Dose-Intensified CHOP with Rituximab (R-Double-CHOP) Followed by Consolidating High-Dose Chemotherapy Is An Effective Treatment for Younger Patients with Advanced Diffuse Large B-Cell Lymphoma

In the previous study, we demonstrated the efficacy and safety of dose-intensified CHOP (Double-CHOP) followed by consolidation with high-dose chemotherapy (HDC) for high-risk aggressive non-Hodgkin lymphoma (Yamazaki et al. Leuk Lymphoma 43: 2117–23, 2002). However, after the advent of rituximab, the role of intensive chemotherapy or consolidating HDC for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in primary treatment has been controversial. We therefore investigated the significance of combination chemotherapy consisting of rituximab and Double-CHOP (R-D-CHOP) followed by consolidating HDC for younger patients with advanced DLBCL.

65 years or younger patients with newly diagnosed CD20-positive DLBCL who had 2 or more risk factors in the age adjusted International Prognostic Index (aaIPI = 2, 3) were enrolled in this study. To prevent tumor lysis syndrome, a standard dose of CHOP was given 3 weeks before initiating R-D-CHOP. R-D-CHOP consisted of rituximab (375 mg/m² on day−2), cyclophosphamide (750 mg/m² on day 1, 2), doxorubicin (50 mg/m² on day 1, 2), vincristine (1.4 mg/m² [maximum 2.0 mg/body] on day 1) and prednisolone (50 mg/m² on day 1–5). For patients aged 61–65 years, dosage of cycrophosphamide was reduced. Treatment was given every 3 weeks up to a total of 3 courses with support of granulocyte colony stimulating factor. For responders with good performance status (PS), we planned peripheral stem cell collection after the third cycle of R-D-CHOP with in vivo purge using rituximab and consolidating HDC with cycrophosphamide (60 mg/kg on day−7,−6), etoposide (500 mg/m² on day−6,−5,−4) and ranimustine (250 mg/m² on day−3,−2) followed by autologous stem cell transplantation (ASCT). For poor mobilizers or patients with poor performance status, high-dose methotrexate (HDMTX) (8 g/m² on day 1) with leukovolin rescue was alternatively given.

From January 2001 to November 2010, 51 patients with a median age of 54 years (range 19 – 65) participated in this study. All the patients had Ann Arbor stage III (n = 13) or IV (n = 38) disease with an average 1,005 IU/l of serum lactate dehydrogenase (LDH) concentration (normal upper limit = 220), and 26 (51%) had bulky disease. Of these patients, 49 completed the intended 3 cycles of R-D-CHOP with a median 22 days (range 19 – 62) of interval. The overall response (OR) and the complete response (CR) rate for R-D-CHOP regimen were 94% and 78%, respectively. Of the responders, a total of 30 patients successfully proceeded to HDC/ASCT with an average 4.57 × 10⁶/kg of harvested CD34-positive cells and a median 11 days to neutorophil engraftment (range 9 – 15), whereas 16 received HDMTX. Throughout initial treatment, 17 patients who had residual or suspicious disease received additional irradiation therapy before or after consolidating chemotherapies. With a median 38 months (range 3–119) of follow up, the 3-year overall survival (OS) and the event-free survival (EFS) for all patients were 78% and 61%, respectively. 3-year OS for patients treated with HDC/ASCT and HDMTX were 90% and 72% (p = 0.49), respectively. Overall, Grade 3 – 4 hematological toxicities were common, but no treatment-related death was observed during the observation period.

R-D-CHOP regimen, – followed by consolidating HDC/ASCT or HDMTX –, is a safe and efficacious treatment for younger patients with advanced DLBCL. In addition, HDMTX seems to be a reasonable alternative for patients who are not candidates for HDC/ASCT. Although these results need further evaluation, our data suggest that up-front HDC remains to be a promising strategy for a highly unfavorable subgroup of patients with DLBCL in the rituximab-era.

No relevant conflicts of interest to declare.