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Originally published as JCO Early Release 10.1200/JCO.2006.07.5598 on November 6 2006 © 2006 American Society of Clinical Oncology. Myelodysplastic Syndromes in Patients Younger Than Age 50
From the Department of Hematology, Oncology, and Clinical Immunology, and Institute of Human Genetics, Heinrich-Heine-University, Duesseldorf, Germany Address reprint requests to Andrea Kuendgen, MD, Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Moorenstr 5, D-40225 Düsseldorf, Germany; e-mail: kuendgen{at}med.uni-duesseldorf.de
PURPOSE: Myelodysplastic syndromes (MDS) mainly occur in the elderly but can affect younger individuals too. The latter require special consideration to identify suitable candidates for allogeneic stem-cell transplantation, a potentially curative approach carrying a high risk of treatment-related complications. PATIENTS AND METHODS: We report the largest series of young MDS patients as yet, including 232 patients younger than 50 years. Their clinical characteristics and prognosis are compared with 2,496 patients older than 50 years. RESULTS: Survival was significantly longer in the younger versus older age group (40 v 23 months, respectively; P < .00005). The difference arose from patients belonging to the low- and intermediate-I–risk categories of the International Prognostic Scoring System (median survival not reached v 45 months, respectively; P < .00005). In contrast, survival was identical for both age groups (8 months for both younger and older patients; P = .81) in the intermediate-II–and high-risk categories. Established classification systems and risk scores were applicable to young patients with primary MDS. Interestingly, a particularly large difference in median survival time was seen between the intermediate-I–and intermediate-II–risk groups (176 v 8 months, respectively). For low-risk patients, the overall survival rate was more than 86% at 20 years. CONCLUSION: According to these results, aggressive treatment approaches should rarely be recommended to younger MDS patients belonging to the low and intermediate-I risk groups.
Less than 10% of patients with myelodysplastic syndromes (MDS) are younger than age 50 years.1 Because clinical data relevant to the classification and prognostication of MDS have usually been obtained in patients older than age 60, it is unknown whether prognostic scoring systems derived from such data are suitable for clinical decision making in younger patients. Reports on young MDS patients are scarce and include relatively small numbers of patients. Fenaux et al2 described 37 adults younger than age 50 years. Most of them were treated with intensive chemotherapy or allogeneic stem-cell transplantation (alloSCT). In a series of 52 adult MDS patients younger than age 50 years reported by Chang et al,3 the proportion of patients receiving alloSCT was more than 50%, whereas the frequency of intensive chemotherapy was not mentioned. If a cohort includes a substantial proportion of patients treated with intensive chemotherapy or alloSCT, it is problematic to apply the existing scores, which were developed for patients treated with supportive care only.
Breccia et al4 analyzed 62 conservatively treated patients younger than age 50 years and concluded that age older than 40 years and a high-risk profile according to the International Prognostic Scoring System (IPSS) were predictive of shorter survival. When the IPSS was developed, 205 of 816 patients analyzed were Our MDS Registry includes 232 patients younger than age 50 and is the largest series of younger MDS patients to date. We describe their clinical, cytogenetic, and pathologic features at diagnosis, apply different classifications and scoring systems, and compare these data to 2,496 patients who are 50 years of age or older. This series of 232 patients includes 131 patients with primary MDS who did not receive intensive treatment, mainly because they belonged to a lower risk category or because they were entered onto the registry at a time when intensive treatment was rarely considered for MDS patients. Data from these patients were used to identify prognostic factors influencing survival and acute myelogenous leukemia (AML) evolution.
All blood and bone marrow (BM) smears were examined by the same investigator. The morphologic diagnosis was made according to the proposals of the French-American-British (FAB) and WHO classification.6,7 A differential WBC count was performed on 100 cells in the peripheral blood to determine peripheral blast count and look for dysplastic features. A differential count was also carried out on 500 nucleated cells in the BM to determine the proportion of medullary blasts and to diagnose MDS according to the WHO proposals. Cytogenetic findings were documented according to the International System for Human Genetic Nomenclature.8 Patients were classified according to the IPSS proposal5 (low risk: 5q–, 20q, –Y, and normal karyotype; high risk: aberrations of chromosome 7 and/or complex karyotypes, ie,  three abnormal chromosomes; intermediate risk: all other findings). Patients were observed for survival and leukemic progression through December 31, 2005. The patients were either regularly seen in our outpatient clinic or their primary care physicians were contacted to gather pertinent information on the course of disease.
The product-limit method (Kaplan-Meier) was used to estimate survival. Prognostic factors were determined using the Mantel-Cox test and the stepwise multivariate regression method of Cox. Clinical and hematologic data of patients at the time of diagnosis were compared using the
Patient Characteristics We first compared clinical, hematologic, and cytogenetic data of younger and older MDS patients (Table 1). A total of 2,728 patients were analyzed; 232 were younger than 50 years old, and 2,496 were 50 years old. The incidence of MDS in individuals younger than age 50 remained constant over the whole period of patient accrual to the registry. Treatment-related (secondary) MDS was diagnosed in 14.7% of patients younger than age 50 compared with 4.6% of patients 50 years (P < .00005). For all further evaluations, patients with secondary MDS were excluded from the analysis. Median age at diagnosis was 70.6 years (range, 14 to 96 years) for all MDS patients in the registry and 40.7 years (range, 14 to 49 years) for patients younger than age 50 years. There were significantly more women than men among younger MDS patients, whereas the sex distribution was the reverse in patients older than 50 years (P = .001). Anemia was more pronounced in younger patients.
Among 122 young patients with cytogenetics available, 47.2% had chromosomal aberrations compared with 50% of 736 older patients. Interestingly, cytogenetic findings showed no significant difference between younger and older patients as far as the distribution among cytogenetic risk groups was concerned. Regarding specific karyotypes, complex karyotypes were less frequent in young patients compared with older patients (8.9% v 14.0%, respectively), whereas 7q– was more frequent (7.3% v 3.8%, respectively; Table A1, online only). Next, we assessed morphologic subtypes. According to the FAB classification, the diagnoses in young patients were 76 refractory anemias (RA), 21 refractory anemias with ringed sideroblasts (RARS), 39 refractory anemias with excess blasts (RAEB), 51 RAEB in transformation (RAEB-T), and 11 chronic myelomonocytic leukemias (CMML). Applying the WHO classification, we had 20 RA, 10 RARS, 10 refractory sideroblastic cytopenias with multilineage dysplasia, 45 refractory cytopenias with multilineage dysplasia (RCMD), 20 RAEB I, 40 RAEB II, and nine 5q– syndromes. Younger MDS patients, compared with older patients, showed a higher frequency of RAEB-T according to FAB (25.8% v 13.1%, respectively; P < .00005) and RAEB II according to WHO (25.9% v 17.6%, respectively; P = .012). The incidence of RA with unilineage dysplasia was also higher in younger patients than older patients (13.0% v 8.3%, respectively; P = .01); however, RARS (10.6% v 19.2%, respectively; P = .0002) and CMML according to FAB (5.6% v 13.0%, respectively; P = .001) were less frequent. The distribution among IPSS risk groups was very similar for young and old MDS patients. Induction chemotherapy and alloSCT were performed in 29.8% and 12.1%, respectively, of patients younger than age 50 compared with only 7.4% and 0.7%, respectively, of patients older than age 50. Further patient characteristics are listed in Table 1.
Survival The difference in survival for younger versus older patients was even more pronounced (176 v 25 months, respectively; P < .00005) for patients receiving supportive care only (Fig 1A). The difference arose from patients belonging to the low- and intermediate-I–risk categories (median not reached for younger patients v 45 months for older patients; P < .00005; Fig 1B). In contrast, survival time was identical for both age groups (8 months for both age groups; P = not significant; Fig 1C) in the intermediate-II–and high-risk categories. As expected, outcome was significantly inferior in secondary compared with primary MDS patients; this was true for young patients (11 v 176 months, respectively; P = .0014) as well as older patients (8 v 25 months, respectively; P < .00005).
Regarding intensive chemotherapy and alloSCT, young MDS patients in the low and intermediate-I groups had no measurable benefit from intensive treatment compared with best supportive care (median survival, not reached v not reached, respectively; P = not significant). The situation was different in intermediate-II–and high-risk patients, in whom treatment led to a significant survival benefit in patients younger than 50 years of age compared with no treatment (26 v 8 months, respectively; P = .0011; Fig 2). Median survival time for all patients receiving alloSCT, most of whom belonged to the high-risk group, was 46 months.
Interestingly, the risk of leukemic transformation in younger versus older MDS patients did not differ significantly in any of the subgroups; the cumulative 2-year incidence was 16% v 22% for all patients, 14% v 16% for untreated patients, 15% v 14% for the lower risk groups, and 56% v 69% for the higher risk groups. The cause of death in younger MDS patients was disease related in 67% of cases. AML transformation occurred in 47 patients (49%), and lethal infection or hemorrhage without AML transformation occurred in 14 patients (15%) and three patients (3%), respectively. Three percent of patients died of cardiac disease, 6% died of other causes unrelated to MDS, and 24% died of unknown causes. In MDS patients older than 50 years, causes of death were less frequently disease related compared with younger patients (45% v 67%, respectively). Unfortunately, the cause of death was unknown in a large proportion of patients in the older group (45%). Of note, hemorrhagic complications occurred with similar frequency in younger and older MDS patients (5% v 3%, respectively).
Prognostic Factors
On multivariate analysis, blast count more than 10%, elevated serum lactate dehydrogenase, and high-risk karyotype were identified as significant independent predictors for survival. Peripheral cell counts and sex were not identified as independent prognostic factors (Table A2, online only).
Classification and Scoring Systems The WHO classification was capable of separating patients with a very good prognosis (median survival not reached), namely patients with RA, RARS, or 5q– syndrome, from patients with multilineage dysplasia, who still had a remarkably long survival (RCMD, 180 months; refractory sideroblastic cytopenias with multilineage dysplasia, 176 months). There was also a significant difference in survival between RAEB I (24 months) and RAEB II (13 months) patients (Fig A1, online only). The IPSS score, when applied to younger MDS patients, revealed a marked difference in median survival time between the lower and higher risk groups. The median survival time was not reached in the low-risk group and was 176 months in the intermediate-I–risk group. In contrast, median survival time was only 8 and 7 months for intermediate-II–and high-risk patients, respectively (Fig 4).
AML Transformation AML transformation had a significant influence on survival (P = .00005). Risk factors for this complication, as identified by univariate analysis, were elevated BM blast count (P < .00005), platelet count less than 100 x 109/L (P = .0073), elevated serum lactate dehydrogenase (P = .00005), and cytogenetic risk group (P = .0003). Morphologic classification as well as prognostic scoring systems were able to predict for AML evolution (FAB and WHO classification, IPSS, and Düsseldorf score; P < .00005). Interestingly, none of the patients with a BM blast count of less than 5% (RA, RARS, 5q–, and RCMD) or an IPSS score of low or intermediate-I developed AML at 2 and 5 years. In contrast, the risk of AML transformation was extremely high in patients with a BM blast count of more than 20% (77% at 5 years) and patients with a high-risk karyotype (100% at 5 years). A stable course of disease was associated with a low risk of AML transformation. Among patients with a history of MDS for more than 10 years, none developed acute leukemia. Prognostic factors for survival and AML transformation are listed in Tables 2 and 3, respectively.
Younger patients with MDS deserve special consideration. They seem to have a better prognosis than older patients. However, they are often suggested as candidates for transplantation therapy, which carries considerable risk of treatment-related morbidity and mortality. We report on 232 patients younger than 50 years old who account for 8.5% of all MDS patients seen at our institution between 1982 and 2005. This proportion of younger patients is in accordance with other studies.2,4 Up to now, reports on younger MDS patients were mainly from centers with a focus on BM transplantation.2,3 Accordingly, there is a selection bias with overrepresentation of high-risk MDS patients in these studies. Our analysis showed no significant difference between young and old MDS patients regarding their distribution among IPSS risk groups. With respect to morphologic subtypes, RAEB-T (FAB) and RAEB II (WHO) were somewhat more frequent in young patients. However, this was also true for the very low risk type of RA with unilineage dysplasia (WHO). Our findings of a lower frequency of RARS and CMML (FAB) and a higher frequency of females in the younger age group confirm previous observations.2-4 Distribution among cytogenetic risk groups was not significantly influenced by age, but younger patients had a higher frequency of 7q– as a single aberration and a lower frequency of complex karyotypes. Survival was significantly longer in patients younger than 50 years. However, only patients with a low- or intermediate-I–risk profile contributed to that difference, whereas intermediate-II–and high-risk patients had a short survival independent of age. The survival difference in the lower risk groups probably originates from older patients’ comorbidities, which can only exert their effect if MDS-dependent survival is not limiting. Increased susceptibility to disease-related symptoms, such as thrombocytopenic hemorrhage, or more severe effects of anemia in patients with cardiac disease may also play a role. Unfortunately, the exact cause of death was not determined in a significant proportion of patients, particularly in older individuals who rarely had a postmortem examination. However, for MDS patients younger than age 50, we can say that the majority died of disease-related causes. We confirmed that established classification systems and risk scores are applicable to younger patients with MDS. All systems identified a low-risk group with long survival. A striking difference in median survival was observed between the intermediate-I–and intermediate-II–risk groups according to IPSS (176 v 8 months, respectively). The remarkably long survival of untreated young MDS patients with a low- or intermediate-I–risk profile is relevant for clinical decision making, in particular with respect to alloSCT. In general, the outcome is better if alloSCT is performed early in the course of the disease and in patients belonging to a favorable risk category.10,11 Appelbaum and Anderson10 observed 5-year disease-free survival rates of 60%, 36%, and 28% in patients with low/intermediate-I–, intermediate-II–, and high-risk profiles, respectively. Regarding established treatment guidelines, a group of United Kingdom–based MDS experts,12 as well as the Italian Society of Hematology,13 recommend alloSCT from an HLA-identical sibling donor for young MDS patients with an IPSS risk score of intermediate-I, intermediate-II, and high. For patients who belong to these risk groups and who are younger than 40 years old, alloSCT from an unrelated donor is also recommended. According to the Italian guidelines, patients younger than 40 years old with a low-risk MDS are considered candidates for alloSCT if they have a good performance status and unfavorable cytogenetics or severe cytopenias. Our results, demonstrating a 20-year overall survival rate of 86% for younger MDS patients with a low-risk profile, argue against aggressive treatment approaches in these patients. Similarly, for patients in the intermediate-I category who have a median survival time of 176 months, the risk of morbidity and mortality associated with transplantation is unacceptably high. Our data support the decision analysis performed by Cutler et al14 who examined the optimal timing of BM transplantation for MDS patients with an HLA-identical sibling donor, including data from transplantation and nontransplantation registries. For patients belonging to the low and intermediate-I IPSS groups, the analysis showed that delayed transplantation maximized overall survival, particularly for patients younger than 40 years old. However, the study demonstrated superior results if patients undergo transplantation before leukemic transformation. Therefore, the optimal time for transplantation may be indicated by a relevant worsening of the disease in terms of karyotype evolution or a change in IPSS risk category. Regular follow-up is needed to detect such changes. Recently, the US National Comprehensive Cancer Network published practice guidelines for MDS that do not suggest intensive therapy for low- and intermediate-I–risk MDS.15 However, a delayed transplantation strategy is not reflecting current clinical practice because the intermediate-I–risk category represented the largest group (46%) of MDS patients undergoing alloSCT between 1989 and 1997 according to the International Bone Marrow Transplant Registry.16 Irrespective of their MDS type or risk group, patients with a long history of MDS showed a very low risk of developing AML. Likewise, neither any of our patients with an IPSS score of low or intermediate-I nor any patient with a normal medullary blast count transformed to AML. The prognosis of such patients may be adversely affected by chronic transfusion therapy. Transfusion dependency was recently identified as an unfavorable prognostic factor by Malcovati et al.17 Because it is reasonable to assume that secondary hemochromatosis contributed to this result, adequate iron chelation therapy is recommended for patients with a good prognosis, in particular for younger MDS patients with a low-risk profile. For younger patients with a high-risk profile, our analysis yielded very poor survival data. Here, any kind of intensive treatment, such as chemotherapy or alloSCT, may significantly prolong survival (Fig 2). In summary, MDS in patients younger than 50 years were not markedly different compared with MDS in older patients. A few differences regarding sex distribution, degree of cytopenias, and distribution among morphologic and cytogenetic subgroups did not produce a distinctive pattern of young MDS. Furthermore, in patients belonging to the higher risk groups, younger age did not implicate a better prognosis. The utility of established tools for MDS classification and prognostication was not compromised in young patients. Using these tools, we showed that the difference in survival between lower and higher risk groups was much more pronounced in younger than older patients. This finding should be incorporated into clinical decision making.
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on November 6, 2006. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Germing U, Strupp C, Kundgen A, et al: No increase in age-specific incidence of myelodysplastic syndromes. Haematologica 89:905-910, 2004 2. Fenaux P, Preudhomme C, Helene Estienne M, et al: De novo myelodysplastic syndromes in adults aged 50 or less: A report on 37 cases. Leuk Res 14:1053-1059, 1990[CrossRef][Medline] 3. Chang KL, O’Donnell MR, Slovak ML, et al: Primary myelodysplasia occurring in adults under 50 years old: A clinicopathologic study of 52 patients. Leukemia 16:623-631, 2002[CrossRef][Medline] 4. Breccia M, Mengarelli A, Mancini M, et al: Myelodysplastic syndromes in patients under 50 years old: A single institution experience. Leuk Res 29:749-754, 2005[CrossRef][Medline] 5. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997 6. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 17:3835-3849, 1999 7. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189-199, 1982[Medline] 8. Mitelman F: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 1995 9. Aul C, Gattermann N, Heyll A, et al: Primary myelodysplastic syndromes: Analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 6:52-59, 1992[Medline] 10. Appelbaum FR, Anderson J: Allogeneic bone marrow transplantation for myelodysplastic syndrome: Outcomes analysis according to IPSS score. Leukemia 12:25-29, 1998 (suppl 1)[CrossRef][Medline] 11. Sutton L, Chastang C, Ribaud P, et al: Factors influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: A long-term study of 71 patients Societe Francaise de Greffe de Moelle. Blood 88:358-365, 1996 12. Bowen D, Culligan D, Jowitt S, et al: Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes: UK MDS Guidelines Group. Br J Haematol 120:187-200, 2003[CrossRef][Medline] 13. 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 87:1286-1306, 2002 14. Cutler CS, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104:579-585, 2004 15. Greenberg PL, Baer MR, Bennett JM, et al: Myelodysplastic syndromes clinical practice guidelines in oncology. J Natl Compr Canc Netw 4:58-77, 2006[Medline] 16. Sierra J, Perez WS, Rozman C, et al: Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100:1997-2004, 2002 17. Malcovati L, Porta MG, Pascutto C, et al: Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: A basis for clinical decision making. J Clin Oncol 23:7594-7603, 2005 Submitted May 22, 2006; accepted September 21, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 years of age. Their survival curves were similar to those of older patients, provided that the risk profile was intermediate-II or high. In the low- and intermediate-I–risk groups, younger patients had a significantly better survival.
2 and Wilcoxon rank sum tests. For calculating survival, patients who underwent alloSCT or intensive chemotherapy were excluded from the analysis. Secondary MDS patients were excluded from the analysis of patient characteristics and survival. 
