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Improved survival in MDS patients receiving iron chelation therapy – A matched pair analysis of 188 patients from the Düsseldorf MDS registry
Leukemia Research 36 (2012) 1067–1070
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Improved survival in MDS patients receiving iron chelation therapy – A matched pair analysis of 188 patients from the Düsseldorf MDS registry Judith Neukirchen ∗ , Frank Fox, Andrea Kündgen, Kathrin Nachtkamp, Corinna Strupp, Rainer Haas, Ulrich Germing, Norbert Gattermann Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany
a r t i c l e
i n f o
Article history: Received 2 November 2011 Received in revised form 9 April 2012 Accepted 13 April 2012 Available online 6 May 2012 Keywords: Myelodysplastic syndrome Transfusion therapy Iron overload Iron chelation Survival
a b s t r a c t MDS patients are prone to develop transfusional iron overload. Iron overload may partly explain why transfusion dependency is associated with a decreased likelihood of survival. Our matched-pair analysis included 94 patients on long-term chelation therapy and 94 matched patients without it. All patients had iron overload, defined as serum ferritin (SF) above 1000 ng/ml or a history of multiple transfusions and SF ≥ 500 ng/ml. Median SF was 1954 ng/ml in chelated and 875 ng/ml in non-chelated patients. The difference in median survival (74 vs. 49 months, respectively; p = 0.002) supports the idea that iron chelation therapy is beneficial for MDS patients. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction Patients with myelodysplastic syndromes (MDS) suffer from peripheral blood cytopenias as a result of bone marrow failure. Besides medullary blast count and karyotype, transfusion dependency has been identified as an important prognostic factor [1,2] and has therefore been integrated into the WHO-classification based prognostic scoring system (WPSS) [3]. Despite new treatment options, many MDS patients rely on red blood cell transfusions. Chronic transfusion therapy causes iron overload. Recently, a large retrospective analysis showed that iron overload, defined as a serum ferritin >1000 ng/ml, was a significant prognostic factor for OS and leukemia-free survival in MDS [1]. On multivariate analysis, the influence of iron overload was independent of transfusion requirement. If iron overload shortens the survival of patients with MDS, iron chelation (IC) should do the opposite. This view is supported by a partly retrospective and partly prospective observational study by Rose et al. [4] showing that patients with an IPSS low or intermediate-1 risk profile who received iron chelation therapy lived longer than patients who did not. However, there are as yet no results available from randomized clinical trials to confirm such a
∗ Corresponding author at: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: +49 211 8117720; fax: +49 211 8118853. E-mail address: [email protected] (J. Neukirchen). 0145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2012.04.006
survival benefit. We performed a retrospective matched-pair analysis drawing on the data base of the Düsseldorf MDS registry. 2. Methods At the time of patient selection the Düsseldorf MDS registry included 3552 patients, diagnosed between 1975 and 2008. For matched-pair analysis [5] we identified 94 polytransfused MDS patients who had been receiving long-term chelation therapy. The registry was then searched for matching partners who received supportive care, including growth factors, but neither iron chelators nor diseasemodifying drugs. The following characteristics were used for matching: age at diagnosis (±5 years), gender, MDS type according to WHO classification, and IPSS score. We chose 94 patients fulfilling all selection criteria. The cut-off date for this report was June 30, 2009. To deal with confounding variables, each patient was paired with a randomly chosen matched control. Cases and controls were stratified according to chelation treatment [6].
3. Results Patient characteristics are shown in Tables 1a and 1b. All 188 patients showed iron overload, defined as a serum ferritin ≥1000 ng/ml, or a history of multiple transfusions and a serum ferritin ≥500 ng/ml. All ferritin levels were measured at the time of referral to our center, which was usually early after diagnosis. The proportion of heavily transfusion-dependent patients was largest among patients with del(5q), RCMD, and refractory anemia with excess blasts (RAEB-I and -II). At least 50% of patients with these diagnoses received transfusions of packed red blood cells (PRBC). Mean and median serum ferritin (SF) levels were also highest in patients with del(5q). SF levels were not correlated with gender or
1068
J. Neukirchen et al. / Leukemia Research 36 (2012) 1067–1070
Table 1a Clinical characteristics of chelated and non-chelated patients with MDS. Parameter
Chelated
Non-chelated
p
Median age (range) Gender Ferritin (mean) Karnofsky index < 60% Transfusions at diagnosis Platelets (l) ANC (l) Hemoglobin (g/dl) Medullary blast count Karyotype risk category Low risk Intermediate High risk Ferritin > 1000 ng/ml Ferritin > 500 ng/ml and transfusions AML development Proportion of patients who died during the observation period Death due to infections Death due to bleeding Other causes of death Comorbidities Lung Heart Kidney Liver Solid tumors
64 (18–82) 48% w 2400 25% 75% 229,000 2500 8.7 4%
67.5 (33–89) 42% w 980 31.5% 85% 231,000 3600 9.0 4%
0.005 ns 0.005 ns ns ns ns ns ns
71% 18% 11% 80% 20% 12.9% 56% 35% 4.5% 60.5%
76% 12% 12% 78% 22% 14% 60% 13% 9.5% 77%
7% 23% 3.5% 2% 11%
9% 43% 0% 12% 12%
IPSS risk group. Chelation therapy was started at a median of 21 months after diagnosis (range 0–212 months). 53 patients in the IC group received deferoxamine monotherapy and 47 received deferasirox monotherapy. Deferoxamine followed by deferasirox was used in 14 patients, and deferoxamine followed by deferiprone in 3 patients. Mean duration of chelation therapy was 39 months for deferoxamine and 28 months for deferasirox. There were some patients on long-term treatment with deferoxamine, lasting much longer than any treatment period with deferasirox, simply owing to the time that the latter has been available. Overall, in our hands, deferasirox has not been more difficult to handle than deferoxamine, which poses compliance problems due to its cumbersome parenteral administration. The majority of deferoxamin-treated patients received the drug by continuous infusion overnight, but there were also some patients receiving deferoxamine as regular twice daily subcutaneous bolus injections. Among patients receiving chelation therapy, 56% died during the observation period, as compared to 60% in the group of patients receiving supportive care only (Fig. 1a). Median survival was 75 months in the IC group and 49 months in the supportive care group
Table 1b MDS types and risk profile according to WHO and IPSS classification, respectively, in the iron chelated patients (n = 94). Classification system WHO MDS with del(5q) RA RARS RCMD RAEB-I RAEB-II CMML IPSS Low Intermediate-1 Intermediate-2 High
n (%) 22 (23) 6 (6) 9 (10) 40 (43) 8 (9) 4 (4) 5 (5) 35 (37) 43 (46) 13 (14) 3 (3)
RA, refractory anemia; RARS, refractory anemia with ring sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RAEB, refractory anemia with excess blasts; CMML, chronic myelomonocytic leukemia.
ns ns ns ns ns 0.03
ns ns ns 0.039 ns
(p = 0.002). There was no significant difference regarding risk of AML evolution (Fig. 1b). Cumulative risk of AML transformation in the IC vs. supportive care group was 10% and 12% two years after diagnosis, and 19% and 18% five years after diagnosis, respectively (p = 0.73). There was no significant difference in median survival between chelated and non-chelated individuals in the cohort of patients with higher-risk MDS, whereas a significant difference was found in the lower-risk group (p = 0.008). Causes of death not related to MDS were slightly more frequent in the chelated patient group, but firm conclusions could not be drawn since death certificates were not available in many patients. Data on response to IC were available for 31 patients with stable MDS and ongoing transfusion dependency. Among these, 21 showed stable or decreasing serum ferritin during IC therapy. These patients had a significant survival benefit compared to patients with increasing SF (Fig. 2).
4. Discussion In the field of thalassemia, it is well established that transfusional iron overload limits life expectancy due to toxic effects on heart, liver and other organs. In patients with MDS, the situation is more difficult to understand. Chronic transfusion therapy is clearly associated with a decreased likelihood of overall survival and leukemia-free survival [1,2]. There is a dose-dependent effect of transfusion requirement, and a similar dose-dependent effect of serum ferritin levels, on overall and leukemia-free survival. The similar impact of transfusion requirement and serum ferritin levels could be interpreted as evidence that transfusion dependency causes iron overload, which then worsens the prognosis. However, the data can also be interpreted the other way round: transfusional iron overload reflects severe bone marrow disease as the real cause of shortened survival. Both interpretations are probably correct, because multivariate analyses have shown that iron overload has independent prognostic impact, even if transfusion need is taken into account [1,2]. Assuming that iron overload diminishes the likelihood of survival in MDS, chelation therapy should have an oppositive effect.
J. Neukirchen et al. / Leukemia Research 36 (2012) 1067–1070
1069
Fig. 1. Impact of iron chelation therapy on OS and AML transformation (n = 188).
This was indeed first suggested by a small retrospective analysis from Canada [7,8] and then corroborated by a partly retrospective and partly prospective study from France showing a strong survival benefit of chelation therapy in patients with MDS of low and intermediate-1 risk profile according to IPSS [4]. In our retrospective matched-pair analysis, median overall survival was significantly better in chronically transfused but iron-chelated patients (75 months) than in matched patients without chelation therapy (49 months). In addition, patients with ongoing transfusion need whose serum ferritin decreased over time had a better survival as compared to patients whose ferritin levels increased despite iron chelation. The present analysis has its limitations. The matching procedure did not consider comorbidities and intensity of transfusion
1,0
therapy during the course of disease. Interestingly, liver dysfunction was more frequent among non-chelated patients, but it is unclear whether this can be attributed to the lack of chelation therapy. The retrospective character of our study did not allow us analyze in detail the clinical complications contributing to shortened survival in patients not receiving chelation therapy. Cardiac events and infections were the most frequent causes of death in both patient groups. In contrast to the multivariate analysis of the Spanish multicenter study [1] and other investigations [4,7], our matched-pair analysis did not reveal an impact of chelation therapy on the risk of leukemic transformation. We cannot offer a simple explanation for this discrepancy. However, the practically identical rate of progression to AML in the chelated and non-chelated patients suggests that our matching procedure must have created patient groups that are indeed comparable in terms of disease characteristics. Funding source
,8
This work was supported by Novartis Pharma AG. The sponsor was not involved in collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. Part of the data have been presented at ASH 2009, Abstract 1747.
Cum Surviva al
, ,6
,4
Conflict of interest
,2
U.G. and N.G. received speakers honorary and research support from Novartis Pharma AG. F.F. and A.K. received speakers honorary from Novartis Pharma AG. Acknowledgments
0,0 0
48
96
144
192
240
288
336
384
432
months Fig. 2. Cumulative survival of patients with a stable MDS and ongoing transfusion dependency who responded to iron chelation in comparison to patients with increasing ferritin levels (n = 31).
Contributions. U.G. and N.G. made the conception and design of the study. J.N., U.G. and N.G. were responsible for analysis and interpretation of the data, and J.N. wrote the manuscript. F.F., A.K., N.K. and C.S. acquired the data, U.G. and N.G. revised the article critically and R.H. revised the article critically and gave the final approval.
1070
J. Neukirchen et al. / Leukemia Research 36 (2012) 1067–1070
References [1] Sanz G, Nomdedeu B, Such E, Bernal T, Belkaid M, Ardanaz MT, et al. Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome. Blood 2008;112:238–9. [2] Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol 2005;23:7594–603. [3] Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25:3503–10.
[4] Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients. A multicenter study by the GFM. Leuk Res 2010;34: 864–70. [5] Holt JD. Competing risk analyses with special reference to matched pair experiments. Biometrika 1978;65:159–65. [6] Sahai H, Khurshid A. Statistics and epidemiology: methods, techniques, and applications. Boca Raton: CRC Press; 1995. [7] Leitch HA, Leger CS, Goodman TA, Wong KK, Wong DHC, Ramadan KM, et al. Improved survival in patient with myelodysplastic syndrome receiving iron chelation therapy. Clin Leuk 2008;3:205–11. [8] Leitch HA. Iron chelation therapy in MDS: does it improve survival. Leuk Res 2010;34:852–3.
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Improved survival in MDS patients receiving iron chelation therapy – A matched pair analysis of 188 patients from the Düsseldorf MDS registry Judith Neukirchen ∗ , Frank Fox, Andrea Kündgen, Kathrin Nachtkamp, Corinna Strupp, Rainer Haas, Ulrich Germing, Norbert Gattermann Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany
a r t i c l e
i n f o
Article history: Received 2 November 2011 Received in revised form 9 April 2012 Accepted 13 April 2012 Available online 6 May 2012 Keywords: Myelodysplastic syndrome Transfusion therapy Iron overload Iron chelation Survival
a b s t r a c t MDS patients are prone to develop transfusional iron overload. Iron overload may partly explain why transfusion dependency is associated with a decreased likelihood of survival. Our matched-pair analysis included 94 patients on long-term chelation therapy and 94 matched patients without it. All patients had iron overload, defined as serum ferritin (SF) above 1000 ng/ml or a history of multiple transfusions and SF ≥ 500 ng/ml. Median SF was 1954 ng/ml in chelated and 875 ng/ml in non-chelated patients. The difference in median survival (74 vs. 49 months, respectively; p = 0.002) supports the idea that iron chelation therapy is beneficial for MDS patients. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction Patients with myelodysplastic syndromes (MDS) suffer from peripheral blood cytopenias as a result of bone marrow failure. Besides medullary blast count and karyotype, transfusion dependency has been identified as an important prognostic factor [1,2] and has therefore been integrated into the WHO-classification based prognostic scoring system (WPSS) [3]. Despite new treatment options, many MDS patients rely on red blood cell transfusions. Chronic transfusion therapy causes iron overload. Recently, a large retrospective analysis showed that iron overload, defined as a serum ferritin >1000 ng/ml, was a significant prognostic factor for OS and leukemia-free survival in MDS [1]. On multivariate analysis, the influence of iron overload was independent of transfusion requirement. If iron overload shortens the survival of patients with MDS, iron chelation (IC) should do the opposite. This view is supported by a partly retrospective and partly prospective observational study by Rose et al. [4] showing that patients with an IPSS low or intermediate-1 risk profile who received iron chelation therapy lived longer than patients who did not. However, there are as yet no results available from randomized clinical trials to confirm such a
∗ Corresponding author at: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: +49 211 8117720; fax: +49 211 8118853. E-mail address: [email protected] (J. Neukirchen). 0145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2012.04.006
survival benefit. We performed a retrospective matched-pair analysis drawing on the data base of the Düsseldorf MDS registry. 2. Methods At the time of patient selection the Düsseldorf MDS registry included 3552 patients, diagnosed between 1975 and 2008. For matched-pair analysis [5] we identified 94 polytransfused MDS patients who had been receiving long-term chelation therapy. The registry was then searched for matching partners who received supportive care, including growth factors, but neither iron chelators nor diseasemodifying drugs. The following characteristics were used for matching: age at diagnosis (±5 years), gender, MDS type according to WHO classification, and IPSS score. We chose 94 patients fulfilling all selection criteria. The cut-off date for this report was June 30, 2009. To deal with confounding variables, each patient was paired with a randomly chosen matched control. Cases and controls were stratified according to chelation treatment [6].
3. Results Patient characteristics are shown in Tables 1a and 1b. All 188 patients showed iron overload, defined as a serum ferritin ≥1000 ng/ml, or a history of multiple transfusions and a serum ferritin ≥500 ng/ml. All ferritin levels were measured at the time of referral to our center, which was usually early after diagnosis. The proportion of heavily transfusion-dependent patients was largest among patients with del(5q), RCMD, and refractory anemia with excess blasts (RAEB-I and -II). At least 50% of patients with these diagnoses received transfusions of packed red blood cells (PRBC). Mean and median serum ferritin (SF) levels were also highest in patients with del(5q). SF levels were not correlated with gender or
1068
J. Neukirchen et al. / Leukemia Research 36 (2012) 1067–1070
Table 1a Clinical characteristics of chelated and non-chelated patients with MDS. Parameter
Chelated
Non-chelated
p
Median age (range) Gender Ferritin (mean) Karnofsky index < 60% Transfusions at diagnosis Platelets (l) ANC (l) Hemoglobin (g/dl) Medullary blast count Karyotype risk category Low risk Intermediate High risk Ferritin > 1000 ng/ml Ferritin > 500 ng/ml and transfusions AML development Proportion of patients who died during the observation period Death due to infections Death due to bleeding Other causes of death Comorbidities Lung Heart Kidney Liver Solid tumors
64 (18–82) 48% w 2400 25% 75% 229,000 2500 8.7 4%
67.5 (33–89) 42% w 980 31.5% 85% 231,000 3600 9.0 4%
0.005 ns 0.005 ns ns ns ns ns ns
71% 18% 11% 80% 20% 12.9% 56% 35% 4.5% 60.5%
76% 12% 12% 78% 22% 14% 60% 13% 9.5% 77%
7% 23% 3.5% 2% 11%
9% 43% 0% 12% 12%
IPSS risk group. Chelation therapy was started at a median of 21 months after diagnosis (range 0–212 months). 53 patients in the IC group received deferoxamine monotherapy and 47 received deferasirox monotherapy. Deferoxamine followed by deferasirox was used in 14 patients, and deferoxamine followed by deferiprone in 3 patients. Mean duration of chelation therapy was 39 months for deferoxamine and 28 months for deferasirox. There were some patients on long-term treatment with deferoxamine, lasting much longer than any treatment period with deferasirox, simply owing to the time that the latter has been available. Overall, in our hands, deferasirox has not been more difficult to handle than deferoxamine, which poses compliance problems due to its cumbersome parenteral administration. The majority of deferoxamin-treated patients received the drug by continuous infusion overnight, but there were also some patients receiving deferoxamine as regular twice daily subcutaneous bolus injections. Among patients receiving chelation therapy, 56% died during the observation period, as compared to 60% in the group of patients receiving supportive care only (Fig. 1a). Median survival was 75 months in the IC group and 49 months in the supportive care group
Table 1b MDS types and risk profile according to WHO and IPSS classification, respectively, in the iron chelated patients (n = 94). Classification system WHO MDS with del(5q) RA RARS RCMD RAEB-I RAEB-II CMML IPSS Low Intermediate-1 Intermediate-2 High
n (%) 22 (23) 6 (6) 9 (10) 40 (43) 8 (9) 4 (4) 5 (5) 35 (37) 43 (46) 13 (14) 3 (3)
RA, refractory anemia; RARS, refractory anemia with ring sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RAEB, refractory anemia with excess blasts; CMML, chronic myelomonocytic leukemia.
ns ns ns ns ns 0.03
ns ns ns 0.039 ns
(p = 0.002). There was no significant difference regarding risk of AML evolution (Fig. 1b). Cumulative risk of AML transformation in the IC vs. supportive care group was 10% and 12% two years after diagnosis, and 19% and 18% five years after diagnosis, respectively (p = 0.73). There was no significant difference in median survival between chelated and non-chelated individuals in the cohort of patients with higher-risk MDS, whereas a significant difference was found in the lower-risk group (p = 0.008). Causes of death not related to MDS were slightly more frequent in the chelated patient group, but firm conclusions could not be drawn since death certificates were not available in many patients. Data on response to IC were available for 31 patients with stable MDS and ongoing transfusion dependency. Among these, 21 showed stable or decreasing serum ferritin during IC therapy. These patients had a significant survival benefit compared to patients with increasing SF (Fig. 2).
4. Discussion In the field of thalassemia, it is well established that transfusional iron overload limits life expectancy due to toxic effects on heart, liver and other organs. In patients with MDS, the situation is more difficult to understand. Chronic transfusion therapy is clearly associated with a decreased likelihood of overall survival and leukemia-free survival [1,2]. There is a dose-dependent effect of transfusion requirement, and a similar dose-dependent effect of serum ferritin levels, on overall and leukemia-free survival. The similar impact of transfusion requirement and serum ferritin levels could be interpreted as evidence that transfusion dependency causes iron overload, which then worsens the prognosis. However, the data can also be interpreted the other way round: transfusional iron overload reflects severe bone marrow disease as the real cause of shortened survival. Both interpretations are probably correct, because multivariate analyses have shown that iron overload has independent prognostic impact, even if transfusion need is taken into account [1,2]. Assuming that iron overload diminishes the likelihood of survival in MDS, chelation therapy should have an oppositive effect.
J. Neukirchen et al. / Leukemia Research 36 (2012) 1067–1070
1069
Fig. 1. Impact of iron chelation therapy on OS and AML transformation (n = 188).
This was indeed first suggested by a small retrospective analysis from Canada [7,8] and then corroborated by a partly retrospective and partly prospective study from France showing a strong survival benefit of chelation therapy in patients with MDS of low and intermediate-1 risk profile according to IPSS [4]. In our retrospective matched-pair analysis, median overall survival was significantly better in chronically transfused but iron-chelated patients (75 months) than in matched patients without chelation therapy (49 months). In addition, patients with ongoing transfusion need whose serum ferritin decreased over time had a better survival as compared to patients whose ferritin levels increased despite iron chelation. The present analysis has its limitations. The matching procedure did not consider comorbidities and intensity of transfusion
1,0
therapy during the course of disease. Interestingly, liver dysfunction was more frequent among non-chelated patients, but it is unclear whether this can be attributed to the lack of chelation therapy. The retrospective character of our study did not allow us analyze in detail the clinical complications contributing to shortened survival in patients not receiving chelation therapy. Cardiac events and infections were the most frequent causes of death in both patient groups. In contrast to the multivariate analysis of the Spanish multicenter study [1] and other investigations [4,7], our matched-pair analysis did not reveal an impact of chelation therapy on the risk of leukemic transformation. We cannot offer a simple explanation for this discrepancy. However, the practically identical rate of progression to AML in the chelated and non-chelated patients suggests that our matching procedure must have created patient groups that are indeed comparable in terms of disease characteristics. Funding source
,8
This work was supported by Novartis Pharma AG. The sponsor was not involved in collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. Part of the data have been presented at ASH 2009, Abstract 1747.
Cum Surviva al
, ,6
,4
Conflict of interest
,2
U.G. and N.G. received speakers honorary and research support from Novartis Pharma AG. F.F. and A.K. received speakers honorary from Novartis Pharma AG. Acknowledgments
0,0 0
48
96
144
192
240
288
336
384
432
months Fig. 2. Cumulative survival of patients with a stable MDS and ongoing transfusion dependency who responded to iron chelation in comparison to patients with increasing ferritin levels (n = 31).
Contributions. U.G. and N.G. made the conception and design of the study. J.N., U.G. and N.G. were responsible for analysis and interpretation of the data, and J.N. wrote the manuscript. F.F., A.K., N.K. and C.S. acquired the data, U.G. and N.G. revised the article critically and R.H. revised the article critically and gave the final approval.
1070
J. Neukirchen et al. / Leukemia Research 36 (2012) 1067–1070
References [1] Sanz G, Nomdedeu B, Such E, Bernal T, Belkaid M, Ardanaz MT, et al. Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome. Blood 2008;112:238–9. [2] Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol 2005;23:7594–603. [3] Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25:3503–10.
[4] Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients. A multicenter study by the GFM. Leuk Res 2010;34: 864–70. [5] Holt JD. Competing risk analyses with special reference to matched pair experiments. Biometrika 1978;65:159–65. [6] Sahai H, Khurshid A. Statistics and epidemiology: methods, techniques, and applications. Boca Raton: CRC Press; 1995. [7] Leitch HA, Leger CS, Goodman TA, Wong KK, Wong DHC, Ramadan KM, et al. Improved survival in patient with myelodysplastic syndrome receiving iron chelation therapy. Clin Leuk 2008;3:205–11. [8] Leitch HA. Iron chelation therapy in MDS: does it improve survival. Leuk Res 2010;34:852–3.