Gene expression profiling has revealed that over one third of genes more highly expressed in PMBL than other DLBCLs are characteristically expressed in classical Hodgkin Lymphoma (HL) suggesting a biological relationship (J Exp Med198:851, 2003). PMBL and HL also share mediastinal presentation, young age, female predominance, prominent sclerosis and CD30 expression. Although some cases lie in a pathological “grey zone” between HL and PMBL, the latter is distinguished by robust CD20 expression. Like HL, local mediastinal failure after doxorubicin-based regimens has led to routine mediastinal xRT, which is associated with secondary malignancies and coronary disease. We analyzed the outcome of DA-EPOCH in 36 untreated PMBLs. No pts received xRT except for CNS PMBL. DA-EPOCH was administered with G-CSF for 2 cycles beyond CR for 6 to 8 cycles as described (Blood99:2685, 2002). The first 14 pts were on a DA-EPOCH study and the last 22 on a DA-EPOCH-Rituximab study. Most pts had adverse prognostic features with bulky disease, elevated LDH and extranodal sites, which were balanced among the 2 series. IHC in 34 cases was consistent with gene expression profiling of PMBL with frequent CD20+ 33/33 (100%), infrequent CD10+ 1/26 (4%) and variable BCL-6+ 17/24 (71%) and MUM-1+ 8/22 (36%) expression. Tumor proliferation by MIB-1 was high with a median (range) of 82% (54–98). IHC markers were similar among the 2 series. EFS and OS are shown below with a median follow-up of 8.6 and 3.4 yrs, respectively, for pts receiving DA-EPOCH −/+ R. Rituximab was associated with a significantly improved EFS (p=0.036) and trend in improved OS (p=0.10) by 2-tailed exact log-rank test. In conclusion, pt characteristics were consistent with the clinical-pathological and molecular definition of PMBL and prognostic features were similar to other series (Haematologica87:1258, 2002). These results suggest for the first time that rituximab significantly improves the outcome of PMBL and that DA-EPOCH-R obviates routine mediastinal xRT. DA-EPOCH-R may be more effective than CHOP-based treatment because it overcomes high tumor proliferation and employs pharmacodynamic dosing. Although needing confirmation, our results suggest DA-EPOCH-R without xRT is highly effective for PMBL. Patient Characteristics