The treatment of MDS is dictated by the risks imposed by the disease, age, and patient preference. Suggested guidelines are outlined in Table 6 and discussed later in this chapter.
The use of transfusions affords temporary benefits and is an alternative that can be considered in patients with lower-risk MDS or that otherwise can be used in conjunction with more definitive therapy. To delay or prevent end-organ complications, chelation therapy could be considered when RBC transfusions exceed 25 U or ferritin levels > 1,000 to 2,500 ng/mL. Recent reports suggest that the use of chelation or growth factors may be associated with improved survival but this needs confirmation in randomized clinical trials.
G-CSF and GM-CSF Granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim), [Neupogen]) or granulocyte-macrophage colony-stimulating factor (GM-CSF) may improve neutropenia and decrease infections in up to 70% of patients with MDS, but the effect is usually transient. No increase in the probability of developing AML has been demonstrated with extended use of these cytokines.
Antithymocyte globulin (ATG) has been associated with response (defined as independence from transfusions) in 34% of patients, which was sustained for a median of 36 months in 81% of them. Also, 48% had sustained platelet improvement and 55% had an increase in neutrophils. Younger patients are more likely to respond than older patients.
A simple method for predicting response to immunosuppressive therapy in MDS has been proposed. It is based on the age of the patient, the duration of RBC transfusion dependence, and the HLA (human lymphocyte antigen)-DR15 status. Younger patients with a shorter duration of transfusion requirements have a higher predicted probability of response (40% to 100%), particularly when their status is positive for HLA-DR15. A subsequent validation study showed that age < 60 years is the most powerful predictor for response to ATG.
Cyclosporine significantly increases cell–colony growth in laboratory studies of hypoplastic RA. Responses have been reported in a limited number of patients.
Lenalidomide Lenalidomide (Revlimid) is a thalidomide(Drug information on thalidomide) analog that belongs to the immunomodulatory family of drugs. Lenalidomide has numerous properties that make it attractive for the management of neoplastic and inflammatory conditions, including the inhibition of production of cytokines such as tumor necrosis factor-α (TNF-α), IL-1, IL-6, IL-10, and IL-12. Lenalidomide is markedly more potent than thalidomide (Thalomid) in inhibiting the secretion of TNF-α. In addition, lenalidomide may potentiate erythropoietin(Drug information on erythropoietin)-induced signaling in erythroid progenitors and stimulate stem–cell differentiation to erythroid cells.
Lenalidomide has been approved for the treatment of patients with MDS with abnormalities in the long arm of chromosome 5 (5q− abnormalities), whether they are isolated or present together with other cytogenetic abnormalities. In a study of patients with transfusion-dependent MDS with 5q− abnormalities, 75% of patients responded, with 66% of the total population becoming transfusion-independent. The response rate was similar regardless of whether the cytogenetic abnormality was isolated or seen in conjunction with other cytogenetic abnormalities, and more than half of the responses were durable for more than 1 year. In addition, a cytogenetic response was observed in 70% of patients. Lenalidomide has also been investigated for patients with MDS without 5q− abnormalities. Erythroid responses were seen in over 40%, with 27% of the total population becoming transfusion- independent.
Azacitidine (Vidaza) and 5-Aza-2'-deoxycytidine (Dacogen, DAC, decitabine) are hypomethylating agents that have shown activity in MDS. In a randomized trial, 191 patients with MDS (63% RAEB or RAEB-t) were treated with azacitidine or supportive care. Responses were observed in 60% of those treated with azacitidine (complete response [CR], 6%; partial response [PR], 10%; hematologic improvement, 47%) compared with 5% with supportive care. There was a significant improvement in probability of transformation to AML and overall survival when the confounding effect of early crossover to azacitidine was eliminated.
Azacitidine is approved by the FDA for the treatment of patients with all types of MDS. The standard dose is 75 mg/m2/d subcutaneously for 7 days every 4 weeks for as long as the patient benefits. Responses occur after a median of 3 to 4 cycles, so it is recommended to continue therapy for at least 4 to 6 cycles, unless there is significant toxicity or progression of disease. The dose may be increased to 100 mg/m2/d after 2 cycles if no improvement has occurred. Myelosuppression may occur but is not a reason to discontinue therapy. Rather, patients should be supported during myelosuppression and should continue therapy to give them the best opportunity of response. In a post-approval phase III trial, treatment with azacitidine significantly improved survival by a median of 9 months (median survival, 25 months vs 15 months) compared with a conventional-care arm that included supportive care, low-dose cytarabine(Drug information on cytarabine), and conventional leukemia induction and consolidation therapy.
Decitabine is approved by the FDA for the treatment of patients with all types of MDS. In a multicenter phase II study, 66 patients (73% RAEB or RAEB-t) were treated with decitabine. The overall response rate was 49% (CR, 20%; PR, 4%; improvement, 24%). The actuarial median response duration was 31 weeks, and median survival was 22 months. In addition, 31% of patients with cytogenetic abnormalities presented before treatment achieved a cytogenetic response. Cytogenetic response conferred a survival advantage to these patients. However, in a post-approval phase III trial comparing treatment with decitabine to supportive care, decitabine yielded no survival advantage.
Recently, several studies combining decitabine or azacitidine with valproic acid (a histone deacetylase [HDAC] inhibitor) have shown success in MDS and AML but this needs to be demonstrated in randomized clinical trials.
Steroids, androgens, and pyridoxine(Drug information on pyridoxine) are rarely effective, although they are often used clinically.
The rationale for this strategy stems from the concepts that MDS is a clonal disorder and that MDS and AML are overlapping illnesses with an arbitrary frontier defined by the WHO and FAB classifications (ie, a 20%–30% blast threshold).
The CALGB treated 874 patients with AML and 33 patients with MDS with AML-like chemotherapy. The CR rate was 79% for patients with MDS vs 68% for patients with AML (P = .37), median CR duration was 11 vs 15 months (P = .28), and median survival was 13 vs 16 months. The authors concluded that the FAB distinction between MDS (RAEB and RAEB-t) and AML has minimal therapeutic implications.
Estey et al treated 372 patients with AML, 52 with RAEB, and 106 with RAEB-t with AML-type chemotherapy. CR rates were 62% for patients with RAEB, 66% for those with RAEB-t, and 66% for those with AML (P = .79). Event-free survival was significantly better for patients with AML/RAEB-t than for patients with RAEB. However, when cytogenetics and other prognostic variables were considered in a multivariate analysis, no difference in outcome could be identified among FAB subgroups.
These findings suggest that the prognosis is determined more by cytogenetics and other prognostic features than by the percentage of blasts or FAB classification. However, this finding does not necessarily mean that MDS and AML are biologically equivalent entities.
Combination regimens Different combination chemotherapy regimens have been investigated. The combination of cytarabine (Ara-C) and anthracycline is the cornerstone of intensive chemotherapy, leading to CRs in 40% to 60% of patients. However, despite the fact that cytogenetic remissions frequently accompany hematologic CRs, the median remission duration and survival times are brief, rarely exceeding 1 year. The death rate during induction therapy is 5% to 20%.
Myeloblasts in RAEB-t and secondary AML commonly express the multidrug exporter Pgp, which extrudes anthracyclines and limits their activity. A randomized, controlled trial performed by the SWOG reported a twofold improvement in survival for patients treated with an anthracycline- and Ara-C–containing induction and consolidation regimens with the Pgp antagonist cyclosporine added. It is possible that certain chemotherapeutic agents may be particularly useful in MDS.
Stem cell transplantation is a treatment option for some patients with MDS, although its timing remains controversial. An International Bone Marrow Transplant Registry analysis used a Markov model to examine three transplantation strategies for newly diagnosed MDS: transplantation at the time of diagnosis, transplantation at the time of progression to leukemia, and transplantation at an interval from diagnosis but prior to leukemic progression. Although transplantation at diagnosis may be superior for patients with intermediate-2 and high-risk IPSS scores, delayed transplantation was associated with improved life expectancy.
Allogeneic SCT can be of benefit in a subset of patients with MDS. However, most series have concentrated on younger patients, who constitute a minority of patients with MDS and frequently have favorable cytogenetics and therefore a better prognosis. The best results to date have been reported in patients with a better prognosis (ie, those with RA/RARS). In most series, allogeneic SCT is associated with a long-term remission rate of approximately 40%, a relapse rate of 30%, and a rate of transplant-related death of 30%.
The timing of transplantation remains controversial. Runde et al reported on a group of 131 patients (median age, 33 years; range: 2–55 years) who underwent allogeneic SCT as front-line therapy without prior induction chemotherapy. The 5-year disease-free survival rate was 34%, overall survival rate was 41%, and transplant-related mortality was 38%. The actuarial probability of relapse at 5 years was 39%, with better results observed in the RA/RARS subgroup.
Patients with adverse cytogenetics have a poor outcome with other treatment modalities, and SCT can be considered for such patients during first CR. However, the long-term outcome for these patients after SCT has not proved to be superior to that after any other approach, although the procedure may prove to be curative in a small percentage of patients. SCT should be considered particularly in the setting of a clinical trial.
New applications for allogeneic SCT (eg, nonmyeloablative) to make this option available to the typical patient with MDS (who is frequently older and has other associated medical problems), as well as for matched-unrelated donor SCT, should be investigated further.
Autologous SCT In the majority of patients with MDS, lymphocytes do not appear to be part of the clone, suggesting the presence of normal nonclonal stem cells. De Witte et al described 79 patients with MDS or secondary AML who underwent autologous SCT during first CR. The 2-year survival, disease-free survival, and relapse rates were 39%, 34%, and 64%, respectively. The 2-year survival rate for the MDS group was 40%, and treatment-related mortality was 9%. The best outcome was seen among patients with RA/RARS.
Treatment of patients with MDS is an evolving and controversial issue, and enrollment in a clinical trial should be encouraged. Treatment can be considered according to the IPSS.
Patients with low or intermediate-1 IPSS scores can frequently be treated with supportive measures. Agents such as ATG and cyclosporine could be used alone or in combination. Patients with 5q− benefit from lenalidomide, particularly in terms of erythroid response, and this should be considered the treatment of choice in these patients. Some patients with MDS without the 5q− abnormality may also benefit from lenalidomide, but its use in this setting is still being investigated. Azacitidine should be considered for all patients in view of its effect on survival. Decitabine is another possible option for patients with MDS, although a recent study did not reveal a survival benefit.
Patients with high or intermediate-2 IPSS scores have a significant risk of mortality from cytopenias or AML evolution. They should be considered for treatment options with the intention to cure, extend survival, or delay the progression of AML. In view of the survival effect of azacitidine, it should be considered as first-line therapy for patients with higher-risk disease. Preliminary results of a similar survival study with decitabine administered in the European 3-day schedule compared with best supportive care showed no survival benefit. Intensive chemotherapy did not appear to improve survival in an EORTC study.
SCT is an alternative for younger patients with higher-risk MDS and an HLA-identical donor, particularly patients with adverse cytogenetic abnormalities. However, the best results to date have been reported in patients with a better prognosis (ie, younger patients and those with RA/RARS). Therefore, allogeneic transplantation and other transplant alternatives should be considered preferentially in a research setting (eg, mixed-unrelated donor and minitransplants) or in patients who have failed to respond to other therapies.