R-CHOP average relative dose intensity as an independent outcome predictor in DLBCL

On 10 February 2019, Monika Dlugosz-Danecka from Jagiellonian University, Krakow, PL, and colleagues, published in Cancer Medicine a retrospective analysis investigating the prognostic value of chemotherapy dose intensity for survival outcomes in diffuse large B-cell lymphoma (DLBCL).

Currently, the International Prognostic Index (IPI) provides one of the main tools for outcome prognosis in DLBCL. In this study, the average relative dose intensity (ARDI) of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination was assessed as a potential outcome predictor in DLBCL patients, independently of IPI. The primary endpoint of the study was overall survival (OS). Secondary endpoints included, progression-free survival (PFS), and treatment response.

Study design & baseline characteristics

• N = 223 patients with confirmed DLBCL, who had received immunochemotherapy, including R-CHOP between 2005–2013
• Patient subgroups according to IPI risk groups were as follows:
  • Low risk (IPI: 0–1): 29.60% of patients
  • Intermediate risk (IPI: 2–3): 53.81% of patients
  • High risk (IPI: 4–5): 16.59% of patients
• Patients aged > 60 years: 40.36%
• Eastern Cooperative Oncology Group (ECOG) performance status:
  • < 2: 93.72% of patients
  • ≥ 2: 6.28% of patients
• Patient clinical disease stage (Ann Arbor scale):
  • I–II: 32.74% of patients
  • III–IV: 67.26% of patients
• Response to treatment was evaluated with the Cheson criteria based on computed tomography (CT) and positron emission tomography (PET) scans
• ARDI was calculated for all R-CHOP cycles based on the following:
  • Body surface area (BSA) of the patient
  • Planned drug doses
  • Administered drug doses
  • Planned chemotherapy cycle days
  • Actual chemotherapy cycle days
• R-CHOP was to be repeated every 21 days for six cycles
• No patients with < 4 R-CHOP cycles were included in the analysis

Key results

• Patient responses at the end of first-line treatment:
  • Complete response (CR): 67.26% (n = 150)
  • Partial response (PR): 27.8% (n = 62)
  • Stable disease (SD): 1.3% (n = 3)
  • Progressive disease (PD): 3.1% (n = 7)
• As expected, patients with low IPI had the best prognosis (median PFS [mPFS]: not reached; Six-year OS: not reached) as compared to high IPI patients (mPFS: 1.6 years; mOS: 4.5 years)
• In the whole cohort, IPI risk factors like, age (> 60, HR = 1.73), lactate dehydrogenase (LDH) levels (elevated, HR = 1.70), and extranodal location (HR = 2.14) were the most significant predictors of PD
• PFS was depended on R-CHOP ARDI:
  • In patients with ARDI < 80% (n = 29):
    • mPFS: 1.9 years
  • In patients with ARDI between 80–90% (n = 33):
    • mPFS: 4.1 years
  • In patients with ARDI > 90% (n = 161):
    • mPFS: not reached
  • No significant difference in OS was found between patients with ARDI < 80% and 80–90%. The longest OS was observed in patients with ARDI < 90%
  • Multivariate Cox proportional risk analysis revealed that a high ARDI (> 90%) and a low IPI during R-CHOP treatment were independent and favourable risk factors for PFS and OS prediction
  • The most common reason for decrease ARDI (< 80%) was:
    • Extended time interval between R-CHOP cycles due to neutropenia or infections
  • Anticancer drug dose reductions occurred in 19.7% of patients (n = 44):
    • Rituximab dose reduction occurred in 8.1% of patients (n = 18)
      • Mainly due to ampule dispensing and financial issues
    • Doxorubicin dose reduction occurred in 12.1% of patients (n = 27):
      • Mainly due to cardiotoxicity adverse events (n = 23/27)
    • Vincristine dose reduction occurred in 1.8% of patients (n = 4):
      • Mainly due to neutropenia
    • Cyclophosphamide dose reduction occurred in 0.9% of patients (n = 2):
      • Mainly due to neutropenia
    • Dose reduction of all R-CHOP components occurred in 1.8% of patients (n = 4):
      • Mainly due to neutropenia
    • In total, n = 85 deaths (38.1%) were recorded for the following reasons:
      • PD: n = 58
      • Cardiovascular complications: n = 20
      • Other causes (multiorgan failure, secondary cancers, infections): n = 7

Conclusions

• In DLBCL patients, IPI remains a good and important outcome predictor
• DLBCL patients with ARDI > 90% had significantly better PFS and OS, independent of IPI
• ARDI > 90% could be an independent positive predictor of PFS and OS in DLBCL patients receiving R-CHOP treatment
• The authors suggest that ARDI monitoring in all patients during therapy might allow for early neutropenia and cardiotoxicity prophylaxis