# Tandem combination of ASCT and CAR T-cell therapy in highly refractory CNS lymphomas

Lydia Montes, Sylvain Choquet, Madalina Uzunov, Véronique Morel, Marine Baron, Damien Roos-Weil, Magalie Joris, Caroline Delette, Delphine Lebon, Nabih Azar, et al.

► To cite this version:

Lydia Montes, Sylvain Choquet, Madalina Uzunov, Véronique Morel, Marine Baron, et al. Tandem combination of ASCT and CAR T-cell therapy in highly refractory CNS lymphomas. British Journal of Haematology, 2025, 10.1111/bjh.70132. hal-05240713

HAL Id: hal-05240713

https://u-picardie.hal.science/hal-05240713v1

Submitted on 5 Sep 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
RESEARCH LETTER

BJHaem
BRITISH JOURNAL OF HAEMATOLOGY

Tandem combination of ASCT and CAR T-cell therapy in highly refractory CNS lymphomas

To the Editor,

In patients eligible with central nervous system (CNS) lymphoma, the standard treatment consists of induction with high-dose methotrexate (HD-MTX) and then, if the response is good, consolidation with thiotepa-based high-dose chemotherapy and autologous stem cell transplantation (ASCT).¹,² The prognosis after this treatment is rather good, with 5-year progression-free survival (PFS) and overall survival (OS) rates of 74% and 80% respectively.³ However, 25%–30% of the patients are refractory to HD-MTX⁴ and need salvage treatment followed by ASCT. Schenone et al. have shown that the patients' prognosis after ASCT was closely associated with the number of lines of treatment prior to ASCT.³ The 1-year PFS rate was around 80% for first-line treatment, around 70% for second-line treatment and around 50% for subsequent lines of treatment; this latter value is rather disappointing.

Anti-CD19 chimeric antigenic receptor (CAR) T cells represent one of the last decade's major improvements in the treatment of large B-cell lymphoma (LBCL).<sup>5,6</sup> Whereas CNS lymphomas were initially excluded from the trials on CAR T cells because of the high expected risk of neurotoxicity, several recent studies have highlighted an acceptable safety profile and promising efficacy results in highly pre-treated patients.<sup>7,8</sup> However, the relapse rate following CAR T-cell therapy was still high, and the 1-year PFS rate did not exceed 40%–45%.<sup>7,8</sup>

Furthermore, disease progression prior to ASCT or CAR T-cell treatment is known to be a major factor in the failure of these approaches.<sup>1,7,9</sup>

The treatment of young patients with highly refractory CNS lymphomas must therefore be improved. Since 2023, the French expert network on CNS lymphomas (Lymphomes Oculo-Cérébraux (LOC) network) has considered in this setting a regimen combining ASCT directly followed a several weeks later by CAR T-cell therapy. The aim of this study was to evaluate the efficacy and tolerance of this strategy.

We retrospectively retrieved from the LOC network data-
base the adult patients for whom the intent-to-treat project
of combination of ASCT and CAR T cells was considered
in the context of a refractory CNS LBCL, either primary or
secondary, without any systemic lesions at the time of the
decision. The database was approved by the Institutional

Ethical Committee of the coordinating centre and the French National Data Protection Commission. The medical charts of the patients were also reviewed for detailed information. All patients gave their written informed consent to the collection and use of their personal data.

The treatment response was assessed by reference to the International Primary CNS Lymphoma Collaborative Group criteria.¹⁰ Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the autologous stem cell transplantation (ASTCT) 2019 guidelines.¹¹ Other adverse events were documented with regard to the Common Terminology Criteria for Adverse Events (version 5.0). The PFS and OS were calculated from the date of ASCT. Survival rates were calculated using the Kaplan–Meier method. All statistical analyses were carried out with R software.

Five patients met the study's inclusion criteria (Table 1 and Table S1). The median number of previous lines of treatment was 3 (range: 3–5); these included HD-MTX, high-dose cytarabine, ifosfamide–carboplatin–etoposide and rituximab in all patients. All patients were refractory to first-line treatment and had undergone lymphapheresis prior to ASCT. At the time of ASCT, the median age was 39 (range: 30–53), and the median Karnofsky performance status (KPS) was 70 (range: 60–90); three patients had progressive disease, one had a partial response (PR) and one had a complete response (CR). Four of the five patients received a thiotepa–busulfan–cyclophosphamide regimen, and the fifth received a thiotepa–carmustine regimen. Although the level of post-ASCT toxicity was acceptable in four patients, one patient presented several severe infectious complications and severe bladder bleeding, and we therefore decided not to administer the CAR T cells (Table 2). This patient relapsed (with both systemic and CNS lesions) 8 months after ASCT and received several courses of salvage treatment, including CAR T-cell therapy 12 months after ASCT. Nineteen months after ASCT, he is alive with a CR, but he developed pancytopenia secondary to a ring sideroblastic myelodysplasia with a monosomy 7. In the four remaining patients, the median time interval between ASCT and CAR T-cell infusion was 75 days (range: 67–86). None of the patients received any other cancer treatments in the time interval between ASCT and CAR T-cell therapy. At the time of CAR T-cell infusion, the median KPS was 70 (range: 60–80), three patients showed

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2025 The Author(s). *British Journal of Haematology* published by British Society for Haematology and John Wiley & Sons Ltd.
<table><caption>TABLE 1 Patients' characteristics.</caption><tr><td>N at ASCT/N at CAR T cells</td><td>5/4</td></tr><tr><td>Sex ratio (M/W)</td><td>5/0</td></tr><tr><td>Immunocompetent status at initial diagnosis</td><td>5</td></tr><tr><td>Initial diagnosis</td><td></td></tr><tr><td>PCSNL</td><td>3</td></tr><tr><td>Systemic + CNS DLBCL</td><td>1</td></tr><tr><td>Systemic DLBCL</td><td>1</td></tr><tr><td>Refractory to first-line treatment</td><td>5</td></tr><tr><td>Duration of disease before ASCT: median (range) (months)</td><td>13 (8–139)</td></tr><tr><td>Number of lines of treatment before ASCT: median (range)</td><td>3 (3–5)</td></tr><tr><td>Previous treatments</td><td></td></tr><tr><td>HD-MTX</td><td>5</td></tr><tr><td>HD-AraC</td><td>5</td></tr><tr><td>ICE</td><td>5</td></tr><tr><td>Lenalidomide</td><td>3</td></tr><tr><td>Ibrutinib</td><td>4</td></tr><tr><td>Rituximab</td><td>5</td></tr><tr><td>WBRT</td><td>2</td></tr><tr><td>Leukapheresis before ASCT</td><td>5</td></tr><tr><td>Disease status at ASCT</td><td></td></tr><tr><td>PD</td><td>3</td></tr><tr><td>PR</td><td>1</td></tr><tr><td>CR</td><td>1</td></tr><tr><td>Age at ASCT: median (range)</td><td>39 (30–53)</td></tr><tr><td>KPS at ASCT: median (range)</td><td>70 (60–90)</td></tr><tr><td>HCT regimen</td><td></td></tr><tr><td>TBC</td><td>4</td></tr><tr><td>Thiotepa-carmustine</td><td>1</td></tr><tr><td>Other therapies between ASCT and CAR T cells</td><td>0</td></tr><tr><td>Delay between leukapheresis and CAR T cells: median (range) (days)</td><td>82 (73–97)</td></tr><tr><td>Delay between ASCT and CAR T cells: median (range) (days)</td><td>75 (67–86)</td></tr><tr><td>Disease status at CAR T-cell infusion</td><td></td></tr><tr><td>PR</td><td>1</td></tr><tr><td>CR</td><td>3</td></tr><tr><td>KPS at CAR T-cell infusion: median (range)</td><td>70 (60–80)</td></tr><tr><td>Type of myeloablative CT before CAR T cells</td><td></td></tr><tr><td>Fludarabine-cyclophosphamide</td><td>4</td></tr><tr><td>Type of CAR T cells</td><td></td></tr><tr><td>Axi-cel</td><td>4</td></tr><tr><td>Best response after CAR T cells</td><td></td></tr><tr><td>CR</td><td>4</td></tr><tr><td>Relapse after CAR T cells</td><td>0</td></tr><tr><td>Other therapy after CAR T cells</td><td>0</td></tr></table>

<table><caption>TABLE 1 (Continued)</caption><tr><td>Follow-up from ASCT: median (min-max) (months)</td><td>18 (14–22)</td></tr><tr><td>1-year PFS: % (95% CI)</td><td>80 (52–100)</td></tr><tr><td>1-year OS: %</td><td>100</td></tr></table>

Abbreviations: ASCT, high-dose chemotherapy with autologous stem cell transplantation; axi-cel, axicabtagene ciloleucel; CAR T-cells, chimeric antigen receptor T cells; CNS, central nervous system; CR, complete response; CT, chemotherapy; DLBCL, diffuse large B-cell lymphoma; HCT, high-dose chemotherapy; HD-AraC, high-dose cytarabine; HD-MTX, high-dose methotrexate; ICE, ifosfamide-carboplatin-etoposide; KPS, Karnofsky performance status; M, men; N, number; OS, overall survival; PCNSL, primary central nervous system lymphoma; PD, progressive disease; PFS, progression-free survival; PR, partial response; TBC, thiotepa-busulfan-cyclophosphamide; W, women; WBRT, whole-brain radiotherapy.

a CR and one patient showed a PR. All the patients received axicabtagene ciloleucel. One patient experienced a neurological adverse event (grade 3 ICANS), and four experienced grade 1 CRS. Three patients presented with thrombocytopenia and neutropenia grade ≥3 lasting for more than 28 days after CAR T-cell therapy. Three months after CAR T-cell infusion, two patients still presented grade 3 thrombocytopenia, and one presented grade 3 neutropenia. Two patients were readmitted to hospital within 6 months of the CAR T-cell therapy due to sepsis (Table 2).

All four patients achieved a CR after CAR T-cell therapy. None relapsed or received any subsequent cancer treatments. All four were alive after a median follow-up period of 18 months (range: 14–22 months) after ASCT (median follow-up period of 15 months; range: 12–19 months) from CAR T cells. At last follow-up, the median (range) KPS was 80 (range: 70–90), and all four patients were living at home. Three of the four had returned to work, whereas a return was prevented by the fourth patient's neurological sequelae due to lymphoma.

A combination of ASCT and CAR T-cell therapy has already been reported in patients with poor-risk diffuse LBCL<sup>12,13</sup> or multiple myeloma.<sup>14</sup> In these studies, the CAR T cells were infused a few days after ASCT. The rationale was that myeloablative ASCT might increase the effectiveness of adoptive T-cell immunotherapy, notably by acting on the immune microenvironment. Thus, Wei et al. reported better outcomes in patients with relapsing/refractory LBCL with TP53 alteration who underwent ASCT and treatment with a cocktail of anti-CD19 and anti CD22 CAR T cells, relative to patients who were treated with CAR-T cells only.

In the field of CNS lymphoma, Yu et al. reported on a series of 22 patients: Nine had undergone ASCT and then, a few days later, CAR T-cell therapy.<sup>9</sup> However, it is difficult to draw clear conclusions from these results because Yu et al. did not explain why some patients received the combination and others did not. Moreover, most patients were also treated with various drugs (notably anti-PD-1 agents and Bruton tyrosine kinase inhibitors), and some of the patients were conditioned with a carmustine, etoposide, cytarabine, melphalan (BEAM) regimen, which is not optimal in the context of CNS lymphoma. Data on toxicity following the combination were limited.
<table><caption>TABLE 2 Profile of tolerance and main toxicities after ASCT and CAR T cells.</caption><tbody><tr><td colspan="2">ASCT (N=5)</td></tr><tr><td>Febrile neutropenia following ASCT</td><td>5</td></tr><tr><td>Duration of grade 4 neutropenia after ASCT (days): median (min-max)</td><td>12 (8-20)</td></tr><tr><td>Duration of grade 4 thrombopenia after ASCT (days): median (min-max)</td><td>9 (5-15)</td></tr><tr><td>Grade 3-4 hepatotoxicity after ASCT</td><td>1</td></tr><tr><td>Grade 3-4 nephrotoxicity after ASCT</td><td>1</td></tr><tr><td>Transfer in ICU after ASCT</td><td>2</td></tr><tr><td>Duration of hospitalization for ASCT (days): median (min-max)</td><td>32 (19-136)</td></tr><tr><td>Toxic death after ASCT</td><td>0</td></tr><tr><td colspan="2">CAR T cells (N=4)</td></tr><tr><td>CRS</td><td>4</td></tr><tr><td>Including grade 3-4 CRS</td><td>0</td></tr><tr><td>ICANS</td><td>1</td></tr><tr><td>Including grade 3-4 ICANS</td><td>1</td></tr><tr><td>Grade 3-4 hepatotoxicity after CAR T cells</td><td>0</td></tr><tr><td>Grade 3-4 nephrotoxicity after CAR T cells</td><td>0</td></tr><tr><td>Transfer in ICU after CAR T cells</td><td>1</td></tr><tr><td>Duration of hospitalization for CAR T cells (days): median (min-max)</td><td>26 (22-29)</td></tr><tr><td>Cytopenia grade ≥3 lasting more than 28 days/3 months/6 months after CAR T cells</td><td></td></tr><tr><td>Thrombopenia</td><td>3/2/0</td></tr><tr><td>Neutropenia</td><td>3/1/0</td></tr><tr><td>Anaemia</td><td>0/0/0</td></tr><tr><td>Hypogammaglobulinaemia &lt;4 g/L lasting more than 6 months/12 months</td><td>2/1</td></tr><tr><td>Number of subsequent rehospitalizations during the 6 months following CAR T cells and causes</td><td>4</td></tr><tr><td>Toxic death after CAR T cells</td><td>0</td></tr></tbody></table>

Abbreviations: ASCT, high-dose chemotherapy with autologous stem cell transplantation; CRS, cytokine release syndrome; ICANS, immune effector-cell associated neurotoxicity syndrome; ICU, intensive care unit; N, number.

Our rationale was to try to reduce the tumour burden with ASCT as much as possible, in order to improve the response to CAR T-cell therapy and limit the neurotoxicity induced by the CAR T-cell procedure. In our network, we chose to administer CAR T cells several days after ASCT (median of 75 days). This time interval (i) reduced the likelihood of severe adverse events because thiotepa-based conditioning regimens are known to be more toxic than BEAM regimens, and (ii) allowed us to control the tumour reduction burden before CAR T-cell therapy. Moreover, most patients required emergency ASCT, and the CAR T-cells were not ready at the time of transplantation. Similar strategies have been reported in acute leukaemia, with a combination of chemotherapies and allogeneic transplantation.¹⁵

All the patients in our series had several risk factors for a poor prognosis. They had all been treated extensively prior to ASCT and had highly refractory CNS lymphomas. All were refractory to first-line treatment, and three displayed progressive disease at the time of ASCT. Despite the presence of these factors, the four patients who received the combination

of ASCT and CAR T-cell therapy achieved a CR that has lasted for at least 12 months after CAR T cells, in the absence of other cancer treatment—a very good result in this setting. The level of toxicity observed after the combined treatment appeared to be acceptable in this population of young adult patients in good general condition. Notably, there was only one case of grade 3 neurotoxicity. The level of haematological toxicity after CAR T-cell therapy appeared to be higher than that typically reported in the literature (two patients were readmitted to hospital for infections), but the latter had resolved in all patients within 6 months of CAR T-cell therapy. However, to determine the risk of myelodysplasia associated with this combination treatment, studies with the prolonged follow-up of a larger number of patients will be needed. At last follow-up, all the patients had a reasonable quality of life.

The present results are preliminary and must be confirmed in larger series with a longer follow-up period. Nevertheless, the combination of ASCT with CAR T-cell therapy already appears to be a valuable option in young adult patients suffering from highly refractory CNS lymphomas.
**KEYWORDS**

autologous stem cell transplantation, CART cells,
chemotherapy, lymphoma

**AUTHOR CONTRIBUTIONS**

LM and CH: Acquisition and analysis of data; writing of the manuscript. SC, MU, VM, MB, DRW, MJ, CD, DL, NA, CM, LN, MLGT, CBG, CL, LS, KHX, CS and IB: Acquisition of data; review of the manuscript and approval of the final version.

**Funding Information**

chu amiens.

**ACKNOWLEDGEMENTS**

This study was supported by the French National Cancer Institute (INCa).

**CONFLICT OF INTEREST STATEMENT**

Sylvain Choquet: Novartis, Kite/gilead. Other authors: None.

**DATA AVAILABILITY STATEMENT**

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Lydia Montes<fnref n="1" />

Sylvain Choquet<fnref n="2" />

Madalina Uzunov<fnref n="2" />

Véronique Morel<fnref n="3" />

Marine Baron<fnref n="2" />

Damien Roos-Weil<fnref n="2" />

Magalie Joris<fnref n="1" />

Caroline Delette<fnref n="1" />

Delphine Lebon<fnref n="1" />

Nabih Azar<fnref n="2" />

Carole Metz<fnref n="4" />

Lucia Nichelli<fnref n="5" />

Magali Le Garff-Tavernier<fnref n="6" />

Clémentine Boccon-Gibod<fnref n="2" />

Claire Lacan<fnref n="2" />

Laetitia Souchet<fnref n="2" />

Khê Hoang-Xuan<fnref n="7" />

Carole Soussain<fnref n="8" />

Inès Boussen<fnref n="2" />

Caroline Houillier<fnref n="7" />

**Correspondence**

Lydia Montes, Hematology Department, CHU Amiens, Amiens, France.

Email: montes.lydia@chu-amiens.fr

Caroline Houillier, Onco-Neurology Department, APHP Pitié Salpétrière, Paris, France.

Email: caroline.houillier@aphp.fr

**ORCID**

Lydia Montes<fnref n="1" /> https://orcid.org/0000-0003-3854-4209

Marine Baron<fnref n="1" /> https://orcid.org/0000-0003-0212-8684

Damien Roos-Weil<fnref n="1" /> https://orcid.org/0000-0002-7767-755X

Clémentine Boccon-Gibod<fnref n="1" /> https://orcid.org/0000-0001-6404-1491

Caroline Houillier<fnref n="1" /> https://orcid.org/0000-0003-2931-7522

**REFERENCES**

1. Houillier C, Taillandier L, Dureau S, Lamy T, Laadhari M, Chinot O, et al. Radiotherapy or autologous stem-cell transplantation for primary CNS lymphoma in patients 60 years of age and younger: results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study. J Clin Oncol. 2019;37(10):82333.

2. Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosée P, et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017;4(11):e51023.

3. Schenone L, Houillier C, Tanguy ML, Choquet S, Agbetiafa K, Ghesquières H, et al. Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life—experience of the French Network. Bone Marrow Transplant. 2022;57(6):96674.

4. Houillier C, Soussain C, Ghesquières H, Soubeyran P, Chinot O, Taillandier L, et al. Management and outcome of primary CNS lymphoma in the modern era: an LOC network study. Neurology. 2020;94(10):e1027–e1039. https://doi.org/10.1212/WNL.00000000000008900

5. Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):64054.

6. Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294308.

7. Choquet S, Soussain C, Azar N, Morel V, Metz C, Ursu R, et al. CAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: real-life results of the LOC network. Am J Hematol. 2024;99(7):12409.

8. Ayuk F, Gagelmann N, Von Tresckow B, Wulf G, Rejeski K, Stelljes M, et al. Real-world results of CAR T-cell therapy for large B-cell lymphoma with CNS involvement: a GLA/DRST study. Blood Adv. 2023;7(18):5316–9.

<footnote n="1">¹Hematology Department, CHU Amiens, Amiens, France</footnote>

<footnote n="2">²Hematology Department, APHP Pitié Salpétrière, Paris, France</footnote>

<footnote n="3">³Internal Medicine, APHP Pitié Salpétrière, Paris, France</footnote>

<footnote n="4">⁴Pharmacy Department, APHP Pitié Salpétrière, Paris, France</footnote>

<footnote n="5">⁵Neuro-Radiology Department, APHP Pitié Salpétrière, Paris, France</footnote>

<footnote n="6">⁶Hematology Biology Department, APHP Pitié Salpétrière, Paris, France</footnote>

<footnote n="7">⁷Onco-Neurology Department, APHP Pitié Salpétrière, Paris, France</footnote>

<footnote n="8">⁸Hematology Department, Institut Curie, Paris, France</footnote>
9. Yu W, Huang L, Mei H, Li Y, Niu T, Zou D, et al. Real-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China. J Immunother Cancer. 2024;12(5):e008553.

10. Abrey LE, Batchelor TT, Ferreri AJM, Gospodarowicz M, Pulczynski EJ, Zucca E, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):503443.

11. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):62538.

12. Sauter CS, Senechal B, Rivière I, Ni A, Bernal Y, Wang X, et al. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood. 2019;134(7):62635.

13. Wei J, Xiao M, Mao Z, Wang N, Cao Y, Xiao Y, et al. Outcome of aggressive B-cell lymphoma with TP53 alterations administered

with CAR T-cell cocktail alone or in combination with ASCT. Signal Transduct Target Ther. 2022;7(1):101.

14. Yuan S, Chen Y, Liu H. Progress and prospect of ASCT combined with CAR-T therapy in the treatment of multiple myeloma. Ther Adv Hematol. 2024;15:20406207241237594.

15. Decroocq J, Itzykson R, Vigouroux S, Michallet M, Yakoub-Agha I, Huynh A, et al. Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: a study from the Société francophone de Greffe de Moelle et de Thérapie Cellulaire. Am J Hematol. 2018;93(3):41623.

SUPPORTING INFORMATION

Additional supporting information can be found online in
the Supporting Information section at the end of this article.