Journal of the National Cancer Institute Advance Access originally published online on October 28, 2008
JNCI Journal of the National Cancer Institute 2008 100(21):1542-1551; doi:10.1093/jnci/djn349
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Characteristics of US Patients with Myelodysplastic Syndromes: Results of Six Cross-sectional Physician Surveys
Affiliations of authors: Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH (MAS, JPM); Amgen Ltd, London, UK (WMS); The University of Texas M. D. Anderson Cancer Center, Houston, TX (HK); H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL (AL); Amgen Inc., Thousand Oaks, CA (JF); University of California Los Angeles, Los Angeles, CA (RP)
Correspondence to: Mikkael A. Sekeres, MD, MS, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Desk R35, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: sekerem{at}ccf.org).
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ABSTRACT |
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Background: Myelodysplastic syndromes (MDS) comprise a group of pathologically and cytogenetically distinct bone marrow disorders. Little is known about the characteristics of MDS patients, including their pathological and prognostic classifications, cytopenias, transfusion and supportive care needs, and treatment regimens. We describe these characteristics in a large group of recently diagnosed and existing (ie, established) MDS patients.
Methods: We conducted six consecutive cross-sectional surveys among US hematology and medical oncology specialists (identified from an American Medical Association [AMA] database of physicians who administer chemotherapy) between June 2005 and January 2007. A questionnaire collected data on the characteristics and treatment patterns of the 4–10 most recently seen MDS patients for each physician, including demographic data, transfusion needs, treatment approaches, and consideration for clinical trials or bone marrow transplantation.
Results: A panel of 101 physicians who were geographically representative of physicians registered with the AMA characterized 614–827 patients per survey, for a total of 4514 responses. Among recently diagnosed patients, 55% were male (95% confidence interval [CI] = 52% to 59%), the median age at diagnosis was 71 years (range = 65–80 years), and 10% (95% CI = 8% to 12%) had MDS secondary to chemotherapy, radiation therapy, or environmental exposure. The median duration of MDS in established patients ranged from 13 to 16 months over the six surveys. Among recently diagnosed MDS patients, fewer patients with lower-risk disease than with higher-risk disease were dependent on either red blood cell transfusions (22% vs 68%) or platelet transfusions (6% vs 33%). More than 50% of all newly diagnosed and established patients used erythropoiesis-stimulating agents. A small percentage of all patients either had had or were being considered for bone marrow transplantation (recently diagnosed: 4%; established: 4% or less) or were being treated on clinical trials (recently diagnosed: 1%; established: 4% or less).
Conclusions: MDS patients in the United States have substantial transfusion needs, and use of erythropoiesis-stimulating agents and are seldom considered for bone marrow transplantation or clinical trials. These data may be useful in characterizing the health care resource use and pharmacoeconomic impact of MDS in the United States.
Prior knowledge Myelodysplastic syndromes (MDS) comprise a group of pathologically and cytogenetically distinct bone marrow disorders. Recent changes in the therapeutic options for MDS support the need to characterize MDS patients, including their pathological and prognostic classifications, transfusion and supportive care needs, and treatment regimens. Study design Six consecutive cross-sectional surveys of 101 hematology and medical oncology specialists in the United States were conducted between June 2005 and January 2007 via questionnaires to ascertain the characteristics and treatment patterns of the 4–10 most recently seen MDS patients for each physician. Contribution The physicians characterized 614–827 patients per survey, for a total of 4514 responses. A high proportion of MDS patients were dependent on red blood cell or platelet transfusions. Among recently diagnosed MDS patients, fewer patients with lower-risk disease than with higher-risk disease were dependent on transfusions. More than half of MDS patients were treated with erythropoiesis-stimulating agents. Only a small percentage of MDS patients either had had or were being considered for bone marrow transplantation or were being treated on clinical trials. Implications These data may be useful in characterizing the health care resource use and pharmacoeconomic impact of MDS in the United States. Limitations The data were collected retrospectively by asking physicians to report on their 4–10 most recently seen MDS patients. Because of the lack of unique identifiers for patients and their physicians, it was not possible to identify a cohort of MDS patients who could be followed over time. From the Editors
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Myelodysplastic syndromes (MDS) are a collection of pathologically and cytogenetically distinct bone marrow disorders that have become widely recognized only over the past three decades (1–4). MDS are characterized by peripheral blood cytopenias, which result in an increased risk of bleeding and infectious complications, and MDS patients have a propensity to develop acute myeloid leukemia (AML), particularly those with more advanced MDS subtypes (5–8). Treatments for MDS focus on improving blood counts, minimizing the need for blood transfusions, delaying the progression to AML, improving survival, and maximizing patient quality of life (9–15). The only known curative therapy is bone marrow transplantation (16–18).
The epidemiology of MDS has only recently become clear. MDS is a disease of older adults; the median age of MDS patients at diagnosis is 70 years (6,19). Only a limited number of studies have investigated the descriptive epidemiology of MDS, the majority of which were carried out in Europe (19,20). Primary or de novo MDS arise spontaneously, whereas secondary MDS are caused by previous exposure to chemotherapy (particularly alkylating agents and topoisomerase inhibitors), radiation therapy, and/or environmental factors, such as benzene and its derivatives. In the United States, MDS have only in the past 7 years been included as a cancer diagnosis in the Surveillance, Epidemiology, and End Results (SEER) program database of the National Cancer Institute and the Centers for Disease Control and Prevention. Based on SEER data, the estimated age-adjusted incidence rate of MDS in the United States is 3.4 cases per 100 000 people, which translates to approximately 10 000 new cases per year (21). However, because SEER data derive from cancer registries, they lack detailed patient information other than the patient’s age at diagnosis, sex, and race; the French–American–British (FAB) classification of disease at diagnosis; and survival rates among newly diagnosed MDS patients. Data on treatment, supportive care requirements, blood product transfusion needs, and specific cytogenetic abnormalities are lacking, as are data on the composition and health care needs of existing (ie, established) MDS patients.
Here, we report the results of six consecutive surveys that we conducted among hematologists and/or medical oncologists to obtain information on the characteristics of newly diagnosed and established MDS patients in the United States, including demographics, pathological and prognostic classifications, cytopenias, transfusion and supportive care needs, and treatment regimens. Through this information, we have gained insight into the impact of MDS on health care resource use.
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Methods |
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Physician Sample
We conducted six cross-sectional surveys, at 3- to 5-month intervals, between June 2005 and January 2007; the surveys were mailed to eligible physicians in June and October of 2005; in January, April, and September of 2006; and in January of 2007. Physicians who were eligible to participate in the surveys (eligibility criteria defined below) were identified from an American Medical Association (AMA) database that includes 22 033 medical oncologists, hematologists/oncologists, hematologists, internal medicine physicians with a secondary specialty in oncology, gynecologic oncologists, and urologists who practice in the United States (22). From this database, we identified a sample of 426 physicians who administer chemotherapy and who take part in a regular oncology patient record audit that collects information about the patients seen in their treatment practice (conducted by the US Tandem Oncology Monitor, Synovate Healthcare [Mahwah, NJ] in exchange for remuneration of 30 US dollars for each patient record completed). Data from this sample of 426 physicians were compared by this company with their internal data from more than 50 pharmaceutical and biotechnology companies and were found to be representative in terms of the geographic distribution of the patients who were treated, the tumor types seen in cancer patients, and patient treatment patterns in the United States (C. Humphries, personal communication, Account Manager, US Tandem Oncology Monitor). From this sample of 426 physicians, we identified 101 physicians who treated 10 or more MDS patients per month and who agreed to participate in this series of surveys of patient-specific questionnaires (Figure 1). These 101 specialists were asked to fill out one questionnaire for each of the 4–10 MDS patients they had most recently seen.
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Sample of 426 physicians was compared with internal data from more than 50 pharmaceutical and biotechnology companies and was found to be representative in terms of tumor types seen and treatment patterns in the United States. 
Considered to be representative of the larger group of 426 physicians. AMA = American Medical Association.Data Collection
We developed a questionnaire that was to be completed by the treating physicians to assess MDS patient characteristics and therapeutic modalities in the United States. The questionnaire included sections on the patient's demographics; current laboratory values; MDS classification [including FAB and World Health Organization (WHO) designations (1,4)]; International Prognostic Scoring System (IPSS) score (6); cytogenetic information (including an item requesting a list of specific abnormalities and cytogenetic risk group category according to the IPSS [good, intermediate, and poor]); current blood product transfusion requirements (dependent, not dependent, or never needed); what therapy the patient was currently receiving; and whether the patient was being considered for participation in a clinical trial or for bone marrow transplantation. The questionnaire was slightly modified in surveys 2, 4, and 5 to include information about the reasons for choosing a specific therapy. Information was also collected on all surveys on the physicians who completed the questionnaires, including their subspecialty, type of clinical practice, and patient volume.
All data were collected anonymously (ie, there were no unique identifiers for either the patient or the treating physicians). Patients who were diagnosed during the 2 months before a survey was conducted were considered to be newly diagnosed. All other patients were considered to be established MDS patients. It was not possible to assess which established patients were included in more than one survey. By contrast, each newly diagnosed patient was included as such in only one survey (although he or she may have been included as an established patient in subsequent surveys). Patients with lower-risk MDS were defined as belonging to FAB categories of refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS); WHO categories of RARS, refractory cytopenia with multilineage dysplasia (RCMD), refractory cytopenia with multilineage dysplasia with ringed sideroblasts (RCMD-RS), MDS with deletion of chromosome 5q (del(5q)), and MDS unclassified; and IPSS categories of low and intermediate-1. Patients with higher-risk MDS were defined as belonging to FAB categories of refractory anemia with excess blasts (RAEB) and refractory anemia with excess of blasts in transformation (RAEBt); WHO categories of RAEB-1 and RAEB-2; and IPSS categories of intermediate-2 and high.
Statistical Analyses
All statistical analyses were descriptive in nature. The prevalent patient population was stratified by recently diagnosed MDS patients (ie, those diagnosed during the 2 months before an incident survey) and established MDS patients. To describe the characteristics for the recently diagnosed patients, we collated the results for such patients from all six surveys and calculated overall median values and percentages, along with 95% confidence intervals (CIs). It was not appropriate to use the same approach to describe the characteristics of the established MDS patients, however, because these patients were potentially included in more than one survey. Instead, for established MDS patients, we calculated median values and percentages for each of the six surveys. For the purpose of this analysis, "supportive care" was defined as therapy with growth factors (including erythropoiesis-stimulating agents [eg, erythropoietin, darbepoetin], granulocyte colony-stimulating factor [G-CSF], granulocyte–macrophage colony-stimulating factor [GM-CSF], and pegfilgrastim); vitamins and/or vitamin supplements; glucocorticoids; cytokines (ie, interleukin 11); immunoglobulins; bisphosphonates; and red blood cell and/or platelet transfusions. "Other treatments" (ie, therapies that did not include growth factors) included differentiation agents, such as azacitidine, decitabine, arsenic trioxide, and all-trans-retinoic acid; immunomodulators, such as lenalidomide, thalidomide, CellCept, cyclosporine; and nonablative cytotoxic agents, such as 6-thioguanine, alemtuzumab, amifostine trihydrate, bortezomib, busulfan, cladribine, cyclophosphamide, cytarabine, daunorubicin, etoposide, fludarabine, gemtuzumab, hydroxyurea, idarubicin, melphalan, methotrexate, mitoxantrone, and topotecan.
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Results |
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Characteristics of Responding Physicians
The response rates from the 101 physicians for each of the six surveys ranged from 77% to 97% (Figure 1). These 101 physicians were similar to the total group of physicians in the AMA database with respect to the frequency distributions of practice type and geographic region (Table 1). The regional distribution of their practice sites across surveys are as follows: New England (3%–6%); Mid-Atlantic (20%–26%); North Central (18%–24%); South Atlantic (20%–28%); South Central (20%–28%); Mountain (3%–4%); and Pacific (8%–13%). Among the participating physicians, 68%–76% had an office-based practice, 7%–13% had a university hospital–based practice, 7%–12% had a community hospital–based practice, 3%–8% had a Veterans Affairs hospital–based practice, and 3%–7% had a practice based at a comprehensive cancer center.
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We received 4514 completed patient questionnaires from the physicians; the number of completed questionnaires received per survey ranged from 614 to 827.
Patient Characteristics
Of the 4514 returned questionnaires, 670 were obtained from recently diagnosed patients, of whom 55% were male (Table 2). Among the recently diagnosed patients, the median age at diagnosis was 71 years (range = 65–80 years) and did not differ markedly between men and women (data not shown). Secondary MDS due to chemotherapy, radiation therapy, or chemical exposure was seen in 10% (95% CI = 8% to 12%) of recently diagnosed patients, mostly (76%) following treatment with chemotherapy. The characteristics of established MDS patients were similar to those of recently diagnosed patients (Table 2). Disease duration among the established MDS patients varied widely; the minimum and maximum disease durations were 3 and 250 months, respectively; the median disease duration was less variable, ranging from 13 to 16 months across the six surveys.
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The distributions of MDS subtypes for recently diagnosed and established patients according to FAB and WHO pathological classifications and IPSS risk category are presented in Table 3. Lower-risk MDS (FAB categories of refractory anemia RA and RARS; WHO categories of RARS, RCMD, RCMD-RS, MDS with deletion of chromosome 5q, and MDS unclassified; and IPSS scores of low and intermediate-1) was more common in established MDS patients than in recently diagnosed patients (percentage of lower-risk MDS among established vs recently diagnosed patients: by FAB criteria, 60%–69% across the six surveys vs 50% [95% CI = 46% to 53%]; by WHO criteria: 56%–66% vs 51% [95% CI = 47% to 54%]; and by IPSS criteria 75%–79% vs 64% [95% CI = 61% to 68%]).
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Cytogenetic data were available for approximately 90% of the patients for whom a questionnaire was completed (Table 4). Among the recently diagnosed patients, 51% had an IPSS cytogenetic risk classification of "good," 20% had a risk classification of "intermediate," and 17% had a risk classification of "poor." A higher proportion of recently diagnosed MDS patients than established MDS patients had an IPSS cytogenetic risk classification of either intermediate or poor (range 17%–20% vs 7%–18%, respectively). The most commonly reported cytogenetic abnormality was del(5q), which occurred in 11% (95% CI = 9% to 14%) of recently diagnosed patients and 7%–8% of established patients.
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Among the recently diagnosed MDS patients, the majority were anemic and had mild thrombocytopenia and neutropenia: the median hemoglobin value was 9.1 g/dL (interquartile range [IQR] = 8–10 g/dL), the median platelet count was 100 000/mm3 (IQR = 56 000–150 500/mm3), and the median absolute neutrophil count was 1780/mm3 (IQR = 1070–2800/mm3). A minority of recently diagnosed patients had circulating blasts: 16% of patients (95% CI = 13% to 19%) had 1%–5% blasts in their circulation and 10% of patients (95% CI = 8% to 12%) had more than 5% blasts in their circulation.
Transfusion and Supportive Care Requirements
Among the recently diagnosed MDS patients, those with lower-risk disease were less likely to have received a transfusion than those with higher-risk disease (17% vs 54%) (Table 5). Moreover, fewer recently diagnosed patients with lower-risk disease than with higher-risk disease were dependent on either red blood cell transfusions (22% vs 68%) or platelet transfusions (6% vs 33%) (Figure 2).
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Erythropoiesis-stimulating agents (ie, erythropoietin and/or darbepoetin) were used by the majority (58%) of recently diagnosed patients and by 55%–63% of established patients (Figure 3). When we further subdivided recently diagnosed and established patients into those with lower-risk and higher-risk disease, we observed no clear difference in the proportion of patients in these risk groups who received erythropoiesis-stimulating agents (Table 5). Other growth factors (ie, G-CSF, GM-CSF, or pegfilgrastim) were used by only 10% of recently diagnosed patients and 8%–11% of established patients (Figure 3).
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MDS Therapy
The basis on which physicians chose a particular therapy was similar for recently diagnosed and established MDS patients, with the exception that hemoglobin values were more likely to be used to make therapy decisions for established patients than for recently diagnosed patients (Table 6).
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Among recently diagnosed MDS patients, those with lower-risk disease were more likely to be monitored without treatment (a "watch and wait" approach) than those with higher-risk disease (24% vs 5%) (Table 5). Among established patients who were being monitored without treatment, the average duration of follow-up at the time of the six surveys ranged from 13 to 20 months.
Among recently diagnosed patients, those with higher-risk disease were more likely to use non–growth factor therapies (ie, chemotherapy or biologic or immunologic approaches) than those with lower-risk disease (69% vs 22%) (Table 5). Similar proportions of recently diagnosed and established patients were treated with the non–growth factor therapies azacitidine (16% vs 11%–15%), lenalidomide (8% vs 1%–9%), and decitabine (2% vs 0%–4%) (Figure 3). The use of other non–growth factor drugs was comparatively small. Use of vitamins and/or vitamin supplements was similar between recently diagnosed and established patients and between patients with lower-risk and higher-risk disease (Table 5).
In each of the six surveys, only a small minority of MDS patients was described as having had or being considered for bone marrow transplantation (4% of recently diagnosed patients and 0%–4% of established patients). More than half of bone marrow transplants that were performed or being considered were full myeloablative transplants (as opposed to nonmyeloablative or peripheral blood stem cell transplants, which were performed less commonly [data not shown]). The proportion of MDS patients in clinical trials was similarly low (1% of recently diagnosed patients and 1%–4% of established patients).
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Discussion |
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The range of therapeutic options for the management of MDS has changed dramatically over the past 3 years due to the approval by the US Food and Drug Administration (FDA) of three drugs—azacitidine, lenalidomide, and decitabine—to treat the disease (11,12,15). In addition to these FDA-approved drug options, erythropoiesis-stimulating agents have been used for decades in the supportive setting, either as stand-alone therapy or as adjunctive therapy with non–growth factor approaches (10,13,23,24). With this change in therapeutic landscape came the need to characterize the composition of MDS patients in the United States and the treatments they are receiving.
In this study, we describe the characteristics of a large sample of MDS patients in the United States, including their transfusion and supportive care needs and treatment approaches for a 19-month period that ended in January 2007. The patients included in this study derive mainly from office-based practices, and thus represent a "real-world" glimpse of the makeup of this disease. To our knowledge, this is the first study to describe the characteristics and treatment patterns of established MDS patients.
The proportions of recently diagnosed MDS patients with lower-risk and higher-risk disease were consistent with those reported in a previous study (6). In addition, the signs and symptoms at presentation, baseline laboratory values, and cytogenetic risk distributions among both recently diagnosed and established patients were similar to those reported earlier (2,6,8,25). The majority of lower-risk patients had fewer transfusion needs and was more likely to be followed by a "watch and wait" approach than higher-risk patients, as would be predicted by their longer survival and more indolent disease course. To our knowledge, this is the first report describing the length of time that patients are monitored with a "watch and wait approach" prior to initiating therapy (ie, 13–20 months). These data may be useful in supporting decision models for treating MDS and for describing transfusion, supportive, and therapeutic needs over the entire disease course (15).
It is surprising that despite the high proportion of lower-risk MDS subtypes among recently diagnosed and established patients, a large percentage of patients were reported to currently receive blood and/or platelet transfusions. The majority of the patients with higher-risk disease were dependent on red blood cell transfusions, and a substantial minority was dependent on platelet transfusions. Up to 20% of recently diagnosed lower-risk MDS patients and up to 67% of higher-risk patients were dependent on red blood cell transfusions, and up to 6% of recently diagnosed lower-risk and 33% of higher-risk patients were dependent on platelet transfusions. Among patients with established MDS, the percentages of those requiring red blood cell or platelet transfusions were higher: up to 25% of established lower-risk patients and up to 67% of established higher-risk patients required blood products. Given the estimated 10 000 incident and 50 000 prevalent cases of MDS in the United States each year (21), the public health impact of these transfusion needs may be greater than previously thought, because ultimately the majority of MDS patients may, as they transition from lower-risk disease to higher-risk disease, require blood product transfusions over the rest of their lifetimes. The use of erythropoiesis-stimulating agents was also high: the majority of recently diagnosed and established patients were receiving such agents at the time of survey, either alone or in combination with other therapies. We were surprised to discover that physicians were treating patients with erythropoiesis-stimulating agents in combination with non–growth factor therapy off-study, because combination therapy is just now being explored in phase 1 and phase 2 clinical trials. One caveat to the interpretation of these erythropoiesis-stimulating agent results is that, by design, surveyed physicians demonstrated at least some familiarity with treating MDS patients and thus may have preferentially been referred MDS patients with transfusion or erythropoiesis-stimulating agent needs. Thus, although every attempt was made to demonstrate that physician responders were geographically representative of practices across the country, this potential for a referral bias may mean that their ESA treatment practices do not apply to the full spectrum of MDS patients in the United States.
Other non–growth factor therapies appeared to be used in similar proportions of established and recently diagnosed lower-risk patients but were used more frequently in higher-risk MDS patients than lower-risk patients. It is interesting that among higher-risk patients, non–growth factor therapies appeared to be used in a higher proportion of recently diagnosed patients than of established patients; this difference may signify a greater awareness among treating physicians to initiate therapy quickly in higher-risk MDS patients and/or that established patients have already failed such therapy.
The only curative therapy for MDS is bone marrow transplantation. Despite the wider availability of reduced-intensity conditioning ("nonmyeloablative" or "mini") bone marrow transplants, the percentage of patients who were being considered for or had received these or other transplant modalities remains low. The low percentage of MDS patients being considered for transplantation may indicate a continued reluctance by physicians to pursue aggressive therapies in an older population and/or the recognized lack of available donors; in addition, older MDS patients have correspondingly aged siblings, who also may have substantial comorbidities that would preclude their participation as a donor. Another potential explanation for the low percentage of patients being considered for transplantation in this study is that patients being considered for transplantation would likely have been referred to transplant specialty centers, and thus might have been underrepresented in these survey data. However, it is still fair to conclude that transplantation was an underconsidered treatment modality within our physician sample, which we feel is representative of practice patterns in the Unites States. A similarly low percentage of MDS patients in our sample were enrolled in clinical trials. This finding is compatible with clinical trial enrollment patterns of adults with other types of cancer (26).
Our study has two potential limitations. One is that the data were collected retrospectively by asking physicians to report on the 4–10 most recently seen MDS patients. Although one could argue that physicians may have been more likely to remember the more severe cases of MDS, the heterogeneity of the data belies systematic recall bias. In addition, the sample of physician responders was also restricted to physicians who were familiar with MDS patients, thus lending more credence to the accuracy of the information collected. A second limitation is that because of a lack of unique identifiers for patients as well as their physicians, we were not able to identify a cohort of MDS patients who could be followed over time. In addition, because information on the same established patient may have been provided in more than one survey, it was not possible to pool results of all surveys to explore differences in therapies among established patients.
In conclusion, the majority of MDS patients have lower-risk disease, and 10% have secondary MDS. A high proportion of MDS patients are dependent on red blood cell and platelet transfusions, and the majority of recently diagnosed and established cases are treated with erythropoiesis-stimulating agents. Transplantation and clinical trial involvement continues to be an option for only a minority of MDS patients. These data may be useful for estimating the resource utility and pharmacoeconomic impact of MDS in the United States.
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The research was supported, in part, by the National Institutes of Health (U54RR19397-03 to M.A.S., A.L., and J.P.M.).
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Presented in part at the 9th International Symposium on Myelodysplastic Syndromes on May 18, 2007, in Florence, Italy, and the American Society of Hematology Annual Meeting, on December 9, 2007, in Atlanta, GA.
The authors thank Cathy Humphries at the US Tandem Oncology Monitor for contributions to data collection and analysis. Medical writing assistance was provided by James O’Kelly, an employee of Amgen Inc. M. Sekeres conducts research sponsored by Amgen (the maker of pegfilgrastim, darbepoetin, and erythropoietin) and Celgene Corp. (the maker of lenalidomide) and is a member of the speaker's bureau for Celgene Corp. W. M. Schoonen and J. Fryzek hold stock in Amgen. H. Kantarjian receives research funding from Novartis, BMS, MGI Pharma, and Genzyme (the makers of drugs cited herein). A. List is on the advisory board for scientific information for S*BIO and a consultant for clinical trial design for S*BIO and Sunesis (both of which are developing alternative MDS therapies to those discussed here). He also receives research grants from Celgene Corp. and is a member of their speakers’ bureau. The study sponsor had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.
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Manuscript received June 9, 2008; revised August 12, 2008; accepted August 28, 2008.
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J Natl Cancer Inst 2008 100: 1485.
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