Management of Myelodysplastic Syndromes: Just the Beginning

Drs. Scott and Estey provide an excellent, concise review of current diagnostic and therapeutic approaches for patients with myelodysplastic syndromes (MDS). Both physicians are recognized world leaders in this area. They start their article by reviewing current diagnostic and prognostic classifications of MDS from the initial French-American-British schema, the World Health Organization (WHO) classification, the International Prognostic Scoring System (IPSS), and the most recent WHO Classification-Based Prognostic Scoring System (WPSS) proposal. We agree that most of these classifications have limitations, including the need for subjective manual quantification of blast percentage and morphologic categorization of disease subtype.

Prognostic Issues

In our experience, very few patients are referred to our center with an initial diagnosis based on WHO criteria. Currently at M.D. Anderson Cancer Center (MDACC), we make our therapeutic decisions based on IPSS score,[1] dividing patients into lower-risk (low and intermediate-1) and higher-risk disease (intermediate-2 and high). We favor that classification because it provides information on the natural history of the disease from a group of patients who had not received any prior meaningful therapy. That said, the IPSS score has several major limitations, the most important of which is probably the fact that is not a good tool for predicting prognosis of patients with lower-risk disease. This is important as approximately two-thirds of MDS patients are in that category.

To study this issue, we analyzed the outcomes of a large cohort of patients with lower-risk disease who were referred to MDACC. We developed a simple model that includes age, hemoglobin levels, platelet count, abnormal cytogenetics, and percentage of blasts to predict the overall survival of patients with lower-risk MDS.[2] Survival could range from no median survival in a group of patents with very low risk (mainly younger patients who are transfusion-independent) to a subset of patients with a survival of less than 24 months. Close to 80% of patients were in a higher risk category.

The second finding from this analysis was the fact that a large majority of patients died without having progressed to acute myelogenous leukemia (AML), with the most frequent causes of death being infections and bleeding episodes. This strengthens the notion of the need to develop therapeutic interventions for patients with “early-stage” MDS, the same way we initiate therapy in early chronic phase chronic myelogenous leukemia (CML) without waiting for transformation to accelerated phases.

The main limitation of our analysis is that the study was restricted to patients referred to MDACC and that survival was computed from time to referral and not from initial diagnosis. Nevertheless, this tool is important for tertiary care centers such as the Fred Hutchinson Cancer Research Center. It also should be noted that this new low-risk model was recently validated, in part, by German investigators.[3]

Treatment Issues

In the second section of their article, the authors review current supportive and therapeutic measures in MDS. Although we agree with most of the data presented, some points warrant further discussion. First, we do not completely agree that asymptomatic patients with stable blood counts should simply be observed. Data discussed above indicate that a significant fraction of patients with lower-risk disease would benefit from earlier treatment of their disease if a nontoxic effective therapeutic approach existed.

Such intervention does not currently exist but needs to be developed in clinical trials. Examples at our center could include the use of oral or very low-dose schedules of hypomethylating agents and single-agent use of histone deacetylase inhibitors such as vorinostat (Zolinza) or LBH589. We recommend participation on clinical trials to all patients with MDS who are referred to MDACC. (A complete list of MDS trials at MDACC can be obtained at http://www.mdanderson.org/diseases/mds/.)

We agree that data on monitoring, transfusion thresholds, and use of chelating agents is controversial. However, data on both combination growth factors and iron chelation therapy suggest that these strategies may have an impact on overall survival in patients with very low risk.[4,5] We fully agree that randomized clinical trials are needed to prove the role of both interventions, particularly the growth factor combination for patients early in their disease course and chelation for patients with anticipated long survivals who are heavily red cell transfusion-dependent. Indeed, only a minority of these patients will be candidates for supportive care only. In view of the expected low toxicity from these agents, we think that is generally reasonable to administer them.

Other Therapeutic Options

Two other alternatives exist for patients with lower-risk disease. One includes the use of immunomodulatory approaches such as ATG (Atgam, Thymoglobulin) and cyclosporine combinations, and the other, the use of thalidomide derivates such as lenalidomide (Revlimid). In terms of our experience with ATG, our data are consistent with findings from Mufti et al in London, where most patients who benefited had hypoplastic MDS independent of DR15 positivity.[6] In an ongoing MDACC study of rabbit ATG with cyclosporine, most responses have been observed in patients with aplastic anemia. Therefore, we only recommend ATG-based therapy for older patients with hypoplastic MDS or younger patients without a donor for allogeneic stem cell transplantation (alloSCT).

The role of lenalidomide is clearer. In our opinion, this drug should be used in patients with anemia and a chromosome 5 alteration without significant thrombocytopenia early in the course of their disease. Lenalidomide has remarkable activity in this setting. Outside of this, we still consider its use for lower-risk non-del5q MDS or higher-risk del5q to be investigational. New schedules, agents (ie, CC11006), and combinations (with growth factors or azacitidine [Vidaza]), are already being explored in this population.

Advanced Disease

Other therapeutic alternatives mainly benefit patients with more advanced disease. The most important development in recent years has been the use of hypomethylating agents (azacitidine and 5-aza-2′-deoxycitidine). Data presented by Fenaux et al at the 2007 annual meeting of the American Society of Hematology (ASH) from a randomized phase III study of azacitidine vs other traditional modalities (low-dose cytarabine, “7+3,” or supportive care) clearly indicated that azacitidine has a significant impact on the survival of patients with higher-risk MDS.[7] The results from a similar survival study using 5-aza-2′-deoxycitidine will be presented at the 2008 ASH meeting.

Another important issue is whether one hypomethylating agent is better than the other. No comparative trial has been performed to answer this question, so no recommendations can yet be made.

Intensive Chemotherapy and Stem-Cell Transplant

Finally, we believe that there is currently very little role for intensive chemotherapy approaches and a limited role for alloSCT in MDS patients. Intensive chemotherapy should be restricted to younger patients, probably those with diploid cytogenetics. Treating older patients with complex karyotypes is associated with a high rate of therapy-related mortality and treatment failure, and a short duration of response. At MDACC we do not use any intensive chemotherapy approaches for such patients.

The role of alloSCT is also complex. Although it is the only potential curative approach, a large majority of patients with MDS are disqualified because of age and associated comorbidites, or a lack of related donors or insurance (ie, Medicare in Texas does not cover it), with only a small fraction of patients being transplanted. As discussed in the article by Scott and Estey, data from Cutler et al have indicated that transplanting “early” in MDS may not be associated with longer survival despite worse alloSCT outcomes when delaying the procedure.[8] Therefore, timing of transplantion (later rather than early) and knowledge of donor availability and financial status are fundamental when considering alloSCT. In our practice, most patients who opt for alloSCT tend to be young and have higher-risk disease.

Just the Beginning

We agree that tremendous progress has been made in MDS over the past 10 years. These include the development of new classifications, lenalidomide, hypomethylating agents, and new transplant modalities. However, the outcome of patients with this complex group of disorders is still very poor, and it is unclear whether many of the current approaches have an impact on overall survival. Significant problems still exist, including the development of new therapeutic alternatives for patients with non-del5q MDS and lower-risk disease. These could include some of the options mentioned above as well as the development of new thrombomimetic agents and perhaps low-intensity transplant modalities for patients with a predicted poor prognosis.[2]

The second current major problem is the treatment of patients who have progressed on or not responded to hypomethylating agent–based therapy. At the current time, no such intervention is approved in the United States, but we are in desperate need of such an agent. Initial studies with nucleoside analogs such as clofarabine (Clolar) or sapacitabine may be important leads.

Finally, although the hypomethylating agents are the first group of drugs to benefit a large fraction of MDS patients and to offer a survival advantage (pending publication of the Fenaux data[7]), it is clear that these agents are not curative and that more potent agents or combinations are needed. Perhaps the use of combination epigenetic approaches (hypomethylating agent and a histone deacetylase inhibitor), oral formulations, or upfront use of agents such as clofarabine or sapacitabine may assume that role. That said, their development is going to be arduous and will need to be compared to current standards of care.

Conclusions

In summary, we believe that there is probably no standard of care for most patients with MDS and that patients should be offered some form of investigational approach. The use of modern classification will help in making that decision, and the study of molecular features of this complex group of disorders will lead to the identification of targets for specific subsets of patients. In a way, we are in a situation similar to the pre-imatinib (Gleevec) era in CML.

-Hawk Kim, MD
-Guillermo Garcia-Manero, MD

References:

References

1. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997.
2. Garcia-Manero G, Shan J, Faderl S, et al: A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia 22:538-543, 2008.
3. Kuendgen A, Gattermann N, Germing U: Improving the prognostic evaluation of patients with low risk myelodysplastic syndrome. Leukemia June 12, 2008 (Epub ahead of print).
4. Jadersten M, Malcovati L, Dybedal I, et al: Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol 26:3607-3613, 2008.
5. Rose C, Brechignac S, Vassilief D, et al: Positive impact of iron chelation therapy (CT) on survival in regularly transfused MDS patients. A prospective analysis by the GFM. Blood 110:249, 2007.
6. Lim ZY, Killick S, Germing U, et al: Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 21:1436-1441, 2007.
7. Fenaux P, Mufti G, Santini V, et al: Azacitidine treatment prolongs overall survival in higher risk MDS patients compared with conventional care regimens: Results of the AZA-001 phase III study. Blood 110:250a, 2007.
8. Cutler CS, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104:579-585, 2004.