90 minute process.

The stem cell transplant turned out to be a quiet event, part of a difficult process that one of Anita’s Dr’s referred to as “rugged” when I spoke with her yesterday. I can and probably will go into more detail on what the transplant preparation chemotherapy was like for Anita but not now. The bottom line is that the transplant has been difficult but is going according to her Dr’s plans.

Overall – when you hear the word “transplant” you can think about the hope that it brings but also realize that the hope comes along with a very tough road that includes alot of suffering, risk and difficulty.

Anita is resting now and as of yet has not developed any serious infections due to her chemotherapy treatment. Day by day her recovery should continue.

A lot has happened since my last post regarding Anita’s progress.

To summarize, Anita reached PCR negative status after her two rounds of arsenic based therapy. The PCR negative status was a great milestone for her as it meant that she qualified for a less intense and less risky type of stem cell transplant called an autologous transplant.   An auto transplant allows Anita to to donate her own stem cells, rather than relying receiving stem cells from a sibling or unrelated donor.

With the good result Anita obtained from Arsenic treatment, this set the stage for her to continue on to the stem cell transplant she needs to help prevent the return of her leukemia.

Anita is to receive an autologous transplant at the City of Hope in Duarte, CA. We are fortunate to have access to the City of Hope, especially since some types of insurance coverage won’t always provide access to a specialized cancer treatment facility like COH.

Our insurance coverage is with Kaiser Permanente and they have provided excellent treatment for Anita since her initial diagnosis in late 2001. Through all of Anita’s treatments, including about 150 days of hospitalization in the last 5 years, I never felt that Kaiser did anything “on the cheap.” We also found the Kaiser staff, including Anita’s primary oncologist and the many nurses that have worked with her for the last 5 years to be very dedicated and focused toward her care.

Back to Anita…

Even though Anita reached PCR Negative status after her Arsenic treatment, there were numerous “pre-transplant” tests she had to clear to make sure she was suitable for her treatment. Some of the tests were performed and San Diego and others at the City of Hope.

Anita has been working through the steps to get ready for her transplant for the past few months and she is finally ready – just a few days to go before it “happens.”   We knew the date for the transplant was getting close but we were waiting for a few test results to come in before it could actually be scheduled. This Thursday, Anita’s transplant coordinator nurse called and said the magic words – “it’s on for Monday.”

Basically COH seems to have made a big push to get Anita’s transplant scheduled quickly – to take advantage of the PCR negative result they obtained from her stem cell collection.
The day after the transplant nurse called we packed up Anita’s things and traveled to the City of Hope. Anita will likely be here for between 45 to 60 days with a lengthy series of recurring follow-ups thereafter.
Anita’s will start 6 days of strong chemotherapy tomorrow morning – Monday July 9th. The chemotherapy will work to destroy her existing immune system. After her immune system is destroyed, the stem cells that were gathered about a month ago will be re-infused into her. The re-infused cells will engraft back into Anita’s bones and will grow a new, hopefully healthy, immune system.

When Anita receives her own cells back (that she donated about a month ago) they will be delivered intervenously – just like you would receive blood after an injury (for example). The stem cells are smart – after being re-infused they return back to the interior of her bones and will get to work toward making a new immune system for her.

I spotted this article a few days ago on the ASH website. The article discusses a group of investigators in China that treated 60 APL patients, mainly with ATRA and Arsenic – with no use of traditional chemotherapy such as Ara-C and Idarubicin. Leave it to the Chinese to try something radical like this – they often seem to march to their own drum.

Of course they were likely treating APL with Arsenic close to 2,000 years ago but didn’t know it was called “APL” back then!

The 60 patients will have to be followed over a longer term but it is interesting to see the success the article reports.

Seeing this article makes me wonder if the continued use of traditional chemo for APL might be at least somewhat rooted in practices that existed before the advent of ATRA and arsenic.

***

From the American Society of Hematology 2006 conference

Investigators at the MD Anderson Cancer Center showed that patients with acute promyelocytic leukemia (APL), not ideally suited for chemotherapy, can experience a high rate of complete remission and high likelihood of disease-free survival, albeit with short follow-up, if treated only with all trans-retinoic acid (ATRA) and arsenic trioxide as front-line therapy.[18]

Liu and colleagues[19] from Shanghai, China, presented a cohort of 60 patients treated with 25 mg/m2 oral ATRA plus 0.16 mg/kg intravenous arsenic trioxide daily until complete remission was achieved. Then, 3 courses of consolidation chemotherapy were given, followed by 5 cycles of sequential treatment with ATRA, arsenic trioxide, and 6MP/methotrexate.

In all, 93% of patients achieved remission within a median time to complete remission of 27 days. Two of these patients experienced extramedullary relapse, but all the remaining patients were alive and in a hematologic remission, yielding a 4-year overall and event-free survival of 98% and 94%, respectively.

The most comprehensive randomized study comparing standard ATRA/chemotherapy with ATRA/chemotherapy/arsenic is CALGB 9710, an intergroup study in which patients received 3+7 chemotherapy plus ATRA during induction and then were randomized to receive standard consolidation therapy with ATRA/anthracycline preceded (or not) by arsenic trioxide.

Although the final results of this study were not presented at ASH, Dr. Powell did report aggregate toxicities from this study[20] that indicated that only 10 of the 518 adults and none of the 64 children enrolled experienced a lethal event during induction. The overall results also confirmed the validity of the European risk stratification scheme that defined 3 risk groups: low-risk patients, white count < 10,000 and a platelet count > 40,000; intermediate-risk patients, white count < 10,000 and a platelet count < 40,000; and high-risk patients, white count > 10,000. There was a high rate of induction death and relapse in the high-risk group. This study suggested that if arsenic trioxide is confirmed as therapeutically beneficial in terms of disease-free survival, then the toxicity will be acceptable.

Some interesting molecular correlates of treating patients with APL were presented.[21,22] Prior results indicating that the presence of detectable disease via PCR analysis for the PML-RAR alpha transcript would predict for relapse were not confirmed when a quantitative PCR analysis was employed. A single post-consolidation time point did not predict relapse of APL in patients. A more sensitive assay might improve relapse prediction rate, but this would need to be confirmed with further testing.

The Spanish PETHEMA group[23] demonstrated a very high rate of long-term disease-free survival in APL using retinoic acid plus chemotherapy (without ara-C). In a retrospective study looking at the incidence and risk of thromboembolic events, the group found that these events occurred in about 5% of patients with active APL.[24] Hypofibrinogenemia and the microgranular variant were risk factors for this complication, and tranexamic acid was not a useful prophylactic strategy. Spanish investigators analyzed the impact of FLT3 activating mutations on the outcome of patients with APL, looking at 733 consecutively treated patients.[25] The incidence of FLT3 ITD mutations and FLT3 D835 mutations was 24% and 10%, respectively. Although such mutations were associated with leukocytosis, the microgranular variant, and expression of CD34 surface antigens, they had no independent prognostic significance in patients who received aggressive state-of-the-art treatment.

Summary

In summary, patients with APL can expect to enjoy a greater than 80% long-term disease-free survival whether or not they are treated with chemotherapy plus retinoic acid or arsenic trioxide plus retinoic acid. The value of adding arsenic to chemotherapy plus retinoic acid should be clearer once the unblinded results of CALGB9710 are available.

This article summarized the findings of the European Hematology Association (EHA) in Vienna from 7 through 10 June.    The article summarizes the major research efforts from the European perspective.  Most of the research initiatives that are described revolve around different types of gene therapy.

http://www.medicalnewstoday.com/medicalnews.php?newsid=74127

APL MicroRNA research is mentioned in the above link.    MicroRNA’s sound like they hold alot of promise for the future – time will tell.   One problem with any new treatment is that the existing treatments are pretty good – so “doing better” than the well established Retinoic Acid / Arsenic protocols is not easy.

I appreciate the “higher altitude” view that summary articles like this provide.