Outcome of Patients with Diffuse Large B-cell Lymphoma Relapsing after Autologous Transplant before Availability of CAR-T Cell Treatment

Stefanie von Matt1, Ulrike Bacher2, Yara Banz3, Behrouz Mansouri Taleghani2, Urban Novak1 and Thomas Pabst1

1 Department of Medical Oncology; Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
2 Department of Hematology and Central Hematology Laboratory; Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
3 Institute of Pathology, University of Bern, Bern, Switzerland.

Correspondence to: Prof. Thomas Pabst, MD; Department of Medical Oncology; University Hospital; 3010 Bern; Switzerland. Tel.: +41 31 632 8430; Fax: +41 31 632 3410; E-mail: thomas.pabst@insel.ch.

Published: May 1, 2023
Received: December 30, 2022
Accepted: April 16, 2023
Mediterr J Hematol Infect Dis 2023, 15(1): e2023025 DOI 10.4084/MJHID.2023.025

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Introduction: Autologous stem cell transplantation (ASCT) following high-dose chemotherapy is applied as salvage therapy in patients with relapsed disease or as first-line consolidation in high-risk DLBCL with chemo-sensitive disease. However, the prognosis of relapsing DLBCL post-ASCT remained poor until the availability of CAR-T cell treatment. To appreciate this development, understanding the outcome of these patients in the pre-CAR-T era is essential.
: We retrospectively analyzed 125 consecutive DLBCL patients who underwent HDCT/ASCT.
: After a median follow-up of 26 months, OS and PFS were 65% and 55%. Fifty-three patients (42%) had a relapse (32 patients, 60%) or refractory disease (21 patients, 40%) after a median of 3 months post-ASCT. 81% of relapses occurred within the first year post-ASCT with an OS of 19% versus 40% at the last follow-up in patients with later relapses (p=0.0022). Patients with r/r disease after ASCT had inferior OS compared to patients in ongoing remission (23% versus 96%; p<0.0001). Patients relapsing post-ASCT without salvage therapy (n=22) had worse OS than patients with 1-4 subsequent treatment lines (n=31) (OS 0% versus 39%; median OS 3 versus 25 months; p<0.0001). Forty-one (77%) of patients relapsing after ASCT died, 35 of which due to progression.
: Additional therapies can extend OS but mostly cannot prevent death in DLBCL relapsing/refractory post-ASCT. This study may serve as a reference to emerging results after CAR-T treatment in this population.


Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) responds effectively to immunochemotherapy, with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) being the first-line standard.[1-6] In up to 60% of patients, this treatment provides definite complete remission.[7,8] Nevertheless, 30-50% of patients will suffer from relapsed or progressive disease, mostly within the first two years. The current treatment of choice for this patient population is salvage chemotherapy followed by high-dose chemotherapy (HDCT) with peripheral autologous hematopoietic stem cell transplantation (ASCT).[9-12] The most widely used HDCT regimens are BEAM (carmustine, etoposide, cytarabine, melphalan),[11,13] or BeEAM with bendamustine replacing BCNU.[14,15]
Although HDCT followed by ASCT is a successful treatment option for many patients with relapsed DLBCL or high-risk presentation, this treatment is associated with relevant toxicity; importantly, up to 50% of these patients will still relapse or are refractory to this treatment.[16-19] Prognosis of these patients is dismal, and treatment options have been limited so far. Some r/r patients may not receive further interventions after HDCT/ASCT due to lack of response to salvage chemotherapy, poor general condition, or the patient’s request, and they undergo palliative treatment. For patients eligible for further therapies, options comprise chemotherapy, immunotherapy, radiotherapy, or combinations of these, in selected cases, allogeneic hematopoietic stem cell transplantation, a second ASCT, or, more recently, CAR (chimeric antigen receptor) T-cell therapy.[11,20] CAR T-cell therapy is a promising new option for patients with DLBCL after two or more therapy lines fail. Recent studies have shown remarkable CR rates of between 40% to 58%.[21-26] On the other hand, CAR T-cell therapy can be associated with relevant specific complications, including cytokine release syndrome (CRS) or CAR T-cell-related encephalopathy syndrome (CRES/ICANS).[21-25,27-29] We performed a retrospective study to describe the outcome of patients with DLBCL after HDCT/ASCT and to determine how high-risk or relapsed DLBCL was managed in clinical practice before the availability of CAR-T cell treatment.

Patients and Methods

Patients. This single-center, non-interventional, retrospective study analyzed the outcome of all consecutive patients with relapsed DLBCL or patients with high-risk presentation who underwent HDCT/ASCT between May 2005 and February 2019 at the University Hospital of Bern, Switzerland. Treatment for DLBCL prior to HDCT/ASCT was applied in various referring centers in Switzerland. Inclusion criteria were the diagnosis of either high-risk DLBCL or relapsed DLBCL (with the subtypes shown in Table 1), age of at least 18 years at first diagnosis, and sufficient information on remission status after HDCT with ASCT. Patients with high-risk presentation who were consolidated with ACST after first-line therapy had to have a chemo-sensitive disease and had to achieve partial or complete remission before consolidation.

Table 1
Table 1. Patient characteristics, lymphoma subtypes, stage and international prognostic index, B-symptoms, CNS infiltration and infiltration of bone marrow at first diagnosis in patients with or without relapsed or refractory disease after ASCT.

Patients were divided into two groups depending on their response to HDCT/ASCT. The first group included patients with r/r disease after ASCT. The second group comprised patients in ongoing remission without relapse of DLBCL. All patients gave written informed consent, and this analysis was approved by the local ethics committee of Bern, Switzerland.
Data source.  Clinical data for this study were collected from the local electronic patient information system at the University Hospital Bern. Furthermore, information was obtained from the local Management and Resource System for Stem Cell Transplantation (MARCELL), providing specific information on the stem cell transplantation procedures at the University Hospital Bern.
Methods and Definitions. At first diagnosis, patients were staged according to the Ann Arbor classification,[30] and the international prognostic index (IPI) was used for risk stratification.[31] Remission status was determined according to the revised response criteria of the international working group for malignant lymphoma before ASCT, 100 days after ASCT, and at annual follow-up.[32] Response was classified as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). CR was defined as complete disappearance of clinical lymphoma evidence and disease-related symptoms. PR was defined as a measurable disease reduction of at least 50% and no occurrence of new lesions. Patients with SD did not fulfill CR/PR or PD criteria. The occurrence of new lesions or the increase of previously reported tumor masses by more than 50% were defined as PD.[32,33]
The primary endpoints were overall survival and progression-free survival. PFS was defined as the time from ASCT until the first evidence of relapse/progression or death from any cause. OS was defined as the time from ASCT until death from any cause.
Statistical analysis
.PFS and OS were calculated using the Kaplan-Meier method. Survival differences between subgroups were identified by the log-rank test. Univariate analysis was calculated for the factors: age at first diagnosis, transformed lymphoma vs. de novo origin, presence of B-symptoms at first diagnosis, bone marrow infiltration at first diagnosis, radiotherapy administered during first or second-line therapy, the interval between first-line therapy until relapse/progression, the performance of CD34+ cell positive selection, remission status at ASCT, the interval from ASCT to relapse/progression, number of therapies prior to HDCT/ASCT, and number of further therapies after post-ASCT relapse. P values of <0.05 were assumed to be statistically significant. All data were conducted with GraphPad Prism, and calculations were done by Excel.


Patient characteristics. This study included 125 consecutive patients with DLBCL who received HDCT/ASCT either as first-line consolidation due to high-risk presentation or as salvage therapy for relapsed DLBCL. Clinical characteristics at first diagnosis are summarized in Table 1. 63% of the patients were male. The median age at first diagnosis was 58 years (range, 23-76 years). DLBCL NOS (not otherwise specified) was the most common lymphoma subtype (48%). B-symptoms at first diagnosis were present in 44 patients (35%), bone marrow infiltration and central nervous system infiltration were observed in 27 (22%) and 13 patients (10%), respectively.
Transformed lymphoma was present in 23 patients, with 16 (70%) being initially diagnosed with follicular lymphoma, five (22%) with CLL, and one patient (4%) each with marginal zone lymphoma or nodular lymphocyte-predominant Hodgkin lymphoma. 73% of the patients had advanced-stage disease with Ann Arbor stages III (29 pts; 24%) or IV (59 pts; 49%). IPI for risk stratification at first diagnosis was a high-intermediate risk in 35 patients (38%) and high risk in 27 patients (29%).
As described above, patients were distributed into two groups depending on the disease control (relapse or progression) after HDCT/ASCT. Both cohorts were comparable regarding age, gender, lymphoma subtypes, stages, and IPI at first diagnosis (Table 1).
Previous therapies before ASCT. Details on the treatment given before HDCT/ASCT are presented in Table 2. Patients had a median of two treatment lines before ASCT (range 1-3). Fifty-one patients (41%) received HDCT/ASCT after only one line of therapy due to high-risk presentation, 68 patients (55%) after two, and 6 patients (5%) after three lines of treatment. For first-line treatment, 93% of patients received the CHOP regimen, and 94% of CHOP chemotherapies were combined with rituximab.

Table 2
Table 2. Overview on therapies used in one to three previous lines before ASCT.

High-dose chemotherapy and autologous stem cell transplantation. HDCT/ASCT was performed after a median interval of 8 months from the initial diagnosis. Conditioning regimens in 93% were either the BeEAM (59%) or BEAM (34%). 7% of patients received either melphalan alone or the combination of carmustine and thiotepa as conditioning treatment. Detailed information on HDCT and ASCT is presented in Table 3.

Table  3
Table 3. Characteristics of autologous stem cell transplantation (ASCT) in patients with or without relapsed/ refractory disease after ASCT.

Salvage therapy at relapse/progression after HDCT/ASCT. Fifty-three patients (42%) developed relapse or progression after a median interval of 3 months from ASCT (range 1 to 145 months). Thirty-one patients - 58% of all patients with relapse/progression, respectively - received further therapies. Twenty-one patients were treated with one therapy line, and ten patients had two to four treatment lines for relapsing disease after ASCT, with a median of one therapy line (range 0 to 4 lines). 22 patients had no further therapy due to poor general condition or by the patient’s wish.
The following further therapies were administered: cytotoxic chemotherapy (25 patients), radiotherapy (five patients), second HDCT/ASCT (three patients), and allogeneic hematopoietic stem cell transplantation (three patients). Three patients received immunotherapy targeting PD-1 (nivolumab: two patients; pidilizumab: one patient), one patient had blinatumomab, five patients were given ibrutinib, and one patient received the antibody-drug conjugate brentuximab vedotin, as listed in Table 4.

Table 4
Table 4. Therapies patients with relapsed or refractory disease received after ASCT.

Outcome. Details on the outcome of the patients after HDCT/ASCT are depicted in Table 5. The median follow-up of the entire patient cohort was 26 months. Forty-four patients (35%) died after a median of six months (range 1-64), 35 (80% of the patients) due to disease progression, six due to therapy-related reasons (in five cases due to HDCT associated toxicities, and in one case related to subsequent allogeneic transplantation) and six from other causes.

Table 5
Table 5. Outcome of patients with or without relapsed or refractory disease after ASCT. Median follow up, overall survival, progression-free survival, state of remission, relapse and death.

The median OS of the entire population was 26 months, and the OS rate at the last follow-up was 65% (Figure 1C). As expected, patients with r/r disease after ASCT had worse overall survival compared to patients in ongoing remission (OS at last follow-up: 23% vs. 96%; median OS: 9 vs. 38 months; p <0.0001; Figure 1D). Progression-free survival (PFS) of the entire cohort at the last follow-up was 55%, with a median duration of response of 19 months (Figure 1A). Relapsed or refractory disease occurred in 42% of patients after a median interval of 3 months.
Four factors were identified to be associated with survival rates: interval of relapse from first-line therapy and interval from HDCT/ASCT, number of therapies prior to HDCT/ASCT, and the number of treatment lines after post-ASCT relapse. 38% of patients showed an early relapse after first-line therapy, defined as relapsed disease or progression within the first year. These patients had inferior OS and PFS compared to patients who relapsed after 12 months or later (OS rate at 26 months: 48% vs. 75%, p = 0.0008; PFS rate: 33% vs. 69%, p < 0.0001; Figure 3A/B).
When only patients with r/r disease (n=53) following HDCT/ASCT were considered, early relapse or progression within the first 12 months after ASCT occurred in 81% of these patients. 19% of the patients had a late-onset relapse (an occurrence of relapse ≥ 12 months after ASCT). Patients with early relapse or progression had lower OS than patients with late onset of relapse post-ASCT (OS rate at 26 months: 19% vs. 40%, p= 0.0009, Figure 3D).
Comparing the patients’ outcome regarding the number of therapies prior to HDCT/ ASCT, a significant benefit was observed in those patients who received HDCT/ASCT after the first-line therapy because of high-risk presentation (n= 51), compared to those patients who had two to three lines of treatment prior to HDCT/ASCT (OS rate at 26 months: 78% vs. 55%, p= 0.0161; PFS rate: 75% vs. 42%, p= 0.0054; Figure 4 A/B).
Considering all patients with r/r disease following HDCT/ASCT, the OS rate was only 23% after a median follow-up of 26 months after ASCT. Patients who received no other therapy despite relapse/progression after ASCT due to poor general condition or according to the patient’s wish had an even worse outcome compared to patients with additional treatment line(s) in this situation (OS rate at 26 months 0% vs. 39%, p >0.0001, Figure 2A). 42% of patients received no further therapy, 40% were treated with one, and 19% with two or more therapy lines, corresponding to OS rates of 0% vs. 24% vs. 70% (p> 0.0001; Figure 2B). Thus, in relapsed patients, the OS was longer with an increasing number of therapy lines.

Figure 1 Figure 1. Progression-free survival (PFS) and overall survival (OS) from ACST represented as the whole cohort of patients (A and B) and compared according to their response to ASCT (C and D).

Figure 2 Figure 2. Progression-free survival (PFS) and overall survival (OS) from ASCT in patients with relapsed or refractory disease after ASCT depending on receiving further therapies or not (A and B) and on number on subsequent therapy lines (C and D).

Figure 3 Figure 3. PFS and OS from ASCT depending on the time of relapse after first-line therapy (A and B) or after ASCT (C and D).

Figure 4 Figure 4. PFS and OS from ASCT depending on number of therapy lines prior to HDCT/ACST (A and B).

No differences were detected in OS and PFS rates of specific subsets when data were adjusted for the following variables: de novo versus transformed lymphoma (OS p=0.7369; PFS p=0.7909), age higher/lower than 60 years (OS p= 0.3617; PFS p= 0.2655), B-symptoms present at first diagnosis yes/no (OS p=0.9446; PFS p=0.7619), bone marrow infiltration present at first diagnosis yes/no (OS p=0.6139; PFS p=0.3870), radiotherapy administered before ASCT yes/no (OS p=0.4674; PFS p=0.8150), and CR at ASCT yes/no (OS p=0.4271; PFS p=0.1398) (Supplementary material, Figure S1).


Considering the introduction of CAR-T cell therapies for aggressive lymphatic malignancies in Europe and elsewhere,[24,25] we aimed to further characterize the outcomes of patients with DLBCL with a specific focus on those with failure after HDCT/ASCT. We retrospectively investigated a cohort of 125 patients with DLBCL treated with HDCT/ASCT in a single academic/ tertiary center and studied, in particular, the subset of patients who relapsed or developed progression following HDCT/ASCT and who could have benefited from CAR-T therapy, had it then been available.
Confirming reports by others, the present study demonstrates that HDCT, followed by ASCT, provides excellent long-term outcomes in patients with relapsed or refractory DLBCL, achieving stable remission after this salvage therapy option.[9,34,35] In our analysis comprising 125 recipients of HDCT/ASCT due to relapsed DLBCL or high-risk presentation, the ORR was 61% for the total cohort. That 55% of patients in ongoing remission following HDCT/ASCT showed encouraging OS and PFS of 96% with a median duration of 38 months.
In contrast, the prognosis for patients with r/r disease after HDCT/ASCT is poor, especially in those with characteristics such as high IPI or early relapse within 12 months following ASCT.[11,34] In our study, 42% of patients developed relapses or showed progression after HDCT/ASCT. Although 58% of these patients with failure of HDCT/ASCT received other therapeutic approaches, 77% rapidly died after a median interval of 6 months, mostly due to lymphoma progression. Likewise, in the CORAL study, 29% of patients with r/r DLBCL after ASCT had poor survival, with a median OS of 10 months and a 1-year OS of 39.1%.[35]
We evaluated the impact of various parameters on the outcomes of our HDCT/ASCT cohort. Significant impact on survival could only be verified for the duration of the response to first-line therapy, the duration of response after HDCT/ASCT, the number of therapies prior to HDCT/ASCT, and the number of subsequent therapies after post-ASCT relapse. We documented a median interval to progression following ASCT of only 3 months, and 81% of relapses occurred within 12 months after ASCT, demonstrating that DLBCL relapses are associated with rapid kinetics, early manifesting after HDCT/ASCT. Furthermore, the OS rate was only 19% in patients with early relapses (<12 months) post-ASCT, as compared to late relapses (≥12 months after ASCT) with an OS rate of 40%. These results correspond with previous studies demonstrating early relapses following ASCT in 65-80% of patients, associated with a significantly worse OS compared to later time points of relapse.[12,36] Other parameters such as the histopathological origin (transformed vs. de novo DLBCL) [37-41] and CD34+ selection[42-45] had no significant impact on the prognosis of the recipients of HDCT/ASCT in our cohort.
Treatment options for patients with r/r DLBCL following ASCT were so far limited. Allogeneic stem cell transplantation may provide a certain graft versus lymphoma effect.[46-48] However, only a few DLBCL patients are, in fact, candidates for this approach due to its high transplant-related mortality and high relapse rates. Only three patients in our cohort received an allogeneic SCT, which is representative of the limited use of this option for r/r DLBCL patients.
CAR-T cell therapies, recently introduced, offer patients with r/r DLBCL a promising new option with CR rates of up to 58%.[24,49,50] In several studies, ORR of 52-85% with 40-58% CR rates were achieved by CAR-T cell therapy in patients with r/r DLBCL.[21,24-26,51,52] However, long-term outcomes will still be awaited in the next decades.
In addition, novel immunotherapies such as polatuzumab vedotin,[53] tafasitamab,[54] glofitamab, or mosunetuzumab are additional promising new options for DLBCL patients ineligible for HDCT/ASCT or for those whom CAR-T therapy is no option due to its toxicity, or due to its logistic or financial obstacles.
An obvious limitation of our study is its retrospective single-center design covering a large timespan, including various DLBCL subtypes, heterogeneity in conditioning regimen, and inevitable lack of some data in a few patients. Nevertheless, our study demonstrates the adverse prognosis of DLBCL patients after HDCT/ASCT failure and the limited efficacy of subsequent therapeutic approaches, including a second HDCT/ASCT, allogeneic SCT, radiation, cytotoxic treatment, and traditional monoclonal antibody therapies. Our study emphasizes the urgent need to make CAR-T cell therapies available to all patients with r/r DLBCL following HDCT/ASCT failure.[21]


  1. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105-116. doi:10.1016/S1470-2045(08)70002-0 https://doi.org/10.1016/S1470-2045(08)70002-0 PMid:18226581  
  2. Pfreundschuh M, Trümper L, Österborg A, et al. 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. 2006;7(5):379-391. doi:10.1016/S1470-2045(06)70664-7 https://doi.org/10.1016/S1470-2045(06)70664-7 PMid:16648042
  3. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(19):3121-3127. doi:10.1200/JCO.2005.05.1003 https://doi.org/10.1200/JCO.2005.05.1003 PMid:16754935
  4. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23(22):5027-5033. doi:10.1200/JCO.2005.09.137 https://doi.org/10.1200/JCO.2005.09.137 PMid:15955905  
  5. Tilly H, Gomes da Silva M, Vitolo U, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Supplement 5):vii78-vii82. doi:10.1093/annonc/mdv304 https://doi.org/10.1093/annonc/mdv304 PMid:26314773
  6. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the groupe d'etude des lymphomes de l'adulte. J Clin Oncol. 2005;23(18):4117-4126. doi:10.1200/JCO.2005.09.131 https://doi.org/10.1200/JCO.2005.09.131 PMid:15867204
  7. Coiffier B, Lepage E, Brière J, et al. CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma. N Engl J Med. 2002;346(4):235-242. doi:10.1056/NEJMoa011795 https://doi.org/10.1056/NEJMoa011795 PMid:11807147
  8. Coiffier B, Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure-what to do? Hematology. 2016;2016(1):366-378. doi:10.1182/asheducation-2016.1.366 https://doi.org/10.1182/asheducation-2016.1.366 PMid:27913503 PMCid:PMC6142522
  9. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous Bone Marrow Transplantation as Compared with Salvage Chemotherapy in Relapses of Chemotherapy-Sensitive Non-Hodgkin's Lymphoma. N Engl J Med. 2002;333(23):1540-1545. doi:10.1056/nejm199512073332305 https://doi.org/10.1056/NEJM199512073332305 PMid:7477169
  10. Camus V, Tilly H. Managing early failures with R-CHOP in patients with diffuse large B-cell lymphoma. Expert Rev Hematol. 2017;10(12):1047-1055. doi:10.1080/17474086.2016.1254547 https://doi.org/10.1080/17474086.2016.1254547 PMid:27791447
  11. Gisselbrecht C, Van Den Neste E. How I manage patients with relapsed/refractory diffuse large B cell lymphoma. Br J Haematol. 2018;182(5):633-643. doi:10.1111/bjh.15412 https://doi.org/10.1111/bjh.15412 PMid:29808921 PMCid:PMC6175435
  12. Nagle SJ, Woo K, Schuster SJ, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88(10):890-894. doi:10.1002/ajh.23524 https://doi.org/10.1002/ajh.23524 PMid:23813874
  13. Friedberg JW. Relapsed / Refractory Diffuse Large B-Cell Lymphoma. Am Soc Hematol. Published online 2011:498-505. https://doi.org/10.1182/asheducation-2011.1.498 PMid:22160081
  14. Gilli S, Novak U, Taleghani BM, et al. BeEAM conditioning with bendamustine-replacing BCNU before autologous transplantation is safe and effective in lymphoma patients. Ann Hematol. 2017;96(3):421-429. doi:10.1007/s00277-016-2900-y https://doi.org/10.1007/s00277-016-2900-y PMid:28011985
  15. Prediletto I, Farag SA, Bacher U, et al. High incidence of reversible renal toxicity of dose-intensified bendamustine-based high-dose chemotherapy in lymphoma and myeloma patients. Bone Marrow Transplant. 2019;54(12):1923-1925. doi:10.1038/s41409-019-0508-2 https://doi.org/10.1038/s41409-019-0508-2 PMid:30890768
  16. Betticher C, Bacher U, Legros M, et al. Prophylactic corticosteroid use prevents engraftment syndrome in patients after autologous stem cell transplantation. Hematol Oncol. 2021;39(1):97-104. doi:10.1002/hon.2813 https://doi.org/10.1002/hon.2813 PMid:32979278
  17. Vose JM, Bierman PJ, Anderson JR, et al. Progressive disease after high-dose therapy and autologous transplantation for lymphoid malignancy: clinical course and patient follow-up. Blood. 1992;80(8):2142-2148. https://doi.org/10.1182/blood.V80.8.2142.2142 PMid:1356515  
  18. Robinson SP, Boumendil A, Finel H, et al. Autologous stem cell transplantation for relapsed/refractory diffuse large B-cell lymphoma: Efficacy in the rituximab era and comparison to first allogeneic transplants. A report from the EBMT Lymphoma Working Party. Bone Marrow Transplant. 2016;51(3):365-371. doi:10.1038/bmt.2015.286 https://doi.org/10.1038/bmt.2015.286 PMid:26618550  
  19. Eicher F, Mansouri Taleghani B, Schild C, Bacher U, Pabst T. Reduced survival after autologous stem cell transplantation in myeloma and lymphoma patients with low vitamin D serum levels. Hematol Oncol. 2020;38(4):523-530. doi:10.1002/hon.2774 https://doi.org/10.1002/hon.2774 PMid:32594534
  20. Skrabek P, Assouline S, Christofides A, et al. Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma. Curr Oncol. 2019;26(4):253-265. doi:10.3747/co.26.5421 https://doi.org/10.3747/co.26.5421 PMid:31548805 PMCid:PMC6726277
  21. Sermer D, Brentjens R. CAR T‐cell therapy: Full speed ahead. Hematol Oncol. 2019;37(S1):95-100. doi:10.1002/hon.2591 https://doi.org/10.1002/hon.2591 PMid:31187533
  22. Chavez JC, Locke FL. A Possible Cure for Refractory DLBCL: CARs Are Headed in the Right Direction. Mol Ther. 2017;25(10):2241-2243. doi:10.1016/j.ymthe.2017.09.005 https://doi.org/10.1016/j.ymthe.2017.09.005 PMid:28941574 PMCid:PMC5628929  
  23. Lekakis LJ, Moskowitz CH. The Role of Autologous Stem Cell Transplantation in the Treatment of Diffuse Large B-cell Lymphoma in the Era of CAR-T Cell Therapy. HemaSphere. 2019;3(6). doi:10.1097/HS9.0000000000000295 https://doi.org/10.1097/HS9.0000000000000295 PMid:31976472 PMCid:PMC6924546
  24. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018;380(1):45-56. doi:10.1056/NEJMoa1804980 https://doi.org/10.1056/NEJMoa1804980 PMid:30501490
  25. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447 https://doi.org/10.1056/NEJMoa1707447 PMid:29226797 PMCid:PMC5882485
  26. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. The Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0 https://doi.org/10.1016/S0140-6736(20)31366-0 PMid:32888407
  27. Titov A, Petukhov A, Staliarova A, et al. The biological basis and clinical symptoms of CAR-T therapy-associated toxicites. Cell Death Dis. 2018;9(9). doi:10.1038/s41419-018-0918-x https://doi.org/10.1038/s41419-018-0918-x PMid:30181581 PMCid:PMC6123453
  28. Bishop MR, Maziarz RT, Waller EK, et al. Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion. Blood Adv. 2019;3(14):2230-2236. doi:10.1182/bloodadvances.2019000151 https://doi.org/10.1182/bloodadvances.2019000151 PMid:31332046 PMCid:PMC6650727
  29. Pabst T, Joncourt R, Shumilov E, et al. Analysis of IL-6 serum levels and CAR T cell-specific digital PCR in the context of cytokine release syndrome. Exp Hematol. 2020;88:7-14.e3. doi:10.1016/j.exphem.2020.07.003 https://doi.org/10.1016/j.exphem.2020.07.003 PMid:32673688
  30. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res. 1971;31(11):1860.  
  31. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard international prognostic index remains a valid predictor of outcome for patients with aggressive CD20 + B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(14):2373-2380. doi:10.1200/JCO.2009.26.2493 https://doi.org/10.1200/JCO.2009.26.2493 PMid:20385988
  32. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586. doi:10.1200/JCO.2006.09.2403 https://doi.org/10.1200/JCO.2006.09.2403 PMid:17242396
  33. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol Off J Am Soc Clin Oncol. 1999;17(4):1244. doi:10.1200/JCO.1999.17.4.1244 https://doi.org/10.1200/JCO.1999.17.4.1244 PMid:10561185  
  34. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: Results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. doi:10.1182/blood-2017-03-769620 https://doi.org/10.1182/blood-2017-03-769620 PMid:28774879 PMCid:PMC5649550
  35. Van Den Neste E, Schmitz N, Mounier N, et al. Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: An analysis of patients included in the CORAL study. Bone Marrow Transplant. 2017;52(2):216-221. doi:10.1038/bmt.2016.213 https://doi.org/10.1038/bmt.2016.213 PMid:27643872  
  36. González-Barca E, Boumendil A, Blaise D, et al. Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (. Bone Marrow Transplant. 2020;55(2):393-399. doi:10.1038/s41409-019-0650-x https://doi.org/10.1038/s41409-019-0650-x PMid:31541205
  37. Wagner-Johnston ND, Link BK, Byrtek M, et al. Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood. 2015;126(7):851-857. doi:10.1182/blood-2015-01-621375 https://doi.org/10.1182/blood-2015-01-621375 PMid:26105149 PMCid:PMC4543911
  38. Sorigue M, Garcia O, Baptista MJ, et al. Similar prognosis of transformed and de novo diffuse large B-cell lymphomas in patients treated with immunochemotherapy. Med Clínica Engl Ed. 2017;148(6):243-249. doi:https://doi.org/10.1016/j.medcle.2017.03.004 https://doi.org/10.1016/j.medcle.2017.03.004
  39. Ghesquières H, Berger F, Felman P, et al. Clinicopathologic Characteristics and Outcome of Diffuse Large B-Cell Lymphomas Presenting With an Associated Low-Grade Component at Diagnosis. J Clin Oncol. 2006;24(33):5234-5241. doi:10.1200/JCO.2006.07.5671 https://doi.org/10.1200/JCO.2006.07.5671 PMid:17043351
  40. Guirguis HR, Cheung MC, Piliotis E, et al. Survival of patients with transformed lymphoma in the rituximab era. Ann Hematol. 2014;93(6):1007-1014. doi:10.1007/s00277-013-1991-y https://doi.org/10.1007/s00277-013-1991-y PMid:24414374
  41. Montoto S, Fitzgibbon J. Transformation of Indolent B-Cell Lymphomas. J Clin Oncol. 2011;29(14):1827-1834. doi:10.1200/JCO.2010.32.7577 https://doi.org/10.1200/JCO.2010.32.7577 PMid:21483014  
  42. Berger MD, Branger G, Leibundgut K, et al. CD34+ selected versus unselected autologous stem cell transplantation in patients with advanced-stage mantle cell and diffuse large B-cell lymphoma. Leuk Res. 2015;39(6):561-567. doi:10.1016/j.leukres.2015.03.004 https://doi.org/10.1016/j.leukres.2015.03.004 PMid:25890431
  43. Gribben JG, Freedman AS, Neuberg D, et al. Immunologic Purging of Marrow Assessed by PCR before Autologous Bone Marrow Transplantation for B-Cell Lymphoma. N Engl J Med. 1991;325(22):1525-1533. doi:10.1056/NEJM199111283252201 https://doi.org/10.1056/NEJM199111283252201 PMid:1944436
  44. Sharp JG, Kessinger A, Mann S, et al. Outcome of high-dose therapy and autologous transplantation in non-Hodgkin's lymphoma based on the presence of tumor in the marrow or infused hematopoietic harvest. J Clin Oncol. 1996;14(1):214-219. doi:10.1200/JCO.1996.14.1.214 https://doi.org/10.1200/JCO.1996.14.1.214 PMid:8558200
  45. Williams C D, Goldstone, A H,R M Pearce R M, Philip T, Hartmann O, Colombat P, Santini G, Foulard L, C GN. Purging of bone marrow in autologous bone marrow transplantation for non-Hodkin's lymphoma: a case-matches comparsion with unpurged cases by the European Blood and Marrow Transplant Lymphoma Registry. J Clin Oncol. 1996;14(9):2454-2464. https://doi.org/10.1200/JCO.1996.14.9.2454 PMid:8823323  
  46. Klyuchnikov E, Bacher U, Kroll T, et al. Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: Who, when and how. Bone Marrow Transplant. 2014;49(1):1-7. doi:10.1038/bmt.2013.72 https://doi.org/10.1038/bmt.2013.72 PMid:23708703
  47. Doocey RT, Toze CL, Connors JM, et al. Allogeneic haematopoietic stem-cell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma. Br J Haematol. 2005;131(2):223-230. doi:10.1111/j.1365-2141.2005.05755.x https://doi.org/10.1111/j.1365-2141.2005.05755.x PMid:16197454
  48. Van Kampen RJW, Canals C, Schouten HC, et al. Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: An analysis of the European Group for Blood and Marrow Transplantation registry. J Clin Oncol. 2011;29(10):1342-1348. doi:10.1200/JCO.2010.30.2596 https://doi.org/10.1200/JCO.2010.30.2596 PMid:21321299  
  49. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7 https://doi.org/10.1016/S1470-2045(18)30864-7 PMid:30518502  
  50. Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018;36(15_suppl):7505-7505. doi:10.1200/JCO.2018.36.15_suppl.7505 https://doi.org/10.1200/JCO.2018.36.15_suppl.7505  
  51. Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(16):1803-1813. doi:10.1200/JCO.2016.71.3024 https://doi.org/10.1200/JCO.2016.71.3024 PMid:28291388 PMCid:PMC5455597  
  52. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol Ther. 2017;25(1):285-295. doi:10.1016/j.ymthe.2016.10.020 https://doi.org/10.1016/j.ymthe.2016.10.020 PMid:28129122 PMCid:PMC5363293  
  53. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172 https://doi.org/10.1200/JCO.19.00172 PMid:31693429 PMCid:PMC7032881
  54. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4 https://doi.org/10.1016/S1470-2045(20)30225-4 PMid:32511983

Online Supplement

Suppl Figure 1 Supplementary Figure S1. PFS and OS analyzed according to various parameters like presence or absence of CD34+ stem cell selection (Figure A and B), transformed versus de novo lymphoma (Figure C and D), age at first diagnosis < versus ≥ 60 years (Figure E and F), presence or absence of b symptoms (Figure G and H) and bone marrow infiltration (Figure I and J) at first diagnosis, radiotherapy given during first- or second line therapy (Figure K and L) and remission state at ASCT (Figure M and N).
Suppl Figure 1.2