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RESEARCH

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Blood Res (2024) 59:2

Published online February 19, 2024

https://doi.org/10.1007/s44313-024-00006-w

© The Korean Society of Hematology

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

Naree Warnnissorn1*, Nonglak Kanitsap2, Pimjai Niparuck3, Paisarn Boonsakan4, Prapasri Kulalert5, Wasithep Limvorapitak2, Lantarima Bhoopat2, Supawee Saengboon2, Chinnawut Suriyonplengsaeng6, Pichika Chantrathammachart3, Teeraya Puavilai3 and Suporn Chuncharunee3

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1Department of Pathology, Faculty of Medicine, Thammasat University, Pathumthani, Thailand. 2Division of Hematology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand. 3Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 4Department of Pathology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 5Department of Clinical Epidemiology, Faculty of Medicine, Thammasat University, Pathumthani, Thailand. 6Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand.

Correspondence to : *Naree Warnnissorn
nareeaw@tu.ac.th

Received: November 9, 2023; Accepted: January 10, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

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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 resource-limited settings. Multiple independent confirmatory studies from a large cohort of lymphoma registries have provided additional evidence for the clinical utility of DE.

Graphical Abstract

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Keywords: DLBCL, MYC/BCL2 double expression, R-CHOP, Prognosis, NCCN-IPI, REMARK

Article

RESEARCH

Blood Res 2024; 59():

Published online February 19, 2024 https://doi.org/10.1007/s44313-024-00006-w

Copyright © The Korean Society of Hematology.

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

Naree Warnnissorn1*, Nonglak Kanitsap2, Pimjai Niparuck3, Paisarn Boonsakan4, Prapasri Kulalert5, Wasithep Limvorapitak2, Lantarima Bhoopat2, Supawee Saengboon2, Chinnawut Suriyonplengsaeng6, Pichika Chantrathammachart3, Teeraya Puavilai3 and Suporn Chuncharunee3

1Department of Pathology, Faculty of Medicine, Thammasat University, Pathumthani, Thailand. 2Division of Hematology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand. 3Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 4Department of Pathology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 5Department of Clinical Epidemiology, Faculty of Medicine, Thammasat University, Pathumthani, Thailand. 6Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand.

Correspondence to:*Naree Warnnissorn
nareeaw@tu.ac.th

Received: November 9, 2023; Accepted: January 10, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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 resource-limited settings. Multiple independent confirmatory studies from a large cohort of lymphoma registries have provided additional evidence for the clinical utility of DE.

Keywords: DLBCL, MYC/BCL2 double expression, R-CHOP, Prognosis, NCCN-IPI, REMARK

Fig 1.

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Figure 1.Participant flow diagram
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00006-w

Fig 2.

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Figure 2.Kaplan–Meier survival curves: A progression-free survival and B overall survival
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00006-w

Fig 3.

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Figure 3.Kaplan–Meier progression-free survival curves: A DE (P = 0.046) and B NCCN-IPI (P < 0.001)
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00006-w

Patient characteristics.


CharacteristicAll Number (%)DE Number (%)Non-DE Number (%)P
Total111 (100)43 (39)68 (61) NA
Sex0.437
Male51 (46)22 (51)29 (43)
Female60 (54)21 (49)39 (57)
Age, median (range)62 (26–88)66 (28–80)62 (26–88)0.374
LDH ratio >167 (60)25 (58)42 (62)0.842
Stage III–IV60 (54)21 (49)39 (57)0.437
Extranodal site45 (41)13 (30)32 (47)0.112
ECOG ≥213 (12)6 (14)7 (10)0.561
NCCN-IPI low3 (3)1 (1)2 (3)0.721
LI60 (54)21 (49)39 (57)
HI39 (35)18 (42)21 (31)
High9 (8)3 (7)6 (9)
Tumor size ≥ 10 cm28 (25)8 (19)20 (29)0.263
Follow-up without progression, median (range)5.3 (2.6–7.6)5.1 (3.0–6.6)5.7 (2.6–7.6)0.076
Complete response97 (87)35 (81)62 (91)0.151
Progression51 (46)24 (56)27 (40)0.119
Death37 (33)17 (40)20 (29)0.305

DE double expression of MYC and BCL2 proteins, ECOG Eastern Cooperative Oncology Group Performance Status, HI High intermediate, LDH Lactate dehydrogenase, LI Low intermediate, NA not applicable, NCCN-IPI National Comprehensive Cancer Network International Prognostic Index.

Estimated 5-year progression-free survival probabilities of DE and NCCN-IPI.


VariablesNumber (%)5-y PFS (95% CI)P
Non-DE43 (39)60 (46–71)0.046
DE68 (61)47 (31–62)
NCCN-IPI Low3 (3)100 (.-.)< 0.001
LI60 (54)64 (50–75)
HI39 (35)46 (30–61)
High9 (8)22 (3–51)

DE double expression of MYC and BCL2 proteins, HI high-intermediate, LI low-intermediate, NCCN-IPI National Comprehensive Cancer Network Internal Prognostic Index, PFS Progression-free survival.

Prognostic strength of DE for prediction of progressionfree survival.


EffectProgression-free survival
Value (95% CI)P
Unadjusted
HR of DE1.7 (1.0–3.0)0.051
c-index of DE0.56 (0.49–0.64)NA
Adjusted
NCCN-IPI adjusted HR of DE1.6 (0.9–2.8)0.117
c-index of NCCN-IPI0.63 (0.56–0.71)NA
c-index of NCCN-IPI + DE0.66 (0.58–0.74)NA
c-index difference0.03 (-0.01–0.06)0.119
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