DLBCL

R-CHOP versus DA-EPOCH-R as frontline therapy for DLBCL: Results from a phase III trial

On 2 April 2019, Nancy Bartlett from Washington University School of Medicine, St Louis, MO, USA and colleagues, published in the Journal of Clinical Oncology results from a phase III clinical trial that compared the efficacy of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for diffuse large B-cell lymphoma (DLBCL).

In this randomized, Alliance/CALGB 50303 study (NCT00118209), the efficacy and safety of DA-EPOCH-R and R-CHOP were compared as frontline treatment for patients with DLBCL. The primary endpoint was progression-free survival (PFS), while secondary endpoints included response rates, overall survival (OS), and safety.

Study design & baseline characteristics
  • N = 491 previously-untreated patients with disease stage II−IV DLBCL or stage I primary mediastinal large B-cell lymphoma (PMBCL), were 1:1 randomized to either:
    • DA-EPOCH-R: n = 241 or;
    • R-CHOP: n = 250
  • Median time from diagnosis to initiation of therapy:
    • DA-EPOCH-R: 21 days
    • R-CHOP: 18 days
  • Median patient age: 58 years
  • Baseline characteristics were well balanced between the two arms

 

DA-EPOCH-R arm

R-CHOP arm

Eastern Cooperative Oncology Group (ECOG) performance status:

 

ECOG 0

46.9%

40.6%

ECOG 1

39.8%

47.8%

ECOG 2

13.3%

11.6%

Missing

n = 0

n = 1

International Prognostic Index (IPI) risk groups:

 

Low

25.1%

26.6%

Low-intermediate

35.3%

38.6%

High-intermediate

26.0%

24.9%

High

13.6%

10.0%

Missing

n = 6

n = 9

Treatments
  • Dosing (six 21-day cycles):
    • DA-EPOCH-R:
      • Etoposide: 50 mg/m2 daily intravenously (IV) on Days 1, 2, 3, and 4
      • Doxorubicin: 10 mg/m2 daily IV on Days 1, 2, 3, and 4
      • Vincristine: 0.4 mg/m2 daily IV on Days 1, 2, 3, and 4
      • Cyclophosphamide: 750 mg/m2 IV on Day 5
      • Prednisone: 60 mg/m2 daily, orally on Days 1, 2, 3, 4 and 5
      • Rituximab: 375 mg/m2 IV on Day 1 prior to EPOCH chemotherapy
      • Dose-adjustment occurred based on absolute neutrophil count (ANC) levels, as previously reported here
    • R-CHOP:
      • Standard dosing
    • Consolidative radiotherapy was not allowed
  • Patients who received a full six-cycle treatment:
    • DA-EPOCH-R: 82.0%
    • R-CHOP: 88.0%
  • Reasons for early treatment discontinuation in DA-EPOCH-R versus R-CHOP:
    • Disease progression: 1.3% versus8%
    • Adverse events (AEs): 6.3% versus0%
    • Death: 2.5% versus6%
    • Patient withdrawal after initiating treatment: 2.9% versus2%
    • Patient withdrawal before beginning protocol treatment: 1.7% versus4%
    • Alternative therapy: 1.3% versus8%Other missing reasons: 2.9% versus 1.6%
Key findings
  • At a median follow-up of 5.2 years (range, 4.8−4), 159 patients had a PFS event and 109 died
  • There was no statistical difference in PFS between the DA-EPOCH-R and R-CHOP arms (HR = 0.93; [95% CI, 0.68−27]; P = 0.65)
  • There was no statistical difference in OS between the DA-EPOCH-R and R-CHOP arms (HR = 1.09; [95% CI, 0.75−59]; P = 0.64)

 

DA-EPOCH-R arm

R-CHOP arm

Full cohort

Two-year PFS rate

78.9%

75.5%

77.1% (95% CI, 73.5−81)

Five-year PFS rate

68.0%

66.0%

67.1% (95% CI, 62.8−71.6)

Five-year OS rate

77.5%

78.5%

78.0% (95% CI, 74.3−81.9)

Overall response rate

86.7%

88.0%

-

Complete response (CR) and unconfirmed CR (CRu) rate

58.5%

59.6%

-

 

P = 0.67

-

  • Patients older than 60 years had inferior PFS compared to younger patients (HR = 1.43; [95% CI, 1.04−95]; P = 0.26)
  • PFS was significantly associated with IPI (P < 0.001):
    • For IPI 0−1: two-year PFS was 91.7% (95% CI, 86.9−96.8)
    • For IPI 2: two-year PFS was 76.5% (95% CI, 70.4−83.2)
    • For IPI 3: two-year PFS was 70.7% (95% CI, 63−79.4)
    • For IPI 4−5: two-year PFS was 62.2% (95% CI, 50.7−76.4)
  • Post hoc subgroup analyses based on age, lactate dehydrogenase levels, ECOG performance status, extranodal disease, and IPI risk, revealed the following statistical differences:
    • PFS was higher in the DA-EPOCH-R arm in patients with high-risk IPI 4−5 (HR = 0.46; [95% CI, 0.21−01]; P = 0.052)
    • PFS was higher in the DA-EPOCH-R arm in patients with IPI 3−5 (HR = 0.63; [95% CI, 0.41−99]; P = 0.041; Unplanned, not powered analysis)
    • No differences in OS or PFS between arms was observed for any other subgroup analysis
  • Central nervous system (CNS) relapse occurred in:
    • DA-EPOCH-R: 3.3% of patients
    • R-CHOP: 4.0% of patients
Safety
  • Treatment-related deaths:
    • DA-EPOCH-R: 2.1% (n = 5)
      • Infection: n = 2
      • Cardiac issues: n = 1
      • Sudden death: n = 1
      • Multiorgan failure: n = 1
    • R-CHOP: 2.1% (n = 5)
      • Infection: n = 2
      • Cardiac issues: n = 1
      • CNS hemorrhage: n = 1
      • Unknown: n = 1
    • Grade 3−5 treatment-related AEs occurred in:
      • DA-EPOCH-R: 98.3% of patients
      • R-CHOP: 78.2% of patients
      • Comparison: P < 0.001
    • Grade 3−4 treatment-related hematological (97.5% versus7%; P < 0.001) and non-hematological (72.2% versus 43.2%; P < 0.001) AEs were more common in the DA-EPOCH-R arm than the R-CHOP arm
    • Late cardiac events occurred in:
      • DA-EPOCH-R: n = 2 patients
        • Atrial fibrillation (n = 1)
        • Myocardial infraction with heart failure (n = 1)
      • R-CHOP: n = 6 patients
        • Left ventricular systolic dysfunction (n = 5)
        • Atrial fibrillation (n = 1)
Conclusion
  • DA-EPOCH-R was associated with greater toxicity and did not improve PFS, OS or response rate when compared to R-CHOP, as frontline treatment in naïve patients with DLBCL or PMBCL
References
  1. Bartlett N.L. et al. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Apr 2:JCO1801994. DOI: 10.1200/JCO.18.01994 [Epub ahead of print].
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