13-30: Chronic Lymphocytic Leukemia

CLL is a clonal malignancy of B lymphocytes. The disease is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes. These cells are immune-incompetent and respond poorly to antigenic stimulation.

CLL is manifested clinically by immunosuppression, bone marrow failure, and organ infiltration with lymphocytes. Immunodeficiency is also related to inadequate antibody production by the abnormal B cells. With advanced disease, CLL may cause damage by direct tissue infiltration.

CLL usually pursues an indolent course, but some subtypes behave more aggressively; a variant, prolymphocytic leukemia, is more aggressive. The morphology of the latter is different, characterized by larger and more immature cells. In 5–10% of cases, CLL may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. In approximately 5% of cases, while the systemic disease remains stable, an isolated lymph node transforms into an aggressive large-cell lymphoma (Richter syndrome).

Information about CLL is evolving rapidly, with new findings in biology and new treatment options; outcomes are improving significantly.

A. Symptoms and Signs

CLL is a disease of older patients, with 90% of cases occurring after age 50 years and a median age at presentation of 70 years. Many patients will be incidentally discovered to have lymphocytosis. Others present with fatigue or lymphadenopathy. On examination, 80% of patients will have diffuse lymphadenopathy and 50% will have enlargement of the liver or spleen.

The long-standing Rai classification system remains prognostically useful: stage 0, lymphocytosis only; stage I, lymphocytosis plus lymphadenopathy; stage II, organomegaly (spleen, liver); stage III, anemia; stage IV, thrombocytopenia. These stages can be collapsed into low risk (stages 0–I), intermediate risk (stage II), and high risk (stages III–IV).

B. Laboratory Findings

The hallmark of CLL is isolated lymphocytosis. The white blood cell count is usually greater than 20,000/mcL (20 × 10⁹/L) and may be markedly elevated to several hundred thousand. Usually 75–98% of the circulating cells are lymphocytes. Lymphocytes appear small and mature, with condensed nuclear chromatin, and are morphologically indistinguishable from normal small lymphocytes, but smaller numbers of larger and activated lymphocytes may be seen. The hematocrit and platelet count are usually normal at presentation. The bone marrow is variably infiltrated with small lymphocytes (eFigures 13–30 and 13–31). The immunophenotype of CLL demonstrates coexpression of the B lymphocyte lineage marker CD19 with the T lymphocyte marker CD5; this finding is commonly observed only in CLL and mantle cell lymphoma. CLL is distinguished from mantle cell lymphoma by the expression of CD23, low expression of surface immunoglobulin and CD20, and the absence of a translocation or overexpression of cyclin D1. Patients whose CLL cells have mutated forms of the immunoglobulin gene (IgVH somatic mutation) have a more indolent form of disease; these cells typically express low levels of the surface antigen CD38 and do not express the zeta-associated protein (ZAP-70). Conversely, patients whose cells have unmutated IgVH genes and high levels of ZAP-70 expression do less well and require treatment sooner. The assessment of genomic changes by FISH provides important prognostic information. The finding of deletion of chromosome 17p (TP53) confers the worst prognosis, while deletion of 11q (ATM) confers an inferior prognosis to the average genotype, and isolated deletion of 13q has a more favorable outcome.

Hypogammaglobulinemia is present in 50% of patients and becomes more common with advanced disease. In some, a small amount of IgM paraprotein is present in the serum.

Few syndromes can be confused with CLL. Viral infections producing lymphocytosis should be obvious from the presence of fever and other clinical findings; however, fever may occur in CLL from concomitant bacterial infection. Pertussis may cause a particularly high total lymphocyte count. Other lymphoproliferative diseases such as Waldenström macroglobulinemia, hairy cell leukemia, or lymphoma (especially mantle cell) in the leukemic phase are distinguished on the basis of the morphology and immunophenotype of circulating lymphocytes and bone marrow. Monoclonal B-cell lymphocytosis is a disorder characterized by fewer than 5000/mcL B cells and is considered a precursor to B-CLL.

The treatment of CLL is evolving as several active targeted agents have emerged. Most cases of early indolent CLL require no specific therapy, and the standard of care for early-stage disease has been observation. Indications for treatment include progressive fatigue, symptomatic lymphadenopathy, anemia, or thrombocytopenia. These patients have either symptomatic and progressive Rai stage II disease or stage III/IV disease. Initial treatment for patients with CLL consists of targeted biologic therapy in most cases. Options include ibrutinib (a Bruton tyrosine kinase inhibitor targeting B-cell receptor signaling) or venetoclax (a bcl2 inhibitor resulting in apoptosis) in combination with anti-CD20 antibody therapy. Choice between these agents is based on toxicity as well as preference. Ibrutinib is a well-tolerated, oral agent given at 420 mg daily; it can be associated with hypertension, cardiac arrhythmias, rash, and increased infections. Caution should be exercised when this agent is used in conjunction with CYP3A inhibitors or inducers. In addition, there is a potential for serious bleeding when it is used in patients taking warfarin. Venetoclax (slowly titrated up to 400 mg daily) is usually given for a shorter course of therapy and is associated with tumor lysis syndrome and neutropenia; some patients may require hospitalization for initial therapy. Venetoclax has to be combined with a monoclonal CD20 antibody, usually obinutuzumab, which can result in infusion reactions. Traditional combination chemotherapy is used only in selected cases (see Table 39–3). For older patients, chlorambucil, 0.6–1 mg/kg orally every 4 weeks, in combination with obinutuzumab is another therapy option.

For patients with relapsed or refractory disease, both venetoclax and ibrutinib or another BTK inhibitor, acalabrutinib, demonstrate significant activity, even for patients with high-risk genetics. Other options include idelalisib and duvelisib (inhibitors of PI3 kinase delta), which are associated with higher toxicity. The dosage for idelalisib is 150 mg orally twice a day, and the dosage for duvelisib is 25 mg orally twice a day. There are risks for colitis, liver injury, and fatal infectious complications in patients treated with PI3k inhibitors. Patients should be given antimicrobial prophylaxis and monitored closely while taking these agents.

Of note, BTK and PI3k inhibitors can be initially associated with marked lymphocytosis due to release of tumor cells from the lymph nodes into the peripheral blood. This results in a significant early reduction in lymphadenopathy but a potentially misleading, more delayed clearance of lymphocytes from peripheral blood and bone marrow.

Associated autoimmune hemolytic anemia or immune thrombocytopenia may require treatment with rituximab, prednisone, or splenectomy. Fludarabine should be avoided in patients with autoimmune hemolytic anemia since it may exacerbate it. Rituximab should be used with caution in patients with past hepatitis B virus (HBV) infection since HBV reactivation, fulminant hepatitis, and, rarely, death can occur without anti-HBV agent prophylaxis. Patients with recurrent bacterial infections and hypogammaglobulinemia benefit from prophylactic infusions of gamma globulin (0.4 g/kg/month), but this treatment is cumbersome and expensive, justified only when these infections are severe. Patients undergoing therapy with a nucleoside analog (fludarabine, pentostatin) should receive anti-infective prophylaxis for Pneumocystis jirovecii pneumonia, herpes viruses, and invasive fungal infections until there is evidence of T-cell recovery.

Allogeneic transplantation offers potentially curative treatment for patients with CLL, but it should be used only in patients whose disease cannot be controlled by the available therapies. Nonmyeloablative allogeneic transplant can result in over 40% long-term disease control in CLL but with risk of moderate toxicity.

Therapies have changed the prognosis of CLL. Patients with stage 0 or stage I disease have a median survival of 10–15 years, and these patients may be reassured that they can live a normal life. Patients with stage III or stage IV disease had a median survival of less than 2 years in the past, but with current therapies, 2-year survival is more than 90% and the long-term outlook appears to be substantially changed. For patients with high-risk and resistant forms of CLL, there is evidence that allogeneic transplantation can overcome risk factors and lead to long-term disease control.

All patients with CLL should be referred to a hematologist.

Hospitalization is rarely needed.