Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era

Abstract

Purpose: Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown.

Patients and methods: Patients with CD20(+) DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT.

Results: The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001).

Conclusion: In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP.

Trial registration: ClinicalTrials.gov NCT00137995.

Fig 1.

CONSORT diagram of distribution of patients according to arm resulting from the first random assignment. CRF, case report forms; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; R-DHAP, rituximab, dexamethasone, high-dose cytarabine, cisplatin; BEAM, carmustine, etoposide, cytarabine, melphalan; ASCT, autologous stem-cell transplantation.

Fig 2.

Treatment protocol. R1, first random assignment; R-DHAP, rituximab, dexamethasone, high-dose cytarabine, cisplatin; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; PBPC, peripheral-blood progenitor cells; CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease; BEAM, carmustine, etoposide, cytarabine, melphalan; ASCT, autologous stem-cell transplantation; R2, second random assignment.

Fig 3.

(A) Overall survival according to the first random assignment (intent to treat). (B) Progression-free survival according to treatment arm. (C) Event-free survival (EFS) according to prior rituximab treatment and relapse less than 12 months after diagnosis. (D) EFS according to prior rituximab treatment and relapse more than 12 months after diagnosis. R-ICE, rituximab, ifosfamide, carboplatin, etoposide; R-DHAP, rituximab, dexamethasone, high-dose cytarabine, cisplatin.

Fig 4.

(A) Progression-free survival (PFS) of patients undergoing autologous stem-cell transplantation (intent to treat; n = 206). (B) PFS according to response after salvage regimen (including death) for all patients: complete response (CR) plus unconfirmed complete response (CRu; n = 147) and partial response (PR; n = 98).

Fig A1.

(A) Progression-free survival (PFS) according to prior exposure to rituximab (intent to treat [ITT]). (B) PFS according to time to failure from diagnosis (ITT). (C) PFS of induction ITT population according to autologous stem-cell transplantation (ASCT) or no ASCT in patients with prior rituximab and failure from diagnosis less than 12 months. NA, not available.