Combination of COO and CNS-IPI improves CNS relapse prognosis in DLBCL

On 7 January 2019, Magdalena Klanova, from Charles University, First Faculty of Medicine, Prague, CZ, and colleagues, published in Blood a secondary analysis from the phase III trial GOYA (NCT01287741) were diffuse large B-cell lymphoma (DLBCL) were treated with either obinutuzumab or rituximab, plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; G-CHOP versus R-CHOP).

The aim of this analysis was to investigate the impact of cell-of-origin (COO), central nervous system (CNS)-International Prognostic Index (IPI), and BCL2/MYC double-expression on CNS relapse in these patients. The primary endpoint of this retrospective analysis was time to CNS relapse.

Study design

• N = 1418 previously untreated DLBCL patients, aged ≥ 18 with IPI ≥ 2 or IPI = 1 due to age alone or IPI = 0 with bulky disease (one lesion ≥ 7.5cm), Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and ≥ 1 bi-dimensionally measurable lesion
• In the GOYA phase III trial, these patients were 1:1 randomized according to planned number of CHOP cycles, IPI, and geographic region to either:
  • G-CHOP (n = 706) or;
  • R-CHOP (n = 712)
• Dosing:
  • G-CHOP: 1000 mg of G on Day 1,8, and 15 of cycle 1 and on Day 1 of cycles 2−8. CHOP for 6 or 8 cycles every 21 days
  • R-CHOP: 375 mg/m² of R on Day 1 on cycles 1−8. CHOP for 6 or 8 cycles every 21 days
• COO was assessed using gene expression profiling
• BCL2 and MYC expression was assessed by immunohistochemistry
• The impact of COO, CNS-IPI, and BCL2/MYC dual expression on CNS relapse was assessed with a multivariate Cox regression model on all N = 1418 randomized patients in the GOYA trial
• Baseline characteristics:
  • CNS-IPI score:
    • Low risk: 19.7% of patients
    • Intermediate risk: 63.0% of patients
    • High risk: 17.3% of patients

Key results

• COO analysis was possible in n = 933 patients, of whom:
  • Germinal center B-cell (GCB) subtype: 57.9% of patients
  • Activated B-cell (ABC) subtype: 26.0% of patients
  • Unclassified DLBCL: 16.1% of patients
• Both COO and BCL2/MYC protein expression were available in n = 688 patients, of whom:
  • BCL2/MYC double-expressors: 42.9% of patients
• More patients with the ABC subtype were BCL2/MYC double-expressors (70.5%) than those with the GCB subtype (30.7%) or unclassified DLBCL (36.8%)
• After a median follow-up of 29 months (range, 24.5−4):
  • CNS relapse: n = 38 (2.7%) patients
    • Of those with CNS relapse, n = 37 patients had radiological signs of CNS relapse and/or infiltrated cerebrospinal fluid
  • Most CNS relapses were localized in the brain parenchyma (71.1%), the rest were leptomeningeal only (15.8%) or parenchymal and leptomeningeal (7.9%) or intraocular (2.6%) or data were unavailable (2.6%)
  • Median time to CNS relapse (range): 8.5 (0.9−43.5) months
  • The majority of CNS relapses occurred within two years from patient randomization (89.5%)
  • Two-year CNS relapse rates:
    • Total cohort: 2.8%
    • Low risk (CNS-IPI): 0.8% (95% CI, 0.0−1.9)
    • Intermediate risk (CNS-IPI): 1.9% (95% CI, 0.9−2.9)
    • High risk (CNS-IPI): 8.9% (95% CI, 4.7−12.9)
    • Patients receiving CNS prophylaxis: 2.8%
    • Patients not receiving CNS prophylaxis: 2.6%
    • In patients with COO available:
      • ABC subtype: 6.9%
      • GCB subtype: 1.3%
      • Unclassified DLBCL: 4.8%
      • Low risk (CNS-IPI): 1.4% (95% CI, 0.0−3.2)
      • Intermediate risk (CNS-IPI): 2.2% (95% CI, 0.9−3.5)
      • High risk (CNS-IPI): 9.6% (95% CI, 4.5−14.5)
    • Median survival after CNS relapse: 5.9 months
    • CNS relapses were similar in the G-CHOP and R-CHOP arms (20 versus 18), with no impact of the treatment on CNS relapse incidence rates
    • No significant association between BCL2/MYC double-expression and the risk of CNS relapse was identified by univariate analysis (P = 0.3196; two-year CNS relapse rate: double-expressors [4%] versus non-double-expressors [2.2%]; n = 688)
    • Multivariate analysis revealed the following factors associated with higher CNS relapse risk:
      • ABC subtype: HR = 5.2; (95% CI, 2.1−12.9); P = 0.0004
      • Unclassified COO subtype: HR = 4.2; (95% CI, 1.5−11.7); P = 0.006
      • High CNS-IPI: HR = 4.0; (95% CI, 1.3−12.3); P = 0.02
    • CNS-IPI and COO were combined to create a modified risk stratification model (CNS-IPI-C):
      • According to this model, three CNS-IPI-C subgroups were identified as having low (48.2%), intermediate (one risk factor; 43.7%) and high (two risk factors; 8.0%) CNS relapse risk
      • The two-year CNS relapse rates were:
        • Low CNS-IPI-C risk: 0.5% (95% CI, 0.0−1.3)
        • Intermediate CNS-IPI-C risk: 4.4% (95% CI, 2.2−6.6)
        • High CNS-IPI-C risk: 15.2% (95% CI, 5.4−24.0)
      • This modified model resulted in a 22-fold higher risk of CNS relapse in the high versus low CNS-IPI-C groups

Conclusions

• There was no difference in CNS relapse in newly-diagnosed DLBCL patients treated with either G-CHOP or R-CHOP
• High CNS-IPI score and ABC or unclassified COO subtypes were independent risk factors for CNS relapse in DLBCL
• Combining CNS-IPI score and COO improved identification of DLBCL patients with different CNS relapse risks
• No significant difference in the incidence of CNS relapse was observed between the intermediate and low risk CNS-IPI subgroups