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Harrison’s Manual of Medicine



Acute Myeloid Leukemia
Chronic myeloid Leukemia (CML)
Myelodysplastic Syndromes (MDS)
Myeloproliferative Syndromes

Polycythemia Vera

Idiopathic Myelofibrosis

Essential Thrombocytosis

Acute myeloid leukemia (AML) is a clonal malignancy of myeloid bone marrow precursors in which poorly differentiated cells accumulate in the bone marrow and circulation.
Signs and symptoms occur because of the absence of mature cells normally produced by the bone marrow including granulocytes (susceptibility to infection) and platelets (susceptibility to bleeding). In addition, if large numbers of immature malignant myeloblasts circulate, they may invade organs and rarely produce dysfunction. Distinct morphologic subtypes exist (Table 63-1) that have largely overlapping clinical features. Of note is the propensity of pts with acute promyelocytic leukemia (APL) (FAB M3) to develop bleeding and DIC, especially during induction chemotherapy, because of the release of procoagulants from their cytoplasmic granules.

Table 63-1 Acute Myeloid Leukemia (AML) Classification Systems

INCIDENCE AND ETIOLOGY   About 7000 cases occur each year. AML accounts for about 80% of acute leukemias in adults. Etiology is unknown for the vast majority. Three environmental exposures increase the risk: chronic benzene exposure, radiation exposure, and prior treatment with alkylating agents and topoisomerase II inhibitors (e.g., doxorubicin and etoposide). Chronic myeloid leukemia, myelodysplasia, and myeloproliferative syndromes may all evolve into AML. Certain genetic abnormalities are associated with particular morphologic variants: t(15;17) with APL, inv(16) with eosinophilic leukemia; others occur in a number of types. Chromosome 11q23 abnormalities are often seen in leukemias developing after exposure to topoisomerase II inhibitors. The particular genetic abnormality has a strong influence on treatment outcome. Expression of MDR1 (multidrug resistance efflux pump) is common in older pts and adversely affects prognosis.
CLINICAL AND LABORATORY FEATURES   Initial symptoms of acute leukemia have usually been present for ❤ months; a preleukemic syndrome may be present in some 25% of pts with AML. Signs of anemia, pallor, fatigue, weakness, palpitations, and dyspnea on exertion are most common. WBC may be low, normal, or markedly elevated; circulating blast cells may or may not be present; with WBC >100 × 109 blasts per liter, leukostasis in lungs and brain may occur. Minor pyogenic infections of the skin are common. Thrombocytopenia leads to spontaneous bleeding, epistaxis, petechiae, conjunctival hemorrhage, gingival bleeding, bruising, especially with platelet count <20 × 109/L. Anorexia and weight loss are common; fever may be present.
Bacterial and fungal infection are common; risk is heightened with total neutrophil count <0.5 × 109/L, breakdown of mucosal and cutaneous barriers aggravates susceptibility; infections may be clinically occult in presence of severe leukopenia, and prompt recognition requires a high degree of clinical suspicion.
Hepatosplenomegaly occurs in about one-third of pts; leukemic meningitis may present with headache, nausea, seizures, papilledema, cranial nerve palsies.
Metabolic abnormalities may include hyponatremia, hypokalemia, elevated serum lactate dehydrogenase (LDH), hyperuricemia, and (rarely) lactic acidosis. With very high blast cell count in the blood, spurious hyperkalemia and hypoglycemia may occur.

Leukemic cell mass at time of presentation may be 1011–1012 cells; when total leukemic cell numbers fall below ~109, they are no longer detectable in blood or bone marrow and pt appears to be in complete remission (CR). Thus aggressive therapy must continue past the point when initial cell bulk is reduced if leukemia is to be eradicated. Typical phases of chemotherapy include remission induction and postremission therapy, with treatment lasting about 1 year.
Supportive care with transfusions of red cells and platelets (from CMV- seronegative donors, if pt is a candidate for bone marrow transplantation) is very important, as are aggressive prevention, diagnosis, and treatment of infections. Colony-stimulating factors offer little or no benefit; some recommend their use in older pts and those with active infections. Febrile neutropenia should be treated with broad-spectrum antibiotics (e.g., ceftazidime 1 g q8h); if febrile neutropenia persists beyond 7 days, amphotericin B should be added.
60–80% of pts will achieve initial remission when treated with cytarabine 100–200 mg/m2/d by continuous infusion for 7 d and daunorubicin [45 mg/ m2/d] or idarubicin [12–13 mg/m2/d] for 3 d. Addition of etoposide may improve CR duration. Half of treated pts enter CR with the first cycle of therapy and another 25% require two cycles. 10–30% of pts achieve 5-year disease-free survival and probable cure. Response to treatment after relapse is short, and prognosis for pts who have relapsed is poor. In APL, addition of trans-retinoic acid (tretinoin) to chemotherapy induces differentiation of the leukemic cells and may improve outcome. Arsenic trioxide also induces differentiation in APL cells.
Bone marrow transplantation from identical twin or HLA-identical sibling is effective treatment for AML. Typical protocol uses high-dose chemotherapy ± total-body irradiation to ablate host marrow, followed by infusion of marrow from donor. Risks are substantial (unless marrow is from identical twin). Complications include graft-versus-host disease, interstitial pneumonitis, opportunistic infections (especially CMV). Comparison between transplantation and high-dose cytarabine as postremission therapy has not produced a clear advantage for either approach. Up to 30% of otherwise end-stage pts with refractory leukemia achieve probable cure from transplantation; results are better when transplant is performed during remission. Results are best for children and young adults.

CML is a clonal malignancy usually characterized by splenomegaly and production of increased numbers of granulocytes; course is initially indolent but eventuates in leukemic phase (blast crisis) that has a poorer prognosis than de novo AML; rate of progression to blast crisis is variable; overall survival averages 4 years from diagnosis.
INCIDENCE AND ETIOLOGY   About 4000 cases occur each year. Over 90% of cases have a reciprocal translocation between chromosomes 9 and 22, creating the Philadelphia (Ph)chromosome and a fusion gene product called bcr-abl (bcr is from 9, abl from 22). The chromosome abnormality appears in all bone marrow–derived cells except T cells. The protein made by the chimeric gene is 210 kDa in chronic phase and 190 kDa in acute blast transformation. In some pts, the chronic phase is clinically silent and pts present with acute leukemia with the Ph chromosome.
CLINICAL AND LABORATORY FEATURES   Symptoms develop gradually; easy fatigability, malaise, anorexia, abdominal discomfort and early satiety from the large spleen, excessive sweating. Occasional pts are found incidentally based upon elevated leukocyte count. WBC count is usually >25 × 109/L with the increase accounted for by granulocytes and their precursors back to the myelocyte stage; bands and mature forms predominate. Basophils may account for 10–15% of the cells in the blood. Platelet count is normal or increased. Anemia is often present. Neutrophil alkaline phosphatase score is low. Marrow is hypercellular with granulocytic hyperplasia. Marrow blast cell count is normal or slightly elevated. Serum levels of vitamin B12, B12-binding proteins, and LDH are elevated in proportion to the WBC. With high blood counts, spurious hyperkalemia and hypoglycemia may be seen.
NATURAL HISTORY   Chronic phase lasts 2–4 years. Accelerated phase is marked by anemia disproportionate to the disease activity or treatment. Platelet counts fall. Additional cytogenetic abnormalities appear. Blast cell counts increase. Usually within 6–8 months, overt blast crisis develops in which maturation ceases and blasts predominate. The clinical picture is that of acute leukemia. Half of the cases become AML, one-third have morphologic features of acute lymphoid leukemia, 10% are erythroleukemia, and the rest are undifferentiated. Survival in blast crisis is often <4 months.

Chronic-phase disease may be treated with interferon-a (IFN) at 3 million units SC daily or tiw. The majority of pts obtain a hematologic response, and ~15% obtain cytogenetic remissions. Allopurinol, 300 mg/d, prevents urate nephropathy. The only curative therapy for the disease is HLA-matched allogeneic bone marrow transplantation. The optimal timing of transplantation is unclear, but transplantation in chronic phase is more effective than transplantation in accelerated phase or blast crisis. Transplantation appears most effective in pts treated within a year of diagnosis who have not received long- term IFN. Long-term disease-free survival may be obtained in 50–60% of transplanted pts. Infusion of donor lymphocytes can restore remission in relapsing pts. In pts without a matched donor, autologous transplantation may be helpful using peripheral blood stem cells. Treatment of pts in blast crisis is generally ineffective.

These are clonal abnormalities of marrow cells characterized by varying degrees of cytopenias affecting one or more cell lines. These entities have been divided into five clinical syndromes (Table 63-2). Other terms that have been used to describe one or more of the entities include preleukemia and oligoblastic leukemia.

Table 63-2 French-American-British (FAB) Classification of Myelodysplastic Syndromes

INCIDENCE AND ETIOLOGY   About 3000 cases occur each year, mainly in people >50 years old. Like AML, exposure to benzene, radiation, and chemotherapeutic agents may lead to MDS. Chromosome abnormalities occur in up to 80% of cases, including deletion of part or all of chromosomes 5, 7, and 9 (20 or 21 less commonly) and addition of part or all of chromosome 8.
CLINICAL AND LABORATORY FEATURES   Symptoms depend on the affected lineages. 85% of pts are anemic, 50% have neutropenia, and about one-third have thrombocytopenia. The pathologic features of MDS are a cellular marrow with varying degrees of cytologic atypia including delayed nuclear maturation, abnormal cytoplasmic maturation, accumulation of ringed sideroblasts (iron-laden mitochondria surrounding the nucleus), uni- or bilobed megakaryocytes, micromegakaryocytes, and increased myeloblasts. Table 63-2 lists features used to identify distinct entities.

Allogeneic bone marrow transplantation is the only curative therapy and may cure 60% of those so treated. However, the majority of pts with MDS are too old to receive transplantation. Chemotherapy has not clearly altered the natural history of disease. Pts with low erythropoietin levels may respond to erythropoietin, and a minority of pts with neutropenia respond to granulocyte colony-stimulating factor. Supportive care is the cornerstone of treatment.

The three major myeloproliferative syndromes are polycythemia vera, idiopathic myelofibrosis, and essential thrombocytosis. All are clonal disorders of hematopoietic stem cells.
Polycythemia Vera
The most common myeloproliferative syndrome, this is characterized by an increase in RBC mass, massive splenomegaly, and clinical manifestations related to increased blood viscosity, including neurologic symptoms (vertigo, tinnitus, headache, visual disturbances) and thromboses (myocardial infarction, stroke, peripheral vascular disease; uncommonly, mesenteric and hepatic). It must be distinguished from other causes of increased RBC mass (Chap. 27). This is most readily done by assaying serum erythropoietin levels. Polycythemia vera is associated with very low erythropoietin levels; in other causes of erythrocytosis, erythropoietin levels are high. Pts are effectively managed with phlebotomy. Some pts require splenectomy to control symptoms, and those with severe pruritus may benefit from psoralens and UV light. 20% develop myelofibrosis, <5% acute leukemia.
Idiopathic Myelofibrosis
This rare entity is characterized by marrow fibrosis, myeloid metaplasia with extramedullary hematopoiesis, and splenomegaly. Evaluation of a blood smear reveals tear-drop shaped RBC, nucleated RBC, and some early granulocytic forms, including promyelocytes. However, many entities may lead to marrow fibrosis and extramedullary hematopoiesis, and the diagnosis of primary idiopathic myelofibrosis is made only when the many other potential causes are ruled out. The following diseases are in the differential diagnosis: CML, polycythemia vera, Hodgkin’s disease, cancer metastatic to the marrow (especially from breast and prostate), infection (particularly granulomatous infections), and hairy cell leukemia. Supportive therapy is generally used; no specific therapy is known.
Essential Thrombocytosis
This is usually noted incidentally upon routine platelet count done in an asymptomatic person. Like myelofibrosis, many conditions can produce elevated platelet counts; thus, the diagnosis is one of exclusion. Platelet count must be >500,000/µL, and known causes of thrombocytosis must be ruled out including CML, iron deficiency, splenectomy, malignancy, infection, hemorrhage, polycythemia vera, myelodysplasia, and recovery from vitamin B12 deficiency. Although usually asymptomatic, pts should be treated if they develop migraine headache, transient ischemic attack, or other bleeding or thrombotic disease manifestations. Interferon-a is effective therapy, as are anagrelide and hydroxyurea. Treatment should not be given just because the absolute platelet count is high in the absence of other symptoms.

For a more detailed discussion, see Young NS: Aplastic Anemia, Myelodysplasia, and Related Bone Marrow Failure Syndromes, Chap. 109, p. 692; Spivak JL: Polycythemia Vera and Other Myeloproliferative Diseases, Chap. 110, p. 701; and Wetzler M, Byrd JC, Bloomfield CD: Acute and Chronic Myeloid Leukemia, Chap. 111, p. 706, in HPIM-15.



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