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.