This study investigated the activity of lenalidomide in patients with relapsed/ refractory chronic lymphocytic leukemia (CLL). Lenalidomide was given at 10 mg daily with dose escalation up to 25 mg daily. Three patients (7%) achieved a complete response (CR), one a nodular partial remission, and 10 patients a partial remission (PR), for an overall response (OR) rate of 32%. Treatment with lenalidomide was associated with an OR rate of 31% in patients with 11q or 17p deletion, of 24% in patients with unmutated V H , and of 25% in patients with fludarabine-refractory disease. The most common toxicity was myelosuppression, and the median daily dose of lenalidomide tolerated was 10 mg. Plasma levels of angiogenic factors, inflammatory cytokines, and cytokine receptors were measured at baseline, day 7, and day 28. There was a dramatic increase in median interleukin (IL)-6, IL-10, IL-2, and tumor necrosis factor receptor-1 levels on day 7, whereas no changes were observed in median vascular endothelial growth factor levels (20 patients studied). According to our experience, lenalidomide given as a continuous treatment has antitumor activity in heavily pretreated patients with CLL. This trial is registered at http://www.clinicaltrials.gov as no. NCT00267059. (Blood. 2008;111: 5291-5297)

Expression of the human oncogene TCL1 in transgenic mice produces B-cell tumors that resemble chronic lymphocytic leukemia (CLL) suggesting its role in B-cell tumorigenesis. To clarify the expression pattern and regulation of TCL1 in CLL, we assessed 213 primary tumors by immunohistochemistry (IHC), flow-cytometry and/or Western blot, using a new monoclonal antibody. TCL1 protein was detectable in the majority of CLL (90% by IHC) but showed marked variations across cases with virtual absence in approximately 10% of tumors. Higher TCL1 levels correlated with markers of the 'pre-germinal center' CLL subtype including unmutated VH status (P ¼ 0.005), ZAP70 expression (P ¼ 0.007), and presence of chromosome 11q22-23 deletions (P ¼ 0.04). Intratumoral heterogeneity in TCL1 levels was also prominent and explained in part by markedly lower TCL1 expression in proliferating tumor cells. In vitro exposure of CLL cells to interleukin-4 (but not other growth factors) produced progressive and irreversible decrease in TCL1 protein levels in association with the onset of proliferation. TCL1 expression patterns in CLL are complex and highly dynamic and appear to reflect both the histogenetic subtypes of the disease and the growth parameters of individual tumors. The observed regulation pattern suggests that TCL1 may exert its effects predominantly in the unmutated/ZAP70-positive tumor subset.

Purpose The clinical course for patients with chronic lymphocytic leukemia (CLL) is diverse; some patients have indolent disease, never needing treatment, whereas others have aggressive disease requiring early treatment. We continue to use criteria for active disease to initiate therapy. Multivariable analysis was performed to identify prognostic factors independently associated with time to first treatment for patients with CLL. Patients and Methods Traditional laboratory, clinical prognostic, and newer prognostic factors such as fluorescent in situ hybridization (FISH), IGHV mutation status, and ZAP-70 expression evaluated at first patient visit to MD Anderson Cancer Center were correlated by multivariable analysis with time to first treatment. This multivariable model was used to develop a nomogram—a weighted tool to calculate 2- and 4-year probability of treatment and estimate median time to first treatment. Results There were 930 previously untreated patients who had traditional and new prognostic factors evaluated; they did not have active CLL requiring initiation of treatment within 3 months of first visit and were observed for time to first treatment. The following were independently associated with shorter time to first treatment: three involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum lactate dehydrogenase, and unmutated IGHV mutation status. Conclusion We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials.

Key Points Histologically aggressive CLL differs from histologically indolent CLL. Patients with different CLL phases but similar SUVmax have similar outcomes. FDG/PET is a useful diagnostic tool for patients with CLL and suspected transformation.

Successful treatment of diffuse large B-cell lymphoma (DLBCL) is frequently hindered by development of resistance to conventional chemotherapy resulting in disease relapse and high mortality. High expression of anti-apoptotic and/or drug transporter proteins induced by oncogenic signaling pathways has been implicated in the development of chemoresistance in cancer. Previously, our studies showed high expression of ATP-binding cassette drug transporter ABCG2 in DLBCL correlated inversely with disease-free and failure-free survival. In this study, we have implicated activated hedgehog (Hh) signaling pathway as a key factor behind high ABCG2 expression in DLBCL through direct upregulation of ABCG2 gene transcription. We have identified a single binding site for GLI transcription factors in the ABCG2 promoter and established its functionality using luciferase reporter, site-directed mutagenesis and chromatin-immunoprecipitation assays. Furthermore, in DLBCL tumor samples, significantly high ABCG2 and GLI1 levels were found in DLBCL tumors with lymph node involvement in comparison to DLBCL tumor cells collected from pleural and/or peritoneal effusions. This suggests a role for the stromal microenvironment in maintaining high levels of ABCG2 and GLI1. Accordingly, in vitro co-culture of DLBCL cells with HS-5 stromal cells increased ABCG2 mRNA and protein levels by paracrine activation of Hh signaling. In addition to ABCG2, co-culture of DLBCL cells with HS-5 cells also resulted in increase expression of the antiapoptotic proteins BCL2, BCL-xL and BCL2A1 and in induced chemotolerance to doxorubicin and methotrexate, drugs routinely used for the treatment of DLBCL. Similarly, activation of Hh signaling in DLBCL cell lines with recombinant Shh N-terminal peptide resulted in increased expression of BCL2 and ABCG2 associated with increased chemotolerance. Finally, functional inhibition of ABCG2 drug efflux activity with fumitremorgin (FTC) or inhibition of Hh signaling with cyclopamine-KAAD abrogated the stroma-induced chemotolerance suggesting that targeting ABCG2 and Hh signaling may have therapeutic value in overcoming chemoresistance in DLBCL.

BACKGROUND The optimal management of patients with splenic marginal zone lymphoma/marginal zone lymphoma (SMZL) is controversial. The objective of this retrospective study was to compare the outcomes of patients with SMZL who received treatment with rituximab, rituximab plus chemotherapy, or chemotherapy alone. METHODS The Leukemia Service database was searched for patients with splenic lymphoma who were registered between May 1995 and October 2004. The indications for treatment were the same as those used for patients with chronic lymphocytic leukemia. RESULTS SMZL was confirmed in 70 patients. The median age was 64 years. The median number of CD20 molecules per cell was 69 × 103. Forty‐three patients required systemic therapy; rituximab in 26 patients, chemotherapy plus rituximab in 6 patients, and chemotherapy alone in 11 patients. Ten additional patients underwent splenectomy, and 17 patients were in the observation group. The overall response rates were 88% with rituximab, 83% with rituximab plus chemotherapy, and 55% with chemotherapy alone; the 3‐year survival rates were 95%, 100%, and 55%, respectively. The 3‐year failure‐free survival (FFS) rates were 86%, 100%, and 45% in the rituximab, rituximab plus chemotherapy, and chemotherapy alone groups, respectively. Rituximab treatments resulted in longer survival and FFS compared with chemotherapy. Rituximab alone resulted in disappearance of splenomegaly in 92% of patients and normalization of absolute lymphocyte counts. In univariate analysis, younger age and rituximab‐based therapy were predictive of longer FFS. CONCLUSIONS Rituximab with or without chemotherapy was found to have major activity in patients with SMZL. These results may be associated with high levels of cellular CD20 antigen sites. Rituximab should be the treatment of choice, at least in older patients with SMZL who have comorbid diseases. Cancer 2006. © 2006 American Cancer Society.

Survivin is expressed in approximately half of ALCL tumors and independently predicts unfavorable clinical outcome. Modulation of survivin expression or function may provide a novel target for experimental therapy in patients with ALCL.

Array-based comparative genomic hybridization (array CGH) provides a powerful method for simultaneous genome-wide scanning and prognostic marker assessment in chronic lymphocytic leukemia (CLL). In the current study, commercially available bacterial artificial chromosome and oligonucleotide array CGH platforms were used to identify chromosomal alterations of prognostic significance in 174 CLL cases. Tumor genomes were initially analyzed by bacterial artificial chromosome array CGH followed by confirmation and breakpoint mapping using oligonucleotide arrays. Genomic changes involving loci currently interrogated by fluorescence in situ hybridization (FISH) panels were detected in 155 cases (89%) at expected frequencies: 13q14 loss (47%), trisomy 12 (13%), 11q loss (11%), 6q loss (7.5%), and 17p loss (4.6%). Genomic instability was the second most commonly identified alteration of prognostic significance with three or more alterations involving loci not interrogated by FISH panels identified in 37 CLL cases (21%). A subset of 48 CLL cases analyzed by six-probe FISH panels (288 total hybridizations) was concordant with array CGH results for 275 hybridizations (95.5%); 13 hybridizations (4.5%) were discordant because of clonal populations that comprised less than 30% of the sample. Array CGH is a powerful, cost-effective tool for genome-wide risk assessment in the clinical evaluation of CLL.