Leukemia & Lymphoma

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Graphical representation of clinical outcomes for patients with myelodysplastic syndromes David P. Steensma To cite this article: David P. Steensma (2015): Graphical representation of clinical outcomes for patients with myelodysplastic syndromes, Leukemia & Lymphoma, DOI: 10.3109/10428194.2015.1061191 To link to this article: http://dx.doi.org/10.3109/10428194.2015.1061191

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Date: 09 November 2015, At: 02:40

Leukemia & Lymphoma, 2015; Early Online: 1–4 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1061191

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Graphical representation of clinical outcomes for patients with myelodysplastic syndromes David P. Steensma

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Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

listed as the sole cause of death in 35%, while post-MDS AML was the primary cause of death in 65% of the patients who had more than one coded diagnosis [3]. Causes of death in patients diagnosed with MDS include complications of blood cytopenias and functional blood cell defects: infections from neutropenia and granulocyte dysfunction, hemorrhage from thrombocytopenia and impaired platelet activity and ischemic events from chronic anemia [4]. Progression to secondary (post-MDS) AML represents another major MDS-associated cause of death [5] as, even among the sub-set of patients with secondary AML who are candidates for intensive therapy, long-term survival is ⬍ 10% [6]. In addition, repeated red cell transfusions for MDS-associated anemia can lead to iron overload, which may contribute to organ failure and possibly increase the risk of progression to AML [7]. Rarer causes of MDS-associated death include adverse effects of medications other than myelosuppression, non-iron-related transfusion reactions, accidents while traveling to medical appointments, iatrogenic clinical errors and complications of allogeneic stem cell transplant (SCT) such as graft-vs-host disease. Patients with therapyrelated MDS may still be at risk of relapse and death from the primarily neoplasm for which treatment induced MDS. Finally, because the median age at MDS diagnosis is in the early 70s, patients with MDS are susceptible to the broad range of causes of death that are common to geriatric populations and the presence of non-MDS co-morbid conditions is clearly associated with worse outcomes [8,9]. High-quality data on specific causes of death in large, unselected populations with MDS are scarce [10]. In addition, multiple factors can contribute to the death of an individual patient, making it difficult to identify a primary cause of death with certainty and requiring anyone representing MDS-associated causes of death graphically to make assumptions and estimates. Infection is usually cited as the most common cause of MDS-associated death and this fits with clinical experience, but only a few series have reported the specific frequency of infection. One of the earliest of these was an 86 patient Veterans Administration series, in which

Abstract The causes of death in patients with myelodysplastic syndromes (MDS) are diverse: infections, hemorrhage, complications of chronic anemia and repeated blood transfusions, and complications of progression to acute myeloid leukemia. Since most patients with MDS are diagnosed late in life, some individuals with MDS will succumb to an unrelated condition, such as one of the disorders that are common in geriatric populations. Currently, only a small proportion of patients with MDS – less than 5% – undergo allogeneic stem cell transplantation, a procedure that offers the only possibility of cure. This brief review summarizes outcomes for patients diagnosed with MDS using a pictographical format that illustrates both the challenges patients face and the pressing need for development of novel therapies, as well as highlighting the potential for increased use of allogeneic stem cell transplant. This informational graphic may be useful for teaching or in counseling certain patients. Keywords: Patient outcomes, myelodysplastic syndromes, infographic, stem cell transplantation, causes of death

Graphical representations allow complex information to be presented in a clear, easily understood format [1]. Trends or patterns are often easier to discern when numeric data are represented graphically, compared to presentation as lists or tables. Along these lines, the “infographic” depicted in Figure 1 may aid patients, family members, clinicians and policymakers in understanding the outcomes of patients diagnosed with myelodysplastic syndromes (MDS), as well as the critical need for additional research to improve matters. Most patients who are diagnosed with MDS will die because of the disease. In a registry study of 1056 patients with MDS in North-East Italy who died between 2008–2011, MDS was coded as the underlying cause of death in 41% of cases and MDS with progression to acute myeloid leukemia (AML) in 16% [2]. In a 2005–2006 US registry study of more than 28 000 deaths that included an MDS code, MDS was

Correspondence: David Steensma, MD FACP, Department of Medical Oncology, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, 450 Brookline Ave, D2037, Boston, MA 02215, USA. Tel: ⫹ 1 617 632 3712. Fax: ⫹ 1 617 582 7840. E-mail: [email protected] Received 22 May 2015; revised 30 May 2015; accepted 3 June 2015

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Figure 1. Causes of death in patients with MDS in the US, depicted as if all diagnosed patients were represented as 100 people. The four individuals who survive transplant for MDS or post-MDS AML and are cured of the disorder are depicted with gold boxes; they will eventually be added to the 29 who die of unrelated causes. Only ∼ 6% of patients (at most) undergo allogeneic SCT, of whom 30–40% are cured; most of the rest relapse, while some will die of GVHD or another SCT complication. Younger patients are more likely to be transplanted. As antimicrobial therapy has improved since the 1980s, older estimates of infectious death in 38–65% of patients may be higher than seen at present. Bleeding was the primary cause of death in 10% of patients in one MDS series, 13% in another and was a contributing factor to death in 14–24% in other series. In the international cohort used to derive the IPSS-R prognostic model, 24% of patients developed AML. The most difficult group to estimate accurately are those who die of cardiovascular causes or iron overload; some of those who die of “unrelated” causes may actually die of anemia-exacerbated vascular events. The proportion of patients in individual groups will vary in different populations. CVA, cardiovascular accidents; MI, myocardial infarction; MDS, myelodysplastic syndromes; AML, acute myeloid leukemia; GVHD, graft-vs-host disease; IPSS-R, Revised International Prognostic Scoring System; SCT, stem cell transplant. A version of Figure 1 was presented in oral format at the 13th International Symposium on Myelodysplastic Syndromes, Washington DC, April 29–May 2, 2015.

64% of patients diagnosed with MDS prior to 1986 died from infection, some of them after AML progression [11]. In a single-center series of 273 patients seen between 1980–2004 with lower-risk MDS as assessed by the International Prognostic Scoring System (IPSS) – patients with lower-risk disease represent ∼ 51% of all patients with MDS using the IPSS [12] – infection was the primary cause of death in 38%,

AML in 15% and hemorrhage in 13%. In another more recent series of 497 patients diagnosed with MDS, 15% developed an infection requiring hospitalization within 1 year of MDS diagnosis and bacterial pneumonia was the most commonly diagnosed infection [13]. In one series, bleeding was the primary cause of death in 10% of 460 patients with coded causes of death and was

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Graphical depiction of MDS outcomes 3 a contributor to death in 20%, while, in a literature review, the frequency of hemorrhagic events as a major contributor to death was reported to be 14–24% [14]. Cardiovascular events, to which anemia or iron overload may contribute, represented the most common “other” cause of death in these series. In patients with higher-risk disease, causes of death related to MDS and AML would be expected to represent a greater proportion of mortality. Among the International MDS Risk Assessment Workshop cohort of patients with de novo MDS used to derive the 1997 IPSS, 20% of 816 patients died of AML, while in the 2012 revised IPSS (IPSS-R), 24% of 7012 patients died of AML (13% in the lowest risk group, 33% in the highest risk group) [12,15]. The IPSS-R probably provides a better estimate, since the cohort used to derive IPSS-R was 8 times larger than the IPSS cohort. None of the patients used to derive the IPSS or IPSS-R received intensive chemotherapy followed by allogeneic SCT, which can salvage a few patients who develop secondary AML. The incidence of AML progression is likely to be considerably higher in those with therapy-related MDS, who were also excluded from the IPSS and IPSS-R. Although it is to some degree artificial to define an “MDS death” as distinct from an “AML death”, since these diseases represent a biological continuum, from a regulatory and statistical standpoint these entities are coded differently (e.g. on death certificates and in cancer registries). It is particularly difficult to assess the contribution of MDS to deaths adjudicated as due to cardiovascular disease. Cardiovascular disease has a very high prevalence in the general population and represents either the leading or second most frequent cause of death in most nations of the developed world. However, the exceptionally high frequency of cardiac deaths in some reported cohorts of patients with MDS (e.g. heart failure or arrhythmias represented 51% of non-MDS causes of death in a 467 patient series from Pavia, Italy [16]) suggests that at least a fraction of patients with MDS who die of cardiovascular causes would not have done so, or would have lived longer, if they did not have MDSassociated anemia. Similarly, it is challenging to accurately estimate the magnitude of risk from iron overload compared to competing disease-associated risks [7]. Iron loading of the myocardium to the degree that is associated with mortality in thalassemic populations is uncommon, even in heavily transfused patients with MDS [17], but iron could also contribute to death by other mechanisms: promoting leukemia progression (e.g. by initiating DNA mutations with redoxactive labile iron species), increasing infections with siderophoric organisms or making subsequent SCT less successful [18]. Conversely, even the finding of high concentrations of iron in an organ such as the heart at autopsy does not mean that the iron contributed to death. It is unclear how chelation therapy modifies survival in MDS; no prospective studies have yet shown a survival benefit and retrospective studies are confounded by patient selection bias [19]. The only potentially curative therapy for MDS is allogeneic SCT [20]. Reports from the Center for International Blood and Marrow Transplant Research (CIBMTR) indicate that ∼ 1000 patients per year undergo SCT for MDS or myeloproliferative neoplasms (MPN) in the US and long-term survival

now exceeds 30–40% [21]. This represents ∼ 6% of those diagnosed with MDS or MPN using estimates from the Survey, Epidemiology and End Results (SEER) database [22]. However, if the annual incidence of MDS in the US is actually closer to 30 000–35 000 patients per year – a reasonable estimate derived from combining registry data with claims-based data [23–25] – and 20% of the 1000 transplants per year for MDS/MPN are for MPN, then only ∼ 2% of patients with MDS undergo SCT and Figure 1 would look even more dire. The proportion of patients with MDS who undergo transplant is likely to be even smaller outside the US. These data and their graphical representation highlight the grim outcome for most patients diagnosed with MDS, the need for research into disease pathobiology and the urgency of development of novel therapies [26]. The data also highlight the potential for greater use of allogeneic SCT, which increases cost and risk, but may also augment the number of long-term survivors of MDS and secondary AML [27]. Outcomes for allogeneic SCT among older patients are improving and many centers now routinely perform unrelated donor allogeneic SCT for selected patients with MDS or AML up to age 70–75 [28,29]. However, some patients with MDS who might be eligible for SCT are never referred to a transplant center because of clinical inertia, lack of education of referring physicians or economic concerns [30,31]. Other barriers to greater use of transplant for MDS include lack of a suitable donor and fear of the risks of transplant or the effect of SCT on lifestyle [32,33]. Regardless, outcomes associated with an MDS diagnosis are currently poor and new approaches are needed. Potential conflict of interest: Disclosure forms provided by the author are available with the full text of this article at www.informahealthcare.com/lal

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Graphical representation of clinical outcomes for patients with myelodysplastic syndromes.

The causes of death in patients with myelodysplastic syndromes (MDS) are diverse: infections, hemorrhage, complications of chronic anemia and repeated...
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