Chronic Lymphocytic Leukemia
Summary of Key Points
• Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia and is defined by a distinctive immunophenotype of CD19+, CD20+, CD5+, CD23+, and surface immunoglobulin (sIg)-positive cells.
• The environmental or genetic cause of CLL in most patients is not known, although 8% to 10% of patients have a first-degree relative with this diagnosis.
• CLL lacks a single driving mutation that defines the disease, although autonomous B-cell receptor signaling appears to be important; the role of stem cells remains controversial.
• Classic staging for CLL at diagnosis is not helpful in most patients for risk stratification, but new prognostic factors such as immunoglobulin variable heavy chain (IGHV1) mutational status, interphase cytogenetics, β2-microglobulin, and thymidine kinase activity have improved staging of this disease.
• Common disease-related complications associated with CLL include immune deficiency with associated infections, autoimmune complications, secondary cancers, and Richter transformation.
• CLL is treated only when it becomes symptomatic, based on earlier studies showing no survival advantage to early intervention. This same approach is followed for all patients irrespective of genetic risk.
• The current standard treatment for young and older patients with CLL is chemotherapy combined with an anti-CD20 monoclonal antibody. Although this prolongs survival in CLL, it does not cure the disease.
• Reduced-intensity allogeneic stem cell transplant is curative in a subset of CLL patients but still carries with it treatment-related morbidity and mortality.
• B-cell receptor antagonists offer great promise as a new targeted therapy for CLL.
1. A 50-year-old patient was recently seen by his primary care physician and noted to have leukocytosis with a predominate mature lymphoid differential. Immune phenotype was performed on these cells showing CD19, CD5, CD20, CD23+ with surface immunoglobulin dimly positive. He is referred for initial consultation, where he lacks symptoms of disease or abnormal findings on physical examination. Which of the following tests or interventions is least helpful in his initial evaluation?
2. A 55-year-old truck driver with stage 0 CLL has new-onset dyspnea and fatigue. He has a palpable spleen, hemoglobin value of 5 g/dL, normal platelet count, and unchanged lymphocyte count and examination since last being seen 3 months ago. The most appropriate interventions would include all the following except:
A Obtaining a direct antiglobulin test (DAT), haptoglobin, and reticulocyte count
B Performing a bone marrow biopsy and aspirate
D Initiation of fludarabine, cyclophosphamide, and rituximab
3. A 56-year-old man with a 4-year history of CLL is seen in the clinic with progressive symptoms of anemia, thrombocytopenia, increasing lymph node enlargement, and interphase cytogenetics showing a del(11q22.3) as a sole abnormality. Bone marrow shows effacement of CLL, and workup for autoimmune complications is negative. The most appropriate therapy for this patient is
4. All of the following are true about reduced-intensity allogeneic stem cell transplantation in CLL except
A It is the only potentially curative therapy for CLL.
B It requires control of CLL before initiation.
C Common complications include acute and chronic graft-versus-host disease.
D It is an appropriate component of initial therapy for a high-risk CLL patients with del(13q14).
E There is less limitation on age or organ function for performing this type of transplant.
5. Appropriate correct statements about rituximab in CLL include all of the following except
A Rituximab therapy can increase the risk of hepatitis B reactivation.
B Rituximab maintenance therapy extends progression-free survival.
C Autoimmune hemolytic anemia and idiopathic thrombocytopenia purpura are responsive to rituximab.
D Rituximab infusion toxicity is not related to elevated blood lymphocyte count.
1. Answer: C. At initial diagnosis, both interphase cytogenetics and immunoglobulin gene mutational analysis can be helpful in further predicting outcome of chronic lymphocytic leukemia (CLL) progression and survival. Although these tests are not essential to do because they do not change therapy, they can provide the patient with more information about the disease. CLL has a higher frequency of secondary malignancies, so being diligent about appropriate screening is good practice. Similarly, CLL has a higher frequency of infections due to the immune suppression associated with the disease. The immune deficiency associated with CLL makes administration of a live vaccine such as the varicella vaccine contraindicated. Other vaccines for pneumococcus and influenza A are not live vaccines and can be safely administered.
2. Answer: D. This patient very likely has autoimmune hemolytic anemia (AIHA), a complication that arises in approximately 20% of CLL patients. Its genesis is often quick, with presentation often being dyspnea and fatigue. Diagnostic laboratory tests such as a DAT, haptoglobin, and reticulocyte count with a bone marrow biopsy can assist in differentiating this process from CLL progression. In general, AIHA initially is treated with prednisone. The use of chemotherapy or chemoimmunotherapy for AIHA is reserved for poorly responsive patients.
3. Answer: A. For many years, therapy for CLL was not associated with a survival advantage and many different approaches were utilized. The German CLL8 study compared fludarabine-cyclophosphamide-rituximab compared with fludarabine-cyclophosphamide and demonstrated that this therapy had an improved response, progression-free survival, and overall survival. The benefit of fludarabine-cyclophosphamide-rituximab compared with the other regimens is particularly pronounced in patients with del(11q22.3).
4. Answer: A. The application of reduced-intensity allogeneic stem cell transplantation can be extended to individuals in their seventh decade. Because of the reduced preparative regimen intensity, it is essential that this be applied when patients have reasonable control of disease. Bulky lymph nodes (>5 cm) is a common feature associated in many series with high risk of relapse. Although acute graft-versus-host disease is less common with this approach, it can occur. Chronic graft-versus-host disease occurs in 40% to 50% of patients and is predicted on the donor graft. Because of the adverse outcome associated with select high-risk genomic patients such as those with del(17p13.1), allogeneic transplant is an acceptable consideration for consolidation after the first treatment. It is not appropriate for a favorable-prognosis patient with del(13q14).
5. Answer: B. Rituximab is a highly effective therapy and prolongs survival when combined with fludarabine and cyclophosphamide in CLL. In NHL and CLL the use of rituximab can cause reactivation of hepatitis B. In some cases this can be fatal. It is therefore important to assess for evidence of active hepatitis B before starting therapy with rituximab and to monitor for reactivation if this is present. Rituximab infusion toxicity can occur in any CLL patient, and studies to date have not shown a relationship of this to elevated blood lymphocyte count. Although rituximab is effective for autoimmune cytopenias, it has not definitively shown benefit as a maintenance therapy for CLL.
