Change of prognosis of patients with myelodysplastic syndromes during the last 30 years

doi:10.1016/j.leukres.2015.04.001

Leukemia Research

Volume 39, Issue 7, July 2015, Pages 679-683

https://doi.org/10.1016/j.leukres.2015.04.001 Get rights and content

Highlights

•
We analyzed the survival of MDS patients diagnosed since 1982.
•
We found a significant longer survival in those patients diagnosed since 2002.
•
The survival benefit was seen especially in high-risk patients.
•
It was also evident in patients receiving best supportive care.
•
We assume a multifactorial cause, especially an improvement of BSC.

Abstract

During the last years, more and more treatment modalities are available for MDS patients. Therefore, we were interested if this is reflected in an improvement of the outcome of the patients. We analyzed the survival and rate of leukemic progression of 4147 patients from the Duesseldorf MDS registry diagnosed during the last 30 years and found an improvement of survival in those patients diagnosed after 2002 (30 vs. 23 months, p < 0.0001). In detail, the improvement of the prognosis was restricted to high-risk MDS patients diagnosed between 2002 and 2014 in comparison to the patient group diagnosed between 1982 and 2001 (19 vs. 13 months, p < 0.001), whereas the prognosis of low-risk MDS patients did not change significantly. The improvement of survival was still measurable after exclusion of RAEB-t patients and of those, that received an allogeneic stem cell transplantation. In line with this finding, we found a lower AML progression rate in the later diagnosed group. Unfortunately, we could not identify a clear reason for this finding but rather a multifactorial cause should be assumed. As death due to bleeding complications and infections was significantly lower, an improvement of BSC may be one of the underlying causes.

Introduction

Myelodysplastic syndromes (MDS) are clonal stem cell disorders and are characterized by a dysplastic hematopoiesis in the bone marrow and various degrees of cytopenia in the peripheral blood [1]. Accordingly, clinical symptoms vary from anemia with transfusion dependency, bleeding complications, fatigue and an increased risk of infections. Approximately 20% of the patients develop an acute myeloid leukemia (AML). The classification system of the World Health Organization (WHO) is based on cytomorphologic criteria, the bone marrow blast count, chromosomal findings and cell counts [2]. To assess the prognosis of MDS patients, the International Prognostic Scoring System (IPSS) has served as a gold standard since its publication and was revised by the International Working Group for Prognosis in MDS (IWG-PM) taking into account five rather than three cytogenetic risk groups including a number of less common cytogenetic alterations, new categories of marrow blast percentage values and a substitution of the number of cytopenias by the depth of cytopenias [3], [4]. As MDS is more frequent in elderly patients, most of them are no suitable candidates for intensive treatment and allogeneic stem cell transplantation as the only curative therapy for MDS patients. Therefore, best supportive care (BSC) remains the most often-indicated treatment option. During the last decade, the amount of potential treatment options grew. Beside intensive chemotherapy and allogeneic transplantation, hypomethylating agents have shown to improve overall survival in high-risk MDS patients [5]. In addition to transfusion of red blood cells or platelets, growth factors as erythropoiesis stimulating agents alone or in combination with granulocyte growth factors and thrombopoietin analogs can improve the cytopenia in the peripheral blood [6], [7], [8]. Additionally, there is an increasing amount of clinical trials investigating new treatment options for MDS patients.

Despite the growing treatment modalities, an improvement of survival of MDS patients receiving best supportive care during the last decades has not been shown [9]. The aim of our study was to analyze if the survival and leukemic progression rates of treated as well as untreated MDS patients has changed over a period of 30 years.

Section snippets

Methods

In this retrospective analysis, 4147 patients from the Düsseldorf MDS registry were included. As all patients within the registry are followed on the basis of standardized procedures, an evaluation of prognosis can be performed. The 30-year period between 1982 and 2002 was divided into six quinquennial intervals (1982–1986, 1987–1991, 1992–1996, 1997–2001, 2002–2006, and 2007–2011). Patients were allocated depending on their dates of diagnosis. In a first step, we determined the survival times

Results

In a first step, we determined the survival times of the patients diagnosed within the six quinquennials and found that those patients diagnosed between 1982 and 2001 had a similar survival within the four five-year time intervals covering this period. In contrast, since 2002 the survival time was significantly longer. Therefore, we merged the patients diagnosed within the respective quinquennials and continued our evaluation with these two patient groups, named in the following as the early

Discussion

In the present analysis, we could find an improvement of the survival of high-risk MDS patients diagnosed since 2002 in comparison to those patients diagnosed between 1982 and 2001. In the earlier diagnosed patient group were more patients included with RAEB-t that are now classified as AML. Therefore, we performed the same analysis excluding RAEB-t patients but revealed the same results, suggesting that these patients are not the explanation for the improved survival in MDS patients diagnosed

Conflict of interest statement

J. Neukirchen, K. Nachtkamp, J. Schemenau, C. Aul, C. Strupp and R. Haas have no financial disclosures. A. Giagounidis received speaker's honorary and consultancy from Celgene and Novartis, A. Kuendgen received research funding from Celgene, G. Kobbe received research funding and speaker's honorary from Celgene, Novartis and Amgen and U. Germing received research funding from Celgene, Novartis, Janssen-Cilag, Amgen and speaker's honorary from Celgene, Novartis and Janssen-Cilag.

Acknowledgements

J.N. wrote the manuscript; J.N. and U.G. were the principal investigators and take primary responsibility for the paper; U.G. and J.N. performed the statistical analysis; K.N. and R.H. provided helpful corrections for the manuscript; J.S., A.K., C.A., A.G., G.K. and C.S. provided patient data for the registry. All authors approved the final version to be submitted.

References (14)

P. Greenberg et al.
International scoring system for evaluating prognosis in myelodysplastic syndromes
Blood
(1997)
P.L. Greenberg et al.
Revised international prognostic scoring system (IPSS-R) for myelodysplastic syndromes
Blood
(2012)
P. Fenaux et al.
Efficacy of azacitidine compared to that of conventional care regimes in the treatment of higher-risk myelodysplastic syndromes: a randomized, open label, phase III study
Lancet Oncol
(2009)
E. Hellström-Lindberg et al.
Erythropoiesis stimulating agents and other growth factors in low-risk MDS
Best Pract Clin Res Haematol
(2013)
V. Santini et al.
Can the revised IPSS predict response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-1 MDS
Blood
(2013)
K. Nachtkamp et al.
Impact on survival of different treatments for myelodysplastic syndromes (MDS)
Leuk Res
(2009)
U. Germing et al.
Myelodysplastic syndromes: diagnosis, prognosis and treatment
Dtsch Arztebl Int
(2013)

There are more references available in the full text version of this article.

Cited by (17)

10-year nationwide trends in incidence, treatment patterns, and mortality of patients with myelodysplastic syndromes in Denmark
2023, Leukemia Research
Further temporal data on incidence, treatment patterns, and prognosis for patients with myelodysplastic syndromes (MDS) are needed. This study examined 10-year trends in incidence, treatment patterns, and all-cause mortality in a population-based cohort of 2309 MDS patients using Danish nationwide registries (2010–2019). We computed annual incidence rates overall and according to sex and age-groups. We examined temporal changes in the cumulative incidence of MDS specific treatments initiated within one year from diagnosis and temporal changes in the absolute risk of death and five-year adjusted hazard ratios (aHRs) for death, adjusting for age, sex and comorbidity. The age-standardized incidence rate of MDS per 100,000 person-years increased slightly from 5.3 in 2010 to 6.4 in 2019. Between 2010-2012 to 2016–2017, the use of azacitidine increased overall (8% to 22%), in patients with intermediate risk MDS (12% to 34%), and in patients with high-risk MDS (22% to 50%), while it remained stable (around 5%) for patients with low-risk MDS. The five-year aHR for death in the most recent calendar period compared to the earliest calendar period remained unchanged in patients with low-risk MDS, aHR = 0.90 (95% CI, 0.72–1.12) and in patients with high-risk MDS, aHR = 1.19 (95% CI, 0.89–1.61), while survival improved over time among patients with intermediate risk MDS, aHR = 0.67 (95% CI, 0.48–0.92). In conclusion the incidence of MDS slightly increased during a 10-year period in Denmark. The use of azacitidine increased markedly but five-year overall survival remained unchanged.
Myeloid malignancies in the real-world: Occurrence, progression and survival in the UK's population-based Haematological Malignancy Research Network 2004-15
2016, Cancer Epidemiology
Citation Excerpt :
As well as variations in case definition, making comparisons between the rates generated by different registries is further complicated by the fact that standard populations with widely differing age structures are often used for age-adjustment. European registries have, for example, generally used the 1976 European standard [19–24], US SEER registries the US 2000 standard [16,17], and registries from elsewhere in the world their own country specific standards and/or the 1996 World standard [25–27]. Since 2001, continued advances in genomics and diagnostic technologies have led to further WHO revisions, and haemato-oncology continues to be one of the most rapidly evolving fields in cancer research [1,2].
Population-based information on cancer incidence, prevalence and outcome are required to inform clinical practice and research; but contemporary data are lacking for many myeloid malignancy subtypes.
Set within a socio-demographically representative UK population of ∼4 million, myeloid malignancy data (N = 5231 diagnoses) are from an established patient cohort. Information on incidence, survival (relative & overall), transformation/progression, and prevalence is presented for >20 subtypes.
The median diagnostic age was 72.4 years (InterQuartile Range 61.6–80.2), but there was considerable subtype heterogeneity, particularly among the acute myeloid leukaemias (AML) where medians ranged from 20.3 (IQR 13.9–43.8) for AML 11q23 through to 73.7 (IQR 57.3–79.1) for AML with no recurrent genetic changes. Five-year Relative Survival (RS) estimates varied hugely; from <5% for aggressive entities like therapy-related AML (2.6%, 95% Confidence Interval 0.4–9.0) to >85% for indolent/treatable conditions like chronic myeloid leukaemia (89.8%, 95% CI 84.0–93.6). With a couple of notable exceptions, males experienced higher rates and worse survival than females: the age-standardized incidence rates of several conditions was 2–4 higher in males than females, and the 5-year RS for all subtypes combined was 48.8% (95% CI 46.5–51.2) and 60.4% (95% CI 57.7–62.9) for males and females respectively. During follow-up (potential minimum 2 years and maximum 11 years) myelodysplastic syndrome (MDS) progression to AML ranged from 25% for refractory anaemia with excess blasts through to 5% for refractory anaemia with ring sideroblasts: the median interval between MDS and AML diagnosis was 9.0 months (IQR 4.8–17.4 months).
The marked incidence and outcome variations seen by subtype, sex and age, confirm the requirement for “real-world” longitudinal data to inform aetiological hypotheses, healthcare planning, and future monitoring of therapeutic change. Several challenges for routine cancer registration were identified, including the need to link more effectively to diagnostic and clinical data sources, and to review policies on the recording of progressions and transformations.
Primary Myelodysplastic Syndromes: The Mayo Clinic Experience with 1000 Patients
2015, Mayo Clinic Proceedings
Citation Excerpt :
The survival of our patients diagnosed after 2005 remained poor despite approximately half (226 of 469) of these patients having received disease-modifying therapy including allogeneic transplant. This is in contrast to a recently published large study of 4147 patients with MDS from the Düesseldorf MDS Registry that found an improved prognosis in both treated and untreated high-risk patients with MDS diagnosed after 2002, mainly because of reduction in deaths from infectious and bleeding complications due to improvement in supportive care.35 However, there was no difference in death due to LT in patients diagnosed before and after 2002.35
To share our 25 years of experience with patients with primary myelodysplastic syndromes (MDS) and to describe the natural history of the disease including presenting clinical and laboratory characteristics and long-term disease outcomes.
One thousand consecutive patients with primary MDS evaluated at Mayo Clinic between January 1, 1989, and May 1, 2014, were considered. The Revised International Prognostic Scoring System and other risk models were applied for risk stratification. Separate analyses were conducted for patients diagnosed before 2005 (n=531) and after 2005 (n=469).
Eighty-five percent of patients were older than 60 years (median age, 72 years), with 69% being men. The median follow-up period was 27 months (range, 0-300 months), during which time 808 (81%) deaths and 129 (13%) leukemic transformations were documented. Median survival and leukemic transformation rates were similar in patients diagnosed before or after 2005, despite the significantly higher use of hypomethylating agents in the latter group: 33 months vs 28 months (P=.46) and 13% vs 10% (P=.92), respectively. Revised International Prognostic Scoring System risk distribution was similar in patients diagnosed before or after 2005 (P=.23): 17% were categorized as very low, 36% low, 21% intermediate, 15% high, and 11% very high risk, with a median survival of 72, 43, 24, 18, and 7 months, respectively (P<.001). We found Revised International Prognostic Scoring System cytogenetic risk categorization to be suboptimal in its performance, whereas contemporary prognostic models were broadly similar in their performance.
The poor outcome in patients with MDS does not appear to have improved over time. Current risk stratification systems for MDS are not substantially different from each other. There is a dire need for drugs that are truly disease modifying and risk models that incorporate prognostically relevant mutations.
Treatment options and survival in real life during the past three decades in patients with chronic myelomonocytic leukemia
2023, Wiener Medizinische Wochenschrift
Analysis of the impact of adherence to guidelines and expert advice in patients with myelodysplastic syndromes
2021, Annals of Hematology
Molecular genetics in allogeneic blood stem cell transplantation for myelodysplastic syndromes
2019, Expert Review of Hematology

View all citing articles on Scopus

^☆: Part of the data have been presented orally at the International Symposium on Myelodysplastic syndromes in Berlin 2013.

View full text

Change of prognosis of patients with myelodysplastic syndromes during the last 30 years☆

Highlights

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Conflict of interest statement

Acknowledgements

Blood

Blood

Lancet Oncol

Best Pract Clin Res Haematol

Blood

Leuk Res

Myelodysplastic syndromes: diagnosis, prognosis and treatment

Dtsch Arztebl Int