The relevance of transfusion‐dependency in the prognostic assessment of patients with myeloid neoplasms
Authors: Luca Malcovati, Mario Cazzola
Journal: American Journal of Hematology (2011)

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by a variable degree of peripheral blood cytopenia and an increased risk of progression into acute myeloid leukemia (AML). MDS represent one of the most common hematologic malignancies in Western countries, their incidence increasing dramatically with age, exceeding 40 cases per 100,000 persons per year over the age of 65. Recently, molecular studies identified several genetic lesions implicated in the pathogenesis of MDS, either as initiating events or involved in multistep disease progression. Interestingly, most of these defects can be detected in other myeloid neoplasms, including not only AML but also myeloproliferative neoplasms (MPN), suggesting a close connection among myeloid neoplasms. Indeed, although each subgroup has peculiar features, these disorders present substantial overlap with entities having clinical and biological characteristics belonging to different groups. The clinical course of MDS is highly variable, ranging from indolent conditions with a near-normal life expectancy to forms approaching acute leukemia. Thus treatment strategies adapted to the individual patient risk are mandatory. In 1997, Greenberg and coworkers developed the International Prognostic Scoring System (IPSS) for MDS, based on percentage of bone marrow blasts, cytogenetic abnormalities, and number of cytopenias [1]. The IPSS has been used widely in clinical decision-making and clinical trials, and also by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) in their approvals of novel drugs for MDS. The World Health Organization (WHO) classification of myeloid neoplasms represents a very useful tool for defining the different subtypes, and provides also prognostic information. In fact, unilineage dysplasia is associated with a better prognosis compared with multilineage dysplasia, while the presence of excess blasts involves a worse prognosis [2]. Anemia is the most relevant clinical problem for the majority of patients with MDS. More than 90% of MDS patients are anemic at the time of diagnosis, and severe anemia is observed in about 60% of cases. Once anemia is symptomatic, red blood cell (RBC) transfusions are the mainstays of therapy. We found that the onset of a regular transfusion requirement in MDS patients is associated with a worsening of prognosis in multivariable analysis, and hence, transfusion-dependency can be viewed as an independent indicator of the severity of the disease and an independent prognostic factor. The prognostic value of transfusion-dependency was found to be associated with transfusion burden and intensity of transfusion requirement [2]. Based on these observations, we developed a prognostic model that accounts for the WHO categories, cytogenetics and transfusion dependency [3]. This WHO classification-based prognostic scoring system (WPSS) is able to classify patients into five risk groups with different survival and probability of leukemic evolution. More importantly, it predicts survival and leukemia progression at any time during follow-up, and can therefore be used for implementing risk adapted treatment strategies. Moderate to severe anemia at diagnosis was also found to be of additive prognostic value to IPSS in terms of overall survival, and independently stratified patients within the intermediate IPSS risk categories [4]. Specifically, patients with hemoglobin levels equal or lower than 10 g/dL had a lower life expectancy than those with hemoglobin levels higher than 10 g/dL. Recently, transfusion-dependency and transfusion history were also found to affect the outcome of MDS patients undergoing allogeneic stem cell transplantation [5]. Anemia is a relevant clinical problem not only in MDS, but also in other myeloid neoplasms. In primary myelofibrosis (PMF), anemia is a risk factor recognized by almost all prognostic scoring systems. Recently an international effort allowed the formulation of an International Prognostic Scoring System (IPSS) to predict survival at diagnosis in PMF. This model considers five different parameters, including hemoglobin level lower than 10 g/dL. The IPSS risk factors were then included in a time-dependent model generating a time-dependent prognostic score (Dynamic International Prognostic Scoring System, DIPSS), in which the prognostic power of anemia acquired during follow-up was even enhanced [6]. In a more recent study patients who began red blood cell transfusions anytime had a significantly worse survival compared to those who continue follow-up without transfusions. RBC transfusion-dependency retained an independent prognostic impact on survival in a multivariable analysis adjusted for DIPSS categories [7]. This evidence led to a refinement of this scoring system (DIPSS Plus) incorporating transfusion status [8]. Taken together, these evidences clearly prove the relevance of anemia and RBC transfusion-dependency, as a surrogate of severe anemia, in patients with myeloid neoplasms. Several components likely concur to the negative impact of severe anemia and transfusion-dependency on the clinical outcome. It has been recently suggested that the presence and severity of anemia in both myelodysplastic syndromes and primary myelofibrosis signify a clonally advanced and biologically more aggressive disease, and that this is the primary reason for the negative prognostic impact of anemia in these diseases [9]. This is probably true for primary myelofibrosis but does not explain the increased risk of non-leukemic death observed in transfusion-dependent MDS patients. In our opinion this latter risk is related to the detrimental effect of chronic anemia per se and to the organ dysfunction that can result from transfusion iron overload in low risk MDS patients [10]. Chronic anemia is known to be associated with increased morbidity and mortality in community-dwelling older adults and patients with chronic heart failure [11]. A high prevalence of co-morbid diseases has indeed been reported in MDS patients, cardiac disease representing the most frequently observed comorbidity and the main causes of non-leukemic death (NLD) [12]. In MDS, extra-hematological comorbidity is known to affect the eligibility to allogeneic stem cell transplantation as well as the outcome of the procedure [13]. Recently, by combining the effect of five comorbidity factors, we developed a dynamic MDS-specific Comorbidity Index (MDS-CI) that proved to be able to identify three groups of MDS patients with different probability of non-leukemic death and survival. In low-risk patients, in whom non-leukemic death represents the leading cause of death, comorbidity affects the natural history of MDS directly increasing the risk of death by negatively interacting with anemia [12]. Finally, transfusion-dependent patients invariably develop secondary iron-overload. Serum ferritin was found to independently affect survival of transfusion-dependent patients [2], and parenchymal iron deposits were demonstrated in patients with long-lasting transfusion history [14]. However, no prospective data are available to elucidate whether iron loading may concur to the negative prognostic impact of transfusion-dependency in MDS. In this issue of the American Journal of Hematology, Pereira and coworkers [15] report an interesting study aimed at investigating the relative value of RBC transfusion burden and intensity of transfusion requirement in patients with MDS by using a comprehensive statistical approach including Cox regression models with time-dependent covariates, and a multi-state model recapitulating the natural course of the disease. The results of this study confirm the relevant impact of transfusion-dependency on the outcome of MDS patients, evaluated as a combined endpoint of death or progression to acute myeloid leukemia, and substantiate the critical role of anemia and transfusion-dependency in the prognostic assessment of MDS patients. However, despite the large evidence supporting the incorporation of transfusion-dependency in determining the prognosis of patients with myeloid neoplasms, several controversies remain to be solved. The first is to work out a reliable and widely-agreed definition of transfusion-dependency, which is important not only for prognostic assessment but also for defining response in clinical trials of therapy-interventions. The International Working Group (IWG) in MDS in 2006 proposed RBC transfusions given for hemoglobin values of 9.0 g/dL or less as clinically relevant transfusion-dependency [16]. However, the frequency of RBC-transfusions and the minimal surveillance period were not specified. In the WPSS study, we found that even patients with a minimal but regular RBC transfusion need (i.e. less than one RBC unit per month) had a worse outcome, and defined RBC-transfusion-dependence as receiving at least one RBC transfusion every 8 weeks over a surveillance period of 4 months [3]. The International Working Group for Myelofibrosis Research and Treatment defined RBC-transfusion-dependency in patients with MPN-associated myelofibrosis as receiving two or more RBC units for 28 days for a hemoglobin lower than 8.5 g/dl [17]. More recently, a consensus conference using structured expert-panel consensus techniques identified an average transfusion volume of two RBC units per month over a three-month interval to be the most appropriate frequency of transfusions to define a person as RBC-transfusion-dependent [18]. Finally, in the refined DIPSS (DIPSS Plus) the actual number of transfusions was not considered in labeling a patient transfusion dependent or not [8]. The second critical issue in the use of transfusion-dependency and -independency is how to measure transfusion needs and its variation in time. Several parameters have been considered but none is adequate. Pre-transfusion hemoglobin levels are considerably influenced by transfusion strategy and do not reflect the true patient hemoglobin value. The total number of transfusions is an easily quantifiable parameter; however it strongly depends on the duration of follow-up that may confound the proper estimate of its prognostic value. The study by Pereira and colleagues [15] confirm that the intensity of transfusion requirement is probably the most reliable measure of the prognostic effect of transfusion-dependency and largely accounts for most of the prognostic strength of transfusion-dependency. Nevertheless, some concern remains on how this intensity should be calculated. These critical issues strongly sustain additional studies aimed at recognizing the clinical variables concurring to the prognostic value of transfusion-dependency, and at integrating them in the prognostic assessment of patients with MDS. Several factors may influence an individual patient transfusion program and contribute to inter-subject variation in transfusion needs. These include age, sex, baseline hemoglobin level, rate of hemoglobin decrease, performance status, extra-hematological comorbidity. An objective assessment of comorbidity and the identification of age- and sex-specific clinically relevant hemoglobin thresholds appear to be key steps to make the assessment of the prognostic value of anemia and transfusion-dependency in myeloid neoplasms more objective.