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Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
Locke, F. L., Filosto, S., Chou, J., Vardhanabhuti, S., Perbost, R., Dreger, P., Hill, B. T., Lee, C., Zinzani, P. L., Kröger, N., et al
Nature medicine. 2024
Abstract
The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10(-9) for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10(-9) for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
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Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline
Bayas, A., Berthele, A., Blank, N., Dreger, P., Faissner, S., Friese, M. A., Gerdes, L. A., Grauer, O. M., Häussler, V., Heesen, C., et al
Therapeutic advances in neurological disorders. 2023;16:17562864231180730
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Editor's Choice
Abstract
BACKGROUND While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. OBJECTIVE To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. METHODS An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. RESULTS We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). CONCLUSION Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages. Autologous haematopoietic stem cell transplantation for multiple sclerosis Substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS) during the last 20 years. However, in a relevant percentage of patients, the disease cannot completely be contained. Autologous haematopoietic stem cell transplantation (AHSCT) enables rebuilding of a new and healthy immune system and to potentially stop the autoimmune disease process for a long time. A number of studies documenting 4000 cases cumulatively over the past 20 years reported high efficacy of AHSCT in controlling MS inflammatory disease activity. These data and improved safety profiles of the treatment procedures spurred interest in using AHSCT as a treatment option for MS. An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of video calls to develop recommendations and outline a registry study project. We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS. Current data indicate that patients are most likely to benefit from AHSCT if they are young, ambulatory, with high disease activity, that is, relapses or new magnetic resonance imaging (MRI) lesions. Treatment data with AHSCT will be collected within the German REgistry Cohort of autoLogous haematopoietic stem cell transplantation MS (RECLAIM). Further clinical trials including registry-based analyses and systematic follow-up are urgently needed to better define the optimal patient characteristics as well as the efficacy and safety profile of AHSCT compared with other high-efficacy therapies. These will help to position AHSCT as a treatment option in different MS disease stages. eng
PICO Summary
Population
An expert panel of multiple sclerosis (MS) neurologists in Germany (n=25)
Intervention
Development of a position paper and registry outline on the up-to-date optimal use of autologous transplant in in managing MS
Comparison
None
Outcome
Current data indicate that patients who are most likely to benefit from autologous transplantation have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM).
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Hematopoietic stem cell boost for persistent neutropenia after CAR-T cell therapy: a GLA/DRST study
Gagelmann, N., Wulf, G. G., Duell, J., Glass, B., Heteren, P. V., von Tresckow, B., Fischer, M., Penack, O., Ayuk, F. A., Einsele, H., et al
Blood advances. 2022
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Editor's Choice
Abstract
Hematotoxicity after chimeric antigen receptor (CAR)-T cell therapy is associated with infection and death but management remains unclear. We report results of 31 patients receiving hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic) for either sustained severe neutropenia of grade 4 (<0.5 x109/l), sustained moderate neutropenia (less than or equal to 1.5 x109/l) and high risk of infection, or neutrophil count less than or equal to 2.0 x109/l and active infection. Median time from CAR-T cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia prior to HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia (p=0.007). All non-responders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia ≤38 days (85%) versus neutropenia >38 days prior to HSCB (44%; p=0.029). In conclusion, early or prophylactic HSCB showed quick response and improved outcomes for sustained moderate to severe neutropenia after CAR-T.
PICO Summary
Population
Adults with persistent neutropenia after CAR-T cell therapy (n=31)
Intervention
Hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic)
Comparison
None
Outcome
Median time from CAR-T cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia prior to HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia. All non-responders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia ≤38 days (85%) versus neutropenia >38 days prior to HSCB (44%).
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Durable benefit of rituximab maintenance post-autograft in patients with relapsed follicular lymphoma: 12-year follow-up of the EBMT lymphoma working party Lym1 trial
Pettengell, R., Uddin, R., Boumendil, A., Johnson, R., Metzner, B., Martín, A., Romejko-Jarosinska, J., Bence-Bruckler, I., Giri, P., Niemann, C. U., et al
Bone marrow transplantation. 2021
Abstract
We report the 12-year follow-up of the prospective randomized EBMT LYM1 trial to determine whether the benefit of brief duration rituximab maintenance (RM) on progression-free survival (PFS) in patients with relapsed follicular lymphoma (FL) receiving an autologous stem cell transplant (ASCT) is sustained. One hundred and thirty-eight patients received RM with or without purging. The median follow-up after random assignment is 12 years (range 10-13) for the whole series. The 10-year PFS after ASCT is 47% (95% CI 40-54) with only 4 patients relapsing after 7.5 years. RM continues to significantly improve 10-year PFS after ASCT in comparison with NM [P?=?0.002; HR 0.548 (95% CI 0.38-0.80)]. Ten-year non-relapse mortality (NRM) was not significantly different between treatment groups (7% overall). 10-year overall survival (OS) after ASCT was 75% (69-81) for the whole series, with no significant differences according to treatment sub-groups. 10-year OS for patients who progressed within 24 months (POD24T) was 60%, in comparison with 85% for patients without progression. Thus the benefit of rituximab maintenance after ASCT on relapse prevention is sustained at 12 years, suggesting that RM adds to ASCT-mediated disease eradication and may enhance the curative potential of ASCT.
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Long-term survival in a fraction of patients with metastatic breast cancer who received consolidation therapy with high-dose chemotherapy and autologous stem cell transplant between 2000 and 2015: an EBMT registry-based study
Martino, M., Pitino, A., Gori, M., Viens, P., Siena, S., Tripepi, G., Canale, F. A., Ballestrero, A., Zamagni, C., Musso, M., et al
Bone marrow transplantation. 2021
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Haematopoietic stem cell transplantation in adult soft-tissue sarcoma: an analysis from the European Society for Blood and Marrow Transplantation
Heilig, C. E., Badoglio, M., Labopin, M., Fröhling, S., Secondino, S., Heinz, J., Nicolas-Virelizier, E., Blaise, D., Korenbaum, C., Santoro, A., et al
ESMO open. 2020;5(5)
Abstract
BACKGROUND The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups. METHODS The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016. RESULTS Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact. CONCLUSIONS Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.
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Autologous stem cell transplantation in multiple myeloma patients: utilization patterns and hospital effects
Jansen, L., Merz, M., Engelhardt, M., Weisel, K., Scheid, C., Straka, C., Langer, C., Salwender, H., Einsele, H., Kroger, N., et al
Leukemia & lymphoma. 2020;:1-10
Abstract
Evidence on volume outcome associations for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is limited. We investigated ASCT utilization patterns and volume outcome associations in the German National Registry for Stem Cell Transplants (DRST). MM patients with an upfront ASCT between 1998 and 2014 registered in the DRST were included. ASCT utilization increased strongly from 6% to 17% between 1999 and 2013 with the largest increase for patients aged 60-64 years (8-34%). The mean number of ASCTs conducted in the hospitals per year varied (quintiles, Q1:0.0-8.2 to Q5:31.0-102.7). Center volume was not associated with survival after upfront ASCT (lowest vs. highest center volume, hazard ratios and 95% confidence intervals: 0.95 (0.76-1.18), p = 0.92). Our findings may reflect a high standard of care and degree of specialization of centers performing ASCT for MM in Germany.
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Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor
Sureda, A., Chabannon, C., Masszi, T., Pohlreich, D., Scheid, C., Thieblemont, C., Wahlin, B. E., Sakellari, I., Russell, N., Janikova, A., et al
Bone marrow transplantation. 2019
Abstract
Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups.
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Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT
Kanate, A. S., Kumar, A., Dreger, P., Dreyling, M., Le Gouill, S., Corradini, P., Bredeson, C., Fenske, T. S., Smith, S. M., Sureda, A., et al
JAMA oncology. 2019
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Abstract
Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naive high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naive FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.
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Autologous stem cell transplantation for HIV-associated lymphoma in the antiretroviral and rituximab era: a retrospective study by the EBMT Lymphoma Working Party
Hubel, K., Re, A., Boumendil, A., Finel, H., Hentrich, M., Robinson, S., Wyen, C., Michieli, M., Kanfer, E., Diez-Martin, J. L., et al
Bone marrow transplantation. 2019
Abstract
The present study aimed at describing the outcome of patients with HIV-associated lymphomas following autologous hematopoietic stem cell transplantation (autoHCT) in the rituximab and combined antiretroviral therapy (cART) era. Eligible for this retrospective study were HIV-positive patients with lymphoma who received autoHCT between 2007 and 2013. A total of 118 patients were included with a median age of 45 years (range 24-66). Underlying diagnoses were diffuse large B cell lymphoma in 47%, Hodgkin lymphoma in 24%, Burkitt lymphoma in 18%, and plasmablastic lymphoma in 7% of patients. Disease status at autoHCT was complete remission in 44%, partial remission (PR) in 38%, and less than PR in 18% of the patients. With a median follow-up of 4 years, 3-year non-relapse mortality, incidence of relapse, progression-free survival (PFS) and overall survival (OS) were 10%, 27%, 63% and 66%, respectively. By multivariate analysis, disease status less than PR but not CD4+ cell count at the time of autoHCT was a significant predictor of unfavorable PFS and OS. In conclusion, in the era of cART and chemoimmunotherapy, the outcome of autoHCT for HIV-related lymphoma is driven by lymphoma-dependent risk factors rather than by characteristics of the HIV infection.