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Originally published as JCO Early Release 10.1200/JCO.2007.15.4906 on June 16 2008 © 2008 American Society of Clinical Oncology. Erythropoietin and Granulocyte-Colony Stimulating Factor Treatment Associated With Improved Survival in Myelodysplastic Syndrome
From the Karolinska Institutet, Department of Medicine, Division of Hematology, Clinical Epidemiology Unit, and Department of Pathology, Karolinska University Hospital, Stockholm, Sweden; Department of Hematology, and Department of Medicine, University of Pavia and Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy; and the Department of Hematology, Rikshospitalet Hospital, Oslo, Norway Corresponding author: Martin Jädersten, MD, Hematology Center M54, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden; e-mail: martin.jadersten{at}ki.se
Purpose To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS). Patients and Methods We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex). Results The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype. Conclusion The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.
The bone marrow malignancy myelodysplastic syndrome (MDS) affects 15,000 Americans each year.1 Ninety percent of patients develop a transfusion need during the course of their disease, severely impairing their quality of life, and 30% to 40% transform into acute myeloid leukemia (AML).2 Although erythropoietin (EPO) is not licensed for MDS in any country, most treatment guidelines recommend EPO with or without granulocyte-colony stimulating factor (G-CSF), acting in synergy with EPO,3-5 as first-line therapy for anemia in low-risk MDS.6,7 EPO plus G-CSF treatment gives a 38% to 80% erythroid response rate, depending on patient selection, with a median response duration of around 2 years.3-5,8,9 Treatment response is associated with an improved quality of life.10-12 A predictive model based on serum EPO level and transfusion need identifies patients with reasonable chances of response.10 It is currently debated whether treatment with hematopoietic growth factors negatively affects outcome in patients with cancer. Some reports suggest that EPO increases the risk of relapse in head-and-neck carcinoma13 and decreases overall survival in cervical, breast, and non–small-cell lung cancer.14-16 Other studies indicate that G-CSF may increase the risk of AML evolution in aplastic anemia and severe congenital neutropenia.17,18 A recent study suggests a positive impact of erythroid growth factors on survival in MDS, although not adjusting for all currently used prognostic factors such as multilineage dysplasia and level of transfusion need in the multivariate analysis.19 Due to the rising concern of growth factor therapy in cancer, we performed a comprehensive study—for the first time taking into account all major prognostic variables—in order to identify any potential increased risk of EPO plus G-CSF treatment for MDS.
Patients The EPO plus G-CSF treated cohort (n = 129) included all patients from three Nordic phase II trials performed 1990 to 1999.4,10,20 Inclusion criteria were refractory anemia (RA), RA with ringed sideroblasts (RARS), or RA with excess blasts (RAEB), according to the French-American-British classification,21 in combination with hemoglobin lower than 10 g/dL (31%) or regular RBC transfusion need (69%). Exclusion criteria were ongoing bleeding, transfusion-dependent thrombocytopenia, or eligibility for allogeneic transplantation. The poor predictive group for erythroid response (serum EPO > 500 U/L and requirement of  2 units of RBC per month),10 was ineligible for the third study. Six of 129 patients did not complete the first 6 weeks of treatment and were nonassessable for response, and seven of 48 responders did not receive maintenance treatment and were nonassessable for response duration.9 All patients were reclassified according to the WHO classification22 as previously described.23 The control cohort (n = 272) was selected from an Italian cohort of consecutive untreated patients with MDS based on the same criteria as for the EPO plus G-CSF studies. All patients were reclassified according to the WHO classification by two independent cytologists.24 Except for supportive care, the patients remained untreated during the follow-up period in line with the current practice in Italy at the time. The patients were observed at the centers of the Nordic MDS Group and at the study center in Pavia. Bone marrow sampling was performed regularly and in case of clinical signs of progression in both cohorts, and the diagnosis of AML was always based on written morphology reports. Thus, the risk of differential bias regarding outcome measures was low.
Both cohorts were enrolled during the same time-period in Western Europe, with detailed recording of important prognostic factors, and only a few patients received iron-chelation therapy. Eight of 129 EPO plus G-CSF patients and 35 of 272 untreated patients lacked information about
Treatment and Response Criteria Induction treatment with EPO and G-CSF was given for 12 to 18 weeks, and followed by maintenance treatment at the lowest effective dose in case of a response.4,9,10,20 The definition of complete erythroid response was an increase in hemoglobin level to at least 11.5 g/dL without transfusion need, while a partial response required an increase in hemoglobin level of 1.5 g/dL for patients with nontransfused anemia, or an abolished transfusion need. Both response criteria fulfilled the revised International Working Group criteria for erythroid response.26 The date of relapse was defined as the date of first transfusion.
Statistical Analysis To adjust for the variable time between diagnosis and start of EPO plus G-CSF treatment (in median 6 months; interquartile range, 2.0 to 16.3), a multivariate Cox model with delayed entry, or left truncation, was used. This allowed measurement of the survival-time from the time of MDS diagnosis also in the treated patients. However, at each observed event only those patients who had entered the study by that specific time point affected the analysis.27 Though this is a potential source of bias, its effect can be considered negligible under the reasonable assumption that the patients entering the EPO plus G-CSF studies were representative of untreated patients with MDS with similar survival. Adjustment was also made for all major prognostic variables, and they were modeled as continuous (age, number of RBC units per month, absolute neutrophil count, serum EPO, serum lactate dehydrogenase (LDH), and platelet count) or as indicator (EPO plus G-CSF treatment, WHO group, karyotype risk group, and sex) covariates. Log-transformation and interval division into categoric measures modeled as binary dummy variables were explored for skewed measures (serum EPO, serum LDH, and platelet count), and exponential transformation was explored for age. We investigated the proportional hazard assumption by testing for a nonzero slope in a generalized linear regression of the scaled Schoenfeld residuals on functions of time. In both survival and AML, the test was nonsignificant, thus indicating no major deviations from this assumption. In order to address possible differences in age-specific mortality between the countries, the directly standardized mortality rates of Italy and Sweden were calculated by applying the calendar year–, age-, and sex-specific mortality rates of each country (as provided by the respective national institutes of statistics) to a reference population with uniform age and sex distribution.28
Response Characteristics Forty-eight (39%) of 123 assessable patients had an erythroid response. Twenty-five (29%) of 85 transfusion-dependent patients became transfusion independent, and all patients responding to treatment stabilized their serum ferritin levels during the course of the response. The median response duration was 23 months (range, 3 to 116+), and 20% of responses lasted more than 4 years.
Optimization of the Multivariate Analysis
Treatment Associated With Better Overall Survival
An exploratory analysis identified an interaction between Internation Prognostic Scoring System (IPSS) risk group and treatment. An analysis stratified by IPSS group showed a significant association of treatment and survival in the low IPSS risk group (HR, 0.45; 95% CI, 0.21 to 0.94; P = .033), while no significant association was seen in the higher IPSS risk groups. In order to further investigate the association between disease risk and effect of treatment, we defined low and high risk based on bone marrow blasts lower or higher than 10%, and found a positive association of treatment on survival in both groups (HRlow, 0.68; 95% CI, 0.47 to 0.99; P = .046; HRhigh, 0.29; 95% CI, 0.12 to 0.69; P = .006). There was no significant association with AML evolution in any risk stratum. Next, we investigated the potential effect of the exclusion of eight of 129 treated and 35 of 272 untreated patients due to missing variables included in the overall multivariate analysis. When only adjusting for age, WHO group, sex, EPO plus G-CSF treatment, and transfusion dependency, all but six patients could be kept in the analysis. A similar association of EPO plus G-CSF treatment with improved survival was seen both among the unselected and selected patients (HR, 0.66; 95% CI, 0.49 to 0.89; P = .006; and HR, 0.59; 95% CI, 0.44 to 0.81; P = .001, respectively). Finally, when using separate Cox models for males and females, and patients younger and older than 70 years of age, the association of treatment with improved survival was highly similar in all subsets (data not shown).
Association With Better Survival Limited to Patients With Low Transfusion Need
The proportions of patients with IPSS low/intermediate 1 versus intermediate 2/high did not differ significantly between treated and untreated patients in the two strata (P = .96 and .21, respectively). The response rate for the less compared with the more heavily transfused patients was higher, 56% versus 18% (P < .001), although the response duration was similar (P = .57). As expected due to the higher response rate, the less transfused patients received EPO plus G-CSF for a longer time period than the more heavily transfused patients (47% and 11%, respectively, were on therapy 6 months, P < .001). There was no association between treatment and risk of leukemic transformation for patients with low or high transfusion need (HR, 0.87; 95% CI, 0.45 to 1.66; P = .67; and HR, 0.92; 95% CI, 0.28 to 3.03; P = .89, respectively).
Treatment Response Correlated With Favorable Outcome
Similar Age-Specific Mortality in the Patients’ Countries of Origin
Recent reports of potential adverse effects of EPO treatment in patients with solid tumors have challenged the use of EPO with or without G-CSF also for the anemia in MDS and launched an active discussion in the US Food and Drug Administration aiming at defining the role of EPO in patients with malignancies.13-16,29,30 After reviewing the existing literature, the recent American Society of Clinical Oncology/American Society of Hematology guideline still recommends treatment with erythroid growth factors for patients with low-risk MDS, however, EPO is not indicated for other patients with cancer with disease-related anemia.31 Furthermore, they comment that there is no evidence of improved survival by EPO treatment in any type of cancer. Recent data in MDS suggest that EPO with or without G-CSF improves overall survival without affecting the rate of progression to AML.19 In order to more thoroughly explore this issue we designed a comprehensive study comparing a well defined cohort of patients treated with EPO plus G-CSF4,9,10,20 and a suitable cohort of untreated patients.24 Despite the fact that the EPO plus G-CSF patients were significantly older and more frequently transfused than the untreated patients, which per se would imply a worse prognosis for this group,24,25,32 a comparison using a multivariate Cox analysis adjusting for all major prognostic variables demonstrated that EPO plus G-CSF treatment was associated with significantly enhanced overall and nonleukemic survival. In an analysis stratified by transfusion burden, the association with improved survival was restricted to patients requiring fewer than 2 units of RBC per month, which was not unexpected since these patients responded better to EPO plus G-CSF compared with the more heavily transfused. There was no association between treatment and AML evolution in the overall analysis or in any IPSS risk group in the stratified analysis. Hence, neither prolonged exposure in responding patients, nor short-term exposure in high-risk patients was associated with disease progression. A valid comparison of the two cohorts requires the assumption that the natural history of untreated MDS patients in the Nordic Countries and Italy was similar during the study period. After the introduction of the French-American-British classification in 1982, the diagnosis and management of MDS have been uniformed and are therefore comparable in most western countries. Furthermore, the survival according to IPSS prognostic groups has been shown to be overlapping in several countries, hence, making this assumption reasonable.25,32 In addition, the standard mortality ratio of Sweden versus Italy showed a similar mortality during the years of patient enrollment, even somewhat higher in Sweden, leaving it unlikely that a difference in age-specific mortality confounded the analyses. The observation that EPO plus G-CSF treatment was associated with longer survival only in patients with nontransfusion dependent anemia or a moderate transfusion need, raises several hypotheses. The patients may benefit from correction of anemia in terms of improved cardiac function and performance status. Anemia is associated with a significant decline in physical performance in persons 70 years or older,33 and a poorer outcome in patients with heart failure.34 Anemia in MDS not only deteriorates the quality of life,10,35 but is also associated with poor outcome25 and increased incidence of heart failure.36 We recently showed that the onset of RBC transfusion need worsens the survival of patients with MDS, in part due to a higher risk of heart failure–related death.24,32 This adverse outcome might be explained by the fact that transfused patients often show lower hemoglobin levels over time compared with untransfused patients. Another positive effect of treatment response may be attributed to the prevention of progressive iron overload, by elimination of the transfusion dependency. Progressive iron overload is inversely correlated to survival in transfusion-dependent patients with MDS.24 EPO also has an intriguing impact on the immune system. EPO has been shown to induce an antitumor effect in a multiple myeloma mouse model, presumably mediated by activation of CD8-positive T cells,37 and recently similar effects on T-cells in MDS have been reported. 38 Moreover, EPO-G diminishes the relative CLIP (class II-associated invariant chain peptide) amount on hematopoietic precursor cells, conceivably increasing their ability to present tumor antigens to the T helper cells.39 EPO receptors have been found in several types of primary tumor samples and tumor cell lines, although the effects of EPO on these cells in vitro have been somewhat conflicting and it is debated whether all EPO receptors are functional.40,41 Around 60% of patients with AML have EPO receptors present on their leukemic blasts, although few are sensitive to EPO in vitro.42 Bone marrow progenitors from low-risk patients with MDS also express EPO receptors, however, the expression is lower than on normal progenitors.43 In addition, we have shown that EPO has negligible proliferative effect on MDS progenitors carrying a 5q deletion in vitro, while normal progenitors respond with rapid proliferation.44,45 Moreover, recent data also suggest a positive impact of EPO on survival of critically ill trauma patients, conceivably by nonhematopoietic EPO effects.46 Regarding the effects of G-CSF in MDS, it has been shown that subclones of cells with a deletion of chromosome 7 have a growth advantage over diploid cells when exposed to G-CSF in vitro.47 A preliminary reported randomized study of chronic G-CSF treatment versus placebo in high-risk patients with MDS (n = 102) showed no increased risk of AML-evolution in the treatment arm.48 In our treated cohort as many as half of the patients were treated within 6 months of diagnosis, however, this time interval until start of treatment potentially gives rise to selection effects that could affect outcome. A longer disease duration before starting treatment implies a longer time of suffering from the negative effects of anemia and chronic transfusions. Also, a patient with longer disease duration may have a more stable disease, with lower risk of leukemic transformation, although the contrary is also conceivable. However, any such effects were adjusted for using Cox regression with delayed entry (or left truncation), which is generally considered to be the preferred method since it minimizes potential bias introduced by such selection effects.27 Therefore, we interpret the observed increased survival in the EPO plus G-CSF treated patients as a likely effect of treatment. We stress that patients should be selected in a rational way before commencing treatment, by excluding patients in the poor predictive group for response.9,10 Furthermore, that EPO plus G-CSF should be administered at the lowest possible maintenance dose, and should be discontinued at the time of relapse of transfusion dependency, in order to avoid futile treatment with undocumented long-term effects on outcome. We conclude that EPO plus G-CSF treatment deserves its prominent place in the treatment of anemia in low-risk MDS since it is associated with better overall survival in patients with no or low transfusion need, without any apparent affect on the risk of leukemic transformation.
The author(s) indicated no potential conflicts of interest.
Conception and design: Martin Jädersten, Luca Malcovati, Scott M. Montgomery, Cristiana Pascutto, Mario Cazzola, Eva Hellström-Lindberg Financial support: Mario Cazzola, Eva Hellström-Lindberg Provision of study materials or patients: Martin Jädersten, Luca Malcovati, Ingunn Dybedal, Matteo Giovanni Della Porta, Rosangela Invernizzi, Mario Cazzola, Eva Hellström-Lindberg Collection and assembly of data: Martin Jädersten, Luca Malcovati, Ingunn Dybedal, Matteo Giovanni Della Porta, Rosangela Invernizzi, Mario Cazzola, Eva Hellström-Lindberg Data analysis and interpretation: Martin Jädersten, Luca Malcovati, Scott M. Montgomery, Cristiana Pascutto, Anna Porwit, Mario Cazzola, Eva Hellström-Lindberg Manuscript writing: Martin Jädersten, Luca Malcovati, Scott M. Montgomery, Mario Cazzola, Eva Hellström-Lindberg Final approval of manuscript: Martin Jädersten, Luca Malcovati, Ingunn Dybedal, Matteo Giovanni Della Porta, Rosangela Invernizzi, Scott M. Montgomery, Cristiana Pascutto, Anna Porwit, Mario Cazzola, Eva Hellström-Lindberg
We are deeply indebted to all members of The Nordic MDS Group who were involved in the erythropoietin plus granulocyte-colony stimulating factor studies.
published online ahead of print at www.jco.org on June 16, 2008. Supported by grants from Associazione Italiana per la Ricerca sul Cancro, Milan; Fondazione Cariplo, Milan; Fondazione Ferrata Storti, Pavia; and Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy (M.C.), Cancer Society in Stockholm (A.P.), and Swedish Cancer Society 3689-B06-12XCC, 4912-B07-04PDF, Cancer Society Stockholm 051143 (E.H.-L.). M.J. and L.M. contributed equally to this article. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
