Gascoyne, R. D.

8038 Background: P21 is a downstream effector protein of p53 that induces cell cycle arrest by inhibiting cyclin/cyclin dependent kinase (cdK) complexes. In this prospective correlative study, we investigated the prognostic significance of p21, p53, Bcl-6, and Bcl-2 in diffuse large B cell lymphoma (DLBCL) in the context of E4494, a randomized trial comparing conventional CHOP to rituximab(R)-CHOP induction, and maintenance R (MR) to observation for responding patients. Methods: Protein expression was quantified by immunohistochemical (IHC) staining of 198 DLBCL paraffin-embedded biopsy specimens and scored by an expert panel of hematopathologists. Results: No differences in the distribution of patient characteristics were detected between p21+ and p21- cases and between p53+ and p53- cases as well as across treatment arms. Among all study patients, there were no differences in clinical outcomes between p21+ and p21- cases. However, when analyzed by induction arm (removing the effect of MR), R-CHOP patients had marginally better FFS (p=0.06) if p21+; among CHOP-treated patients, p21 status had no effect on outcome. For R-CHOP patients but NOT CHOP patients, p21+ was an independent, favorable prognostic factor after adjusting for Bcl-6, IPI and Bcl-2 in multivariate analysis (FFS relative risk 0.3; p=0.003; OS relative risk 0.4; p=0.02). P21+ patients treated with R-CHOP had higher %FFS at 5 years compared to p21+ patients treated with CHOP (61 ± 7% vs. 24 ± 7%; p=0.007) but p21- R-CHOP and CHOP patients had similar FFS (37 ± 7% vs. 35 ± 7%; p=0.64). P53 staining (+ scored as either >20% or 50%) did not predict for FFS or OS in uni- or multivariate analyses. The p53+/p21- phenotype, a possible surrogate for mutated p53, was not prognostic. Further, no significant correlation was seen between p53 and p21 expression by IHC. Conclusions: These data suggest that p21 expression by IHC predicts for favorable outcome in older DLBCL patients treated with R-CHOP but not in those treated with CHOP. Furthermore, p21+ identifies patients who benefit from the addition of rituximab to CHOP. Complex interactions between p53, p21, and Bcl-6, as well as other unknown pathways, may account for this treatment-related effect and should be further investigated. [Table: see text]

Abstract We studied 25 T-cell chronic lymphocytic leukemia (T-CLL) cases collected over a 15-year period. Immunophenotypic analysis was performed in each case; 12 cases were evaluated by cytogenetics, and gene rearrangement studies were performed in 14 cases. The median age was 57 years with a male predominance (M:F, 15:10). The median presenting lymphocyte count was 36.3 x 10(9)/L (range, 3.9 to 438 x 10(9)/L). Fourteen patients (56%) had shotty adenopathy and ten (40%) had mild-to-moderate splenomegaly at presentation; four (16%) had erythematous skin lesions. The lymphocytes were predominantly small; some cases had a minor component of medium-sized cells (< 10%). The nuclear: cytoplasmic ratios were uniformly high with round to oval nuclei; however, a wide spectrum of nuclear outlines could be found, ranging from minimally to markedly convoluted. Nucleoli were either absent or small and inconspicuous. These lymphocytes did not have the morphology of prolymphocytes and did not contain cytoplasmic granules. Bone marrow infiltration was generally in an interstitial pattern; the degree of involvement ranged from 15% to 90%. Immunophenotyping showed that the lymphocytes were mature T-cells with a predominant CD4+ immunophenotype. Three cases displayed a CD8+ immunophenotype. The patients were treated with a variety of chemotherapeutic regimens with only a minimal response observed in two of 20 patients. We conclude that T-CLL is an uncommon chronic lymphoproliferative disorder (CLPD) that can be morphologically similar to B-CLL, is distinct from T- prolymphocytic leukemia, and has an aggressive clinical course that is refractory to therapy. It may also be difficult to distinguish T-CLL from other T-CLPD, especially the leukemic phase of peripheral T-cell lymphoma and some cases of Sezary syndrome.

We studied 25 T-cell chronic lymphocytic leukemia (T-CLL) cases collected over a 15-year period. Immunophenotypic analysis was performed in each case; 12 cases were evaluated by cytogenetics, and gene rearrangement studies were performed in 14 cases. The median age was 57 years with a male predominance (M:F, 15:10). The median presenting lymphocyte count was 36.3 x 10(9)/L (range, 3.9 to 438 x 10(9)/L). Fourteen patients (56%) had shotty adenopathy and ten (40%) had mild-to-moderate splenomegaly at presentation; four (16%) had erythematous skin lesions. The lymphocytes were predominantly small; some cases had a minor component of medium-sized cells (< 10%). The nuclear: cytoplasmic ratios were uniformly high with round to oval nuclei; however, a wide spectrum of nuclear outlines could be found, ranging from minimally to markedly convoluted. Nucleoli were either absent or small and inconspicuous. These lymphocytes did not have the morphology of prolymphocytes and did not contain cytoplasmic granules. Bone marrow infiltration was generally in an interstitial pattern; the degree of involvement ranged from 15% to 90%. Immunophenotyping showed that the lymphocytes were mature T-cells with a predominant CD4+ immunophenotype. Three cases displayed a CD8+ immunophenotype. The patients were treated with a variety of chemotherapeutic regimens with only a minimal response observed in two of 20 patients. We conclude that T-CLL is an uncommon chronic lymphoproliferative disorder (CLPD) that can be morphologically similar to B-CLL, is distinct from T- prolymphocytic leukemia, and has an aggressive clinical course that is refractory to therapy. It may also be difficult to distinguish T-CLL from other T-CLPD, especially the leukemic phase of peripheral T-cell lymphoma and some cases of Sezary syndrome.