Differential Diagnosis

Few syndromes can be confused with chronic lymphocytic leukemia. Viral infections producing lymphocytosis should be obvious from the presence of fever and other clinical findings. Other lymphoproliferative diseases such as Waldenstrom’s Waldenström’s macroglobulinemia, hairy cell leukemia, or lymphoma in the leukemic phase are distinguished on the basis of the morphology of circulating lymphocytes and bone marrow.

Treatment

Most cases of early indolent chronic lymphocytic leukemia require no specific therapy. Indications for treatment include progressive fatigue, troublesome lymphadenopathy, or the development of anemia or thrombocytopenia. These patients have either symptomatic and progressive stage II disease or stage III/IV disease. Initial therapy is with chlorambucil, 0.6–1 mg orally every 3 weeks. Complications such as autoimmune hemolytic anemia or immune thrombocytopenia may be treated with high-dose prednisone but often require splenectomy for control. Fludarabine is a new agent which is useful in treating disease refractory to other agents. As initial therapy, fludarabine produces faster and more complete responses than chlorambucil, and the duration of remissions is considerably longer. However, fludarabine causes long-term immunosuppression, and it remains to be determined if it should be used as primary therapy or reserved for use later in the disease. The rare young patient (age under 50) with aggressive disease may be a candidate for allogeneic bone marrow transplantation.

Prognosis

Median survival is approximately 6 years, and 25% of patients live more than 10 years. Patients with stage 0 or I disease have a median survival of 10 years. It is important to reassure these patients that despite the frightening diagnosis of “leukemia” they can live a normal life for many years. Patients with stage III or IV disease have a median survival of less than 2 years. Chronic lymphocytic leukemia is managed in palliative fashion. Patients with advanced disease benefit only briefly from intensive therapy.

Clinical Findings
A. Symptoms and Signs: Chronic lymphocytic leukemia is a disease of the elderly, with 90% of cases occurring after age 50 and a median age at presentation of 65. Many patients will be incidentally discovered to have lymphocytosis. Others present with fatigue or lymphadenopathy. On examination, 80% of patients will have lymphadenopathy and half will have enlargement of the liver or spleen.

A prognostically useful staging system has been developed as follows: stage 0, lymphocytosis only; stage I, lymphocytosis plus lymphadenopathy; stage II, organomegaly; stage III, anemia; stage IV, thrombocytopenia.

Chronic lymphocytic leukemia usually pursues an indolent course but occasionally will present as a rapidly progressive disease. These patients usually have larger, less mature-appearing lymphocytes and are said to have “prolymphocytic” leukemia. In 5–10% of cases, chronic lymphocytic leukemia may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. In approximately 5% of cases, while the systemic disease remains stable, an isolated lymph node will be transformed into an aggressive large cell lymphoma (Richter’s syndrome).

B. Laboratory Findings: The hallmark of chronic lymphocytic leukemia is isolated lymphocytosis. The white blood count is usually greater than 20,000/mL and may be markedly elevated. Usually 75–98% of the circulating cells are lymphocytes. Lymphocytes appear small and “mature,” with condensed nuclear chromatin, and are morphologically indistinguishable from normal small lymphocytes. The hematocrit and platelet count are usually normal at presentation. The bone marrow is variably infiltrated with small lymphocytes. (See Supplemental Figures 13–28 and 13–29.) The malignant cells weakly express surface immunoglobulin, and the monoclonal nature of the cells can be demonstrated by the finding of a single light chain type on the surface. The immunophenotype of CLL is unique in that it co-expresses B lymphocyte lineage markers such as CD19 with the T lymphocyte marker CD5. Other B cell malignancies do not express CD5.

Hypogammaglobulinemia is present in half of cases and becomes more common with advanced disease. In some instances, a small amount of IgM paraprotein is present in the serum. Pathologic changes in lymph nodes are the same as in diffuse small cell lymphocytic lymphoma.

Chronic lymphocytic leukemia (CLL) a B lymphocyte (rarely T lymphocytes) clonal malignancy. The disease is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes. These cells are immunoincompetent and respond poorly to antigenic stimulation.

Chronic lymphocytic leukemia is manifested clinically by immunosuppression, bone marrow failure, and organ infiltration with lymphocytes. Immunosuppression, bone marrow failure, and infiltration of organs account for most clinical manifestations. Immunodeficiency is also related to inadequate antibody production by the abnormal B cells. With advanced disease, chronic lymphocytic leukemia may cause damage by direct tissue infiltration.

Prognosis

Approximately 70–80% of adults with acute myelogenous leukemia under age 60 achieve complete remission. High-dose postremission chemotherapy leads to cure in 30–40% of these patients, and high-dose cytarabine has been shown to be superior to therapy with lower doses. Allogeneic bone marrow transplantation (for younger adults with HLA-matched siblings) is curative in approximately 60% of cases. Autologous bone marrow transplantation is a promising new form of therapy that may cure 50–70% of patients in first remission. One recent study demonstrated the superiority of this approach to nonablative chemotherapy. Older adults with acute myelogenous leukemia reportedly achieve complete remission approximately 50% of the time. In selected cases, older patients may be treated with intensive chemotherapy with curative intent.

Ninety percent of adults with acute lymphoblastic leukemia achieve complete remission. Subsequent postremission chemotherapy is curative in 30–50% of adults. Acute lymphoblastic leukemia in children is much more responsive to therapy, with 95% achieving complete remission and 60–70% of these being cured with postremission treatment that is far less toxic than that necessary for adults.

Once leukemia has recurred (“relapsed”) after initial chemotherapy, bone marrow transplantation (BMT) is the only curative option. Allogenic BMT can be used for those under age 55 with histocompatible sibling donors and is successful in 30–40% of cases. Autologous BMT may be curative in 30–50% of cases after a second remission is achieved.

Differential Diagnosis

Acute myelogenous leukemia must be distinguished from other myeloproliferative disorders, chronic myelogenous leukemia, and myelodysplastic syndromes. It is important to distinguish acute leukemia from a left-shifted bone marrow that is recovering from a previous toxic insult. If the question is in doubt, a bone marrow study should be repeated in several days to see if maturation has taken place. Acute lymphoblastic leukemia must be distinguished from other lymphoproliferative disease such as chronic lymphocytic leukemia, lymphomas, and hairy cell leukemia. It may also be confused with the atypical lymphocytosis of mononucleosis. An experienced observer can distinguish these entities based on morphology.

Treatment

Most young patients with acute leukemia are treated with the objective of effecting a cure. The first step in treatment is to obtain complete remission, defined as normal peripheral blood with resolution of cytopenias, normal bone marrow with no excess in blasts, and normal clinical status. However, complete remission is not synonymous with cure, and leukemia will invariably recur if no further treatment is given.

Acute myelogenous leukemia is treated initially with intensive combination chemotherapy, including daunorubicin and cytarabine. Effective treatment produces aplasia of the bone marrow, which takes 2–3 weeks to recover. During this period, intensive supportive care, including transfusion and antibiotic therapy, is required. Once complete remission has been achieved, several different types of postremission therapy are potentially curative. Options include repeated intensive chemotherapy, high-dose chemoradiotherapy with allogeneic bone marrow transplantation, and high-dose chemotherapy with autologous bone marrow transplantation. Recently, progress has been made in the treatment of acute promyelocytic leukemia (M3). The addition of all-trans retinoic acid to initial chemotherapy has improved the results of both initial treatment and long-term survival. Retinoic acid appears to induce terminal differentiation in the malignant cell and hence to induce remission without cytotoxic effect.

Acute lymphoblastic leukemia is treated initially with combination chemotherapy, including daunorubicin, vincristine, prednisone, and asparaginase. Remission induction therapy for acute lymphoblastic leukemia is less myelosuppressive than treatment for acute myelogenous leukemia and does not necessarily produce marrow aplasia. After achieving complete remission, patients receive central nervous system prophylaxis so that meningeal sequestration of leukemic cells does not develop. As with acute myelogenous leukemia, patients may be treated with either chemotherapy or high-dose chemotherapy plus bone marrow transplantation.

Clinical Findings
A. Symptoms and Signs: Most patients with acute leukemia present with an acute illness and have been ill only for days or weeks. Bleeding (usually due to thrombocytopenia) is usually in the skin and mucosal surfaces, manifested as gingival bleeding, epistaxis, or menorrhagia. Less commonly, widespread severe bleeding is seen in patients with disseminated intravascular coagulation (seen in acute promyelocytic leukemia and monocytic leukemia). Infection is due to neutropenia, with the risk of infection becoming high as the neutrophil count falls below 500/mL. Patients with neutrophil counts less than 100/mL almost invariably become infected within several days. The most common pathogens are gram-negative bacteria (E coli, Klebsiella, Pseudomonas) or fungi (Candida, Aspergillus). Common presentations include cellulitis, pneumonia, and perirectal infections. Septicemia in severely neutropenic patients can cause death within a few hours if treatment with appropriate antibiotics is delayed.

Patients may also seek medical attention because of gum hypertrophy and bone and joint pain. The most dramatic presentation is hyperleukocytosis, in which a markedly elevated circulating blast count (usually > 200,000/mL) leads to impaired circulation, presenting as headache, confusion, and dyspnea. Such patients require emergent leukapheresis and chemotherapy.

On examination, patients are usually pale and have purpura, petechiae, and various signs of infection. Stomatitis and gum hypertrophy may be seen in patients with monocytic leukemia. There is variable enlargement of the liver, spleen, and lymph nodes. Bone tenderness, particularly in the sternum and tibia, may be present.
B. Laboratory Findings: The hallmark of acute leukemia is the combination of pancytopenia with circulating blasts. However, blasts may be absent from the peripheral smear in as many as 10% of cases (“aleukemic leukemia”). The bone marrow is usually hypercellular and dominated by blasts. More than 30% blasts are required to make a diagnosis of acute leukemia.

A number of other laboratory abnormalities may be present. Hyperuricemia may be seen. If disseminated intravascular coagulation is present, the fibrinogen level will be reduced, the prothrombin time prolonged, and fibrin degradation products or fibrin D-dimers present. Patients with acute lymphoblastic leukemia (especially T cell) may have a mediastinal mass visible on chest radiograph. Patients with meningeal leukemia will have blasts present in the spinal fluid. This is seen in approximately 5% of cases at diagnosis and is more common in monocytic types of acute myelogenous leukemia.

Acute leukemia should be classified as either acute lymphoblastic or acute myelogenous leukemia, also called acute nonlymphocytic leukemia. Patients with acute myelogenous leukemia may have granules visible in the blast cells. The Auer rod, an eosinophilic needle-like inclusion in the cytoplasm, is pathognomonic of acute myelogenous leukemia. To confirm the myeloid nature of the cells, histochemical stains demonstrating myeloid enzymes such as peroxidase or chloroacetate esterase may be useful. Monocytic lineage can be demonstrated by the finding of butyrate esterase. Acute lymphoblastic leukemia should be considered when there is no morphologic or histochemical evidence of myeloid or monocytic lineage. The diagnosis is confirmed by demonstrating surface markers characteristic of primitive lymphoid cells. Terminal deoxynucleotidal transferase (TdT) is present in 95% of cases of acute lymphoblastic leukemia. A variety of monoclonal antibodies have been used to define other phenotypes of acute lymphoblastic leukemia. Primitive B lymphocyte antigens include CD10 and CD19. T cell acute lymphoblastic leukemia is diagnosed by the finding of CD2, CD5, and CD7.

Acute myelogenous leukemia is usually categorized on the basis of morphology and histochemistry as follows: Acute undifferentiated leukemia (M0), acute myeloblastic leukemia (M1), acute myeloblastic leukemia with differentiation (M2), acute promyelocytic leukemia (M3), acute myelomonocytic leukemia (M4), acute monoblastic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7).

Acute lymphoblastic leukemia is most usefully classified by immunologic phenotype as follows: common, early B lineage, and T cell.

Cytogenetic studies have emerged as the most powerful prognostic factor in the acute leukemias. Favorable cytogenetics in acute myeloid leukemia include t(8;21), t(15;17), and inv(16)(p13;q22), These patients have a higher chance of achieving both short- and long-term disease control. Favorable cytogenetics in acute lymphoblastic leukemia are the hyperdiploid states. Unfavorable cytogenetics are monosomy 5 and 7, Philadelphia chromosome, and abnormalities of 11q23.

Acute leukemia is a hematopoietic progenitor cell malignancy. These cells proliferate in an uncontrolled fashion and ultimately replace normal bone marrow elements. Most cases arise with no clear cause. However, radiation and some toxins (benzene) are clearly leukemogenic. In addition, a number of chemotherapeutic agents (especially procarbazine, melphalan, other alkylating agents, and etoposide) may cause leukemia. The leukemias seen after toxin or chemotherapy exposure often develop from a myelodysplastic prodrome and are associated with abnormalities in chromosomes 5 and 7. Although a number of other cytogenetic abnormalities are seen in certain types of acute leukemia, their exact role in pathogenesis remains unclear.

Most of the clinical findings in acute leukemia are due to bone marrow failure, which results from replacement of normal bone marrow elements by the malignant cell. Less common manifestations include direct organ infiltration (skin, gastrointestinal tract, meninges). Acute leukemia is one of the outstanding examples of a once invariably fatal disease that is now treatable and potentially curable with combination chemotherapy.

Acute lymphoblastic leukemia (ALL) comprises 80% of the acute leukemias of childhood. The peak incidence is between 3 and 7 years of age. However, ALL is also seen in adults and comprises approximately 20% of adult acute leukemias. Acute myelogenous leukemia (AML; acute nonlymphocytic leukemia [ANLL]) is chiefly an adult disease with a median age at presentation of 50 years and an increasing incidence with advanced age. However, it is also seen in young adults and children.