Steven Applebaum, M.D. and John Barstis, M.D.

Case Report

An 86-year-old woman had been followed for a few years with a mildly elevated white blood cell count. She had refused further work-up given her advanced age and impairment from a stroke many years in the past. She had been followed closely by her internist, with no adenopathy or constitutional symptoms. Her white cell count averaged 14,000 over many months, with a predominance of mature lymphocytes and a hemoglobin minimally depressed at 11.5 grams per deciliter and a normal platelet count. She became dizzy while in Las Vegas and was taken to a local emergency room. She was noted to have a hemo-globin of 8.5. A red blood cell transfusion was ordered, and the blood bank reported a warm IgG autoantibody. They were able to find compatible blood, and she received 3 units of packed red blood cells without incident, then returned home.

Her past medical history includes a stroke that left her aphasic and with a mild hemiparesis, and an early stage breast cancer treated with surgery over 30 years ago. She had no prior history of transfusions.

Further testing, including flow cytometric analysis of her peripheral blood, confirmed the diagnosis of chronic lymphocytic leukemia (CLL). Other labora-tory results reviewed from her hospitalization in Las Vegas also showed an elevated lactate dehydrogenase and slight elevation of her indirect bilirubin. She was started on prednisone, and her hemoglobin increased to 11.2 grams per deciliter, and the dose of prednisone has been tapered down to 5 mg per day after 3 months.

Discussion

Chronic lymphocytic leukemia is a disease consisting of an abnormal population of monoclonal lympho-cytes which do not respond to normal restraints on their clonal size. It is still not well understood precisely how this population develops. It appears that a genetic abnormality develops that causes this loss of growth control, possibly in conjunction with abnormal sensitivity to foreign or autoantigen stimu-lation. Thus, CLL is a much more diverse disease than previously thought. There are clearly cases of the disease which will progress relentlessly and prove fatal, and others which will allow normal survival without ever requiring treatment. Presently available testing does not allow precise differentiation of these types, but that is likely to change soon. For now, determination of zeta-chain associated protein (ZAP-70) is the most useful available assay to assess for a poor prognosis. This protein is not usually found in normal lymphocytes, and high levels are correlated with an aggressive course.

Chronic lymphocytic leukemia is a fairly common disease with an estimated 10,000 new cases diag-nosed in 2004. It is often discovered on a routine blood analysis, as most patients are asymptomatic at the time of diagnosis. Ninety percent of patients will be older than 50 years at time of diagnosis, and there is a male predominance. The hallmark of the diag-nosis is a persistent lymphocytosis of over 15,000 per microliter. The cells are indistinguishable from mature lymphocytes. morphologically. A bone marrow biopsy has been the standard diagnostic inter-vention, revealing excess numbers of lymphocytes, and in a diffuse rather than nodular pattern. However, a pathognomonic pattern on flow cytometry of peripheral blood is also diagnostic. Given its ease for the patient, it is generally the preferred method for initial diagnosis. A bone marrow biopsy is still often obtained at some point as a part of full evaluation to assess the degree of replacement by lymphocytes.

Chronic lymphocytic leukemia is not curable, and there is no convincing evidence so far that early or aggressive treatment improves survival. Availability of new markers such as ZAP-70 may lead to clinical trials demonstrating benefit from early intervention in poor prognostic groups, but until this information is available, therapy is usually instituted only when symptoms or problems develop, which can include bulky adenopathy, splenomegaly, fevers/chills, night sweats, fatigue, cytopenias or organ involvement. A high white blood count unaccompanied by any of the above findings is not strictly an indication for treat-ment; however, many hematologists will treat patients whose only abnormality is a white blood count inexcess of 100,000.

Alkylating agents such as chlorambucil have long been the most commonly used chemotherapy. However, concern about the leukemogenic potential of alkylators in patients who may have a very prolonged survival has led to a decline in their usage. Many new agents have been introduced in recent years, with improved efficacy. The most commonly used agents are fludarabine, a purine analog, and monoclonal antibodies, especially rituximab. The former is extremely well-tolerated symptomatically, with no gastrointestinal toxicity or alopecia, but is very immunosuppressive and often is given with prophylactic antibiotics. Rituximab is a humanized anti-CD-20 antibody, which is present on the surface of all B-lymphocytes, but not stem cells. It generally is non-toxic, but requires great care and expertise to administer for the first dose because of hypersensi-tivity reactions. These 2 agents are most often given as single agents, but also work well in combination with each other.

While many patients will develop a slowly progres-sive anemia from marrow suppression or replace-ment, an estimated 5% to 10% will have an acute drop in their hemoglobin or platelets due to immune destruction. Chronic lymphocytic leukemia-associ-ated autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia purpura (ITP) are thought to be due to abnormal immunoregulation, especially from cytokine dysfunction. Markedly increased levels of autoantibodies are frequent in CLL patients, even though they might not have clinically evident immune destruction. The neoplastic clone of B-cells can produce the autoantibody. However, clinically evident AIHA or ITP does not confer a worse prog-nosis.

The presentation is similar to any autoimmune hemolytic process, with symptoms of a rapid drop in the hemoglobin, including syncope, fatigue, dyspnea on exertion, or chest pain. The laboratory evaluation generally demonstrates an elevated reticulocyte count, a positive Coombs' test, and elevation of the indirect bilirubin and lactate dehydrogenase. Autoimmune hemolysis is a spontaneous event, and should be differentiated from patients who develop treatment-related hemolysis, which has been extensively reported related to the purine analogues.

Treatment for autoimmune hemolysis has primarily involved the use of steroids to suppress production of the autoantibody. Transfusion support must also be employed if the clinical circumstances require an immediate rise in the hemoglobin. Prednisone is the most commonly used steroidal agent, often started at high doses of 60 to 100 mg daily, and slowly tapered as allowed by the degree of ongoing hemolysis. Newer therapies have also been incorporated, including rituximab, which is highly effective in all forms of autoimmune hemolysis, not just those cases associated with CLL. Rituximab has replaced splenectomy as the treatment of choice for CLL-asso-ciated AIHA or ITP refractory steroids.