Table 1.
Selected Phase 3 Randomized Controlled Trials to Improve Upon R-CHOP-21
| Clinical Trial | Comparison Groups | Patient Population | Outcomes | Conclusions |
|---|---|---|---|---|
| Studies of R-CHOP-21 Intensification | ||||
| Habermann, 200622 | Maintenance rituximab vs observation after R-CHOP-21 or CHOP-21 | 632 patients aged 60 y or older with untreated DLBCL | 2-y FFS rate was higher with maintenance rituximab after CHOP (74% vs 45% with observation alone), but not with maintenance rituximab after R-CHOP (79% vs 77% with observation alone). | Negative: No benefit was found for maintenance rituximab after R-CHOP. |
| Pfreundschuh, 200833 (RICOVER-60) | 6 or 8 cycles of CHOP-14 or R-CHOP-14 | 1222 patients aged 61–80 y with untreated DLBCL | 3-y EFS was 47% after 6 cycles of CHOP-14, 53% after 8 cycles of CHOP-14, 67% after 6 cycles of R-CHOP-14, and 63% after 8 cycles of R-CHOP-14. | Positive: 6 cycles of R-CHOP-14 significantly improved EFS, PFS, and OS vs 6 cycles of CHOP-14, although no increase in OS was found for 8 cycles of R-CHOP-14 or CHOP-14 compared with 6 cycles. |
| Récher, 201130 (LNH03-2B) | R-ACVBP vs R-CHOP-21 | 380 patients aged 18–59 y with untreated DLBCL and age-adjusted IPI 1 | 3-y OS was 92% in the R-ACVBP group and 84% in the R-CHOP group. | Positive: Compared with standard R-CHOP, R-ACVBP significantly improved EFS, PFS, and OS. |
| Delarue, 201334 (LNH03-6B) | R-CHOP-14 vs R-CHOP-21 | 602 patients aged 60–80 y with untreated DLBCL and age-adjusted IPI 1 | 3-y EFS was 56% in the R-CHOP-14 group and 60% in the R-CHOP-21 group. | Negative: R-CHOP-14 did not improve efficacy compared with R-CHOP-21. |
| Cunningham, 201335 | R-CHOP-14 vs R-CHOP-21 | 1080 patients aged >18 y with untreated DLBCL | 2-y OS was 83% in the R-CHOP-14 group and 81% in the R-CHOP-21 group. | Negative: R-CHOP-14 was not superior to R-CHOP-21. |
| Chiappella, 201736 (DLCL04) | R-CHOP-14 vs R-MegaCHOP-14 with or without consolidative transplantation | 399 patients aged 18–65 y with untreated DLBCL and age-adjusted IPI 2–3 | 5-y OS was 78% in the consolidative transplant group and 77% in the non-transplant group. | Negative: R-MegaCHOP plus consolidative transplant did not improve OS. |
| Vitolo, 201737 (GOYA) | G-CHOP-21 vs R-CHOP-21 | 1418 patients aged >18 y with untreated advanced-stage DLBCL and IPI ≥2, IPI 1 if age ≤60 y, or IPI 0 and bulky disease | 3-y PFS was 70% in the G-CHOP group and 67% in the R-CHOP group. | Negative: G-CHOP did not improve PFS compared with R-CHOP. |
| Lugtenburg, 202038 (HOVON-84) | R-CHOP-14 vs RR-CHOP-14 (R-CHOP-14 with extra rituximab on day 8 of the first 4 cycles) | 574 patients aged 18–80 y with untreated stage II-IV DLBCL and age-adjusted IPI 1–3 for ages 18–65 y and age-adjusted IPI 0–3 for ages 66–80 y | 3-y OS was 81% in the R-CHOP-14 group and 76% in the RR-CHOP-14 group. | Negative: RR-CHOP-14 did not improve CR rate, PFS, or OS compared with R-CHOP-14. |
| Ohmachi, 202139 (JCOG0601) | R-CHOP-21 with 8 doses of rituximab once every 3 wk vs RW-CHOP-21 (CHOP-21 with 8 doses of weekly rituximab) | 421 patients aged 20–79 y with untreated DLBCL | 3-y OS was 89% in the R-CHOP-21 group and 90% in the RW-CHOP-21 group. | Negative: RW-CHOP-21 did not improve PFS compared with R-CHOP-21. |
| XR-CHOP Studies | ||||
| Seymour, 201440 (MAIN) | Bevacizumab + R-CHOP (RA-CHOP) vs R-CHOP | 787 patients aged > 18 y with untreated DLBCL | Median PFS was 40 mo in the RA-CHOP group and 43 mo in the R-CHOP group. | Negative: The trial was stopped early because of increased cardiotoxicity of RA-CHOP without prolongation of PFS. |
| Thieblemont, 201741 (REMARC) | Maintenance lenalidomide or placebo following first-line treatment with R-CHOP Cell of origin assessment |
650 patients aged 60–80 y with untreated stage II-IV DLBCL and age-adjusted IPI ≥ 1 who achieved a PR or CR after first-line R-CHOP | 2-y PFS was 80% in the lenalidomide maintenance group and 75% in the placebo maintenance group. | Positive: Median PFS was significantly longer with maintenance lenalidomide than with placebo, although without a significant difference in OS. Median PFS was significantly longer with lenalidomide than with placebo for the GCB cell of origin group, although not for the non-GCB cell of origin group. |
| Davies, 201942 (REMoDL-B) | Bortezomib + R-CHOP-21 (RB-CHOP) vs R-CHOP-21 Cell of origin assessment |
918 patients aged > 18 y with untreated DLBCL | 30-mo PFS was 70% in the R-CHOP-21 group and 74% in the RB-CHOP-21 group. | Negative: RB-CHOP-21 did not improve PFS compared with R-CHOP-21. Further, bortezomib did not significantly affect PFS in either the ABC or GCB cell of origin group. |
| Younes, 201943 (PHOENIX) | Ibrutinib + R-CHOP-21 vs R-CHOP-21 Cell of origin assessment |
838 patients aged > 18 y with untreated non-GC–type stage II-IV DLBCL and IPI ≥1 | 3-y EFS was 70% in the ibrutinib + R-CHOP-21 group and 67% in the R-CHOP-21 group | Negative: Ibrutinib + R-CHOP-21 did not improve EFS, PFS, or OS compared with R-CHOP-21. Further, the addition of ibrutinib did not improve EFS in the ABC cell of origin group. |
| Nowakowski, 202144 (ROBUST) | Lenalidomide + R-CHOP-21 (R2-CHOP) vs R-CHOP-21 Cell of origin assessment |
570 patients aged > 18 y with untreated ABC-type stage II-IV DLBCL and IPI ≥2 | 2-y PFS was 67% in the R2-CHOP-21 group and 64% in the R-CHOP-21 group. | Negative: R2-CHOP-21 did not improve PFS compared with R-CHOP-21. |
ABC, activated B-cell; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; FFS, failure-free survival; GCB, germinal center B-cell; G-CHOP, obinutuzumab plus CHOP; IPI, International Prognostic Index; mo, months; OS, overall survival; PFS, progression-free survival; PR, partial response; R-ACVBP, rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone; R-CHOP, rituximab plus CHOP; R-MegaCHOP, rituximab, cyclophosphamide, doxorubicin, and vincristine on day 1, and prednisone on days 1–5; R2-CHOP, lenalidomide and rituximab plus CHOP; RA-CHOP, bevacizumab and rituximab plus CHOP; RB-CHOP, bortezomib and rituximab plus CHOP; RR-CHOP, R-CHOP with extra rituximab; RW-CHOP, CHOP with weekly rituximab; wk, weeks; XR-CHOP, addition of a new therapeutic (“X”) to the R-CHOP backbone; y, year(s).