MYC/IG rearrangements are not responsible for poor survival in double-/triple-hit lymphoma

In November 2018, Ellen McPhail from Mayo Clinic, MN, US, and colleagues, published in Haematologica a research study investigating the prognostic value of low-grade transformation, cytological characteristics (high-grade versus large-cell), cell of origin (CoO) and MYC rearrangements in the outcomes of double-/triple-hit lymphoma patients.

It is well-established that high-grade B-cell lymphoma with genetic rearrangements in MYC, BCL2 and/or BCL6 (double-/triple-hit [DH/TH]) presents with a very aggressive clinical phenotype and a varied cytological morphology. The possibility to use such cytological and genetic differences as prognostic markers of survival outcomes in DH/TH lymphoma patients remains unclear. The aim of this study was to address this likelihood in DH/TH lymphoma patients, by investigating overall survival (OS), event-free survival (EFS), and EFS12, defined as event-free status at 12 months following diagnosis.

Study design

• N = 100 DH/TH lymphoma patients who transformed from low-grade lymphoma and had received anthracycline-based chemotherapy at DH/TH diagnosis
• Median age (range) at DH/TH diagnosis = 61 (29–87) years
• DH/TH lymphoma was identified:
  • At initial diagnosis (n = 67)
  • At the time of transformation from low-grade lymphoma (n = 22)
  • From a recurrent specimen in previously-diagnosed lymphoma with large-cell or high-grade features without previous diagnosis (n = 11)
• CoO was determined with Hans classifier and genetic rearrangements were examined with fluorescence in situ hybridization (FISH)
• Therapeutic regimens received by the participating patients were:
  • R-CHOP (n = 36)
  • Dose-adjusted EPOCH-R (n =17)
  • R-CODOX-M/IVAC (n = 17)
  • R-hyper-CVAD and cytarabine (n =6)
  • Platinum-based salvage (n =10)
  • Non-anthracycline-based regimens (n = 14)
  • Twelve patients received consolidation with autologous stem cell transplant (ASCT)
• Median follow-up (range): 21 (1–87) months

Results

• In n = 65 cases consensus diagnosis was reached. Of those:
  • 60% had high-grade morphological features (n =39)
  • 40% had large-cell morphological features (n = 26)
• Based on Hans classifier, the observed phenotypes were:
  • 91% germinal center B-cell (GCB; n =91)
  • 6% non-GCB
  • 3% unknown
• The following MYC rearrangement partners were identified:
  • IG gene (n = 52)
  • Non-IG gene (n = 35)
  • Unknown (n = 13)
• The following DH/TH rearrangements were detected:
  • MYC/BCL2 (n = 59)
  • MYC/BCL6 (n = 13)
  • MYC/BCL2/BCL6 (n = 20)
  • MYC/BCL2 (unknown BCL6; n = 8)
• The MYC rearrangement partner (IG versus non-IG) was not associated with morphological features (P = 0.96), CoO (P = 0.18) or BCL2 rearrangements (P = 0.27)
• However, MYC immunohistochemistry was more common in IG/MYC (95%) than non-IG/MYC (74%) samples (P = 0.049)
• No significant association was observed between BCL2 rearrangements and morphological features (P = 0.16)
• At the median follow-up of 21 months:
  • Median OS: 22 months (95% CI, 13 months–not reached)
• At a 5-year follow-up:
  • OS rate: 49% (95% CI, 37–64%)
• Patients with DH/TH lymphoma at the time of transformation from low-grade lymphoma presented with inferior outcomes to patients with de novo DH/TH lymphoma diagnosis:
  • Median OS:8 months versus 22 months, respectively (P = 0.008)
  • EFS12: 10% versus 52%, respectively
• Patients with high-grade morphological features showed no significant changes in outcomes (OS and EFS12) compared to those with large-cell morphological features (P = 0.09)
• There was no significant association between MYC partner and OS (P = 0.99)
• No significant differences in outcomes (OS and EFS12) were observed between patients with MYC/BCL6 (BCL2 negative) rearrangements and those with BCL6 rearrangements (P = 0.16)

These results indicate that subgroups within the DH/TH lymphoma category have different clinical outcomes, with patients transforming from low-grade lymphoma having an inferior OS when compared to patients with de novo DH/TH lymphoma. According to the authors, this study suggests that the genetic partners of MYC rearrangements have no prognostic value (IG versus non-IG gene) on the outcomes of patients with DH/TH lymphoma. Further research is needed to validate these interesting preliminary findings.