Spanish Lymphoma Oncology Group report on tFL predictors

On 6 March 2019, Miriam Méndez from University Hospital Puerta de Hierro-Majadahonda, Madrid, SP, and colleagues, published in Hematological Oncology a report on behalf of the Spanish Lymphoma Oncology Group regarding the treatment of transformed follicular lymphoma (tFL) in the rituximab era.

It has been estimated that histological transformation of follicular lymphoma occurs in approximately 10% of FL cases, leading to a transition from an indolent lymphoma to a more aggressive disease phenotype. There is a current need for accurate diagnostic markers and predictors for tFL, as well as efficient treatment strategies to improve patient survival. The main aim of this multicenter, retrospective study was to evaluate patients from the Spanish Lymphoma Oncology Group registry (GOTEL) in order to identify potential early clinical predictors of tFL.

Study design

• N = 975 FL patients diagnosed between 1990−2016 in any of 39 Spanish hospitals belonging to GOTEL
  • Patients with tFL: n = 64
  • Patients without tFL: n = 911
• Eligible patients had FL Grade 1−3a
  • Patients with FL Grade 3b and patients with co-diagnosis of diffuse large B-cell lymphoma (DLBCL) were excluded
• Patients without tFL (N = 911):
  • Males: 47%
  • Median age (range): 57.5 (18−92) years
  • Median follow-up (range): 4.8 (2.3−8.5) years
  • FL histological grades:
    • Grade 1: 34% (n = 287)
    • Grade 2: 32% (n = 272)
    • Grade 3: 34% (n = 290)
  • FL International Prognostic Index (FLIPI) score:
    • 0: 15% (n = 137)
    • 1: 28% (n = 251)
    • 2: 31% (n = 281)
    • 3: 16% (n = 146)
    • 4: 8% (n = 76)
    • 5: 2% (n = 20)
  • Eastern Cooperative Oncology Group (ECOG) performance status:
    • 0: 57% (n = 534)
    • 1: 34% (n = 297)
    • 2: 6% (n = 53)
    • 3: 2% (n = 21)
    • 4: 1% (n = 4)
  • Disease stage:
    • Stage I: 12% (n = 112)
    • Stage II: 14% (n = 131)
    • Stage III: 27% (n = 241)
    • Stage IV: 47% (n = 426)
  • Aged ≥ 60 years: 45% (n = 409)
  • Bone marrow (BM) involvement: 39% (n = 352)
  • Treatments:
    • Wait & watch: 2% (n = 19)
    • No anthracycline-based regimens: 76% (n = 686)
    • No rituximab-based regimens: 76% (n = 689)
  • Patients with tFL (n = 64):
    • Males: 39%
    • Median age (range): 57 (25−80) years
    • Histological samples were obtained both at diagnosis and upon transformation in 45% of these patients (n = 29)
    • The majority of these patients transformed to DLBCL (87%)
    • FL histological grades:
      • Grade 1: 27% (n = 17)
      • Grade 2: 38% (n = 24)
      • Grade 3: 35% (n = 23)
    • FL International Prognostic Index (FLIPI) score:
      • 0: 11% (n = 7)
      • 1: 11% (n = 1)
      • 2: 35% (n = 22)
      • 3: 27% (n = 18)
      • 4: 14% (n = 9)
      • 5: 2% (n = 1)
    • Eastern Cooperative Oncology Group (ECOG) performance status:
      • 0: 41% (n = 26)
      • 1: 53% (n = 34)
      • 2: 6% (n = 4)
      • 3: 0% (n = 0)
      • 4: 0% (n = 0)
    • Disease stage:
      • Stage I: 6% (n = 4)
      • Stage II: 17% (n = 11)
      • Stage III: 41% (n = 26)
      • Stage IV: 36% (n = 23)
    • Aged ≥ 60 years: 56% (n = 36)
    • BM involvement:30% (n = 19)
    • Treatments:
      • Wait & watch: 20% (n = 13)
      • No anthracycline-based regimens: 56% (n = 36)
      • No rituximab-based regimens: 63% (n = 40)

Key results

• Median time from FL diagnosis to tFL: 24 months
• Thirty percent of patients transformed during the first year after FL diagnosis
• From the fifth year onwards the transformation rate remained constant until it reached a plateau after 14 years
• Cumulative incidence of transformation within 5 years: 7.3% (95% CI, 5−9%)
• Univariate analysis identified the following predictors of tFL:
  • Lactate dehydrogenase (LDH) levels: patients with high LDH presented more frequently with tFL (OR = 1.83)
  • FLIPI score: patients with intermediate (FLIPI 2 vs 0−1; OR = 2.16) or high (FLIPI 3−5 vs 0−1; OR = 3.21) FLIPI scores were more frequently presented with tFL
  • B symptoms: patients with B symptoms were more frequently presented with tFL (OR = 2.46)
  • A significant correlation between the "wait & watch" therapeutic option and the occurrence of tFL was identified (P = 0.0001) as well as with the absence of rituximab- or anthracycline-based treatments (P = 0.018 and P = 0.001, respectively)
• Multivariate analysis identified the following factors correlating to tFL:
  • Low FLIPI score (vs intermediate [OR = 2; 95% CI, 1−4; P = 0.035] or high [OR = 2.7; 95% CI, 1.3−5.3; P = 0.004])
  • B symptoms (OR = 2; 95% CI, 1.2−3; P = 0.01)
• Five-year overall survival (OS) rates:
  • Patients with no tFL: 85% (95% CI, 82−87%)
  • Patients with tFL: 66% (95% CI, 51−76%)
    • Comparison: P = 0.0012 
  • tFL patients with clinically confirmed transformation: 51% (95% CI, 30−69%)
  • tFL patients with histologically confirmed transformation: 71% (95% CI, 52−83%)
    • Comparison: P = 0.4 
  • tFL patients receiving chemotherapy at some point throughout the evolution of the disease: 55% (95% CI, 38−69%)
  • tFL patients not receiving chemotherapy throughout the evolution of the disease: 81% (95% CI, 53−93%)
    • Comparison: P = 0.009
  • tFL patients treated with rituximab before transformation (n = 38): 58% (95% CI, 39−72%)
  • tFL patients treated with rituximab after transformation (n = 22): 75% (95% CI, 51−89%)
    • Comparison: P = 0.07
• Of the 64 tFL patients, 33% died in the first two years
• Statistically significant worst outcome(death) predictors in tFL patients were:
  • Disease stage IV (OR = 34.5; 95% CI, 1.3−15; P = 0.02)
  • ECOG ≥ 2 (OR = 2.4; 95% CI,1.1−5.2; P = 0.02)
• Statistically significant better outcome predictors in tFL patients were:
  • Normal beta-2 microglobulin levels at the time of transformation (OR = 0.3; 95% CI, 0.2−0.8; P = 0.01)

Conclusions

• FL transformation rates in patients from the GOTEL Spanish registry were lower than those described in the literature (7.3% versus ~10%)
• In this population, there was a high transformation rate within the first year of FL diagnosis but no transformation occurred after 14 years of follow-up
• Factors associated with tFL incidence were elevated LDH, intermediate-high FLIPI scores, B symptoms or ECOG 1
• Disease stage IV or ECOG ≥ 2 were associated with an increased risk of death after tFL
• The "wait & watch" or the no-use of rituximab or anthracyclines regimens seem to be associated with an increased risk of tFL
• There was a trend towards increased survival in patients who were not treated before transformation with rituximab or chemotherapy compared to those who were treated after transformation with rituximab or chemotherapy