A MYC-rearrangement is a negative prognostic factor in stage II, but not in stage I diffuse large B-cell lymphoma

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The clinical diversity in outcome among patients with diffuse large B-cell lymphoma (DLBCL) is heterogeneous and originates, in part, from genetic variation.1-3 MYC rearrangements (MYC-R) are prevalent genetic aberrations in patients with DLBCL. Upon overexpression, MYC acts as an oncogene contributing to tumorigenesis.4,5 While the prognostic impact of MYC-R on survival has been extensively explored in advanced stage6-8, its significance in stages I and II (limited stage; LS) DLBCL remains uncertain. To gain more insight into this, we utilized data from the population-based Netherlands Cancer Registry (NCR) to investigate the impact of MYC-R on progression-free survival (PFS) and overall survival (OS) in LS DLBCL patients.

Netherlands Cancer Registry

The NCR, maintained and hosted by the Netherlands Comprehensive Cancer Organisation (IKNL), has nationwide coverage of at least 95% of all malignancies since 1989. The NCR relies on comprehensive case notification through the Nationwide Histopathology and Cytopathology Data Network and the Nationwide Registry of Hospital Discharges (i.e. inpatient and outpatient discharges). Clinical and epidemiological information is routinely recorded in the NCR through retrospective medical records review in the Dutch hospitals by trained registrars of the NCR. Information on last known vital status for all patients (i.e. alive, dead, or emigration) is obtained through annual linkage with the Nationwide Population Registries Network that holds vital statistics on all residents of the Netherlands. Since January 1st, 2014, detailed information on diagnostic and treatment characteristics for all hematological malignancies diagnosed in the Netherlands is routinely recorded.

Outcomes and clinical implications

Using the NCR, we were in the unique position to analyze clinical outcomes of 1,434 LS DLBCL patients diagnosed between 2014 and 2020. Due to the increased recognition of MYC as a potential prognostic factor within the study period, the frequency of MYC-R assessment by fluorescent in situ hybridization (FISH) increased for LS DLBCL patients from 18% in 2014 to 83% in 2020.

Our results demonstrate that stage I DLBCL patients with and without a MYC-R had a similar 2-year PFS (89% and 93%, p = 0.63) and OS (both 95%, p = 0.22). Conversely, in stage II DLBCL, PFS and OS were inferior for patients with a MYC-R as compared to patients without a MYC-R (PFS 70% vs. 89%, p = 0.001; OS 79% vs. 94%, p < 0.0001). Both single MYC-R and concurrent BCL2 and/or BCL6 rearrangements (double/triple hit lymphoma) were associated with increased risks of relapse and mortality.

The excellent outcome of stage I MYC-R DLBCL patients in this study does not justify treatment with more intensive immunochemotherapy regimens. Instead, we propose the inclusion of stage I MYC-R DLBCL patients in potential future studies aiming to reduce treatment intensity.  Moreover, the excellent outcome of stage I MYC-R DLBCL patients challenges the necessity to perform MYC-R screening by FISH in patients with stage I DLBCL disease. For stage II DLBCL patients, MYC FISH is inevitable and should be used as guidance for new treatment strategies for these patient.

Taken together, our comprehensive analysis using the NCR affirms a negative association between MYC-R and survival in stage II DLBCL, but unveils a non-prognostic value in stage I disease. This leaves no justification for more intensive treatment and challenges diagnostic MYC fluorescent in situ hybridization (FISH) in stage I DLBCL patients.

 

References

  1. Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171:481–494.e415. https://doi.org/10.1016/j.cell.2017.09.027
  2. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378:1396–407. https://doi.org/10.1056/NEJMoa1801445
  3. Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24:679–90. https://doi.org/10.1038/s41591-018-0016-8
  4. Dang CV. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med. 2013;3(8). doi: 1101/cshperspect.a014217
  5. Gabay M, Li Y, Felsher DW. MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb Perspect Med. 2014;4(6). doi: 1101/cshperspect.a014241
  6. Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28:3360–5. https://doi.org/10.1200/JCO.2009.26.3947
  7. Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114:3533–7. https://doi.org/10.1182/blood-2009-05-220095
  8. Rosenwald A, Bens S, Advani R, Barrans S, Copie-Bergman C, Elsensohn ME, et al. Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2019;37:3359–68. https://doi.org/10.1200/JCO.19.00743

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B-cell Lymphoma
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Haematological Diseases > Haematological Cancer > Lymphoma > Non-hodgkin Lymphoma > B-cell Lymphoma
B-cell Lymphoma
Life Sciences > Biological Sciences > Cancer Biology > Cancers > Haematological Cancer > Lymphoma > Non-hodgkin Lymphoma > B-cell Lymphoma