Deborah A. Bowen

Phase I Trial of Daily Oral Polyphenon E in Patients With Asymptomatic Rai Stage 0 to II Chronic Lymphocytic Leukemia

PURPOSE To define the optimal dose of Polyphenon E for chronic daily administration and tolerability in patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS Previously untreated patients with asymptomatic Rai stage 0 to II CLL were eligible for participation. Polyphenon E with a standardized dose of epigallocatechin-3-gallate (EGCG) was administered using the standard phase I design with three to six patients per dose level (range, 400 to 2,000 mg by mouth twice a day). Trough plasma EGCG levels were measured 1 month after initiation of therapy. Response was classified using the National Cancer Institute (NCI) Working Group (WG) Criteria. RESULTS Thirty-three eligible patients were accrued to dose levels 1 to 8. The maximum-tolerated dose was not reached. The most common adverse effects included transaminitis (33%, all grade 1), abdominal pain (30% grade 1, 0% grade 2, and 3% grade 3), and nausea (39% grade 1 and 9% grade 2). One patient experienced an NCI WG partial remission. Other signs of clinical activity were also observed, with 11 patients (33%) having a sustained > or = 20% reduction in absolute lymphocyte count (ALC) and 11 (92%) of 12 patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas during treatment. Trough plasma EGCG levels after 1 month of treatment ranged from 2.9 to 3,974 ng/mL (median, 40.4 ng/mL). CONCLUSION Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase I trial. Declines in ALC and/or lymphadenopathy were observed in the majority of patients. A phase II trial to evaluate efficacy using 2,000 mg twice a day began in November 2007.

Phase 2 trial of daily, oral polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia

The objective of the current study was to follow up the results of phase 1 testing by evaluating the clinical efficacy of the green tea extract Polyphenon E for patients with early stage chronic lymphocytic leukemia (CLL).

Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features

Chronic lymphocytic leukemia (CLL) patients with aggressive molecular characteristics such as deletion of 17p13.1 do not respond to conventional treatments and have a shorter survival. Studies suggest that high-dose methylprednisolone (HDMP) has activity in such patients and combining HDMP with rituximab may enhance efficacy. We identified 37 patients with CLL treated with the HDMP-rituximab who had follow-up at Mayo Clinic. Nine of 27 (33%) had deletion of 17p13.1 and six of 27 (22%) had deletion of 11q22.3. After a median of one cycle of HDMP-rituximab, 29 (78%) patients had an objective response according to the National Cancer Institute CLL Working Group Criteria including five of nine patients with deletion of 17p13.1. Eight (22%) patients had a complete clinical response. Although well tolerated, 11 (29%) patients developed infectious complications before completing one month of therapy. Three-year survival was 41% (95% CI: 26 – 66%). HDMP-rituximab is an active regimen in patients with relapsed, refractory, and cytogenetically high-risk CLL. Further evaluation of this regimen in controlled trials appears warranted.

The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma

The development of cytopenia in chronic lymphocytic leukaemia (CLL) patients can predict poor prognosis. All CLL patients seen in the Division of Hematology at Mayo Clinic Rochester from 1 January 1995 to 31 December 2004 (n = 1750) were evaluated for cytopenia, aetiology of cytopenia and clinical outcome. Cytopenia occurred in 423 (24·2%) patients and was attributable to CLL in 303 (17·3%) cases, with 228 (75%) of these having bone marrow (BM) failure and 75 (25%) having autoimmune disease (AID). Survival from onset of cytopenia was significantly better for patients with AID (median 9·1 years) compared to patients with BM failure (median 4·4 years, P < 0·001). Patients with AID diagnosed within 1 year of the diagnosis of CLL (n = 35) had similar survival from diagnosis compared to patients without CLL‐related cytopenia (median 9·3 vs. 9·7 years, P = 0·881). Although cytopenia caused by BM failure predicted a poorer prognosis in CLL, cytopenia caused by AID was not an adverse prognostic factor. These findings suggest that patients with cytopenia due to AID cannot be meaningfully classified by the current clinical staging systems. Revisions of the National Cancer Institute Working Group 96 criteria should consider the aetiology of cytopenia in staging CLL patients.

Age at Diagnosis and the Utility of Prognostic Testing in Patients With Chronic Lymphocytic Leukemia

A study was undertaken to analyze the survival of chronic lymphocytic leukemia (CLL) patients relative to age‐matched individuals in the general population and determine the age‐stratified utility of prognostic testing.

Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab

Patients with chronic lymphocytic leukemia (CLL) usually are treated only for progressive disease. However, the discovery of biologic predictors of a high risk of disease progression, together with the development of newer, more targeted therapies, could change this paradigm. In this phase 2 study, the authors tested the safety and efficacy of early treatment for patients with high‐risk CLL using alemtuzumab and rituximab.

Validation of a new prognostic index for patients with chronic lymphocytic leukemia

The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. A prognostic index based on widely available clinical and laboratory features was recently developed to predict survival among patients with previously untreated CLL. This index requires validation in an independent series of patients before widespread use can be recommended.

Prognostic importance of T and NK-cells in a consecutive series of newly diagnosed patients with chronic lymphocytic leukaemia.

Patients with chronic lymphocytic leukaemia (CLL) have a variable clinical course. The identification of modifiable characteristics related to CLL‐specific survival may provide opportunities for therapeutic intervention. The absolute number of T‐cell and natural killer (NK)‐cells was calculated for 166 consecutive patients with CLL evaluated by flow cytometry at Mayo Clinic ≤2 months of diagnosis. The size of the T‐cell/NK‐cell compartment relative to the size of the malignant monoclonal B‐cell (MBC) compartment was evaluated by calculating NK:MBC and T:MBC ratios. Patients exhibited substantial variation in the absolute number of T‐ and NK‐cells as well as T:MBC and NK:MBC ratios at diagnosis. Higher T:MBC and NK:MBC ratios were observed among patients with early stage and mutated IGHV genes (all P ≤ 0·0003). As continuous variables, both T:MBC ratio (P‐value = 0·03) and NK:MBC ratio (P‐value = 0·02) were associated with time to treatment (TTT). On multivariate Cox modelling including stage, CD38, absolute MBC count, NK:MBC ratio and T:MBC ratio, the independent predictors of TTT were stage, T:MBC ratio and NK:MBC ratio. These findings suggest that measurable characteristics of the host immune system relate to the rate of disease progression in patients with newly diagnosed CLL. These characteristics can be modified and continued evaluation of immunomodulatory drugs, vaccination strategies and cellular therapies to delay/prevent disease progression are warranted.

Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia

Previous studies suggested that patients with chronic lymphocytic leukaemia (CLL) are at a three‐ to fivefold increased risk of developing a second lymphoproliferative disorder (LPD). This observational cohort study used the Mayo Clinic CLL Database to identify factors associated with developing a second LPD. A second LPD was identified in 26 (2·7%) of 962 CLL patients during a median follow‐up of 3·3 years. Diffuse large B‐cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Patients previously treated for CLL had a trend toward higher prevalence of second LPD (4%) compared with previously untreated patients (2%; P = 0·053). More strikingly, patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5·2%) compared with patients who had not received PNA (1·9%; P = 0·008). No statistically significant association was observed between risk of second LPD and other CLL characteristics (ZAP‐70, CD38, IgVH mutation status or cytogenetic abnormalities). In this series, prior treatments with PNA or anthracyclines were the only significant factors associated with risk of developing a second LPD in patients with CLL. Physicians should strictly adhere to established criteria to initiate treatment for CLL patients who are not participating in clinical trials.

Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia

Abstract CpG oligonucleotide 7909 (CpG 7909, PF-03512676), a synthetic 24mer single stranded agonist of TLR9 expressed by B cells and plasmacytoid dendritic cells, is immunomodulatory and can cause activation-induced death of chronic lymphocytic leukemia (CLL) cells. We report a phase I study of CpG 7909 in 41 patients with early relapsed CLL. A single intravenous dose of CpG 7909 was well tolerated with no clinical effects and no significant toxicity up to 1.05 mg/kg. Single dose subcutaneous CpG 7909 had a maximum tolerated dose (MTD) of 0.45 mg/kg with dose limiting toxicity of myalgia and constitutional effects. Multiple weekly subcutaneous doses at the MTD were well tolerated. CpG 7909 administration induced immunologic changes in CLL and non-malignant cells that were dose and route dependent. We conclude that multidose therapy with subcutaneous CpG 7909 (0.45 mg/kg) could be used in future phase II combination clinical trials for CLL.