CLL and Hemolytic Anemia

By Charles Hesdorffer, MD, National Institute of Health. Dr. Hesdorffer reports no financial relationship relevant to this field of study.

A 67-year-old previously healthy man was referred from his primary care physician because of an abnormal CBC. Although he had noted gradually increasing fatigue over approximately six months, this had become noticeably worse and, for this reason, he went to the doctor. He had not experienced night sweats or weight loss and had no localizing symptoms.

Upon physical exam, there was notable pallor. He was afebrile, his blood pressure was 118/76, and his pulse was 100. There was no palpable lymphadenopathy, but the spleen was palpable 4 cm below the left costal margin. The remainder of his physical examination was normal.

Complete blood count revealed a WBC of 44,000/cu mm, with a differential of 14% neutrophils, 4% bands, 2% monocytes, and 80% small lymphocytes with "smudge" cells noted. Hemoglobin was 6.5 g/dL, hematocrit was 20%, and MCV was 88.

Diagnostic Considerations

There is very little doubt that this individual has a leukemic process, most likely chronic lymphocytic leukemia or CLL. This degree of lymphocytosis, the characteristic lymphocyte predominance with such a high absolute lymphocyte count, and the presence of smudge cells are all typical features, and are diagnostic of little else. At this juncture, the questions are: What type of CLL does he have, does he have clinical issues that arise from his CLL that require therapeutic intervention, and what is his prognosis?

Required vs. optional Diagnostic confirmation and testing

A bone-marrow test may be helpful but frequently is not necessary to establish the diagnosis of CLL. One can confirm the diagnosis with peripheral blood flow cytometry. Marrow analysis may be useful in certain situations. For example, a patient who is treated for active, symptomatic disease and appears to have responded clinically but without improvement counts. Here the question is whether the patient's disease is refractory or the marrow has become hypoplastic due to the treatment.

I would, thus, start with laboratory studies to define the nature and extent of the disease. Flow cytometry would confirm the presence of a B- or T-cell CLL vs. any other similar chronic lymphoid malignancy, such as LGL leukemia or Hairy Cell Leukemia, with the typical finding of a B-cell phenotype, usually lambda or kappa light-chain restricted, confirming clonality and expressing CD20 (usually dim), CD23 and, in most patients, CD5 and CD52, with CD10 being negative.

Additional blood studies should include: a chemistry profile (for renal and hepatic function), B2-microglobulin, LDH, ESR, CRP, iron panel, ferritin, reticulocyte count, red cell folate level, haptoglobin, Coombs test, immunoglobulin panel, and IPEP, as hypogammaglobulinemia is both common in untreated and especially in patients treated with CD20 antibody (rituxan and ofatumumab). Many patients also may have a monoclonal serum spike that should be followed carefully through the course of their disease (especially in the setting of patients who have an IgM spike and who may thus have a Waldenstrom's macroglobulinemia).

A CT scan of neck, chest, abdomen, and pelvis should be obtained and followed as clinically indicated. Finally, although CNS involvement with CLL is extremely uncommon, if patients present with neurological signs, the initial workup should include brain CT, MRI, and lumbar punctures.

The current case highlights one of the nuances of CLL in that the disease is occasionally associated with autoimmune features, such as ITP or hemolytic anemia. Under such circumstances, the diagnostic strategy could include a bone marrow aspirate to confirm the presence of adequate or increased red cell and platelet precursors. For anemic patients, a Coombs and reticulocyte count are useful to discriminate between hemolysis and decreased marrow production.

Treatment Considerations

CLL is characterized by a highly variable clinical course. Some patients are symptomatic at diagnosis, or early thereafter, and require early therapy. Others have no or minimal symptoms for many years, and may have a normal life expectancy. Treatment of early-stage and low-risk patients has not been shown to prolong survival. Nonetheless, recently introduced, highly effective, and potentially curative interventions have resulted in a need to reassess this position. Therapies, including monoclonal antibodies directed against specific cell surface markers, used alone or in combination with other antibodies or chemotherapy, and autologous or allogeneic stem-cell transplantation hold the promise of more effectively reducing tumor burden to the point where prolonged survival and even disease eradication (allogeneic transplantation only) in selected patients would be expected. Our improved understanding of the molecular pathophysiology of CLL, and of the underlying immune deficiency, have made decisions regarding treatment both more rational but also more complicated because of the conflicting features of the disease in many patients.

The progress in understanding the pathogenesis, as well as in predicting outcomes, has led to the development of curtailed and potentially less toxic treatments. A number of clinical and biological markers of prognostic relevance have been identified. These include clinical characteristics (e.g., age, stage, gender, and performance status), as well as laboratory parameters (e.g., lymphocyte count, lactate dehydrogenase [LDH], marrow infiltration pattern, lymphocyte doubling time, soluble CD23 [sCD23], beta 2-microglobulin [B2-MG], or thymidine kinase [TK]). More recently, prognostic markers related to the biology of CLL have been identified.

Defined Treatments and Strategies

High-risk Patients: In the setting of any patient with a 17p deletion, since the prognosis is the worst for these patients based on almost all studies reviewed, no matter how many other mitigating prognostic factors these patients may have, this group, in general, can be dealt with by advising the patient to enter a clinical trial. Alternatively, bone-marrow transplantation is an acceptable modality of treatment for this select group of patients. However, the benefit of this modality of therapy is restricted by age (generally < age 60, which is in and of itself an issue of great controversy) and the general performance status of the patient. Furthermore, its use is also clearly dependent upon the accessibility of a matched-related or unrelated donor, although giant strides are possible in the near future in terms of the use of cord blood or haploid identical donors.

An antibody that interacts with the CD56 surface antigen on B and T cells, alemtuzumab has been demonstrated to improve the survival of these patients. However, this agent causes significant and prolonged immune deficiency, and prophylactic use of antimicrobial antibiotics is recommended.

Most other treatment strategies generally used in CLL, such as rituxan, fludarabine and, thus far, bendamustine, have proven to be relatively inactive in changing the natural history of patients with this poor prognostic marker.

Low-risk Patients: Patients who demonstrate a full set of good prognostic features (low burden of disease, normal B2-microglobulin, the absence of any clinical features indicating complications from CLL, 13q deletion, mutated Ig H chain, and absent CD38 surface marker) should receive no treatment and be watched until such time as either they demonstrate complications from their disease or some form of transformation to a higher grade of disease is noted.

Additionally, treatment for autoimmune complications are important as the sudden development of anemia and thrombocytopenia can be debilitating and if immune mediated can readily reversed. Thus, in the case presented here, I would elect to treat with single-agent rituximab (anti-CD20) and follow carefully to assess whether such treatment reverses what I believe to be a CLL-associated autoimmune hemolytic anemia.

In summary, most patients will be treated with their risk stratification being a thoughtful compilation of all risk factors by the treating physician. Hopefully, in the next few years, longitudinal and epidemiological studies will allow even more precise risk stratification, and our ever-increasing understanding of the molecular and genetic alterations that characterize this disorder will result in selected therapies that will more effectively alter the natural history of this disorder.


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3. Doney KC, et al. Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplantation. 2002;29:817–823.

4. Wierda WG, et al. Novel immune-based treatment strategies for chronic lymphocytic leukemia. J Clin Oncol. 2005;23;6325-6332.