Chemotherapy may be instituted when symptoms begin. Symptoms that prompt treatment include

Alkylating drugs, especially chlorambucil, alone or with corticosteroids, have long been the usual therapy for B-cell CLL. However, fludarabine is more effective. Combination chemotherapy with fludarabine, cyclophosphamide, and rituximab more often induces complete remissions. It also lengthens remission duration and prolongs survival. Interferon alfa, deoxycoformycin, and 2-chlorodeoxyadenosine are highly effective for hairy cell leukemia. Patients with prolymphocytic leukemia and lymphoma leukemia usually require multidrug chemotherapy and often respond only partially.

Ibrutinib is a novel, oral inhibitor of Bruton tyrosine kinase. Bruton tyrosine kinase is an enzyme essential for activation of several downstream B-cell mediated pathways that enhance survival of CLL cells. Ibrutinib appears to be highly active in CLL and has induced durable remissions in some patients with relapsed or refractory CLL. Its role as a single agent or as part of combination chemotherapy is evolving.

Immunohemolytic anemia and thrombocytopenia are indications for corticosteroids. Prednisone 1 mg/kg po once/day may occasionally result in striking, rapid improvement in patients with advanced CLL, although response is often brief. The metabolic complications and increasing rate and severity of infections warrant caution in its prolonged use. Prednisone used with fludarabine increases the risk of Pneumocystis jirovecii and Listeria infections.

Rituximab is the first monoclonal antibody used in the successful treatment of lymphoid cancers. In previously untreated patients, the response rate is 75%, with 20% of patients achieving complete remission. Alemtuzumab has a 33% response rate in previously treated patients refractory to fludarabine and a 75 to 80% response rate in previously untreated patients. More problems with immunosuppression occur with alemtuzumab than with rituximab. Rituximab has been combined with fludarabine and with fludarabine and cyclophosphamide; these combinations have markedly improved the complete remission rate in both previously treated and untreated patients. Alemtuzumab is now being combined with rituximab and with chemotherapy to treat minimal residual disease and has effectively cleared bone marrow infiltration. Reactivation of cytomegalovirus and other opportunistic infections has occurred with alemtuzumab. Reactivation of hepatitis B infection may occur with rituximab.

Obinutuzumab is a newer monoclonal antibody that targets the same CLL cell surface protein as rituximab. The combination of obinutuzumab and chlorambucil was recently found to be superior to rituximab in prolonging progression-free survival and achieving a complete response to treatment.

Obinutuzumab plus chlorambucil has now been approved as frontline therapy for elderly patients or frail patients with comorbidities (1). In the specific instance of CLL with a deletion of 17p, the Bruton tyrosine kinase inhibitor ibrutinib has shown excellent activity. Single-agent ibrutinib is an approved frontline treatment for such patients. This is distinct from the group of CLL patients with deletion 11q abnormalities, who seem to benefit most from initial alkylator therapy. In patients with relapsed or refractory disease, new options include idelalisib (a phosphoinositide 3-kinase inhibitor) plus rituximab and monotherapy with ibrutinib.

In general, monoclonal antibodies are well tolerated, although they may cause allergic reactions and significant immunosuppression. This favorable toxicity profile allows these agents to be combined with conventional chemotherapy, often with excellent clinical efficacy.

Local irradiation for palliation may be given to areas of lymphadenopathy or for liver and spleen involvement that does not respond to chemotherapy. Total body irradiation in small doses is occasionally successful in temporarily ameliorating symptoms.

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