Incremental Gains and a Long Road Ahead in MDS

Since the topic of risk-stratified management of patients with myelodysplastic syndromes (MDS) was last reviewed in ONCOLOGY in 2007,[1] a few additional clinically relevant studies have emerged that can help inform decision-making in the consultation room.

The most widely publicized MDS clinical trial result of the past year was the first report of the AZA-001 study, which enrolled 358 patients with higher-risk MDS and was presented at the American Society of Hematology annual meeting in December 2007.[2] A 9-month survival advantage (24 vs 15 months) was observed with azacitidine (Vidaza) compared to conventional care (ie, mostly supportive therapy with transfusions). This represented the first time a drug therapy has been associated with improved life expectancy in a subset of patients with MDS. It is not yet known whether decitabine (Dacogen) administered on an optimal schedule is associated with a similar survival benefit in higher-risk patients, or whether lower-risk MDS patients also obtain a survival benefit from azacitidine.

Prognostic Parameters

Although all recent clinical trials in MDS have used the 1997 International Prognstic Scoring System (IPSS)[3] to stratify patients into risk groups, the limitations of the IPSS are now well recognized. Drs. Scott and Estey mention two variables that have been reported to offer IPSS-independent prognostic information in MDS: red cell transfusion requirement[4] and flow cytometric findings.[5,6] Other easily obtainable prognostic parameters include the absolute lymphocyte count,[7] serum lactate dehydrogenase level,[8] marrow cellularity,[9,10] and a long list of recurrent MDS-associated cytogenetic abnormalities that were not included in the IPSS but were recently enumerated by a German-Austrian consortium.[11] Newer molecular techniques such as single nucleotide polymorphism arrays (SNP-A) may offer additional insight into gene copy-number variation and loss of heterozygosity, and preliminary reports suggest such information may have prognostic value in MDS in patients with normal karyotypes.[12,13]

Ongoing Debates

Scott and Estey nicely summarize some of the evolving safety concerns with the erythropoiesis-stimulating agents (ESAs) epoetin alfa (Epogen, Procrit) and darbepoetin (Aranesp) in cancer-associated anemia, including the uncertainty regarding the safety of these agents in MDS. Retrospective studies have suggested the relative safety of ESAs in MDS, but retrospective data can be misleading, and only prospective studies can answer these important questions definitively. One of the few prospective controlled studies of ESAs in MDS already conducted-the Eastern Cooperative Oncology Group E1996 trial-was presented in abstract form in 2004[14] but has not yet appeared in a peer-reviewed journal. Although we still await final publication of these data, the E1996 results seem unlikely to resolve anything, as the study enrolled only 105 patients and employed a crossover design that may obfuscate any changes in long-term survival with ESA use. Additional trials will be required.

Several studies in the past year have called into question the likelihood that iron chelation therapy provides meaningful clinical benefit to patients with MDS.[15-18] As Scott and Estey state in their review, the role of iron chelation therapy in MDS is currently one of the most controversial areas in clinical practice.[19] Because iron chelation is costly and can cause serious adverse events, and because evidence for benefit is scant, we feel that the burden of proof of a favorable risk-benefit ratio has not yet been met. Until further data emerge, iron chelation should be used only in exceptional cases, such as patients with “pure” sideroblastic anemia (ie, no dysplasia in nonerythroid cells, no excess blasts, and a normal karyotype), who have a very long life expectancy yet may be transfusion-dependent for many years. A high serum ferritin level also clearly portends a poorer prognosis in patients undergoing allogeneic stem cell transplantation, but whether iron chelation can modify that outlook is unknown.[20]

Another challenge in caring for patients with MDS is knowing which patients to refer for allogeneic stem cell transplantation and, once the decision to undertake a transplant has been made, how best to prepare the patient for this procedure. The roster of patients eligible for transplant is expanding, as is the repertoire of available pretransplant treatments. These are encouraging developments, but they raise many new questions. All of us have our own biases, and since randomized trial data of transplant strategies in MDS are almost nonexistent, there is a great deal of work to do to clear up our collective thinking. Drs. Scott and Estey work at the busiest stem cell transplantation center in the United States, so these difficult decisions are very familiar to them.

Final Considerations

Despite recent incremental advances, fundamentally the outlook for most patients with MDS remains grim and has not substantially improved in the past 2 decades. This is especially true for elderly patients and for those with secondary, treatment-related MDS. We do not mean to minimize the striking responses seen in some patients with the three US Food and Drug Administration–approved MDS therapies (azacitidine, decitabine, and lenalidomide [Revlimid]). Moreover, we recognize that allogeneic stem cell transplantation plays an expanding role in MDS management and is sometimes curative. Yet the bleak fact is that most patients with MDS still do not obtain any meaningful benefit from existing therapies and will die of complications of the disease.

Only a minority of patients with MDS are referred to tertiary centers, and an even tinier proportion are enrolled in clinical trials. Until we obtain a better understanding of MDS pathobiology and come up with systematic solutions to improve trial accrual, this difficult situation is not likely to improve.

-David P. Steensma, MD
-Ayalew Tefferi, MD

References:

References
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2. Fenaux P, Mufti GJ, Santini V, et al: Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional care regimens (CCR): Results of the AZA-001 phase III study (abstract 817). Blood 110:250a, 2007.
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18. Chee CE, Steensma DP, Wu W, et al: Neither serum ferritin nor the number of red blood cell transfusions affect overall survival in refractory anemia with ringed sideroblasts. Am J Hematol 83:611-613, 2008.
19. Tefferi A: Iron chelation therapy for myelodysplastic syndrome: If and when. Mayo Clin Proc 81:197-198, 2006.
20. Armand P, Kim HT, Cutler CS, et al: Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 109:4586-4588, 2007.