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Pathophysiology of Myelodysplastic Syndromes and Treatment Strategies to Change its Natural History

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE - Viewpoint based on presentations from the Toronto Myelodysplastic Syndromes Symposium: Progress and Challenges

Toronto, Ontario / May 21-22, 2009

Reviewed and edited by:

Rena J. Buckstein, MD, FRCPC

Head, Hematology Site Group, Co-Director, MDS Research Group, Odette Cancer Centre, Sunnybrook Health Sciences Centre

Assistant Professor of Medicine, University of Toronto, Toronto, Ontario

Myelodysplastic syndrome (MDS) is a heterogeneous oncological disorder resulting in abnormalities in the blood or bone marrow, which range in clinical severity and in risk of an adverse outcome. The World Health Organization has defined six major classifications of MDS organized by blood and marrow findings. However, risk of adverse outcomes is not only defined by classification but also by a variety of other patient characteristics (such as the number of cell lines reduced) and measures of disease severity (such as red cell transfusion dependence). Importantly, the recent progress in understanding the pathophysiology of specific types of MDS has been reinforced by the identification of effective therapies active in molecular pathways suspected of driving disease.

According to Dr. Mikkael Sekeres, Cleveland Clinic Foundation, Ohio, progress in understanding the abnormalities that define the specific types of MDS has been exponential in recent years. In his focus on the current indications for the oral immunomodulatory agent lenalidomide in MDS, he described a series of pharmacologic effects, including suppression of the 5q clone, that have been consistent with the clinical activity documented in controlled trials. He described lenalidomide as a good demonstration of the intersection of therapeutic development in MDS with a growing body of pathobiologic knowledge. On the basis of the clinical trials, lenalidomide has been approved in Canada and the US for the treatment of MDS with chromosome 5q deletion (del 5q). Although del 5q has a relatively indolent course, its association with severe anemia can produce transfusion dependence which, in itself, is associated with reduced survival in low-risk patients and an increased likelihood of progressing to acute myeloid leukemia (AML).

Altering Disease Course

The most significant contribution of lenalidomide may be its ability to eliminate the need for transfusion in about two-thirds of transfusion-dependent del 5q MDS patients. This was an important result in an influential phase II study (List et al. N Engl J Med 2006;355:1456-65). To contextualize these findings, Dr. Sekeres carried out a meta-analysis looking at 20 years of published literature and found that transfusion independence was achieved on average in only 31.4% of patients. The 67% rate of transfusion independence in the phase II trial represented more than a doubling of what had been achieved previously (Table 1). Additionally, these patients had a mean rise of 5.4 g/dL in hemoglobin and a median duration of response of 2.2 years.

Table 1.


While it is not curative in the del 5q patient population, lenalidomide did demonstrate a disease-modifying effect by inducing a cytogenetic improvement in 73% of patients (i.e. in those who could be cytogenetically analyzed) with implications for survival.

In the study by List et al., estimated survival at 10 years is 75% for responders to lenalidomide vs. 4% for those who do not respond. Similarly, the predicted freedom from AML at 10 years was 85% vs. 33% for non-responders, further reinforcing evidence that it may change the course of disease.

In the non-del 5q population, Dr. Sekeres presented data showing lenalidomide delivered 26% transfusion independence (consistent with results of the meta-analysis) for a duration of 41 weeks (Raza et al. Blood 2008;111(1):86-93).

The criteria for defining more advanced disease may be evolving based on risk stratifications presented by Dr. John M. Bennett, University of Rochester Medical Center, New York. He noted that although cytogenetics is a criterion for the International Prognostic Scoring System (IPSS) method of risk stratification, appreciation for other important prognostic factors has led to an initiative to revisit the methodology for risk assessment. For example, he noted that any transfusion, even as little as a single unit per month, is associated with an adverse effect on survival. He anticipated that such factors would be incorporated in a new and more precise prognostic scoring system that is expected next year.

First Findings on Improved Survival in Higher-risk MDS/AML

In higher-risk MDS, the most significant recent advance has been documented in a publication of a phase III multicentre study that associated the hypomethylating agent azacitidine with a survival benefit (Fenaux et al. Lancet Oncol 2009;10:223-32). Conducted in 358 patients with IPSS intermediate-2 or high-risk MDS including WHO-defined MDS/AML, it is the first study to associate any chemotherapy with an overall survival benefit in higher-risk MDS/AML (24.5 vs. 15 months). The 9.4-month improvement in median survival at a median of two years of follow-up generated a hazard ratio (HR) of 0.58, indicating a 42% risk reduction (95% CI, 0.43-0.
e 1).

Figure 1.

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There was also an improvement in the time to leukemia in the patients who received azacitidine compared with best supportive care (26.1 vs. 12.4 month; P=0.004). In this landmark study, higher-risk MDS patients were randomized to receive either azacitidine or conventional care (best supportive care, low-dose cytarabine or intensive chemotherapy as selected by investigators before randomization). Azacitidine is a drug of interest in MDS because hypomethylation may restore normal expression of genes that are critical to differentiation and proliferation.

In an overview of the azacitidine study, Dr. Lewis R. Silverman, Mount Sinai School of Medicine, New York, New York, identified a number of interesting findings that may provide insight into the activity of this agent. One of the most striking was that responses continued to accrue over a far longer period than is typical with conventional chemotherapy, with some patients still developing a complete remission (CR) 12 or more months after initiating therapy. Moreover, CR, which was achieved in 17% of patients, was not necessary for benefit. Indeed, 45% of patients achieved transfusion independence on azacitidine compared with 11.4% on conventional care. Independent of CR status, azacitidine is the first agent to demonstrate an improvement in survival in higher-risk MDS patients.

Expanding the Role of Iron Chelation Therapy

On the basis of current evidence, 10 out of 10 guidelines now recommend iron chelation therapy (ICT) in selected MDS patients, according to Dr. Heather A. Leitch, Division of Haematology, St. Paul’s Hospital, University of British Columbia, Vancouver. However, there is still limited availability in parts of Canada.

ICT was introduced because of the abundant indirect evidence that iron overload is associated with a poor prognosis, including reduced survival in MDS. In patients who receive red blood cell (RBC) transfusions, iron overload is essentially inevitable because it leads to saturation of transferrin, the major transporter of iron. Serum ferritin levels >1000 ng/mL decrease overall survival (Figure 2). For every increase of 500 ng/mL above 1000 ng/mL, the hazar
eases by 30% (J Clin Oncol 2005;23(30):7594-603).

Figure 2.

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Clearing excess iron with ICT has a broad number of expected benefits on organs sensitive to iron, including the heart, but the indication for ICT may be increasingly based on hypothesized survival benefits. Despite the large number of factors that influence MDS survival, including the transfusions that contribute to iron overload, improved rates of survival have now been attributed to ICT in several retrospective case-control clinical studies.

In a retrospective evaluation of 178 MDS patients at St. Paul’s Hospital, the four-year survival of 18 low or intermediate-1 IPSS patients who received ICT was 64% vs. 43% (P=0.003) for those who did not. In another study that evaluated 165 MDS patients, median survival was 115 months from time to diagnosis in chelated patients but 51 months in non-chelated patients (P<0.0001) (Rose et al. Blood 2007;110(11): Abs 249). After adjusting for other prognostic parameters, the median overall survival in those with an IPSS of 0 was not reached in chelated patients but was 69 months in non-chelated patients (P=0.002). Limitations of these case-control studies include the potential for undetected biases favouring improved survival in chelated vs. the non-chelated patients that are independent of the “matched for” prognostic markers and age.

Current Canadian guidelines do not recommend ICT in all MDS patients, but there is a substantial benefit expected in those who are indicated for treatment (Wells et al. Leuk Res 2008;32:1338-53). Under Canadian guidelines, all candidates should be transfusion-dependent, have a serum ferritin >1000 mg/L and have a life expectancy of at least one year. Two specific groups are identified: MDS patients with a good prognosis such as low or intermediate IPSS score, and MDS patients with a higher score if they are candidates for allogeneic stem cell transplantation.

One of the developments that have greatly facilitated treatment of iron overload is the availability of the oral chelator deferasirox. Dr. Leitch indicated that oral chelator agents could alter the decision tree because of better acceptance by patients and ease of use. With other therapies emerging in MDS with the ability to prolong life, the potential yet unproven survival benefit associated with ICT becomes a more urgent concern. Once primarily listed among strategies within best supportive care to improve quality of life (QOL), ICT can be incorporated into a management goal of extending survival, contributing to other efforts to change the natural history of MDS.

The Complexity of Measuring QOL

The effects of therapies that can alter the natural history of MDS have important public health implications in an aging population. MDS demographics document a steep increase in the incidence of MDS starting at about age 65. Based on MDS incidence rates, which do not appear to vary substantially by country or geographic region, there might be as many as 10,000 Canadians living with MDS at present. The median age of diagnosis is 73. Due to the aging Canadian population, a substantial increase in the prevalence of MDS is anticipated even if the incidence rates remain unchanged. In the MDS population, most domains of QOL are impaired and symptoms of fatigue and dyspnea are increased compared to normative controls, and these are highly correlated with hemoglobin and transfusion dependence.

Recent efforts to weigh the costs of MDS therapy in relation to its effect on outcomes, including those involving QOL, indicate that likely much of the burden of MDS is underappreciated. For example, transfusion independently impairs physical and social functioning, it incurs global fatigue and it increases financial costs even before considering the impact on independent measures of QOL.

Data collection in order to evaluate the costs of medical care deserves to be conducted in a rational and objective manner of the type now being undertaken at Sunnybrook. Although access to therapies for MDS is granted in several Canadian provinces based on current data, it is not clear that all provinces are employing the same evidence-based approach. A uniform method for calculating the value of specific therapies is an essential task for fair distribution of limited funds.

Summary

The opportunities for improving outcome in MDS have been generated by a series of recent developments that suggest the potential to reduce transfusion requirements, lower the risk of AML transformation and prolong survival. Active therapies that reverse underlying cytogenetic abnormalities represent an important departure from past strategies. The potential to improve outcome places the importance of effective supportive care, including ICT, in a new context. The second of regularly held annual symposia on MDS throughout Canada will contribute to the task of documenting progress in this field. We expect future meetings to allow an assembly of active investigators from centres within and without Canada to exchange findings and insights.

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