High CR Rate and Prolonged EFS in aaIPI 2 – 3 Diffuse Large B-Cell Lymphoma Following High-Dose Sequential Chemotherapy and In Vivo Rituximab-Purged Stem Cell Autografting (R-HDS Regimen): Results of a Prospective Phase II Multicenter Study Sponsored by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi).

Background. Recent reports have shown that Rituximab added to conventional chemotherapy may significantly improve the prognosis of CD20-positive Diffuse Large B-cell Lymphoma (DLB-CL). However, patients with unfavorable clinical presentation still have a poor outcome. Other studies have documented an increased anti-lymphoma activity upon addition of Rituximab to intensified treatments with autologous peripheral blood stem cell (PBSC) transplantation. Based on these premises, a prospective multicenter study has been performed on the use of a Rituximab-supplemented high-dose sequential (R-HDS) chemotherapy schedule with PBPC autografting in patients with unfavorable DLB-CL, defined as score 2 and 3 (intermediate-high or high) according to the age-adjusted International Prognostic Index (aaIPI).

Methods. The R-HDS regimen included: (i) an initial debulkying with 3 APO courses; (ii) a high-dose (hd) phase consisting in the sequential administration, at 15–20 day intervals, of hd- cyclophosphamide (7gr/sqm, with two Rituximab doses at 375 mg/sqm), hd-Ara-C (2gr/sqm b.i.d. for 6 days with Rituximab), and hd etoposide + Cisplatin; (iii) a final myeloablative phase (hd-Mitoxantrone + L-Pam) with PBSC autografting and 2 more doses of Rituximab. Involved-field radiotherapy was scheduled on areas of previous bulky disease or residual lesions. Six Centers affiliated to the GITIL group (Gruppo Italiano Terapie Innovative nei Linfomi) participated in the multicenter study. Patient enrollment started in November 1999 and was closed in September 2004.

Results. Overall, 112 previously untreated patients aged ≤ 60 years, with CD20-positive DLB-CL and aaIPI score 2 (74 pts) or 3 (38 pts), entered the study protocol and are evaluable. There were 5 early toxic deaths (3 sepsis in the hd-phase, 1 pneumonia and 1 leucoencephalopathy from JC-virus infection after autografting) and one late toxic death due to pneumonia which occurred at 10 mos. after R-HDS. The TRM was 5.3%. Ninety patients (80 %) achieved Complete Remission (CR). At a median follow-up of 24 mos, 90 patients (80%) are alive and 83 (74%) are in continuous CR (CCR), leading to a 5.3-yr event-free survival (EFS) projection of 71%. There was a trend towards a better outcome in aaIPI 2 vs. 3, although the difference was not statistically significant.

Conclusions. The CR, OS and EFS rates observed after R-HDS compare favorably with the poor outcome anticipated in aaIPI 2–3 patients managed with conventional chemotherapy. The results of this phase II study prompted an ongoing phase III GITIL multicenter study to compare R-CHOP vs. R-HDS in younger patients with high-risk DLB-CL.