Dose-Adjusted EPOCH Plus Rituximab in Untreated Patients with Poor Prognosis Large B-Cell, with Analysis of Germinal Center and Activated B-Cell Biomarkers. A Phase IV Study Conducted by the Spanish PETHEMA Group

. This prospective multi-institutional phase IV study was designed within the Spanish PETHEMA Group to assess the efficacy and safety of dose adjusted EPOCH plus Rituximab (DA-EPOCH-R) infusional therapy (as previously reported*) in untreated patients with poor prognosis large B-cell lymphomas. All cycles were supported with G-CSF. Additional analysis of the clinical outcome and the influence of biomarkers associated with tumor proliferation (Ki67) and cellular differentiation was performed. Patients and Methods. Eighty-one untreated patients diagnosed of DLBCL (68), PMLBL (6) and FL grade 3 (7), with an age-adjusted IPI higher than 1 (or equal to 1 plus bulky disease), were enrolled and evaluable. Radiation consolidation was permitted to patients with bulky disease at diagnosis. Histology was centrally reviewed. Fifty tumor tissue samples (61.7% of patients) were analyzed by immunohistochemistry for biomarkers of proliferation (Ki67) and cellular differentiation (CD10, Bcl6, GCET1, MUM1 and FOXP1). Results. The median age was 52 (range, 21–77) years, with 52% older than 60. 92.5% had intermediate-high or high risk score according to aaIPI criteria. The median number of cycles administered was 6 (range, 1–8). Treatment was discontinued in 7 patients: disease progression (2) and death (5: 2 unrelated and 3 for disease progression). Radiotherapy (30 Gy maximum) was given to 37 patients (45.7%). A median of 3 escalation level (range, 0–6) was achieved. Toxicity was assessed during 470 cycles administered. Grade 3–4 anaemia was reported in 240 cycles (51%) and in 84% of patients; and grade 3–4 thrombocytopenia in 176 cycles (37%) and in 71.6% of patients. There were 54 episodes of neutropenic fever (11.5% of cycles) in 37 patients (45.7%). On an intention-to-treat basis, 64 (79.1%) patients achieved a complete response (CR or uCR) and 8 (9.9%) a partial response (PR) with an overall response rate (ORR) of 89%. 19.8% (16) of patients who achieved CR (or uCR) relapsed between 6 to 12 months after the beginning of EPOCH-R therapy. With a median follow-up of 55 months (range, 23–100 months), overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were 63.1% (95% CI 50.1%–76.1%), 62.01% (95% CI 50.8%–73.2%), and 59.7% (95% CI 48.5%–70.9%) respectively; and disease-free survival for patients who achieved CR or uCR was 72.1% (95% CI 60.95%–83.3%). Neither aaIPI risk factors nor IPI were associated with poorer response, PFS (p=0.418 and p=0.099 respectively) or OS (p=0.458 and p=0.141 respectively). There was only a slight association between ß2 microglobulin levels (>3.5mg/L) and OS (p=0.015). High tumor proliferation (Ki67>75%) was not associated with neither poorer OS (p= 0.461) nor poorer PFS (p=0.769). After having ruled out other non-DLBCL histologies, 39 patients were analyzed for germinal center (GC) or activated B-cell (ABC) biomarkers using Hans and Choi algorithms. No differences were found neither in OS (p=0.972 and p=0.673, respectively) nor PFS (p=0.215 and p=0.433, respectively). Conclusion. DA-EPOCH-R shows a promising outcome in Intermediate-High and High risk aaIPI subgroups of large B-cell lymphoma patients with an acceptable toxicity profile. Further studies (some of them are now in process) are needed to verify its actual role in the ABC subtype of DLBCL. DA-EPOCH-R outcome was no affected by high tumor proliferation. * Wilson WH et al. JCO 2008: 26:2717-24.

No relevant conflicts of interest to declare.