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CLL Complications

The Dark Side of Epoetin

November 22, 2003

by Chaya Venkat

Anemia in CLL - Unwanted Side-effects of Epoetin Drugs

One of the classic symptoms of advanced tumor load in CLL is anemia. Several different mechanisms have been identified for reduced levels of hemoglobin, red blood cell counts etc (Link: what needs to be fixed with Rai staging), but the independent of the reason for the anemia, the symptoms are all too similar: fatigue, tiredness, shortness of breath upon exertion. These are all important quality of life issues, and invariably they have an impact on the mental state of the patient as well. It is hard to remain cheerful and optimistic, when the vital transport of oxygen from your lungs to your body is compromised, and every cell of your body is clamoring for more juice.

Recent development of human epoetin drugs such as Epogen and Procrit have become household words thanks to very effective ad campaigns on commercial TV, depicting very human situations that every one can identify with. ("Epogen" and "Procrit" are different trade names for the same drug marketed by two different companies, Amgen and Ortho Biotech respectively. "Epoetin" is the generic name, "epoetin alpha" and "epoetin beta" are the same molecule, for all practical purposes).

Until recently, the problem was getting local oncologists to prescribe (and insurance companies to pay for) these drugs as suggested in national guidelines. But the overwhelming evidence of improved red blood cell counts, higher hemoglobin levels, and most importantly, improved quality of life for patients, has made their acceptance quicker than usual. Cancer patients who have been through epoetin therapy can attest to the remarkable change in energy and overall quality of life after therapy using these drugs. Now come reports of some disturbing side-effects that give pause. Once more we are faced with the stark truth that nothing is simple or risk-free in this cancer business.

The majority of clinical trials using Epogen and Procrit looked at end points such as RBC, hemoglobin, hematocrit levels, freedom from transfusion dependency and improvement in symptoms of fatigue, quality of life issues. The abstract below fits the bill perfectly, epoetin was a success story on all counts. End of story, right? Not quite, it seems.

Abstract:

J Clin Oncol. 2002 May 15;20(10):2486-94.

Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies.

Osterborg A, Brandberg Y, Molostova V, Iosava G, Abdulkadyrov K, Hedenus M, Messinger D; Epoetin Beta Hematology Study Group.

Department of Oncology (Radiumhemmet), Karolinska Hospital, S-17176 Stockholm, Sweden.

PURPOSE: To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM).
PATIENTS AND METHODS: Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale.
RESULTS: Transfusion-free (P =.0012) survival and transfusion- and severe anemia-free survival (P =.0001) were significantly greater in the epoetin beta group versus placebo (Wald chi(2) test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P <.0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P <.05); this improvement correlated with an increase in Hb concentration (> or = 2 g/dL). A target Hb that could be generally recommended could not be identified.
CONCLUSION: Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.

PMID: 12011126
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The Dark Side: The latest article in Lancet identifies the dark side of epoetin therapy. (See abstract below). The study was directed at patients with solid tumors of the head and neck, that were to receive radiation therapy. One of the mechanisms of cell kill by radiation is due to creation of toxic "reactive oxygen species". In other words, cancer cells are more prone to cell kill by radiation when there is plenty of oxygen around. Based on this, the study looked at the effect of giving patients epoetin ahead of the radiation therapy, making sure that the patients were not anemic as they went into therapy. This is an elaborate and well defined clinical study, all the bells and whistles such as double blinding and placebo control in place. The results are therefore that much more concrete and hard to discount. I am sure the researchers fully expected that the patient group who got the epoetin ahead of radiation would do a lot better than the control group that did not get the epoetin.

To everyone's consternation, the group that had received the epoetin ahead of time did much worse than the control group, if one looked at overall survival and disease progression after therapy. There are no two ways of interpreting the data in the abstract below: epoetin improved hemoglobin levels but not only did it not improve survival risk for patients, it actually made it worse. Sure, the anemia resolved in 82% of epoetin-treated patients, compared with only 15% of those who received placebo. But compared to the control group, patients in the epoetin group were 69% more likely to experience disease progression (p = 0.007) and 39% more likely to die (p = 0.02). The "p" values in parenthesis are statistical indicators of the significance of the results, any "p" value less than 0.02 is considered to be highly significant and no way due to happenstance.

Dr. Henke, the lead author of this study agrees that his study did not address the effect of erythropoietin in other settings and for other cancers, but he believes that it would be similar. "The hemoglobin effect, in which there is a poor prognosis whenever the hemoglobin is low, applies equally to all cancer types and to anemias associated with other diseases, so I don't think the effect on survival we observed in this study is specific to head and neck cancers," he said. "If epoetin stimulates tumor growth, it shouldn't matter which specific compound you use," Dr. Henke said. In other words, the results are not likely to be different whether one used epoetin alpha or epoetin beta.

Abstract:

Lancet. 2003 Oct 18;362(9392):1255-60.

Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.

Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C, Frommhold H.

Abteilung Strahlenheilkunde der Radiologischen Universitatsklinik, Hugstetter Strasse 55, D-79106, Freiburg, Germany.

BACKGROUND: Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer.
METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin <120 g/L in women or <130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat. FINDINGS: 148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02).
INTERPRETATION:
Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.

PMID: 14575968
______________

When it rains, it pours. The Lancet article is no aberration, the two abstracts below are also hot off the presses, and they spell out the message quite unambiguously: Epoetin regulates growth of several types of human cancer, improving their ability to survive and proliferate. The "mystery" was not so hard to understand, once researchers focused on it. Epoetin was not only involved in increasing the number of red blood cells, it was also involved in creating new blood vessels to carry the traffic of the new red blood cells created!

We have discussed angiogenesis as a mechanism used by cancer cells to create new blood vessels to feed the growing tumors, and more recently we discussed how various markers that control angiogenesis such as VEGF and VEGF-receptor are involved in the communication systems of cancer cells (Do you like drinking green tea?). Viewed from this perspective, giving a cancer patient epoetin is like giving the cancer cells exactly what they were looking for: a way to improve their supply/logistic support by creating new blood vessels to supply them with oxygen and nutrients, and create the microenvironment complete with good communication facilities that gives them a survival advantage.

Abstract:

Erythropoietin regulates tumour growth of human malignancies.

Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A, Onozaki M, Hashimoto M, Musha T, Ogawa K, Fujita H, Nakamura Y, Shiozaki H, Utsumi H.

Department of Anatomy, Division 1, Kinki University School of Medicine, Osaka-Sayama, Japan.

In addition to the chief function of erythropoietin (Epo) in promoting erythropoiesis, some other roles have been found in the brain and uterus. We have reported that signalling pathways of Epo and Epo receptor (EpoR) are involved in the tumourigenesis of ovarian and uterine cancers. To determine whether Epo plays a similar role in other malignancies, we studied the expression of Epo in several malignant human cell lines. We found that 24 malignant human cell lines examined express Epo and EpoR regardless of their origins, types, genetic characteristics and biological properties and secrete a very small amount of Epo individually and that most of them respond to hypoxic stimuli by enhanced secretion of Epo. To determine whether the Epo-EpoR pathway operates in tumours of these cell lines, we transplanted several cell lines into nude mice and confirmed the presence of Epo-responsive sites in xenografts in which the phosphorylation of the STAT5 (signal transducer and activator of transcription) is detectable. Furthermore, in nude mice we blocked the Epo signalling in xenografts of two representative cell lines, stomach choriocarcinoma and melanoma, by i.p. injections of EpoR antagonist and found inhibition of angiogenesis and survival of tumour cells leading to destruction of tumour masses and disturbances of phosphorylation of STAT5. In contrast, Epo mimetic peptide promotes angiogenesis and tumour cell survival. These findings suggest that Epo is indispensable for the growth and viability of malignant tumour and also that the deprivation of Epo signalling may be a promising therapy for human malignancy.

PMID: 12807756
______________

Lab Invest. 2003 Oct;83(10):1477-87

Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival.

Batra S, Perelman N, Luck LR, Shimada H, Malik P.

Division of Hematology-Oncology, Childrens Hospital Los Angeles, California, USA.

Erythropoietin was traditionally considered an erythroid-restricted cytokine, but recent evidence indicates a broader role for it in nonhematopoietic tissues, specifically in neural development. Pediatric solid tumors are mostly developmental in origin, and more than 50% of the solid tumors are neural in origin. We found erythropoietin receptor and erythropoietin expression in common pediatric tumor cells: neuroblastomas, Ewing's sarcoma family of tumors, pediatric brain tumors (medulloblastoma, astrocytoma, and ependymoma), Wilms tumors, rhabdomyosarcomas, and hepatoblastomas (n = 24), and in cell lines derived from some of these tumors (n = 25). Expression of erythropoietin in tumor cell lines was hypoxia-inducible. Addition of exogenous erythropoietin to tumor cell lines expressing erythropoietin receptor increased nuclear DNA binding activity of nuclear factor kappa B and increased the expression of the antiapoptotic genes bcl-1, bcl-xL, and mcl-1. Additionally, exogenous erythropoietin increased production and secretion of angiogenic growth factors, vascular endothelial growth factor, or placenta growth factor from the tumor cell lines, which promoted endothelial cell proliferation and chemotaxis. Erythropoietin receptor expression that promotes tumor cell survival and releases angiogenic growth factors in pediatric tumors has not been previously described. Therefore, a careful evaluation of the impact of erythropoietin is warranted in vivo, in xenograft models of pediatric tumors, followed by evaluation in pediatric patients with cancer.

PMID: 14563949
______________

Just in case you do not remember, here are a couple of abstracts that make it clear that angiogenesis is indeed important in hematological malignancies, not just in solid cancers. In fact, the abstract below suggests angiogenesis as a prognostic indicator in CLL, and the second one suggests that approaches to blocking angiogenesis may be good therapy to kill CLL cells.

Abstracts:

Blood. 2002 Nov 1;100(9):3344-51.

Prognostic value of enhanced bone marrow angiogenesis in early B-cell chronic lymphocytic leukemia.

Molica S, Vacca A, Ribatti D, Cuneo A, Cavazzini F, Levato D, Vitelli G, Tucci L, Roccaro AM, Dammacco F.

Department of Hematology/Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Viale Pio X, I-88100 Catanzaro, Italy.

Because tumor progression is angiogenesis-dependent, angiogenesis density was investigated by immunohistochemistry and computed image analysis in bone marrow (BM) biopsies of 45 newly diagnosed patients with Binet stage A B-cell chronic lymphocytic leukemia (BCLL) and correlated to upstaging and progression-free survival during a 40-month follow-up period. Their microvessel areas and counts were significantly higher than those of patients with anemia due to iron or vitamin B(12) deficiencies. A cutoff value of 0.90 mm(2) x 10(-2) or greater of the microvessel area identified patients with earlier upstaging and shorter progression-free survival. When the cutoff was applied to the Rai subclassification, both Rai 0 and Rai I-II patients who upstaged and shortened the progression-free survival were classified correctly. Information of this type was not given by the microvessel counts. The cutoff did not correlate with other predictors representative of tumor mass or disease progression. The microvessel area correlated with the expression of angiogenic vascular endothelial growth factor (VEGF) by tumor tissue, and serum levels of VEGF were found to be of prognostic value. A causal relationship between risk of progression and BM angiogenesis in BCLL is suggested. A risk stratification inside Rai is proposed. The prognostic usefulness of BM angiogenesis in patients with BCLL is envisaged.

PMID: 12384436
______________

Oncologist. 2001;6 Suppl 5:4-7.

Angiogenic growth factors: autocrine and paracrine regulation of survival in hematologic malignancies.

Gabrilove JL.

Division of Medical Oncology, Department of Medicine, The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.

Recent research has focused on the role of angiogenic growth factors and their ability to mediate tumor growth and metastases, both in solid tumors and in hematologic malignancies. The bone marrow microenvironment is the setting for a wealth of complex interactions that include cell-to-cell contacts as well as secretion of and response to soluble factors. Abundant evidence supports the role of basic fibroblast growth factor (bFGF) in contributing to the dysregulation of apoptosis that is the hallmark of chronic lymphocytic leukemia (CLL). In fact, CLL cells themselves express bFGF; intracellular levels of this cytokine correlate with clinical CLL stage. Other stromal factors mediate the inhibition of apoptosis in CLL as well, suggesting that strategies to block the responses of CLL cells to these factors may represent effective therapies. More broadly, the class of agents known as angiogenesis inhibitors may offer important advantages with respect to the treatment of numerous types of malignancies. Currently, a number of clinical trials are under way to evaluate the clinical potential of several different angiogenesis inhibitors in several hematologic neoplasms.

PMID: 11700386
______________

Where does all this leave us?

Should we shun Epogen and Procrit as too dangerous to use? Most definitely not!!

If you are anemic, before you say no to epoetin, just consider this: deep and prolonged anemia is a certain killer, besides making life miserable enough that you might not particularly care one way or the other. With that as a trade-off, signing up for Epogen / Procrit is a no-brainer. What this new information does point out, one more time, is that there is no free lunch. You may want to think twice about getting into long term maintenance type approaches to using these drugs, and certainly it brings into question the use of these drugs ahead of real medical need for their assistance. Can this pesky little problem be fixed? Possibly, by further refinement of the drugs, by combining them with anti-angiogenic drugs and by better risk classification of patients so that the drugs are used only in cases where their benefits outweigh their potential risks. It is too soon to tell. In the mean time, we will be keeping an eye on future developments in this area, looking to see if anyone comes up with bright ideas on how to get the benefit but not the risk in using these drugs.

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