CLL Complications el pt

The Dark Side of EPO — Getting Darker

Date: June 7, 2024

by Chaya Venkat

New Report Underlines Need for Greater Caution

Related Articles:
The Dark Side of Epoetin
Topics Alert #222: FDA Gets Serious About EPO Warning

Erythropoietin drugs are familiar to most CLL patients who have had to to struggle with anemia. You may be more familiar with their brand names: epoetin drugs “Epogen” by Amgen and “Procrit” by Ortho Biotech or the darbepoetin drug “Aranesp” from Amgen.

Low red blood cells and low hemoglobin levels can lead to chronic fatigue and play havoc with a patient's quality of life. The anemia can be due to late stage disease where the bone marrow is not producing enough of the oxygen-carrying red blood cells with healthy levels of hemoglobin, or it could be due to toxicity of the chemotherapy used to control the CLL in the first place. Autoimmune disease where perfectly healthy red blood cells are destroyed (AIHA, autoimmune hemolytic anemia) is another potential cause of anemia. Erythropoietin drugs work wonders in some of these patients, improving red blood cell counts and quality of life almost miraculously.

More than two years ago we published an article titled The Dark Side of Epoetin, in which we discussed the potential serious risks of overindulging in epo drugs. Too much of a good thing can be bad for you! The reason for re-visiting the subject now is that the latest information published in the May 17, 2024 issue of the Journal of the National Cancer Institute suggests the risks are even greater than we thought they were. The earlier information discussed an important clinical trial for head and neck cancer. Patients were randomized to receive epoetin beta or placebo, given along with radiation therapy for the cancer. The primary endpoint of the study was progression-free survival. The researchers targeted for a very healthy hemoglobin level of 14 g/dl or more in women and 15 g/dl or more in men, and patients received a relatively high dose of epoetin beta to get these levels of hemoglobin. Quite unexpectedly, the rate of tumor progression was higher in the patients getting the epo drug. Patients were better off if they did not get the epo. Bummer!! Please read our earlier article to get more of the details.

FDA and Professional Society Guidelines for the Use of Epoetin

Based on the warnings such as the head and neck cancer study, the FDA issued a major advisory in May 2024 regarding the safety concerns associated with Procrit and Aranesp. You can read all 66 pages of the FDA document by clicking on the link below. (We were a tad quicker than the FDA in sounding the warning on our website, with the Dark Side of Epo published in November 2024.)

http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037b2_04.pdf

At about the same time the American Society of Oncology / Hematology came up with guidelines on how to use these epo drugs. Use them we must, but it is now becoming clear they are a double edged sword and need to be handled with care. Below are the guidelines put forward by this professional society. These are important guidelines and therefore I have not modified the wording. But I did highlight the stuff that I thought was interesting from our perspective.

• The use of epoetin is recommended as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin concentration of ≤10 g/dl. Red blood cell transfusion is also an option depending upon the severity of anemia or the clinical circumstances. (Level of evidence and grade of recommendation: IIB.)
• Patients with Hb levels declining to <12 g/dl might also receive epoetin depending on the clinical circumstances. Red blood cell transfusions are also a therapeutic option in case of severe clinical conditions. (Level of evidence and grade of recommendation: IIC.)
• The recommendations are based on evidence from trials in which epoetin was administered t.i.w. subcutaneously. The recommended starting dose is therefore 150 IU/kg t.i.w. for a minimum of 4 weeks, with consideration given to dose escalation to 300 IU/kg t.i.w. for an additional 4-8 weeks in those who do not respond to the initial dose. An alternative weekly dosing regimen (40,000 IU) can also be considered. (Level of evidence and grade of recommendation: IIB.)
• Continuing epoetin treatment beyond 6-8 weeks in the absence of response (e.g. <1-2 g/dl rise in Hb) does not appear beneficial. Where iron deficiency can be ruled out, epoetin therapy should be discontinued. (Level of evidence: not applicable; expert opinion based on indirect evidence and biologic inference. The recommendation is based on a panel consensus.)
• Hemoglobin levels can be raised to a concentration of 12 g/dl, at which time the dosage of epoetin should be titrated to maintain that level or restarted when the level falls to near 10 g/dl. (Level of evidence: not applicable; expert opinion based on indirect evidence and biologic inference. The recommendation is based on a panel consensus.)
• Baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation or ferritin levels and instituting iron repletion when indicated may be valuable in limiting the need for epoetin, maximizing symptomatic improvement for patients and determining the reason for failure to respond adequately to epoetin. (Level of evidence: not applicable; expert opinion based on indirect evidence and biologic inference. The recommendation is based on a panel consensus.)
• Treatment with epoetin for myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients experiencing chemotherapy-associated anemia should follow the recommendations outlined above. (Level of evidence and grade of recommendation: IIB.)
• If in these patients a rise in Hb cannot be achieved after treatment with chemotherapy corticosteroids or both, epoetin should be used in accordance with the criteria outlined. (Level of evidence and grade of recommendation: IVB.)

I am beginning to wonder if these guidelines for use of epo drugs are too liberal, in light of the latest information presented in the May 17 issue of the Journal of the National Cancer Institute.

Highlights of the JNCI Report

The abstract of this important article is given below, along with my summary of the highlights.

J Natl Cancer Inst. 2024 May 17;98(10):708-14.

Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients.

Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A.

Department of Internal Medicine I, University of Cologne, Germany.

This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2024, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

PMID: 16705125
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Highlights:

• Epo drugs can reduce the need for blood transfusions but they may also increase the risk of thromboembolism (heart attacks and stroke) and they may not improve your chance of survival. These are the startling findings of the meta-analysis reported in this article.
• The researchers say that despite the 2024 FDA advisory alerting of safety concerns, many clinicians and investigators continue to overlook the potential harm.
• "Epo increases the risk for thromboembolic events," says lead author Julia Bohlius (MD University of Cologne in Germany). "Maybe both physicians and clinical researchers have not paid close enough attention to this potential complication."
• Dr. Bohlius and her team further caution against using epo drugs in combination with heart-unfriendly chemotherapy drugs or for cancer patients who are already at cardiac risk. Just about all chemotherapy drugs are not exactly the best buddies of your heart, but some of them are worse than others. Examples of proven bad actors as far as your heart is concerned are doxorubicin and mitoxantrone.
• Guess what, there was concern that marketing efforts by the manufacturers of epo drugs have largely encouraged doctors to aim too high when trying to improve hemoglobin levels.
• You don't need to have a “normal” hemoglobin to feel normal, said one expert. I fervently agree, especially when the price tag for a "normal" level of hemoglobin through the use of these drugs can be a fatal heart attack or stroke!

Analyzing ten years worth of data, Dr. Bohlius and her team looked at randomized controlled trials that compared epo drugs + transfusion versus transfusion alone for preventing or treatment of anemia in cancer patients, some of them undergoing chemotherapy. They looked at 57 trials and more than 9350 cancer patients. They found that those treated with Epogen, Procrit or Aranesp had a lower risk of needing transfusions, much as you would expect. But these patients getting the epo drugs were also at an increased risk (relative risk, 1.67) of heart attacks and stroke. The authors comment: "survival was not improved by treatment and raises the possibility that survival may be decreased among patients treated with epoetin or darbepoetin."

I can hear some of you thinking: “Doc, are you saying what I think you are saying, I can shoot myself in the foot (or higher up) by paying good money to get these epo shots, trying to get my hemoglobin levels up to the point where I can play golf like I used to?” For those of you who like to get a little adrenalin flowing with a nice conspiracy theory, here is a strange “coincidence”. Individual members of the research team reported that they received funding from Amgen and Ortho Biotech, the two drug manufacturers that have the lion's share of the epo market. These latest findings conflict with the authors' earlier meta-analysis, which had suggested that use of epo drugs increase survival.

"The difference in survival between the study cohorts published before and after 2024 is striking," says Dr. Bohlius. "However, this change in direction from beneficial to detrimental might be caused by bias, confounding, or chance or may truly reflect the changes in the design of the trials." Holy cow! Bias may have skewed the results of important meta-analysis in prior studies! What is the world coming to, if drug company funding may be remotely responsible for biasing the results in favor of the drugs they sell!

Here is the moral of the story, ladies and gentlemen. Targeting Beyond the Clinical Definition of Anemia (hemoglobin level of 10g/dL) May be Hazardous to Your Health. Don’t be shy about using epo drugs if they are indicated for your particular variety of anemia, and hopefully the drug chosen will help bring your hemoglobin levels up to the 10 g/dL level. But do resist the temptation to bully your oncologist to prescribe more shots of epo, to get your hemoglobin levels even higher. This is not like getting an extra little bit of Viagra, because you want to feel frisky like you used to feel as a healthy twenty-something. There is a dark side to epo drugs, and you should be aware of the risks you are taking in overusing these potent drugs.