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Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin lymphoma (NHL) and accounts for 30-40% of all NHLs [1]. Since 1970, the standard therapeutic option in the treatment of DLBCL has been a chemotherapy regimen with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) which is associated with a 50% complete remission (CR) [2]. The current standard is immunochemotherapy with rituximab plus cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) which is associated with a 60% CR [3]. Even after achieving a CR, 30-40% of patients relapse [4]. Among patients who relapse or who are refractory to first-line treatment, 40% are eligible for high-dose chemo with autologous stem cell transplantation (ASCT) [5]. After ASCT, 50% of patients relapse [6] with a median survival of 3 months [7]. The treatment of choice in patients who are not eligible for high-dose chemo with ASCT (60%) [5] is GemOx (gemcitabine-oxaliplatin), bendamustine, gemcitabine, dexamethasone, and cisplatin (GDP), lenalidomide (activated B-cell - non--germinal center B-cell (GCB) and ibrutinib (non-GCB) [8-12].

aaIPI  --age-adjusted international prognostic index
OS     --overall survival
PFS    --progression-free survival
DLBCL  --diffuse large B-cell lymphoma
HR     --hazard ratio
CI     --confidence interval
CR     --complete response
PR     --partial response
SD     --stable disease
PD     --progressive disease
NHL    --Non-Hodgkin lymphoma
CHOP   --cyclophosphamide, adriamycin, vincristine, prednisone
R-CHOP --rituximab plus cyclophosphamide, adriamycin,
         vincristine, prednisone
ASCT   --autologous stem cell transplantation
CORAL  --Cardiovascular Outcome in Renal Atherosclerotic
CAR    --chimeric antigen receptor
GCB    --germinal center B-cell
R-ICE  --rituximab, ifosfamide, carboplatin, etopside

This research aimed to estimate the overall survival (OS) and progression-free survival (PFS) in patients with relapsed DLBCL. We have also examined the impact of age-adjusted International Prognostic Index (aaIPI) and time to the first relapse on the OS and PFS after the beginning of the second line treatment; the impact of time to disease relapse after the first line of treatment (early or late relapse) on OS, and time to disease progression after the second line of treatment.

Material and Methods

The research included patients with relapsed DLBCL who were treated at the Oncology Institute of Vojvodina, Serbia from January 2013 to December 2015. The data were obtained from the medical histories of patients and the following characteristics were analyzed: sex, age at the time of diagnosis, germinal center B-cell (GCB)/non-GCB subtype [14], initial treatment, time of disease relapse (early relapse [less than or equal to] 12 months from the end of the first-line treatment, late relapse > 12 months from the end of the first line of treatment). The same parameters were evaluated at the time of the first and the second relapse. The OS was calculated from the time of initiation of the second-line treatment until death or the last follow-up visit. The PFS was calculated from the start of the second-line treatment until disease progression.

The primary endpoint of our study was to estimate OS and PFS from the initiation of treatment post-relapse using Kaplan--Meier curves. The statistical data analysis was performed by using MedCalc statistical software (version 18.10).


The research included 36 patients, with average age of 56 years, ranging from 22 to 78 years. Sixteen out of 36 (44%) were male, 20 (55%) were female. According to Ann Arbor classification at the time of diagnosis,

4 patients had stage I (11%), 6 had stage II (16%), 13 had stage III (36%) and 13 stage IV (36%). Thirteen patients had GCB subtype, while 11 had non-GCB. According to aaIPI at the time of initial diagnosis: 13 patients were low risk (0-1), while 19 were high risk patients (2-3). All patients were treated with R-CHOP regimen in the first line of treatment, 15 (41%) with six cycles, whereas 21 (58%) received eight cycles. After the first line of treatment, 23/36 (33%) had a CR, 18 (50%) had a partial response (PR), 1 (2.7%) patient had a stable disease (SD), while 5 (13.8%) had a progressive disease (PD).

At the time of the first relapse, Ann Arbor stage was available for 33 patients, 6 (18%) had stage I, 7 (21%) had stage II, 7 (21%) had stage III, while 13 (39%) had stage IV. AaIPI score at the time of relapse was available for 26 patients; 13 were low risk (0-1) while the remaining 13 (50%) were high risk patients (2-3). Late relapse occurred in 21/36 (58%), while 14 (42%) patients had an early relapse. In the second-line treatment, 12/32 (37.5%) patients were treated with platinum-based regimen, 12 (37.%) with ifosfamide-based regimen, while 8 (25%) patients were treated with one of various CHOP-like regimens. Data on response to treatment were collected for 30 patients: CR and PR were achieved in 9 (30%) and 10 (33%) patients, respectively; SD was not registered in any patient, while PD occurred in 11 (36.6%). Among patients who achieved CR or PR, 3 eventually received ASCT.

Data on Ann Arbor stage were available for 18 patients after the second relapse staged from I to I V: 2 (11.1%), 3 (16.6%), 2 (11.1%) and 11 (61.1%), respectively. AaIPI score was collected for 18 patients with second relapse: 10 (55.5%) were low risk (0-1), while 8 (44.5%) were high risk (2-3). In the third-line treatment 4 (22%) out of 18 patients were treated with ifosfamide-based regimen, 8 (44.4%) received one of CHOP-like regimens, 3 (16.6%) platinum-based regimen, while 2 (11.1%) received cyclophosphamide, vincristine sulfate, adriamycin, dexamethasone (hyper CVAD). Response to treatment was collected for 16 patients: CR, PR, SD and PD occurred in 6 (37.5%), 1 (6.25%), 1 (6.25%), 8 (50%) patients, respectively.

In overall patients, median OS (5-year follow-up) was 18 months (7-44) (Graph 1). Median OS in the group of patients with aaIPI 0 - 1 (low risk) was 44 months in comparison to aaIPI 2-3 (high risk patients) with median OS 6 months hazard ratio (HR) 0,4 (confidence index (CI) 0,16-0,99), p = 0,03 (Graph 2). Median OS in early-relapsed patients was 7 months, versus 25 months in late-relapsed patients, HR 0,55 (CI 0,25-1,19), p = 0,12.

In overall patients, median PFS was 4 months (0-9) (Graph 3). In early-relapse subgroup of patients, median PFS was 0 months, versus 10 months in late-relapse subgroup, HR 0,34 (CI 0,12-1,00), p = 0,0017 (Graph 4). Median PFS of patients who were treated with third-line treatment was 0 months (0-4) (Graph 5).


Patients with refractory or relapsed DLBCL after first-line treatment are candidates for salvage treatment [15]. The overall response rate to various salvage protocols is 42-64% [16-20]. Patients who achieve a response to salvage therapy receive high dose chemo with ASCT [21]. All our patients were treated with R-CHOP as the first-line regimen. At first relapse, different salvage protocols were used. The median OS from the beginning of salvage treatment was 18 months, while survival at 5 years was 27%, regardless of the salvage protocol used. The (CORAL) study reported 62% of patients treated with R-CHOP protocol. At first relapse, patients were treated with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) or R-DHAP (rituximab, dexamethasone, cisplatin, cytarabine) and after achieving a response they proceeded to ASCT. The OS at 3 years was 49% [22]. Paul et al. performed a study where all patients were treated with CHOP regimen at first-line and ICE salvage protocol; the OS at 4 years was 34% [23]. Rachel et al. reported 5-year OS (38%) in patients treated with various salvage protocols and eventually ASCT [24]. We observed a significant difference in OS among our patients with low-risk aaIPI 0-1 (45%, median OS 44 months) in comparison to patients with high-risk aaIPI 2-3 (10% - median OS 6 months). Three-year OS in low-risk patients in CORAL trial was 62%, versus 32% in high-risk patients (p < .001) [22]. Another trial also reported a significant difference in 4-year OS in patients with low, intermediate and high risk, (74% v 49% v 18%, respectively) [23]. Rachel at al. reported that median OS in low-risk patients was 27 versus 5 months in high-risk patients (p < .001) [24]. According to our data, after a 3-year follow up, PFS was 16%, calculated from the start of the second-line treatment. There was a significant difference in PFS after initiation of the second-line treatment. Three-year PFS in patients with late relapse was 22%, median PFS 10 months, compared to early-relapsed patients with a second relapse in the first months of the second-line treatment (median 0 months). The

CORAL trial reported 3-year PFS, post-second-line treatment initiation, to be 37% in overall patient population, and it did not differ in the subpopulation with late relapse. In early-relapse patients, PFS was 23% [22].

Our results are comparable to the data reported by above mentioned authors and confirm the fact that patients with relapsed/refractory DLBCL have a very poor prognosis [22-24]. SCHOLAR-1 trial reported that OS of patients who relapsed in less than 12 months post ASCT, with all treatments available, was 6,3 months [25]. Chimeric antigen receptor (CAR)-T cell therapy proved effective in patients with relapsed/refractory DLBCL [25]. ZUMA trial treated patients with refractory DLBCL with axicabtagene ciloleucel (anti-CD19 CAR T-cell) [26]. The treatment response rate was 82% and CR was achieved in 54% patients. After 15,4 month follow up, 42% of patients still responded to the treatment, while 40% still had CR [26]. In JULIET trial, patients with relapsed/refractory DLBCL were treated with tisagenlecleucel [27]. The overall response rate was 54%, 40% had CR, while 13% had PR. The median duration of response was not achieved after 19 months of follow up [27]. Polatuzumab vedotin (anti-CD79 antibody-drug conjugate) in combination with bendamustine and rituximab vs. bendamustine alone in relapsed/refractory DLBCL patients who were not eligible for ASCT accomplished significantly longer OS and PFS [28]. A CR was achieved in 40% of patients who were treated with polatuzumab vedotin in combination with bendamustine and rituximab in comparison to 13% of patients who were treated with bendamustine and rituximab [28].


The age-adjusted international prognostic index score calculation significantly influences the overall survival in patients with relapsed/refractory diffuse large B-cell lymphoma. Time to the first relapse significantly impacts the time to disease progression after the second-line treatment initiation in these patients, so this subpopulation warrants novel therapeutic options in the future.


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Rad je primljen 19. XII 2019.

Recenziran 1. I 2019.

Prihvacen za stampu 15. I 2019.


Maja POPOVIC (1, 2), Gorana MATOVINA BRKO (1), Dragana PETROVIC (1), Bojana VRANJKOVIC (1), Jelena RADIC (1,2) and Lazar POPOVIC (1,2)

Oncology Institute of Vojvodina, Sremska Kamenica (1)

University of Novi Sad, Faculty of Medicine Novi Sad (2)

Corresponding Author: Dr Maja Popovic, Institut za onkologiju Vojvodine, 21204 Sremska Kamenica, Put dr Goldmana 4, E-mail:
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Title Annotation:Professional article/Strucni clanak
Author:Popovic, Maja; Matovina Brko, Gorana; Petrovic, Dragana; Vranjkovic, Bojana; Radic, Jelena; Popovic,
Publication:Medicinski Pregled
Article Type:Report
Date:Jan 1, 2019

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