HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL TRANSPLANTATION IN FIRST LINE TREATMENT FOR HIGH-RISK DIFFUSE LARGE B CELL LYMPHOMA (DLBCL) IN THE RITUXIMAB ERA: AN INTENTION TO TREAT-ANALYSIS

Background: The combination of Rituximab and CHOP (R-CHOP) is considered to be the standard treatment for patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Treatment results are still unsatisfactory in a significant proportion of patients, particularly in those with a high-risk disease defined by the IPI score. The use of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) is standard clinical practice for patients with relapsed/refractory DLBCL, while its significance as consolidation in first-line treatment remains unclear. Aims: We analyzed safety and effectiveness of R-CHOP followed by salvage chemotherapy and ASCT for patients with young (<65 years) high-risk DLBCL, defined by an age-adjusted IPI score of 2/3, for whom from 2004 on our institutional guidelines recommended ASCT as consolidation. We analyzed prognostic factors in this group. Methods: The treatment program consisted of 4 cycles R-CHOP-14 followed by 3 cycles of a DHAP-like salvage regimen, R-MICMA (Sorà et al, Cancer 2006; 106: 859), and consolidation with Busulfan-Melphalan supported with ASCT. We observed 76 consecutive patients (median age 50 years, range 15- 64 years; 32 females and 44 males) diagnosed between May 2004 and January 2013 with DLBCL who had an age-adjusted IPI score of 2 or 3. Response was assessed according to Cheson criteria (Cheson et al, JCO 1999; 17:1244). Results: Nine of 76 patients (12%) were not eligible for the treatment program that included ASCT. Reasons were important comorbidities in 6 pts (1 cardiac, 2 neurologic, 1 hepatic, 1 hematologic, 1 renal) and start of another treatment regimen (CODOX-M/IVAC in the suspicion of a Burkitt lymphoma) in 3 pts. Response after 4 cycles R-CHOP was CR/CRu in 40/67 pts (60%), PR in 21/67 pts (31%) and NR in 6/67 (9%). Sixty-one patients went on to salvage chemotherapy with R-MICMA, while 6 pts in CR/CRu continued R-CHOP, and 53 pts were transplanted. Reasons not to proceed to transplant were progressive disease (3 pts), infections (3 pts), mobilization failure (1 pt) and patient’s decision (1 pt). The 3-year EFS and OS of the entire group of 76 patients were 67% (95% CI, 55-76) and 71% (95% CI, 59-80%), respectively. The 3-year EFS and OS of transplanted patients were 70% (95% CI, 55-80) and 76% (95% CI, 62-85). Factors associated with inferior EFS were age-adjusted IPI score (2 vs. 3, p=0.004) and disease status after 4 cycles R-CHOP (p=0.01) in univariate and multivariate analysis. These differences were also retained in the group of patients who received ASCT, with a three-years EFS of 78% in pts with an age-adjusted IPI score 2 vs 46% in pts with an age-adjusted IPI score 3 (p=0.003), suggesting that ASCT is insufficient for highest risk patients. Summary and Conclusions: Our findings of an intention-to-treat, single centre experience indicate that 88% of patients with high-risk DLBCL and age <65 years are eligible for a treatment strategy that includes ASCT, and 70% will eventually receive ASCT as part of their first-line treatment. Consolidation with upfront ASCT for high-risk DLBCL is a feasible and promising therapy also in the Rituximab era, but there are still subsets of patients that continue to have a poor prognosis despite ASCT, and addition of new biologic drugs, as tyrosine kinase inhibitors, have to be tested to improve outcome in these patients.