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Spring 1997Volume 4, Number 1 |
The term myelodysplastic syndrome (MDS) is used to describe a condition characterized by refractory cytopenias in patients whose bone marrows reveal dysplastic changes in at least two of the three hematopoietic cell lines. MDS often undergoes transformation into acute myeloid leukemia (AML), and the leukemias in these patients are generally less responsive to standard induction chemotherapy than those which arise de novo. Therefore, although the morphology of AML is similar regardless of whether the disease develops de novo or after transformation from MDS, the biology of the disease is not.
Variations in marrow morphology and differing potentials for survival and transformation to AML among cases of MDS have led to the establishment of a morphologic classification scheme with five subgroups (see table on this page): refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML).1 RA and RARS patients have fewer than 5% blasts in their bone marrow; RAEB patients have 5-20% blasts, and RAEB-T patients 20-30% blasts. Patients with AML have more than 30% blasts in their bone marrow. MDS can develop de novo (primary MDS) or can arise as a result of prior chemotherapy or chemoradiotherapy for other malignancies or as a result of exposure to a variety of marrow toxins (secondary MDS). Approximately 40-60% of patients with primary MDS have cytogenetic abnormalities at diagnosis, whereas more than 80% of patients with secondary MDS have abnormal karyotypes.2 Patients with more aggressive disease and those in leukemic transformation tend to have more complex abnormal karyotypes. Structural and numeric chromosomal abnormalities are seen in MDS, and deletions are extremely common. The 5q- abnormality is most commonly observed in patients with RA; monosomy 7 is seen most often in patients with secondary MDS. Chromosomal abnormalities in primary and secondary MDS can involve chromosomes 5, 7, 8, 11, 12, and 20.2,3
MDS occurs most commonly in patients older than 50 years of age; it is unusual in children.4 More than 80% of patients are above 60 years of age at diagnosis. Most patients present with the signs and symptoms of bone marrow failure anemia, neutropenia, and thrombocytopenia, causing fatigue, infection, and bleeding, respectively. Patients may have no symptoms; abnormal blood counts noted on routine examination may lead to the diagnosis. Bone marrow cellularity is usually normal or increased,5 and dysmorphology may be present in any or all three cell lineages. Erythrocytes are most commonly affected; anemia occurs due to ineffective erythropoiesis as demonstrated by low reticulocyte counts despite normal numbers of erythroid progenitor cells.5,6 The clinical course of MDS is highly variable, and the median survival in most studies ranges from 20 to 36 months.
| The mainstay of therapy has been supportive care, including red blood cell and platelet transfusions for symptomatic anemia and thrombocytopenia and antibiotics for infection. |
The mainstay of therapy has been supportive care, including red blood cell and platelet transfusions for symptomatic anemia and thrombocytopenia and antibiotics for infection. MDS is generally an indolent disease affecting the elderly. Therefore, any attempt at systemic treatment must cause very limited toxicity. Stratification according to the risk categories described above is necessary to determine the therapeutic efficacy of various treatment regimens. A younger patient with a more aggressive form of MDS probably warrants aggressive systemic treatment, while an elderly patient with an indolent form of the disease probably should receive only supportive care.
Chemotherapeutic options for this condition range from intensive cytotoxic therapy to low-dose treatment modalities. The use of intensive chemotherapy for MDS has led to variable complete remission (CR) rates (13-51%) with significant morbidity and mortality.7,8 The best results have been achieved in younger patients and in those with more favorable karyotypes. Low-dose cytosine arabinoside therapy for MDS has a very low CR rate (8%) and produces no improvement in long-term survival.9 Corticosteroids and androgens have also been tried. Some patients respond transiently, but no benefit in long-term survival has been achieved.9
| SUBTYPES OF MYELODYSPLASTIC SYNDROME (FAB COOPERATIVE GROUP CRITERIA) | |||||
| Bone Marrow Blasts (%) | Peripheral Blood Blasts (%) | Ring Sideroblasts >15% of Nucleated | Auer Rods >1 × 109/L | Monocytes Marrow Cells | |
| RA | <5 | </=1 | - | - | - |
| RARS | <5 | </=1 | ± | - | - |
| RAEB | 5-20 | <5 | ± | - | - |
| CMML | </=20 | <5 | ± | - | ± |
| RAEB-T | 21-30 or | >/=5 | ± | ± | ± |
Granulocyte-macrophage colony stimulating factor (GM-CSF) has been used in MDS with modest success. In many patients, the neutrophil count rises and remains elevated as long as the drug is continued. However, side effects (flu-like syndrome, bone pain, hyperleukocytosis) cause up to 25% of patients to discontinue growth factor treatment.10 Granulocyte colony stimulating factor (G-CSF) has also been used and is better tolerated than GM-CSF. Use of G-CSF resulted in persistent improvement in neutrophil counts, improved granulocyte maturation in 10 of 11 patients, and decreased red blood cell transfusion requirements in 2 of 4 patients who were transfusion-dependent.11 Not surprisingly, no significant change in platelet count occurs with G-CSF therapy. A randomized multi-institutional study is currently underway to more fully evaluate the role of G-CSF in the treatment of MDS.
| To date, allogeneic bone marrow transplantation using an HLA-matched sibling donor is the only treatment proven to achieve long-term disease free survival (DFS) in MDS patients. |
To date, allogeneic bone marrow transplantation using an HLA-matched sibling donor is the only treatment proven to achieve long-term disease free survival (DFS) in MDS patients. In a large study from the Netherlands conducted during the 1980s, the DFS, relapse (including progression), and nonrelapse mortality (treatment- and nontreatment-related) were 41%, 28%, and 43%, respectively, at four years.12 Multivariate analysis revealed that patients younger than 40 years of age and <5% marrow blast counts had a better prognosis (62% DFS). Patients with secondary MDS had a 25% DFS in that study. A recent study from Seattle evaluated myeloablative therapy followed by allogeneic transplantation using unrelated donors. The two-year DFS was 38%, with relapse and nonrelapse mortality of 28% and 48%, respectively.13 Again, younger patients with fewer than 5% blasts in the bone marrow had the best prognosis. These results indicate that matched unrelated donor transplantation may be an effective treatment for MDS in young patients with few blasts.
In summary, MDS is characterized by dysplastic changes in at least two of the three blood cell lineages in the bone marrow. MDS most commonly occurs in elderly patients and frequently pursues an indolent disease. Generally, the most appropriate treatment is supportive. For younger patients, allogeneic bone marrow transplantation, using either a matched sibling or unrelated donor, is the only available treatment that has resulted in long-term disease-free survival. Patients with secondary MDS and those who are in transformation to overt leukemia are more resistant to therapy and have a worse prognosis.
Jay Feingold, MD, PhD
Director, Pediatric Bone Marrow Transplant Program
University of Connecticut
Farmington, Connecticut
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