Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy.

BACKGROUND: Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. PATIENTS AND METHODS: We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. RESULTS: PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. CONCLUSIONS: This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies.

PURPOSE: The botanical formulation, PHY906, has been used widely in Eastern countries to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. PHY906 may also have anti-tumor properties and may potentiate the action of several chemotherapeutic agents based on pre-clinical studies. We conducted a Phase I study using PHY906 in combination with capecitabine in patients with advanced pancreatic and gastrointestinal malignancies to determine the maximum tolerated dose (MTD) of capecitabine in combination with PHY906. PATIENTS AND METHODS: This study was a single institution, open-label, Phase I study of PHY906 800mg BID on days 1-4 in combination with escalating doses of capecitabine (1000, 1250, 1500, and 1750mg/m(2)) orally twice daily on days 1-7 of a 14-day cycle (7/7 schedule). Capecitabine was increased until the appearance of dose limiting toxicities (DLTs). Measurements of efficacy included tumor response by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Twenty-four patients with a median age of 67 years (range 40-84) with pancreatic cancer (15), colon cancer (6), cholangiocarcinoma (1), esophageal cancer (1) and unknown primary (1) received a total of 116 cycles (median 5 cycles; range 1-17 cycles) over 4 dose levels of capecitabine. One DLT (Grade 4 AST/ALT, Grade 3 hyponatremia) was observed in the 1000mg/m(2) cohort of patients. No further DLT was observed in the subsequent cohorts and doses of capecitabine were escalated to 1750mg/m(2) BID. There were no DLTs at the maximum dose level of 1750mg/m(2), however, the delivered dose-intensity of capecitabine was similar at the 1750mg/m(2) dose level as the 1500mg/m(2) dose level. Therefore, the MTD was defined at 1500mg/m(2) of capecitabine in this dosing schedule with PHY906. One patient achieved a partial response, and 13 patients had stable disease that lasted more than six weeks. CONCLUSION: The MTD of capecitabine was determined to be 1500mg/m(2) BID administered in a 7/7 schedule, in combination with PHY906 800mg BID on days 1-4. This combination was well tolerated and warrants further study.

Aberrant B cell receptor signaling from B29 (Igbeta, CD79b) gene mutations of chronic lymphocytic leukemia B cells.

Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low or undetectable surface B cell receptor (BCR) and diminished responses to BCR-mediated signaling. These features suggest that CLL cells may have sustained mutations affecting one or more of the BCR proteins required for receptor surface assembly and signal transduction. Loss of expression and mutations in the critical BCR protein B29 (Igbeta, CD79b), are prevalent in CLL and could produce the hallmark features of these leukemic B cells. Because patient CLL cells are intractable to manipulation, we developed a model system to analyze B29 mutations. Jurkat T cells stably expressing micro, kappa, and mb1 efficiently assembled a functional BCR when infected with recombinant vaccinia virus bearing wild-type B29. In contrast, a B29 CLL mutant protein truncated in the transmembrane domain did not associate with mu or mb1 at the cell surface. Another B29 CLL mutant lacking the C-terminal immunoreceptor tyrosine activation motif tyrosine and distal residues brought the receptor to the surface as well as wild-type B29 but showed significant impairment in anti-IgM-stimulated signaling events including mitogen-activated protein kinase activation. These findings demonstrate that B29 mutations previously identified in CLL patients can affect BCR-dependent signaling and may contribute to the unresponsive B cell phenotype in CLL. Finally, the features of the B29 mutations in CLL predict that they may be generated by somatic hypermutation.