Chapter 44: Myelodysplastic Syndromes (Clonal Cytopenias and Oligoblastic Myelogenous Leukemia)

• Myelodysplasia or myelodysplastic syndrome (MDS) is the term used, as a generalization, to encompass a diverse group of myeloid neoplasms that have in common (1) their origin in a somatically mutated multipotential hematopoietic cell, (2) ineffective hematopoiesis (late precursor apoptosis) leading to cytopenias despite a normocellular or hypercellular marrow, and (3) a propensity to undergo clonal progression to acute myelogenous leukemia (AML).

• The spectrum ranges from (1) indolent disorder with mild or moderate anemia to (2) more troublesome multicytopenias without morphologic evidence of leukemic cells to (3) oligoblastic (subacute) myelogenous leukemia with leukemic blast cells in the marrow and blood.

• Clonal cytopenia refers to disorders without increased leukemic blast cells in the marrow or blood. The manifestations vary from isolated cytopenia (eg, anemia) with a marrow with erythroid dysmorphia to severe multicytopenias with hypercellular marrow and with dysmorphia of marrow precursors in each major lineage and of blood neutrophils, red cells, and platelets.

• Because the neoplasm originates in a multipotential hematopoietic cell (eg, the lymphohematopoietic stem cell), careful inspection of blood and marrow will usually identify mild involvement of all three major lineages (eg, low normal blood cell counts) or subtle morphological abnormalities.

• Oligoblastic or subacute myelogenous leukemia (synonym: refractory anemia with excess blasts) refers to patients with cytopenias and with marrow containing 3% to 19% leukemic blast cells. (The World Health Organization [WHO] currently uses the range of 5% to 19% blast cells.)

• If the marrow blast cell count is 20% or higher, the disease is considered AML and so treated.

• The use of less than 5% marrow blasts as a demarcation between a normal and pathological blast percentage is an anachronism dating from a decision made in 1955, at which time the first definition of a remission in childhood acute lymphoblastic leukemia used less than 5% marrow blasts (and other salutary changes) to avoid additional cytotoxic treatment in an era without platelet transfusion, potent wide-spectrum antibiotics, or other support for children treated with multidrug regimens. Also, only light microscopy was available to distinguish nonleukemic lymphocytes in treated marrows from residual leukemic lymphoblasts. This so-called “5 percent rule,” however, is not relevant at the time of diagnosis, especially in the case of myeloid neoplasms, has not been validated, but it has been ensconced.

• The use of less than or greater than or equal to 20% blasts to distinguish oligoblastic myelogenous leukemia (refractory anemia with excess blasts) from AML is arbitrary and without pathobiologic foundation. Studies have shown no difference in phenotypic manifestations or survival between populations with 10% to 19% as compared to 20% to 30% leukemic myeloblasts. The physician should determine management of the case by several factors (eg, physiologic age, severity of cytopenias, cytogenetic or oncogene risk category, transfusion requirements, frequency and severity of infections), not principally whether a patient with myelogenous leukemia has 10%, 15%, 20%, or 25% blast cells.

• More rarefied diagnostic categories are in the WHO classification shown in Table 44–1 and are currently being revised. These categories are useful in ensuring comparable populations in therapeutic or prognostic clinical trails. In individual patients, management is best assessed by the clinical manifestations and clinical setting of the patient under one’s care and the risk of progression as judged by factors discussed below under “Risk Categories.”

• The fundamental alteration is a somatically mutated lymphohematopoietic stem cell or a very closely related multipotential progenitor, resulting in trilineage blood cell abnormalities in most cases. Even in clonal anemia in which the neutrophils count and platelet count are within the normal range, evidence of dysmorphia in neutrophil and megakaryocyte-platelet lineages may be evident on careful examination.

• Epigenetic modification contributes to the hematopoietic abnormalities and is a target for therapy.

• Overt cytogenetic abnormalities are found in approximately 15% of patients with clonal anemia, but these abnormalities increase in prevalence to about 70% in patients with oligoblastic myelogenous leukemia. Overall, approximately 50% of patients have an overt chromosome abnormality.

• DNA-damaging chemotherapeutic agents (especially alkylating agents and topoisomerase II inhibitors) or high-dose radiation can increase the risk of developing myelodysplasia (as well as AML). High-dose, prolonged benzene exposure, rare in countries with workplace regulations, and long-standing tobacco smoking are external risk factors. Obesity may be an endogenous risk factor.

• Exaggerated apoptosis of late hematopoietic precursors results in blood cytopenias in the face of a hypercellular marrow.

• A very small fraction of patients (approximately 5%) may have hypocellular marrows akin to the similar small fraction with hypocellular AML.

• Mutation of SF3B1 (encodes a splicing factor) is present in approximately 2% of patients (Table 44–2). It is the only somatic mutation in MDS patients that confers a favorable prognosis (longer overall survival and lower frequency of clonal evolution to AML). This mutation has a predictive value of 98% for the presence of ringed sideroblasts in the marrow.

• Mutation of JAK2 is associated with clonal anemia with ringed sideroblasts and thrombocytosis.

• Mutation of TP53 is associated with complex karyotypes and a less favorable prognosis.

• Incidence increases exponentially from age 40 (0.2/100,000 persons) to age 85 years (45 per 100,000 persons) in the United States (Figure 44–1).

• In younger adults, the onset is often preceded by chemotherapy or irradiation (treatment-related myelodysplasia) for another neoplasm (eg, breast, ovary) or a severe autoimmune disease.

• Male-to-female ratio is about 1.5:1 (except in 5q- syndrome, in which females predominate).

• Children 0.5 to 15 years have an incidence rate of 0.1 per 100,000/year.

• Children usually have more advanced types (oligoblastic myelogenous leukemia).

• Childhood cases may evolve from predisposing inherited syndromes such as Fanconi anemia.

• Disease may be asymptomatic if mild anemia is the principal feature, with little or no reductions in platelet and neutrophil counts.

• If moderate or severe anemia and/or neutropenia and thrombocytopenia develop, loss of sense of well-being, pallor, dyspnea on exertion, easy bruising, and slow healing of minor cuts may be evident. The presence and intensity of these manifestations are a function of the gradient from mild anemia to severe pancytopenia.

• Hepatomegaly or splenomegaly are uncommon findings (< 10%).

• Hypothalamic malfunction with loss of libido and diabetes insipidus, neutrophilic dermatosis (Sweet syndrome), and inflammatory syndromes mimicking lupus erythematosus are each rare associated findings.

• Anemia occurs in more than 85% of patients and may be macrocytic, with rare circulating nucleated red cells. Misshapen cells (eg, elliptocytes, other poikilocytes), anisochromia, and basophilic stippling are hallmarks of the red cell dysmorphia in the blood film (see Figure 44–2).

• Hemoglobin F levels may be increased; hemoglobin H may be present, rarely (with red cell shape and inclusions simulating α-thalassemia); and red cell enzyme activities may be abnormal.

• Neutropenia occurs in at least 50% of cases. Coarse chromatin, nuclear hyposegmentation (acquired Pelger-Huèt abnormality), and decreased cytoplasmic granulation of neutrophils commonly occur.

• Monocytosis often found and rarely may be the principal abnormality.

• Thrombocytopenia or occasionally thrombocytosis may be present. The latter is especially notable in the 5q- syndrome. Platelets may be large, with decreased or fused granules. Platelet aggregation tests may be abnormal. Micromegakaryocytes may enter the blood.

• Marrow abnormalities include (1) hypercellularity, (2) delayed nuclear maturation of red cell precursors, (3) abnormal cytoplasmic maturation of red cell and neutrophil precursors, (4) pathologic sideroblasts (eg, ringed sideroblasts), (5) megakaryocytes with unilobed or bilobed nuclei or odd number of nuclear lobes, (6) micromegakaryocytes, and (7) an increased fraction of myeloblasts. In approximately 5% of patients, the marrow may be hypocellular, simulating aplastic anemia. Careful search may show unequivocal clusters of dysmorphic hematopoietic precursors and cytogenetic analysis may uncover a clonal abnormality, either or both indicative of myelodysplasia. Immunophenotyping to rule out paroxysmal nocturnal hemoglobinuria should be done in this setting (see Chap. 43).

• Chromosomal abnormalities occur in up to 70% of patients with oligoblastic myelogenous leukemia by G-banding or fluorescent in situ hybridization. The most common abnormalities (very similar to those in AML) are del(5q), -7/del(7q), trisomy 8, -18/del(18q), and del(20q) but innumerable other less common clonal cytogenetic changes may be present as may complex abnormalities (more than three abnormalities).

  — del(5q) occurs in approximately 15% of patients. Small deletions in 5q32-33.3 are associated with a favorable prognosis and with increased sensitivity to lenalidomide. Sole del(5q) in this region is the only genetically defined subtype of MDS. Some may have “5q minus syndrome” (see “5q- Syndrome,” below). Larger or different deleted areas on 5q in patients with MDS may confer a poorer risk.

  — Monosomy 7 or del(7q) found in approximately 5% of patients has adverse prognostic import.

  — Monosomy 17 or del(17p) has an adverse prognosis and may be associated with TP53 mutation.

• Occasional patients with thrombocytosis may have an abnormality of chromosome 3.

• Common translocations such as t(8;21), t(15;17), or t(16;16), seen in AML, especially in younger patients, are not features of the cells in MDS.

• Ferritin levels are often increased at diagnosis as a result of a shift in erythron iron to the storage compartments in proportion to the degree of anemia and as a result of increased iron absorption.

• Table 44–3 contains guidelines for arriving at a diagnosis of an MDS.

Clonal (Refractory) Sideroblastic Anemia

Clinical and Laboratory Features

• Most patients are older than 50 years of age and have anemia.

• Anemia may be mild to severe.

• Macrocytosis with anisochromia (hypochromia and normochromia) of red cells is common.

• Basophilic stippling of red cells and anisocytosis are common.

• Reticulocyte response is inadequate to degree of anemia.

• Ineffective erythropoiesis with impaired heme synthesis and mitochondrial iron overload are characteristic findings.

• Approximately 90% of patients have hematopoietic cells containing the SF3B1 mutation.

• Marrow cellularity is increased, with defective cytoplasmic maturation of erythroblasts, and ringed sideroblasts are present.

• Serum iron, ferritin levels, and saturation of transferrin are increased. Prussian blue stain of marrow shows increased storage iron.

• A smaller proportion of patients may have overtly abnormal granulopoiesis or megakaryocytopoiesis.

• Neutropenia or thrombocytopenia present in a modest proportion and may not be consequential functionally.

Treatment

• Treatment options are predicated on specific abnormalities and prognostic category (see “Risk Categories” section below).

• The same treatment options are available for patients in any subtype of myelodysplasia depending on morbid manifestations.

• The main considerations in all subtypes are (1) severity of anemia (demethylating agents, erythropoietic stimulants), (2) severity of neutropenia and infections (antibiotics), (3) severity of thrombocytopenia and evidence of bleeding (platelet transfusion), (4) special case of hypoplastic marrow (immunosuppressive therapy), and (5) evidence of progressive leukemic hematopoiesis (blast level) requiring acute leukemia type cytotoxic therapy or allogeneic hematopoietic stem cell transplantation. See following details.

• Asymptomatic patients without evidence of progression may not require treatment.

• Disorder may not progress for many years.

• Folic acid (1 mg/d orally) should be used if serum and red cell folic acid content are low.

• Pyridoxine (200 mg/d orally) can be tried if sideroblastic anemia is symptomatic, but success is rare.

• Danazol (200 to 400 mg/d orally) has occasionally increased platelet count or decreased frequency of platelet transfusion.

• In uncommon patients with clonal cytopenia and hypoplastic marrows, cyclosporine and antithymocyte globulin have resulted in improvement in hematopoiesis (see Chap. 3).

• Human recombinant erythropoietin (EPO) coupled with granulocyte colony-stimulating factor (G-CSF) may improve moderately severe anemia or may markedly decrease transfusion requirements. This combination is usually not beneficial unless (1) the serum EPO level is less than 500 units/L and (2) the transfusion requirement is less than 2 units of red cells per month.

• 5-Azacytidine, 75 mg/m² per day, subcutaneously (or intravenously) for 7 days every 28 days can be useful in patients with symptomatic anemia and requirement for frequent transfusions. About 40% of patients have a very good response as judged by the increase in hemoglobin levels or a significant decrease in transfusion frequency. Heretofore, the drug was used in patients failing to respond to EPO and G-CSF but evidence that its use may delay progression of the disease and prolong survival in responders is likely to make it a first choice in such patients, administered before the results of EPO + G-CSF are evident. Although 5-azacytidine is an antimetabolite, its benefit is thought to be related principally to its demethylating effects (reversing deleterious epigenetic effects).

• 5-Azacytidine may initially cause a fall in blood cell counts, even in responders, and transfusion requirements may increase during the first one to several weeks of therapy. It may take four to five cycles of therapy to achieve a response and maximum responses may not occur for nine to ten cycles.

• Decitabine, another cytotoxic agent with demethylating effects, has been approved for use in lieu of 5-azacytadine. One regimen proposed is 20 mg/m² intravenously over 1 hour daily for 5 days to be repeated every 4 weeks for a total of three cycles. Worsening of cytopenias may occur initially, but some experts recommend that unless a complication of cytopenia develops or other serious side effects occur, the treatment program should not be modified.

• Red cell transfusion may be necessary if severe anemia or if coincidental ischemic diseases (eg, angina or heart failure) are present with moderate anemia.

• Some patients with high red cell transfusion requirements develop iron overload and should receive iron chelation therapy. Oral deferasirox, 20 mg/kg per day, has been approved by the US Food and Drug Administration for this purpose. It can produce nausea, vomiting, abdominal pain, skin rash, and other adverse effects (see Chap. 9).

• One guideline for use of iron chelator therapy requires three criteria to be met: (1) probable survival for at least 1 year, (2) receipt of more than 20 units of red cells, and (3) a serum ferritin of greater than 1000 μg/L.

• Some patients do not progress or may live for many years before progression occurs. Others may have worsening hematopoiesis, more severe cytopenias, and morbidity and mortality from recurrent severe infections or hemorrhage.

• On average, a normal or only slightly abnormal neutrophil and platelet count suggests a better prognosis. A mild anemia not requiring transfusions also portends a better outcome on average.

• About 10% of patients progress to AML over a 10-year period of observation.

• Median survival is about 7 to 9 years in different studies.

Clonal (Refractory) Nonsideroblastic Anemia

• This is similar to refractory sideroblastic anemia in all respects but without or with rare pathologic sideroblasts in the marrow. (The WHO currently defines this category as having less than or equal to 15% ringed [pathologic] sideroblasts; however, a proportion of patients carry the SF3B1 mutation.) Given the data accruing on the relationship of SF3B1 mutation and marrow sideroblasts, the WHO will probably reclassify this disorder to be aligned with the absence of the SF3B1 mutation and not related to the percent marrow sideroblasts. This change would probably reduce the frequency of sideroblasts in this category to nil (more properly aligned with its designation).

Clonal Multicytopenia with Hypercellular Marrow

• These patients present with clonal cytopenias with neutropenia and/or thrombocytopenia, as well as anemia.

• The blood and marrow findings are as described for clonal anemia, although neutropenia and/or thrombocytopenia are more prominent. Dysmorphic neutrophils (acquired Pelger-Huèt nuclear and/or granule abnormalities) and platelets (giant size, abnormal granulation) may be evident in the blood. Dysmorphic neutrophil precursors and megakaryocytes with nuclear and cytoplasmic abnormalities are usually evident (eg, abnormal neutrophil precursor granulation and nuclear hyposegmentation or hypersegmentation, hypolobulated or hyperlobulated megakaryocyte nuclei, micromegakaryocytes).

• Marrow and blood picture can be seen in patients with the acquired immunodeficiency syndrome, but progression to acute leukemia is not a feature.

• Fever, especially in the setting of neutropenia, should be evaluated promptly and a suspected infection treated with broad-spectrum antibiotics, unless and until culture results permit more specific therapy.

• Therapy is as described in more detail in the section “Clonal (Refractory) Sideroblastic Anemia: Treatment” above. One or more of the following may be required: (1) EPO and G-CSF, (2) 5-azacytidine or decitabine, and (3) red cell and platelet transfusions.

• In patients with severe morbidity and a suitable donor, allogeneic hematopoietic stem cell transplantation may be considered (using either myeloablative or nonmyeloablative conditioning depending on patient age, comorbid conditions, and other individual factors).

• Median survival is about 2.5 to 4 years in different studies. AML develops in about 50% of patients, and about 25% die of infection or hemorrhage.

• Patients with complex cytogenetic patterns have a worse prognosis.

The 5q– Syndrome

• Patients have a refractory anemia, with marrow abnormalities of dyserythropoiesis; erythroid multinuclearity; and hypolobulated, small megakaryocytes (see Figure 44–3).

• Most patients do not have consequential neutropenia or thrombocytopenia.

• A proportion of patients have thrombocytosis (> 450 × 10⁹/L). About 40% of patients with clonal anemia and thrombocytosis have hematopoietic cells carrying the Janus Kinase 2 (JAK 2) mutation. This variant has a favorable prognosis.

• The syndrome is most common in older women, but it occurs in children.

• Marrow cells have deletion of long arm of chromosome 5 (5q-). In contrast to the 5q- lesion associated with other subtypes of MDS or AML, the break is between q32-q33, whereas in the other cases it is between the commonly deleted region is larger.

• Some patients do not require treatment at the time of diagnosis.

• Significant or symptomatic anemia is improved or ameliorated in the majority of patients treated with lenalidomide, 10 mg/d orally, until improvement occurs or toxicity requires cessation. Improvement ranges from disappearance of signs of the disease, including the 5q-abnormality, to a decrease in transfusion requirements. The maximal response occurs on an average after approximately 5 weeks of treatment.

• Refractory patients with significant anemia may require red cell transfusions. Iron chelation therapy should be instituted based on the three criteria discussed under “Clonal (Refractory) Sideroblastic Anemia: Treatment” above.

• Median survival is approximately 10 years.

• The risk of progression to AML is about 5% to 10% over a prolonged period of observation.

Monosomy 7-Associated Syndromes

• These syndromes are often seen in patients who develop the neoplasm after chemotherapy or high-dose radiotherapy.

• Transformation to AML is common.

• Usually, these conditions are not associated with special clinical features in adults.

• Children often have associated atypical myeloproliferative disease, subacute myelomonocytic leukemia, or juvenile myelomonocytic leukemia that rapidly progresses to AML (see Chap. 46).

Clinical Features

• Patients have 3% to 19% leukemic blasts in the marrow and 0% to 10% in the blood and may survive for months or years without specific or effective antileukemic therapy.

• These leukemias are also known as smoldering leukemia, pauciblastic leukemia, subacute myelogenous leukemia, or refractory anemia with excess blasts.

• Patients are usually older than 50 years of age, with cytopenias or qualitative cellular abnormalities, as in the clonal cytopenias.

• Thrombocytopenia and/or neutropenia virtually always accompany anemia.

• Evolution into overt polyblastic or AML occurs in approximately 50% of cases.

• Median survival is about 14 to 24 months in different studies, and individual survival in large studies has ranged from 1 to 160 months, highlighting the heterogeneity of disease severity and progression.

• Older age, complex cytogenetics, high blast cell proportions in marrow or blood, and high transfusion requirements are poor prognostic indicators.

• The WHO distinguish patients who have less than or more than 10% blasts in marrow into a type 1 and type 2, respectively.

Treatment

• Therapy should be individualized to the morbidity present, comorbid disorders (eg, physiologic age, diabetes mellitus, heart failure) and the evidence of progression. Some patients may not require treatment initially.

• Periodic patient evaluations are used to detect deteriorating blood counts in a timely manner.

• 5-Azacytidine or decitabine may be used to improve anemia or decrease red cell transfusion requirements. The very good response rate is below 30% of patients treated (see “Clonal (Refractory) Sideroblastic Anemia: Treatment” above for dosing details).

• Therapy with red cell transfusion often is required. If so, iron-chelation therapy should be used if the three criteria (endogenous EPO level, frequency of red cell transfusion needed, and ferritin level) specified in the treatment of “Clonal (Refractory) Sideroblastic Anemia: Treatment,” above, are met (see Chap. 9).

• Platelet transfusion may be required for (1) platelet counts under 5.0 × 10⁹/L, (2) evidence of exaggerated mucocutaneous bleeding, or (3) other significant bleeding episodes.

• ∈-Aminocaproic or tranexamic acid, both antifibrinolytic agents, may be used to decrease the amount of thrombocytopenic bleeding.

• Thrombopoiesis-stimulating agents (eg, thrombopoietin receptor agonists) are under study for their utility in ameliorating thrombocytopenia in patients with myelodysplasia. Results in a study in low-risk patients have shown effectiveness of romiplostim in half of those treated with platelet counts less than 30 × 10⁹/L.

• Neutropenic fever should be treated promptly with broad-spectrum antibiotics after appropriate cultures for bacteria and fungi are performed.

• If the disease progresses to AML, standard therapy for AML can be considered (see Chap. 45); the remission rate is low and long-term responses are unusual in most patients and especially in patients over age 60 years.

• In patients older than 70 years or who have comorbid conditions or other frailties, attenuated AML therapy can be considered (see Chap. 45).

• In patients not suitable for standard or attenuated standard therapy, a variety of approaches, including low-dose cytarabine, 5-azacytidine or decitabine, etoposide, hydroxyurea, glucocorticoids, singly or in combination, have been tried with limited success.

• The response rate to most therapies is in the range of 5% to 20%. One or another approach accomplishes improvement in different patients, making a standardized approach difficult at this time.

• Allogeneic hematopoietic stem cell transplantation can be curative. The younger the patient, the better the results are with transplantation. The transplant physician involved should make an assessment of all related variables: patient’s age, comorbid conditions, prior cytotoxic therapy, probability of a salutary outcome with the disease characteristics in question, patient’s level of understanding and interest in the procedure, and others.

• Patients with MDS have wide variations in manifestations within a subtype and among subtypes. For example, the number of cytopenias and severity of cytopenias are quite varied among patients.

• Some patients in the same diagnostic subtype do not require treatment, whereas others have highly morbid manifestations, which are life-threatening.

• In order to accommodate this variation among and within subtypes, patients with myelodysplasia have been stratified into prognostic or risk categories using three variables: (1) marrow blast percentage, (2) prognostic category of their cytogenetic findings (good risk, intermediate risk, poor risk), and (3) number of cytopenias (1, 2, or 3; see Table 44–4).

• In the aggregate, these prognostic categories predict the median survival, on average, and the likely requirement for early therapy. (See Tables 44–5 and 44–6.)

• Details of therapeutic approaches based on prognostic score can be found in Williams Hematology, 9th ed, Chap. 87. These approaches use the same therapy described in this chapter under the subtypes of myelodysplasia: red cell transfusion, iron chelation, immunosuppression, DNA-demethylating agents, platelet transfusions, antibiotics, AML therapy, allogeneic hematopoietic stem cell transplantation, and experimental therapies.

• This syndrome usually follows chemotherapy, radiation therapy, or combined modality therapy for solid tumors or lymphomas. Conditioning regimens for autotransplantation in lymphoma and myeloma result in secondary myelodysplasia.

• These cases have a poorer prognosis than de novo cases and are excluded from the calculations of prognostic indices.

• Therapy is very difficult because patients often have another cancer, have gone through periods of intensive cytotoxic therapy, may have other comorbidities, and are often of advanced age.

• Allogeneic hematopoietic stem cell transplantation may be useful in younger patients with a suitable donor and without comorbidities.

• In the 1950s through the early 1980s, MDS was erroneously described as preleukemia. This descriptive categorization has been discarded. Because these syndromes are clonal, they are neoplastic, and the vital and most critical transition in cell pathology, from polyclonal to monoclonal hematopoiesis, has occurred.

• Many cases have leukemic hematopoiesis in the classic sense (evident leukemic myeloblasts in marrow and blood) and all are leukemic in the pathobiologic sense, because they are all a clonal (neoplastic) disorder originating in a multipotential hematopoietic cell.

• Some polyclonal syndromes are truly preleukemic in the pathobiologic sense, polyclonal disorders that have a propensity to evolve into AML or oligoblastic myelogenous leukemia. Examples are inherited conditions, such as Fanconi anemia, and acquired conditions, such as aplastic anemia. These preleukemia states are listed in Chap. 45, Table 45–1.

The term “refractory” is an 80-year-old anachronistic designation, used before these diseases were known to be clonal (neoplastic). Moreover, the response to demethylating agents indicates that many are not “refractory.” The term “excess blasts” is not a pathophysiological entity. These are leukemic blasts qualitatively (genetically) different from normal myeloblasts. Ringed sideroblasts are closely correlated with the mutation SF3B1, and the distinction between less than or equal to and more than 15% sideroblasts in prior classifications is not valid; that breakpoint has never had a pathobiological justification for its use. This gene mutation does confer a more favorable prognosis and a decreased propensity of that clone to undergo evolution to AML. Search for this gene mutation should be a part of the diagnosis and classification of clonal anemia. The distinction in blast count of 5 to 9 and 10 to 19 among cases with overt leukemic hematopoiesis is questionable based on a single marrow examination. There are some distinctions in group data, but they are of little usefulness in individual cases in which one must evaluate the degree of abnormality of hematopoiesis globally; determine the patient’s progress over time; and whether and when to use some form of therapy for symptomatic or progressive disease.

Addendum: In May 2016, as Williams Manual of Hematology, 9th edition, was being prepared for press, the World Health Organization(WHO) published a modification of the classification of myelodysplastic syndromes as shown in the following Table 44–7.

• Important changes include the elimination of the term “refractory” in describing clonal cytopenias such as “refractory anemia”, a 40 year old anachronism.

• The new classification uses “MDS” to initiate each subtype, thereby choosing to retain an anachronism, “dysplasia” to describe neoplasias. (Hypoplasia, hyperplasia, metaplasia, dysplasia, and neoplasia are distinctive pathological entities. Neoplasia is distinguished from dysplasia and other pathological tissue abnormalities cited by being the only one that is monoclonal.)

• MDS is followed by modifiers including: (i) single lineage dysplasia; (ii) multilineage dysplasia; (iii) ring sideroblasts; (iv) isolated del (5q); excess blasts.

• The term “excess blasts” has been retained despite its misleading connotation. Neoplastic (leukemic) blast cells are qualitatively different from normal blast cells and indicate an oligoblastic myelogenous leukemia. The term “excess” is a quantitative distinction, implying hyperplasia not neoplasia, and, thus, pathobiologically erroneous.

• The use of at least 10% dysplastic cells in a lineage to assign it as dysplastic is reaffirmed with important caveats.

• Thresholds are given to define cytopenias: hemoglobin < 10g/dL, neutropenia < 1.0 × 10⁹/L, thrombocytopenia < 100 × 10⁹/L. The physician should recognize that these thresholds are arbitrary and not based on pathophysiology. Patients with MDS may present with abnormally low blood cell counts that have not reached these levels.

• The WHO has recognized that percentage of ring sideroblasts is of no prognostic significance. If the SF3B1 mutation is uncovered, the diagnosis of MDS-RS(ring sideroblasts) should be made if marrow contains ≥5% ring sideroblasts. In the absence of the SF3B1 mutation, the diagnosis of MDS-RS(ring sideroblasts) requires ≥15% ring sideroblasts in the marrow.

• The use of the % blast cells to % myeloid cells ratio to correct (increase) the blast percentage in cases with > 50% erythroblasts in marrow has been revisited and has resulted in a change of the diagnosis of acute erythroid leukemia in such cases to MDS unless the blasts represent ≥20% of all marrow cells or the erythroid cells are > 80% and 30% are proerythroblasts.

• The reader is referred to Arber D, Orazi A, Hasserjian R, et al. The 2016 revision of the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391-2405, 2016 for further details.