Myelodysplastic syndromes (MDS) with del(5q) are considered to have a benign course of the disease. In order to address the issue of the propensity of those patients to progress to acute myeloid leukemia (AML), data on 381 untreated patients with MDS and del(5q) characterized by low or intermediate I International Prognostic Scoring System (IPSS) risk score were collected from nine centers and registries. Median survival of the entire group was 74 months. Transfusion-dependent patients had a median survival of 44 months vs 97 months for transfusion-independent patients (P<0.0001). Transfusion need at diagnosis was the most important patient characteristic for survival. Of the 381 patients, 48 (12.6%) progressed to AML. The cumulative progression rate calculated using the Kaplan–Meier method was 4.9% at 2 years and 17.6% at 5 years. Factors associated with the risk of AML transformation were high-risk World Health Organization adapted Prognostic Scoring System (WPSS) score, marrow blast count >5% and red-cell transfusion dependency at diagnosis. In conclusion, patients with MDS and del(5q) are facing a considerable risk of AML transformation. More detailed cytogenetic and molecular studies may help to identify the patients at risk of progression.
In 1975, van den Berghe1 first described the deletion of parts of the long arm of chromosome 5 with particular clinical features as a distinct entity known as 5q- syndrome. This subtype was found to share many characteristics with myelodysplastic syndromes (MDS) and was included into the World Health Organization (WHO) classification systems as a specific entity of MDS.2, 3 The patients with 5q- syndrome are considered to have a good prognosis compared with other MDS types.4, 5, 6 Although the International Prognostic Scoring System (IPSS)7 has been used for the prognostication of patients with primary MDS, there are no sufficient data on the value of this system for patients with MDS and del(5q).
Patients with isolated del(5q) without increased medullary blasts have a shorter life expectancy of 5–7 years compared with healthy age- and gender-matched cohorts.4 This may be partially related to a transformation into acute myeloid leukemia (AML). Greenberg7 reported on 48 patients with del(5q) having a cumulative risk of AML evolution of about 25% after 4 years. This cohort included patients with the 5q- syndrome with or without excess blasts. In several countries where lenalidomide is available, the majority of patients with MDS and del(5q) are treated with this compound. Some concern has been raised whether this drug may accelerate the conversion into AML. To address this issue more detailed information on the natural course of the disease are needed as data on the parameters influencing the prognosis with regard to survival and risk of AML evolution are scarce at best.
We therefore performed a retrospective multicenter analysis of patients with MDS and del(5q) belonging to the IPSS low and intermediate I risk groups. We evaluated established prognostic parameters and included newly proposed parameters like transfusion need.8 The strength of this analysis lies in the rigorous selection of a patient population without treatment to exclude any potential effects related to a particular type of therapy.
Patients and methods
The Düsseldorf MDS registry, operative since 1982,9 has provided key clinical information on MDS patients, including the information used in formulating the IPSS,7 in validating the WHO adapted Prognostic Scoring System (WPSS),8 and the WHO classification3 was combined with data from several academic centers in a multicenter collaboration. All patients with MDS and del(5q) belonging to the IPSS low or intermediate I risk group were collected from nine centers and registries from Europe, USA and Australia by using a uniform minimal data set. As a prerequisite, the exact date of diagnosis by means of bone marrow examination and cytogenetic assessment had to be documented. All but five patients were diagnosed in so-called ‘MDS centers of Excellence’. Exact WHO type, medullary blast count, differential count, blood cell counts, karyotype, and transfusion requirement were documented and confirmed at each participating institution. Transfusion dependency was defined as described by Malcovati et al.,8 meaning that at least 4 units of red blood cell (RBC) transfusions had to be administered within 8 weeks.
A total of 210 patients from the German–Austrian–Swiss MDS group, 84 patients from the French MDS registry, 26 patients from the registry of Prague, 41 patients from the Greek registry, and 20 patients from the Cleveland and Melbourne registries, were entered. Only patients treated with best supportive care, defined as transfusions, chelation therapy and erythropoiesis-stimulating agents were accepted. A total of 71 patients who received lenalidomide were registered, but censored at the time of treatment onset. Data collection and evaluation was performed after obtaining institutional review board/ethics committee approval at individual institutions.
For the analysis of survival and progression to AML, patients who were still alive were censored at the date of last observation. Survival time was counted from diagnosis. Overall survival was analyzed with the Kaplan–Meier estimator.10 Progression to AML was analyzed with cumulative incidence competing risks method.11 Patients either progressed to AML (the event of interest) or died without prior progression (the competing event), or were censored if none of these events occurred. For comparison of Kaplan–Meier curves and for cumulative incidence competing risks method, the log-rank test and the Gray-test12 were used, respectively. When considering covariates, survival was modeled with the Cox regression (with a time-varying effect). Within the competing risks framework the cause-specific hazards were analyzed with the Cox model13 for both events, progression to AML and death without prior progression. Backward selection was applied for both models. P-values <0.05 were considered significant. Owing to the exploratory character of this work, no adjustment of significance levels was done. Statistical analyses were performed by the Institute for Medical Information Sciences, Biometry, and Epidemiology, at Ludwig-Maximilians-University of Munich (ML, JH).
At the time of diagnosis the median age of the 381 patients (70% females) included into this retrospective evaluation was 67 years (range, 28–95). While 46 patients (12%) were diagnosed as refractory anemia with excess blasts I, all other patients had a medullary blast count of <5%. The median baseline hemoglobin level was 9.3 g/dl, median white blood cell count was 3900 per μl, median absolute neutrophil count was 2100 per μl and the median platelet count was 250 000 per μl (Table 1). As a result, 68% of the patients were anemic, while only 37% and 12% presented with granulocytopenia or thrombocytopenia, respectively. At the time of diagnosis, 42% of the patients needed RBC transfusions regularly. Of the 251 patients initially not requiring RBC transfusion, 113 became transfusion dependent at a median time of 9.8 months after the diagnosis was made. The great majority of patients (82%) had a single del(5q) aberration, while in 14% one additional aberration and in 4% of them a complex karyotype including del(5q) were found.
During the median follow up time of 49.8 months (range, 1–350), there were 146 patients (38%) who died of various reasons. As a result, the median time of survival from diagnosis was 75 months (range, 1.7–350). In other words, the survival probability after 2 and 5 years from diagnosis was 85.9% and 60.9%, respectively. Using univariate analysis we looked for parameters potentially associated with the time of survival (Table 2). Male gender, age above 65 years, medullary blasts ⩾5%, complex karyotype and the need for RBC transfusions at diagnosis (Figure 1) were associated with a worse prognosis. In a multivariate analysis, transfusion dependency, anemia, thrombocytopenia, cytogenetic status and age group were independent parameters for the time of survival. For cytogenetic status, we did not find a difference between favorable and intermediate group, but both had a significantly lower risk than the group with complex karyotype. Age group was modeled with a time-varying effect, meaning that risk for patients with an age of 65 years or above increased disproportionately with time compared with the younger group (Table 3).
Analyzing the prognostic value of the IPSS in this cohort, we found that in 75 months compared with 71 months there was no significant difference in the time of survival between patients belonging to the IPSS low (49%) and intermediate I risk group (51%). When looking at the WPSS, 9% from the IPSS intermediate-risk group were assigned to the WPSS very low-risk group, 33% to the low-risk group, 29% to the intermediate-risk group and 29% to the high-risk group. The very low-risk group had a median survival of 107 months in comparison with 75 months in the intermediate-risk group, 57 months in the low-risk group and 45 months in the high-risk group (Figure 2).
Figure 3 illustrates the estimated survival probabilities based on the Cox Model with regard to the impact of the major prognostic factors on the outcome as compared with patients with isolated del(5q) with medullary blasts <5% without transfusion need. The presence or the onset of one of these risk factors should prompt the clinician to consider the initiation of a specific treatment. Finally we analyzed the prognostic factors for survival only within the group of patients with <5% medullary blasts and isolated del(5q), the MDS with del(5q) according to the WHO proposals (Table 4). The cox model shows that even in this group transfusion need together with age remain important prognostic factors.
There were 48 (12.6%) of the 381 patients who developed AML within the follow-up time. On the basis of the competing risk method, the probability of transforming into AML was 4.7% after2 years of diagnosis and 14.7% after 5 years. The corresponding figures were 4.9 and 17.6% when the Kaplan–Meier method was used. We then examined by univariate analysis the influence of several parameters on the risk of AML progression, and found that transfusion dependency and medullary blast count of >5% were associated with an increased risk of AML evolution. At the time of 2 years following diagnosis, the probability of developing AML was 11% for the patients who presented with transfusion dependency compared with 2% for patients without transfusion dependency (Figure 4). Survivors of the first year of transfusion dependency, instead, did not have an increased risk of transformation to AML anymore.
In a multivariate analysis, transfusion need and increased medullary blast count were identified to be independent risk factors for AML progression (Tables 5 and 6). In the proportional hazards model for cause-specific hazard of transformation to AML, transfusion need during and after the first years has a role. This is modeled as a time-varying effect with a cut point at 3 years. Patients who are transfusion dependent have a worse outcome, but this is changing after about 3 years. When having survived 3 years without transforming to AML, the predictive value of transfusion dependency vanishes. The majority of those patients who were transfusion independent at diagnosis became transfusion dependent later on and, therefore, the characteristics of both the groups became similar.
Considering the model for the competing event, death without prior progression, it becomes clear that transfusion dependency is also a strong predictor for death. One reason for the change in effects at 3 years might be that those who have survived 3 years without transformation to AML are a selection of patients with otherwise low risk. We also analyzed the parameters associated with death without progression within the group of patients with <5% medullary blasts and isolated del(5q). The cox model showed that transfusion dependency, age and neutropenia were independent parameters (Table 7).
The IPSS that lacks information about transfusion dependency was not able to separate the risk groups with respect to AML evolution. When assessing the prognostic value of the WPSS, which takes into account transfusion dependency as well as karyotype anomalies, we found that this score was able to predict the risk of AML evolution. The cumulative incidence of AML at 2 years from diagnosis was 19% in the high-risk group in comparison to only 2% in the very low-risk group (Figure 5). Finally we analyzed the prognostic factors for AML progression only within the group of patients with <5% medullary blasts and isolated del(5q), the MDS with del(5q) according to the WHO proposals. In this analysis we could not identify any prognostic factors anymore.
To the best of our knowledge, this is the largest study including 381 patients with MDS and del(5q) belonging exclusively to the low and intermediate I risk group according to the IPSS. These patients only received best supportive care permitting us to evaluate progression risk and overall survival independent of any treatment modality, leading to robust findings with regard to prognosis of this rare MDS type:
We found that the risk of progression to AML was 4.9% after 2 and 14.7% after 5 years using the Kaplan–Meier method. This attribute obviously is a disease-inherent phenomenon, as risk of progression primarily is unrelated to any disease-modifying compound. The risk of progression is similar to the risk in patients with refractory cytopenia with multilineage dysplasia.9
It became evident that the need for RBC transfusion at diagnosis is a very important parameter indicating an increased risk for progression into AML. Early progression within the first 2 years following the diagnosis of MDS was mainly seen in transfusion-dependent patients at diagnosis. It is interesting to note that transfusion-dependent patients not evolving to AML during the first 4 years, apparently, do not have an increased risk to develop AML thereafter. This could be attributed to different reasons: transfusion dependency in del(5q) disease typically develops slowly, with increasing transfusion needs at later stages of the disease. Pereira et al.,14 recently showed that transfusion intensity, rather than the fact of transfusion dependency itself, is the factor influencing the prognosis of MDS patients. These patients with del(5q) who have a notoriously slow progressive disease and who are transfusion independent at diagnosis will most probably develop a greater need for transfusions much slower than patients who already require transfusions at the time of diagnosis. A smaller study presented by Patnaik et al.,15 reported that the need for transfusion was a major prognostic factor as well. In that study on 88 patients with MDS and del(5q) an age of >70 years and the presence of dysgranulopoiesis were associated with a shorter time of survival.
On the basis of our data, it became evident, that increased medullary blast count is associated with a higher risk of progression in patients with MDS and del(5q). This phenomenon is also well recognized in various MDS types, especially in the refractory anemia with excess blasts I and refractory anemia with excess blasts II types.5, 6
The presence of more than one additional chromosomal aberration is associated with an increased risk of progression. This is in line with the only large study evaluating progression features in patients affected with del(5q) that was recently presented by Mallo et al.16 This study focused primarily on cytogenetic features, comprising 541 patients with different French-American-British subtypes of MDS, including patients with medullary blasts of up to 20% with or without additional chromosomal abnormalities. Chromosomal complexity, platelet count and percentage of marrow blast were the most important factors predictive for the risk of AML progression in that study. In addition, age and gender were also patients’ characteristics relevant for the prognosis as far as overall survival was concerned. As in the study of Mallo et al., the proportion of patients with del (5q) alone was only 55% and the rate of complex karyotypes was much greater than in our study (28% vs 4%), their data set allowed to evaluate and analyze precisely the influence of the impact of various karyotype abnormalities on survival and the risk of AML progression. Different from their results, the proportion of del(5q) metaphases as well as of breakpoints of deletion of 5q was not related to the time of survival or risk of AML progression. Similar results with regard to the prognostic relevance of additional karyotype alterations were published by the German–Austrian MDS Group.17 Using comparative genome hybridization, Evers et al.18 and Thiel et al.19 were also able to show the prognostic value of additional abnormalities. Moreover, it has been shown recently that the status of p53 expression at baseline is an important driver for disease progression in del(5q). p53 accumulation promotes transcription of its many target genes, leading to cell cycle arrest and apoptosis.20 This mechanism is likely to lead to early hematopoietic failure or progression. Patients with normal p53 expression, instead, might experience prolonged phases of transfusion dependency. In addition, mutation of p53 are also seen in patients with MDS, including those with del(5q) and are discussed to be associated with increased risk of progression, but this could not be properly addressed in a large enough patient group.21, 22, 23, 24
Our data indicate that the WPSS is more feasible to prognosticate patients with MDS and del(5q) as compared with the IPSS. The WPSS is the only prognostic scoring system taking into account transfusion dependency in patients with MDS permitting the identification of patients at higher risk for progression. This was not possible when the IPSS was used.
Our data contribute to the knowledge on disease progression in MDS with del(5q) and therefore could be used to be compared with patients who received therapy with Lenalidomide. Ades et al.25 presented a study of 194 patients with regard to disease progression in a cohort-controlled analysis, including patients treated with lenalidomide compared with those treated with best supportive care. These data showed that there was no significant difference between the groups with regard to AML progression. In his study, as well as in a study presented by Göhring et al.,26 it is shown that within the study population treated with lenalidomide the progression rate to AML was higher in those patients who did not respond to lenalidomide. Therefore, suppression of the del(5q) clone in lenalidomide responders might reduce the clone size, slowing down mutational events and preventing progression. On the other hand, non-responders might be prone to more rapid disease progression due to disease-inherent features like p53 mutations or over expression.
It became clear that although patients with del(5q) are facing a certain risk for disease progression, the overall survival is relatively good. This may be partly because of the fact that the vast majority of patients present with normal or elevated platelet count and normal or only slightly decreased neutrophils. As a result, there are no imperative reasons for bleeding complications and infections, which are the most frequent causes of death in the general MDS population.27 Another clinical difference between MDS without del(5q) and MDS with del(5q) contributing to the good overall survival are age and gender: MDS with del(5q) more frequently affects females and the median age at diagnosis is between 5 and 10 years lower than that in the other MDS patients. Again, transfusion dependency, along with low platelet count and complex karyotype were the most important risk factors in our study. The prognostic meaning of del(5q) in MDS also seems to be influenced by genetic background. Data from Japan,28 China29 and Korea30 not only show that del(5q) is less frequent in those populations than in western countries, but also31 that in the Eastern hemisphere, there is no clear-cut association with good prognosis. Therefore, patients from far east with MDS, especially those with del(5q) have to be regarded as different from the western type patients.
Substantial improvements to the prognosis of patients with myeloid malignancies have been made by eliminating or at least suppressing the aberrant clone. This principle is effective using tyrosine kinase inhibitors in Bcr–Abl-positive chronic myeloid leukemia, and also in lenalidomide-treated MDS with del(5q). Owing to the fact that AML evolution cannot be suppressed by treatment with lenalidomide and the risk of progression was lower in responders,32, 33 there might be underlying unknown molecular mechanisms that promote or allow progression. As the response to Lenalidomide very often occurs very quickly during the first 1–4 months of treatment, non-responders should discontinue the drug and move to other therapeutic modalities. Physicians should take into account transfusion dependency, karyotypic features and percentage of blasts, and monitor their patients carefully to develop age-adjusted long-term treatment strategies.
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This work was supported by Celgene.
U Germing, P Fenaux, J Maciejewski, D Haase, U Platzbecker, KA Kreuzer and A Giagounidis are on the advisory board as well as have received research funding from Celgene. M Pfeilstöcker, T Nösslinger, M Sekeres, J Seymour, P Valent and A Kündgen are on the advisory board of Celgene. M Kenealy and R Weide have received research funding from Celgene.
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Germing, U., Lauseker, M., Hildebrandt, B. et al. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study. Leukemia 26, 1286–1292 (2012) doi:10.1038/leu.2011.391
- MDS and del(5q)
- transfusion need
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