Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population

doi:10.21203/rs.3.rs-4855200/v1

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Research Article

Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population

https://doi.org/10.21203/rs.3.rs-4855200/v1

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Background

Recent breakthrough advances in the treatment of DLBCL, such as the antibody-drug conjugate Polatuzumab vedotin, have yielded clinical survival benefit over R-CHOP for the first time in 20 years since the advent of the Rituximab era. We thus examine the outcomes of standard immunochemotherapy for DLBCL in our multi-ethnic Asian population, so as to determine the real-world clinical need to adopt new therapeutics in this disease entity.

Methods

We conducted a retrospective study involving patients (n = 1071) diagnosed with DLBCL at the National Cancer Centre Singapore from 2010–2022, and treated with first-line rituximab-based regimens. The median follow-up duration was 48 months. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models.

Results

The cohort consisted of 590 male and 481 female patients with a median age of 63.8 years (range, 19.3–93.6). Most were stage III-IV at diagnosis (60.9%) and of non-germinal center B-cell like (non-GCB) subtype by Han’s criteria (56.5%). The vast majority received R-CHOP(-like) regimens (n = 997, 93.1%), including EPOCH-R (n = 95), achieving a 5-year progression-free survival (PFS) and overall survival (OS) of 64.5% and 74.7% respectively. Male sex (p = 0.0294), age > 60 years (p < 0.0001), poor ECOG scores (2–4) (p < 0.0001), advanced stage (III-IV) (p < 0.0001), presence of B-symptoms (p = 0.0305), raised LDH (p = 0.0161) were independent predictors of OS, 4 of which are risk factors in the International Prognostic Index (IPI). In the intermediate to high-risk subgroup (IPI scores 2–5; n = 752), the 5-year PFS and OS were only 59.0% and 69.8% respectively. EBV status, as was high-risk lymphoma (MYC and/or BCL2/BCL6 rearrangements), were not significantly associated with survival outcomes. EPOCH-R was used more frequently than R-CHOP in patients with MYC rearrangements (n = 82, p < 0.0001), including those with MYC/BCL2 double-hit genetics (n = 31, p < 0.0001). Notably, neither regimen significantly affected survival outcomes, both in MYC-rearranged (PFS: HR 0.60, p = 0.1704; OS: HR 0.49, p = 0.0852), and in MYC/BCL2 double-hit DLBCL (PFS: HR 1.30, p = 0.6433; OS: HR 1.02, p = 0.9803).

Conclusion

Our study demonstrates that our local population has similar clinicopathological and prognostic characteristics of DLBCL as compared to global findings. It also highlights the limitations of R-CHOP(-like) regimens in contemporary DLBCL management and therefore an ongoing need for improved therapeutic strategies.

Polatuzumab vedotin

CAR-T cells

cell-of-origin

double-hit

bispecific antibody

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin’s Lymphoma (NHL). It is very aggressive but responds favourably to chemotherapy. Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and prednisolone (R-CHOP) has been the standard of care treatment regimen for DLBCL¹ since the early 2000s. As compared to CHOP therapy, R-CHOP provided significantly higher rates of complete response (CR) and longer overall survival (OS) durations in both the elderly population² and younger patients³. The MabThera International Trial (MInT) Group showed that 6 cycles of R-CHOP therapy improved 6-year event-free survival (EFS) to 74.3% as compared to 55.8% for the CHOP group and 6-year OS to 90.1% from 80.0%⁴.

Following the inclusion of anti-CD20 monoclonal antibody Rituximab to first-line therapy in DLBCL, there has been limited success in attempts made to improve upon this treatment regimen, with candidate drugs often failing to show benefit in phase III trials or causing an unacceptable increase in toxicity. Dose-intensified Rituximab, Doxorubicin, Cyclophosphamide, Vindesine, Bleomycin and Prednisolone (R-ACVBP) was shown to improve PFS and OS in patients aged 15–59 years, but was eventually not prescribed widely due to its high incidence of haematological toxic effects and limited applicability.⁵ Other treatment options such as consolidation therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) improved treatment response and progression-free survival (PFS), but did not result in prolonged OS^6,7. Consequently, the survival outcomes in DLBCL improved only modestly during the rituximab era, demonstrating the limited efficacy of those novel therapeutics over the current standard of care⁸.

Polatuzumab vedotin is an antibody-drug conjugate (ADC) directed at CD79b, a part of the heterodimeric signalling component of B-cell NHLs. It demonstrated good efficacy against NHL and DLBCL in initial in vivo and early clinical trials^9,10. In 2023, a double-blind, placebo-controlled phase 3 trial showed that Polatuzumab vedotin in combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisolone (pola-R-CHP) improved PFS in the overall cohort over R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL (IPI 2–5)¹¹. Even though the OS data was considered to be immature and did not differ between both arms, the significant survival benefit from PFS prolongation paired with its acceptable side-effect profile and reasonable cost earned Polatuzumab vedotin health regulatory approvals in the UK¹², US¹³ and Singapore¹⁴ for use in previously untreated DLBCL with International Prognostic Index (IPI) of 2–5.

In Singapore, a country with a diverse multi-ethnic population, the first-line treatment for DLBCL is that of six 21-day cycles of R-CHOP immunochemotherapy¹⁵, in line with global guidelines¹⁶. The efficacy of R-CHOP over CHOP in our patient population is supported by the last large-scale Singapore DLBCL study done in 2008 showing a significantly higher 2-year survival of R-CHOP compared to CHOP alone (85.6% vs 64.7%)¹⁷.

Given this recent breakthrough of Polatuzumab vedotin in the treatment of previously untreated DLBCL, we sought to review the current efficacy of the current standard-of-care treatment regimens for DLBCL in Singapore. Through this, we confirm the unmet clinical need of novel effective therapeutics in the treatment of DLBCL in our local population in a real-world setting.

Study cohort

Patients who were diagnosed with diffuse large B-cell lymphoma (DLBCL) and seen at the National Cancer Centre Singapore and Singapore General Hospital between 2010 and 2022 were retrospectively analysed. A total of 1071 patients who were treated with rituximab-based immunochemotherapy regimens were included in the final analysis. The median follow-up duration for this group of patients was 48 months.

Relevant demographical and clinicopathological information were collected and summarised for the analysis. Demographical information available included sex, age and ethnicity. Clinical characteristics of each patient including B-symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, disease stage, number of extranodal site involvement, chemotherapeutic regimen used and survival outcomes were included in the study. Finally, pathological information such as immunohistochemical markers (BCL2, BCL6, CD10, MUM1, MYC), gene rearrangements (BCL2, BCL6, MYC), and DLBCL cell-of-origin by Han’s algorithm¹⁸ were included in the analysis. All data was obtained at the time of diagnosis or subsequent follow-up.

The research study was carried out with approval from the SingHealth Centralised Institutional Review Board. Informed consent for the use of biospecimens was obtained in accordance with the Declaration of Helsinki and all methods were carried out in accordance with relevant guidelines and regulations. All data was obtained at the time of diagnosis or subsequent follow-up. Participants and/or their legal guardians provided informed consent for their data to be used in this research. The datasets created and analysed during this study are available from the corresponding authors upon reasonable request.

Statistical Analysis

The outcomes of interest in this study are progression-free survival (PFS) and overall survival (OS). PFS was defined as the time elapsed between the date of diagnosis to the date of relapse, progression, or death from any cause. OS was calculated from the date of diagnosis up to the date of death from any cause, or was censored at the date of last follow-up for survivors. For each individual clinicopathological parameter, Kaplan-Meier survival curves were plotted to estimate survival. The log-rank test was then used to determine hazard ratio (HR), the corresponding 95% confidence intervals of mortality and the p-values for each individual clinicopathological parameter. Parameters found to be significant on univariate analysis using a two-sided test with significance level of 0.05 were identified. These parameters were then used in the generation of Multivariate Cox regression models via a backwards procedure to test for independence of significant parameters for PFS and OS.

MYC rearrangement and double-hit DLBCL were tested for association with choice of chemoimmunotherapy regimen with the chi-squared test. Kaplan-Meier survival curves were then plotted for R-CHOP vs EPOCH-R in patients with MYC rearrangement and double-hit DLBCL. All tests were performed using MedCalc statistical Software for Windows version 19.0.4 (MedCalc Software, Ostend, Belgium).

Patient demographics and clinicopathological characteristics

The overall cohort consisted of 590 male and 481 female patients with a median age of 63.8 years (range, 19.3–93.6). Most were stage III-IV (60.9%) and of non-germinal center B-cell like (non-GCB) subtype by Han’s criteria (56.5%). Clinical and demographic characteristics of the whole study cohort are summarised in Table 1.

Table 1

Clinical and pathological characteristics of the overall cohort, n = 1071
Characteristic	n (%)
Total	1071 (100%)
Sex
Male	590 (55.1%)
Female	481 (44.9%)
Age
≤ 60	415 (38.7%)
> 60	656 (61.3%)
Ethnicity
Chinese	766 (71.5%)
Malay	177 (16.5%)
Indian	39 (3.6%)
Others	83 (8.3%)
ECOG performance status
0–1	1002 (93.6%)
2–4	69 (6.4%)
Stage
I-II	416 (39.1%)
III-IV	649 (60.9%)
B-Symptoms
Present	315 (29.4%)
Absent	756 (70.6%)
LDH
Raised	830 (77.5%)
Not raised	241 (22.5%)
Extranodal sites
>1	284 (26.5%)
≤1	787 (73.5%)
IPI
0–1	255 (23.8%)
2	343 (32.0%)
3	301 (28.1%)
4–5	172 (16.1%)
Cell of Origin
GCB	423 (43.5%)
Non-GCB	549 (56.5%)
HIV status
Positive	20 (1.9%)
Negative	1009 (98.1%)
HBsAg
Positive		78 (7.8%)
Negative		919 (92.2%)
Anti-HBc Total
Positive		320 (31.9%)
Negative		683 (68.1%)
HCV status
Positive		20 (1.9%)
Negative		1011 (98.1%)
MYC/BCL2 double expressor
Yes		157 (40.6%)
No		230 (59.4%)
MYC rearrangement
Present		86 (19.6%)
Absent		353 (80.4%)
Both MYC and BCL2 rearrangement
Present		32 (7.2%)
Absent		412 (92.8%)
Both MYC and BCL6 rearrangement
Present		18 (4.1%)
Absent		424 (95.9%)
EBER
Positive		32 (6.3%)
Negative		476 (93.7%)
*Missing data: Stage (n = 6), COO (n = 99), HIV status (n = 42), HBsAg (n = 74), Anti-HBc Total (n = 68), HCV status (n = 40), MYC/BCL2 double expressor (n = 684), MYC rearrangement (n = 632), MYC/BCL2 rearrangement (n = 627), MYC/BCL6 rearrangement (n = 629), EBER status (n = 563)

The vast majority of the patient cohort received R-CHOP(-like) regimens (n = 997, 93.1%), including MR-CHOP (n = 78) and EPOCH-R (n = 95). This sub-cohort consisted of 544 males and 453 females, of which most were also stage III/IV (60.6%) and of non-germinal center B-cell like (non-GCB) subtype by Han’s criteria (56.1%). Clinical and demographic characteristics of the sub-cohort that received R-CHOP(-like) regimens are summarised in Table 2.

Table 2

Clinical and pathological characteristics of patients treated with R-CHOP(-like) regimens, n = 997
Characteristic	n (%)
Total	997 (100%)
Sex
Male	544 (54.6%)
Female	453 (45.4%)
Age
< 60	597 (59.9%)
≥ 60	400 (40.1%)
Ethnicity
Chinese	719 (72.1%)
Malay	159 (15.9%)
Indian	36 (3.6%)
Others	83 (8.3%)
ECOG performance status
0–1	938 (94.1%)
2–4	59 (5.9%)
Stage
I-II	391 (39.4%)
III-IV	602 (60.6%)
B-Symptoms
Present	292 (29.3%)
Absent	705 (70.7%)
LDH
Raised	771 (77.3%)
Not raised	226 (22.7%)
Extranodal sites
>1	262 (26.3%)
≤1	735 (73.7%)
IPI
0–1	245 (24.6%)
2	319 (32.0%)
3	279 (28.0%)
4–5	154 (15.4%)
Cell of Origin
GCB	398 (43.9%)
Non-GCB	509 (56.1%)
HIV status
Positive	19 (2.0%)
Negative	940 (98.0%)
HBsAg
Positive		76 (8.2%)
Negative		853 (91.8%)
Anti-HBc Total
Positive		306 (32.7%)
Negative		630 (67.3%)
HCV status
Positive		20 (2.1%)
Negative		942 (97.9%)
MYC/BCL2 double expressor
Yes		146 (40.4%)
No		215 (59.6%)
MYC rearrangement
Present		82 (19.9%)
Absent		330 (80.1%)
Both MYC and BCL2 rearrangement
Present		31 (7.4%)
Absent		386 (92.6%)
Both MYC and BCL6 rearrangement
Present		17 (4.1%)
Absent		398 (95.9%)
EBER
Positive		30 (6.4%)
Negative		439 (93.6%)
*Missing data: Stage (n = 4), COO (n = 90), HIV status (n = 38), HBsAg (n = 68), Anti-HBc Total (n = 61), HCV status (n = 35), MYC/BCL2 double expressor (n = 636), MYC rearrangement (n = 585), MYC/BCL2 rearrangement (n = 580), MYC/BCL6 rearrangement (n = 582), EBER status (n = 528)

Molecular pathological characteristics

For the overall patient cohort, fluorescence in-situ hybridization in a subgroup with available data revealed that MYC rearrangement was present in 86/439 (19.6%) cases, double-hit DLBCL with both MYC and BCL2 rearrangement was found in 32/444 (7.2%) cases and double-hit DLBCL with both MYC and BCL6 rearrangement was detected in 18/444 (4.1%) cases. MYC/BCL2 double expressor status was present in 157/387 (40.6%) cases. In another subgroup with available data, Epstein-Barr virus was positive in 32/508 (6.3%) cases.

Survival analyses

The patient sub-cohort that received R-CHOP(-like) regimens achieved a 5-year progression-free survival (PFS) and overall survival (OS) of 64.5% and 74.7% respectively (Fig. 1). At the point of data analysis, 274 patients (27.5%) had died. Further analysis will be performed in this sub-cohort of patients treated with R-CHOP(-like) regimens.

Univariate analysis for OS revealed that male sex (HR 1.39, 95% CI 1.13–1.70, p = 0.0020), age > 60 (HR 1.53, 95% CI 1.24–1.89, p = 0.0001), ECOG performance status ≥ 2 (HR 3.90, 95% CI 2.36–6.42, p = < 0.0001), Stage III or IV (HR 2.33, 95% CI 1.89–2.87, p = < 0.0001), presence of B-symptoms (HR 1.51, 95% CI 1.20–1.91, p = 0.0004), raised LDH (HR 1.62, 95% CI 1.28–2.07, p = 0.0001), non-GCB cell of origin by Han’s algorithm (HR 1.40, 95% CI 1.12–1.74, p = 0.0029) and MYC/BCL2 double expressor status (HR 1.62, 95% CI 1.15–2.29, p = 0.0059) were all predictors for worse PFS (Table 3).

Table 3

Univariable analysis for OS and PFS for patients treated with R-CHOP(-like) regimens, n = 997
	Overall survival			Progression-free survival
Characteristic	HR	95% CI	p-value	HR	95% CI	p-value
Sex (Male vs Female)	1.38	1.09–1.75	0.0084	1.39	1.13–1.70	0.0020
Age (> 60 vs ≤ 60)	2.11	1.66–2.69	< 0.0001	1.53	1.24–1.89	0.0001
ECOG Performance Status (2–4 vs 0–1)	4.73	2.68–8.34	< 0.0001	3.90	2.36–6.42	< 0.0001
Stage (III-IV vs I-II)	2.15	1.69–2.74	< 0.0001	2.33	1.89–2.87	< 0.0001
B-Symptoms (Present vs Absent)	1.67	1.28–2.17	0.0001	1.51	1.20–1.91	0.0004
LDH (Raised vs Not Raised)	1.87	1.42–2.46	< 0.0001	1.62	1.28–2.07	0.0001
Extranodal sites (> 1 vs ≤ 1)	1.87	1.41–2.47	< 0.0001	1.62	1.27–2.07	0.0001
IPI Risk Groups			< 0.0001			< 0.0001
Cell Of Origin (Non-GCB vs GCB)	1.31	1.02–1.69	0.0328	1.40	1.12–1.74	0.0029
HIVs status (Positive vs Negative)	1.11	0.47–2.59	0.8134	0.99	0.47–2.98	0.9787
HBsAg (Positive vs Negative)	1.28	0.81–2.01	0.2896	1.11	0.75–1.65	0.5883
Anti-HBc Total (Positive vs Negative)	1.21	0.93–1.57	0.1513	1.10	0.88–1.39	0.3774
HCV Status (Positive vs Negative)	0.87	0.38–1.99	0.7434	0.93	0.45–1.91	0.8376
MYC/BCL2 Double Expressor (Yes vs No)	1.43	0.97–2.11	0.0714	1.62	1.15–2.29	0.0059
MYC Rearrangement (Present vs Absent)	1.16	0.72–1.85	0.5425	1.10	0.73–1.66	0.6500
Both MYC and BCL2 Rearrangement (Present vs Absent)	0.94	0.47–1.90	0.8681	1.35	0.71–2.54	0.3611
Both MYC and BCL6 Rearrangement (Present vs Absent)	1.43	0.51–4.03	0.4970	1.45	0.60–3.49	0.4078
EBER (Positive vs Negative)	0.65	0.32–1.30	0.2228	0.91	0.49–1.68	0.7627

For OS, male sex (HR 1.38, 95% CI 1.09–1.75, p = 0.0084), age > 60 (HR 2.11, 95% CI 1.66–2.69, p = < 0.0001), ECOG performance status ≥ 2 (HR 4.73, 95% CI 2.68–8.34, p = < 0.0001), Stage III or IV (HR 2.15, 95% CI 1.69–2.74, p = < 0.0001), presence of B-symptoms (HR 1.67, 95% CI 1.28–2.17, p = 0.0001), raised LDH (HR 1.87, 95% CI 1.42–2.46, p = < 0.0001), presence of extranodal sites (HR 1.87, 95% CI 1.41–2.47, p = < 0.0001) and non-GCB cell of origin by Han’s algorithm (HR 1.40, 95% CI 1.12–1.74, p = 0.0029) were all predictive of poorer outcomes on univariate analysis (Table 3).

Following multivariate analysis of significant clinicopathological parameters, male sex (HR 1.33, 95% CI 1.03–1.73, p = 0.0294), age > 60 (HR 2.35, 95% CI 1.76–3.12, p < 0.0001), ECOG performance status ≥ 3 (HR 2.27, 95% CI 1.53–3.36, p < 0.0001), Stage III-IV (HR 1.92, 95% CI 1.42–2.59, p < 0.0001), presence of B-symptoms (HR 1.34, 95% CI 1.03–1.76, p = 0.0305) and raised LDH (HR 1.58, 95% CI 1.09–2.31, p = 0.0161) were independently prognostic for worse OS (Table 4).

Table 4

Multivariable analysis for OS and PFS for patients treated with R-CHOP(-like) regimens, n = 997
	Overall survival			Progression-free survival
Parameter	HR	95% CI	p-value	HR	95% CI	p-value
Sex
Female	1	1.03–1.73	0.0294	1	1.16–2.38	0.0051
Male	1.33	1.03–1.73	0.0294	1.67	1.16–2.38	0.0051
Age
≤ 60	1	1.76–3.12	< 0.0001	1	1.33–2.84	0.0006
> 60	2.35	1.76–3.12	< 0.0001	1.95	1.33–2.84	0.0006
ECOG Performance Status
0–1	1	1.53–3.36	< 0.0001	1	1.22–3.21	0.0054
2–4	2.27	1.53–3.36	< 0.0001	1.98	1.22–3.21	0.0054
Stage
I-II	1	1.42–2.59	< 0.0001	1	1.28–2.87	0.0015
III-IV	1.92			1.92
B-Symptoms
Absent	1	1.03–1.76	0.0305	1	0.99–2.06	0.0574
Present	1.34			1.43
LDH
Not Raised	1	1.09–2.31	0.0161	-	-	-
Raised	1.58
MYC/BCL2 Double Expressor
Absent	-	-	-	1	1.02–2.03	0.0404
Present				1.43

In the intermediate to high-risk subgroup (IPI scores 2–5; n = 752), the 5-year OS and PFS were only 69.8% and 58.0%, respectively (Fig. 1). EBV status, MYC and/or BCL2 rearrangements were not significantly associated with survival outcomes.

MYC rearrangement and Double-hit DLBCL

For patients treated with R-CHOP(-like) regimens, EPOCH-R was used more frequently than R-CHOP in patients with MYC rearrangements (n = 82, p < 0.0001), including those with MYC/BCL2 double-hit genetics (n = 31, p < 0.0001). Patients with MYC rearrangements achieved a 5-year OS of 70.7%, while those with both MYC and BCL2 rearrangements achieved a 5-year OS of 76.6% (Fig. 2).

Notably, neither immunochemotherapy regimen significantly affected survival outcomes, both in MYC-rearranged (PFS: HR 0.60, p = 0.1704; OS: HR 0.49, p = 0.0852), and in MYC/BCL2 double-hit DLBCL (PFS: HR 1.30, p = 0.6433; OS: HR 1.02, p = 0.9803) (Fig. 3).

Our study is the largest clinical study investigating the treatment outcomes of DLBCL with standard R-CHOP(-like) immunochemotherapy regimens in Singapore to date. Survival outcomes in our study cohort are largely similar to existing major trial data for DLBCL treated with R-CHOP(-like) immunochemotherapy regimens. The LNH-98.5 trial reported a 10-year PFS of 36.5% in R-CHOP treated DLBCL¹⁹, while a retrospective Sweden study showed a 5-year OS of 65.3% in curative-intent DLBCL patients²⁰. Our study also is in keeping with current consensus that up to 40% patients relapse or are refractory to first-line therapy²¹.

Current literature is still unclear on the optimal immunochemotherapy regimen for double-expressor and high-grade DLBCLs with MYC translocations or double-hit/triple-hit genetics. While Dodero et al. suggest that EPOCH-R over RCHOP significantly improves 2-year PFS in younger DLBCL patents < 65 years²², the landmark Phase III Alliance/CALGB 50303 study revealed that EPOCH-R had higher toxicity and did not improve either OR or PFS as compared to R-CHOP²³. A systemic review and meta-analysis in 2015 found that EPOCH-R first-line treatment significantly reduced progression risk as compared to R-CHOP in double-hit lymphomas²⁴, while a later prospective study showed that EPOCH-R yielded a good 48-month event-free survival (EFS) of 71.6% and OS of 70.7%²⁵. However, a recent large retrospective study showed that there was no difference in 4-year OS between R-CHOP and EPOCH-R treated high-grade DLBCLs²⁶. In our study, intensification of treatment regimen with EPOCH-R in MYC rearranged or double hit (MYC/BCL2) DLBCL did not significantly change treatment outcomes. However, this finding is limited by the relatively small number of such patients in our study and lack of both R-CHOP and EPOCH-R dosing information. Overall results suggest the potential survival benefit of EPOCH-R over R-CHOP in double-hit and high-grade DLBCLs remains controversial and to be further resolved. Due to the high rate of relapsed/refractory DLBCLs after first-line chemoimmunotherapy and the mediocre outcomes of regimen intensification in high risk DLBCLs, novel therapeutics for all DLBCL entities are sorely warranted.

The main limitation of our study is its retrospective design and its resultant lack of specific clinicopathological information and loss to follow up of some cases. However, our study involves the largest cohort of DLBCLs treated with R-CHOP(-like) regimens to date in Singapore with comprehensive coverage of both demographical and clinicopathological factors in survival outcome analysis.

In conclusion, our study showcases the real-world outcomes of DLBCL treated with frontline R-CHOP(-like) regimens in an Asian multi-ethnic population, which is similar to global outcomes. We thus highlight the crucial need for improved therapeutic strategies for DLBCL, especially for high-risk cases.

COMPETING FINANCIAL INTERESTS STATEMENT

All authors declare no competing financial interests.

Author Contribution

RML and JYC analysed the data and drafted the manuscript; JYT, YHT, ZEH, LCN, FLL, YTG, STL obtained patient data; RML and JYC designed the study, interpreted the results, and revised the manuscript; and all authors read and approved the final version of the manuscript.

ACKNOWLEDGEMENTS

This work was supported by the Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health’s National Medical Research Council Research Transition Award (TA21jun-0005), Large Collaborative Grant (OFLCG18May-0028), and TETRAD II Collaborative Centre Grant (CG21APR2002) as well as the SingHealth Duke-NUS AM/ACP-Designated Philanthropic Fund Grant Award (08/FY2023/EX/27-A65). We would like to thank all subjects who have participated in this study.

Data Availability

The datasets created and analysed during this study are available from the corresponding authors upon reasonable request.

Sehn LH, Donaldson J, Chhanabhai M et al (2005) Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23(22):5027–5033. 10.1200/JCO.2005.09.137
Coiffier B, Lepage E, Brière J et al (2002) CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma. N Engl J Med 346(4):235–242. 10.1056/NEJMOA011795/ASSET/123FAC68-22CE-4D83-9337-C261227D7454/ASSETS/IMAGES/LARGE/NEJMOA011795_T4.JPG
Pfreundschuh M, Trümper L, Österborg A et al (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7(5):379–391. 10.1016/S1470-2045(06)70664-7
Pfreundschuh M, Kuhnt E, Trümper L et al (2011) CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12(11):1013–1022. 10.1016/S1470-2045(11)70235-2
Récher C, Coiffier B, Haioun C et al (2011) Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378(9806):1858–1867. 10.1016/S0140-6736(11)61040-4
Chiappella A, Martelli M, Angelucci E et al (2017) Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol 18(8):1076–1088. 10.1016/S1470-2045(17)30444-8
Stiff PJ, Unger JM, Cook JR et al (2013) Autologous Transplantation as Consolidation for Aggressive Non-Hodgkin’s Lymphoma. N Engl J Med 369(18):1681–1690. 10.1056/NEJMOA1301077/SUPPL_FILE/NEJMOA1301077_DISCLOSURES.PDF
Epperla N, Vaughn JL, Othus M, Hallack A, Costa LJ (2020) Recent survival trends in diffuse large B-cell lymphoma––Have we made any progress beyond rituximab? Cancer Med 9(15):5519. 10.1002/CAM4.3237
Polson AG, Yu SF, Elkins K et al (2007) Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma. Blood 110(2):616–623. 10.1182/BLOOD-2007-01-066704
Pfeifer M, Zheng B, Erdmann T et al (2015) Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 2015 29:7. ;29(7):1578–1586. 10.1038/leu.2015.48
Tilly H, Morschhauser F, Sehn LH et al (2022) Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med 386(4):351–363. 10.1056/NEJMOA2115304/SUPPL_FILE. /NEJMOA2115304_DATA-SHARING.PDF
Overview | Polatuzumab vedotin in combination for untreated diffuse large B-cell lymphoma | Guidance | NICE
FDA approves polatuzumab vedotin-piiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma | FDA. Accessed May 22 (2024) https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-previously-untreated-diffuse-large-b-cell-lymphoma-not
Driving Better Decision-Making in Healthcare Polatuzumab vedotin for previously untreated diffuse large B-cell lymphoma Technology Guidance from the MOH Drug Advisory Committee Guidance Recommendations Technology Guidance. Published online 2024.
Chan JY, Somasundaram N, Grigoropoulos N et al (2023) Evolving therapeutic landscape of diffuse large B-cell lymphoma: challenges and aspirations. Discover Oncol 14(1). 10.1007/S12672-023-00754-8
Tan D, Chan JY, Wudhikarn K et al (2024) Unmet needs in the first-line treatment of diffuse large B-cell lymphoma: Expert recommendations from the Asia-Pacific region with a focus on the challenging subtypes. Clin Lymphoma Myeloma Leuk Published online May 20. 10.1016/J.CLML.2024.05.013
Ngo L, Hee SW, Lim LC et al (2008) Prognostic factors in patients with diffuse large B cell lymphoma: Before and after the introduction of rituximab. Leuk Lymphoma 49(3):462–469. 10.1080/10428190701809156
Hans CP, Weisenburger DD, Greiner TC et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103(1):275–282. 10.1182/BLOOD-2003-05-1545
Coiffier B, Thieblemont C, Van Den Neste E et al (2010) Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 116(12):2040. 10.1182/BLOOD-2010-03-276246
Harrysson S, Eloranta S, Ekberg S et al (2021) Incidence of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) including CNS relapse in a population-based cohort of 4243 patients in Sweden. Blood Cancer J 11(1):9. 10.1038/S41408-020-00403-1
Coiffier B, Sarkozy C (2016) Diffuse large B-cell lymphoma: R-CHOP failure—what to do? Hematology: Am Soc Hematol Educ Program 2016(1):366. 10.1182/ASHEDUCATION-2016.1.366
Dodero A, Guidetti A, Tucci A et al (2019) Dose-adjusted EPOCH plus rituximab improves the clinical outcome of young patients affected by double expressor diffuse large B-cell lymphoma. Leukemia 2019 33:4. ;33(4):1047–1051. 10.1038/s41375-018-0320-9
Bartlett NL, Wilson WH, Jung SH, Dose-Adjusted EPOCH-R, Compared With et al (2019) R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol 37(21):1790–1799. 10.1200/JCO.18.01994
Howlett C, Snedecor SJ, Landsburg DJ et al (2015) Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol 170(4):504–514. 10.1111/BJH.13463
Dunleavy K, Fanale MA, Abramson JS et al (2018) A Prospective Multicenter Phase 2 Study of Dose-Adjusted-EPOCH-R in Untreated MYC-Rearranged Aggressive B-cell Lymphoma. Lancet Haematol 5(12):e609. 10.1016/S2352-3026(18)30177-7
Magnusson T, Narkhede M, Mehta A et al (2021) No difference in overall survival between R-CHOP and R-EPOCH among patients with advanced stage MYC-rearranged, double hit, or triple hit diffuse large B-cell lymphoma. Abstract #S224. Presented at the EHA2021 Virtual Congress, June 9–17

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Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population

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Abstract

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INTRODUCTION

PATIENTS AND METHODS

Study cohort

Statistical Analysis

RESULTS

Patient demographics and clinicopathological characteristics

Molecular pathological characteristics

Survival analyses

DISCUSSION

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COMPETING FINANCIAL INTERESTS STATEMENT

Author Contribution

ACKNOWLEDGEMENTS

Data Availability

References

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