Randomized Phase II Study of R-CHOP-14 Versus R-CHOP-14 Followed By Chaser As Induction Therapy for High-Dose Chemotherapy (HDT), LEED, and Autologous Stem-Cell Transplantation (ASCT) in Poor-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Japan Clinical Oncology Group (JCOG) Study (JCOG0908)

Background:HDT with ASCT (HDT/ASCT) is an option as the upfront consolidation for poor-risk DLBCL. However, its role remains controversial and the more effective induction therapy with HDT/ASCT might improve the outcomes. To select a better induction therapy, JCOG conducted a randomized selection phase II study in previously untreated DLBCL patients (pts) with the high-intermediate (HI) or high (H) risk on age-adjusted International Prognostic Index (aaIPI) (UMIN000003823).

Methods: Previously untreated CD20+ DLBCL pts with aaIPI of HI and H were eligible. Other main inclusion criteria were: aged 20 to 65; stage II bulky, III or IV; ECOG performance status 0-2, at least 1 measurable lesion and preserved organ functions. Pts were randomized to receive induction therapy with six cycles of R-CHOP-14 (rituximab [R] 375 mg/m², cyclophosphamide [CPA] 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² [max 2 mg], all IV on day (d) 1, and prednisone 100 mg PO on d 1-5, every 2 weeks) (Arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (R 375 mg/m² on d 1, CPA 1,200 mg/m² on d 2, Ara-C 2 g/m² on d 3-4, dexamethasone (DEX) 40 mg/body on d 2-4 and etoposide (ETP) 100 mg/m² on d 2-4, every 3weeks) (Arm B). Randomization was balanced by institution and aaIPI score. Peripheral blood stem cells (PBSCs) with minimum of 2 x 10⁶ CD34+ cells/kg were harvested after the 4th cycle of R-CHOP-14 or the 1st cycle of CHASER. Pts who achieved a complete response (CR) or partial response (PR) after induction therapy proceeded to HDT with LEED (melphalan 130 mg/m² on d -1, CPA 60 mg/kg on d -4 and -3, ETP 500 mg/m² on d -4 to -2 and DEX 40 mg/body on d -4 to -1) and ASCT on d 0. Radiation therapy was allowed to a residual disease after ASCT. The primary endpoint was 2-year (yr) progression-free survival (PFS). Secondary endpoints included overall response rates (ORR) and CR rates of both the induction phases and the entire treatment courses, 2-yr and 5-yr overall survival (OS) rates, 5-yr PFS rate, and safety. Assuming at least 65% of 2-yr PFS in both arms, sample size of 30 evaluable pts per arm would provide a correct selection probability of 80% in observing 10% better 2-yr PFS in one arm than in another. Estimating that up to 10% of pts would be ineligible, a sample size was set at 35 in each arm.

Results: Between June 2010 and February 2015, a total of 71 pts were randomized to Arm A (N=35) and Arm B (N=36). Baseline characteristics were (Arm A vs Arm B): male 18 (51%) vs 18 (50%); median (range) age 57 (23-64) vs 55.5 (30-65) yrs; aaIPI HI/H 24 (69%)/11 (31%) vs 28 (78%)/8 (22%). Thirty-two (91%) pts in Arm A and 33 (92%) in Arm B completed induction therapy, and 30 (86%) and 28 (78%) did study treatment per protocol, respectively (Figure 1). Progressive disease and discontinuation of the treatment due to toxicity were observed in 4 and 0 pts in Arm A and 1 and 5 in Arm B, respectively, before HDS/ASCT. In Arm A, 33 out of 35 pts yielded more than 2 x 10⁶ CD34+ cells/kg and 34/36 pts in Arm B. With the median follow-up of 44.9 months (range: 4.2-75.9) among all pts, 2-yr PFS in Arms A and B were 68.6% (95% confidence interval [CI], 50.5-81.2%) and 66.7% (95%CI, 48.8-79.5%), respectively (Figure 2). OS at 2-yr were 74.3% (95%CI, 56.4-85.7%) in Arm A and 83.3% (95%CI, 66.6-92.1%) in Arm B. After induction therapy, ORR and CR rate were 88.6% and 62.9% in Arm A and 94.4% and 61.1% in Arm B, respectively, while 82.9% and 68.6 % in Arm A and 69.4% and 63.9% in Arm B, respectively, after entire therapy. Exploratory subgroup-analyses revealed a tendency of better PFS and OS in Arm B than those in Arm A in pts with aaIPI-H, bulky lesions (>=10cm) or stage non-IV. Of most common hematologic toxicities, grade (G) 3/4 neutropenia and G 3/4 thrombocytopenia were observed in 65.7% and 0 % respectively in induction phase of Arm A, 100% and 100% in induction phase of Arm B, and 97% and 100% in LEED (HDT/ASCT). G3 febrile neutropenia was observed in 17.1% in induction of Arm A, 55.6% in induction of Arm B and 44.8% in HDT/ASCT. In induction phase of Arm A and Arm B, 45.7% and 75.0% of pts had G_3 non-hematologic toxicities, respectively. Secondary malignancies were observed in 3 pts including: 1 prostatic cancer and 1 rectal cancer in Arm A and 1 lung cancer in Arm B.

Conclusions: R-CHOP-14 showed higher 2-yr PFS and less toxicity compared with R-CHOP-14/CHASER for HDT/ASCT in HI/H risk DLBCL pts by aaIPI. Thus, R-CHOP-14 was considered to be more promising induction regimen.

View largeDownload slide

View largeDownload slide

Close modal