Highlights from: The 48th Annual Meeting of the American Society of Hematology; Orlando, FL

Supportive Cancer Therapy

Meeting

Highlights from the 48th Annual Meeting of the American Society of Hematology Orlando, FL • December 9-12, 2006

Long-Term Effects of the Novel Thrombopoietic Agent AMG-531 in Patients with Immune Thrombocytopenic Purpura Thrombocytopenia is a chronic condition in adult patients with immune thrombocytopenic purpura, resulting from a combination of increased platelet turnover and decreased platelet production. Thrombopoietin regulates the development of megakaryocytes and promotes platelet production in concert with several other cytokines, including interleukin (IL)–3, IL-6, and IL-11. Several recombinant growth factors involved in platelet production have been assessed in clinical trials, including a truncated pegylated recombinant human megakaryocyte growth and development factor (rHuMGDF) and a full-length recombinant human thrombopoietin.1,2 The clinical development of pegylated rHuMGDF was discontinued in the United States, and other recombinant growth factors have had limited clinical impact because of the development of neutralizing antibodies against the recombinant and endogenous growth factors, resulting in worsening thrombocytopenia.3 AMG-531 (Figure 1), a novel thrombopoiesis-stimulating peptide fused to an

Figure 1

Structure of AMG-531

Figure 2

AMG-531 Treatment Schema6 Treatment Period

Fc Carrier Domain Peptide Receptor-Binding Domain

immunoglobulin Fc carrier, has shown clinical potential in the management of thrombocytopenia. The peptide component of AMG-531 was selected from a peptide library for its ability to activate the thrombopoietin receptor without inducing thrombopoietin-neutralizing antibodies. Early-phase trials have demonstrated that AMG-531 was well tolerated and increased platelet counts in patients with immune thrombocytopenic purpura (ITP).4,5 In the phase II portion of the Bussel et al study, the targeted platelet count (50450 × 109/L) was achieved in 10 of 16 patients treated with AMG-531 at doses of 1 mg/kg or 3 mg/kg per week for 6 weeks. In a follow-up study, the long-term effects of AMG-531 were evaluated in patients with ITP. The results of the study were presented by Kuter et al at the 48th Annual Meeting of the American Society of Hematology (ASH), in Orlando, FL, December 9-12,

S C R E E N I N G

Day –8

AMG-531 Starting dose of 1 μg/kg or previous dose administered every week

E N D

Planned enrollment = 200

O F

AMG-531 dose adjustment every 2 weeks any time on study based on platelet count Concurrent ITP therapies may be adjusted any time on study when Study Day 1 First Dose Study Drug Administered Weekly

2006.6 The major findings of the study are summarized herein. Patients with ITP who had been previously treated on an AMG 531 study were enrolled in the study. Patients previously treated with subcutaneous injections of AMG-531 received the same starting dose as the final dose given previously, whereas patients previously treated with placebo on previous studies were treated with a 1-μg/kg dose (Figure 2).6 Depending on the platelet response, doses were skipped, decreased, maintained, or increased. Patients who

Prepared by: G. Kesava Reddy, PhD; Latha Shivakumar, PhD; Sabeeha Muneer, PhD Reviewed by: Jeffrey Crawford, MD

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S T U D Y

Volume 4, Number 2 • January 2007

Table 1

Long-Term Effects of AMG-531: Safety and Efficacy6 Adverse Events (All Grades)

Patients (n = 36)

Headache

19 (53)

Upper Respiratory Infection

15 (42)

Fatigue

14 (39)

Epistaxis

11 (31)

Back Pain

10 (28)

Nasopharygitis

10 (28)

Diarrhea

9 (25) Efficacy

Platelet Response

31 (86)

Median Duration of First Response, Weeks (Range)

31 (21-60)

Patients with ≥ 150 × 109/L Platelet Count at Any Time

29 (81)

Patients with ≥ 400 ×

15 (42)

109/L

Platelet Count at Any Time

Values in parentheses are percentages unless otherwise indicated.

exhibited stable dose for  3 weeks (later amended to  4 weeks) were allowed to self-administer the drug. A total of 104 patients with ITP were enrolled, and 36 patients from an earlier phase II trial were included in a planned analysis. The longest treatment duration of AMG-531 was 90 weeks. Of the 36 patients, 29 had completed  48 weeks of AMG-531 treatment. The mean age was 50 years ± 13 years (standard deviation) and 30 of the 36 patients (83%) had a splenectomy. The long-term treatment (up to 96 weeks) of AMG-531 was well tolerated, with 29 of 36 patients receiving treatment for  48 weeks. The most commonly occurring adverse events (AEs) included headache (53%), upper respiratory infection (42%), and fatigue (39%; Table 1).6 Treatment-related serious AEs occurred in 4 patients (11%) and included vaginal hemorrhage/anemia (n = 1), diffuse reticulin formation in the bone marrow (n = 1), bone pain (n = 1), and 1 instance of transverse sinus thrombosis with papilledema and temporary decrease in visual acuity in a 64-year-old patient with diabetes mellitus who had a platelet count of

293 × 109/L at the time the AE occurred. Currently, 31 of the 36 patients remain on treatment, 3 patients have discontinued treatment because of AEs, and 2 have discontinued treatment for other reasons. Of the 36 patients, 31 (86%) had a platelet response with AMG-531 therapy. The median duration of first response was 31 weeks (range, 21-60 weeks). Twentynine of the 31 responding patients had platelet counts  150 × 109/L at any time, and 15 patients had platelet counts  400 × 109/L at any time (Table 1). The use of concurrent corticosteroids was discontinued in 6 of the 9 patients and reduced in 1 patient while maintaining a safe platelet count with AMG-531 therapy.

Clinical Relevance The interim findings of the study demonstrate that the long-term administration of AMG-531 is feasible with a promising clinical activity in thrombocytopenic patients with ITP. Platelet responses were maintained for up to 72 weeks with individualized weekly dosing. No anti-AMG 531–neutralizing antibodies have been detected in patients with ITP. Additional safety analysis of long-term dosing are needed to determine the role of individualized AMG-531 dosing for patients with ITP.

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A Phase II Study of Eltrombopag in the Treatment of Thrombocytopenia in Patients with Relapsed/ Refractory Idiopathic Thrombocytopenic Purpura Thrombopoietic agents might be effective in the treatment of thrombocytopenia associated with ITP. Eltrombopag, a small-molecule, noncompetitive thrombopoietin receptor agonist, was found to stimulate proliferation and differentiation of megakaryocytes, which further differentiates into platelets.7,8 Eltrombopag was found to increase platelet counts in normal volunteers. Eltrombopag is orally bioavailable and, being a nonpeptide small molecule, has low immunogenic potential. The safety and efficacy of eltrombopag is currently being evaluated in an international, randomized, doubleblind, placebo-controlled phase II study in patients with chronic ITP. Patients who were diagnosed with chronic ITP for  6 months before screening with platelet counts < 30 × 109/L and who were nonresponders to previous therapy or who experienced relapse after  1 previous therapy were eligible for this phase II study of eltrombopag. The primary endpoint of the study was identification of patients with platelet counts > 50 × 109/L after up to 6 weeks of treatment with eltrombopag. The secondary endpoints included safety and tolerability, bleeding symptoms, pharmacodynamic parameters, and quality of life. Patients were randomized (1:1:1:1) to receive placebo (n = 29), eltrombopag 30 mg (n = 30), eltrombopag 50 mg (n = 30), or eltrombopag 75 mg (n = 28) orally once daily for 6 weeks (Figure 3).9 Treatment was discontinued upon achieving platelet counts  200 × 109/L during the treatment period. Bleeding events were assessed weekly during treatment and biweekly after completion of treatment as per the World Health Organization

Supportive Cancer Therapy

Meeting Highlights Figure 3

Phase II Study of Eltrombopag in ITP-Related Thrombocytopenia: Treatment Schema9

Eltrombopag 30 mg Supportive Care (n = 30) Eltrombopag 50 mg Supportive Care (n = 30) Eltrombopag 75 mg Supportive Care (n = 28)

Phase III Trial

Interim Analysis

Placebo Supportive Care (n = 29)

Bleeding Scale (grade 0: no bleeding; grade 1: mild; grade 2: moderate; grade 3: gross; grade 4: debilitating blood loss). The interim results of this study were presented by Bussel et al at the 48th Annual Meeting of ASH in Orlando, FL, in December 2006.9 The median age of the 117 patients enrolled in this study was 50 years. Upon completion of 42 days of therapy, the median platelet counts in the 30mg, 50-mg, and 75-mg cohorts were 26 × 109/L, 128 × 109/L, and 183 × 109/L, respectively, in comparison with 16 × 109/L in the placebo group (Table 2).9 Among patients in the 50mg cohort, 70% had a platelet response, and 37% had a platelet count  200 Table 2

× 109/L. Similar results were seen in the 75-mg cohort, with 81% having a platelet response and 43% achieving a platelet count  200 × 109/L. After treatment with eltrombopag, the odds ratio for an increase in platelets to  50 × 109/L was 3.09 (P = 0.07), 21.96 (P < 0.001), and 38.82 (P < 0.001) for the patient cohorts treated with 30 mg, 50 mg, and 75 mg, respectively, compared with placebo. The incidence of on-therapy bleeding events, including epistaxis, gingival bleeding, contusions, and menorrhagia, was 16%, 3%, and 4% in the 30-mg, 50-mg, and 75-mg arms, respectively, versus 10% in the placebo group (Table 2). The bleeding events that occurred after discontinuation of treatment included gingival bleeding, conjuctival hemorrhage, contusion, epitaxis, rectal hemorrhage, menstrual disorder, petechiae, and menorrhagia. The most common AE reported in this study was mild to moderate headache in 21% of patients who received placebo and 13%, 10%, and 21% of patients in the 30-mg, 50-mg, and 75-mg cohorts, respectively.

Clinical Relevance Treatment with eltrombopag 50 mg and 75 mg was effective in increasing platelet count and reducing bleeding. Eltrombopag was found to be safe and tolerable in this study. Based on the encouraging results from this phase II study, phase III studies have been initiated with eltrombopag 50 mg as the starting dose and increasing to 75 mg after 3 weeks if the platelet count is < 50 × 109/L.

Phase II Study of Eltrombopag in ITP-Related Thrombocytopenia: Results9

Treatment Group

Placebo (n = 29)

Median Platelet Counts on Day 43 16 × 109/L

Odds Ratio for Increase Bleeding Events (All Grades), % in Platelet Counts to > 50 × 109/L On Therapy After Therapy on Day 43 –

10

14

Eltrombopag 30 mg (n = 30)

26 ×

3.09 (P = 0.07)

16

13

Eltrombopag 50 mg (n = 30)

128 × 109/L

21.96 (P < 0.001)

3

10

Eltrombopag 75 mg (n = 28)

109/L

38.83 (P < 0.001)

4

7

183 ×

109/L

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Studies to assess long-term use of eltrombopag in the treatment of ITP-associated thrombocytopenia are also under way.

Preliminary Results of a Phase II Dose-Finding Study of Subcutaneous Hematide™ in Patients with Cancer Receiving Chemotherapy Approximately 60% of patients with cancer who undergo myelosuppressive chemotherapy as treatment for their malignancy experience debilitating symptoms of anemia,10 which has been associated with shorter survival.11 An effective treatment option for management of chemotherapyinduced anemia in patients with cancer is recombinant erythropoeitic therapy with erythropoiesis-stimulating agents, including darbepoetin alfa, epoetin alfa, and epoetin beta.12 Hematide™ is a novel erythropoiesis-stimulating agent currently being evaluated for the treatment of anemia associated with chronic kidney disease and cancer.13 This investigational drug is a synthetic pegylated erythropoietin-mimetic peptide dimer that induces erythropoiesis via activation of the erythropoietin receptor, which, in turn, results in the proliferation and differentiation of erythroid progenitor cells. Preclinical studies suggest that its extended half-life, slow clearance time, and similar erythrogenic responses to intravenous and subcutaneous delivery might be amenable for a once-monthly schedule of subcutaneous Hematide™ administration. The pharmacologic active intravenous dose of 0.1 mg/ kg and the safety profile of Hematide™ was established in a phase I placebocontrolled, dose-escalation study in 28 healthy male volunteers. Administration of Hematide™ resulted in a statistically significant increase in hemoglobin from baseline compared with placebo (1.36 ± 0.39 g/dL vs. 0.39 ± 0.38 g/dL; P < 0.001) that persisted for > 1 month.13,14 Based on these results, a phase II open-label study was initiated in patients with cancer

Volume 4, Number 2 • January 2007

Table 3

Phase II Study of Subcutaneous Hematide™ in Patients with Chemotherapy-Induced Anemia: Change from Baseline in Hemoglobin16 Week 7 (n = 10 )

Week 9 (n = 11 )

Hemoglobin Increase ≥ 1 g/dL (No. of Patients)

7 (70%)

10 (91%)

Mean Hemoglobin Increase from Baseline (g/dL)

1.6 ± 1.8

2.2 ± 1.79

undergoing myelosuppressive chemotherapy. This dose-finding study will evaluate the safety, pharmacodynamics, and pharmacokinetics of Hematide™ administered subcutaneously every 3 weeks in patients with cancer receiving chemotherapy.15 Preliminary results of the first cohort of patients of the phase II trial was reported at the 48th Annual Meeting of ASH and are summarized herein.16 Eligible patients enrolled in the trial included those with confirmed solid tumors or lymphoma who are scheduled to receive  9 weeks of chemotherapy for their malignancy. Patients with acute or chronic leukemia, myelodysplastic syndrome, multiple myeloma, history of hemoglobinopathy, hemolysis, or symptomatic inflammatory disease were excluded from the study. The baseline hemoglobin level was required to be  8 g/dL and < 11 g/dL. Intravenous iron supplementation was allowed in order to maintain hemoglobin value within the aforementioned range  1 week before the start of the study but required biweekly monitoring thereafter until an increase of  0.5 g/dL from the previous week was observed. Baseline serum or red cell folate and a vitamin B12 levels above the lower limit of normal were also required. Cohorts of 15 patients received 4 doses of subcutaneous Hematide™ every 3 weeks for 4 doses starting with an initial dose of 0.1 mg/kg. The objective of the study was to determine the Hematide™ dose required to increase hemoglobin by  1 g/dL in patients who are concurrently receiving chemotherapy. Of the 15 patients enrolled in the first cohort, 9 patients completed 12 weeks of follow-up. In 10 patients for whom data was available at week 7, mean hemoglobin

increased by 1.6 g/dL ± 1.8 g/dL from baseline (Table 3).16 Of these 10 patients, 7 showed an increase in hemoglobin  1 g/dL (range, 1.7-3.7 g/dL) at 7 weeks; 2 patients showed an increase of 1.65 g/dL and 1.1 g/dL, respectively, at week 9; and the third patient showed an increase of 1.7 g/dL at week 12. Another patient with missing week 7 evaluations showed hemoglobin increases of 1.8 g/dL at week 6 and 3.4 g/dL at week 9. In 11 patients who had data available from the week 9 follow-up, a mean hemoglobin increase of 2.2 g/dL ± 1.79 g/dL from baseline was observed. Of these 11 patients, 10 showed hemoglobin increases of  1 g/dL (range, 1.1-5.2 g/dL) at week 9, and 1 patient showed an increase of 1.7 g/dL at week 12. Three patients experienced 4 nonstudy drug-related serious AEs. Six patients discontinued treatment as a result of nonstudy drug-related reasons, including serious AEs (n = 2), remission of cancer (n = 1), and transfusions (n = 3).

Clinical Relevance Preliminary findings from this dose-finding phase II study suggest that subcutaneous Hematide™ administered every 3 weeks concurrently with myelosuppressive chemotherapy is well tolerated and increases hemoglobin levels  1 g/dL by week 7 in a majority of patients with cancer. Further follow-up is needed to determine the maximum tolerated dose of Hematide™ that maintains hemoglobin in the normal range in patients with chemotherapy-induced anemia, its duration of hemoglobin response, and pharmacokinetic profile. Treatment with Hematide™ represents a promising alternative strategy to the current erythropoietic therapy for the management of anemia in patients with cancer undergoing chemotherapy.

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Long-Term Analysis of the Safety and Tolerability of the Oral Iron Chelator Deferasirox in Patients with Transfusional Iron Overload Iron overload or hemosiderosis is characterized by increased iron deposition within the tissues and leads to various pathophysiologic complications, including diabetes, cardiac toxicity, arthritis, liver disease, and early mortality.17 Iron overload can result from genetic/inherited defects in iron metabolism or from secondary causes such as red blood cell transfusions in chronic anemias. Iron chelation therapy is the conventional treatment option for the management of iron overload and can effectively reduce iron stores or maintain iron balance.18 In the United States, the Food and Drug Administration–approved agents for iron chelation therapy are deferoxamine and deferasirox. Another orally active iron chelator, deferiprone, is available worldwide as second-line therapy in patients with transfusion-dependent thalassemia major but is not licensed for clinical use in the United States. The limitations of the hexadentate iron chelator deferoxamine is that it requires prolonged infusions to reduce iron burden and is associated with toxicities such as tachyphylaxis, leading to poor patient compliance. In contrast, the orally active tridentate iron chelator deferasirox is as effective as deferoxamine in addition to being easier to administer and tolerable.18-20 Five clinical trials have demonstrated the safety and tolerability of 1 year of deferasirox in the treatment of transfusional overload in adults and pediatric patients with a variety of transfusion-dependent anemias.21 In the extension phase of these trials, the patient cohort then received deferasirox for up to 4 years after completion of the 1-year core phase. The cumulative long-term safety data during deferasirox treatment for the entire cohort was reported at the 48th Annual Meeting of ASH and is summarized herein.

Supportive Cancer Therapy

Meeting Highlights Figure 4

Severity of Common (> 4%) Deferasirox Treatment-Related Adverse Events in Patients with Anemia21

120 100 Number of Patients

12

80

2 18

60 40

4 85 71

20 0

Severe AEs Moderate AEs Mild AEs

2

Nausea

Diarrhea

11

1 8

37

40

Abdominal Vomiting Pain

4 16 29 Rash

1 9 34

Upper Abdominal Pain

In the 5 trials, deferasirox was administered to a total of 1033 patients. Of these, 703 patients had received deferasirox during the 1-year core phases and represent the deferasirox cohort. The remaining 330 patients had initially received deferoxamine but crossed over to receive deferasirox in the extension phases to represent the crossover cohort. There were 433 pediatric patients (aged between 2 years and < 16 years) in the total cohort of 1033 patients (41.9%) of which 289 were in the deferasirox cohort and 144 were in the crossover cohort. The demographic subgroups included patients with -thalassemia (n = 749), sickle cell disease (n = 185), myelodysplastic syndromes (n = 47), Diamond-Blackfan anemia (n = 30), and other anemias (n = 22). In the deferasirox cohort, a mean dose of deferasirox 20.5 mg/kg daily was administered for a median of 2.5 years. The crossover cohort, which had previously received a mean deferoxamine dose of 42.2 mg/kg daily, received a mean dose of 21 mg/kg daily deferasirox for a median of 1.5 years. Safety analysis included monthly assessments of the incidence and type of AEs and measurements of laboratory parameters. The most common drugrelated AEs, occurring in > 4% of all patients, were nausea (9.6%), diarrhea (8.8%), abdominal pain (5%), vomiting (4.7%), rash (4.7%), and upper

abdominal pain (4.3%; Figure 4).20 Whereas majority of these AEs were of mild severity, < 2% were of moderate severity, and < 1% were severe; all drug-related AEs were transient. All treatment, age, and pathologic anemic groups showed a similar AE profile and rate of incidence. The reasons for deferasirox-related discontinuation in the core and extension phases included AEs (n = 72; 7%), consent withdrawal (n = 62; 6%), unsatisfactory therapeutic effect (n = 29; 2.8%), and other reasons (n = 37; 3.6%). During the deferasirox treatment, 15 non–drug-related deaths occurred (1.5%). Markers of liver or renal function were found to be similar during the 4-year extension phase and the core study phase. Urinary total protein/creatinine ratio was found to be > 1 in 10 patients (1%) at 2 successive follow-ups. However, no clinical or biochemical evidence was noted in these patients, which might be indicative of renal insufficiency or failure. All pediatric patients showed normal physical and sexual development.

Clinical Relevance The results of this analysis show that the safety and tolerability of deferasirox was similar in patients receiving therapy for 1 year and for a longer duration of up to 2.5 years. The AEs reported were transient and easily manageable, with a similar profile to previous reports from other studies. It is encouraging that this long-term safety analysis did not show any greater toxicity risks to the younger patient population or clinical manifestations of progressive renal disease in the entire cohort. Although preclinical studies indicate that deferasirox is as effective as deferiprone in chelating cardiac iron stores,22 longer follow-up is needed to assess longterm effects of deferasirox on cardiac-related morbidities. The results of the reported study suggest that long-term deferasirox therapy is a reasonable treatment option for adults and pediatric patients with chronic transfusiondependent anemias.

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References 1. Fanucchi M, Glaspy J, Crawford J, et al. Effects of polyethylene glycol–conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med 1997; 336:404-409. 2. Vadhan-Raj S, Patel S, Bueso-Ramos C, et al. Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia. J Clin Oncol 2003; 21:3158-3167. 3. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001; 98:3241-3248. 4. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP [published erratum in: N Engl J Med 2006; 355:2054]. N Engl J Med 2006; 355:1672-1681. 5. Newland A, Caulier MT, Kappers-Klunne M, et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol 2006; 135:547-553. 6. Kuter D, Bussel J, George J, et al. Long-term dosing of AMG 531 in thrombocytopenic patients with immune thrombocytopenic purpura: 48-week update. Blood 2006; 108:168 (Abstract #476). 7. Luengo JI, Duffy KJ, Shaw AN, et al. Discovery of SB-497115, a small-molecule thrombopoietin (TPO) receptor agonist for the treatment of thrombocytopenia. Blood 2004; 104:795a (Abstract #2910). 8. Erickson-Miller C, Delorme E, Giampa L, et al. Biological activity and selectivity for TPO receptor of the orally bioavailable, small molecule TPO receptor agonist, SB-497115. Blood 2004; 104:796a (Abstract #2912). 9. Bussel JB, Cheng G, Saleh M, et al. Analysis of bleeding in patients with immune thrombocytopenic purpura (ITP): a randomized, double-blind, placebo-controlled trial of eltrombopag, an oral platelet growth factor. Blood 2006; 108:144a (Abstract #475). 10. Groopman JE, Itri LM. Chemotherapyinduced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999; 91:16161634. 11. Caro JJ, Salas M, Ward A, et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001; 91:2214-2221. 12. Pronzato P. Cancer-related anaemia management in the 21st century. Cancer Treat Rev 2006; 32(suppl 2):S1-S3. 13. Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol 2006; 34:13031311. 14. Stead RB, Lambert J, Wessels D, et al. Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-

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controlled, dose-escalation study in healthy volunteers. Blood 2006; 108:1830-1834. 15. Hematide_pII. A phase 2, open-label, multicenter dose escalation study of the safety, pharmacodynamics, and pharmacokinetics of subcutaneously administered Hematide™ injection in anemic cancer patients receiving chemotherapy. Available at: http://www.clinicaltrials.gov/ct/show/NCT00272662?order=4. Accessed February 4, 2007. 16. Pickering L, Cwiertka K, Jasem J. Hematide, a synthetic peptide-based erythropoiesis stimulating agent (ESA), assessed for correction of anemia in oncology patients receiving

chemotherapy. Blood 2006; 108:11 (Abstract #1290). 17. Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann N Y Acad Sci 1998; 850:191-201. 18. Kalinowski DS, Richardson DR. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev 2005; 57:547-583. 19. Porter J, Vichinsky E, Rose C. A phase II study with ICL670 (Exjade®), a once-daily oral iron chelator, in patients with various transfusion-dependent anemias and iron overload. Blood 2004; 104:872a (Abstract

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#3193). 20. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a oncedaily oral iron chelator, in patients with betathalassemia. Blood 2006; 107:3455-3462. 21. Cappellini M, Giardina P, Porter J. Long-term safety and tolerability of the once-daily, oral iron chelator deferasirox (Exjade, ICL670) in patients with transfusional iron overload. Blood 2006; 108:11 (Abstract #1768). 22. Wood JC, Otto-Duessel M, Gonzalez I, et al. Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil. Transl Res 2006; 148:272-280.