Rodak's Hematology Clinical Principles and Applications

PART V

Leukocyte Disorders

CHAPTER 34

Myelodysplastic syndromes

Bernadette F. Rodak

OUTLINE

Etiology

Morphologic Abnormalities in Peripheral Blood and Bone Marrow

Dyserythropoiesis

Dysmyelopoiesis

Dysmegakaryopoiesis

Differential Diagnosis

Abnormal Cellular Function

Classification of Myelodysplastic Syndromes

French-American-British Classification

World Health Organization Classification

Myelodysplastic/Myeloproliferative Neoplasms

Chronic Myelomonocytic Leukemia

Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative

Juvenile Myelomonocytic Leukemia

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Cytogenetics, Molecular Genetics, and Epigenetics

Cytogenetics

Molecular Alterations

Epigenetics

Prognosis

Treatment

Future Directions

Objectives

After completion of this chapter, the reader will be able to:

  1. Define myelodysplastic syndromes (MDSs).
  2. Explain the etiology of MDS.
  3. Recognize morphologic features of dyspoiesis in bone marrow and peripheral blood.
  4. Discuss abnormal functions of granulocytes, erythrocytes, and thrombocytes in MDS.
  5. Correlate peripheral blood, bone marrow, and cytogenetic and molecular findings in MDS with classification systems.
  6. Compare and contrast the French-American-British and the 2008 World Health Organization classifications of MDS.
  7. Discuss prognostic indicators in MDS.
  8. Indicate modes of management for MDS.
  9. Review the epidemiology of MDS and apply it as a contributor in differential diagnosis.
  10. Suggest laboratory tests and their results that would rule out MDS in the differential diagnosis.
  11. Explain the rationale for the category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN).
  12. Correlate peripheral blood, bone marrow, and cytogenetic findings in MDS/MPN with disease classification.
  13. Review prognostic indicators in MDS.
  14. Discuss treatment in MDS, including novel therapies.

CASE STUDY

After studying the material in this chapter, the reader should be able to respond to the following case study:

A 43-year-old man experienced fatigue and malaise. He presented with pancytopenia (WBC count of 2.2 × 109/L, hemoglobin of 6.1 g/dL, platelet count of 51 × 109/L). The WBC differential was essentially normal. Mean cell volume was 132 fL (reference range, 80 to 100 fL), and vitamin B12 and folate levels were normal. The bone marrow was normocellular with a myeloid-to-erythroid ratio of 1:1 and adequate megakaryocytes. The erythroid component was dysplastic with megaloblastic features. No abnormal localization of immature precursors was noted. Chromosome analysis indicated direct duplication of chromosome 1q. The patient was maintained with transfusions over the next 6 years. At that time, his bone marrow revealed increased erythropoiesis, decreased granulopoiesis, and megakaryopoiesis, all with dysplastic changes. There were 50% to 60% ring sideroblasts.

  1. What should be included in the differential diagnosis of patients with pancytopenia and elevated mean cell volume?
  2. Given the normal vitamin B12and folate levels, what is the patient’s probable diagnosis?
  3. In which WHO 2008 classification does this disorder belong?

For decades, laboratory professionals have observed a group of morphologic abnormalities in peripheral blood films and bone marrow smears of elderly patients. The findings were heterogeneous and affected all cell lines, and the condition either remained stable for years or progressed rapidly to death.

Historically, this pattern of abnormalities was referred to as refractory anemia, smoldering leukemia, oligoblastic leukemia, or preleukemia. 1-3 In 1982 the French-American-British (FAB) Cooperative Leukemia Study Group proposed terminology and a specific set of morphologic criteria to describe what are now known as myelodysplastic syndromes (MDSs).4 In 1997 agroup from the World Health Organization (WHO) proposed a new classification that included molecular, cytogenetic, and immunologic criteria in addition to morphologic features.5, 6The WHO classification was revised in 2008. Both the FAB and WHO classifications are discussed in this chapter.

MDSs are a group of acquired clonal hematologic disorders characterized by progressive cytopenias in the peripheral blood, reflecting defects in erythroid, myeloid, and/or megakaryocytic maturation.7, 8 The median age at diagnosis is 70. MDSs rarely affect individuals younger than age 50 unless preceded by chemotherapy or radiation for another malignancy.1, 9 Cases in young adults and children have been reported, however.10, 11 The incidence of these disorders seems to be increasing, but this apparent increase may be attributable in part to improved techniques for identifying these diseases and to improved classification.12-14 At this time, the fastest-growing segment of the population is the group older than 60 years of age. MDSs are becoming a more common finding in the hematology laboratory, and familiarity with these disorders is an essential part of the body of knowledge of all medical laboratory professionals.

Etiology

MDS may arise de novo (primary MDS) or as a result of therapy (therapy-related MDS). Although MDSs are a group of heterogeneous diseases, all are the result of proliferation of abnormal stem cells.7, 8, 15 The initiating defect in most cases is at the level of the myeloid stem cell, because primarily the erythroid, myeloid, and megakaryocytic cells are affected. It may be that the affected hematopoietic stem cell has lost its lymphopoietic potential, because only rarely does MDS transform to acute lymphoblastic leukemia.16, 17 The abnormal stem cell may be the result of the cumulative effects of environmental exposure in susceptible individuals. Mutations may be caused by chemical insult, radiation, or viral infection. There also may be an association with smoking.18 An association with inherited hematologic disorders has also been found.19 The mutated stem cell produces a pathologic clone of cells that expands in size at the expense of normal cell production.20 Because each mutation produces a unique clone with a specific cellular defect, MDSs have a multitude of expressions. Two morphologic findings are common to all types of MDSs, however; the presence of progressive cytopenias despite cellular bone marrows and dyspoiesis in one or more cell lines.

Disruption of apoptosis may be responsible for the ineffective hematopoiesis in MDS.21-26 Apoptosis (programmed cell death) regulates cell population by decreasing cell survival. In MDS, apoptosis is increased in early disease, when peripheral blood cytopenias are evident. Later in MDS, when progression toward leukemia is apparent, apoptosis has been shown to be decreased, which allows increased neoplastic cell survival and expansion of the abnormal clone.27-30 Other important factors include the levels of antiangiogenic cytokines, tumor necrosis factor, and cellular components of the immune system, as well as the interaction between MDS clonal cells and the hematopoietic inductive microenvironment. Patients with MDS have increased levels of angiogenic growth factors, including vascular endothelial growth factor.31, 32

Therapy-related MDS (t-MDS) occurs in patients who have been treated previously with chemotherapy or radiotherapy or both. Median onset of therapy-related MDS varies with the agents used and is usually 4 to 7 years after therapy was initiated.20, 33 Patients who have received cytokines, such as G-CSF or GM-CSF, for bone marrow stimulation are also at an increased risk for developing t-MDS.34 Therapy-related MDS often is more aggressive and may evolve quickly into acute myeloblastic leukemia (AML).20, 33, 35 The 2008 WHO classification places therapy-related MDSs into the AML category of therapy-related myeloid neoplasms (Chapter 35).

Morphologic abnormalities in peripheral blood and bone marrow

In MDS each of the three major myeloid cell lines has dyspoietic morphologic features. The following sections provide descriptions of common abnormal morphologic findings.4, 9, 19These descriptions are not all-inclusive because of the large number of possible cellular mutations and combinations of mutations.

Dyserythropoiesis

In the peripheral blood, the most common morphologic finding in dyserythropoiesis is the presence of oval macrocytes (Figure 34-1). When these cells are seen in the presence of normal vitamin B12 and folate values, MDS should be included in the differential diagnosis. Hypochromic microcytes in the presence of adequate iron stores also are seen in MDS. A dimorphic red blood cell (RBC) population (Figure 34-2) is another indication of the clonality of this disease. Poikilocytosis, basophilic stippling, Howell-Jolly bodies, and siderocytes also are indications that the erythrocyte has undergone abnormal development.36


FIGURE 34-1 Oval macrocytes in peripheral blood (×1000).


FIGURE 34-2 Dimorphic erythrocyte population, including macrocytic and microcytic cells (in peripheral blood, ×500).

Dyserythropoiesis in the bone marrow is evidenced by RBC precursors with more than one nucleus or abnormal nuclear shapes. The normally round nucleus may have lobes or buds. Nuclear fragments may be present in the cytoplasm (Figure 34-3). Internuclear bridging is occasionally present (Figure 34-4).37 Abnormal cytoplasmic features may include basophilic stippling or heterogeneous staining (Figure 34-5). Ring sideroblasts are a common finding. Megaloblastoid cellular development in the presence of normal vitamin B12 and folate values is another indication of MDS. The bone marrows in these cases may have erythrocytic hyperplasia or hypoplasia (Box 34-1).


FIGURE 34-3 Bone marrow specimen showing erythroid hyperplasia and nuclear budding in erythroid precursors (×1000).


FIGURE 34-4 Erythroid precursors showing nuclear bridging (arrow) (bone marrow, ×1000).


FIGURE 34-5 Bone marrow specimen showing heterogeneous staining in a bilobed erythroid precursor (×1000).

BOX 34-1

Morphologic Evidence of Dyserythropoiesis

Oval macrocytes

Hypochromic microcytes

Dimorphic red blood cell (RBC) population

RBC precursors with more than one nucleus

RBC precursors with abnormal nuclear shapes

RBC precursors with uneven cytoplasmic staining

Ring sideroblasts

Dysmyelopoiesis

Dysmyelopoiesis in the peripheral blood is suspected when there is a persistence of basophilia in the cytoplasm of otherwise mature white blood cells (WBCs), indicating nuclear-cytoplasmic asynchrony (Figure 34-6). Abnormal granulation of the cytoplasm of neutrophils, in the form of larger than normal granules, hypogranulation, or the absence of granules, is a common finding. Agranular bands can be easily misclassified as monocytes (Figure 34-7). Abnormal nuclear features may include hyposegmentation, hypersegmentation, or nuclear rings (Figure 34-8).38


FIGURE 34-6 This myelocyte (right) in peripheral blood has a nucleus with clumped chromatin and a basophilic immature cytoplasm showing asynchrony. Note also the agranular myeloid cell (left) (×1000).


FIGURE 34-7 Agranular myeloid cells (peripheral blood, ×1000).


FIGURE 34-8 Nuclear ring in myeloid cell (peripheral blood, ×1000).

In the bone marrow, dysmyelopoiesis may be represented by nuclear-cytoplasmic asynchrony. Cytoplasmic changes include uneven staining, such as a dense ring of basophilia around the periphery with a clear unstained area around the nucleus or whole sections of cytoplasm unstained, with the remainder of the cytoplasm stained normally (Figure 34-9). There may be abnormal granulation of the cytoplasm in which promyelocytes or myelocytes or both are devoid of primary granules (Figure 34-10), primary granules may be larger than normal, or secondary granules may be reduced in number or absent, and there may be an occasional Auer rod.39, 40 Agranular promyelocytes may be mistaken for blasts; this could lead to misclassification of the disease in the AML scheme. Abnormal nuclear findings may include hypersegmentation or hyposegmentation and possibly ring-shaped nuclei (Box 34-2).


FIGURE 34-9 Uneven staining of white blood cell cytoplasm (bone marrow, ×1000).


FIGURE 34-10 Promyelocyte or myelocyte devoid of granules and an agranular neutrophil (bone marrow, ×1000).

BOX 34-2

Morphologic Evidence of Dysmyelopoiesis

Persistent basophilic cytoplasm

Abnormal granulation

Abnormal nuclear shapes

Uneven cytoplasmic staining

The bone marrow may exhibit granulocytic hypoplasia or hyperplasia. Monocytic hyperplasia is a common finding in dysplastic marrows.

Abnormal localization of immature precursors is a characteristic finding in bone marrow biopsy specimens from patients with MDS.41 Normally, myeloblasts and promyelocytes reside along the endosteal surface of the bone marrow. In some cases of MDS, these cells tend to cluster centrally in marrow sections.

Dysmegakaryopoiesis

Platelets also exhibit dyspoietic morphology in the peripheral blood. Common changes include giant platelets and abnormal platelet granulation, either hypogranulation or agranulation (Figure 34-11). Some platelets may possess large fused granules. Circulating micromegakaryocytes may be present in peripheral blood from patients with MDS (Figure 34-12).9


FIGURE 34-11 Abnormal platelet granulation (arrow) (peripheral blood, ×1000).


FIGURE 34-12 Micromegakaryocyte (peripheral blood, ×1000).

The megakaryocytic component of the bone marrow may exhibit abnormal morphology: large mononuclear megakaryocytes, micromegakaryocytes, or micromegakaryoblasts. The nuclei in these cells may be bilobed or have multiple small, separated nuclei (Figure 34-13; Box 34-3).9


FIGURE 34-13 Megakaryocyte with small separated nuclei (bone marrow, ×1000).

BOX 34-3

Morphologic Evidence of Dysmegakaryopoiesis

Giant platelets

Platelets with abnormal granulation

Circulating micromegakaryocytes

Large mononuclear megakaryocytes

Micromegakaryocytes or micromegakaryoblasts or both

Abnormal nuclear shapes in the megakaryocytes/blasts

Differential diagnosis

Dysplasia by itself is not sufficient evidence for MDS, because several other conditions can cause similar morphologic features. Some examples are vitamin B12 or folate deficiency, which can cause pancytopenia and dysplasia, and exposure to heavy metals. Copper deficiency may cause reversible myelodysplasia.9 Some congenital hematologic disorders, such as Fanconi anemia and congenital dyserythropoietic anemia, may also present with dysplasia. Parvovirus B19 and some chemotherapeutic agents may give rise to dysplasia similar to that in MDS. Paroxysmal nocturnal hemoglobinuria has similar features, as does human immunodeficiency virus (HIV).42 Therefore, a thorough history and physical examination, including questions about exposure to drugs and chemicals, are essential.9

Abnormal cellular function

The cells produced by abnormal maturation not only have an abnormal appearance but also have abnormal function.9, 43 The granulocytes may have decreased adhesion,44, 45 deficient phagocytosis,45 decreased chemotaxis,44, 45 or impaired microbicidal capacity.46 Decreased levels of myeloperoxidase and alkaline phosphatase may be found.47 The RBCs may exhibit shortened survival,48 and erythroid precursors may have a decreased response to erythropoietin that may contribute to anemia.49 Patients may experience increased bleeding despite adequate platelet numbers.9, 50, 51 The type and degree of dysfunction depend on the mutation present in the hematopoietic stem cell.

Classification of myelodysplastic syndromes

French-american-british classification

In an effort to standardize the diagnosis of MDSs, the FAB created five classes of MDS, each with a specific set of morphologic criteria. The categories were defined by the amount of dysplasia and the number of blasts in the bone marrow. The diagnosis of acute leukemia required at least 30% blasts in the bone marrow.4 The FAB classification included the following:

  1. Refractory anemia
  2. Refractory anemia with ring sideroblasts (RARS)
  3. Refractory anemia with excess blasts (RAEB)
  4. Chronic myelomonocytic leukemia (CMML)
  5. Refractory anemia with excess blasts in transformation (RAEB-t)

The FAB classification provided a framework for discussion of a seemingly heterogeneous group of disorders; however, its reliance on morphology alone limited its usefulness as a prognostic indicator. In addition, the FAB classification did not view MDSs in their totality because it did not address therapy-related or hereditary forms, and childhood MDS was not considered. Advances in medical knowledge, including molecular analysis, have allowed integration of clinical, immunologic, genetic, and molecular data with morphologic features. The WHO classification retains many of the FAB features, while recognizing molecular, cytogenetic, and immunologic characteristics of these disorders. The WHO classification also removed the problematic categories of CMML and RAEB-t and placed them in MDS/MPD and acute leukemia, respectively.19, 52

World health organization classification

The original modifications from the FAB classification of MDS included a reduction in the percentage of blasts required for diagnosis of AML from 30% to 20% and the recognition of two new classifications: refractory cytopenia with multilineage dysplasia (RCMD) and del(5q) syndrome. The 2008 revision of the WHO criteria added the category of refractory cytopenia with unilineage dysplasia (RCUD), refined some categories, and added the provisional category of childhood MDS, also called refractory cytopenia of childhood. The 2008 WHO classification is outlined in Box 34-4 and detailed in Table 34-1. The classification is extensive, and only the highlights are presented in this chapter.19

TABLE 34-1

Peripheral Blood and Bone Marrow Findings in Myelodysplastic Syndromes (MDSs)

Disease

Blood Findings

Bone Marrow Findings

Refractory cytopenia with unilineage dysplasia (RCUD); refractory anemia (RA); refractory neutropenia (RN); refractory thrombocytopenia (RT)

Unicytopenia*
No or rare blasts (< 1%)†

Unilineage dysplasia: ≥10% of cells in one myeloid lineage < 5% blasts
< 15% of erythroid precursors are ring sideroblasts

Refractory anemia with ring sideroblasts (RARS)

Anemia
No blasts

≥15% of erythroid precursors are ring sideroblasts
Erythroid dysplasia only
< 5% blasts

Refractory cytopenia with multilineage dysplasia (RCMD)

Cytopenia(s)
No or rare blasts (< 1%)†
No Auer rods
< 1 × 109/L monocytes

Dysplasia in ≥10% of cells in two or more myeloid lineages (neutrophil and/or erythroid precursors and/or megakaryocytes)
< 5% blasts in marrow
No Auer rods
±15% ring sideroblasts

Refractory anemia with excess blasts 1 (RAEB-1)

Cytopenia(s)
< 5% blasts
No Auer rods
< 1 × 109/L monocytes

Unilineage or multilineage dysplasia
5%–9% blasts†
No Auer rods

Refractory anemia with excess blasts 2 (RAEB-2)

Cytopenia(s)
5%–19% blasts
± Auer rods‡
< 1 × 109/L monocytes

Unilineage or multilineage dysplasia
10%–19% blasts†
± Auer rods‡

Myelodysplastic syndrome, unclassified (MDS-U)

Cytopenia(s)
≤1% blasts†

Unequivocal dysplasia in < 10% of cells in one or more myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS
< 5% blasts

MDS associated with isolated del(5q)

Anemia
Usually normal or increased platelet count
No or rare blasts (< 1%)

Normal to increased megakaryocytes with hypolobulated nuclei
< 5% blasts
Isolated del(5q) cytogenetic abnormality
No Auer rods

* Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U.

† If the marrow myeloblast percentage is less than 5%, but there are 2% to 4% myeloblasts in the blood, the diagnostic classification is RAEB-1. Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U.

‡ Cases with Auer rods and less than 5% myeloblasts in the blood and less than 10% myeloblasts in the marrow should be classified as RAEB-2.

From Swerdlow SH, Campo E, Harris NL, et al, editors: WHO classification of tumours of haematopoietic and lymphoid tissues, ed 4, Lyon, France, 2008, IARC Press.

BOX 34-4

World Health Organization Classification of Myelodysplastic Syndromes (2008)

Refractory cytopenia with unilineage dysplasia

Refractory anemia with ring sideroblasts

Refractory cytopenia with multilineage dysplasia

Refractory anemia with excess blasts

Myelodysplastic syndrome with isolated del(5q)

Myelodysplastic syndrome, unclassifiable

Childhood myelodysplastic syndrome (provisional)

From Swerdlow SH, Campo E, Harris NL, et al, editors: WHO classification of tumours of haematopoietic and lymphoid tissues, ed 4, Lyon, France, 2008, IARC Press.

Refractory cytopenia with unilineage dysplasia

Presenting symptoms of RCUD are related to the cytopenia—namely, fatigue or shortness of breath if anemia is present; increased infections from neutropenia; and petechiae, bruising, or bleeding if thrombocytopenia is present. This category includes MDS cases with less than 1% blasts in the peripheral blood and less than 5% blasts in the bone marrow. Dysplasia must be present in more than 10% of a single myeloid lineage. Included in RCUD is refractory anemia with only dyserythropoiesis (but less than 15% ring sideroblasts), refractory neutropenia, and refractory thrombocytopenia.52 Although cytogenetic abnormalities may be seen in up to 50% of cases of refractory anemia, none is specific to the diagnosis. Median survival is generally 2 to 5 years, with only a 2% risk of transformation to acute leukemia.52, 53

Refractory anemia with ring sideroblasts

In RARS, anemia and dyserythropoiesis are present, and more than 15% of the bone marrow erythroid precursors are ring sideroblasts. To be considered a ring sideroblast, an erythroid precursor must contain at least five iron granules per cell, and these iron-containing mitochondria must circle at least one third of the nucleus (Figure 34-14).54 In the peripheral blood there may be a dimorphic picture, with a population of hypochromic cells along with a majority of normochromic cells. RARS occurs primarily in the older population. Mean survival is 69 to 108 months.55 Refractory anemia with ring sideroblasts and marked thrombocytosis and JAK2 V617F mutation are discussed with the myelodysplastic/myeloproliferative neoplasms.56 Acquired sideroblastic anemia, which is not considered MDS, is discussed in Chapter 20.


FIGURE 34-14 Ring sideroblast (arrows) (bone marrow, Prussian blue stain, ×1000).

Refractory cytopenia with multilineage dysplasia

RCMD is categorized by one or more cytopenias, dysplasia in two or more myeloid cell lines, less than 1% blasts in peripheral blood, and less than 5% blasts in the bone marrow. In RCMD, the myeloblasts do not contain Auer rods; if Auer rods are noted, the disorder is classified as RAEB-2.57 Some cases of RCMD have more than 15% ring sideroblasts, but the dyspoiesis in more than the erythroid line places them in the RCMD rather than the RARS category.53 This distinction is important, because RCMD has a more aggressive course than RARS.33

Refractory anemia with excess blasts

Trilineage cytopenias, as well as significant dysmyelopoiesis, dysmegakaryopoiesis, or both, are common in RAEB. According to the WHO classification, the peripheral blood must contain 2% to 19% blasts. In the bone marrow, blasts number 5% to 19%. RAEB is distinguished from RCMD by myeloblast percentage. Because there are significant differences in survival and because evolution to AML may occur, the WHO classification divided RAEB into two types, depending on the percentage of blasts in blood and bone marrow:

RAEB-1—5% to 9% blasts in the bone marrow or 2% to 4% blasts in the peripheral blood

RAEB-2—10% to 19% blasts in the bone marrow and 5% to 19% blasts in the peripheral blood

The presence of Auer rods, regardless of blast count, qualifies a case as RAEB-2. RAEB with greater than 10% myeloblasts has a more aggressive course, with a greater percentage of cases transforming to AML.53, 57

Myelodysplastic syndrome with isolated del(5q) (5q– syndrome)

In patients who have only the deletion of 5q (5q–), MDS represents a fairly well-defined syndrome, affecting predominantly women and occurring at a median age of 67. These patients typically have refractory anemia without other cytopenias and/or thrombocytosis, hypolobulated megakaryocytes, and erythroid hypoplasia.58-60 There are less than 1% blasts in the peripheral blood, and Auer rods are not seen.61 Patients with MDS with isolated del(5q) have long-term stable disease (median survival, 145 months). The thalidomide analogue lenalidomide (Revlimid) has proven to be effective in patients with isolated del(5q), as well as in those with del(5q) and additional cytogenetic abnormalities.58-60

Myelodysplastic syndrome, unclassifiable

The category of myelodysplastic syndrome, unclassifiable refers to subtypes of MDS that initially lack the specific changes necessary for classification into other MDS categories. If characteristics of a specific subtype develop later, the case should be reclassified into the appropriate group.62

Childhood myelodysplastic syndromes

De novo MDS in children is very rare, and although some of the characteristics of adult MDS are present, there are also some distinct differences. The 2008 WHO classification introduced a provisional category of refractory cytopenia of childhood. Several authors have addressed this provisional category in detail.10, 52

Myelodysplastic/myeloproliferative neoplasms

The MDS/MPN category includes myeloid neoplasms with clinical, laboratory, and morphologic features that are characteristic of both MDS and MPN. Included in this classification are chronic myelomonocytic leukemia; atypical chronic myeloid leukemia; juvenile myelomonocytic leukemia; and MDS/MPN, unclassifiable, with a provisional subtype of refractory anemia with ring sideroblasts and thrombocytosis (Box 34-5).52

BOX 34-5

Classification of Myelodysplastic Syndromes/Myeloproliferative Neoplasms

Chronic myelomonocytic leukemia

Atypical chronic myeloid leukemia, BCR/ABL1 negative

Juvenile myelomonocytic leukemia

Myelodysplastic/myeloproliferative neoplasm, unclassifiable

From Swerdlow SH, Campo E, Harris NL, et al, editors: WHO classification of tumours of haematopoietic and lymphoid tissues, ed 4, Lyon, France, 2008, IARC Press.

Chronic myelomonocytic leukemia

CMML is characterized by a persistent monocytosis of more than 1.0 monocyte × 109/L, absence of the BCR/ABL1 fusion gene, less than 20% blasts and promonocytes in the peripheral blood and bone marrow, and dysplasia in one or more myeloid cell line. Patients usually have an increased leukocyte count with absolute monocytosis. Dysgranulopoiesis is evident, but neutrophil precursors make up less than 10% of the total leukocytes.63 Splenomegaly may be present due to infiltration of leukemic cells. Although cytogenetic abnormalities are found in up to 40% of patients, there is none specific for CMML. Prognosis varies, depending on the number of blasts plus promonocytes. If there are less than 5% blasts and promonocytes in the peripheral blood and less than 10% in the bone marrow, the disease is classified as CMML-1 and the prognosis is better than in those cases in which there are 5% to 19% blasts and promonocytes in the peripheral blood or 10% to 19% in the bone marrow (classified as CMML-2).52, 63

Atypical chronic myeloid leukemia, BCR/ABL1 negative

Atypical CML, BCR/ABL1 negative (aCML), is characterized by leukocytosis with morphologically dysplastic neutrophils and their precursors. Basophilia may be present, but it is not a prominent feature. Multilineage dysplasia is common. The BCR/ABL1 fusion gene is not present, but a variety of other karyotypic abnormalities may be seen. Dyspoiesis may be seen in all cell lines, but it is most remarkable in the neutrophils, which may exhibit Pelger-Huët–like cells, hypogranularity, and bizarre segmentation.64, 65 The prognosis is poor for patients with aCML, who either progress to AML or succumb to bone marrow failure.66

Juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia is a clonal disorder characterized by proliferation of the granulocytic and monocytic cell lines and affects children from 1 month to 14 years of age. There is a strong association with neurofibromatosis type 1.67 Allogeneic stem cell transplantation is effective in about 50% of patients.68

Myelodysplastic/myeloproliferative neoplasm, unclassifiable

The designation MDS/MPN, unclassifiable is used for cases that meet the criteria for MDS/MPN but do not fit into one of the specified subcategories.69 Within this group there is a provisional entity that has features of refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and also carries the JAK2 V617F mutation.56

Cytogenetics, molecular genetics, and epigenetics

Cytogenetics

Chromosome abnormalities are found in about 50% of cases of de novo MDS and 90% to 95% of t-MDS.70 Karyotype has a major effect on prognosis in MDS patients, and specific karyotypes can be used cautiously to predict response to certain treatments.70 Balanced translocations, which are common among patients with AML, are found only rarely in cases of de novo MDS.19, 70 Except for del(5q), no cytogenetic abnormality is specific to subtype. The most common abnormalities involve chromosomes 5, 7, 8, 11, 13, and 20.9, 19 The most common single abnormalities are trisomy 8 and monosomy 7.71, 72 Less common abnormalities in MDS are 12p–, iso 17, –22, and loss of the Y chromosome.73

Molecular alterations

Advances in molecular genetic testing have made testing more available for routine use, and such information could be used to strengthen other prognostic indicator schemes.74 Likewise, identification of genetic defects may allow development of targeted therapies.75 Although not specific to MDS, the most common mutations include those in the TP53 gene,74 RUNX1,76, 77and TET2.78 NRAS has been detected in a small percentage of MDS patients.79, 80 It appears that a multistep process is required for transformation of MDS to AML. Some gene mutations, such as TET2, confer a more favorable prognosis,78 while others such as TP53 confer a higher risk of transformation.79

Epigenetics

The term epigenetics describes changes in gene expression that occur without altering the DNA sequence. Gene function is affected through selective activation or inactivation, rather than a change in the primary nucleotide sequence itself.81, 82 In oncogenesis, regions of a gene with specific regulatory functions, such as apoptosis, may be hypermethylated.83 Incorporation of demethylating agents into the DNA appears to slow the progression of MDS, although the mechanism is not clearly understood.82-84

Prognosis

In 1997 the International Prognostic Scoring System (IPSS) was developed to predict prognosis of patients with primary untreated MDS.85 In 2012 a refinement of the IPSS scoring system integrated newer cytogenetic groupings and depth of cytopenias into the equation, defining five major prognostic categories. The basis of the revised system retained three of the original parameters—cytogenetics, bone marrow blast percentage, and cytopenias—but divided the cytogenetic groups into five rather than the original three, split the blast percentage into more groups, and addressed the depth of cytopenias. Other features that affected survival but not transformation into AML included patient age, serum ferritin, patient performance status, and lactate dehydrogenase levels.86 Recently, levels of specific cytokines have been shown to affect disease progression in MDS.87 Table 34-2 summarizes the revised IPSS.

TABLE 34-2

Revised International Prognostic Scoring System for MDS

SCORE VALUE

0

0.5

1

1.5

2

3

4

Cytogenetics

Very Good

—

Good

—

Intermediate

Poor

Very Poor

BM Blasts (%)

≤2%

—

> 2% to < 5%

—

5% to 10%

> 10%

—

Hemoglobin (g/dL)

≥10

—

8 to < 10

< 8

—

—

—

Platelets (×109/L)

≥100

50 to < 100

< 50

—

—

—

—

ANC (×109/L)

≥0.8

< 0.8

—

—

—

—

—

Risk Score and Median Survival (All Ages)

Karotype

Very Low

≤1.5 (8.8 years)

Very Good

−Y, del(11q)

Low

> 1.5 to 3 (5.3 years)

Good

Normal, del(5q), del(12p), del(20q), double incl del 5(q)

Intermediate

> 3 to 4.5 (3.0 years)

Intermediate

Del(7q), +8, +19, i(17q), any other single or double abnormality

High

> 4.5 to 6 (1.6 years)

Poor

−7, inv(3)/t/del(3q), double incl −7/del(7q), complex 3 abnormalities

Very High

> 6 (0.8 years)

Very Poor

Complex > 3 abnormalities

Median survival is also adjusted for age and decreases with age

Adapted from Greenberg et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120(12):2454-2465.

Treatment

Treatment of MDS patients is challenging because many are older and have coexisting illnesses, and the heterogeneity of the disease makes the use of one standard treatment impossible. The overall goal of treatment is to provide improved quality of life and to prolong survival.

Supportive care has been the predominant mode of treatment for most MDS patients, except those who qualify for stem cell transplantation. Supportive care includes administration of blood products (RBCs and platelets as necessary) and prevention or treatment of infections with antibiotics.

Recently, however, three drugs (lenalidomide, azacitidine, and decitabine) have been approved by the U.S. Food and Drug Administration (FDA) that show promise when used either alone or in combination with other therapies.84, 88 Azacitidine and decitabine belong to a group of drugs that deplete intracellular methyltransferases (DMNTs) and are effective in low dose, with minimal side effects, and have improved the quality of life for patients with high-grade MDS.84 Therapies are usually stratified into those used in low-risk disease and those in higher-risk MDS cases.

Treatment for patients with low-risk MDS is aimed at maintaining residual function of the bone marrow through the use of hematopoietic growth factors such as erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor. Although levels of these growth factors are often normal in MDS patients, there is a subset of patients who respond to their use.88-90

In patients with low-risk MDS, immunosuppressive therapy with drugs such as antithymocyte globulin and cyclosporine has resulted in decreased risk of leukemic transformation.

Lenalidomide (Revlimid; Celgene, Summit, NJ), a thalidomide analogue that is less toxic than thalidomide, was approved by the FDA in 2005 for use in patients with low- or intermediate-risk MDS.93-95 It has shown remarkable promise, especially in patients with the 5q chromosome arm deletion. Transfusion independence was achieved in 64% of patients, and a median increase of 3.9 g/dL of hemoglobin was achieved in patients taking the drug. Complete cytogenetic remission was seen in 55% of MDS patients taking lenalidomide, whereas in MDS patients taking erythropoietin, cytogenetic remission is rare.93 Lenalidomide has immunomodulatory and antiangiogenic effects.88-90 The apparent efficacy of lenalidomide must be weighed against its ability to cause significant myelosuppression.88, 93

NRAS is mutated in about 20% of MDS patients. Farnesyltransferase inhibitors interfere with this process.90, 96 Patients with high-risk MDS benefit from treatment with hypomethylating agents such as azacitidine and, to a lesser extent, decitabine.81, 82, 84, 88, 97-99

The only cure is hematopoietic stem cell transplantation. Patients with an IPSS score of intermediate 2 or higher and patients with more than 10% blasts should be considered for allogeneic stem cell transplantation.100, 101 Stem cell transplantation is most successful in patients younger than age 70 with no comorbidity.9

Future directions

As research addressing the role of apoptosis in MDS continues, future therapies may be aimed at controlling apoptosis, with or without the use of chemotherapeutic agents. Because effective treatment for MDS remains limited, it has been suggested that patients be provided with information on the prognosis for their type of MDS, available therapies, and success rates and should take part in making decisions regarding their treatment.102, 103 As more is learned about the molecular biology of MDS, it may be possible to develop customized treatment plans for individual patients.104

Summary

  • MDSs are a group of clonal disorders characterized by progressive cytopenias and dyspoiesis of the myeloid, erythroid, and megakaryocytic cell lines.
  • The dyspoiesis is evidenced by abnormal morphologic appearance and abnormal function of the cell lines affected.
  • The WHO classification of MDSs is based on morphologic, molecular, cytogenetic, and immunologic characteristics of blood cell lines.
  • Prognosis in MDS depends on several factors, including percentage of bone marrow blasts, depth of cytopenias, and karyotypic abnormalities.
  • Treatment of MDS depends on the prognosis. If the prognosis is favorable, patients may receive only supportive therapy.
  • Other treatments that have met with limited success include chemotherapeutic agents and epigenetic modifiers.
  • Currently, the only cure for MDS is bone marrow or hematopoietic stem cell transplantation.
  • Future treatment possibilities include the use of apoptosis-controlling drugs.

Now that you have completed this chapter, go back and read again the case study at the beginning and respond to the questions presented.

Review questions

Answers can be found in the Appendix.

  1. MDSs are most common in which age group?
  2. 2 to 10 years
  3. 15 to 20 years
  4. 25 to 40 years
  5. Older than 50 years
  6. What is a major indication of MDS in the peripheral blood and bone marrow?
  7. Dyspoiesis
  8. Leukocytosis with left shift
  9. Normal bone marrow with abnormal peripheral blood features
  10. Thrombocytosis
  11. An alert hematologist should recognize all of the following peripheral blood abnormalities as diagnostic clues in MDS except:
  12. Oval macrocytes
  13. Target cells
  14. Agranular neutrophils
  15. Circulating micromegakaryocytes
  16. For an erythroid precursor to be considered a ring sideroblast, the iron-laden mitochondria must encircle how much of the nucleus?
  17. One quarter
  18. One third
  19. Two thirds
  20. Entire nucleus
  21. According to the WHO classification of MDS, what percentage of blasts would constitute transformation to an acute leukemia?
  22. 5%
  23. 10%
  24. 20%
  25. 30%
  26. A patient has anemia, oval macrocytes, and hypersegmented neutrophils. Which of the following tests would be most efficient in differential diagnosis of this disorder?
  27. Serum iron and ferritin levels
  28. Erythropoietin level
  29. Vitamin B12and folate levels
  30. Chromosome analysis
  31. A 60-year-old woman comes to the physician with fatigue and malaise. Her hemoglobin is 8 g/dL, hematocrit is 25%, RBC count is 2.00 × 1012/L, platelet count is 550 × 109/L, and WBC count is 3.8 × 109/L. Her WBC differential is unremarkable. Bone marrow shows erythroid hypoplasia and hypolobulated megakaryocytes; granulopoiesis appears normal. Ring sideroblasts are rare. Chromosome analysis reveals the deletion of 5q only. Based on the classification of this disorder, what therapy would be most appropriate?
  32. Supportive therapy; lenalidomide if the disease progresses
  33. Aggressive chemotherapy
  34. Bone marrow transplantation
  35. Low-dose cytosine arabinoside, accompanied by cis-retinoic acid
  36. Which of the following is leastlikely to contribute to the death of patients with MDS?
  37. Neutropenia
  38. Thrombocytopenia
  39. Organ failure
  40. Neuropathy
  41. Into what other hematologic disease does MDS often convert?
  42. Megaloblastic anemia
  43. Aplastic anemia
  44. AML
  45. Myeloproliferative disease
  46. Chronic myelomonocytic leukemia is classified in the WHO system as:
  47. A myeloproliferative neoplasm
  48. Myelodysplastic syndrome, unclassified
  49. MDS/MPN
  50. Acute leukemia

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