Mielodisplasie Utilizzo dei chelanti del ferro M. D

Mielodisplasie Utilizzo dei chelanti del ferro M. D
Mielodisplasie Utilizzo dei chelanti del ferro M.D.Cappellini Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena IRCCS Università di Milano Corso Nazionale di Aggiornamento in Ematologia Clinica Roma , Ambasciatori Palace Hotel 8-9 Novembre 2006

Conditions associated with secondary iron overload
Thalassaemia major/intermedia Blackfan Diamond Anaemia Fanconi’s Anaemia Early stroke with HbSS Severe haemolytic anaemias Aplastic anaemia Myelodysplasia (MDS) Repeated myeloablative chemotherapy Typically adult

Iron gain in iron-loading anaemias
Macrophages g Daily uptake ~1 mg Daily losses Urine, faeces, nails, hair, skin Liver, other parenchymal organs, myoglobin in muscle Menstrual or other blood loss Ineffective erythropoiesis Bone marrow erythroblasts Stimulation of intestinal iron uptake Iron gain in iron-loading anaemias Duodenum Transferrin Plasma Circulating haemoglobin g This is due to ineffective erythropoiesis, which, in MDS as well as in thalassaemia and other conditions, sends out a signal that stimulates intestinal iron uptake. Despite many years of research, we still do not know which molecule represents the signal. Chronic stimulation of intestinal iron uptake contributes to iron overload in MDS, but it is not the main cause.

Serum ferritin at diagnosis of MDS
8000 7794 6980 6000 5000 Ferritin, ng/mL 4000 4176 3839 3526 2980 2500 At the time opf diagnosis, we rarely see MDS patients with a serum ferritin above 1000 ng/ml. Here are the ferritin levels of 650 patients in the Düsseldorf MDS Register for whom serum ferritin was documented at the time of diagnosis. We surmise that the few outliers with very high ferritins were already receiving blood transfusions before the diagnosis of MDS was made. 2555 2690 2284 2500 2000 1980 2283 2136 2000 2000 1800 1830 2000 1749 1500 1590 1309 1290 RA RARS RAEB RAEB-T CMML FAB classification Dusseldorf MDS register

Iron balance in transfusion
Daily losses 1 mg 1 blood unit 200–250 mg . . . and daily losses are only about 1 mg, iron overload is unavoidable. However, iron overload in MDS starts developing even before transfusion therapy is initiated.

Transfusion Dependance in MDS
IPSS Category RBC Transfusion Dependant Low Risk 39% INT -1 Risk 50% INT -2 Risk 63% High Risk 79%

Iron accumulation Transfusion In MDS ~0.5 mg iron/mL of whole blood
~200 mg iron/donor blood unit (400 mL) ~20 g iron transfused with 100 blood units Normal body iron: 3-4 g In MDS ~90% of patients with MDS become transfusion dependent 200–250 mg iron Clearly the most important cause of iron overload in MDS is transfusion therapy. A single unit of donor blood provides at least 200 mg of iron. With 100 blood units transfused, a patient has received 20 g of iron, while the normal amount of body iron is 3 to 4 g. 20 g approaches the amount of body iron that patients with hereditary hemochromatosis may have accumulated when they start showing clinical manifestations. If a patient with MDS needs 2 units of blood per month, he will get 24 units per year, and will have received 100 units after 4 years. 2 units/month  24 units/year  100 units/4 years  ~20 g iron

Iron turnover in transfusional overload
Parenchyma Hepatocytes Erythron 20–40 mg/day (0.3–0.7 mg/kg/day) Parenchyma Hepatocytes NTBI Red Macrophages Transferrin Gut Porter JB. Hematol Oncol Clin North Am. 2005;19:1-6.

Consequences of Iron-Mediated Toxicity
Increased “free” iron Hydroxyl radical generation Organelle damage Lipid peroxidation TGF-β1 Collagen synthesis Lysosomal fragility Enzyme leakage Cell death Fibrosis TGF = transforming growth factor Adapted from Porter JB. Hematol Oncol Clin North Am. 2005;19(suppl 1):7-12, with permission from Elsevier. 19

Organs susceptible to iron overload
Clinical sequelae of iron overload Pituitary → impaired growth Heart → cardiomyopathy, cardiac failure Liver → hepatic cirrhosis Pancreas → diabetes mellitus Gonads → hypogonadism, infertility Excess iron is deposited in major organs, resulting in organ damage. The liver is the principal site for iron storage and has the largest capacity for excess iron storage. When the liver capacity is exceeded, iron is deposited in other organs

Patients with cardiac iron deposits at post-mortem in the pre-chelation era
131 transfused adult patients 101 leukaemias 30 other anaemias 100 80 Patients with cardiac iron (%) 60 40 20 0–25 26–50 51–75 76–100 101–200 201–300 Units of blood transfused Buja LM, Roberts WC. Am J Med. 1971;51:

Correlation of heart iron with blood transfusion and liver iron in pre-chelation era
Adapted from Buja & Roberts, 1971 10 10 y = 0.016x r = 0.67 y = 0.125x r = 0.76 7.5 7.5 5 5 Heart iron mg/g dry wt 2.5 2.5 100 200 300 400 10 20 30 40 Liver iron mg/g dry wt Units blood transfused

Iron Concentration and Risk?
Absence of pathology Heterozygotes of HH where liver levels <7mg/g dry wt Liver Pathology Abnormal ALT if LIC >17mg/g dry wt (Jensen, Blood 2003) Liver fibrosis progression if LIC >16mg/g dry wt (Angelucci, Blood 2002) Cardiac pathology at high levels [Liver iron] >15mg/g dry wt. association with cardiac death all of 15/53 TM patients who died (Brittenham, NEJM, 1994)

Iron overload in MDS: clinical consequences
A study by Schafer AI et al : Objective: assess the clinical outcome of iron overload in 15 nonthalassemic adult patients Iron loading had been present for less than 4 years in 14 of the patients Manifestations possibly attributable to iron overload: Endocrine abnormalities (most prominent) Diabetes and inadequate hypothalamic pituitary adrenal reserve Impaired glucose tolerance (even in patients with a relatively short exposure to excess iron levels) N Engl J Med 1981;304:319-24

A study by Schafer AI et al : Left ventricular dysfunction and supraventricular arrhythmias in heavily transfused patients Clinical heart failure and ventricular arrhythmias in patients with concomitant coronary artery disease ? The relative contributions of myocardial iron deposition and chronic anemia Vs. the development of functional abnormalities N Engl J Med 1981;304:319-24

A study by Jaeger et al: 46 patients with MDS who had received at least 50 units of packed RBC Clinical signs of iron overload: 20 patients Heart failure  arrhythmias: ALL Hepatic impairment :12 patients Diabetes mellitus: 5 patients Death due to refractory congestive heart failure: 14 patients Death from hepatic insufficiency: NONE CARDIAC ABNORMALITIES ARE THE MOST FREQUENT AND SERIOUS CLINICAL COMPLICATIONS IN PATIENTS WITH MDS Beitr Infusionsther 1992;30:464-8

Other Reports of Iron Overload in MDS
Author Year # of Pts Organ Damage Schafer et al 1981 10 8 15 Hepatic fibrosis,  LIC LV dysfunction, arrhythmia Glucose intolerance  Pituitary-adrenal reserve Walterova 1983 deceased 20 cardiac failure Cazzola 1988 14 18 Abn GTT (6 DM) Abn LFT’s (1 died of cirrhosis) Jaeger 1992 20 11 5 arrhythmias, CHF hepatic fibrosis, abn LFT’s diabetes mellitus RARS subtype – most complications Frame 1994 1 Gynecomastia, skin bronzing, increasing transfusion requirement

Increased heart iron by MRI (SIR), in relation to transfusion, in unchelated MDS patients
Adapted from Jensen et al,Blood:101, 2003 20 18 16 14 12 Estimated heart iron (µmol/g) 10 8 Upper Normal limit 6 4 2 25 50 75 100 125 150 Blood Units Transfused

Iron chelation in MDS Do we need iron chelation therapy for patients with MDS? Which patients with MDS may benefit from iron chelation? Which chelator can be used? The questions is: Do we need this drug for patients with MDS? Or, to put it less provocatively: which patients with MDS may benefit from iron chelation? In patients with thalassaemia, it has been demonstrated unequivocally in a number of studies that effective chelation therapy improves survival. We tend to presume that we can transfer our experience with iron overload from thalassemia to MDS. But is that correct?

Secondary iron overload in transfusion-dependent MDS patients
L.Malcovati,2005

Overall survival of transfusion-dependent patients according to iron overload
RA/RARS/5q- (HR=1.42, P<.001) RCMD/RCMD-RS (HR=1.33, P=.07) L.Malcovati,2005

MDS without excess blasts
Probability of non-leukemic death in MDS patients according to transfusion-dependency MDS without excess blasts (HR=1.7, P=.03) MDS with excess blasts (P=.38) L.Malcovati,2005

Iron Overload in MDS Consensus Meeting
Nagasaki, Japan May 11, 2005 Since there is no firm data to draw upon, a consensus meeting on iron overload in MDS was convened earlier this year in Nagasaki on the occasion of the 8th International Symposium on Myelodysplastic Syndromes. About 30 doctors from many countries in the world participated in this consensus meeting. Let me briefly summarized the consensus statements.

Consensus reached Questions Consensus
How frequently would you monitor iron overload? Which tools would you use to diagnose and monitor iron overload? What would you use most frequently? When would you start chelation therapy? For how long would you continue chelation therapy? Consensus At least every 3 months in patients receiving transfusion Serum ferritin Transferrin saturation Liver MRI Serum ferritin > 1,000–2,000 ng/mL considering rate of transfusions As long as transfusion therapy continues (as long as iron overload is clinically relevant) . . . which means that in patients receiving regular blood transfusions, iron overload should be monitored at least every 3 months. Serum ferritin was considered to be the most practical tool for monitoring iron overload. It certainly has its limitations, but in terms of cost-benefit-ratio, there is as yet no good alternative. Transferritin saturation is an additional tool to diagnose iron overload, but it is not well suited for follow-up. Liver MRI may become the method of choice, but it requires further standardization and there may be problems with its availability. Accordingly, serum ferritin is most frequently used for monitoring iron overload. The start of chelation therapy was of course an important question.The group decided that no universally applicable threshold value could be given, because the individual rate of transfusion must of be considered. In a patient who has only recently become transfusion dependent but needs a lot of blood, it may be prudent to not to wait until he has reached a serum ferritin level of 2000 ng/ml. It was also quite clear that it is impossible to define in terms of months or years for how long chelation therapy must be continued. It must continue as long as transfusion therapy continues, unless iron overload becomes clinically irrelevant, for example when the patient develops acute leukemia. MRI = magnetic resonance imaging. Hematol Oncol Clin North Am. 2005;19 Suppl 1.

Consensus reached Consensus Transfusion-dependent patients
Low risk MDS: IPSS low or Int-1 WHO-type RA and RARS and 5q– syndrome Candidates for allografting MDS patients with documented stable disease Serum ferritin levels > 1,000–2,000 ng/mL or other evidence of significant tissue iron overload Absence of comorbidities severely limiting prognosis Questions What is the profile of a patient who might benefit from the treatment of iron overload? The group agreed on the following profile of patients who might benefit from the treatment of iron overload. The patient must be transfusion-dependent and should have a low-risk MDS, which means an IPSS score of low or intermediate-1. Certainly patients with the WHO-type of RA and RARS, as well as patients with 5q- syndrome are candidates if they are transfusion-dependent. Irrespective of their FAB- or WHO-type, patients who are candidates for allografting may be candidates for iron-chelation therapy as well, because it is important to avoid iron-related organ damage in patients who will undergo allogeneic transplantation. It was felt that patients with an unfavourable FAB- or WHO-type of MDS should not be excluded if they have documented stable disease. As mentioned above, ferritin levels should be above 1000 or 2000 ng/ml, or, in cases where the ferritin is suspected to be unreliable, there should be other evidence of significant tissue iron overload. For obvious reasons, our patient profile requires the absence of comorbidities that severely limit the patient’s prognosis.

Iron chelators Deferoxamine (Desferal®; DFO) Starch DFO HBED
Parenteral medications Deferoxamine (Desferal®; DFO) Starch DFO HBED Oral medications Deferiprone (Ferriprox; L1; DFP) Deferasirox (Exjade®) 2nd-generation hydroxypyridinones DFT derivatives GT (Deferitrin) Registered medications Investigational medications HBED = N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid.

Standard treatment: deferoxamine
Hexadentate (1:1) iron chelator 1 molecule of DFO binds 1 atom of iron Forms a stable complex Excreted via the bile and urine Can provide effective chelation therapy Over 35 years of clinical experience Standard treatment employs deferoxamine, a hexadentate iron chelator. One molecule of DFO binds one atom of iron, forming a stable complex that is excreted via the bile and the urine. Desferal can provide effective chelation therapy, as shown by over 35 years of clinical experience. DFO = deferoxamine

The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload
P. D. JENSEN,1 L. HEICKENDORFF,2 B. PEDERSEN,3 K. BENDIX-HANSEN,4 F. T. JENSEN,5 T. CHRISTENSEN,5 A. M. BOESEN1 AND J. ELLEGAARD1 1Department of Medicine and Haematology, 2Department of Clinical Biochemistry, 3Department of Cytogenetics, Danish Cancer Society ,4Institute of Pathology, Aarhus Amtssygehus, and 5Centre for Nuclear Magnetic Resonance, Skejby Sygehus, Aarhus University Hospital, Denmark The effect of desferal treatment on haemopoiesis in MDS patients with transfusional iron overload was investigated by Jensen from Aarhus in Denmark. Br J Haematol 1996;94:288-99

11 MDS patients followed for up to 60 months (during and after treatment with DFO)
Reduction (≥ 50%) in transfusion requirement in 7/11 (64%) patients 5 patients became transfusion independent (46%) All patients in whom iron chelation was highly effective showed improvement of erythropoietic output The most obvious reasons for lack of response to treatment were a high blood-transfusion requirement eventually combined with hypersplenism or insufficient iron chelation The authors followed 11 MDS for up to 60 months and found that iron chelation achieved a more than 50% reduction in transfusion requirement in 7 of 11 patients. Five patients became transfusion independent. All patients in whom iron chelation was highly effective showed improvement of erythropoietic output. The authors commented that the most obvious reasons for lack of response to treatment were a high blood transfusion requirement eventually combined with hypersplenism or insuffient iron chelation. I think that the erythropoietic response to iron chelation in this study is quite impressive, but I should like to know whether the personal experience of people in the audience confirms the data from Denmark. Jensen P et al. Br J Haematol 1996;94:288-99

Limitations of deferoxamine therapy
Poor oral bioavailability and a short plasma half-life Slow subcutaneous infusion –7 times weekly Inconvenient administration Treatment with Desferal is demanding. The drug has poor oral bioavailability and a short plasma half-life. Therefore, slow subcutaneous infusions are necessary 3 to 7 times weekly. Because of injection site reactions and pain, the administration is inconvenient, and equipment isnot available in many countries. These factors lead to poor compliance, which in turn leads to increased mortality. Poor compliance reported to lead to increased mortality Injection-site reactions and pain Equipment not widely available in many countries

DFP (Ferriprox) Side-effects Neutropenia/agranulocytosis
History Patented 1982; licensed in EU 1999 Pharmacology Bidentate, short plasma half-life, given 3 times/day, rapidly glucuronidated Urinary excretion Efficacy Indicated for “treatment of iron overload in patients with thalassemia major when deferoxamine therapy is contra-indicated or inadequate” 1 May be less effective than DFO in reducing LIC low efficiency (7%) Possible cardioprotective effect8 Side-effects Neutropenia/agranulocytosis weekly neutrophil count recommended1 Nausea, vomiting, abdominal pain Arthralgia and arthritis (variable; 4–50%) Hematologic toxicity Neutropenia and risk of agranulocytosis (severe neutropenia) Weekly neutrophil count recommended1 Non-hematologic toxicities Nausea, vomiting, abdominal pain Arthralgia Efficacy May be less effective than deferoxamine in reducing LIC1 Reports of increased risk of liver fibrosis1,2 Only for second-line use in patients with thalassemia major when deferoxamine therapy is contraindicated or inadequate Not approved in US or Canada In a safety trial of deferiprone, 21 of 187 patients (11%) had to discontinue therapy because of adverse events3 References Ferriprox® [package insert]. Berkshire, UK: Apotex Europe Ltd; 1999 Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med. 1998;339:417–423 Cohen A, Galanello R, Piga A, et al. A multi-center safety trial of the oral iron chelator deferiprone. Ann N Y Acad Science. 1998;850:223–226

Iron overload in polytransfused patients with MDS: use of L1 for oral iron chelation
M. JAEGER, C. AUL, D. SÖHNGEN, U. GERMING, AND W. SCHNEIDER Haematology and Oncology Division, Department of Internal Medicine, Heinrich Heine University, Moorenstrasse 5, 4000 Düsseldorf 1, Germany The only publication I was able to find comes from our own institution. However, this paper is hardly worth mentioning, because . . . Drugs Today 1992;28(Suppl A):143-7

L1 treatment in MDS Number of blood units Transfusion Requirement,
PRC units/month Iron excretion under L1, mg per 24 h urine (mean) 1500 mg 2000 mg 2500 mg Treatment Period, weeks Side effects Pt. Age None Zinc defic. Mild nausea only three patients were treated and the dosage of deferiprone was insufficient. The pilot study was not continued because the first and last authors were rather apprehensive of the risk of agranulocytosis. Does anybody know of other published trials of deferiprone in MDS? If not, I am eager to hear about your unpublished experience. Up to now, deferiprone has been the only alternative to desferal, defic. = deficiency; PRC = pure red cells; pt. = patient

Clinical trial formulation
Deferasirox (Exjade) Selected from more than 700 compounds tested Tridentate* iron chelator an oral, dispersible tablet highly specific for iron 70% oral bioavailability, increased with food Half-life of 8 to 16 hours supports once-daily dosing Chelated iron excreted mainly in faeces (< 10% in urine) O OH HO N Fe * Deferasirox is a novel, orally active tridentate iron chelator with a high affinity and specificity for iron Clinical trial formulation Nick H et al. Curr Med Chem ;10:

Deferasirox: clinical development
Single dose, safety and tolerability study 24 adult β-thal. patients Multiple dose iron balance study Randomized deferasirox vs DFO safety and LIC study adult β-thal. patients Single arm safety and liver iron concentration (LIC) study paediatric β-thal. patients Randomized deferasirox vs DFO LIC and tolerability 586 paediatric/adult β-thal. pts Single arm LIC and tolerability 184 paediatric/adult patients: β-thal, MDS, rare anaemias Randomized deferasirox vs DFO safety and LIC study paediatric/adult SCD Study 101 Study 104 (12 days) Study 105 (48 weeks) Study 106 Study 108 (1 year) Study 107 Study 109 1998 1999 2000 2001 2003 2004 2005 2006 2002 Phase I Phase II Phase III Extension DFO = deferoxamine.

Efficacy results: Study 107 Change in LIC by dose group
5 Change in LIC (mg Fe/g dry weight) –5 –10 DFO, mg/kg/day Deferasirox, mg/kg/day –15 –20 DFO < –< –50 ≥ 50 Deferasirox n Cappellini MD, et al Blood. 2006

Efficacy results: Study 107 Change in ferritin by dose group
3,000 2,000 1,000 Change in serum ferritin (μg/L) –1,000 DFO, mg/kg/day Deferasirox, mg/kg/day –2,000 –3,000 DFO < –< –50 ≥ 50 Deferasirox n Cappellini MD, et al Blood. 2006

Study 0108

Study 0108: Phase II Single-Arm Trial  Thalassemia and Other Anemias
Study design 1-year trial 85 patients with β thalassemia 99 patients with rare anemia Patients treated with deferasirox for 1 year LIC assessed by liver biopsy or SQUID Ongoing safety and serum ferritin monitoring

47 Disease # of patients MDS Alpha Thal 1 Thal Intermedia
Fanconi's anemia Chronic autoimmune hemolytic anemia Congenital diserythropoietic anemia Pyruvate kinase deficiency 2 Myelofibrosis 3 Pure Red Cell Aplasia Aplastic anemia 4 Congenital Sideroblastic Anemia 5 unknown/Other 9 Diamond Blackfan 26 MDS 47 Beta Thal 84 TOTAL 184

Change in LIC by Dose : Overall Population

Change in LIC by Dose : MDS Population

Change in Serrum Ferritin by Dose : MDS Population

Deferasirox: Safety and Tolerability Profile
Most common adverse experiences in trials were nausea (10%), vomiting (9%), abdominal pain (14%), diarrhea (12%) and skin rash (8%) that rarely required discontinuation of study drug Mild increases in creatinine occurred in some patients (3% exceeded ULN in thalassemia, 16% exceeded ULN in rare anemias) No agranulocytosis observed in over 800 patients Generally well tolerated in patients as young as two years of age

Serum Creatinine Changes During One Year of Deferasirox Therapy
Patients with normal creatinine levels: Patients with increased creatinine ≥ 33% at 2 consecutive post-baseline measures: Patients with dose reductions for sustained creatinine increases: 64% (415/652) 36% (237/652) 10% (68/652) III The deferasirox clinical trial protocols were designed using an increase of serum creatinine > 33% over baseline to trigger dose reduction to achieve subsequent stabilization or reduction of creatinine Serum creatinine concentrations are influenced by many factors including muscle mass, gender, height, weight and diet In these trials, mild, non-progressive increases in serum creatinine, mostly within the normal range, occurred in about 34% of patients. These were dose-dependent, often resolved spontaneously and were sometimes alleviated by reducing the dose Only a small percentage of patients had creatinine values >ULN. The exception was the rare anemias group where the patients tended to be older and a number had serum creatinine values at ULN at baseline No patients had a progression following the initial increase. Progression is defined as continuously increasing creatinine despite appropriate dose adjustment With deferasirox therapy, the glomerular filtration rate may be re-set; a similar observation has been made with ACE inhibitors. To date, no renal insufficiency has been observed in patients treated with deferasirox for up to 3 years Increases in serum creatinine were mild, non-progressive and dose-dependent No moderate to severe renal insufficiency or renal failure observed Studies 106, 107, 108 and 109 Creatinine increase at ≥ 2 consecutive post-baseline visits Patients, n (%) Pooled β-thalassemia (n = 421) SCD (n = 132) Rare anemias (n = 99) > 33% and < ULN 137 (32.5) 48 (36.4) 23 (23.2) > 33% and > ULN 10 (2.4) 3 (2.3) 16 (16.2) Total 147 (34.9) 51 (38.7) 39 (39.4) Each patient with an increase in serum creatinine is included in only one of the above categories

Results to Date Literature documents the effects of iron overload on cardiac, hepatic and endocrine function in MDS Small series indicate the benefits of chelation in MDS Ph. II and III trials show that deferasirox produces statistically significant and clinically relevant reductions in LIC in Iron overloaded patients

Summary Transfusional iron overload Complications of chronic anaemia
Problems of aging Clinical problems in MDS Complications of marrow failure It is not easy to assess the relative importance of transfusional iron overload in MDS, because clinical problems also arise from complications of chronic anemia and other complications of marrow failure. Problems of normal ageing and of concomitant diseases tend to aggravate the clinical impact of iron overload, while leukemic transformation limits this problems by causing a bigger one. Concomitant diseases Leukaemic transformation

Summary How much morbidity and mortality is attributable to iron overload? Clinical studies Thalassaemia experience Prognostic assessment of MDS “Expert opinions”/common sense How can we know how much morbidity and mortality in MDS is attributable to iron overload? Since there is lack of specific clinical studies, we should try to design them. Some guidance is available from the vast experience with thalassaemia, although we must be aware that we are dealing with elderly MDS patients rather than young thalassaemia patients. Prognostic assessment of myelodysplastic syndrome also helps to decide whether a patient is likely to have the time to develop clinical problems from iron overload. Finally, “expert opinions“, which should no deviate too much from common sense, may be helpful. Let us harness all these tools today in order to reach some reasonable consensus.

Mielodisplasie Utilizzo dei chelanti del ferro M. D

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