DLBCL

DA-EPOCH-R versus R-CHOP for double hit DLBCL

On 10 January 2019, Anna Dodero and Anna Guidetti from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, IT, and colleagues published in Leukemia a retrospective study investigating the efficacy and safety of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in double-hit diffuse large B-cell lymphoma (DLBCL) patients.

In this retrospective study the outcomes of DLBCL double expressors were compared after DA-EPOCH-R or R-CHOP treatment, which was administered in a similar period in three different Italian institutions. The primary endpoints of this study were progression-free survival (PFS), and overall survival (OS). Secondary endpoints included survival comparisons according to different subgroup analyses (age, genetic abnormalities etc.). 

Study design & baseline characteristics 
  • N = 114 double-hit DLBCL patients
  • Patients were treated with either:
    • DA-EPOCH-R (n = 51)
    • R-CHOP (n = 63)
  • Dosing:
    • DA-EPOCH-R (n = 51; six 21-cycles):
      • Etoposide: 50 mg/m2 intravenously (IV) on Day 1, 2, 3, and 4
      • Doxorubicin: 10 mg/m2 IV on Day 1, 2, 3, and 4
      • Vincristine: 0.4 mg/m2 IV on Day 1, 2, 3, and 4
      • Cyclophosphamide: 750 mg/m2 IV on Day 5
      • Prednisone: 60 mg/m2 orally on Day 1, 2, 3, 4 and 5
    • R-CHOP (n = 63): usual dosing every 21 days
  • Central nervous system (CNS) prophylaxis was administered when necessary according to institutional guidelines
    • Patients in the R-CHOP group received less CNS prophylaxis (30%) than those in the DA-EPOCH-R group (96%)
  • All patients underwent computed tomography (CT) scan, positron emission tomography scan (PET), bone marrow (BM) biopsy and diagnostic lumbar puncture, including cytological and immunophenotypic analyses at baseline
  • An intermediate CT was performed after 3−4 DA-EPOCH-R or R-CHOP cycles
    • Patients exhibiting a less than partial response (PR) or disease progression (PD) were moved to second line regimens according to institutional guidelines
  • Clinical response evaluation was performed at the end of treatment cycle 6 by CT, PET, and BM biopsy
  • Disease assessment was performed at follow-up (three month intervals) for the first two years; every six months until the fifth year; annually thereafter
  • Baseline characteristics were well balanced between the two groups 
Key findings
  • CNS relapses:
    • DA-EPOCH-R: n = 1 patient
    • R-CHOP: n = 3 patients
  • Consolidative radiotherapy administration:
    • DA-EPOCH-R: 21% of patients
    • R-CHOP: 35% of patients
  • DA-EPOCH-R group median follow-up: 20 months
  • R-CHOP group median follow-up: 49 months
  • Two-year PFS (before inverse probability of treatment weight [IPTW] Cox modelling):
    • DA-EPOCH-R: 62% (95% CI, 45−84%)
    • R-CHOP: 54% (95% CI, 43−69%)
  • Two-year OS (before IPTW Cox modelling):
    • DA-EPOCH-R: 85% (95% CI, 74−98%)
    • R-CHOP: 70% (95% CI, 60−83%)
  • Two-year PFS (after IPTW Cox modelling):
    • DA-EPOCH-R: 57%
    • R-CHOP: 51%
    • Comparison: P = 0.198
  • Two-year OS (after IPTW Cox modelling):
    • DA-EPOCH-R: 90%
    • R-CHOP: 67%
    • Comparison: P = 0.07
  • IPTW Cox modelling was used to investigate the effect of patient age, International Prognostic Index (IPI) or DLBCL molecular subgroup on patient outcomes:
    • Age was the only statistically significant influencing variable. In patients aged < 65 years:
    • DA-EPOCH-R:
      • PFS: 82% (95% CI, 66−100%)
      • OS: 90% (95% CI, 74−100%)
    • R-CHOP:
      • PFS: 43% (95% CI, 26−73%)
      • OS: 62% (95% CI, 43−88%)
    • PFS comparison: P = 0.02
    • OS comparison: P = 0.04
Safety
  • Death occurred in:
    • DA-EPOCH-R: 12% of patients (n = 6)
      • PD: n = 4
      • Pneumonia: n = 1
      • Suicide: n = 1
    • R-CHOP: 35% of patients (n = 22)
      • PD: n = 20 patients
      • Drug toxicity: n = 2 patients
    • Treatment discontinuation due to adverse events (AEs) occurred in:
      • DA-EPOCH-R: n =2 patients (pneumonia [Grade 5] and infection [alive patient in CR])
      • R-CHOP: n = 2 patients (both Grade 5 drug toxicity)
    • EPOCH dose adjustment was performed successfully in the majority of patients aged ≤ 65 years (73% of patients escalated to ≥ 3 dose level). However, the majority of patients > 65 years received only dose level one of EPOCH
Conclusions
  • Age and genetic abnormalities play a key role in patient outcomes of DLBCL double expressors
  • DA-EPOCH-R treatment was associated with a better PFS than R-CHOP in young double-hit DLBCL patients (< 65 years old)
  • DA-EPOCH-R treatment was associated with a better OS than R-CHOP in young double-hit DLBCL patients (< 65 years old)
  • Patient subgroup analysis for genetic abnormalities revealed that DA-EPOCH-R leads to a better PFS than R-CHOP in such patient populations
References
  1. Dodero A. and Guidetti A. et al. Dose-adjusted EPOCH plus rituximab improves the clinical outcome of young patients affected by double expressor diffuse large B-cell lymphoma. Leukemia. 2019 Jan 10. DOI: 10.1038/s41375-018-0320-9 [Epub ahead of print].
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