Iron chelation therapy in MDS: what have we learnt recently?

Blood Reviews 23 Suppl. 1 (2009) S21–S25

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REVIEW

Iron chelation therapy in MDS: what have we learnt recently? Mathias Schmid* University of Ulm, Ulm, Germany

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abstract

Keywords: Myelodysplastic syndromes Iron overload Iron chelation therapy Deferasirox

Patients with myelodysplastic syndromes (MDS) who receive chronic blood transfusions for anaemia are at risk of developing iron overload, which can negatively affect organ function and survival. Evidence suggests that iron chelation therapy can restore iron balance in these patients and may improve their chances of survival. Recently, several guidelines on the management of patients with MDS have been published that address iron overload and the use of iron chelation therapy. While these guidelines differ in some specific details, they generally agree that patients with lower-risk MDS are most likely to develop iron overload and therefore benefit from iron chelation therapy. The oral iron chelator, deferasirox, has been shown to reduce serum ferritin levels and labile plasma iron in patients with MDS, and has an acceptable safety profile. Unlike other iron chelators, deferasirox also appears to inhibit the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-úB) pathway in MDS blast cells, which may lead to additional beneficial effects. © 2009 Elsevier Ltd. All rights reserved.

Introduction Most patients with myelodysplastic syndromes (MDS) present with anaemia at diagnosis, and approximately 60% of them will develop severe anaemia at some point during the course of the disease.1 In most cases, transfusion of red blood cells (RBCs) can effectively manage the symptoms associated with anaemia. However, chronic blood transfusions can lead to iron overload. If left untreated or inadequately managed, iron overload increases morbidity and mortality due to cardiac, hepatic, and endocrine complications.1 Iron chelation therapy has been shown to be beneficial in other patients with transfusion-dependent anaemia, such as b-thalassaemia major. In 97 patients with b-thalassaemia major, maintenance of serum ferritin levels <2500 mg/L was shown to be the major determinant of cardiac disease-free survival.2 Low serum ferritin levels were also associated with a reduction in end-organ toxicity. Few studies have assessed the survival advantage of iron chelation therapy in patients with MDS, but retrospective data suggest that efficient iron chelation may prolong survival.3–5 One such analysis evaluated the effects of iron chelation therapy on survival in patients with lower-risk MDS (mainly Low- or Intermediate [Int]-1-risk MDS, according to the International Prognostic Scoring System [IPSS]).6 Of the 165 evaluable patients, 76 (46%) received chelation therapy for at least 6 months: 60 received various schedules of deferoxamine, five received deferiprone, five received * Corresponding author. Mathias Schmid, PD, Dr. Med, Universitatsklinikum ¨ Ulm, Innere Medizin III, Albert-Einstein-Allee 23, 89081 Ulm, Germany. Tel.: +49 731 500 45537; fax: +49 731 500 45515. E-mail address: [email protected] (M. Schmid). 0268-960X /$ – see front matter © 2009 Elsevier Ltd. All rights reserved.

deferoxamine and deferiprone in combination, and six received deferasirox. Median overall survival was significantly longer in patients who received iron chelation therapy than in those who did not (115 vs 51 months; p < 0.0001). The survival benefit of iron chelation therapy remained significant after adjusting for other prognostic parameters (e.g. sex, age, IPSS Low vs Int-1 risk, and blood transfusion requirements). Although the “prospective” nature of this non-randomised, uncontrolled trial has been questioned, it offers evidence that the management of iron overload with iron chelation therapy can have a positive effect on survival in patients with lower-risk MDS. Recently, multiple guidelines have been published on the management of patients with MDS that provide recommendations regarding iron overload and the use of iron chelation therapy. This article reviews the major similarities and differences between these guidelines, as well as some of the recently reported key clinical data on the use of iron chelation therapy in MDS. Guidelines for iron chelation therapy In 2008, several national and international groups published updated guidelines on the management of MDS, including the use of iron chelation therapy to treat iron overload. The role of iron chelation therapy had been discussed in previously published guidelines developed in Italy and the UK, and in the Nagasaki consensus statement published in 2005, which was developed by an international panel of experts.7–9 The guidelines published in 2008 take into account some of the recent advances in the treatment of MDS and new data on the effects of iron chelation therapy, particularly the role of deferasirox, in patients with MDS. Countries

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Table 1 Overview of 2008 guidelines on the use of iron chelation therapy in MDS.1,10–15 Country

Target serum ferritin level (mg/L)

Criteria for initiating iron chelation therapy Transfusion status

Serum ferritin (mg/L)

Patient status / risk level

Austria10

>2 RBC units/month

>2000

Life expectancy >1 year or candidate for SCT, or organopathy resulting from iron overload

NRM; continue chelation as long as response can be maintained, or if patient is transfusion-dependent with high serum ferritin or severe organopathy is present

Spain11

Transfusion-dependent anaemia

>1000

IPSS Low or Int-1; WPSS Very Low, Low, Intermediate; IPE Low; or candidate for SCT

NRM

Israel12

20–25 RBC units

>1000

IPSS Low or Int-1 or candidate for SCT

<500–<1000

Japan13

>40 Japanese RBC units*

>1000

Life expectancy >1 year

500–1000

Canada14

NRM

>1000

Life expectancy >1 year or candidate for SCT

NRM; reduce dose when <2000 mg/L; discontinue chelation when <1000 mg/L

USA (NCCN)15

>20–30 RBC units (≥5–10 g iron)

>2500

IPSS Low or Int-1

<1000

MDS Foundation1

2 RBC units/month for ≥1 year

>1000

Life expectancy >1 year or candidate for SCT

NRM

*Equivalent to 20 Western RBC units. Int = intermediate; IPE = Spanish Prognostic Index; IPSS = International Prognostic Scoring System; MDS = myelodysplastic syndromes; NCCN = National Comprehensive Cancer Network; NRM = no recommendation made; RBC = red blood cell; SCT = stem cell transplantation; WPSS = World Health Organization classification-based Prognostic Scoring System.

that developed new guidelines or updated previous guidelines in 2008 include Austria, Spain, Israel, Japan, Canada, and the USA.10–15 In addition, the MDS Foundation has recently published a consensus statement on iron overload in MDS.1 While these guidelines often differ in specific details (Table 1),1,10–15 there is general agreement on many of the key aspects of management of iron overload. All of these guidelines generally agree that RBC transfusions are beneficial in those patients with MDS who exhibit symptomatic anaemia, and that chronic blood transfusions lead to iron overload with an increase in patient morbidity and mortality. Patients who are most likely to benefit from iron chelation therapy are those with lower-risk MDS (e.g. IPSS Low or Int-1) and a life expectancy of >1 year. Various parameters are used to describe transfusion status, reflecting regional practice differences. In general, the guidelines recommend considering iron chelation therapy for patients who have received a total of 20–30 RBC units or are currently receiving two or more RBC units per month. Most of the guidelines agree that iron chelation therapy should be considered when serum ferritin levels exceed 1000 mg/L, with the exception of the Austrian guidelines, which suggest a threshold of 2000 mg/L, and the guidelines of the National Comprehensive Cancer Network (NCCN) in the USA, which recommend a threshold of 2500 mg/L. Some guidelines suggest discontinuing iron chelation therapy once serum ferritin levels reach 500–1000 mg/L, whereas others offer minimal to no guidance on the optimal target of therapy. The international consensus statement developed by the MDS Foundation provides detailed recommendations regarding iron overload and the use of iron chelation therapy in MDS.1 The MDS Foundation recommends that patients with MDS be assessed for iron overload at the time of diagnosis and at regular intervals thereafter, depending on the rate of blood transfusion. Transfusiondependent patients should be monitored every 3 months, and those patients receiving iron chelation therapy should be further monitored according to the specific product information guidelines. The international guidelines suggest that serum ferritin levels, transferrin saturation, and liver magnetic resonance imaging (MRI) be utilised as modalities to assess iron overload in patients with MDS. Measuring serum ferritin levels is relatively easy, inexpensive, and is widely accepted. However, caution is warranted when basing clinical decisions solely on single serum ferritin levels, as they can

be influenced by inflammation, infections, concomitant medication, and other factors. Serial serum ferritin levels are recommended; and transferrin saturation, when combined with serum ferritin levels, may provide a better assessment of iron overload, and can be useful in measuring the effects of iron chelation therapy. Liver MRI provides a reliable and non-invasive approach to measure liver iron concentration (LIC), which has been shown to directly correlate with total body iron levels in thalassaemia patients.16 According to the MDS Foundation guidelines, patients with lower-risk disease (World Health Organization [WHO] classification refractory anaemia with or without ringed sideroblasts, chromosome 5q deletion syndrome or Low- or Int-1-risk disease by IPSS), transfusion-dependent anaemia requiring ≥2 units of packed RBCs/month for >1 year, and serum ferritin levels >1000 mg/L may benefit from iron chelation therapy.1 Patients with a life expectancy of <1 year should probably not be considered for iron chelation therapy, because complications related to iron overload generally take at least a year to become apparent. However, iron chelation therapy may be considered in patients with a short life expectancy who already show signs of iron-related organ complications. Patients with increased iron levels prior to receiving an allograft may also benefit from iron chelation therapy. Preallograft iron chelation therapy may help to avoid iron-related organ dysfunction, which contributes to transplant-related morbidity and mortality. This treatment should also be considered for patients who are unresponsive to, or ineligible for, primary therapy such as hormonal or hypomethylation therapy.

Iron chelation therapy with deferasirox Although three iron chelators (deferoxamine, deferiprone, and deferasirox) are commercially available at present, only limited data are available on the efficacy and safety of deferoxamine and deferiprone in patients with MDS. Initial studies on the oral iron chelator, deferasirox, in patients with MDS have shown that serum ferritin levels and LIC were stabilised at doses of 10 mg/kg/day and reduced at doses of 20–30 mg/kg/day.17 These results were later confirmed in the larger US03 and EPIC studies.18,19 The US03 study was a 12-month prospective trial that evaluated the effects of deferasirox on serum ferritin levels and changes

M. Schmid / Blood Reviews 23 (2009) S21–S25

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Table 2 Reduction in mean serum ferritin over 12 months of treatment with deferasirox.18

Mean serum ferritin ± SEM (mg/L)

Baseline (n = 176)

3 months (n = 143)

6 months (n = 126)

9 months (n = 109)

12 months (n = 93)

3397±233

3057±144

2802±128

2635±148

2501±139

SEM = standard error of the mean.

in labile plasma iron (LPI) in 176 patients with Low- or Int-1risk MDS.18 LPI (the redox-active and chelatable component of non-transferrin-bound iron [NTBI]) appears in plasma when the iron-binding capacity of transferrin is exhausted. It is capable of permeating into organs and inducing tissue iron overload. At baseline, the mean age of the patients in US03 was 70 years and their mean serum ferritin level was 3397 mg/L. Elevated LPI, defined as values of ≥0.5 mmol/L was recorded in 41% of patients.18 A significant reduction in serum ferritin levels was evident after 3 months and was maintained for 12 months with deferasirox treatment. In patients with elevated LPI, sustained suppression of LPI to normal range was achieved after 3 months of deferasirox treatment (Table 2). Adverse events led to discontinuation of deferasirox therapy in 13% of patients; the most common adverse events were diarrhoea, rash, and nausea. A total of 18% of patients experienced an increase in serum creatinine to above the upper limit of normal (ULN) on ≥2 consecutive visits. The EPIC study was a multicentre open-label study of deferasirox that enrolled 1744 patients with transfusion-dependent anaemias, including 341 with MDS, making it the largest study of iron chelation therapy conducted to date.20 In the overall MDS cohort, deferasirox reduced the serum ferritin levels by 26% on average after 12 months.21 Improvement was seen at all dose levels of deferasirox in patients who had received prior iron chelation therapy (mean reduction of 22%) and in those who had not (mean reduction of 35%).19 Notably, the reduction in serum ferritin levels correlated with reductions in alanine transaminase (ALT) levels, suggesting that deferasirox treatment was associated with improvements in liver function.22 The effects of deferasirox on LPI were also assessed in the EPIC study.23 In the 305 patients with MDS for whom LPI data were available, mean LPI prior to deferasirox therapy was 0.53±0.63 mmol/L (normal range, 0–0.40 mmol/L). Two hours after administration of deferasirox, mean LPI levels decreased to 0.02 mmol/L (Table 3)23 and remained within the normal range throughout the 12-month study period (both pre- and postadministration). Thus, it appears that once-daily administration of deferasirox provides a sustained reduction in toxic LPI and prevents rebounds in LPI levels in between doses. These effects may help to prevent iron overload, particularly in the heart and liver. In the EPIC study, 78 patients (23%) discontinued treatment due to adverse events.20 These events were deemed drug related in 44 cases (13%). Most events (95%) were mild-to-moderate in severity. The commonest drug-related adverse events were gastrointestinal (GI) disturbances, including diarrhoea, nausea, vomiting, abdominal pain, and constipation. Only 25 patients discontinued treatment due to drug-related GI events. Serum creatinine increased >33% from baseline at two consecutive visits, Table 3 Reduction in LPI following treatment with deferasirox in 305 patients with MDS.22 Week 52

Baseline Mean LPI ± SD (mmol/L)*

two measurements >ULN or both were recorded in 14.7%, 10.6% and 24.9% of patients, respectively. Increased ALT >10 × ULN at two consecutive visits was observed in one patient with normal ALT at baseline.19 The effect of deferasirox on patient quality of life and adherence was also assessed in the EPIC study.24,25 The results of this study indicated that quality of life improved after initiating iron chelation therapy.24 Mean summary scores for the Short Form with 36 questions (SF-36) quality of life measures improved from baseline and approached normal levels by week 4 of treatment. This effect was maintained throughout the study.24 Patient satisfaction was measured using the validated questionnaire known as the Satisfaction with Iron Chelation Therapy (SICT) questionnaire.25 Of the 87 MDS patients who had received prior iron chelation therapy, 57 completed the SICT both prior to and after 12 months of deferasirox study treatment. Significant improvements from baseline were seen in SICT scores for side effects, acceptance, and iron chelation therapy burden.25 Scores reflecting the perceived efficacy of iron chelation therapy did not change significantly. Adherence to treatment also improved during deferasirox treatment in the subset of patients who had received prior iron chelation therapy. After 12 months of treatment with deferasirox, more patients reported that they always followed the treatment regimen, and more patients reported that they had never thought about stopping iron chelation therapy, compared with scores prior to onset of therapy.25 These improvements in quality of life, satisfaction with treatment, and adherence may substantially improve long-term health outcomes for these patients. Results from two small single-centre trials of deferasirox have recently been published.26,27 In the first study, 14 patients with MDS received low doses of deferasirox (13–20 mg/kg/day) for 24 months.26 Their median age was 71 years and their median serum ferritin levels at baseline were high (3929 mg/L). In 13 of these 14 patients, deferasirox treatment reduced serum ferritin levels. In four patients, serum ferritin levels were reduced to <2000 mg/L. Adverse events were generally mild. In the second study, 12 patients with MDS received deferasirox at doses of 20– 30 mg/kg/day for 12 months.27 Compared with the first study, this study population was slightly older (median age 76 years) and had lower median serum ferritin levels at baseline (1575 mg/L). Nevertheless, treatment with deferasirox reduced serum ferritin levels by 67.5%. In addition, the LIC as measured by MRI decreased from 315 to 230 mmol/g of liver tissue. Out of eight patients assessed for cardiac iron load by MRI, six showed improvements in cardiac iron load, including two patients in whom cardiac T2* had normalised by the end of the study. The most common adverse events were mild GI disturbances and skin rash. Serum creatinine levels increased and creatinine clearance decreased in a transient, non-progressive fashion. Although these studies were carried out in a small number of patients, they provide further evidence to support the efficacy and safety of deferasirox treatment in patients with MDS.

Pre

Post

Pre

Post

0.53±0.63

0.02±0.11

0.14±0.32

0.02±0.07

*Normal levels are 0–0.40 mmol/L. LPI = labile plasma iron; SD = standard deviation.

Additional potential mechanisms of action of iron chelation therapy in MDS Beyond the restoration of iron balance and removal of excess iron, iron chelation therapy appears to have other potentially beneficial

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effects. Iron overload is associated with increased oxidative stress, and iron chelation therapy has been shown to improve several important parameters of oxidative stress.28 The accumulation of NTBI as a result of chronic blood transfusions results in excess extracellular LPI and intracellular labile iron pools (LIPs). These pools are thought to be primary sources of reactive oxygen species (ROS) generation and may lead to oxidative damage in these patients. In a study of 19 patients with lower-risk MDS (mainly IPSS Low or Int-1), levels of LPI, LIPs, and oxidative-stress parameters improved following 3 months of treatment with deferasirox.28,29 Specifically, a significant decrease was observed in ROS, lipid peroxidation, and LIPs, concomitant with an increase in glutathione. These improvements were seen primarily in RBCs, but some improvements were also seen in platelets and polymorphonuclear leucocytes. In addition, after treatment with deferasirox, increases of 28% and 60% were found in patients with high baseline serum and urinary levels of hepcidin, respectively.29 ROS generation can inhibit hepcidin.30 Therefore, it is likely that the reduction in oxidative stress by iron chelation therapy resulted in an increase in serum and urinary hepcidin levels in these patients. Recent evidence also suggests that deferasirox may have an effect on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-úB) activity. NF-úB is abnormally activated in MDS blast cells, and the NF-úB pathway can be further stimulated by the ROS generated by iron overload. In peripheral blood samples taken from 40 patients with MDS or secondary acute myelogenous leukaemia, 14 patients were found to have abnormal NF-úB activity. Exposure to deferasirox reduced NF-úB activity in these samples.31 Notably, exposure to deferoxamine or deferiprone had no effect on NF-úB activity, suggesting that this effect is not a result of iron chelation therapy, but a specific effect of deferasirox on MDS blast cells. This may partly explain the increase in haemoglobin levels and reduced transfusion needs observed in some patients treated with deferasirox.18 However, further trials are necessary to test this hypothesis. Conclusions Due to new treatment options for patients with MDS, overall survival has been improved in these myeloid disorders. Therefore, we must pay attention to secondary problems, such as those related to chronic transfusions, including iron overload. Recent studies, such as the EPIC 2409 trial, clearly show that consequent iron chelation with deferasirox can eliminate iron from parenchymal organs such as the liver or heart and therefore preserve organ function. Additional data suggest that overall survival and quality of life are improved in well chelated patients. Nevertheless, MDS patients seem to have more adverse events compared to younger patients, probably due to their age, co-morbidity, and/or concomitant medications. Therefore, iron chelation is a substantial and important treatment option in MDS patients with secondary iron overload but they must be closely monitored for drug-related side effects. Future studies should be conducted to explore the effect of deferasirox on the malignant MDS clone itself, as suggested by recent studies. Practice points • Iron chelation therapy is effective and may improve survival in carefully selected patients with MDS. • Guidelines for the management of iron chelation therapy converge towards a consensus on the subgroups of patients with MDS who should receive iron chelation therapy. • In general, patients with lower-risk MDS and life expectancy >1 year will benefit most from iron chelation therapy.

• Data show that deferasirox is an effective oral iron chelator in patients with MDS and has a manageable safety profile. • Deferasirox may have additional effects, such as reduction of ROS and inhibition of NF-úB, which may translate into additional beneficial effects for patients with MDS. Disclosures Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The author is fully responsible for the content and editorial decisions for this manuscript. Ryan Blanchard is thanked for medical editorial assistance with this manuscript. Conflict of interest and funding Dr Mathias Schmid has received speaker’s honoraria and research funding from Novartis. He has previously participated in Novartissponsored advisory boards. References 1. Bennett JM; MDS Foundation’s Working Group on Transfusional Iron Overload. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol 2008;83:858–1. 2. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous b-thalassemia. N Engl J Med 1994;331:574–8. 3. Leitch HA, Goodman TA, Wong KK, et al. Improved survival in patient with myelodysplastic syndrome (MDS) receiving iron chelation therapy. Blood 2006;108: abstract 249. 4. Leitch HA. Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using iron chelation therapy. Leuk Res 2007; 31(Suppl 3):S7–9. 5. Takatoku M, Uchiyama T, Okamoto S, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anaemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol 2007;78:487–4. 6. Rose C, Brechignac S, Vassilief D, et al. Positive impact of iron chelation therapy (CT) on survival in regularly transfused MDS patients. A prospective analysis by the GFM. Blood 2007;110: abstract 249. 7. Alessandrino EP, Amadori S, Barosi G, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica 2002;87:1286– 306. 8. Bowen D, Culligan D, Jowitt S, et al. Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol 2003;120:187–200. 9. Gattermann N, Porter JB, Lopes LF, et al. Consensus statement on iron overload in myelodysplastic syndromes. Hematol Oncol Clin North Am 2005;19(Suppl 1): 18–25. 10. Valent P, Krieger O, Stauder R, et al. Iron overload in myelodysplastic syndromes (MDS) – diagnosis, management, and response criteria: a proposal of the Austrian MDS platform. Eur J Clin Invest 2008;38:143–9. 11. Arrizabalaga B, del Canizo ˜ C, Remacha A, et al. Gu´ıa cl´ınica de quelacion ´ del paciente con s´ındrome mielodisplasico. ´ Haematologica [Spanish edition] 2008; 93(Suppl 1):3–10. 12. Mittelman M, Lugassy G, Merkel D, et al. Iron chelation therapy in patients with myelodysplastic syndromes: consensus conference guidelines. Isr Med Assoc J 2008;10:374–6. 13. Suzuki T, Tomonaga M, Miyazaki Y, et al. Japanese epidemiological survey with consensus statement on Japanese guidelines for treatment of iron overload in bone marrow failure syndromes. Int J Hematol 2008;88:30–5. 14. Wells RA, Leber B, Buckstein R, et al. Iron overload in myelodysplastic syndromes: a Canadian consensus guideline. Leuk Res 2008;32:1338–53. 15. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines. Myelodysplastic Syndromes, v.2.2008. Available at www.nccn.org. 16. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 2000;343:327–31. 17. Porter JB, Galanello R, Saglio G, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008;80:168–76. 18. List AF, Baer MR, Steensma D, et al. Iron chelation with deferasirox (Exjade® ) improves iron burden in patients with myelodysplastic syndromes (MDS). Blood 2008;112: abstract 634. 19. Gattermann N, Schmid M, Della Porter M, et al. Efficacy and safety of deferasirox (Exjade® ) during 1 year of treatment in transfusion-dependent patient with myelodysplastic syndromes: results from EPIC trial. Blood 2008;112: abstract 633.

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