Autologous Stem Cell Transplant during first complete remission does not significantly prolong survival in patients with Double-Hit Lymphoma

On 5^th May 2017, the Journal of Clinical Oncology published an article by Daniel J. Landsburg from the University of Pennsylvania, Philadelphia, USA, and colleagues reporting the results of their large multicenter analysis of the impact of front-line therapy and Autologous Stem Cell Transplant (autoSCT) on relapse and survival in patients with Double-Hit Lymphoma (DHL) who achieved First Complete Remission (CR1) after completion of first-line therapy with R-CHOP or intensive therapy.

A landmark analysis was carried out, using 3 months after completion of front-line therapy as the definition of time zero. If patients relapsed before or were not followed until that time were excluded from the study. In total, 159 patients from 19 American academic medical centers were included.

Key Highlights:

Patients

• Statistically significant differences between non-autoSCT (n=97) and autoSCT (n=62) pts were:
  • Age >60 years (49% vs. 29%; P = 0.01)
  • Bone marrow involvement (33% vs. 19%; P = 0.04)
  • Prior indolent lymphoma (6% vs. 23%; P = 0.002)
• Median follow-up = 26.5 months (range, 0.2–114.6 months) from time zero

3-year RFS:

• For all pts = 80%
• In pts with de novo (n=139) and transformed indolent (n=20) disease = 78% vs. 94%; P = 0.18
• In pts with IPI score <3 (n=84) vs. ≥3 (n=71) = 75% vs. 87%; P = 0.38
• In pts who harbored BCL2 rearrangement = 79%; BCL6 rearrangement = 77%; BCL2/BCL6 rearrangement (triple-hit lymphoma) = 70%; MYC-IG translocation (n=35) = 77%
• Non-autoSCT and autoSCT pts in CR1 = 75% vs. 89%; P = 0.12
• Non-autoSCT (n=91) and autoSCT (n=48) pts with de novo disease = 74% vs. 88%; P = 0.15
• Differed significantly among pts treated with R-CHOP (n=35), DA-EPOCH-R (n=81), R-hyperCVAD (n=32), and R-CODOX-M/IVAC (n=11): 56% vs. 88% vs. 87% vs. 91%, respectively; P = 0.003
• In intensive front-line therapy cohort (n = 124; DA-EPOCH-R, R-hyperCVAD, and R-CODOX-M/IVAC) = 88%; P = 0.002 compared with R-CHOP
• For pts receiving R-CHOP: without autoSCT in CR1 (n=27) = 51%; with autoSCT (n=8) = 75%
• For pts receiving intensive therapy: without autoSCT in CR1 (n=70) = 86%; with autoSCT (n=54) = 91%

3-year OS rate:

• In all pts = 87%
• In pts with de novo and transformed indolent disease = 86% vs. 93%; P = 0.54
• In pts with IPI score <3 vs. ≥3 = 87% vs. 89%; P = 0.69
• In pts who harbored BCL2 rearrangement = 86%; BCL6 rearrangement = 80%; BCL2/BCL6 rearrangement (triple-hit lymphoma) = 73%; in pts with MYC-IG translocation = 77%
• Non-autoSCT and autoSCT pts in CR1 = 85% vs. 91%; P = 0.74
• Non-autoSCT and autoSCT pts with de novo disease = 84% vs. 91%; P = 0.68
• Did not differ significantly among pts treated with R-CHOP, DA-EPOCH-R, R-hyperCVAD, and R-CODOX-M/IVAC: 77% vs. 87% vs. 90% vs. 100%, respectively; P = 0.36
• In intensive front-line therapy cohort = 90%; P = 0.13 compared with R-CHOP
• For pts receiving R-CHOP without autoSCT in CR1 = 75%; with autoSCT = 83%
• For pts receiving intensive therapy: without autoSCT in CR1 = 89%; with autoSCT = 92%

Relapses and Death

• Relapses occurred in 25 pts
• Median OS = 8.6 months (range, 0–43.0 months) after relapse
• 1-year post-relapse survival rate = 37%
• Post-relapse survival did not differ by treatment with:
  • R-CHOP (n=13; 10.0 months) vs. intensive (n=12; 6.0 months) front-line therapy; P = 0.23
  • AutoSCT (n=6; 9.7 months) vs. non-autoSCT (n=19; 3.8 months) in CR1; P = 0.12
• Of pts with prior indolent lymphoma, only one experienced relapse, which was of high-grade histologic classification
• CNS relapse was diagnosed in 5 pts, 3 had received CNS prophylaxis with front-line therapy
• In total, 19 pts died; 5 deaths occurred during remission (amyotrophic lateral sclerosis, lung cancer, and an unknown cause in non-autoSCT pts, and infection and AML autoSCT pts)

The authors concluded by stating that “survival of patients with DHL achieving CR1 is not significantly prolonged by receipt of autoSCT, regardless of front-line therapy received.” Moreover, it was found that front-line therapy with R-CHOP resulted in inferior 3-year RFS compared to intensive therapy. Lastly, the group stated that their analysis supports the use of intensive front-line therapy without consolidative autoSCT in CR1 for fit patients with DHL.

Abstract:

Purpose: Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear.

Methods: Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded.

Results: Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months.

Conclusion: In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.