Expert Review of Hematology, May 2015;8(S1):S1–S32 Informa UK, Ltd. ISSN: 1747-4086 print/ ISSN1747-4094 (electronic) DOI: 10.1586/17474086.2015.1044965
EDITORIAL
3rd Mediterranean Multidisciplinary Course on Iron Anemia
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
April, 17th–18th 2015, Rome, Italy A new–old problem in medically ill: anaemia of chronic disease Sandro Barni Director of Oncology Department, Medical Oncology Unit, A.O. Treviglio (BG), Italy
underreported, is a mild form of anaemia, linked to interference with specific (tyrosine-kinase) associated receptors expressed on hematopoietic cells. In particular, multitarget tyrosine-kinase (e.g sunitinib) or mTOR inhibitors used for treating solid tumours, are able to increase by 5–10% the risk of anemia (mainly of low grade) that are overall reported with a rate of 50% in major randomized trials. We have two main ways of treating anaemia (other than treating cancer itself) in these conditions: exogenous iron and erythropoiesis stimulating agents (ESAs). The history of ESAs was troubled by safety concerns raised from old studies where they were inappropriately prescribed, but we have learned that if they are used on-label, they are safe and can prevent transfusions and improve fatigue. The association of ESA and iron has been underused, even if it represents the best way to treat cancer-related anaemia when ESAs are prescribed. In particular, we know that iv. iron is effective and quickly increases Hb level when associated with ESAs in cancer patients. Now we have available a new oral iron formulation, in particular a liposomeencapsulated pyrophosphate iron product that improves gastric tolerability, ameliorates intestinal absorption and showes similar efficacy of iv. iron, and similar results when coupled to ESAs. We have specific indications for ESAs administration, in particular, they must be used for chemotherapy-induced anaemia, when Hb level falls below 10 g/dl with the aim to prevent transfusions. Usually, they should be associated with iron (preferably iv. formulations) to improve hematologic response and potentially reduce time on ESAs treatment and spare costs. The availability of an optimally absorbed oral iron formulation (liposomial ferric pyrophosphate) could permit to reduce iv. iron utilisation, to minimize potentially life-threatening allergic reactions, and retain a similar therapeutic effect. A preliminary mono-institutional experience with a preventive use of liposomial iron in mildly anaemic cancer patients before starting chemotherapy seems to maintain Hb level through the first 3 months of treatment. Liposomial iron (Sideral) represents a relatively new but still unique preparation of ferric pyrophosphate conveyed through a phospholipid and sucrose esters of fatty acids matrix, that appears useful in all that conditions associated with chronic inflammation or iron deficiency in, and not only, onco-haematology diseases. Gastroenterology and nephrology specialists, for example, can now beneficiate from this new formulation, and onco-haematologist can safely replace older iron tablets, usually associated with bothersome gastrointestinal adverse events, with liposomial iron (Sideral). The new frontiers of treating anaemia in internal medicine, deserves today an appropriate international audience, well performed in this 3rd Mediterranean Multidisciplinary Course on
Edited By Dr Sandro Barni, Director of Oncology Department, Medical Oncology Unit, A.O. Treviglio (BG). The present Supplement has been prepared in collaboration with Dr Germano Tarantino, Scientific Director, Pharmanutra SpA. The fall of haemoglobin (Hb) below the normal level (anaemia) is encountered so frequently in clinical practice that it embraces almost all internal medical specialities and is associated with several chronic disease conditions. We now recognize that the protein called hepcidin, produced by the liver under inflammatory processes, is the primary checkpoint for iron absorption through the intestinal wall, and one of the major factors responsible for anaemia associated with chronic conditions. In particular, in onco-hematology we see high ferritin deposits but low iron utilisation in red blood cells, making this condition a “functional” anaemia. To so depicted landscape we add further exogenous insults as cytotoxic drugs, radiation, immunosuppressors, malnutrition due to cancer anorexia, and new molecular agents, that with previously unknown pathway, can further decrease red blood cells production. Anaemia in oncology is first of all associated with symptoms and quality of life parameters. This is true especially when Hb falls to a level below 12 g/dl but still remains above 10 g/dl, that is commonly defined as grade 1 anaemia. So it is expected that earlier correction of Hb in cancer patients could improve well-being and reduce fatigue. Cytotoxics are almost entirely associated with a reduction in erythropoiesis, even if red blood progenitors are least susceptible to cytotoxic drugs during treatment. Retrospective reviews of the incidence of anaemia that required red blood cells transfusions in patients who received chemotherapy for non-myeloid malignancies, indicate that the highest frequency occurs in those patients with lymphomas, lung tumours and gynaecologic (ovarian) or genitourinary tumours. The common agents used in these settings are platinum agents, which are more frequently linked to chemotherapy-related anaemia. We now have several new agents available to fight cancer, namely molecularly targeted agents. They have largely improved the final outcome, but have further added new side effects. Among them, one of the most frequent, but almost 1
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
S2 3rd Mediterranean Multidisciplinary Course on Iron Anemia Proceedings
Iron Anemia held in Rome on 17th and 18th April 2015, of which we report official congressional acts. The 3rd Mediterranean Multidisciplinary Course on Iron Anemia represented an important opportunity to share different opinions and convey various clinical experiences, mainly about the recent evidences of oral liposomial iron (Sideral) on treating iron deficiency anemia. Anaemia is a ‘global’ problem that involves a lot of medical specialities due to common etiopathogenetic noxae. Collecting and interchange opinions and experiences are of paramount importance for our patients, most of them suffer of one or more chronic diseases. The exploiting of new targeted treatments, in particular in oncology and haematology, renews the problem of anaemia, usually depicted as a chemotherapy-related adverse event. Reporting all hematologic effects of new drugs, recognizing and explaining mechanisms that are the basis of these forms of anaemia, treating earlier anaemic patients, preventing transfusions and costs of ESAs represent an emerging endpoints of future studies in cancer scenario. The 3rd Mediterranean Multidisciplinary Course on Iron Anemia is supported by an unrestricted educational grant from Pharmanutra Spa, Italy and Zambon S.A.U., Spain and Portugal.
Abstracts Management of iron-deficiency anemia and funcional iron-deficiency in cancer patients Pere Gascon Director, Division of Medical Oncology, Hospital Clinic, University of Barcelona, Spain Anemia is a common manifestation in oncology. It develops in more than 80% of cancer patients undergoing chemotherapy. Anemia in the oncology patient can be caused by the same tumor or by the effects or complications of cancer treatments. Anemia is multifactorial: bone marrow infiltration by cancer cells; nutritional deficits such as vitamin B12, folic acid or iron; hemolysis; myelosupression secondary to chemotherapy or radiotherapy; blood loss; toxicity induced by the new anti-targeted therapies; low endogenous erythropoietin levels; and anemia of chronic disease, also known as ‘functional iron deficiency’ (FID) (FIGURE 1). Anemia in cancer can also be caused indirectly by the same inflammatory process associated with the disease. In this case, some cytokines are produced and play a role in anemia. Two of them, interleukin-1 (IL-1a,b) and tumor necrosis factor (TNF-a), are known to inhibit the production of erythropoietin by the kidneys. Another important cytokine is IL-6, a pro-inflamamatory cytokine, that acts on the liver to induce the production of hepcidin, a small peptide, that has an important role in iron regulation. It is considered the most important factor in the anemia of ‘chronic disease’ also known as FID. Hepcidin works in the duodenum by inhibiting the oral absorption of iron and, in the bone marrow by blocking the release of the iron contained in the macrophages. It is understandable that with this scenario, the red blood cells progenitors lack the two major sources of iron for
The tumor itself Infiltration of the bone marrow
Hemolysis
Myelosuppression by chemotherapy/radiotherapy
Anemia
Abnormal iron metabolism Low erythropoetin levels
Blood loss Anemia of chronic disease functional iron deficiency
Nutritional deficits (Iron, Vitamin B12, Folic acid)
Figure 1. Causes of anemia in the cancer patient.
new red blood cell formation: the gastrointestinal tract where the enterocytes are unable to absorb either nutritional or therapeutic iron and, the bone marrow where the macrophages, scavenger cells do not release the sequestrated iron obtained from the senescent red blood cells. Because the complexity of causes leading to anemia in the cancer setting, the correction and management of anemia should always consider ruling out common causes such as pure iron deficiency (bleeding in a GI tumor) or folic acid or vitamin B12. Once, these causes are ruled out, we would know that we are dealing with chemotherapy-induced anemia and FID. How to manage then cancerassociated anemia? Two agents will play a major role: Erythropoiesis stimulating agents (ESAs) and iv. iron. Since cancer patients present a poor erythropoietin response to low hemoglobin levels, the use of ESAs will compensate for the low endogenous levels of erythropoietin, The use of iv. iron is to provide bio-available iron for the production of red blood cells since there is a significant poor absorption of oral iron, at least with the common preparations, due to the effect of hepcidin. Although ESAs are widely used in oncology to correct the anemia associated with chemotherapy and most patients benefit from their use, the fact is that their response rate has been suboptimal, ranging from 50 to 70.5% in most published clinical trials. Several explanations have been found, but in general it is accepted that the cause is FID. The remarkable improvements in the response rate observed with the concommittant administration of iv. iron to ESAs strongly suggests this possibility. Parenteral iron therapy has subsequently become an important adjunct to obtaining and maintaining adequate haemoglobin levels in patients with cancer receiving chemotherapy. A new type of oral iron, a liposomial preparation, that is being absorbed by the Gastrointestinal tract independtly of hepcidin levels may prove to be another and new tool for oncologists to correct the anemia in cancer patients. Over the last few years, seven studies have been conducted and their results published over the use of iv. iron supplementation. In all cases, iv. iron was delivered concomitantly with ESAs in the treatment of anemia secondary to chemotherapy. Except in one study, the study all others were favorable to the arm of iv. iron. On adding iv. iron to ESAs, responses are faster and more robust. Most guidelines (ASH/ASCO, EORTC and NCCN) recommend initiating ESAs for Hb < 10 g/dl and to stop when Hb levels reach 12 g/dl. ESAs are safe as long as they are used according to label. There are no alarm signals when ESAs are used in chemotherapy-induced anemia and according to guidelines. The use of blood transfusions shoul be restricted for acute
Abstracts S3
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
ane`mia in the case of bleeding or to those symptomatic patients with severe anemia Hb
EDITORIAL
3rd Mediterranean Multidisciplinary Course on Iron Anemia
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
April, 17th–18th 2015, Rome, Italy A new–old problem in medically ill: anaemia of chronic disease Sandro Barni Director of Oncology Department, Medical Oncology Unit, A.O. Treviglio (BG), Italy
underreported, is a mild form of anaemia, linked to interference with specific (tyrosine-kinase) associated receptors expressed on hematopoietic cells. In particular, multitarget tyrosine-kinase (e.g sunitinib) or mTOR inhibitors used for treating solid tumours, are able to increase by 5–10% the risk of anemia (mainly of low grade) that are overall reported with a rate of 50% in major randomized trials. We have two main ways of treating anaemia (other than treating cancer itself) in these conditions: exogenous iron and erythropoiesis stimulating agents (ESAs). The history of ESAs was troubled by safety concerns raised from old studies where they were inappropriately prescribed, but we have learned that if they are used on-label, they are safe and can prevent transfusions and improve fatigue. The association of ESA and iron has been underused, even if it represents the best way to treat cancer-related anaemia when ESAs are prescribed. In particular, we know that iv. iron is effective and quickly increases Hb level when associated with ESAs in cancer patients. Now we have available a new oral iron formulation, in particular a liposomeencapsulated pyrophosphate iron product that improves gastric tolerability, ameliorates intestinal absorption and showes similar efficacy of iv. iron, and similar results when coupled to ESAs. We have specific indications for ESAs administration, in particular, they must be used for chemotherapy-induced anaemia, when Hb level falls below 10 g/dl with the aim to prevent transfusions. Usually, they should be associated with iron (preferably iv. formulations) to improve hematologic response and potentially reduce time on ESAs treatment and spare costs. The availability of an optimally absorbed oral iron formulation (liposomial ferric pyrophosphate) could permit to reduce iv. iron utilisation, to minimize potentially life-threatening allergic reactions, and retain a similar therapeutic effect. A preliminary mono-institutional experience with a preventive use of liposomial iron in mildly anaemic cancer patients before starting chemotherapy seems to maintain Hb level through the first 3 months of treatment. Liposomial iron (Sideral) represents a relatively new but still unique preparation of ferric pyrophosphate conveyed through a phospholipid and sucrose esters of fatty acids matrix, that appears useful in all that conditions associated with chronic inflammation or iron deficiency in, and not only, onco-haematology diseases. Gastroenterology and nephrology specialists, for example, can now beneficiate from this new formulation, and onco-haematologist can safely replace older iron tablets, usually associated with bothersome gastrointestinal adverse events, with liposomial iron (Sideral). The new frontiers of treating anaemia in internal medicine, deserves today an appropriate international audience, well performed in this 3rd Mediterranean Multidisciplinary Course on
Edited By Dr Sandro Barni, Director of Oncology Department, Medical Oncology Unit, A.O. Treviglio (BG). The present Supplement has been prepared in collaboration with Dr Germano Tarantino, Scientific Director, Pharmanutra SpA. The fall of haemoglobin (Hb) below the normal level (anaemia) is encountered so frequently in clinical practice that it embraces almost all internal medical specialities and is associated with several chronic disease conditions. We now recognize that the protein called hepcidin, produced by the liver under inflammatory processes, is the primary checkpoint for iron absorption through the intestinal wall, and one of the major factors responsible for anaemia associated with chronic conditions. In particular, in onco-hematology we see high ferritin deposits but low iron utilisation in red blood cells, making this condition a “functional” anaemia. To so depicted landscape we add further exogenous insults as cytotoxic drugs, radiation, immunosuppressors, malnutrition due to cancer anorexia, and new molecular agents, that with previously unknown pathway, can further decrease red blood cells production. Anaemia in oncology is first of all associated with symptoms and quality of life parameters. This is true especially when Hb falls to a level below 12 g/dl but still remains above 10 g/dl, that is commonly defined as grade 1 anaemia. So it is expected that earlier correction of Hb in cancer patients could improve well-being and reduce fatigue. Cytotoxics are almost entirely associated with a reduction in erythropoiesis, even if red blood progenitors are least susceptible to cytotoxic drugs during treatment. Retrospective reviews of the incidence of anaemia that required red blood cells transfusions in patients who received chemotherapy for non-myeloid malignancies, indicate that the highest frequency occurs in those patients with lymphomas, lung tumours and gynaecologic (ovarian) or genitourinary tumours. The common agents used in these settings are platinum agents, which are more frequently linked to chemotherapy-related anaemia. We now have several new agents available to fight cancer, namely molecularly targeted agents. They have largely improved the final outcome, but have further added new side effects. Among them, one of the most frequent, but almost 1
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
S2 3rd Mediterranean Multidisciplinary Course on Iron Anemia Proceedings
Iron Anemia held in Rome on 17th and 18th April 2015, of which we report official congressional acts. The 3rd Mediterranean Multidisciplinary Course on Iron Anemia represented an important opportunity to share different opinions and convey various clinical experiences, mainly about the recent evidences of oral liposomial iron (Sideral) on treating iron deficiency anemia. Anaemia is a ‘global’ problem that involves a lot of medical specialities due to common etiopathogenetic noxae. Collecting and interchange opinions and experiences are of paramount importance for our patients, most of them suffer of one or more chronic diseases. The exploiting of new targeted treatments, in particular in oncology and haematology, renews the problem of anaemia, usually depicted as a chemotherapy-related adverse event. Reporting all hematologic effects of new drugs, recognizing and explaining mechanisms that are the basis of these forms of anaemia, treating earlier anaemic patients, preventing transfusions and costs of ESAs represent an emerging endpoints of future studies in cancer scenario. The 3rd Mediterranean Multidisciplinary Course on Iron Anemia is supported by an unrestricted educational grant from Pharmanutra Spa, Italy and Zambon S.A.U., Spain and Portugal.
Abstracts Management of iron-deficiency anemia and funcional iron-deficiency in cancer patients Pere Gascon Director, Division of Medical Oncology, Hospital Clinic, University of Barcelona, Spain Anemia is a common manifestation in oncology. It develops in more than 80% of cancer patients undergoing chemotherapy. Anemia in the oncology patient can be caused by the same tumor or by the effects or complications of cancer treatments. Anemia is multifactorial: bone marrow infiltration by cancer cells; nutritional deficits such as vitamin B12, folic acid or iron; hemolysis; myelosupression secondary to chemotherapy or radiotherapy; blood loss; toxicity induced by the new anti-targeted therapies; low endogenous erythropoietin levels; and anemia of chronic disease, also known as ‘functional iron deficiency’ (FID) (FIGURE 1). Anemia in cancer can also be caused indirectly by the same inflammatory process associated with the disease. In this case, some cytokines are produced and play a role in anemia. Two of them, interleukin-1 (IL-1a,b) and tumor necrosis factor (TNF-a), are known to inhibit the production of erythropoietin by the kidneys. Another important cytokine is IL-6, a pro-inflamamatory cytokine, that acts on the liver to induce the production of hepcidin, a small peptide, that has an important role in iron regulation. It is considered the most important factor in the anemia of ‘chronic disease’ also known as FID. Hepcidin works in the duodenum by inhibiting the oral absorption of iron and, in the bone marrow by blocking the release of the iron contained in the macrophages. It is understandable that with this scenario, the red blood cells progenitors lack the two major sources of iron for
The tumor itself Infiltration of the bone marrow
Hemolysis
Myelosuppression by chemotherapy/radiotherapy
Anemia
Abnormal iron metabolism Low erythropoetin levels
Blood loss Anemia of chronic disease functional iron deficiency
Nutritional deficits (Iron, Vitamin B12, Folic acid)
Figure 1. Causes of anemia in the cancer patient.
new red blood cell formation: the gastrointestinal tract where the enterocytes are unable to absorb either nutritional or therapeutic iron and, the bone marrow where the macrophages, scavenger cells do not release the sequestrated iron obtained from the senescent red blood cells. Because the complexity of causes leading to anemia in the cancer setting, the correction and management of anemia should always consider ruling out common causes such as pure iron deficiency (bleeding in a GI tumor) or folic acid or vitamin B12. Once, these causes are ruled out, we would know that we are dealing with chemotherapy-induced anemia and FID. How to manage then cancerassociated anemia? Two agents will play a major role: Erythropoiesis stimulating agents (ESAs) and iv. iron. Since cancer patients present a poor erythropoietin response to low hemoglobin levels, the use of ESAs will compensate for the low endogenous levels of erythropoietin, The use of iv. iron is to provide bio-available iron for the production of red blood cells since there is a significant poor absorption of oral iron, at least with the common preparations, due to the effect of hepcidin. Although ESAs are widely used in oncology to correct the anemia associated with chemotherapy and most patients benefit from their use, the fact is that their response rate has been suboptimal, ranging from 50 to 70.5% in most published clinical trials. Several explanations have been found, but in general it is accepted that the cause is FID. The remarkable improvements in the response rate observed with the concommittant administration of iv. iron to ESAs strongly suggests this possibility. Parenteral iron therapy has subsequently become an important adjunct to obtaining and maintaining adequate haemoglobin levels in patients with cancer receiving chemotherapy. A new type of oral iron, a liposomial preparation, that is being absorbed by the Gastrointestinal tract independtly of hepcidin levels may prove to be another and new tool for oncologists to correct the anemia in cancer patients. Over the last few years, seven studies have been conducted and their results published over the use of iv. iron supplementation. In all cases, iv. iron was delivered concomitantly with ESAs in the treatment of anemia secondary to chemotherapy. Except in one study, the study all others were favorable to the arm of iv. iron. On adding iv. iron to ESAs, responses are faster and more robust. Most guidelines (ASH/ASCO, EORTC and NCCN) recommend initiating ESAs for Hb < 10 g/dl and to stop when Hb levels reach 12 g/dl. ESAs are safe as long as they are used according to label. There are no alarm signals when ESAs are used in chemotherapy-induced anemia and according to guidelines. The use of blood transfusions shoul be restricted for acute
Abstracts S3
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
ane`mia in the case of bleeding or to those symptomatic patients with severe anemia Hb
