DLBCL

Induction with R-ACVBP is not superior compared to R-CHOP14, and PET driven consolidation appears feasible, in patients with newly diagnosed CD20+ DLBCL

On 12th July 2017, in Blood, Rene-Olivier Casasnovas from Hopital Le Bocage and INSERM UMR1231, Dijon, France, et al. published final results from their randomized phase II study aiming to assess the efficacy of either R-ACVBP or R-CHOP14 induction and a PET-driven Autologous Stem Cell Transplant (ASCT) or Standard Immunochemotherapy (SIC) consolidation in aaIPI2–3, newly diagnosed, CD20+ Diffuse Large B-Cell Lymphoma (DLBCL) patients.

In the LNH2007-3B study (NCT00498043), patients were randomly assigned to an induction immuno-chemotherapy with 4 cycles of either R-ACVBP14 or R-CHOP14. Consolidation treatment was determined by PET carried out at baseline, after 2 cycles (PET2), and after 4 cycles (PET4) of induction therapy and was centrally assessed using International Harmonization Project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- ASCT, and PET4+ patients treated with investigator' choice. The study’s primary endpoint was the 2007 International Working Group (IWG) CR rate after induction.

Key Highlights:
  • Patients randomized to: R-ACVBP = 109; to R-CHOP14 = 102
  • CR rate according to IWG 2007 criteria: R-ACVBP = 45% (51/109; 95% CI, 38–67%); R-CHOP14 = 39% (40/102; 95% CI, 28–54%); P = 0.076
  • PET4 negativity: R-ACVBP = 53% (58/109); R-CHOP14 = 41% (42/102); P = 0.08
  • One hundred pts achieved PET4 negativity; SIC (PET2-) versus ASCT (PET2+) consolidation: R-ACVBP arm = 26% vs 28%; R-CHOP14 arm = 23% vs 18%
  • Ninety-one pts were administered planned treatment: SIC = 58 pts (98%); ASCT = 40 pts (83%)
  • Median follow-up = 45 months (range, 1–63); 55 pts (26%) had progressed/relapsed; 39 pts (18%) had died
  • 4-year EFS: R-ACVBP = 43% (95% CI, 34–52); R-CHOP14 = 31% (95% CI, 22–40); P = 0.0094
  • 4-year PFS: R-ACVBP = 75%; R-CHOP14 = 74%); P = 0.77
  • 4-year OS: R-ACVBP = 85%; R-CHOP14 = 81%); P = 0.6
  • PET2-/PET4- and PET2+/PET4- patients had similar outcome
  • Outcome of PET2-/PET4- pts (26%) who received SIC was non-significantly different from PET2-/PET4+ pts (24%) who mostly received ASCT: 4-year PFS was 75% vs 85% (P = 0.28) and 4-year OS was 89.6% vs 4% (P = 0.21), and similar in both randomization arms (P = 0.09)
  • Outcome of PET2+/PET4- pts who received ASCT (n=40) was non-significantly different from PET2-/PET4- who received SIC: 4-year PFS was 87.2% vs 5% (P > 0.14) and 4-year OS was 89.8% vs 90.2% (P = 0.9)
  • ΔSUVmaxPET0-4>70% was associated with better outcome (4-year PFS: 84% vs 35%; 4-year OS: 91% vs 57%; P < 0.0001) whatever the consolidation
  • Incidence of hematological toxicity was higher, mucositis was more frequent, and infections were more common with R-ACVBP versus R-CHOP14
  • Transfusions were more common in the R-ACVBP arm versus the R-CHOP14 arm: received ≥1 red blood cell transfusion = 72 pts (64%) vs 29 pts (27%; P < 10-5); received ≥1 platelets transfusion = 20 pts vs 3 pts (P < 0.0003)
  • Two secondary primary malignancies were reported for the R-ACVBP and R-CHOP14 arms; no secondary AML or MDS observed

Overall, the authors concluded that the superiority of induction with R-ACVBP compared to R-CHOP14 could not be confirmed. They went on to say that PET driven consolidation appears feasible in a multicenter setting. Furthermore, they found that sequential ΔSUVmax assessment was more reproducible than IHP and improved the likelihood of interim PET better characterizing most patients eligible for SIC, those requiring upfront ASCT, and refractory patients requiring alternative strategies.

The results of this trial formed that basis of the randomized, phase III GAINED trial (NCT01659099) aiming to determine if AVCBP is superior to CHOP14 as well as prospectively validating ΔSUVmax guided consolidation in younger patients with high-risk DLBCL.

Abstract:

Dose-dense induction and upfront consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating high-risk diffuse large B cell lymphoma patients. GELA designed a randomized phase II trial evaluating the efficacy of either R-ACVBP or R-CHOP14 induction and a PET-driven ASCT or standard immunochemotherapy (SIC) consolidation in aaIPI2-3 patients. PET was done at baseline, after 2 (PET2) and 4 induction cycles (PET4) and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- ASCT and PET4+ patients treated with investigator' choice. The primary end-point was the 2007 international working group CR rate after induction. ΔSUVmax PET assessment was explored. 211 patients were randomized to R-ACVBP (n=109) or R-CHOP14 (n=102). PET4-/CR rates were 53/47% with R-ACVBP and 41/39% with R-CHOP14 (CR 95%CI: 38%-67% v 28%-54%; p=0.076). Consolidation in the R-ACVBP and R-CHOP14 arms was SIC in 26% and 23% of patients and ASCT in 28% and 18%, respectively. PET4 positivity was higher with R-CHOP14 (54% v 41%; p=0.08) leading to more salvage therapy (37% v 26%; p=0.07) and lower EFS (4y-EFS= 31% v 43%; p<0.01) but PFS and OS were similar in both arms. PET2-/PET4- and PET2+/PET4- patients had similar outcome. Using ΔSUVmax, 79% patients were PET2-/PET4-. ΔSUVmaxPET0-4>70% was associated with better outcome (4y-PFS: 84% v 35%; 4y-OS: 91% v 57%, p<0.0001) whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing alternative to SIC, including ASCT.

Reference:

1. Casasnovas R.O. et al. A FDG-PET driven consolidation strategy in diffuse large B-cell lymphoma: Final results of a randomized phase II study. Blood. 2017 Jul 12. pii: blood-2017-02-766691. DOI: 10.1182/blood-2017-02-766691. [Epub ahead of print].