Alemtuzumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia

OBJECTIVES:

• To determine the safest dose of alemtuzumab as consolidation therapy in patients in second remission after fludarabine phosphate alone; fludarabine phosphate and cyclophosphamide; fludarabine phosphate, cyclophosphamide, and rituximab; bendamustine hydrochloride alone; or bendamustine hydrochloride and rituximab.
• To determine the frequency of cytomegalovirus reactivations or infections during or after alemtuzumab treatment.
• To determine which dose of alemtuzumab is efficient to eliminate minimal residual disease in peripheral blood and bone marrow (i.e., to turn a clinical partial remission into a clinical complete remission [CR], to turn a flow cytometry-positive CR into a flow cytometry-negative CR, or to turn a PCR-positive CR into a PCR-negative CR).
• To determine the pharmacokinetic profile of alemtuzumab.
• To compare the pharmacokinetic profile between intravenous versus subcutaneous administration of alemtuzumab.

OUTLINE: This is a multicenter, dose-escalation study of alemtuzumab.

• Group 1: Patients receive escalating doses of alemtuzumab IV over 2 hours once weekly for 8 weeks until the maximum tolerated dose (MTD) is determined.
• Group 2: Patients receive escalating doses of alemtuzumab subcutaneously once weekly for 8 weeks, beginning with the MTD determined in group 1 until a second MTD is determined.

Patients undergo bone marrow and blood sample collection periodically for laboratory and pharmacokinetic studies. Samples are analyzed for minimal residual disease and T-cell subsets (i.e., CD4 and CD8) via quantitative-PCR analysis and flow cytometry and cytomegalovirus antigens via PCR.

After completion of study treatment, patients are followed at 3, 6, 9, 12, 18, and 24 months.

DISEASE CHARACTERISTICS:

Inclusion criteria

• Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL)
• Disease in complete or partial remission after completion of 4-6 courses of second-line cytoreductive therapy no less than 90 days and no more than 150 days ago

• Second-line cytoreductive therapy must comprise 1 of the following regimens:

• Fludarabine phosphate alone (F)
• Fludarabine phosphate and cyclophosphamide (FC)
• Fludarabine phosphate, cyclophosphamide, and rituximab (FCR)
• Bendamustine hydrochloride alone (B)
• Bendamustine hydrochloride and rituximab chemotherapy (BR)
• Complete minimal residual disease response defined by the following:

• At least negativity of 4-color-cytometry and/or even PCR-amplifiable clonal CDR III rearrangement of the IgV_H

• For PCR analysis, blood sample need to be taken at beginning or during second-line cytoreductive therapy before achievement of a clinical complete remission
• Disease not refractory to first-line F/FC/FCR/B/BR if received such therapy

Exclusion criteria

• Presence of bulky lymph nodes (> 5 cm) after second-line F/FC/FCR/B/BR
• Clinically apparent autoimmune cytopenia (i.e., autoimmune hemolytic anemia, autoimmune thrombocytopenia, or pure red cell aplasia)
• CNS involvement with B-CLL

PATIENT CHARACTERISTICS:

Inclusion criteria

• ECOG performance status 0-1
• ANC ≥ 1,500/µL
• Platelets ≥ 50,000/µL
• Creatinine ≤ 1.5 times the upper normal limit (ULN)
• Conjugated bilirubin ≤ 2 times ULN
• Thyroid function normal
• Not pregnant or nursing
• Fertile patients must use effective contraception

Exclusion criteria

• Severe infection during second-line treatment with F/FC/FCR/B/BR, meeting any 1 of the following criteria:

• Any episode of NCI grade 4 infection
• More than 1 episode of NCI grade 3 infection
• Medical condition requiring long-term use of oral corticosteroids for more than 1 month
• Active bacterial, viral, or fungal infection
• HIV, hepatitis B virus, and/or hepatitis C virus-positive serum status
• Concurrent severe diseases that exclude the administration of protocol therapy, including any of the following:

• NYHA class III-IV heart insufficiency
• Severe chronic obstructive lung disease with hypoxemia
• Severe ischemic cardiac disease
• Active secondary malignancy other than B-CLL prior to the study
• Known hypersensitivity or anaphylactic reaction against murine proteins or one of the drug components

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No more than 2 prior chemotherapies, including F/FC/FCR/B/BR therapy
• No more than 1 pretreatment (before second-line therapy) with chlorambucil or F/FC/FCR/B/BR
• No chemotherapy or radiotherapy for any neoplastic disease other than B-CLL prior to the study