Blood Res.  2024;59:2. 10.1007/s44313-024-00006-w.

Adding MYC/BCL2 double expression to NCCN‑IPI may not improve prognostic value to an acceptable level

• Warnnissorn N
• Kanitsap N
• Niparuck P
• Boonsakan P
• Kulalert P
• Limvorapitak W
• Bhoopat L
• Saengboon S
• Suriyonplengsaeng C
• Chantrathammachart P
• Puavilai T
• Chuncharunee S

• KMID: 2552885
• DOI: http://doi.org/10.1007/s44313-024-00006-w

Abstract

Background
MYC/BCL2 double expression (DE) is associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). This study aimed to determine whether the addition of DE to the National Comprehensive Cancer Network Internal Prognostic Index (NCCN-IPI) could improve the prediction of disease progression in patients with DLBCL treated with R-CHOP.
Methods
This confirmatory prognostic factor study retrospectively recruited patients with newly diagnosed DLBCL between January 1, 2014, and January 31, 2018, at Ramathibodi Hospital (RA) and Thammasat University Hospital (TU). The follow-up period ended on July 1, 2022. Tumors expressing MYC ≥ 40% and BCL2 ≥ 50% were classified as DE. We calculated the hazard ratios (HR) for progression-free survival (PFS) from the date of diagnosis to refractory disease, relapse, or death. Discrimination of the 5-year prediction was based on Cox models using Harrell’s concordance index (c-index).
Results
A total of 111 patients had DE (39%), NCCN-IPI (8%), and disease progression (46%). The NCCN-IPI adjusted HR of DE was 1.6 (95% confidence interval [CI]: 0.9–2.8; P = 0.117). The baseline NCCN-IPI c-index was 0.63. Adding DE to the NCCN-IPI slightly increased Harrell’s concordance index (c-index) to 0.66 (P = 0.119).
Conclusions
Adding DE to the NCCN-IPI may not improve the prognostic value to an acceptable level in resourcelimited settings. Multiple independent confirmatory studies from a large cohort of lymphoma registries have provided additional evidence for the clinical utility of DE.

Keyword

DLBCL; MYC/BCL2 double expression; R-CHOP; Prognosis; NCCN-IPI; REMARK

Figure

• 

  Fig. 1 Participant flow diagram

• 

  Fig. 2 Kaplan–Meier survival curves: A progression-free survival and B overall survival

• 

  Fig. 3 Kaplan–Meier progression-free survival curves: A DE (P = 0.046) and B NCCN-IPI (P < 0.001)

Reference

1. Coiffier B, Sarkozy C. 2016; Diffuse large B-cell lymphoma: R-CHOP failure-what to do? Hematology Am Soc Hematol Educ Program. 2016:366–78. DOI: 10.1182/asheducation-2016.1.366. PMID: 27913503. PMCID: PMC6142522.

2. Zhou Z, Sehn LH, Rademaker AW, et al. 2014; An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 123:837–42. DOI: 10.1182/blood-2013-09-524108. PMID: 24264230. PMCID: PMC5527396.

3. Ruppert AS, Dixon JG, Salles G, et al. 2020; International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 135:2041–8. DOI: 10.1182/blood.2019002729. PMID: 32232482.

4. Biccler J, Eloranta S, de Nully BP, et al. 2018; Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCN-IPI. Cancer Med. 7:114–22. DOI: 10.1002/cam4.1271. PMID: 29239133. PMCID: PMC5773951.

5. Li L, Li Y, Que X, et al. 2018; Prognostic significances of overexpression MYC and/or BCL2 in R-CHOP-treated diffuse large B-cell lymphoma: a systematic review and meta-analysis. Sci Rep. 8:6267. DOI: 10.1038/s41598-018-24631-5. PMID: 29674626. PMCID: PMC5908914.

6. Hwang J, Suh C, Kim K, et al. 2021; The incidence and treatment response of double expression of MYC and BCL2 in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis. Cancers (Basel). 13:3369. DOI: 10.3390/cancers13133369. PMID: 34282799. PMCID: PMC8268769. PMID: 94f30a306c3444039ed930e7f1ac0ce5.

7. Scott DW, King RL, Staiger AM, et al. 2018; High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood. 131:2060–4. DOI: 10.1182/blood-2017-12-820605. PMID: 29475959. PMCID: PMC6158813.

8. Laude MC, Lebras L, Sesques P, et al. 2021; First-line treatment of double-hit and triple-hit lymphomas: survival and tolerance data from a retrospective multicenter French study. Am J Hematol. 96:302–11. DOI: 10.1002/ajh.26068. PMID: 33306213.

9. Huang S, Nong L, Wang W, et al. 2019; Prognostic impact of diffuse large B-cell lymphoma with extra copies of MYC, BCL2 and/or BCL6: comparison with double/triple hit lymphoma and double expressor lymphoma. Diagn Pathol. 14:81. DOI: 10.1186/s13000-019-0856-7. PMID: 31315646. PMCID: PMC6637540. PMID: 04bc133684d3447190e9746852831366.

10. Chen H, Qin Y, Liu P, et al. 2023; Genetic profiling of diffuse large B-cell lymphoma: a comparison between double-expressor lymphoma and non-double-expressor lymphoma. Mol Diagn Ther. 27:75–86. DOI: 10.1007/s40291-022-00621-2. PMID: 36401148.

11. Stein H, Chan JK, Warnke RA. Swerdlow SH, Campo E, Harris NL, editors. 2008. Diffuse large B-cell lymphoma, NOS. WHO classification of tumours of hematopoietic and lymphoid tissues. 4th ed. International Agency for Research on Cancer;Lyon: p. 233–8. DOI: 10.53347/rid-53114.

12. Cheson BD, Fisher RI, Barrington SF, et al. 2014; Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 32:3059–68. DOI: 10.1200/JCO.2013.54.8800. PMID: 25113753. PMCID: PMC4979083.

13. Johnson NA, Slack GW, Savage KJ, et al. 2012; Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 30:3452–9. DOI: 10.1200/JCO.2011.41.0985. PMID: 22851565. PMCID: PMC3454768.

14. Harrell FE Jr, Califf RM, Pryor DB, et al. 1982; Evaluating the yield of medical tests. JAMA. 247:2543–6. DOI: 10.1001/jama.1982.03320430047030. PMID: 7069920.

15. van der Windt DA, et al. Riley RD, editor. 2019. Prognostic factor research. Prognosis Research in Healthcare: Concepts, Methods, and Impact. Oxford Academic;Oxford: https://doi.org/10.1093/med/9780198796619.003.0007. Accessed 17 Dec 2019. DOI: 10.1093/med/9780198796619.003.0007.

16. Newson RB. 2010; Comparing the predictive powers of survival models using Harrell's C or Somers' D. Stand Genomic Sci. 10:339–58. DOI: 10.1177/1536867X1001000303.

17. Altman DG, McShane LM, Sauerbrei W, et al. 2012; Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS Med. 9:e1001216. DOI: 10.1371/journal.pmed.1001216. PMID: 22675273. PMCID: PMC3362085. PMID: 81e548a8be3d485992c1d71d5cee349b.

18. Kluin PM, Campo E, Harris NL, et al. Swerdlow SH, Campo E, Harris NL, editors. 2017. High-grade B-cell lymphoma. WHO classification of tumours of haematopoietic and lymphoid tissues. IARC;Lyon: p. 335–41. DOI: 10.53347/rid-9250.

19. Yan LX, Liu YH, Luo DL, et al. 2014; MYC expression in concert with BCL2 and BCL6 expression predicts outcome in Chinese patients with diffuse large B-cell lymphoma, not otherwise specified. PLoS One. 9:e104068. DOI: 10.1371/journal.pone.0104068. PMID: 25090026. PMCID: PMC4121314. PMID: 37a653bcd3ee47a5a0c9781a8ea6623e.

20. Perry AM, Alvarado-Bernal Y, Laurini JA, et al. 2014; MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol. 165:382–91. DOI: 10.1111/bjh.12763. PMID: 24506200.

21. Ye Q, Xu-Monette ZY, Tzankov A, et al. 2016; Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma. Oncotarget. 7:2401–16. DOI: 10.18632/oncotarget.6262. PMID: 26573234. PMCID: PMC4823044.

22. Prochazka KT, Posch F, Deutsch A, et al. 2018; Immunohistochemical double hit score enhances NCCN-IPI and is associated with detrimental outcomes in refractory or relapsing patients with diffuse large B cell lymphoma. Br J Haematol. 183(1):142–6. DOI: 10.1111/bjh.14912. PMID: 28875547.