Acute Leukemias



In acute leukemias immature hematopoietic cells proliferate without differentiation into nor­mal mature blood cells. The proliferating cells, whether myeloblasts or lymphoblasts, do not allow the normal production of erythrocytes, granulocytes, and platelets to take place. This leads to the major clinical complications of the disease: anemia, susceptibility to infection, and bleeding.

In most cases of acute leukemia, one finds no recognizable predisposing condition or event. In a few circumstances, however, an association with a possible leukemogenic agent(s) has been identified. Known agents associated with the de­velopment of acute leukemia include radiation, viruses, genetic predisposition, and chemicals (Table 54-8). How these agents interact with nor­mal marrow stem cells so as to produce a malig­nant clone that lacks the ability to differentiate is not known.

Acute leukemias are divided into two broad cat­egories: acute lymphoblastic leukemia (ALL) and acute myeloblasts leukemia (AML). ALL is pri­marily a disease of children, AML primarily of adults. Approximately 20 per cent of adult leu­kemias, however, are of the lymphoblastic type. Because the natural history and the treatment of these two types of leukemia differ, it is important to distinguish between them. The major distinc­tion lies in bone marrow morphology; histochem-ical stains and surface and cytoplasmic markers are also useful (Table 54-9). Chromosome anal­ysis of the acute leukemias has not identified a consistent abnormality; however, various abnor­mal karyotypes are described.

Because of heterogeneity within the two broad categories of acute leukemia, a French, American, and British (FAB) group recently has developed a subdividing classification that has proved useful in studying the course and therapy of the acute leukemias (Table 54-10). Among the myeloblastic leukemias the morphologic subtypes possess relatively distinctive clinical correlation. For ex­ample,, acute promyelocytic leukemia (M3) is as­sociated with disseminated intravascular coagulation (DIC); the prominent cytoplasmic granules in the promyelocytes release enzymes that stimulate the coagulation cascade and pro­mote intravascular coagulation. Acute monocytic leukemia (M5) is associated with skin and gum infiltration with leukemic cells. Among lym­phoblastic leukemias, the Lt subtype is found pre­dominantly in children and the L2 subtype is found primarily in adults. The L3 subtype is un­common and carries a poor prognosis.

The diagnosis of acute leukemia is rarely dif­ficult. The patient is usually acutely ill and pre­sents with symptoms that indicate abnormal bone marrow function: infection due to granulocyto­penia, bleeding due to thrombocytopenia, and/or anemia due to lack of erythroid maturation. Bone pain due to the expanded leukemic marrow may be present. In ALL, lymphadenopathy and sple­nomegaly are common. The total white blood count usually is elevated, sometimes above 100,000/u.l, but can be normal or even low (OOOO/ul). The blood smear is almost always ab­normal, snowing predominantly blast cells with only a few normal mature leukocytes present. The hemoglobin and platelet count are almost always depressed. The blood uric acid is usually elevated due to the increased white cell turnover; clinical gout is rare but renal damage due to the hyperuricemia may occur. A bone marrow aspirate and biopsy make the diagnosis. The marrow is almost always hypercellular or “packed” with sheets of monotonous undifferentiated cells that replace the normal marrow elements.

The diagnosis of acute leukemia represents a medical emergency. The initial hours or days after diagnosis should be spent stabilizing the patient and preparing him for treatment. If the white blood count is greater than 100,000/u.l, the patient is at high risk for cerebral hemorrhage caused by leukostasis, that is, obstruction of and damage to blood vessels plugged with rigid blasts. In this set­ting, immediate steps should be taken to reduce the white count by initiating chemotherapy, if possible, or performing leukapheresis. Allopuri-nol, a xanthine oxidase inhibitor, is given con­currently to decrease the uric acid formation that results when treatment begins to destroy leuko­cytes. Antibiotics may be needed to treat infec­tions, which can be life-threatening when patients have few or no mature granulocytes. Transfusion with red cells to maintain adequate blood he­moglobin levels and/or platelets to prevent hem­orrhage is usually required. Acute leukemia is one of the most dreaded diagnoses that a patient can receive. The initial management must include enough time spent with the patient and his family to reassure them and to explain the treatment and support programs.

The specific treatment of acute leukemia con­sists primarily of chemotherapy; radiotherapy sometimes may be used as an adjunct. The total leukemic cell burden is estimated to be from 10″ to 1012 cells at clinical presentation. Chemother-apeutic drugs follow first-order kinetics. This means that the drugs kill a constant percentage of cells (e.g., 99 per cent) with each administration. A clinically complete remission with disappear­ance of all detectable leukemia in the blood and bone marrow may mean a reduction in tumor bur­den from 1012 to 109 cells. A similar amount of treatment is needed to reduce the number of cells from 109 to 107. Thus, the eradication of the last leukemia cell by chemotherapy becomes almost an impossible task.

Chemotherapeutic drugs are administered with the goal of stopping cells from proliferating. The drugs are targeted against different phases of the cell cycle, with specific programs designed to fol­low the kinetics of the cell cycle. An example of a treatment program for acute lymphoblastic leu­kemia is outlined in Table 54-11. Similar pro­grams are used in the treatment of AML, in which case the major drugs are cytosine arabinoside and daunorubicin.

Cure of acute leukemia with rigorous chemo­therapy programs and meticulous supportive care is sometimes possible, although the encouraging results achieved in children with ALL (i.e., over 60 per cent alive in complete remission and prob­ably cured at five years] have not been reproduced in adults. About 30 per cent of adults with ALL may obtain a long-term remission. The percentage is considerably smaller in AML, with only 10 to 20 per cent surviving five years in remission, al­though 60 to 70 per cent of patients achieve a first remission averaging one year in duration.

Bone marrow transplantation from a related HLA-matched donor is being investigated as a treatment for patients with acute leukemia. Pa­tients under age 30 who achieve an initial com­plete remission with chemotherapy can be con­sidered possible candidates for this experimental procedure if they have a suitable donor. The com­plications of bone marrow transplantation are substantial, however, and include acute and/or chronic graft-versus-host disease, interstitial pneumonias, and the infections and hemorrhagic complications expected during an initial period of bone marrow aplasia. Late recurrence of the leukemia is still a major concern and is believed to represent inadequate eradication of the leu­kemic clone by the initial cytotoxic treatment. Since in one case, however, post-transplant re­currence in a male patient involved a female’s donor cells, it appears possible that the recipient passed a transmittable agent to the new cell line.

Other innovative approaches to the cure of acute leukemias include the use of monoclonal antibodies directed to leukemia-associated cell surface antigen. The technology of this approach is progressing rapidly and may be incorporated into future treatment programs.

refractory to standard therapy. Affected patients are usually elderly; however, in recent years an increasing number of younger patients have de­veloped myelodysplastic syndromes following prior treatment with radiotherapy, combination chemotherapy, or both, for another neoplasm such as Hodgkm’s disease or ovarian carcinoma. Typically, the patient presents with the insidious onset of increasing fatigability and decreasing ex­ercise tolerance; often the patient ascribes the symptoms to “growing old.” Physical examina­tion may reveal pallor, and laboratory examina­tion shows an anemia that may be profound. The anemia is typically macrocytic, with an MCV of 100 to 110 u.; the peripheral smear may show a dimorphic erythrocyte population, and the pa­tients may also have leukopenia with or without thrombocytopenia. The bone marrow is hyper-cellular, with increased iron stores and morpho­logically abnormal erythroid precursors (dyseryth-ropoiesis) as well as an increased percentage of early myeloid cells. This syndrome has been called “refractory anemia” or “preleukemia” in the past. Because the initial presentation and the course are variable, the condition is now referred to as the myelodysplastic syndrome and further defined according to a classification proposed by the FAB co-operative group mentioned above. Table 54-12 outlines the major clinical features and relative incidence of the five types of mye­lodysplastic syndromes. For refractory anemia (with or without ringed sideroblasts), the median survival time is approximately three to four years. The other three categories (refractory anemia with excess blasts, chronic myelomonocytic leukemia, and refractory anemia in transformation) carry a survival of one to two years or less. The risk of developing acute leukemia increases with the number of blasts in the bone marrow at presen­tation; thus, about 20 to 30 per cent of patients with refractoryanemia (type 1 or 2) develop acute leukemia, but over 60 per cent of patients with refractory anemia with excess blasts in transfor­mation will develop acute leukemia.

Treatment of the myelodysplastic syndrome is primarily directed toward improving the anemia. Blood transfusions are a mainstay of treatment. A few patients with refractory anemia with ringed sideroblasts respond to large doses of vitamin B6. Chemotherapy has been used when increased numbers of blasts appear in the bone marrow. The role for chemotherapy, either in conventional doses or in low doses, is still being studied.