Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide. Although substantial improvement has been achieved by the frontline rituximab-based chemoimmunotherapy, up to 40%–50% of patients will eventually have relapsed or refractory disease, whose prognosis is extremely dismal.
We have carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP (#NCT01202448 and #NCT02474550). In the current report, we describe the outcomes of refractory DLBCL patients. Patients were defined to have refractory DLBCL if they met one of the followings, not achieving at least partial response after 4 or more cycles of R-CHOP; not achieving at least partial response after 2 or more cycles of salvage therapy; progressive disease within 12 months after autologous stem cell transplantation.
Among 1,581 patients, a total of 260 patients met the criteria for the refractory disease after a median time to progression of 9.1 months. The objective response rate of salvage treatment was 26.4%, and the complete response rate was 9.6%. The median overall survival (OS) was 7.5 months (95% confidence interval, 6.4 to 8.6), and the 2-year survival rate was 22.1%±2.8%. The median OS for each refractory category was not significantly different (p=0.529).
In line with the previous studies, the outcomes of refractory DLBCL patients were extremely poor, which necessitates novel approaches for this population.
Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide, accounting for 30%–40% of non-Hodgkin’s lymphoma cases. For patients with newly-diagnosed DLBCL, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard of care for nearly 20 years [
The prognosis of patients who have experienced relapsed or refractory disease after R-CHOP treatment remains poor [
The Consortium for Improving Survival for Lymphoma (CISL) has carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP. The PROCESS cohort (#NCT01202448, CISL1006) comprises 595 DLBCL patients recruited from 26 tertiary institutes from August 2010 to August 2012 [
In both cohorts, the diagnosis of DLBCL was established according to the World Health Organization (WHO) classification [
The common variables of the two cohort studies include age, sex, Eastern Cooperative Oncology Group performance status, Ann-Arbor stage, serum lactate dehydrogenase (LDH) level, number of extranodal involvement, presence of B symptom(s), bone marrow involvement, and cell-of-origin classification by immunochemical stain using the Hans criteria [
In the GIRAFFE-B cohort, response to therapy was deter-mined by investigators according to the Lugano criteria incorporating positron emission tomography–computed tomography (PET-CT) [
In the PROCESS cohort, the complete or partial response from R-CHOP treatment was achieved in 534 patients (89.7%). The remaining 61 patients included those with stable disease (n=3), disease progression during treatment (n=38), and an undetermined response (n=20). After a median follow-up duration of 49.7 months (95% confidence interval [CI], 47.0 to 52.4), 151 cases were lost to follow-up, and 115 relapsed, or refractory disease cases were documented. Among them, a total of 57 patients were included in the refractory cohort for the following reasons: (1) no response during > 4 cycles of induction therapy (n=31); (2) no response during 2 cycles of salvage therapy (n=23); (3) relapse within 12 months from ASCT (n=3). In the GIRAFFE-B cohort, complete or partial response was achieved from R-CHOP treatment in 896 patients (90.9%). The remaining 90 patients included those with stable disease (n=13), disease progression during treatment (n=67), and an undetermined response (n=10). After a median follow-up duration of 44.1 months (95% CI, 42.0 to 46.2), 252 cases were lost to follow-up, and 202 relapsed or refractory disease cases were documented. Among them, a total of 203 patients were included in the refractory cohort for following reasons: (1) no response during > 4 cycles of induction therapy (n=71); (2) no response during 2 cycles of salvage therapy (n=110); (3) relapse within 12 months from ASCT (n=22). Collectively, 260 patients were included in the pooled analysis (
At the time of primary diagnosis of DLBCL, the median age was 63 (range, 22 to 85), and 166 patients (63.8%) were male. In terms of IPI risk group, 41 (15.8%), 66 (25.4%), 85 (32.7%), 68 (26.2%) were classified into low, low-intermediate (LI), high-intermediate (HI), and high-risk group, respectively. Bone marrow involvement was present in 53 patients (20.4%), and B symptom was present in 63 patients (24.2%). The cell-of-origin was available in 204 cases in which 69 (33.8%) and 135 patients (66.2%) were classified into germinal center B-cell (GCB) and non-GCB subtype, respectively. The details are described in
Patients had the refractory disease at the median age of 65 years (range, 23 to 87 years) after a median time to progression of 9.1 months (95% CI, 7.8 to 10.4) from the start of R-CHOP treatment, of which median cycle of treatment was 6 (range, 1 to 8).
Response rates were similar between the two data sets, as overall response rates of the PROCESS and the GIRAFFE-B cohort were 24.0% and 27.1%, respectively (p=0.663). However, a complete response (CR) rate was slightly higher in the PROCESS cohort (14.0% vs. 9.9%), but it was not significantly different (p=0.442). Collectively, a CR rate was 9.6%, and an overall response rate was 26.4% (
Platinum-based regimens including ICE (ifosfamide, carboplatin, etoposide, and dexamethasone), DHAP (cytarabine, cisplatin, dexamethasone), ESHAP/Ox (etoposide, methyl-prednisone, cytarabine, cisplatin or oxaliplatin), and GP/Ox (gemcitabine, cisplatin or oxaliplatin) were the most commonly used salvage regimens (n=228), which were followed by methotrexate-based ones (IMVP16: ifosfamide, methotrexate, etoposide, and prednisone; IVAM: ifosfamide, etoposide, cytarabine, and methotrexate; SMILE: etoposide, cyclophosphamide, asparaginase, and methotrexate; high-dose methotrexate; n=35) and bendamustine-rituximab (n=16). A total of 47 patients were treated with anti-CD20 monoclonal antibodies, including rituximab (n=40) and ofatumumab (n=7). Overall response rates from the platinum-based regimens, methotrexate-based regimens, and bendamustine-rituximab were 26.3% (47/279), 31.2% (10/32), and 14.3% (2/14), which were not significantly different (p=0.125). Similarly, the addition of anti-CD20 monoclonal antibodies did not draw a significant difference (p=0.946) (
The median OS from the start of salvage treatment for the refractory disease was 7.5 months (95% CI, 6.4 to 8.6) (
The present study analyzed the outcomes of refractory DLBCL after R-CHOP treatment. Out of 1,581 patients from the two prospective cohorts, 260 patients (16.4%) met the criteria for the refractory disease of the SCHOLAR-1 study [
R-CHOP has been the standard of care for nearly 20 years. Though the combination has been validated for efficacy and safety, it is now regarded that up to 40%–50% of patients will relapse. For those who have relapsed or refractory disease, platinum-based salvage therapy with or without consolidating ASCT is the current standard of care depending on patients’ fitness. However, several factors, including low response rates of salvage treatment, the impracticability of ASCT due to age, performance status, or comorbidity, and frequent relapses after ASCT frequently render a group of patients succumbs to the disease. Recent advances, including chimeric antigen receptor T-cell therapies [
The outcomes depend on the relapse timing, as patients with early relapse show significantly poor compared to patients with late relapse [
To define the high-risk DLBCL, several prognostic indices have been used including IPI. In the current study, 107 (41.2%) and 153 (58.8%) patients were categorized into low/LI - and HI/high-risk groups, respectively. In the two original cohorts, the numbers of the patient in the relevant group were 1,001 (63.3%) and 580 (36.7%), respectively, which can be translated into an odds ratio of 2.99 (95% CI, 2.28 to 3.94) of developing refractory disease for patients with HI/high-risk patients. However, once the refractory disease developed, no variables including age, stage, number of extranodal involvement, or elevation of serum LDH could probably discriminate OS, as they were collected at the time of initial disease diagnosis, not after the determination of refractory disease. Interestingly, the cell-of-origin classification that is not expected to be changed during treatment showed some impact on survival. Patients with the GCB subtype showed trends for prolonged OS compared to the non-GCB subtype (median, 7.9 vs. 6.6 months; p=0.066).
The optimal salvage treatment has not been determined for RR DLBCL patients. However, platinum-based regimens including ICE, DHAP, ESHAP, or DHAP have been widely accepted as a standard of treatment, and they have been used interchangeably. In the current study, the platinum regimens were the most frequently used treatment (n=202), as expected. Still, several other combinations, including methotrexate-based (n=35) or bendamustine-based (n=16) regimens, were also used, among which no significantly different response rates were observed. The use of anti-CD20 monoclonal antibody also did not impact on response rate suggesting the necessity of novel treatments such as CD19 or CD79b targeting therapies in this setting. Although OS difference in the current study was not observed between salvage therapy followed by ASCT (n=10) and chemo-only arm (n=51), that may be contributed from the small number of the subset and insufficient response before ASCT (only 5 of the 10 patients achieved CR and proceeded to ASCT). Indeed, in these high-risk patients, the benefit of ASCT after salvage treatment was shown in larger-scaled trials [
The current study has several limitations. First, a relatively large portion of the patient was lost to follow-up. Of the 1,581 patients, 403 (25.5%) were lost to follow-up during or immediately after R-CHOP treatment. Although the reasons are unknown, some of these losses could have been due to the rapidly progressive disease. Second, immunohistochemical features including double-expressor status and cytogenetic features including double-hit status as well as molecular profiles have not been collected. Thus, their roles in the development of refractory disease could not be assessed. Third, the responses were examined by individual investigators. However, as we assessed OS, we believe the conclusive data have validity.
In conclusion, this study confirms the devastating prognosis of patients with refractory DLBCL defined by the SCHOLAR-1 study. They were not likely to respond to subsequent treatment with the ORR of 26% and were inevitably associated with poor survival with the median OS barely exceeding 7 months. Therefore, these patients should promptly be approached to novel therapies.
The protocol was reviewed and approved by the institutional review board of each participating center, and all patients provided written informed consent before treatment initiation; Gachon University Gil Medical Center: GCIRB2015-74, Gyeongsang National University Hospital: GNUH 2015-02-012, Dongsan Medical Center: DSMC 2015-03-015, Korea University Anam Hospital: ED15-024(AN15024-001), Kosin University Gospel Hospital: KUGH 2017-09-008, National Cancer Center: NCC 2015-0091, Dong-A University Medical Center: DMC 15-037, Pusan National University Hospital: H-1701-011-051, Samsung Medical Center: SMC 2014-07-181, Seoul National University Hospital: H-1504-119-667, Asan Medical Center: S2015-0302-0001, Soonchunhyang University Hospital: SCHUH 2015-05-007, Soonchunhyang University Bucheon Hospital: SCHBC 2015-07-008, Wonju Severance Christian Hospital: CR315002-002, Ajou University Hospital: AJIRB-MED-OBS-14-254, Yeungnam University Medical Center: YUMC 2015-03-016, Korea Cancer Center Hospital: K-1409-001-001, Ulsan University Hospital: UUH 2015-11-007, Inje University Sanggye Paik Hospital: SGPAIK 2015-06-002, Inje University Ilsan Paik Hospital: ISPAIK 2015-07-002, Inje University Busan Paik Hospital: BS 2015-0110, Jeonbuk National University Hospital: CUH 2015-02-034, Chonnam National University Hwasun Hospital: TMP-2015-023, Chung-Ang University Hospital: C2015048(1506), Chungnam National University Hospital: CNUH 2015-10-060, Chungbuk National University Hospital: CBNUH 2015-03-006, Hallym University Sacred Heart Hospital: HUH 2015-I043.
Conceived and designed the analysis: Yi JH, Jeong SH, Kim SJ, Yoon DH, Koh Y, Kim JS.
Collected the data: Lee WS, Yang DH, Do YR, Kim MK, Yoo KH, Choi YS, Yun WJ, Park Y, Jo JC, Park BB, Kang HJ, Yun WJ, Kwon JH, Hong DS, Lee HS, Lee GW.
Contributed data or analysis tools: Eom HS, Kwak JY, Shin HJ, Yi SY, Oh SY, Kim HJ, Sohn BS, Won JH.
Performed the analysis: Yi JH, Suh C.
Wrote the paper: Yi JH, Kim WS.
Conflict of interest relevant to this article was not reported.
Patient inclusion and flow diagram. ASCT, autologous stem cell transplantation; CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
Overall survival from commencement of salvage therapy: overall population (A); by refractory category (B); by tumor response (C); by cell-of-origin subtype (D). ASCT, autologous stem cell transplantation; CR, complete response; GCB, germinal center B-cell; PD, progressive disease; PR, partial response; SD, stable disease.
Baseline characteristics of the refractory cohort (n=260)
Characteristic | PROCESS cohort | GIRAFFE-B cohort | Total |
---|---|---|---|
|
59 (26–85) | 64 (22–85) | 63 (22–85) |
≤ 60 | 30 (52.6) | 87 (42.9) | 117 (45.0) |
> 60 | 27 (47.4) | 116 (57.1) | 143 (55.0) |
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Male | 42 (73.7) | 124 (61.1) | 166 (63.8) |
Female | 15 (26.3) | 79 (38.9) | 94 (56.2) |
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0–1 | 45 (78.9) | 50 (24.6) | 95 (36.5) |
2–4 | 12 (21.1) | 153 (75.4) | 165 (63.5) |
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I–II | 16 (28.1) | 51 (25.1) | 67 (25.8) |
III–IV | 41 (71.9) | 152 (74.9) | 193 (74.2) |
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0–1 | 25 (43.9) | 96 (47.3) | 121 (46.5) |
2 or more | 32 (56.1) | 107 (52.7) | 139 (53.5) |
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Within normal limit | 11 (19.3) | 55 (27.1) | 66 (25.4) |
Elevated | 46 (80.7) | 148 (72.9) | 194 (74.6) |
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Low | 7 (12.3) | 34 (16.7) | 41 (15.8) |
Low-intermediate | 15 (26.3) | 51 (25.1) | 66 (25.4) |
High-intermediate | 29 (50.9) | 56 (27.6) | 85 (32.7) |
High | 6 (10.5) | 62 (30.5) | 68 (26.2) |
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Absent | 41 (71.9) | 166 (81.8) | 207 (79.6) |
Present | 16 (28.1) | 37 (18.2) | 53 (20.4) |
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Absent | 41 (71.9) | 156 (76.8) | 197 (75.8) |
Present | 16 (28.1) | 47 (23.2) | 63 (24.2) |
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GCB subtype | 13 (38.2) | 56 (32.9) | 69 (33.8) |
Non-GCB subtype | 21 (51.8) | 114 (67.1) | 135 (66.2) |
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Primary refractory | 31 (54.4) | 71 (35.0) | 102 (39.2) |
Refractory to salvage treatment | 23 (40.4) | 110 (54.2) | 133 (51.2) |
Relapse ≤ 12 mo post-ASCT | 3 (5.3) | 22 (10.8) | 25 (9.6) |
Values are presented as median (range) or number (%). ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B-cell; IPI, international prognostic index; LDH, lactate dehydrogenase.
Response to chemotherapy after refractory disease
PROCESS | GRAFFE-B | Pooled | |
---|---|---|---|
|
50 | 181 | 231 |
|
7 (14.0) | 18 (9.9) | 25 (9.6) |
|
5 (10.0) | 31 (17.1) | 36 (13.8) |
Overall response | 12 (24.0) | 49 (27.1) | 61 (26.4) |
|
10 (20.0) | 24 (13.3) | 34 (14.7) |
|
28 (56.0) | 108 (59.7) | 136 (58.9) |
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Primary refractory (n=102) | - | - | 28 (27.5) |
Refractory to salvage treatment (n=133) | - | - | 26 (19.5) |
Relapse ≤ 12 mo post-ASCT (n=25) | - | - | 7 (28.0) |
Values are presented as number (%). ASCT, autologous stem cell transplantation; CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Response according to salvage regimens
Total/Evaluable | CR | PR | |
---|---|---|---|
Platinum-based regimens | 202/179 | 17 (9.5) | 30 (16.8) |
Methotrexate-based regimens | 35/32 | 5 (15.6) | 5 (15.6) |
Bendamustine-rituximab | 16/14 | 1 (7.1) | 1 (7.1) |
Miscellaneous | 7/6 | 2 (33.3) | 0 |
With anti-CD20 monoclonal antibodies | 47/41 | 6 (14.6) | 5 (12.2) |
Without anti-CD20 monoclonal antibodies | 213/190 | 19 (10.0) | 31 (16.3) |
Values are presented as number (%). Platinum-based regimens include ICE (ifosfamide, carboplatin, etoposide, and dexamethasone), DHAP (cytarabine, cisplatin, dexamethasone), GDP (gemcitabine, cisplatin, and dexamethasone) and ESHAP/Ox (etoposide, methyl-prednisone, cytarabine, cisplatin or oxaliplatin); Methotrexate-based regimens include IMVP16 (ifosfamide, methotrexate, etoposide, and prednisone), IVAM (ifosfamide, etoposide, cytarabine, and methotrexate), and high-dose methotrexate; bendamustine-based regimens include benda-mustine with or without rituximab; miscellaneous regimens included brentuximab-vedotin (n=1), CODOX-M/IVAC (n=1), HyperCVAD (n=2), ibrutinib (n=1), and tafasitamab (n=2). CR, complete response; PR, partial response.
Outcomes of patients with refractory DLBCL who met the criteria of the SCHOLAR-1 study
No. (%) | Overall response rate (%) | Overall survival (95% CI, mo) | Overall survival rate (%) | |
---|---|---|---|---|
|
636 (100) | 26 | 6.3 (5.9–7.0) | 1-Year: 28, 2-Year: 20 |
Primary refractory | 178 (28.0) | 20 | 7.1 | |
Refractory to salvage treatment | 318 (50.0) | 26 | 6.1 | |
Relapse ≤ 12 mo post-ASCT | 140 (22.0) | 34 | 6.2 | |
|
350 (100) | 30 | 5.9 (5.5–7.1) | 2-Year: 16 |
Primary refractory | 181 (51.7) | 39 | 5.9 (5.5–7.1) | |
Refractory to salvage treatment | 148 (42.3) | 18 | 5.9 (3.2-not reached) | |
Relapse ≤ 12 mo post-ASCT | 21 (6.0) | 24 | ||
|
260 (100) | 26.4 | 7.5 (6.4–8.6) | 2-Year: 22.1 |
Primary refractory | 102 (39.2) | 27.5 | 7.5 (5.2–9.8) | |
Refractory to salvage treatment | 133 (51.2) | 19.5 | 7.6 (6.5–8.7) | |
Relapse ≤ 12 mo post-ASCT | 25 (9.6) | 28.0 | 7.0 (5.6–8.4) |
ASCT, autologous stem cell transplantation; CI, confidence interval; DLBCL, diffuse large B-cell lymphoma.