Leukemia and related disorders

Introduction

The term leukemia refers to a family of malignant neoplasms of the bone marrow characterized by clonal proliferation of hematopoietic cells and often accompanied by circulating immature cells in the peripheral blood. Leukemia is often accompanied by suppression of normal hematopoiesis, leading to pancytopenia. Neutropenia (<500 neutrophils per microliter of blood) and thrombocytopenia (<20,000 platelets per microliter of blood) increase the risk of life-threatening sepsis and bleeding in patients with leukemia. Leukemic infiltration of vital organs can lead to life-threatening organ failure.

Leukemia may be subclassified as acute or chronic, and myeloid or lymphoid ( Table 13.1 ). Myeloblasts and lymphoblasts can be recognized by their expression of specific markers ( Fig. 13.1 ). Whereas in acute leukemia, there is a predominance of immature cells (lymphoblasts, myeloblasts, promyelocytes, or promonocytes), in chronic leukemia, there is a predominance of more mature cells (lymphocytes, myelocytes, metamyelocytes, bands, or neutrophils). In acute myelogenous leukemia (AML), the proliferating tumor cells may be myeloblasts, promyelocytes (in acute promyelocytic leukemia), promonocytes (in acute monocytic leukemia), erythroblasts (in acute erythroid leukemia), or megakaryoblasts (in acute megakaryoblastic leukemia). In acute lymphoblastic leukemia (ALL), the proliferating cells may be B lymphoblasts or T lymphoblasts. In chronic myeloid leukemia (CML) , the proliferating cells range from myeloblasts (<20%) to myelocytes. In chronic myelomonocytic leukemia (CMML), the proliferating cells include a preponderance of promonocytes and monocytes. In B-cell chronic lymphocytic leukemia (CLL) , the proliferating cells are CD5+ B lymphocytes.

The myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs) are myeloid neoplasms with leukemia-like features ( Table 13.2 ). MDSs are characterized by peripheral blood cytopenia (anemia, neutropenia, and/or thrombocytopenia), a variable number of myeloblasts (<20%), and dysplastic maturation. MPNs are characterized by peripheral blood cytosis (erythrocytosis, leukocytosis, and/or thrombocytosis) and a variable number of myeloblasts (<20%). Transformation to AML is seen in both MDS and MPN.

Leukemia is a genetic disease associated with mutations of cellular oncogenes ( Table 13.3 ). Cellular oncogenes are genes that, when expressed under normal circumstances, support essential cellular functions such as mitosis and cell death inhibition. However, when expressed inappropriately, these same oncogene products drive mitosis or block apoptosis in an unregulated fashion. Leukemia develops as a result of uncontrolled cellular proliferation induced by inappropriate expression of growth-promoting or apoptosis-inhibiting (suppressor) oncoproteins. In some cases, oncogenes are created by translocation of cell cycle– or apoptosis-related genes into transcriptionally active regions, for example, c-Myc gene translocation into immunoglobulin gene loci in some cases of B cell (Burkitt type) ALL. In other cases, oncogenes are created by fusion of two genes that yield hybrid fusion proteins with unusual oncogenic activities, such as BCR-ABL protein in CML and promyelocytic leukemia-RARα (PML-RARα) protein in acute promyelocytic leukemia.

Leukemic infiltration of the bone marrow leads to reduction in normal hematopoiesis, leading in turn to reduction in normal blood cell counts (cytopenia). The combination of decreased erythrocyte, neutrophil, and platelet count in peripheral blood is referred to as pancytopenia . Symptoms commonly associated with pancytopenia include pallor, fatigue, and weakness caused by anemia; bacterial or fungal infection caused by neutropenia; and mucocutaneous bleeding caused by thrombocytopenia. Acute promyelocytic leukemia is often accompanied by the bleeding disorder known as disseminated intravascular coagulation ( DIC) . Acute monocytic and myelomonocytic leukemias are sometimes associated with leukemic infiltrates of extramedullary sites, including the gums. ALL may involve the central nervous system (CNS) and often involves lymph nodes and anterior mediastinum. CML, actually classified as an MPN, characteristically involves the spleen, leading to massive splenomegaly.

Patients with leukemia are treated most often with cytotoxic chemotherapeutic drugs followed in many cases by bone marrow stem cell transplantation . The rationale for chemotherapy is that chemotherapeutic suppression of the neoplastic clone allows for repopulation of the marrow by normal residual stem cells. The rationale for stem cell transplantation is that, for some chemoresistant tumors, the high dose of chemotherapy required for tumor eradication leads to loss of normal marrow stem cells ( myeloablative therapy ). Bone marrow stem cell transplantation provides a sufficient number of normal residual stem cells to repopulate the marrow.

Pharmacologic classes of drugs used in leukemia include alkylating agents (cyclophosphamide and busulfan), cell cycle inhibitors (anthracyclines and cytosine arabinoside), cell maturation agents (retinoids), interferons, lymphocytotoxic agents (corticosteroids), and small molecule inhibitors (imatinib). Treatment usually consists of a short course of high-dose induction chemotherapy designed to induce remission (absence of detectable residual disease) followed by a longer course of low-dose maintenance (or consolidation ) therapy to ensure complete tumor cell eradication and long-term remission. Because chemotherapeutic agents administered intravenously do not effectively cross the blood–brain barrier, patients with ALL are often treated with intrathecal chemotherapy to prevent CNS relapse. Some leukemias are treated with drugs that specifically target genetic lesions. Examples include the BCR-ABL inhibitor imatinib for chronic myelogenous leukemia and the vitamin A derivative all- trans retinoic acid (ATRA) for acute promyelocytic leukemia.

Allogeneic (or autologous) stem cell transplantation after induction of remission and high-dose, marrow-toxic intensification designed to eradicate all tumor cells may lead to cure. Typically, relapsed leukemia is highly resistant to chemotherapy. Patients who develop pancytopenia caused by leukemic replacement of the bone marrow may require supportive transfusions of red blood cells (RBCs) and platelets to reduce the associated symptoms. Neutropenia is not usually treated as such by leukocyte transfusions or cytokines, but infection risk may be reduced with prophylactic antibiotics.

Acute myeloid leukemia

Several AML subtypes are defined by an association with a specific chromosomal defect. AML with t(8;21) translocation is morphologically distinctive, is marked by hypergranular myeloblasts and dysplastic myeloid cells and carries a favorable prognosis. Structural abnormalities of chromosome 16 [ inv(16), t(16;16 )] are seen in a type of AML composed of myeloid and monocytic blasts (myelomonocytic) with numerous abnormal eosinophils. This type of AML also carries a favorable prognosis. AML with 11q23 abnormalities involving the MLL gene (histone methyltransferase) most often resembles acute myelomonocytic or acute monocytic leukemia. Acute promyelocytic leukemia (AML-M3) , with numerous abnormal promyelocytes in marrow (and often blood) ( Fig. 13.2 ), is defined by the presence of the t(15;17) translocation that gives rise to the PML-RARα fusion protein ( Fig. 13.3 ). The fusion protein acts by preventing RAR-mediated induction of promyelocyte differentiation. This defect can be overcome by administration of the compound ATRA, which bypasses the defective RAR and induces downstream signaling that leads to cell differentiation beyond the promyelocyte stage. However, because ATRA does not induce leukemia cell death, it must be used with other cytotoxic chemotherapeutic agents.

Nearly half of all AML cases have a normal karyotype, with no chromosome defects detected by classical cytogenetic analysis. In these cases, several recurrent gene mutations have been described, including those of nucleophosmin (NPM1) , CEBPA, KIT , and Fms-like tyrosine kinase (FLT3) . Nucleophosmin is a multifunctional protein that serves as a molecular chaperone, shuttling molecules from nucleus to cytoplasm. CEBPA encodes for a myeloid transcription factor involved in myeloid differentiation. KIT and FLT3 encode for receptor tyrosine kinases that induce cellular proliferation.

The mutations in AML can be broadly classified into 5 functional groups. Class I mutations enhance proliferation and survival, class II mutations inhibit cell differentiation, class III (epigenetic) mutations modify gene expression, class IV mutations interfere with cell adhesion and cell-cell interaction, and class V mutations inhibit DNA repair and RNA splicing ( Fig. 13.4 ).

One form of AML is defined by its occurrence following treatment with alkylating agents or topoisomerase type II inhibitors . This type of AML is marked by numerous cytogenetic defects and a poor prognosis. Another AML subtype that is characterized by a poor prognosis is AML with multilineage dysplasia . Presumably, many of these tumors arise by progression from preexisting but clinically unrecognized myelodysplasia.

Remaining AML subtypes are defined by the morphology and immunophenotype of the blasts. The marrow in AML with minimal differentiation (AML-M0) contains more than 19% CD13/CD33+, myeloperoxidase (MPO)-negative agranular myeloblasts ( Fig. 13.5 ). Given the lack of cellular differentiation, this tumor is morphologically difficult to differentiate from ALL. In contrast to ALL, this form of AML expresses the myeloid cell surface antigen CD13, CD33, or both (see Fig. 13.4 ).

The marrow in AML without maturation (AML-M1) contains more than 19% faintly granular blasts that express small amounts of the primary granule enzyme MPO, as well as the myeloid antigen CD13, CD33, or both. In some cases of AML-M1, aggregated primary granules can be seen as Auer rods ( Fig. 13.6 ).

The marrow in AML with maturation (AML-M2) contains more than 19% granular blasts that are strongly positive for MPO ( Fig. 13.7 ) and myeloid antigen CD13, CD33, or both. The presence of a t(8;21) translocation is associated with a favorable prognosis.

The marrow in AML-M3 contains more than 19% abnormal promyelocytes that are strongly positive for MPO, positive for CD13 and/or CD33, and human leukocyte antigen (HLA)-DR negative. A translocation between the PML and RAR α genes [t(15;17)] is highly characteristic. Patients with AML-M3 often present with DIC caused by release of thrombogenic substances by the tumor cells. Initial cytotoxic chemotherapy is supplemented with ATRA, a vitamin A derivative that, by bypassing the defective retinoic acid receptor, induces maturation of the abnormal promyelocytes to more mature, less proliferative myeloid cells.

The marrow in acute myelomonocytic leukemia (AML-M4) contains an admixture of MPO-positive myeloblasts and nonspecific esterase-positive monoblasts ( Fig. 13.8 ). AML-M4 with marrow eosinophilia (AML-M4Eo) is associated with chromosome 16 defects—inv(16), t(16;16)—and has a more favorable prognosis.

Acute monoblastic/monocytic leukemia (AML-M5) is composed of monoblasts with or without promonocytes. Monoblasts and promonocytes are nonspecific, esterase positive, and MPO negative and have weak CD4+. The mature monocyte antigen CD14 is expressed by promonocytes but only weakly and variably by monoblasts. Whereas the AML-M5a variant is composed of monoblasts only ( Fig. 13.9 ), the AML-M5b variant is composed of both monoblasts and promonocytes ( Fig. 13.10 ). Extramedullary disease is common, with infiltration of the gums, skin, and lymph nodes.

Acute erythroid leukemia (AML-M6) encompasses two distinct entities. The marrow in the more common erythroid/myeloid variant (AML-M6a) contains increased myeloblasts (>19%) in an otherwise markedly erythroid-predominant marrow ( Fig. 13.11 ). The marrow in the rare variant known as pure erythroid leukemia (AML-M6b) contains abnormal proerythroblasts (>19%) in a markedly erythroid-predominant marrow ( Fig. 13.12 ). Myeloblasts are not increased in the AML-M6b variant. The abnormal proerythroblasts in AML-M6b often contain large periodic acid–Schiff–positive vacuoles in the cytoplasm ( Fig. 13.13 ).

The marrow in acute megakaryoblastic leukemia (AML-M7) contains numerous abnormal megakaryoblasts, often with extensive myelofibrosis ( Fig. 13.14 ). Megakaryoblasts express platelet glycoprotein antigens CD41 and CD61 yet are negative for MPO by immunohistochemistry. AML-M7 is the most common AML subtype in Down syndrome.

Acute eosinophilic and basophilic leukemias are very rare and are not discussed here.

The CMLs (chronic myelogenous leukemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia) are discussed in the section on myeloproliferative neoplasms.