Phase 2 Study of Iodine-131 Tositumomab Plus Chemotherapy in Patients With Previously Untreated Mantle-Cell Lymphoma.

BACKGROUND: Mantle-cell lymphoma (MCL) is sensitive to radiotherapy, and the CD20 antigen is relatively highly expressed in MCL. Therefore, radioimmunotherapy using radiolabeled anti-CD20 monoclonal antibodies has the potential to treat MCL. The objective of this study was to investigate the efficacy, pharmacokinetics, and safety of tositumomab (TST) and iodine-131 tositumomab (I-131 TST) followed by 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with previously untreated MCL (ClinicalTrials.govNCT00022945). PATIENTS AND METHODS: In this phase 2 open-label study, patients received dosimetric (day 0: 450 mg TST, then 35 mg I-131 TST [5 mCi]) and therapeutic (between days 7 and 14: 450 mg TST, then an individualized dose of I-131 TST [65-75 cGy]) TST/I-131 TST, with CHOP treatment commencing approximately 13 weeks after the therapeutic dose. The primary end point was the MCL response rate to treatment; secondary end points included confirmed complete response rate and total body residence time. RESULTS: Twenty-six patients were enrolled, and 25 were included in the intent-to-treat population. The overall unconfirmed response rate was 84%, and the confirmed complete response rate was 44%. The median progression free-survival was 27.6 months. The median total body residence time was 94.5 hours. No new or unexpected safety signals were identified. CONCLUSION: Patients with previously untreated MCL who received radioimmunotherapy with TST/I-131 TST followed by CHOP had a high response rate and a long duration of response, indicating that radioimmunotherapy is a therapeutic option in this patient population.

MUC-1 mucin protein expression in B-cell lymphomas.

We have recently shown that MUC1, mapped to the chromosomal band 1q21, is rearranged or amplified in 15% of B-cell lymphomas and that rearrangement led to over-expression of MUC-1 mucin in a case of diffuse large B-cell lymphoma (DLBCL). To determine the incidence of MUC-1 mucin expression and its clinical significance in B-cell lymphomas, we investigated a panel of 113 cases by immunohistochemistry (IHC). MUC-1 mucin expression was detected in the majority of cases (92.9%), with moderate to high levels noted in 50.4% of all histologic subsets comprising DLBCL (82 cases), follicular lymphoma (FL) (15 cases), FL with transformation to DLBCL (4 cases), and other B-cell lymphomas (12 cases). No statistically significant correlation was found between MUC-1 mucin expression and MUC1 genomic status (amplification/rearrangement) evaluated by Southern blot analysis, and 1q21 abnormality by karyotypic analysis. For all cases, MUC-1 mucin expression correlated with a previous history of lymphoma (p=0.003).

Spectral karyotyping identifies new rearrangements, translocations, and clinical associations in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), a histologically well-defined subset of non-Hodgkin lymphoma, is clinically and genetically heterogenous. By G-banding, most cases showed complex hyperdiploid karyotypes and diverse cytogenetic abnormalities that included recurring and nonrecurring translocations, deletions, duplications, and marker chromosomes. While G-banding provided valuable leads to identification of specific rearrangements that enabled gene discovery and clinical correlations, many aberrations remained uncharacterized because of their complexity. The molecular cytogenetic technique spectral karyotyping (SKY), on the other hand, enables complete characterization of all aberrations in a tumor cell karyotype and, hence, precise quantitation of chromosome instability. We report here, for the first time, SKY analysis of a panel of 46 DLBCL cases previously analyzed by G-banding, ascertained at the Memorial Sloan-Kettering Cancer Center. This analysis provided a cytogenetic profile of DLBCL that was characterized by a higher level of instability, qualitatively as well as quantitatively, compared with G-banding. Thus, 551 breakpoints were detected by SKY, in contrast to the 295 by G-banding. Several new recurring breakpoints, translocations, and regions of gain and loss were identified, which included 13 breakpoints not previously identified by G-banding, 10 breakpoints that were underrepresented by G-banding, and 4 previously unrecognized translocations: der(14)t(3;14)(q21;q32), t(1;13)(p32;q14), t(1;7)(q21;q22), and der(6)t(6;8)(q11;q11). We identified new clinical associations involving recurring breakpoints detected by SKY. These studies emphasize the value of SKY analysis for redefinition of chromosomal instability in DLBCL to enhance gene discovery as well as clinical correlation analysis.

Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas.

Although it has been suggested that REL is the critical target gene of 2p12-16 amplification in diffuse large B-cell lymphoma (DLBCL), little experimental evidence supports this notion. In the present study, we sought to evaluate the relationship between REL amplification and REL function in a panel of 46 newly diagnosed DLBCLs and to correlate with DLBCL subgroups as identified by gene expression profiles and clinical features. The results indicate that amplification of the REL locus is not associated with accumulation of the active form of REL, as evaluated by immunofluorescence analysis. Upon subgrouping of the DLBCL cases based on gene expression signatures, REL amplification was detected in all subgroups, while high levels of nuclear-located REL were more frequently detected in activated B-cell-like DLBCL. Correlative analyses of REL copy number and REL nuclear accumulation with clinical parameters did not reveal any significant associations. Together these results indicate that 2p12-16 amplification does not lead to abnormal REL activation, suggesting that REL may not be the functional target of the amplification event. Nonetheless, these data indicate that DLBCLs are heterogeneous with respect to REL and thus nuclear factor-kappaB (NF-kappaB) activity.

Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease.

The prognostic significance of CD20 positive classical Hodgkin's disease (cHD) is uncertain. All cHD cases referred to the Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively identified (5/92-11/00); the samples were immunostained, and clinical data ascertained. Cases were re-reviewed without knowledge of clinical outcome. Univariate and multivariate analyses were performed 248 patients had cHD: 28 CD20(+) (11%); 220 CD20(-). All clinical characteristics were comparable except haemoglobin level at presentation. With a median follow-up of 29.2 months, significant prognostic factors in multivariate analysis were: CD20 positivity, elevated white blood cell count (WBC) and low absolute lymphocyte count for time-to treatment failure (TTF); and for overall survival (OS), CD20 positivity, elevated WBC count, bone marrow involvement and age >/=45 years. TTF was significantly poorer for ABVD-treated patients with CD20(+) cHD as compared with CD20(-) cHD. Among 167 patients treated at MSKCC, both TTF (P < 0.0001) and OS (P = 0.017) were significantly decreased in CD20(+) patients as compared with CD20(-) cHD. CD20(+) cHD is a poor prognostic factor for TTF and OS. All cHD cases should be immunophenotyped for CD20. A large prospective trial is needed to confirm these findings.