Standard antileukemic
chemotherapy induces complete remission in approximately half of patients with high-risk (HR)
myelodysplastic syndrome (MDS). Intensification of induction
therapy by the use of intermediate- or high-dose
cytosine arabinoside in combination with
fludarabine,
idarubicin, or
topotecan seemingly improved complete response (CR) rates, particularly in patients with poor prognosis karyotypes. The various high-intensity regimens appear to be comparable in inducing CR, although some are better tolerated with low mortality even in advanced-age populations with MDS. The encouraging early results with new agents, eg,
topoisomerase inhibitors (
topotecan) and hypomethylating agents (5-azacytidine), have been disappointing because long-term follow-up has shown continuous relapses. Regardless of the intensity of
chemotherapy, remissions are short, even with continuation of intensive postremission
therapy. Long-term disease-free survival remains dismal. In a large population with HR MDS treated with high-dose
chemotherapy, only 5% of patients were alive at 3 years, and a majority of survivors were the younger patients with diploid karyotype
refractory anemia with excess blasts in transformation. Further intensification of either
induction chemotherapy or postremission
therapy is unlikely to improve results with current
drug combinations. With these results at hand, the role of intensive
chemotherapy in the management of MDS remains controversial. Because CR status is associated with clinical benefits and possibly better survival, induction of CR should remain an important aim for HR MDS. The intensive
combination chemotherapy may be integrated as an initial part of the management of HR MDS, as an alternative for patients not eligible for allogeneic
bone marrow transplantation (BMT). Regimens with low early mortality, eg,
topotecan plus intermediate dose
Ara-C, could also be used to reduce
tumor load prior to allogeneic BMT. Induction of CR should be attempted with the most effective and best tolerated regimens, particularly, but not only, in younger patients with good performance status regardless of karyotype. Postremission
therapy remains a major challenge. It should involve either allogeneic BMT or investigational approaches to eliminate or control the
minimal residual disease with different mechanisms In elderly patients, allogeneic "minitransplant" is an investigational alternative seeking to exploit graft-versus-
tumor reaction. New agents, such as farnesyl
transferase inhibitors (ras inhibitors),
drug-antibody conjugates (Myelotarg),
thalidomide,
arsenic trioxide,
maintenance chemotherapy with hypomethylating agents, or oral
topoisomerase inhibitors along with agents modulating factors affecting growth and differentiation, should be explored to maintain remission with minimal compromise of quality of life. Although prognostic scoring systems such as the new International Prognostic Scoring System (IPSS) do not predict for initial response, IPSS continues to predict survival in patients treated with high-dose
chemotherapy. Although activity of new agents could be rapidly assessed in single-arm pilot studies, the final merit of high-dose
chemotherapy could be assessed only in well-designed randomized trials with patients assigned according to risk-based classification and evaluated for response by generally accepted and standardized criteria.