Getting ahead of the curve
I try hard to stay within the lines, report the news as it is presented in professional journals. But once in a while a less-than-well-publicized item catches my eye and the implications are serious enough that I go the extra distance in highlighting it. Hopefully, clear distinction I try to make between my editorial comments and professional opinions are sufficient for you to make your own informed decisions regarding the credibility of what you read on our websites.
Indiscriminate use of Erythropoietin growth factors (used for increasing red blood cell counts) has been one such issue. We have been sounding the alarm about aggressive use of these growth factors (trade names: Procrit, Epogen, Aranesp etc) for several years now. “Darkside of Epo” and “Epo – getting darker” were published in 2003 and 2006 respectively. Since then, it has become more mainstream to caution over-use of these red blood cell growth factors, especially in cancer patients. The reason for visiting the subject today is the publication of new guidelines for use of these drugs, guidelines that are a whole lot more cautious and stringent they they used to be just a couple of years ago. Pardon me for tooting my horn for just a second – looks like my concerns about Epo growth factors were on target.
Epoetin Growth Factors
Newcomers among our readers might find a cheat sheet on Epo growth factors useful. Erythropoietin (sometimes called hematopoietin and often shortened to “EPO”) is a hormone produced by your liver and kidneys. It is responsible for production of red blood cells in your bone marrow. When there is a drop in the amount of oxygen carried in your blood due to anemia, that signals your kidneys / liver to make more of this important growth factor. Epo has two distinct mechanisms for increasing red blood cells available for oxygen transport. First, it increases red blood cell survival by protecting these cells from committing premature suicide. Second, it helps the bone marrow make additional red blood cells by encouraging the formation of red blood cell precursors.
Man-made versions of natural Epo were made as early as 1985. Before long, scientists were adding new twists, teaching Mother Nature a trick or two. Synthetic Epo drugs now have long strings of sugar attached (“glycosylation”). The reason for doing this is that addition of sugar tails makes it harder for the body to get rid of the molecule. As a result, it stays in your body for a longer periods and therefore the effects of the drug last longer.
Initially, Epo drugs were targeted at people suffering from kidney disease, patients undergoing dialysis on a routine basis. Since kidneys are the major source of Epo in the human body (liver makes only about 10% of needed Epo), kidney disease means patients are at risk of having insufficient production of this important red blood cell growth factor. Low Epo levels lead to low red blood cell counts and therefore causes anemia.
More recently the use of EPO drugs has been expanded to cancer patients. Many cancers and chemotherapy regimens used to treat them leave patients vulnerable to low red blood cell counts and it is tempting to consider Epo drugs as a miracle therapy for goosing red blood cell counts in those circumstances. I remember vividly a consumer targeted ad on television that I saw a couple of years ago. The ad opens on a slightly elderly man moping around and looking truly miserable because his chemotherapy induced anemia has left him with no energy. Then they show the same guy after getting a shot of Epo growth factor drug. Wow! What a difference! His anemia is totally resolved, his quality of life takes a huge spike up, he is now full of vigor and playing baseball with picture perfect grand-kids. Better living through modern medical marvels.
If I were in charge of the world (fortunately I have never been elected even as dog catcher), I would make it very difficult for drug companies to be able to showcase such blatantly one-sided advertisements to vulnerable patient populations. The pros and cons of using growth factors such as Epo are very much more complex than this and similar ads imply. Frankly, the downsides are quite numerous and I am happy to see regulators waking up to the facts circulating in professional journals and advocacy sites such as ours. There are many reasons why CLL patients may have low red blood cell counts. It is important to get a handle on why the patient is anemic before hitting him/her with Epo growth factors. In a nut-shell, the message is clear: more is not better when it comes to Epo. Use these drugs with caution and eyes wide open to possibly serious adverse effects.
2010 Guidelines For Use of Red Blood Cell Growth Factors
Below is the abstract of the new 2010 guidelines that have just issued regarding the use of Epo growth factor drugs. Do send me a personal email if you want a copy of the full guidelines article for your own reference library. If you are feeling a tad run down and anemic because of your CLL or therapy designed to control it, if your red blood cell counts are low and your local guy prescribes Procrit or Aranesp shots with no meaningful discussion of the pros and cons, this is an article you should read and take the initiative in having that discussion with your oncologist.
Blood. 2010 Oct 25. [Epub ahead of print]
American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer.
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR.
Medical College of Wisconsin, Milwaukee, WI;
Abstract
Objective: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs)in patients with cancer. Methods: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. Results: The literature search yielded one new individual patient data and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. Recommendations:For patients undergoing myelosuppressive chemotherapy who have hemoglobin (Hb) less than 10 g/dL, the Update Committee recommends that clinicians discuss the potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions)of ESAs, and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should raise Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.
PMID: 20974674
Strong words indeed from Committees generally inclined to be circumspect and not inclined to holler and scream. Now for some of the details highlighted in the guidelines.
- Before any decisions regarding use of Epo drugs, there must be thorough review of drug exposure history, blood smear and bone marrow examination when indicated, analysis of potential deficiency of iron, folate, vitamin B12 etc causing the anemia; also kidney insufficiency, blood loss due to hidden bleeding (stomach ulcers, for example), and any other alternative causes of anemia besides chemotherapy or underlying blood cancer.
- CLL patients may need to get a Coombs test to make sure the anemia is not due to autoimmune disease AIHA (autoimmune hemolytic anemia).
- Epo drugs have fully demonstrated risk of thromboembolism. Folks, the risks of blood clots causing stroke and death are very real. Your risk for thromboembolism is increased if you have a history of blood clots in the past, if you are very sedentary in your habits, or if you have had recent surgery that required immobilization. Hmmm. I wonder if frequent long distance air travel counts towards high risk of blood clots. My recent trips to India have brought into sharp focus how narrow the seats are in coach class. Sitting middle of the row for 17 hour on a non-stop flight (Newark to Mumbai) is bound to cause havoc with good blood circulation.
- Use of Epo drugs for chemotherapy associated anemia where the hemoglobin levels have fallen below 10 g/dl is one option. Red blood cell transfusions are another valid option. The choice depends on the severity of the anemia and clinical circumstances of the individual patient. The committee punts the question a little bit by saying patient preferences should have much more impact in choosing between Epo growth factors versus red blood cell transfusions. Sounds a bit like they are not really sure about the safety of Epo drugs – but I could be reading too much into this statement about taking patient preferences into account. Perhaps they are just being considerate – you think?
- 10g/dl hemoglobin level as the cut-off point is not cast in stone. In general, the rule of thumb seems to be use the lowest dosage adequate to do the job and use it for the shortest possible time consistent with getting adequate response. Higher drug dosage is not necessarily better. The target is to increase hemoglobin levels to the lowest levels needed to avoid transfusions while improving patient symptoms. We are not looking to get patients so pumped with hemoglobin and red blood cells that they can run marathons or play aggressive sports.
- There are many possible reasons for anemia. Patients should be tested and monitored for iron levels, iron binding capacity, trasferrin saturation, folate and vitamin B12 levels etc to rule out other causes.
- Recommendations are not to use Epo drugs in cancer patients who are not also getting myelosuppressive chemotherapy. Many of the drugs used to treat CLL are myelosuppressive – examples are fludarabine, cyclophosphamide, Campath etc. So, if you become anemic as a result of treatment with any of these drugs, using Epo to treat the anemia is a possible option. But if you are anemic because your CLL has infiltrated the bone marrow to the point where it is unable to function, or you have developed AIHA, then using Epo drugs to combat the resulting anemia is not recommended.
- Specific to CLL patients, doctors are recommended to use chemotherapy to address the underlying CLL problems (free the bone marrow space from infiltrating CLL cells clogging it, treat CLL precipitated AIHA) rather than use Epo drugs to address anemia caused by these problems.
I am pretty pleased regulatory guidelines have finally caught up with the cautions being sounded by clinicians treating cancer patients suffering from the debilitating effects of therapy induced anemia. It is no fun when you find it hard climbing the stairs to go to bed, when anemia causes fatigue so deep that it starts to hurt quality of life. But if there is one thing I have learned, it is that there is no free lunch when it comes to CLL treatments. Epo drugs often give patients a quick boost of hemoglobin but they are not a cost-free solution. They are powerful drugs. I am glad we have access to them, but be sure to use them with caution. You don’t want to pay more than you bargained for.
Next week, I plan to write an artcle on the use of the other growth factor drugs that are popular with CLL patients – namely, man-made G-CSF (granulocyte colony stimulating factor) growth factors designed to increase neutrophil counts. Popular brand names of G-CSF drugs are Neupogen and Neulasta. I am beginning to see trends that worry me and I would like to share them with you.
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22 comments on "Use Red Blood Cell Growth Factors (Aranesp, Procrit, Epogen) With Caution"
Thank you Chaya, very informative again.
Abe
Very interesting, Chaya (as usual! ) A little closer to home for me, this time.
I did have AIHA four years ago, and they treated mine with good ol’ prednisone. A friend and neighbor, who is a doctor, was concerned that they started me at such a high dose (120 mg daily) but they tapered that down to 40mg in the first week…and then eventually down to 5 mg at the end of it all two months later.
It worked fine…and my doctor never considered procrit, or any of the other epo brands.
Anxiously waiting your article on neupogen…had a LOT of that during chemo!
Harley
Isn’t it true that some of the recent clinical trials incorporate EPO and G-CSF into the treatment? I am thinking of the PCR – Campath trial that was initiated by Mayo. I guess I am a bit puzzled why EPO is safer if you are getting chemotherapy drugs at the same time? [I think I better go back and read your earlier articles too.]
I was treated with FR in 2008, had a partial response, and currently 31 months to relapse. Re-treatment will be necessary one of these months soon. I discussed FR vs FCR with my oncologist and we agreed to go with FR. My concern (and I might be off the mark here) is that FCR or PCR can increase the need for C-GSF drugs. C-GSF drugs and cytoxan can weaken bones. There may be a greater risk (albiet small @ 3%) of AML with FCR usage (if I read the summer’s CURE article about CLL correctly). Byrd states that FCR is very active with the chromozone 11 involvement in CLL but I don’t have that.
I may not get a deep, negative complete response with FR but I’m comfortable with the trade off if it can minimize a need for red-cell booster drugs. With my treatment in 2008 I was lucky to maintain blood counts in the normal range (excepting the lympocytes of course). I know this is naive, but I’m hoping I get lucky once again. :)
I’m eager to learn what researchers find out about PCI-32765. That is in clinical trial and may interact with the cancer but doesn’t create so much havoc with those red blood cells … or so the scientists hope.
Thank you so much, Chaya, for yet another great entry.
Judy
Judy:
The recommendations are not saying EPO is safer if you are also getting chemotherapy. They are saying that EPO drugs may be the right way to go for anemia caused by chemotherapy – but not if the anemia is due solely due to underlying cancer.
For example, if the anemia is due to bone marrow packed by CLL cells, it is not appropriate to use EPO to rectify the anemia, it is a better choice to use therapy to restore bone marrow function by clearing out the CLL cells. Likewise, if the anemia is due to AIHA, it is recommended to treat the AIHA (steroids, rituxan etc) rather than try and create more red blood cells via tretment with Epo drugs, which in turn end up getting killed.
In other words, it is important to know the cause of anemia before deciding Epo drugs will be the right thing to prescribe. As you can well understand, for a patient suffering from anemia due to iron deficiency, giving a growth factor to goose the bone marrow into increased production of red blood cells is not going to work.
As for your comments re FCR versus FR: a number of experts feel that addition of “C” to the FR combination is beneficial in patients with the 11q deletion. Treatment of this particular chromosomal abnormality seems to benefits when all three drugs are used in combination. Of course, neither FR nor FCR works for 17p deleted patients. For others with lower risk CLL, FR may be a good choice since it may reduce toxicity from the addition of “C”.
Chaya:
Excellent as usual, although first time reading about EPO in a non bicycle/track and field doping context!
Next time you have a long flight make sure you wear your compression socks- I bought them for running and am now using them on all my flights given the space squeeze on many planes.
Just curious have you heard anything from the drug companies in response to the new “guidelines”?
Dan
I have not heard anything, yet, from the manufacturers of Epo drugs. The evidence is pretty solid and I doubt they will spend much more effort in direct-to-consumer marketing.
Surprisingly enough, I did get somewhat negative feedback from one our readers:
“I am not going to go to your website anymore as I find that your articles are generally very negative and I feel that you give people with CLL the feeling that there is no hope which is really sad since people that have CLL are looking for positive support and articles of insiration and new trials/treatments/resources available.”
I see articles such as this as heads-up warnings in an ever changing CLL landscape. My personal bias is towards wanting to know what is coming at me from around the curve. As for positive perspective, I thought the latest article on FCR results was very positive for large percentage of CLL patients!
But I suppose some of my articles can also be cause for depression and negative feelings. The glass is half full or half empty, depending on how you look at it. I fully agree it might be a good idea to take a short (or life time!) vacation from reading my reviews if some of you feel the same way as this member.
A difference is noted between use in palliative care and in first line treatment. Also, CLL is not curable, and is by its nature could be considered palliative, so Dr. Rizzo emphasizes the need to assess each case individually. Anyone taking the agents must be on chemotherapy.
Medscape article link:
http://www.medscape.com/viewarticle/731228
hump39
Chaya please don’t stop your helpful input for those of us who truly need to hear all sides of what CLL is about.
I don’t presume to know all of the facts, be it good or bad and you have helped me understand this beast.
Thank You
An excellent article as usual. I prefer to know the enemy to batle him with the correct arms. How much we know about this disease better we are able to face him. Your articles are always informative and you choose topics that are so importants. Also let us know the researchs with new class of drugs.I will be always grateful with your efforts and work with this site.
Some people would rather not know the full ramifications of cancer. But the good and the bad are all part of the reality, and while hope is essential, especially with new approaches being developed, there is always the hard fact that cancer is not the flu, and there will be negatives, be it side effects, or a turn for the worse, or worse. People can choose to read your site, Chaya, as they do others, with the awareness that there are other sites more preferable to them. The internet is a free forum. You aren’t going to change for every person who wants their own version of reality. It would drive you crazy.
Facts are facts – stick to them!
Thanks for the words of support. I do not plan to change my spots this late in the day.
However, I do think there is some merit to taking a little “vacation” from CLL once in a while. There is danger in letting this disease take over your lives to the exclusion of everything else. Life is worth living and we need to learn how to live with the CLL. If that means you go away for a while, so be it. This website will still be here and you can get back to speed as quickly as you need to.
Neither http://www.clltopics.org or this website are like the daily newspaper where old issues consigned to the trash can. All the articles I have ever published are still there when you need them – with just a little effort on your part searching for them. Articles you find depressing today may have exactly the information you are looking for in a few months or years.
I don’t think your articles are at all negative. Quite the contrary.
My hematologists offer virtually no information and when I ask questions, they dodge and pivot. So, I come here to get educated and then do what I darn well please after carefully reflecting on the science information you analyze. I figured out through your website what bucket I’m in and what the prognosis is. I can live with that. I’m a grownup. As an aside, my hematologists have confirmed my bucket and prognosis, even if I did have to drag it out of them, ha, ha.
There’s no other CLL site like this one. I am grateful for it. Please don’t even think of going away or even hibernating. If you tried, we’d just form a committee to track you down.
Thank you Chaya, for keeping us inform.
Stay well,
Monique
My vote is with Manhattan. The hematologists avoid offering information and almost seem annoyed if you present a list of thoughtful questions which may take them beyond the allotted time schedule. I was told, it was not of any consequences to know as much information, as I requested, in terms of the bucket list lab tests. CLL, he said, was only treated when the symptoms occurred. This attitude does not work for me.
I live by the axiom – Keep your friends close and your enemies closer – CLL continues to be exposed, with all of the twists and detours, due to the dedication and sacrifice, of you and your family, Chaya. With your incredible credentials, you have given this community the power to look at the monster, eye to eye. I trust your complete integrity to feed us the truth – always with a gentle, compassionate glove and a loving dash of wit, Sometimes it is bitter – more often, than not, it is celebrated with hope. It is always an extraordinary Gift to all of us.
Thank you.
Chaya,
Thank you for this very important article. I await the information on Neulasta which I had a few times with Bendamustine.
Many Blessings,
Rita
It’s a free country and nobody is forced to read the important information provided on this site. ‘Incurable’ is a very depressing place to be, but all the info on this site personally gives me hope.
My husband and I had different philosophies about info related to his CLL. I did a lot of reading and he did not.He commented once that he didn’t like the look on my face when I came away from searching for info on the computer. He did die of complications and transformation of the disease withing 2 years of diagnosis. Recently his sibling stem cell donor died of an embolism,( age 55;overweight sedentary smoker treated for renal cancer within 3 months of donating stem cells.) I return to this site to get an understanding of what went wrong and how if affects other members of the family. This site helped us communicate knowledgeably with our medical team.
Thank you Chaya for the consistant feeding with your insightful updates. One can get complacent after coming out from the other side of FCR treatment with minimal residual disease. Your constant vigil updates helps me curb that habit. Currently finishing a 2nd round of antibiotics in a month to combat reaccuring congestion complicated by the high pollen and mold levels at this time of the year in my hometown. MD Anderson physician wants me to continue to have blood monitored for 6 months at my local facility and, if warranted, get a boost with Neulasta. I look forward with great anticipation and concern to your next article re: Neulasta. So glad your eye surgery was successful, you give us ‘clear vision’ into this complicated arena!
Rosymk and I are in the same boat. My father passed away in 2008 following a Richter’s Transformation in winter 2006/2007. I read your site, as well as CLL Canada, and both have helped me to understand the freight train that hit us. I was part of the ACOR list for a few months, and although I don’t have CLL, the kindness and perspective of some list members was invaluable. I also read the medical records. From all that, I stared cancer in the face like I couldn’t before. Understanding is not bliss, but it helps with healing, at least for me. And yes, it is good to take breaks.
Chaya,
I have to add my “Thank You!” for the articles that you bring to the site for commentary. Being newly diagnosed and in my 40’s, CLL Topics has provided me with invaluable information that isn’t available elsewhere in such easy to digest and understand terminology. There’s nowhere else where have I been able to start to put the puzzle pieces together in what I’m hoping will be a very long journey with (or without) this disease.
I don’t look at the warnings on the various drugs/treatments that you provide as “gloom and doom” and a cause for losing hope. Quite the contrary — I appreciate folks caring enough to look out for us and giving us a head’s up on drugs and treatments that may not be to our benefit in every situation. Being better informed, we can make better decisions in our own individual treatment. Having the information lets us research the topic even further and ask our own doctors about the risks/benefits should the treatment become an option.
If I wanted a ‘hand-holding, hugs & kisses can make CLL go away and we’ll all be cured site’, I wouldn’t have stayed on this site past the home page. There are plenty of those ever-so-positive-about-everything websites that offer the hand holding and snake oil cures postings that often go along hand-in-hand.
I want the facts — both good and bad — so I can watch out for those bumps in the road ahead. Thanks to your articles, I let my dermatologist know of my diagnosis (she’s familiar with CLL and the skin cancer relationship) so she’s even more diligent than ever. With a family history of skin cancer, it could have been far more dangerous for me to cover my eyes and ears and pretend that I didn’t know anything about the CLL/skin cancer relationship. But, because I was made aware of the connection, I made changes to help prevent possible skin cancer. And I’m sure after reading the articles that this will be one of the first of many changes that I’m making in my course as I continue down the CLL road.
The articles aren’t “negative”. They’re informative, timely, and more helpful than you could imagine.
Thank you Chaya for another great article. Also, remember to take those walks around the airplane and stand around the back of the plane and chitchat with whoever on those long flights.
Chaya, Thank you for both of these comprehensive articles. I have a couple of scomment though. I first read studies which implicated procrit et al in cancer deaths several years ago. Yet medicine continued to pump cancer patients full of it these last several years. I can almost hear the drug companies thinking out loud that if we stall out on this information we would be able to sell a whole lot of drugs before the information really catches up to us. And so be it with the acceptable loss to the cancer patient who has a recurrence and dies because of it.
I researched it several years ago for my aunt who is a two different type of cancer survivor but who now has a bone marrow depression which causes anemia. She is taking the procrit. This is the kind of thing that makes me crazy and distrustful. I totally understand the risk benefit scenarios since a person can’t live if hct gets too low. However, how in the world is the average patient to know these things?
I might as well get this thought off my chest as well. Why can’t the drug companies come up with something for cll like gleevac that really works without severely compromising the patient. I am simply terrified of my cll needing treatment. I have 5 grandchildren 4 and under. How can I be around them and take these drugs for CLL that turn a patient into practically an AIDS patient? It’s almost a case of if that happens put a deer head on mine and send me out on the first day of hunting season with a bullseye on my chest.
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