WORKUP	Section 5 of 11
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Lab Studies:

• Significant changes are found in the peripheral blood counts and morphology, and bone marrow abnormalities are also present.

• The peripheral blood counts may reflect a single cytopenia (anemia, thrombocytopenia, or neutropenia) in the early phase or bicytopenia (2 deficient cell lines) and pancytopenia (3 deficient cell lines) in later stages.

• Anemia varies in degree from mild to severe.

• It is usually macrocytic (mean cell volume of >100 fL) with oval-shaped RBCs (macro-ovalocytes).

• It is usually dimorphic (>2 populations), consisting of a normal or a hypochromic microcytic population (RARS) coexisting with the macrocytes.

• Punctate basophilia is observed in RBCs.

• Neutropenia may vary from mild to severe.

• Morphologic abnormalities are often observed in the granulocytes. These can include bilobed or unsegmented nuclei (pseudo–Pelger-Huet abnormality) or hypersegmentation on the nuclei (6-7 lobes) similar to megaloblastic diseases.

• Granulation abnormalities vary from an absence of granules to abnormal distribution inside the cytoplasm (Dohle bodies).

• Platelet counts are decreased (rarely increased) and demonstrate morphologic size abnormalities and cytoplasm abnormalities, such as giant hypogranular platelets and megakaryocyte fragments.

• In most cases, bone marrow changes include hypercellularity with trilineage dysplastic changes. A small number of patients may have a hypocellular marrow. This often overlaps with aplastic anemia. Increased marrow fibrosis may be confused with other MPDs.

• Dysplastic changes in RBC lineage (dyserythropoiesis) are characteristic.

• In the absence of vitamin B-12 or folate deficiencies, it usually manifests similar changes in asynchronous maturation of nuclei and cytoplasm as described in megaloblastic anemias.

• Other changes include binuclearity or multinuclearity in the erythroid cell precursor cells and the presence of ringed sideroblasts (iron accumulation in the mitochondria). This property was used by FAB to classify two types of RA, with (RARS) versus without ringed sideroblasts (RA).

• Dysplastic changes in WBC lineage (dysmyelopoiesis) show myeloid hyperplasia with an increased number of myeloblasts and an expanded myelocyte and metamyelocyte population (midstage bulge). This separates it from acute leukemia (leukemic hiatus or absence of mid stage). Percentage of myeloblasts have been used by the FAB classification separating RA (<5%), RAEB (5-20%), RAEB in transformation (>20 <30%), and AML (>30%). See recent WHO modification.

• Morphologic abnormalities are evident in nuclear-cytoplasm dissociation in maturation and when the pseudo-Pelger forms are also present in bone marrow.

• Dysthrombopoiesis in the platelet production cell lineage consists of micromegakaryocytes (dwarf forms) with poor nuclei lobulation and giant platelets budding off from their cytoplasm.

• Cytogenetic studies of the bone marrow cells indicate mutations into clonal cell lines, with abnormal chromosomes in 48-64% in different series.

• Using higher-resolution techniques (fluorescent in situ hybridization), some practitioners claim a 79% rate of chromosomal abnormalities in primary MDS patients.

• Chromosomal abnormalities are clonal and include 5q-, monosomy 7 (-7) or 7q-, trisomy 8 (+8), and numerous other less frequent abnormalities.

• Multiple combinations may be present, which indicate a very poor prognosis.

• A single abnormality, except those involving chromosome 7, usually indicates good prognosis and survival.

Other Tests:

• Cytogenetic techniques have evolved from individual chromosome identification by banding techniques to the new, more sensitive color-coded methods.

• Separating individual chromosomes is dependent on the ability to induce the cell into mitosis to identify abnormalities.

• The new technique using fluorescent in situ hybridization and color-coded chromosomes enables observation of the intact cell without requiring mitosis.

• A newer World Health Organization (WHO) classification is helpful in evaluating patients with MDS in predicting subgroup differences in prognosis and response to treatment.

• Refractory anemia is now divided to a group without (RCMD-) or with multi-lineage dysplasia (RCMD+) with (RCMD+/+RS) or without ringed sideroblasts (RCMD/-RS).

• A new subcategory in RA includes patients with isolated 5q- and <5% blasts called the 5q- syndrome. Identification of the syndrome or presence of this particular cytogenetic abnormality is useful since majority of these patients will respond to the new drug lenalidomide (Revlimid).

• Unclassified by the WHO are the group of patients with MDS who overlap with severe aplastic anemia and paroxysmal nocturnal hemoglobinuria. A group of MDS patients in the FAB-RA subtype who may have a hypoplastic marrow, usually HLA- DR15 phenotype, young age (<60 y), and may have negative cells to CD55 and CD59 respond to immunosuppression with ATG or cyclosporin.

Staging: Because patients with MDS have heterogenous clinical manifestations and varying clinical outcomes, staging the patients according to their prognosis and approaching therapy depending on the severity and stage is necessary. Also, the FAB classification as discussed previously is not an adequate staging mechanism.

• Recently, an international group of experts convened and determined new criteria for staging called the International Prognostic Scoring System (IPSS) for MDS.

• Table 1. IPSS Score for Staging

  Prognostic Variable	0 Points	0.5 Points	1 Point	1.5 Points	2 Points
  Bone marrow blasts, %	<5	5-10	…	11-20	21-30
  Karyotype*	Good	Intermediate	Poor	…	…
  Cytopenias	0/1	2/3	…	…	…

  *Good is no abnormality (46,XX or 46,XY), -Y, del(5q), del(20q); intermediate is other abnormalities, such as trisomy 8 (+8); and poor is complex (33 abnormalities or chromosome 7 abnormality, ie, 7q- or -7).

• The first prognostic factor is the amount or percent of myeloblasts in the patient's bone marrow study. Each increase of 10% over the reference range is equivalent to half a point.

• The number of cytopenias is scored by the presence of 2-3 (anemia plus thrombocytopenia or neutropenia or pancytopenia), which is worth half a point. The presence of none or a single cytopenia indicates a good prognosis.

• The total score is added, and the patient is staged according to the following:
  • Low - 0

  • Intermediate 1 - 0.5-1

  • Intermediate 2 - 1.5-2

  • High - Greater than or equal to 2.5

• Classification of the subtypes or categories of MDS has changed from the FAB classification to the most recent WHO classification.

• Table 2. MDS Categories of FAB Classification Versus WHO Classification
  

  FAB	WHO
  RA (<5% blasts)	RA Refractory cytopenia with multilineage dysplasia MDS-unclassified MDS with isolated del (5q)
  RARS (<5% blasts plus >15% ringed blasts)	RARS Refractory cytopenias with multilineage dysplasia and ringed sideroblasts
  RAEB (5-20% blasts)	RAEB-1 (5-9% blasts) RAEB-2 (10-19% blasts)
  RAEB-T (21-30% blasts)	Acute myeloid leukemia (>20% blasts)

• CMML in the FAB classification requires an actual monocyte count of more than 1000/mL with trilineage dysplasia.

• WHO classifies CMML into the following:

• Juvenile and proliferative CMML under MDS/MPDs have more than 13,000/mL monocytes plus splenomegaly.

• CMML under MDS is limited to monocytosis of less than 13,000/mL with trilineage dysplasia.

	TREATMENT	Section 6 of 11
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Medical Care: The standard care for patients with MDS and decreased blood counts is constantly changing. Supportive therapy, including transfusions of the cells that are missing (ie, RBCs, platelets), and treatment of infections are the main treatments. New drugs such as azacitidine (Vidaza), decitabine (Dacogen), and lenalidomide (Revlimid) are now approved by the US Food and Drug Administration for MDS.

Lenalidomide (Revlimid), a 4-amino-glutarimide thalidomide analogue, which is more potent that thalidomide but lacks its neurotoxicity and teratogenic effects, is active in low and INT-1 (IPSS) risk MDS patients, in particular patients with the karyotype characterized by deletion 5q31 (75% erythroid response), 70% cytogenetic response (26% CR) with 36% achieving a normal BM histologically. A 50% response was observed in non5q-MDS with low/Int-1.

Epigenetic modulation of gene function is a very powerful cellular mechanism showing that DNA methylation leads to silencing of suppressor genes and increasing the risk for AML transformation. A powerful DNA hypomethylating pyrimidine analogues 5-azacytidine (Vidaza) and a new agent recently approved by the FDA, 5-aza-2-deoxycytidine (decitabine [Dacogen]), may reduce hypermethylation and induce reexpression of key tumor suppressor genes in MDS. These agents are effective in Int-2/high-risk IPSS score MDS patients (25% Int-1, 48% in Int-2, and 64% in high risk). Compared to supportive care, both agents show an overall response (60% vs 5%) and a longer time to progression to AML or death and improvement of quality of life but no overall survival advantage.

Treat the symptoms to improve quality of life. These measures are temporary. More long-term measures are necessary to stimulate the patient's bone marrow production of mature blood cells.

• Supportive care includes transfusion of RBCs or platelets. The goal is to replace cells that are prematurely undergoing apoptosis in the patient's bone marrow. Guidelines for transfusion in patients with MDS and bone marrow failure are as follows:

• Decrease transfusion-related complications by using leukocyte-depleted blood products, which has been shown to decrease nonhemolytic febrile reactions, prevent alloimmunization and platelet refractoriness, and prevent cytomegalovirus transmission. Additionally, this practice has been shown to achieve better quality control of blood products compared with bedside filtering and has been shown to be cost effective.

• Patients with moderate-to-severe anemia require RBC replacement.
  • Transfusing packed RBCs for severe or symptomatic anemia benefits the patient temporarily, only for the life span of the transfused RBCs (2-4 wk).

  • Patients with congestive heart failure may not tolerate the same degree of anemia as young patients with normal cardiac function, and slow or small-volume (eg, packed RBCs) transfusions with judicious use of diuretics should be considered.

  • Consider administering iron chelation for patients receiving 20 or more units of packed RBCs in order to prevent tissue damage of the liver, heart, pancreas, and other tissues. The low-Int-1 risk MDS patient with long-term survival will develop transfusion-induced iron overload and can lead to significant organ failure and morbidity. Some evidence suggests that iron overload in the bone marrow adds to the cellular early apoptosis contributed by the microenvironment.

  • Current guidelines recommend starting iron chelation therapy in patients with low-Int-1 risk MDS patients who have received >20-25 units of packed RBC or who have a serum ferritin level of >1000 mcg/L.

  • Deferoxamine (Desferal) is difficult to administer in elderly patients since it has to be given parenterally subcutaneously by pump over 12 hours daily to be effective. It is often given at the same time as the red cell transfusion, which is ineffective.

  • Deferasirox (Exjade) is an oral, dispersible tablet that is dissolved in 7 oz of water and administered by mouth once daily. It is excreted in stools not urine and is 100-fold more active as a chelator of iron. This drug was recently approved by the FDA.

• Platelet transfusion is beneficial to stop active bleeding in thrombocytopenic patients, but the life span for transfused platelets is only 3-7 days.
  • Avoid repeated and frequent platelet transfusions in clinically nonbleeding patients because of low platelet counts (<20,000/mL).

  • Long-term measures to prevent skin and mucosal bleeding may be achieved by administering oral antithrombolytic agents such as prophylactic oral epsilon-aminocaproic acid (Amicar) to avoid alloimmunization.

• Treat infections and neutropenia.
  • Life-threatening infections, especially fungal etiologies, require granulocytes with antifungal agents.

  • Some patients may require granulocyte transfusions, but the risk of alloimmunization is high, as is the risk of developing refractoriness to future transfusion therapy.

• Stimulate bone marrow cell production, and decrease excess bone marrow cell apoptosis.
  • Hematopoietic growth factors such as erythropoietin (Procrit) for anemia have been shown to improve anemia in 20-25% of unselected patients with MDS. The long-acting EPO-analogue, darbepoietin (Aranesp), seems to be at least as effective as epoietins alpha or beta. The phase II study reported a response rate of 60% in a low-risk IPSS score MDS patients with RA and in patients with serum EPO levels below 500 U/L and a transfusion requirement of less than 2 units per month.

  • Of MDS patients with neutropenia, 75% respond to granulocyte colony-stimulating factor (Neupogen).

  • Of MDS patients with anemia and neutropenia, 75% respond to a combination of erythropoietin and granulocyte colony-stimulating factor for their neutropenia, with a 50% increase in erythroid response. Several studies have shown that addition of low doses of G-CSF synergistically enhances the erythroid response to EPO, in particular patients with RARS. A recent reanalysis using the WHO classification demonstrated a significantly better response in RARS (75%) than in RCMD-RS (9%). This may reflect G-CSF's ability to strongly inhibit cytochrome c release and hence mitochondria-mediated apoptosis in RARS erythroblasts.

• Prevent transition to acute leukemia by administering the newly approved demethylating agent azacitidine. A pivotal trial in all stages of MDS showed a 37% response (7% complete response, 16% partial response) versus a 5% response in the control arm (P <0.001) with an improved median time to transformation or death (21 mo for azacitidine vs 13 mo for control, P = 0.001) and transformation to leukemia (15% for azacitidine vs 38% for control, P = 0.001).

Surgical Care: Splenectomy for the cytopenia associated with MDS is dangerous and fraught with complications and is not recommended.

Consultations:

• Patients should be under the care of a hematologist.

• Because most treatments of MDS are not standard and are considered experimental, referral to a tertiary care center is often necessary. Encourage patients to participate in clinical trials to determine the optimal therapy for this condition.

Activity: Other new drugs for MDS are being generated at a brisk pace as new clinical trials continue to make in roads on improving outcomes in quality of life and ultimately in overall survival. Synergy is being sought with new combinations of the active drugs and the less active drugs. As more is being learned about the biology of MDS through the molecular mechanisms and the ability to modify these molecular targets, research has opened new doors for the treatment of this once obscure and poor-outcome disease.

• For practitioners who see these patients in their office, the author would like to keep encouraging them to send them for clinical trials at the Academic Centers and the MDS Centers of Excellence.

	MEDICATION	Section 7 of 11
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Treatment is based on the stage and mechanism of the disease that predominates the particular phase of the disease process. In the early phases, when increased bone marrow apoptosis results in ineffective hematopoiesis, retinoids and hematopoietic growth factors are indicated. In late stages, with inevitable leukemic transformation, cytotoxic chemotherapy and bone marrow transplantation may be necessary. All of these modes of therapy are undergoing clinical trials to determine the overall benefit to quality of life and survival.

Cytotoxic chemotherapy is used in MDS patients with increasing myeloblasts and those who have progressed to acute leukemia. The usual combination treatment is a cytarabine-anthracycline combination, which yields a response rate of 30-40% (high complication rate and morbidity in elderly patients).

New drug combinations using hematopoietic growth factors and new drugs, such as topotecan, are yielding better response rates with lower morbidity. Aggressive chemotherapy may be indicated in small population of elderly patients with good performance status and no associated serious medical comorbidity. Patients with the latter should be treated with less aggressive agents such as Vidaza or Trisenox or they should be entered into a clinical trial. However, these currently are in the early experimental stages.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• If underlying dysplastic changes were missed initially, thrombocytopenia as the presenting symptom may be mistaken for immune thrombocytopenia.

• Splenectomy for the cytopenia in a patient with MDS is dangerous and fraught with complications and is not recommended.