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Rodak's Hematology Notes Chapter 34: Myelodysplastic Syndromes, Study notes of Hematology

Leyte Normal University (LNU)Hematology

This is a study notes from Rodak's Hematology in the Chapter 34: Myelodysplastic Syndromes.

Typology: Study notes

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HEMATOLOGY II
Chapter 34: Myelodysplastic
Syndromes
• Myelodysplastic syndromes (MDS)
→ A group of acquired clonal hematologic disorders
characterized by progressive cytopenias in the
peripheral blood, reflecting defects in erythroid,
myeloid, and/or megakaryocytic maturation.
→ This pattern of abnormalities was referred to as
refractory anemia, smoldering leukemia, oligoblastic
leukemia, or preleukemia.
• MDS may arise de novo (primary MDS) or as a result of
therapy (therapy-related MDS).
• All are the result of proliferation of abnormal stem cells.
• Mutations may be caused by chemical insult, radiation, or
viral infection.
• Disruption of apoptosis may be responsible for the
ineffective hematopoiesis in MDS.
• 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.
• Therapy-related MDS often is more aggressive and may
evolve quickly into acute myeloblastic leukemia (AML).
Dyserythropoiesis
• Presence of oval macrocytes.
• Hypochromic microcytes in the presence of adequate
iron stores also are seen in MDS.
• A dimorphic red blood cell (RBC) population 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.
Dysmyelopoiesis
• Persistence of basophilia in the cytoplasm of otherwise
mature white blood cells (WBCs), indicating nuclear-
cytoplasmic asynchrony.
• 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.
• Abnormal nuclear features may include
hyposegmentation, hypersegmentation, or nuclear rings.
• Agranular promyelocytes may be mistaken for blasts; this
could lead to misclassification of the disease in the AML
scheme.
• 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.
PRELIM TRANSES
Etiology
Morphologic Abnormalities in Peripheral Blood
and Bone Marrow
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Chapter 34 : Myelodysplastic

Syndromes

  • Myelodysplastic syndromes (MDS) → A group of acquired clonal hematologic disorders characterized by progressive cytopenias in the peripheral blood, reflecting defects in erythroid, myeloid, and/or megakaryocytic maturation. → This pattern of abnormalities was referred to as refractory anemia , smoldering leukemia , oligoblastic leukemia , or preleukemia.
  • MDS may arise de novo (primary MDS) or as a result of therapy (therapy-related MDS).
  • All are the result of proliferation of abnormal stem cells.
  • Mutations may be caused by chemical insult, radiation, or viral infection.
  • Disruption of apoptosis may be responsible for the ineffective hematopoiesis in MDS.
  • 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.
  • Therapy-related MDS often is more aggressive and may evolve quickly into acute myeloblastic leukemia (AML). Dyserythropoiesis
  • Presence of oval macrocytes.
  • Hypochromic microcytes in the presence of adequate iron stores also are seen in MDS.
  • A dimorphic red blood cell (RBC) population 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. Dysmyelopoiesis - Persistence of basophilia in the cytoplasm of otherwise mature white blood cells (WBCs), indicating nuclear- cytoplasmic asynchrony. - 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. - Abnormal nuclear features may include hyposegmentation, hypersegmentation, or nuclear rings. - Agranular promyelocytes may be mistaken for blasts; this could lead to misclassification of the disease in the AML scheme. - 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.

PRELIM TRANSES

Etiology

Morphologic Abnormalities in Peripheral Blood

and Bone Marrow

Dysmegakaryopoiesis

  • Platelets also exhibit dyspoietic morphology in the peripheral blood.
  • Circulating micromegakaryocytes may be present in peripheral blood from patients with MDS.
  • The megakaryocytic component of the bone marrow may exhibit abnormal morphology: Large mononuclear megakaryocytes Micromegakaryocytes Micromegakaryoblasts
  • Bilobed or have multiple small, separated nuclei.
    • Examples are vitamin B12 or folate deficiency, which can cause pancytopenia and dysplasia, and exposure to heavy metals.
    • Copper deficiency may cause reversible myelodysplasia.
    • Some congenital hematologic disorders, such as Fanconi anemia and congenital dyserythropoietic anemia, may also present with dysplasia.
    • Paroxysmal nocturnal hemoglobinuria has similar features, as does human immunodeficiency virus (HIV).
    • The granulocytes may have decreased adhesion, deficient phagocytosis, decreased chemotaxis, or impaired microbicidal capacity.
    • Decreased levels of myeloperoxidase and alkaline phosphatase may be found.

Differential Diagnosis

Abnormal Cellular Function

  • Childhood Myelodysplastic Syndromes → De novo MDS in children is very rare, and although some of the characteristics of adult MDS are present. → Refractory cytopenia of childhood. Chronic Myelomonocytic Leukemia
  • Characterized by: Persistent monocytosis of more than 1. monocyte x 109 /L Absence of the BCR/ABL1 fusion gene Less than 20% blasts and promonocytes in the peripheral blood and bone marrow Dysplasia in one or more myeloid cell line
  • Dysgranulopoiesis is evident, but neutrophil precursors make up less than 10% of the total leukocytes.
  • 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.
  • 5% to 19% blasts and promonocytes in the peripheral blood or 10% to 19% in the bone marrow (classified as CMML-2). Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative
  • Characterized by leukocytosis with morphologically dysplastic neutrophils and their precursors.
  • Multilineage dysplasia is common.
  • The BCR/ABL1 fusion gene is not present, but a variety of other karyotypic abnormalities may be seen.
  • May exhibit Pelger-Huët–like cells, hypogranularity, and
  • bizarre segmentation. Juvenile Myelomonocytic Leukemia
  • 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
  • Allogeneic stem cell transplantation is effective in about 50% of patients. Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable - Has features of refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and also carries the JAK V617F mutation. Cytogenetics - Chromosome abnormalities are found in about 50% of cases of de novo MDS and 90% to 95% of t-MDS. - The most common abnormalities involve chromosomes 5, 7, 8, 11, 13, and 20. - The most common single abnormalities are trisomy 8 and monosomy 7. Molecular Alterations - The most common mutations include those in the TP gene, RUNX1, and TET2. - NRAS has been detected in a small percentage of MDS patients. - Some gene mutations, such as TET2, confer a more favorable prognosis, while others such as TP53 confer a higher risk of transformation. 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. - Other features that affected survival but not transformation into AML included patient age, serum ferritin, patient performance status, and lactate dehydrogenase levels.

Myelodysplastic/Myeloproliferative Neoplasms

Cytogenetics, Molecular Genetics, and

Epigenetics

Prognosis

  • Supportive care includes administration of blood products (RBCs and platelets as necessary) and prevention or treatment of infections with antibiotics.
  • 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.
  • 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 has immunomodulatory and antiangiogenic effects.
  • NRAS is mutated in about 20% of MDS patients.
  • The only cure is hematopoietic stem cell transplantation.
  • Stem cell transplantation is most successful in patients younger than age 70 with no comorbidity. 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. References Rodak, B. F. (2016). Myelodysplastic Syndromes. In E. M. Keohane, L. J. Smith, & J. A. Wavelenga, Rodak's Hematology Clinical Principles and Applications (pp. 591 - 600).

Treatment