Acquired disorders of the bone marrow

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D., Rim Halaby, M.D. [2], Serge Korjian M.D.

Overview

Bone marrow disorders may either be congenital or acquired. Only acquired bone disorders are discussed below. Bone marrow disorders may be myelosuppression, myeloproliferation, or mixed/unclassified (features of both).

Classification

Acquired bone marrow disorders include:

• Bone marrow suppression: Reduced numbers of cells in bone marrow

• Bone marrow proliferation: Increased numbers of cells in bone marrow

• Mixed or Unclassified: Difficult to classify as suppression or proliferation at diagnosis or disorder that contains features of both.

Shown below is an algorithm that depicts the classification of acquired bone marrow disorders.

Myelodysplasia

All hematopoietic lineages

Aplastic anemia (aplastic pancytopenia)

Paroxysmal nocturnal hemoglobinuria (PNH)

Myelosuppressive disorders

Pure red cell aplasia (erythroblastopenia)

One lineage

Neutropenia (granulocytopenia and agranulocytosis

Bone marrow suppression

Amegakaryocytic thrombocytopenia

T-cell immunosuppression

Immunosuppression

B-cell immunosuppression

Polycythemia vera

Essential thrombocytopenia

Myeloproliferative disorders

Primary myelofibrosis

Systemic mastocytosis

Acquired bone marrow disorders

Bone marrow proliferation

Chronic myeloid leukemia (CML)

T-cell lymphoproliferative disorder

Immunoproliferation

B-cell lymphoproliferative disorder

Chronic myelomonocytic leukemia (CMML)

Atypical chronic myeloid leukemia (aCML)

Mixed or unclassified

Juvenile myelomonocytic leukemia (JMML)

Unclassifiable myelodysplastic/myeloproliferative disease

Bone Marrow Suppression

Bone marrow suppression may be any of the following:

• Myelosuppression: Involvement of myeloid lineage (RBC, neutrophils, basophils, eosinophils, monocytes, platelets, mastocytes).
• Immunosuppression: Involvement of lymphoid lineage (T-cell, B-cell, NK cell). However, NK cell deficiency is almost always congenital.

Since the majority of bone marrow suppression cases are myelosuppression, the term “myelosuppression” is often synonymous with bone marrow failure.

Myelosuppressive Disorders

Myelosuppression is defined as bone marrow suppression of myeloid progenitor cells (RBC, neutrophils, basophils, eosinophils, monocytes, platelets, mastocytes). The majority of cases of bone marrow failure are due to myelosuppression. Myelosuppression results in either pancytopenia (deficiency of all lineages) or selective lineage deficiency.

All Hematopoietic Lineages

• Myelodysplasia (aka myelodysplastic syndrome): A cause of bone marrow failure characterized by defective stem cells that fail to undergo normal maturation. Bone marrow appears HYPER cellular in myelodysplasia.

• Aplastic anemia (aka aplastic pancytopenia, bone marrow hypoplasia, hypoplastic bone marrow, bone marrow aplasia, aplastic bone marrow, ehrlich anemia): A cause of bone marrow failure that may be hereditary (Fanconi’s anemia) or acquired (drugs, chemicals, radiation, or viruses). It is a distinct disease characterized by an “empty” bone marrow. Pancytopenia is a manifestation of aplastic anemia. Unlike MDS, the bone marrow appears HYPOcellular in aplastic anemia. Aplastic anemia is not characterized by abnormal mature cells, and the few cells that mature are normal in aplastic anemia. Aplastic anemia is a misnomer since not only RBC (anemia) is affected.

• Paroxysmal nocturnal hemoglobinuria: Bone marrow failure characterized by clonal expansion of a mutated hematopoietic stem cell.

Selective Hematopoietic Lineages

• Pure red cell aplasia (aka erythroblastopenia): There is insufficient production of RBC characterized by absence or deficient erythroblasts in the bone marrow.

• Neutropenia (aka granulocytopenia, granulopenia, agranulocytosis, agranulosis, neutrophilic leukopenia, neutrophilic leukocytopenia, neutrophilic leucopenia, neutrophilic leucocytopenia): Neutropenia is defined absolute neutrophil count < 1.5 x 109/L. Agranulocytosis is defined as severe neutropenia < 0.5 x 109/L. Although agranulocytosis and granulocytopenia should include reduced numbers of all granulocytes (either neutrophils, eosinophils, or basophils), the majority of cases of granulocytopenia are actually neutropenia since neutrophils constitute the majority of leukocytes; the term granulocytopenia almost always refers to deficient neutrophils.

• Amegakaryocytic thrombocytopenia: Thrombocytopenia caused by a reduced number of megakaryocytes in the bone marrow.

Acquired Immunosuppression

Although immunosuppression is usually congenital, acquired immunosuppression (aka secondary immunosuppression, acquired Immunodeficiency, secondary immunodeficiency, immunosuppressive disorder, immune deficiency disease) may be due to a disease of the bone marrow or the reticuloendothelial system. Bone marrow etiologies of acquired immunosuppression include: post-transplant immunosuppression, viral disease (eg HIV and AIDS), or drugs. While NK-cell deficiency is almost always congenital, acquired immunodeficiencies may be classified as:

• T-cell immunodeficiency (e.g. AIDS)
• B-cell immunodeficiency aka humoral immune deficiency (e.g. acquired hypogammaglobulinemia)

Bone Marrow Proliferation

Bone marrow proliferation may be any of the following:

• Myeloproliferation: Involvement of myeloid lineage (RBC, neutrophils, basophils, eosinophils, monocytes, platelets, and mastocytes)
• Immunoproliferation: Involvement of lymphoid lineage (T-cell, B-cell, NK cell)

Myeloproliferative Disorders

Myeloproliferation is a malignant disease that causes abnormal growth of mature RBC, WBC, and platelets. Unlike myelodysplastic syndromes, myeloproliferative disorders are characterized by the presence of mature cells. Myelofibrosis is the end-stage of all myeloproliferative disorders and is characterized by replacement of bone marrow by fibrosis, which eventually results in a late state of myelosupression (compared with the the early state of myeloproliferation).

• Polycythemia vera (aka polycythemia rubra vera, erythemia, primary polycythemia): Bone marrow disease characterized by proliferation of RBC

• Essential thrombocytosis (aka essential thrombocythemia, primary thrombocythemia): Bone marrow disease characterized by proliferation of platelets

• Primary myelofibrosis (aka idiopathic myelofibrosis, agnogenic myeloid metaplasia): Idiopathic replacement of bone marrow by fibrosis

• Systemic mastocytosis: Proliferation of mast cells in bone marrow and other organs

• Chronic myelogenous leukemia (CML): Chronic proliferation of myelogenous leukemic blast cells

Immunoproliferative Disorders

Immunoproliferative disease (aka immunoproliferative neoplasm, immunoproliferative disorder) is a bone marrow disease that results in either T-cell proliferation or B-cell proliferation. Examples include certain leukemias, plasma cell disorders (e.g. multiple myeloma, Waldenström macroglobulinemia). Synonyms and related diseases of B-cell lymphoproliferative disease include plasma cell dyscrasias, monoclonal gammopathy, monoclonal gammopathy of undetermined significance, plasmacytosis, plasmacytoma, hypergammaglobulinemia, paraproteinemia, cryoglobulinemia, plasma cell leukemia, primary amyloidosis, light-chain amyloidosis, and AL amyloidosis.

Mixed or Unclassified Disorders

Bone marrow disease that is difficult to classify at diagnosis or that includes features of bone marrow suppression and proliferation simultaneously.

• Chronic myelomonocytic leukemia (CMML)

• Atypical chronic myeloid leukemia (aCML)

• Juvenile myelomonocytic leukemia (JMML)

• Unclassifiable myelodysplastic disease (unclassifiable myeloproliferative disease)

Definitions of other Terms

• Pancytopenia: Reduced numbers of all 3 bone marrow cell types: RBCs + WBCs + platelets. It is not a disease, but rather a lab finding that has several causes (e.g. pancytopenia may be due to insufficient production [aplastic anemia], inability of cells or mature [myelodysplasia], or replacement of normal bone marrow with fibrosis [myelofibrosis]).

• Leukopenia: Deficiency of absolute number of leukocytes (generally either lymphocytes or neutrophils). The majority of cases of leukopenia are actually neutropenia since neutrophils constitute the majority of leukocytes.
  • Neutrophilic leukopenia (aka neutrophilic leukocytopenia, neutrophilic leucopenia, neutrophilic leucocytopenia, neutropenia): Absolute neutrophil count < 1.5 x 109/L
  • Eosinophilic leukopenia (aka eosinophilic leukocytopenia, eosinophilic leucopenia, eosinophilic leucocytopenia, eosinophilopenia): Reduced absolute number of eosinophils
  • Basophilic leukopenia (aka basophilic leukocytopenia, basophilic leucopenia, basophilic leucocytopenia, basophilopenia): Reduced absolute number of basophils

• Lymphopenia (aka lymphocytopenia): Reduced absolute number of lymphocytes (T-cells or B-cells)
• Myelophthisic anemia (aka myelophthisis): A type of bone marrow failure caused by invasion of abnormal constituents (e.g. fibrosis or tumor).