Swami Murugappan MD PhD Hematology Oncology Fellow University of Washington April 27, 2012

Transcription

1 Swami Murugappan MD PhD Hematology Oncology Fellow University of Washington April 27, 2012

2 Outline Clinical indications of recombinant Erythrop0ietin (EPO) Concerns about the use of EPO in chronic kidney disease (CKD) and cancer patients Need for alternative treatment for anemia HIF pathways and EPO production Discussion of the paper Implications in the treatment of anemia

3 Why was EPO developed as a therapeutic agent? Poor clinical outcomes in chronic renal failure patients who had anemia Need for repeated red blood cell transfusions in hemodialysis patients To avoid infectious and non-infections complications of red cell transfusions

4 Commonly used EPO preparations First generation: 1. Epoetin alfa: Epogen (Amgen) and Procrit (J&J) 2. Epoetin beta: Neo-recormon (Roche-Non US territories) Second generation: 1. Darbepoetin alfa: Aranesp (Amgen)

5 FDA-approved indications for EPO Anemia associated with chronic renal failure (predialysis and dialysis patients) Anemia in zidovudine-treated patients with HIV Chemotherapy-associated anemia in cancer patients Off-label use: low risk MDS patients

6 Use of EPO in CKD patients with anemia Benefits: Reduces the frequency of red cell transfusions and improves quality of life Concerns: 1. Increased incidence of adverse cardiovascular and thromboembolic outcomes in patients treated to a higher Hb concentrations (>11 g/dl) 2. Meta-analysis shows that improvements in QOL is modest at best 3. High cost and usually available only to CKD patients who have been referred to a Nephrologist for dialysis

7 Current recommendations for EPO use in CKD patients with anemia Use EPO in CKD patients when Hb<10 gdl No target hemoglobin is recommended currently (previously at g/dl) Individualize dose for each patient and use the lowest EPO dose to decrease the need for red cell transfusions

8 Use of EPO for chemotherapy-induced anemia Epogen and Aranesp increase Hb levels and decrease transfusion needs in cancer patients who have chemotherapy-induced anemia Dose of EPO for treating chemotherapy-induced anemia is three-fold higher than required to treat anemia in patients with renal failure Five randomized trials have shown that parenteral iron increases the Hb response to EPO in cancer patients and decreased transfusion rates

9 Use of EPO in patients with cancer-induced anemia There is no strong evidence to support the use of EPO in cancer patients who have anemia secondary to the cancer or who are not receiving chemotherapy In fact, results from large clinical trials suggest that use of EPO in patients with cancer induced anemia might be harmful

10 Hypoxia-reduction theory Tumor hypoxia is thought to contribute to chemotherapy resistance Anemia was a poor prognostic marker in patients with cancer Studies done in gynecological or head and neck cancers showed that tumor hypoxia correlated with anemia, poor treatment response, and outcomes It was hypothesized that reversal of anemia or prevention of anemia during therapy will enhance efficacy of chemotherapy or radiotherapy

11 Effect of EPO on survival in cancer patients with near normal Hb

12 EPO and thromboembolic risk in cancer patients Use of recombinant erythropoietin and darbopoietin was associated with increased risk of VTE in cancer patients (Bennett C JAMA 2008) In a meta-analysis, the risk of VTE in patients receiving EPO was 7.5% compared to 4.9% in patients not receiving EPO (relative risk of 1.59) The risk of VTE was found elevated in patients who had established risk factors for VTE including surgery, prolonged immobilization, prior history of thrombosis and certain types of cancers (ex: myeloma) Proposed mechanisms include polycythemia, hyper viscosity, thrombocytosis, platelet hyperactivity, activation of coagulation,etc.

13 Current recommendations for the use of EPO in cancer population Chemotherapy-induced anemia when Hb<10 g/dl. Optimal target is not well defined. Should not be used if chemotherapy is used with the intent to cure. Use the lowest dose needed to avoid transfusions. Avoid in patients with cancer associated anemia or who are not receiving chemotherapy Low-risk patients with MDS

14 Economic burden with EPO use. Combined worldwide sales in 2005: Epoetin alfa: US $ billion Darbopoetin: US $ billion Compared with supportive transfusions only, EPO treatments in cancer patients using current guidelines resulted in an incremental cost per quality adjusted life year of greater than $100,000

15 Bottom line. Limited and defined use of EPO in CKD and cancer patients Well documented adverse events with the use of EPO in these patient populations Very expensive, even when used in a conservative fashion

16 Alternatives Return to age-old practice of red cell transfusions with the understanding of the risks involved EPO-mimetics Agents that increase the production of EPO Gene therapy

17 EPO 30kD, 165 amino acid hematopoietic growth factor Produced primarily in the renal tubular and interstitial cells with additional contribution from the liver Produced under conditions of low oxygen tension Results in erythroid precursor cell proliferation, maturation and increase in the red cell production Mediates its effect through EPO receptor

18 HIF stabilizers or GATA inhibitors EPO-mimetics or EPOR modulators

19 Hypoxia inducing factor (HIF) Transcription factor that binds to the hypoxia-responsive element (HRE) on the 3 prime region of EPO gene and induces EPO production Heterodimeric protein consisting of an oxygen sensing alpha subunit (1α, 2α,3α) and a constitutively expressed beta subunit All three alpha subunits are constitutively targeted for proteolytic degradation HIF1α is widely expressed but the expression of HIF2a is more restricted HIF2α is the key regulator of renal and hepatic EPO production as shown in conditional HIF2α deletion studies

20 Regulation of EPO production by HIF/PHD/VHL axis

21 Prolyl hydroxylases 2- oxoglutarate dependent dioxygenases Contain prolyly 4-hydroxylase domain (PHD) Comprises of three members PHD1, PHD2 and PHD3 Requires molecular oxygen and ferrous ion for its function Widely expressed Has differential affinities for HIF members, which is not clearly defined

22 Effect of HIF2 on EPO production and iron metabolism DcytB duodenal cytochrome B DMT1 divalent metal transporter 1 FPN ferroportin Tf transferrin Haase VH, Am J Phys Renal Phys 2010

23 A quick summary. EPO mainly produced in the kidneys and liver Production is increased by HIF HIF is negatively regulated by PHD/VHL under normoxic states HIF improves iron mobilization from the gut and RES through multiple mechanisms including inhibition of hepcidin

24 The HIF Signaling Pathway in Osteoblasts Directly Modulates Erythropoiesis through the Production of EPO

25 Osteoblasts and Hematopoiesis Osteoblasts are required to maintain hematopoiesis in the bone marrow Loss of osteoblasts in conditional ablation studies resulted in loss of early HSC as well as committed erythroid progenitor cells Little is known about the mechanism by which osteoblasts support hematopoiesis, particularly, erythropoiesis Osteoblasts possess HIF/PHD/VHL axis and this plays an important in bone formation. Ablation of HIF results in loss of bone volume

26 HIF signaling directly or indirectly regulates hematopoiesis Deletion of HIF1 in HSC causes loss of HSC quiescence and numbers during stress conditions HIF signaling directly promotes erythroid progenitor survival HIF2 promotes EPO expression in kidney and liver and thus promotes erythroid progenitor viability, proliferation and differentiation

27 How does osteoblasts regulate erythropoiesis and is there a role for HIF signaling pathways in this process?

28 Recap.

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30 Augmented HIF activity in OP cells results in: 1. Increased trabecular bone 2. Increased vascularity 3. Increased numbers of HSC

31 Augmented HIF activity in OP cells results in: 1. Increased trabecular bone (collagen staining) 2. Increased vascularity (CD31 staining) 3. Increased expression of VEGF locally 4. No increase in serum VEGF 5. The increased HSC are functional as measured through repopulation studies

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33 Augmented HIF signaling results in selective erythroid lineage expansion

34 Increased Hct in VHL mutant occurs in an EPO-dependent manner Fig 4

35 Summary -1 Augmentation of HIF-2 pathways in osteoblasts results in: 1) Increased trabecular bone formation 2) Increased HSC numbers 3) Expansion of erythroid lineage in marrow and spleen 4) Increased expression of EPO 5) Elevated Hct secondary to increased EPO

36 What happens if HIF pathway is inactivated in osteoblasts?

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38 Summary -2 Inactivation of the HIF pathways: 1. Decreased HSC numbers 2. Decreased EPO expression and erythroid colonies in the marrow 3. Normal Hct 4. No effect on erythropoietic response with hemolysis (WT and HIF mutant had similar extent of reticulocytosis) HIF signaling in osteoblasts is NOT necessary to ensure normal Hct in either normal or stress conditions but contributes to maintenance of erythroid progenitor pool

39 Recap.

40 Effect of PHD inhibition on Hct and osteoblast EPO expression

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42 Conclusions HIF pathways in osteoblasts maintains erythroid progenitor homeostasis HIF augmentation can induce polycythemia in an EPOdependent manner and protect against stress-induced anemia PHD inhibition induces increases in Hct and EPO expression similar to that of VHL deletion-mediated HIF augmentation PHD inhibitors can be used to treat anemia

43 Osteoblast derived EPO via HIF

44 Issues.. Why does HIF augmentation dramatically decreases the absolute lymphocyte count? What is the serum EPO levels in animals with PHD deletion? Inhibition of PHD does not cause similar extent of polycythemia as HIF augmentation through VHL deletion What happens to other cell counts/lineage with PHD inhibitor? Lymphopenia?

45 PHD inhibitors/hif stabilizers in the treatment of anemia Benefits: 1. Low cost and ease of administration (oral) 2. Increases endogenous EPO (supported by Phase II trials) 3. Improves iron utilization and inhibits hepcidin 4. By augmenting HIF in osteoblasts, increase local EPO expression and promotes erythroid progenitor expansion 5. Increased HIF signaling in the erythroid progenitors promotes survival independent of EPO Problems: 1. Inhibition is non-specific 2. HIF-1, 2 and 3 could be augmented, which may not be desired given their ubiquitous expression and key roles in homeostasis 3. Immediate and long term safety would be a major concern

46 Congenital polycythemia and mutations of HIF-2, PHD2 or VHL genes HIF2 mutation patients: Gain of function mutation. Young age with isolated erythrocytosis with elevated EPO levels. Few patients had episodes of thrombosis, independent of their Hct. Otherwise, unremarkable clinical course. Treated with intermittent venipuncture. (Percy MJ, NEJM 2008) PHD2 mutations: Loss of function mutation. Young age at presentation with increased Hct but normal EPO. Intermittent symptoms of paresthesias but no VTE or other adverse events. VHL ruled out. No cancers in the family. Treated with intermittent venipuncture. (Percy MJ PNAS 2006) VHL mutations: Chuvash polycythemia (VHL 598C>T) with loss of function mutation. Young age at presentation. No tumors. High risk of CVA and peripheral thrombosis. Incidence of VTE nor related to Hb levels. Median survival 55yrs. (Ang, Nature Genetics 2002 and Gordeuk VR, Blood 2004)

47 PHD inhibitors in clinical testing. FG-2216 (Phase II) FG-4592 (Phase II) GSK (Phase II) AKB-6548 (Phase II) BAY (Phase II) PHD2 selective inhibitor that augments HIF2 might be best.stay tuned

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50 Thanks