Population Outcomes of Primary Mediastinal Large B-cell Lymphoma in the Rituximab Era. Karen Ortiz Cruz, MD

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1 Population Outcomes of Primary Mediastinal Large B-cell Lymphoma in the Rituximab Era Karen Ortiz Cruz, MD

2 Introduction Primary Mediastinal Large B-cell Lymphoma (PMLBCL) - a rare entity corresponding to approximately 10% of all diffuse large B-cell lymphomas (DLBCL) Clinical, pathological and molecular features are different from other DLBCL subtypes. Disease affects women more frequently than men and peaks in the third and fourth decades of life Common clinical presentation - local bulky anterior mediastinal mass occasionally with symptoms of superior vena caval syndrome. Less commonly the disease involves extra-nodal sites

3 Introduction Histologically: diffuse proliferation of large B cells, with clear cytoplasm, round nuclei & the presence of variable degrees of sclerosis Cells may lack surface immunoglobulin expression but express B cell markers (such as CD19, CD20, CD22, CD79a), and CD45 Evidence of activation of nuclear factor kappa B (NF-κB) and geneexpression profile that resembles more classical Hodgkin lymphoma than activated B cell type or germinal center type DLBCL Response to initial therapy is critical since salvage treatment for recurrence and progression is of limited efficacy

4 Treatment Historically, in the pre rituximab (R) era, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, produced inferior results compared to MACOP-B and VACOP-B. Superior therapeutic outcomes were noted with the addition of radiation therapy (XRT). Rituximab + CHOP demonstrates a substantial improvement in outcomes with long term survival exceeding 80% in retrospective series and small prospective trials. - Mabthera International Trial showed superior outcomes for PMLBCL patients receiving R-CHOP when compared to patients receiving CHOP only. The role of XRT in the current treatment of PMLBCL remains highly controversial. We intended to test if a positive impact of the use of XRT can be detected at the population level in the rituximab era.

5 Study Design National Cancer Institute s Surveillance Epidemiology and End Results (SEER-18) program to identify PMLBCL (International Classification of Diseases-Oncology, Third Edition, ICD-O-3 code 9679/3) cases and reported outcomes. The SEER-18 register includes Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah, Los Angeles, San Jose-Monterey, Rural Georgia, Alaska Native Tumor Registry, Greater California, Kentucky, Louisiana, New Jersey and Greater Georgia. We included all cases reported from 2001 to Follow up was current up to the end of 2010 (November 2012 submission).

6 Data Total of 315 cases of PMLBCL. Nine cases were subsequently excluded due to absence of stage information, resulting in 306 patients for analysis. Patient characteristics: - Median age at diagnosis was 36 years (IQR ) patients (59.8%) were female patients (78.8%) were white patients (76.8%) had stage I or stage II disease - 71 patients (23.2%) had stage III or stage IV disease - Median follow up was 29.5 months (IQR ) Of the 298 patients with XRT information available, 159 patients (53.3%) received XRT as part of their treatment. Unfortunately, due to the nature of the database, information on chemotherapy utilized and treatment response was not available.

7 Overall survival of patients with PMLBCL registered in the SEER database and diagnosed between 2001 and 2010 according to stage (panel a) and use of radiation therapy (XRT) in stages I/II (panel b) Figure 1a. Overall 3-year survival was 86.4 % (95% C.I. 80.7%-92.1%) for stages I/ II and 71.7% (95% C.I. 57.9% %) for stages III/ IV, P=0.002 Figure 1b. Overall 3-year survival was 90.6% (95% C.I. 84.3%-96.9%) for the 122 patients treated with RT and 83.4 % (95% C.I. 73.1%- 93.7%) for the 88 patients who did not receive radiation, P=0.2

8 Results Overall survival at 3 years was 82.8 % (95% C.I. 77.3%- 88.3%) for the entire group. We found a trend for more frequent use of radiation among male patients with stage I/II disease (65% vs. 54%, P=0.1). Irradiated patients and non-irradiated patients were comparable in terms of age, year of diagnosis, and race. Utilizing Cox proportional hazard regression, we found that none of the variables nor the use of XRT, was associated with increased risk of death.

9 Discussion R-CHOP regimen results in low toxicity and demonstrates comparable responses to those of more intense regimens. The role of mediastinal XRT after completion of systemic treatment remains controversial in PMLBCL. - Xu et al reported 5-year OS and PFS rates of 90% and 81% for patients treated with R-CHOP plus XRT; with much better results of 96.4% and 85.9% respectively, for patients with early stage disease. Excellent results have been achieved with more intense R-based chemotherapy alone in some series. - Dunleavy et al showed high event-free survival (EFS) rate of 93% and OS of 97% with dose adjusted etoposide, doxorubicin and cyclophosphamide with vincristine, prednisone and rituximab (DA- EPOCH -R).

10 Conclusion Our retrospective study review covered an era when the use of rituximab for DLBCL and PMLBCL had been widely adopted in the U.S. We demonstrated that the favorable outcomes seen in the literature for PMLBCL treated in the rituximab era can be verified by SEER data. Although our study was unable to confirm a survival advantage for XRT in early stage PMLBCL, registry analyses such as ours have limitations for dealing with non-comprehensive patient and disease-related datasets. The European study (IELSG37) is actively recruiting patients to evaluate the role of Rituximab based combination chemotherapy followed by observation vs. XRT in PMLBCL.