Pentostatin, Cyclophosphamide, and Rituximab Followed By Campath-1H in Patients With Relapsed or Refractory B-Cell CLL

OBJECTIVES:

Primary

- Determine the objective response rate (complete remission, partial remission [PR], or
nodular PR) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia
(CLL) treated with pentostatin, cyclophosphamide, and rituximab (PCR) followed by
lenalidomide.

- Determine the presence of minimal residual disease in patients treated with this
regimen.

Secondary

- Determine the toxicity of this regimen in these patients.

- Evaluate the toxicity of the combined therapy, PCR with lenalidomide, in patients with
previously treated B-CLL.

- Determine the overall and progression-free survival of patients treated with this
regimen.

- Evaluate the number of patients who after PCR (or during PCR for PD), only achieve a PR,
SD, or PD and who subsequently convert to a higher response category after lenalidomide.

- Correlate V_H gene mutation status and CD38 expression of the CLL B-cell clones with
clinical outcome in patients treated with this regimen.

- Correlate the differential expression of genes in the leukemic cells with clinical
outcome in patients treated with this regimen.

- Correlate surface phenotype and genetic defects of the CLL B-cell clones with clinical
outcome and gene expression patterns in patients treated with this regimen.

Exploratory

- Assess the angiogenic profile (i.e., secretion levels of pro- versus anti-angiogenic
molecules) of CLL B cell clones as well as bone marrow angiogenesis (i.e., vascular
density by immunohistochemistry) at baseline, after PCR, after lenalidomide, every six
months (serum only), and at time of response assessment (marrow).

- Determine the V_H gene mutation status and CD38 expression of the B-CLL clones at study
entry and at the end of the therapy and assess the association between the VH gene
mutation status and CD38 expression and clinical outcome.

- Determine surface phenotype (by flow cytometry) and genetic defects (by CLL FISH panel)
information on CLL-B cell clones and associate with clinical outcome.

- Monitor the T-cell status by repertoire and flow cytometry analysis to determine the
nature and extent of T-cell deficiency induced by the PCR and lenalidomide treatment and
assess any association with clinical outcome and toxicities.

OUTLINE: This is a multicenter study.

Pentostatin, cyclophosphamide, and rituximab (PCR)* therapy: Patients receive pentostatin IV
over 10-30 minutes, cyclophosphamide IV over 30-60 minutes, and rituximab** IV on day 1.
Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 3 or
pegfilgrastim SC on day 1 and continuing until blood counts recover. Treatment repeats every
28 days for a total of 6 courses in the absence of unacceptable toxicity.

NOTE: *Patients demonstrating progression while receiving PCR must have completed 2 courses
of PCR prior to proceeding to lenalidomide therapy.

NOTE: **Patients receive rituximab IV on days 1, 3, and 5 for course 1 only; for courses 2-6,
patients receive rituximab on day 1 only.

Lenalidomide*** therapy: Eight weeks after completion of PCR therapy or when diagnosed with
progressive disease, patients receive lenalidomide orally (PO) on days 1-28. In the absence
of disease progression or unacceptable toxicity, treatment repeats every 28 days for patients
with partial remission (PR), stable disease, or progressive disease after PCR. Patients who
achieve complete remission proceed to clinical observation.

NOTE: ***The alemtuzumab therapy was replaced by lenalidomide therapy in May, 2011.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 26-110 patients will be accrued for this study within 1.5
years.

Inclusion criteria:

- Diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting the following criteria:

- Peripheral blood absolute lymphocyte count greater than 5,000/mm^3

- Lymphocytosis must comprise small to moderate size lymphocytes with no greater
than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically

- Phenotypically characterized CLL defined by the following:

- Predominant population of cells share B-cell antigens with CD5 in the
absence of other pan-T-cell markers (CD3 or CD2)

- B cell expresses either kappa or lambda light chains

- Surface immunoglobulin with low cell surface density expression

- Requires chemotherapy, as indicated by any of the following:

- Disease-related symptoms

- Weight loss of 10% or more within the past 6 months

- Extreme fatigue

- Fevers greater than 100.5°F for 2 weeks without evidence of infection

- Night sweats without evidence of infection

- Evidence of progressive marrow failure manifested by the development of or
worsening anemia (hemoglobin no greater than 10 g/dL) and/or thrombocytopenia
(platelet count no greater than 100,000/mm^3)

- Massive (i.e., greater than 6 cm below left costal margin) or progressive
splenomegaly

- Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or
progressive adenopathy

- Progressive lymphocytosis with an increase of greater than 50% over a 2-month
period OR an anticipated doubling time of less than 6 months

- Demonstrated progression after at least 1 course of either an alkylating agent-based
or purine nucleoside-based (e.g., fludarabine) regimen OR failed to achieve a
meaningful response OR relapsed after prior therapy

- Patients who have relapsed after a pentostatin-based regimen are eligible
provided the response was greater than 12 months prior to study entry

- 18 and over

- ECOG 0-2

- Bilirubin no greater than 2 mg/dL (unless secondary to tumor, hemolysis, or Gilbert
syndrome)

- Creatinine no greater than 2.0 mg/dL

- Creatinine clearance ≥ 30 mL/min

- Negative pregnancy test

- Fertile patients must use 2 methods of effective contraception (including 1 barrier
method) for at least 28 days before starting lenalidomide, while participating in the
study, and for at least 28 days after discontinuation/stopping lenalidomide

- At least 8 weeks since prior rituximab

- At least 6 weeks since prior chemotherapy

- At least 1 year since prior pentostatin, cyclophosphamide, and rituximab (PCR) therapy

- PCR therapy at least 1 year prior to study entry allowed

Exclusion criteria:

- Bone marrow dysplasia related to prior therapy

- New York Heart Association class III or IV heart failure

- Prior lenalidomide

- Other malignancy within the past 2 years except squamous cell or basal cell skin
cancer or carcinoma in situ of the cervix

- Pregnant or nursing

- Concurrent oral or IV antibiotics for active infection