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

Jan 31, 2019

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 versusR-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/m 2of 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 versus18), 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%] versusnon-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 versuslow 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
  1. Klanova M. et al.Integration of COO into the clinical CNS International Prognostic Index could improve CNS relapse prediction in DLBCL. Blood . 2019 Jan 7. DOI: 10.1182/blood-2018-07-862862[Epub ahead of print].