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

Occasionally someone askes me “When will they find a cure for leukemia?”
Of course this is a tremendously naive question that ignores the  tremendous improvements in treatments that have developed in the last  20 years.   I usually answer the question by trying to explain that  cancer has to be fought on hundreds of different fronts and that while  many battles have been won, the war is certainly a long way from being  over.
My answer on this type of question always felt a little bit hollow.   What exactly was a battle in this context?   Why are the survival  statistics for certain types of cancer so much better now than they  were 20 years ago?
Today, I read a short article in the health section of Slate.com  that provided a great explanation on how the treatment of juvenile  leukemia was improved from a 20% to 80% survival rate between the early  70’s and late 90’s.   From my reading across a wide variety of cancer  related subjects, I think this short article provides a good paradigm  for how health treatments are improved for just about every tough  chronic disease.
Here’s the article- http://www.slate.com/id/2193294/  (also pasted below)

Old Drugs, New Tricks Why big health advances rarely involve new medicines.

By Darshak Sanghavi

Posted Tuesday, June 10, 2008, at 1:36 PM ET

Leukaemic cells

Between the early 1970s and the late 1990s, the  long-term survival rate of children with leukemia skyrocketed from less  than 20 percent to around 80 percent. Over this relatively short  period, many children presumed to be dying instead ended up living. As  remarkable as the surge is the reason for it. Dr. Steve Sallan, the  chief of staff at the Dana-Farber Cancer Institute in Boston, recently  told me that not a single newly discovered drug was involved. Nobody  invented some magical genetic therapy either. So what changed?
Too often, medical advances get advertised as the work of  swashbuckling doctors and patients who take big risks against big odds  and seize miraculous results with new treatments taken straight from  the lab. That narrative is misleading. As with pediatric leukemia, the  reality often is far less dramatic but no less impressive, and therein  lie critical lessons for patients with many chronic, tough-to-treat  diseases like asthma, attention-deficit disorder, and obesity.
The leukemia doctors saved lives simply by refining the use of  old-school drugs like doxorubicin and asparaginase. Over the course of  almost a dozen clinical trials, they painstakingly varied the doses of these older drugs, evaluated the benefit of continuing  chemotherapy in some kids who appeared to be in remission, and tested  the benefit of injecting drugs directly into the spinal column. The  doctors gradually learned what drug combinations, doses, and sites of  injection worked best. And they kept at it. With each small innovation,  survival rates crept forward a bit—a few percent here and there every  couple of years—and over decades those persistent baby steps added up  to a giant leap.

Today, we’re far more likely to hear exaggerated tales of  breakthrough new drugs, aggressively marketed and hyped. But it’s the  leukemia story that’s the historical norm. Back in the early 20th century, for example—decades before the discovery of antibiotics—tuberculosis mortality fell almost 70 percent (subscription required) due largely to careful studies of nutrition and hygiene. From 1980 to 2000, death from heart disease plummeted an astonishing 50 percent,  almost entirely from the use of existing medicines and surgical  treatments. These were gradually tweaked, like leukemia therapy, in  response to scores of incremental studies. During the past 30 years,  mortality from diabetes in men also has decreased by half, largely due to improved use of flu vaccines, smoking reduction, and possibly aspirin use—but not a new blockbuster drug.
Of course, new drugs can sometimes change everything. Example: Genentech’s novel angiogenesis inhibitor Lucentis, which restored vision in patients (subscription required) with macular degeneration. But such successes  are incredibly rare and even in cases like Lucentis, often unforeseen.  (James Watson, the co-discoverer of DNA, imprudently predicted in 1998 that angiogenesis inhibitors might “cure cancer in two years”  and said nothing about their use for treating eye disease.) And in  truth, we don’t have that many new drugs to call on anyway. Last year,  for example, the U.S. Food and Drug Administration approved only 19 entirely new drugs, many of which treat pretty rare diseases or offer little benefit over older medications.
If the greatest medical advances depend mostly on small but  consistent improvements in the use of old drugs, why do certain  specialties (such as psychiatry) fall behind others (such as  cardiology) in producing major results, like a 50 percent  population-wide improvement? The difference isn’t related to a lack of  drug choices. A psychiatrist now has a bewildering array of medications  to treat, say, attention-deficit disorder or depression, just as a  cardiologist can choose from dozens of anti-hypertensive pills. And the  influence of pharma companies is roughly equivalent in both specialties.
The real problem for lagging specialties is that they possess  numerous poorly studied, often recently approved drugs instead of a  small core arsenal of older drugs that are well-understood and so can  be dosed systematically. As the experience with leukemia shows, that’s  exactly the wrong way to cure disease. Successful specialties are  anchored by centralized, rigorous professional organizations that  served, over decades, as clearinghouses for study after study aimed at  calibrating therapy. Thus, cardiologists depended on the Framingham  Heart Study and the scientific committees of the American Heart  Association, pediatric oncologists have the Children’s Oncology Group,  and children’s lung specialists have the Cystic Fibrosis Foundation.  These specialties don’t pin all their hopes on new miracle cures;  instead, they do the grunt work of incremental clinical trials with the  pills they have. And as a result, they save many lives.
That doesn’t mean duplicating these successes is easy. Just as no automaker has successfully copied Toyota’s ingrained kaizen culture (which The New Yorker’s James Surowiecki likens to a hard-to-follow “regular, sustained diet”), the incremental doggedness of certain medical subspecialties resists imitation. But the lagging subfields should try.
Doctors in these fields first should take a long, hard look at their  priorities. Lagging fields are often the scene of paralyzing turf  battles between various institutions over clinical trials. By contrast,  the more successful specialties have overcome such pettiness and forged  nationwide partnerships to churn out study after study. The successful  specialties also encourage studies that choose incremental goals over  the big score.
Old Drugs, New Tricks Why big health advances rarely involve new medicines.

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

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
  

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.

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.

I think Arsenic will soon move into a frontline treatment, maybe as a consolidation therapy after Retinoic Acid / Chemo for new APL cases.I run a google-alert on the term ““apl leukemia” and most all the (frequent) press over the last month has been regarding newer study results for Arsenic and how effective it is proving to be.

Keep in mind that there were widely circulated reports of sudden-death and other serious complications when arsenic treatment was brand new. I was terrified by these reports when I read them before Anita’s treatment. Reading further though, it became apparent that the early troubles likely related to failure to closely monitor electrolyte levels (such as Potassium) especially during the first month of treatment.

In Anita’s case, she received her first 30 days of arsenic treatment in the hospital, then her second course as an outpatient. She didn’t have any of the usual side effects from chemo — no mouth sores, hair loss — no neutropenia etc. She actually drove herself to the hospital each day for most of her outpatient arsenic infusions!

Still — arsenic is a serious deal and there are still plenty of unknowns in terms of long term affects. Will it lead to an increased chance of secondary cancers later in life? Anyhow, don’t be so sure we are really “behind the times” here in the USA in terms of jumping into new drugs like Arsenic.

Arsenic is simply amazing for APL and it is pretty much unheard of for a medicine for a relapsed leukemia to be so well tolerated and effective. APL patients are extremely fortunate to have access to this therapy.

Here is one interesting item about Anita’s treatment…

Her Dr’s ran a PCR test about 10 days after Anita’s last dose of arsenic and it came back positive. This was a most unwelcome result. I was remember thinking “Crap – 60 days of arsenic and the leukemia is still present!” Basically we were shooting for a negative PCR test post arsenic therapy as that would allow Anita to get an AUTO transplant, rather than the more difficult ALLO type.

Anyhow, the next step with all of this is often a surprise and her Dr’s simply said – “Let’s run another PCR test – it will have probably converted to PCR negative status on its own after waiting a little longer.” I didn’t hold out a lot of hope for her result to “convert to negative on its own” — but it did!! The initially positive PCR test delayed Anita’s treatment a little bit but I am still very happy that she “went negative.”

So what if you are still “PCR positive” after your arsenic treatment?

Maybe waiting a little longer and running another test will get you your negative result. Some of the literature warns about not jumping into an ALLO just because of an “initially positive” result and the advice seems to be to wait for a “persistently positive” result instead.

Why does waiting sometimes help?

There is a lot of speculation on how Arsenic actually kills APL cells including some very specific ideas about the chemical pathways that are involved. I don’t understand all that really detailed “stuff” but basically I think the idea is that Arsenic doesn’t kill the APL cells directly, rather it reprograms them to assume a more normal life course — so they will die off on their own and not aggressively displace other cell types.

Some of this reminds me of Gleevec and Sprycel for the CML patients. I know very little about CML except that Gleevec and similar drugs have been a huge life-saver for many CML patients. Let’s hope that more and more drugs continue to develop like this — arsenic, gleevec etc etc!!!

Chris

One of the best ways to keep an eye on a subject that you care about is to use Google Alerts. This is a free service that establishes something called a “persistent search” for web pages with keywords that you specify. Google performs a search for the terms that you specify every day and they email links on any “new hits” they find when they occur (each day).

I maintain a Google-Alert search on several terms – one of which is apl leukemia. If something new comes up with APL, Google emails me an alert with a link to the APL related news article. This is a source of comfort for me as I really care about the subject but being busy with so many things I can’t necessarily research progress on APL every day.

Today, I received an alert for a new drug that is active against relapsed APL – it is called Tamibarotene or “AM-80″. Tamibarotene is already approved for recurrent APL in Japan and US rights to this drug were recently acquired by a company called Innovive. You can read more about Tamibarotene and Innovive here.

Like so many new drugs for APL (and other cancers), tamibarotene is not a magic bullet. It could be an important drug – but probably not a magic bullet – sort of a “another log on the fire” – or “another brick in the wall” toward an overall improved treatment.

I was able to find one clinical study (performed in Japan) where Tamibarotene was used to treat 39 relapsed APL patients that were initially treated with Retinoic Acid and Chemo. About 60% of the relapsed APL patients that were treated with Tamibarotene achieved a complete remission.

Time will tell if Tamibarotene will evolve into a very helpful drug for APL. In the near term, it will likely evolve into an important alternative to arsenic for treatment of APL. Arsenic may continue to be the best (perhaps by far) treatment for relapsed APL- but what if arsenic doesn’t work for you?

What if Arsenic creates life threatening complications for you or your loved one? Arsenic – that’s poison, right?

Arsenic treatment for relapsed APL is very effective but some people just cannot tolerate it. It is rare, but Arsenic can cause serious heart and/or liver complications. What if you can’t tolerate Arsenic? You need an alternative – maybe something like tamibarotine.

When Anita relapsed, I knew she would have to take arsenic to try and get back into remission. I remember being very concerned about whether Anita would be able to tolerate Arsenic. When you read about Arsenic for relapsed APL, you quickly learn that there aren’t any great established alternatives.

It is rare, but some people suffer very dangerous heart complications and some (also rare) suffer very serious and sometimes fatal liver complications. My thought was, what will happen if Anita can’t take arsenic- then what? Luckily, she tolerated it well so this was not a concern.

Still though – what about patients that cannot tolerate arsenic? Drugs like Tamibarotene might help – possibly providing an important alternative that could extend life.

Maybe there will be a few patients that cannot tolerate Arsenic will achieve remission with Tamibarotene. Maybe some of these same patients will then go onto a potentially curative transplant. I think that over time this sort of outcome is likely at least for some APL patients.

Anyhow, reading about Tamibarotene got me thinking about the importance of alternative treatments and drugs – leading to this quick post.

Clinical experience with a new synthetic retinoid, tamibarotene (Am-80) for relapsed or refractory acute promyelocytic leukemia

[Article in Japanese]
Takeuchi M.
Division of Hematology, National Hospital Organization Minami-Okayama Medical Center.

A new synthetic retinoid, Am-80 is expected to overcome all-trans retinoic acid (ATRA) resistance, because of several times more potent differentiation activity than ATRA and sustained plasma level during continuous administration due to a lower affinity for cellular retinoic acid binding protein.

In a preliminary study in Japan, 14 (58%) of 24 acute promyelocytic leukemia (APL) patients who had relapsed from ATRA induced complete remission (CR) achieved a second CR. Of these 14 CR patients, 4 of 6 who underwent allogeneic stem cell transplantation (SCT) are alive, and 4 of 8 patients who received only chemotherapy are alive without relapse for >4 years. Adverse events include xerosis, cheilitis, hyperlipidemia and so on, but these were generally milder than ATRA. In a phase 2 clinical trial, 25 (61%) of 41 patients entered CR.

Among 23 first relapsed patients, 18 (78.3%) patients entered CR, indicating excellent salvage effects for ATRA-relapsed patients. Am-80 may improve disease free survival when used as remission induction and/or maintenance therapy, and it may be effective for relapse from ATRA-induced remission and be curative for patients who receive SCT or intensive post remission chemotherapy.

Leafy on the LLS discussion board asked me to dig up the FLT3 / APL articles that I mentioned earlier. I will find these articles soon and will post links to them.

Meanwhile, MichaelM who is really a star over on the LLS board because of his very strong overall knowledge on AML, had some very insightful remarks on the FLT3 discussion.

Basically in this post, I am trying to provide some context and discussion to help support APL patients in trying to decide how much they want to learn about their disease. I especially want to express the notion that we all need to be careful about expecting our “lay person” knowledge to be very helpful in improving our treatment outcomes.

I am going to hop out on a limb and paste MichaelM’s remarks below as they provide context for my more lengthy post which appears thereafter,

MichaelM’s post-

This is a little complex in your situation.

APL is still an AML, and the presence of FLT3 _juxtamembrane_ mutations is always a negative indicator to some extent. In considering most APL to be one of the three better prognosis AMLs, though, the presence of such a mutation is not necessarily as bad as you might otherwise expect. (I’m intentionally hedging here, for obvious reasons.) You’ll have trouble finding a consensus on what, exactly, the impact is.

If you are sure testing for an FLT3 mutation was done, then they likely performed testing to determine BCR status (BCR1, BCR2, BCR3). Do you know which she showed? Other considerations would be whether this is an M3v (variant) AML or not.
If you’re just looking at a report that noted FLT3 somewhere, you should understand that there is a prognostic difference between the juxtamembrane (length) mutations (ITD – internal tandem duplications, and insertions, which are the ‘bad’ ones) and the codon mutations in the kinase region, which are generally felt to have less or no real significant prognostic value). There’s also a prognostic difference if there is a low ratio of mutant FLT3 vs wild (normal) FLT3, as well as if wild FLT3 is absent. The size of the mutation probably impacts the prognosis as well.

I know I have read of some protocols under study that involve FLT3 inhibitors front-loaded with traditional chemo or arsenic trioxide.

Chris’s comments:

MichaelM has obviously worked very hard to develop a robust understanding of AML. He is way ahead of me on this stuff.

It is perilous trying to summarize and simplify what he said as he understands much more of this than I. I think there is always a danger of trying to explain things in a way that is simpler than they really are.

If I understand his post, I believe the general idea is that you can’t really say much about interpreting the significance of FLT3 without also considering the subtype of APL along with other factors.

The APL subtypes I am aware of, are: short, long and variant. Also, I believe that the BCR1,2,3 values he mentioned equate (I don’t remember how each matches up) respectively to: short, long and variant types.

Anita has the M3v type and of course she relapsed at 5 yrs post first CR. I have seen a few studies have suggested that the M3v type is more difficult to deal with.

MichaelM’s other comment is that you cannot interpret the significance of FLT3 very well without knowing the concentration at which it was detected. I like how he said “FLT3 written somewhere on the report.”

I think all of this is very very interesting and I want learn all I can about it. Learning the details is interesting, but I still think it is very important to consider if any of this information can impact your treatment or help you in much of any way.

My question is, how can you use this information to help yourself (or others)? I think it can help a little bit but you need to carefully ponder its limitations.

Another point, is that hard data like “FLT3” is important, but is difficult to apply at least in some respects to an individual’s specific treatment needs. For example, if the individual had an odd liver toxicity issue with certain types of drugs, that could trump all kinds of ideas about making incremental adjustments to how APL should be treated.

I think Anita’s Dr carefully consider’s Anita’s overall status along with her APL treatment needs. Of course that sounds like common sense, but us lay people tend to take a narrower view of what we read in scientific articles about APL. I think we can end up missing the “overall approach” that a good Dr takes toward treating their patients.

What I am suggesting here is that it can take a great deal of experience and judgement to relate what you read in this or that article to a patient’s individual needs. Great Dr’s dedicate spend their entire careers developing the judgment and experience to manage tough diseases like APL.

Michael’s post illustrates is that as you dive deeper into the whole subject of APL, you will find that it drives rapidly into other cross connected areas of knowledge. What is a codon? What is a flow cytometry result? What are all these abbreviations? I think you might see what I am saying here. How far do us lay people really want to go with all this learning and can it really help our loved ones?

So much of this is not really in our control and an individual patient in a typical healthcare setting is not a science project. Oncs tend to be pretty conservative and will provide treatment along established lines that have been developed through phased studies.

MichaelM’s comment that there are possibly some trial studies with FLT3 inhibitors out there is of interest. Trial studies are whole new subject though though. See if you have to go across the country to even participate in many of them!

I get frustrated at times, where I look back and see great results from APL treatments that are standard now, like the blended use of AsO3 and ATRA for initial treatment. Those treatments were not standard 5 yrs ago and Anita did not receive them. Relapse seems to be considerably less likely when these blended treatments are used.

Would she have relapsed if she had received the newer treatment that was more experimental in 2002? We will never know. Think of all the thousands of what-if’s in life. If the slow but more sure approach of phased studies had not been carefully used for so many years would APL treatment had ever advanced to where it even was in 2002?

Moving on here, and back to your original FLT3 question, maybe you could somehow thoroughly anonomize your APL friend’s pathology report that mentioned FLT3. After it is carefully anonomized, I could post a scan of it over on www.aplblog.org and perhaps a few APL’rs could try to provide a few comments.

I am not a Dr or an expert on APL but I do think that there is a need for this kind of more technical discussion among lay people. There is such a huge canyon between the non-expert articles that I read regarding APL and stuff that is easier to understand.

Our Dr’s are just too busy to engage in very much this type of more technical discussion with lay people too so maybe we could just talk a bit about it on our own.

I also think it would likely drive most Dr’s crazy trying to talk all my super wide ranging questions through with me so that is probably the case for other caregivers and APL patients as well.

Chris
www.aplblog.org