Cytogenetic features associated with good prognosis are scored as 0 and include normal karyotype, loss of Y, 5q–, or 20q–; those associated with a poor prognosis are scored as 1.0 and include abnormalities of chromosome 7 or three or more cytogenetic changes; all other cytogenetic abnormalities are scored as 0.5 and are of intermediate prognosis.

A score of 0 refers to a patient with either zero or one cell lineage cytopenia, and a score of 0.5 is assigned to two or more lineage cytopenias. Lineage cytopenias are defined as hemoglobin <10 g/dL, absolute neutrophil count <1800/mm³, and platelet count <100,000/mm³.

^*The overall score is the sum of the scores from the percent of bone marrow myeloblasts, karyotype, and cytopenias.

Data from Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes (published erratum appears in Blood 91:1100, 1998). Blood 89:2079, 1997.

Table 24-3 World Health Organization Classifications of MDS

The World Health Organization has reclassified chronic myelomonocytic leukemia (CMML) within the myeloproliferative disorders (MPD) and RAEB-T to “AML with multilineage dysplasia.” Acute myeloid leukemia (AML) is now classified as ≥20% myeloblasts.

The following are considered AML regardless of blast percentage: t(8;21)-AML1/ETO, t(15;17)-PML/RARA, inv(16) or t(16;16)-CBFβMYH11, and 11q23-MLL.

Table 24-4 World Health Organization–Based Prognostic Scoring System for Predicting Survival in Patients With Myelodysplastic Syndrome

Adapted from Malcovati L, Porta MG, Pascutto C, et al: Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: A basis for clinical decision making, J Clin Oncol 23:7594, 2005.

Management Guidelines for a Newly Diagnosed Patient With Myelodysplasia

The only known curative modality for patients with MDS is SCT. Therefore, all appropriate candidates should be considered for SCT. They include patients younger than 70 years (age 75 years at some centers), with a reasonable performance status and no significant comorbidity. Retrospective data from the International Bone Marrow Transplant Registry suggest that patients with low-risk disease (IPSS low or intermediate-1) should undergo SCT only at the time of disease progression (see Table 24-5). Disease progression includes progressive, clinically significant cytopenias such as progressive RBC or platelet transfusion dependency or transformation to a high-risk disease. Transformation to high-risk MDS typically is manifested by an increase in the number of bone marrow blasts but also could represent accumulation of additional cytogenetic abnormalities.

Patients with low-risk disease should be carefully analyzed for the presence of a deletion of the long arm of chromosome 5. Patients with a deletion of 5q or those who have the 5q syndrome should start taking lenalidomide at the time they become RBC transfusion dependent. For patients with hypoplastic MDS who are younger than 6 years of age, have a low transfusion requirement, and have no increase in marrow myeloblasts, immunosuppressive therapy should be considered with ATG and a calcineurin inhibitor. In all other patients with low-risk MDS, the addition of an ESA should be considered, but only in patients with a serum EPO level less than 500 mU/mL. For patients who do not respond to initial ESAs, addition of a myeloid growth factor (GC-SF or GM-CSF) should be considered. In patients who do not respond or those with an elevated EPO level, aggressive supportive care should continue. The addition of a hypomethylating agent, such as azacytidine or decitabine, may improve the hematologic parameters, but the overall experience of hypomethylating agents in patients with low-risk MDS is limited. The addition of lenalidomide is another option for patients who have isolated anemia, but lenalidomide has no impact on the myeloid or megakaryocytic lineages in patients without the 5q abnormality. Although controversial, iron chelation therapy can be considered for patients with low-risk MDS and a serum ferritin level greater than 1000 mcq/L.

All patients with high-risk MDS classified by an IPSS score of intermediate-2 or higher or patients with more than 10% bone marrow blasts should be seen at a transplant center for consideration of SCT if they are appropriate candidates. For patients who are not eligible for transplantation, a hypomethylating agent should be initiated at the time of presentation. Hypomethylating agents such as azacytidine and decitabine are associated with a small but reproducible complete remission rate, and evidence from Europe has demonstrated that azacytidine may improve the median overall survival. In addition, regardless of the IPSS risk category, all patients should be considered for clinical trial participation. Hopefully, novel strategies will make an impact not only on patient quality of life but also improve the median survival of patients with MDS.

Role of Iron Chelation in the Management of Patients With Myelodysplasia

The development of secondary hemochromatosis is associated with significant morbidity in chronic hemoglobinopathies such as thalassemia major, Blackfan-Diamond syndrome, and sickle cell anemia. Iron chelation therapy has been shown to improve the outcome in patients with these disorders. However, the same cannot be said for patients with MDS. The majority of patients with MDS become RBC transfusion dependent because they are exposed to a significant amount of intravenous iron. Each unit of packed RBCs has approximately 200 to 250 mg of elemental iron. More than 75% of patients with MDS who receive chronic RBC transfusions will develop evidence of secondary hemochromatosis documented by a serum ferritin level of 1000 mg/mL or higher. This typically occurs after patients have received a total lifetime of 40 units of packed RBCs. Nevertheless, it remains difficult to document true organ failure as a result of iron overload in most patients with MDS. In patients with MDS, a serum ferritin level of 1000 mg/mL or higher is associated with a reduced median overall survival. What has not been demonstrated in a prospective fashion is whether the addition of iron chelation therapy can improve survival.

Patients with high-risk MDS have a shortened overall survival time as a result of progressive cytopenias resulting in infection, bleeding diatheses, or transformation to AML. In these patients, the role of iron chelation therapy is unlikely to improve the median survival. However, in patients with low-risk MDS, the natural history of the disease is markedly different. Many patients have an indolent course, with a median overall survival longer than 3 years. In addition, use of disease-modifying agents, such as lenalidomide, in patients with 5q syndrome may alter the natural history of the disease.

Two studies have demonstrated that iron chelation therapy is associated with an improved median survival in patients with low-risk MDS. Both studies have limitations. In the Canadian study, which was a retrospective analysis of 178 patients, only 18 patients received iron chelation therapy. The other study from the French MDS group was a nonrandomized prospective analysis of 165 patients of whom 46% received iron chelation therapy. In this latter study, various regimens of iron chelation were used, but no formal assessment of individual iron stores was made. Thus, the role of iron chelation therapy for patients with MDS is unclear. If it has a role, it should be reserved for patients with low-risk MDS because they are expected to have a prolonged median survival time, especially patients who are benefiting from their therapy.

Myelodysplastic Syndromes in Young Patients

Although MDS typically occurs in patients older than 60 years (median age, 70 years), younger individuals also can be affected. Data on the treatment of young patients with MDS who have an indolent or low-risk presentation are unclear. When the IPSS was developed, few patients were younger than 60 years, but it was clear that young patients within the low and intermediate-1 risk groups had significantly better survival than did older patients within the same IPSS risk group. Because the outcome from SCT is related to patient age, the best approach for young patients with MDS who have a low to intermediate-1 IPSS score remains debated.

Cutler et al ¹ demonstrated a superior outcome when patients in low or intermediate-1 IPSS risk groups were transplanted at the time of disease progression as opposed to the time of their initial diagnosis. Furthermore, data from the German registry revealed that 86% of patients younger than 50 years with low-risk disease were alive at 20 years, and patients with an intermediate-1 IPSS score had a median survival of 176 months. Therefore, patients with low or intermediate-1 risk MDS who are younger than 50 years should be observed, and SCT should be delayed until disease progression. Disease progression includes the development of significant transfusion requirements, progressive cytopenias, or transformation to a higher IPSS subgroup.

Erythropoietin-Stimulating Agents in Patients With Myelodysplastic Syndrome

The safety of ESAs, recombinant human erythropoietin (rh-EPO; Epogen or Procrit), and darbepoetin (Aranesp) has come into question, specifically in patients with chemotherapy-induced anemia and chronic renal failure. ESAs can increase hemoglobin and ameliorate the symptoms from anemia that develop in patients with cancer who are undergoing chemotherapy and those with chronic renal failure. However, treatment also increases the risk of thromboembolic complications. Increased risk of tumor recurrences also has been noted.

For patients with chronic renal failure, two trials have demonstrated that patients assigned to a high targeted hemoglobin experience significantly more adverse events, including death, chronic heart failure, myocardial infarction, and stroke than do patients assigned to lower targeted hemoglobin. Use of ESAs for treatment of anemia in patients with MDS has remained a standard approach used by most physicians. Interestingly, most physicians are unaware that this remains an off-label use because regulatory authorities have not approved ESAs for use in patients with MDS. The efficacy of ESAs in MDS has been difficult to tabulate given the changing definition of response. Now with most authors using the IWG criteria for response, we have a better appreciation for the low but reproducible responses seen with use of ESAs in patients with MDS. The hemoglobin response from an ESA in patients with MDS ranges from 20% to 40%. It is important to note that a major hemoglobin response includes the development of transfusion independence as well as an increase in hemoglobin of at least 2 g/dL from baseline measurements.

There have been many concerns regarding the safety of ESAs in patients with MDS. Importantly, no significant adverse events, including thromboembolic complications, have been noted in multiple studies. Mounting evidence indicates that a lower baseline serum EPO level is associated with a higher response rate; therefore, all patients should have a baseline EPO level measured before initiation of an ESA. Patients with serum EPO levels greater than 500 mU/mL have such a low response rate to ESAs that alternative strategies should be considered first. ESA treatment requires a long duration to see maximum benefit, and because of increased iron utilization, concurrent iron administration may be required to achieve a maximum response. In addition, use of ESAs did not appear to be associated with higher rates of progression to AML. More importantly, it appears that amelioration of chronic anemia in patients with MDS not only may improve their quality of life but also may change the natural history of the disease.

Table 24-5 Decision Analysis of Allogeneic Bone Marrow Transplantation for Myelodysplastic Syndrome

From 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, 2004.

References

1 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. 2004;104:579.