High Response Rate with Favorable Survival Projections in High-Risk Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Receiving R-CHOP-14 or Early Intensified Chemotherapy with Rituximab and Autograft (R-HDS): Results of the Interim Analysis of A GITIL Prospective Multicenter Phase III Study.

The outcome of B-cell diffuse large B-cell lymphoma (DLB-CL) patients has definitely improved since the introduction of therapeutic programs combining chemotherapy and the anti CD20 rituximab. However, the outcome of patients with adverse prognostic factors still needs a substantial improvement and intensive therapy with autologous stem cell transplantation (ASCT) may represent a feasible option. In a previous Phase II study the combination of rituximab and high-dose (HD) sequential chemotherapy, delivered with multiple autologous peripheral blood progenitor cell (PBPC) support (R-HDS regimen), proved effective and well tolerated in previously untreated patients with DLB-CL and age-adjusted International Prognostic Score (aaIPI) score 2-3 (Tarella et al.: Leukemia 2007). Based on this study, a multicenter Phase III study was planned to compare the R-HDS regimen to a standard dose dense, rituximab supplemented R-CHOP-14 chemotherapy program.

The multicenter phase III trial R-HDS 0305 (Clinical Trials.gov.number NCT00355199) was planned to include 240 patients with DLBCL without CNS with stage '2 II B, bulk, age 18-60 years, with ECOG-PS=0-3 and aaIPI 2-3 or age 61-65 years with ECOG-PS=0-2 and IPI 3-5. The control group received 8 courses of R-CHOP-14, supported by GCSF ± involved field radiotherapy (IFRT), if they achieved at least a PR after 4 cycles. Cases refractory to R-CHOP-14 were rescued with R-HDS. Experimental arm (RHDS) included: 3 courses of doxorubicin-containing chemotherapy (APO), followed by sequential administration of cyclophosphamide (CTX) 7 g/sqm, Cytarabine (Ara-C) 2g/sqm every 12 hours for 6 days, etoposide 2 g/sqm plus cisplatin 100 mg/sqm; the program was completed by mitoxantrone plus melphalan (60 and 180 mg/sqm) or BEAM conditioning regimen with ASCT± IFRT. Rituximab (375 mg/sqm) was given for a total of 6 doses, twice after CTX and Ara-C, as in vivo purging before CD 34+ cells harvest, and twice after ASCT. The primary outcomes of the study were CR, DFS, OS, EFS and toxicity. From June 2005 to February 2009, 165 patients were enrolled in the study (R-CHOP-14=83; RHDS=82). The planned interim analysis has been carried out on 119 patients who have been randomized up to March 2008.

The median age was 49 years (range, 18-65), 11 patients (9.2%) were> 60 years and the M/F was 1.38. Patients in two arms presented with comparable adverse features such as advanced stage (87%), BM infiltration (24%), bulky disease (67%), elevated LDH (81%) and beta 2-microglobulin (mean 3.9 mg/dl, SD = 4.5), poor ECOG-PS (60%), B-symptoms (62%), and ≥1 extranodal site (63%). Until now 10 patients (8%) did not complete the planned program because of toxicity or PD, 6 and 4 cases, respectively. One patient resistant to R-CHOP-14 was shifted to R-HDS. Overall, 24 patients (20%) deceased during the course of the study, 20 (17%) died from lymphoma, 2 (2%) due to therapy complications and 2 (2%) from hepatitis B reactivation. Moreover, 6 patients (5%) recovered from severe adverse events: 1 interstitial pneumonia, 1 graft failure, 1 sepsis, 1 colon diverticulitis, 1 shock, 1 prolonged aplasia. The main G>2 hematological toxicity were: anemia, granulocytopenia and thrombocytopenia, in 42%, 60 % and 45 % of patients, respectively. Grade >2 gastrointestinal, hepatic and infectious toxicity were recorded in 32 %, 11 % and 20% of patients, respectively.

One-hundred and eight of 119 patients (91%) were alive and assessable for the response rate and clinical outcome at final restaging. Eighty-nine patients (82%) achieved CR, 8 PR and 7 had SD or PD. With a median follow up of 18.1 months (SD= 9.3, range 0.3–40.6 months) the 2year OS, DFS and EFS of the 119 evaluable patients are 80%, 84% and 74%, respectively.

This interim analysis shows that in high-risk DLBCL patients aged =/<65 years, R-CHOP 14 and R-HDS with ASCT: i. are feasible therapeutic strategies with an acceptable risk profile; ii. induces an overall high response rate, markedly superior to historical results reported for high-risk aggressive lymphoma. The favorable survival projections allow to continue the study protocol until its planned conclusion in order to verify any possible difference between R-CHOP14 and R-HDS in terms of therapeutic efficacy.

No relevant conflicts of interest to declare.