Acute Leukemias

Acute leukemia, now more accurately referred to as acute nonlymphocytic leukemia (ANLL), is the more common form of leukemia in adults. Acute lymphoblastic leukemia is predominantly a disease of children that accounts for approximately 20% of all acute leukemias in adults. ANLL occurs with increasing frequency with advancing age and frequently is preceded by a more chronic hematologic disorder. Multiple myeloma, polycythemia vera, paroxysmal nocturnal hemoglobinuria (PNH), chronic myeloid leukemia (CML), and the myelodysplastic syndromes all have a high propensity to culminate in acute leukemia. When acute leukemia follows these disorders, the prognosis is significantly poorer than de novo leukemia.

Clinical manifestations of the acute leukemias are similar regardless of the cell of origin (lymphocytic or myelogenous). Typically there is an abrupt onset of nonspecific complaints, including fatigue, anorexia, weight loss, and weakness. Hematologic abnormalities frequently lead to the presenting symptoms; thus, anemia contributes to fatigue, thrombocytopenia leads to bleeding and bruising, and lack of mature neutrophils can lead to serious infections and concomitant fevers. Those patients who evolve into AML from a preceding hematologic disorder tend to have a more chronic evolution in their symptoms. The presence of anemia, thrombocytopenia, and granulocytopenia with circulating blast cells are the hallmark of acute leukemia. The marrow, when examined, is hypercellular with a lack of differentiation and a predominance of blasts.

The etiology of the acute leukemias is not completely understood but is thought to be the result of multiple genetic aberrations to a clone of hematopoietic cells. Many genetic defects have been associated with both acute myelogenous leukemia and acute lymphocytic leukemia. These genetic defects tend to be chromosomal translocations and frequently when characterized have involved so-called oncogenes. Many of these abnormalities are thought to be etiologically involved in the evolution of leukemia.

Classification
The acute leukemias are broken down into acute nonlymphocytic leukemia, of which there are seven types, and the acute lymphocytic leukemias, of which there are three types. The lymphocytic leukemias and their subtypes are differentiated from the nonlymphocytic leukemia by the combination of morphology, immunophenotype, and cytogenetics. In some cases, the distinction can be very difficult. Nonetheless, it is important because therapy is directly related to the cell of origin of the leukemia. The most characteristic morphologic features distinguishing acute nonlymphocytic from acute lymphocytic leukemias are the presence of Auer rods and peroxidase stain positivity, which defines the leukemia as acute nonlymphocytic.

Treatment
Acute leukemias have a fulminant course if left untreated, with a median survival of less than 4 months. Death secondary to cytopenias is the rule, with bleeding and infections being very common. The goal of treatment is to induce remission, and currently that requires intensive chemotherapy for both ALL and ANLL. The initial induction chemotherapy is intended to be myeloablative, and thus a prolonged period of cytopenia follows the initiation of therapy.

The chemotherapeutic agents used for remission induction depend on the classification of the leukemia. AML is usually treated with a combination of two drugs, usually cytarabine and an anthracycline such as daunorubicin, given over several days to 1 week. The likelihood of attaining a complete response (CR) with this regimen in patients over 60 is approximately 50% as compared to 70% for younger patients. Factors playing a role in the inability of this group of patients to achieve remission is the high incidence of preexisting hematologic disorders, such as myelodysplastic syndrome, chromosomal abnormalities, and chemotherapy resistance. All of these are poor prognostic factors for achieving remission at any age. In addition to difficulty attaining CR, treatment-related mortality associated with induction can be as high as 25% to 50% in patients over 60 years old as compared to 5% to 15% in younger patients.

The requirements for supportive care through the period of induction are enormous, and in general only hematologists experienced in the care of leukemic patients with adequate blood bank support should treat these patients. Although it has been suggested that a reduced dose of induction therapy is more effective in elderly patients, this remains a controversial area. Several trials have studied the use of hematopoietic growth factor support (G-CSF or GM-CSF) during induction. The growth factors shorten the time of neutropenia but did not impact on early mortality or long-term survival.

Once remission is achieved, additional postremission or consolidation chemotherapy is administered to maximize the odds for a prolonged remission. Several trials support the use of less intense chemotherapy for the elderly during this period without jeopardizing long-term survival.

Much of the effort to have impact on the acute leukemias has been centered on intensification of induction therapy and consolidation therapy with bone marrow transplantation support. This strategy is generally not available to patients over the age of approximately 60 and thus remains of limited value to those patients most commonly affected by these diseases. A more promising approach is the use of moleculary targeted therapy. Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia, is defined by a t(15 : 17) chromosomal translocation. This translocation involves one of the retinoic acid receptor genes. All-trans retinoic acid (ATRA) induces differentiation of leukemic blasts and results in a significant remission. With the use of ATRA, induction doses of chemotherapy in APL have been reduced and the prolonged cytopenia following induction has been significantly decreased. In the future, we may know enough about the pathophysiology of the various forms of leukemia that therapy can be tailored in a much more specific manner, sparing the normal hematopoietic clones.

ALL, which is less common in adults, is treated with multiple drugs. Four drugs are frequently used for induction: vincristine, prednisone, l-asparaginase, and daunorubicin. ALL has rapidly become a curable disease in children, but results in adults are less favorable. Central nervous system treatment is required in all patients. In ALL, once remission is achieved, approximately 2 years of maintenance and consolidation therapy is currently the standard.

Future Directions
As mentioned, most of the progress to date in treating leukemia has centered on optimizing myeloablative approaches. Bone marrow transplantation, which represents the extreme of this approach, was not previously an option in older patients. However, a new approach, the submyeloablative bone marrow transplant, offers a potential cure for some patients over 60 as well. The basis of this approach involves lower doses of chemotherapy with reliance on graft versus leukemia effect to ultimately clear the malignant clone. We need to await results of early trials before we can judge the long-term success of this approach.

Research in immunotherapy is advancing rapidly and offers effective therapy with isolated toxicity. Gemtuzumab ozogamicin (Mylotarg) is an anti-CD33 antibody conjugated with a cytotoxic antitumor antibiotic. CD33 is an antigen found on the surface of myeloblasts. This approach specifically targets the myeloblast and spares other hematologic differentiation pathways. How this cytotoxic antibody will be used in the treatment of acute myeloid leukemia is yet to be determined. Aggressive research and development of molecular-targeted therapy and immunotherapy offers hope for effective treatment options with less toxicity in the future.

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Provided by ArmMed Media
Revision date: July 6, 2011
Last revised: by David A. Scott, M.D.