Getting ahead of the curve

Hemoglobin5I 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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