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The negative influence of baseline cell-free DNA on long-term survival in DLBCL depends on frontline treatment intensity
Desmots, F., Rossille, D., Roussel, M., Pangault, C., Louarn, L., De Saint Jore, M., Le Gouill, S., Bouabdallah, K., Delwail, V., Gressin, R., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023
Abstract
PURPOSE In this study, we address the question of the effect of first-line treatment intensity in de novo DLBCL on the impact of baseline cfDNA on long-term survival. EXPERIMENTAL DESIGN The GOELAMS 075 randomized clinical trial compared R-CHOP with high-dose R-chemotherapy plus autologous stem cell transplantation (R-HDT) for patients aged ≤60. An interim PET assessment was used to refer patients for salvage therapy. With a median follow-up of more than 5.8 years, we analyzed the effects of the treatment arm, salvage therapy, and cfDNA level at diagnosis on overall survival (OS). RESULTS In a representative group of 123 patients, a high cfDNA concentration (>55ng/ml) at diagnosis was associated with poor clinical prognostic factors and constituted a prognostic marker, independently of the age-adjusted International Prognostic Index. A cfDNA level above a threshold value of 55 ng/ml at diagnosis was associated with significantly worse OS. In an intention-to-treat analysis, high-cfDNA R-CHOP patients (but not high-cfDNA R-HDT patients) had worse OS (hazard ratio [95% confidence interval]: 3.99 [1.98-10.74], P=0.006). In patients with high cfDNA levels, salvage therapy and transplantation were associated with a significantly higher OS rate. Among 50 patients with complete response 6 months after the end of treatment, for 11 out of 24 R-CHOP patients, the cfDNA did not fall back to normal values. CONCLUSIONS In this randomized clinical trial, intensive regimens mitigated the negative influence of high cfDNA levels in de novo DLBCL, relative to R-CHOP.
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Humoral immune-depression following autologous stem cell transplantation is a marker of prolonged response duration in patients with mantle cell lymphoma
Bouard, L., Tessoulin, B., Thieblemont, C., Bouabdallah, K., Gastinne, T., Oberic, L., Carras, S., Delette, C., Casasnovas, O., Dartigeas, C., et al
Haematologica. 2022
Abstract
Rituximab maintenance (RM) after autologous stem cell transplantation (ASCT) is standardof-care for young patients with mantle cell lymphoma (MCL). RM may enhance posttransplantation immune-depression and risk of infections. We compared infection incidence and immune consequences of RM versus observation in transplanted MCL patients. All randomized patients included in the LyMa trial were eligible. The following parameters were collected prospectively: occurrence of fever, infection, hospitalization, neutropenia, hypogammaglobulinemia, CD4 lymphopenia and gamma globulin (Ig) substitution. The post-ASCT period was divided into 4 periods in order to assess the possible effects of RM or ASCT on immune status. Each arm included 120 patients. Concerning infection incidence and all biological parameters, there was no difference between the 2 arms during the first year post-ASCT. After this period, RM patients were more exposed to fever (p=0.03), infections (p=0.001), hypogammaglobulinemia (p=0.0001) and Ig substitution (p.
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Outcomes after allogeneic hematopoietic stem cell transplantation for adults with primary mediastinal B cell lymphoma: a SFGM-TC and LYSA study
Le Calvez, B., Tessoullin, B., Renaud, L., Botella-Garcia, C., Srour, M., Le Gouill, S., Guillerm, G., Gressin, R., Nguyen Quoc, S., Furst, S., et al
Acta oncologica (Stockholm, Sweden). 2022;:1-7
Abstract
Background: Despite therapeutic progress, 10 to 30% of adult patients with primary mediastinal B cell lymphoma (PMBCL) are primary refractory or experience early relapse (R/R). Allogeneic stem cell transplantation (allo-HSCT) thus remains a potentially curative option in this setting.Material and Methods: In this multicenter retrospective study, the outcomes of 33 French and Belgian adult patients allo-transplanted for R/R PMBCL between January 1999 and December 2018, were examined.Results: At allo-HSCT time, patients had received a median of 3 treatment lines, 50% of them were in complete response, 40% in partial response and 10% had a progressive disease. Forty-two percent of the donors were siblings and 39% matched related. The median follow-up for alive patients was 78 months (3.5-157). Considering the whole cohort, 2-year overall survival (OS), progression free survival (PFS) and graft-versus-host disease-free/relapse-free survival (GRFS) were 48% (95%CI: 33-70), 47% (95%CI: 33-68) and 38.5% (95%CI: 25-60) respectively. Cumulative incidence of relapse and non-relapse mortality rates were respectively 34% (95%CI: 18-50) and 18% (95%CI: 7-34). Disease status at transplant was the only factor predicting survivals, patients with progressive disease showing significant lower 2-year PFS (HR: 6.12, 95%CI: 1.32-28.31, p = 0.02) and OS (HR: 7.04, 95%CI: 1.52-32.75, p = 0.013). A plateau was observed for OS and PFS after 4 years with 10 patients alive after this date, suggesting that almost one third of the patients effectively salvaged and undergoing allo-SCT could be cured.Conclusion: This study indicates that allo-HSCT is a valid therapeutic option for R/R PMBCL, providing durable remissions.
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Impact of allogeneic stem cell transplantation comorbidity indexes after haplotransplant using post-transplant cyclophosphamide
Jullien, M., Orvain, C., Berceanu, A., Couturier, M. A., Guillaume, T., Peterlin, P., Garnier, A., Le Bourgeois, A., Klemencie, M., Schmidt, A., et al
Cancer medicine. 2021
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Editor's Choice
Abstract
BACKGROUND Three different scoring systems have been developed to assess pre-transplant comorbidity in allogeneic hematopoietic stem cell transplantation (Allo-HSCT): the Hematopoietic Cell Transplantation-Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index. All were devised to predict overall survival (OS) and disease-free survival (DFS) survivals and non-relapse mortality (NRM) in patients receiving HLA-matched Allo-HSCT, but their performance has scarcely been studied in the haploidentical Allo-HSCT setting with post-transplant cyclophosphamide, a procedure in constant expansion worldwide. METHODS To address this issue, their impact on survivals and NRM was examined in a cohort of 223 patients treated with haploidentical Allo-HSCT in four different centers. RESULTS With a median follow-up of 35.6 months, 3-year OS, DFS, and NRM were 48.1% ± 4%, 46.3% ± 4%, and 30.0% ± 3%, respectively. No impact was found for any of the three comorbidity scores in univariate analysis. In multivariate analyses, the only three factors associated with lower OS were DRI (p < 0.001), an older age of recipients (=55 years old, p = 0.02) and of donors (=40 years old, p = 0.005). Older donor age was also associated with lower DFS and higher NRM. CONCLUSION The comorbidity scores do not predict survivals nor NRM in haploidentical Allo-HSCT with PTCY, suggesting that pre-transplant comorbidities should not be a contra-indication to this procedure.
PICO Summary
Population
Patients from four European centres who underwent haploidentical transplantation with post-transplant cyclophosphamide (n=223)
Intervention
Use of three comorbidity scores for each patient: 1) Hematopoietic Cell Transplantation-Specific Comorbidity Index
Comparison
2) Comorbidity/Age index, and 3) the Augmented Comorbidity/Age index
Outcome
With a median follow-up of 35.6 months, 3-year overall survival (OS), disease free survival (DFS), and non-relapse mortality (NRM) were 48.1% ± 4%, 46.3% ± 4%, and 30.0% ± 3%, respectively. No impact was found for any of the three comorbidity scores in univariate analysis. In multivariate analyses, the only three factors associated with lower OS were disease risk index, an older age of recipients (>/=55 years old) and of donors (>/=40 years old). Older donor age was also associated with lower DFS and higher NRM.
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Safety and immunogenicity of a first dose of SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem-cells recipients
Chevallier, P., Coste-Burel, M., Le Bourgeois, A., Peterlin, P., Garnier, A., Béné, M. C., Imbert, B. M., Drumel, T., Le Gouill, S., Moreau, P., et al
EJHaem. 2021
Abstract
This was a monocentric prospective study testing the efficacy and safety of a first injection of BNT162b2 (Pfizer-BioNTech) in 112 Allo-HSCT patients. Antibody response to SARS-CoV-2 spike protein receptor-binding domain was tested at the time of the second injection (Roche Elecsys). The study also included a non-randomized control arm of 26 healthy controls. This study shows that a first dose of SARS-CoV-2 messenger RNA vaccine is safe and provides a 55% rate of seroconversion in allotransplanted patients compared to 100% for the controls (p < 0.001). Factors influencing the absence of response in patients were recent transplantation (<2 years), lymphopenia (<1 × 10(9)/L) and immunosuppressive treatment or chemotherapy at the time of vaccination.
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Oxaliplatin before autologous transplantation in combination with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carboplatin in patients with mantle-cell lymphoma: results from the LyMA prospective trial
Tessoulin, B., Chiron, D., Thieblemont, C., Oberic, L., Bouadballah, K., Gyan, E., Damaj, G., Ribrag, V., Gressin, R., Feugier, P., et al
Bone marrow transplantation. 2021
Abstract
LyMA trial has demonstrated the benefit of rituximab maintenance after autologous stem cell transplantation (ASCT) in previously untreated mantle-cell lymphoma patients (MCL). Induction consisted of four courses of R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and platinum derivative). The platinum derivative (PD) choice was free: R-DHA-cisplatin, R-DHA-carboplatin, or R-DHA-oxaliplatin. We investigated the prognostic impact of each PD. PFS and OS calculated from inclusion and investigated in an intention-to-treat (ITT) (= 298) and per-protocol analyses (PP) (n?=?227). R-DHACis, R-DHACa, or R-DHAOx were used at first cycle in 184, 76, and 38 patients, respectively. Overall, 71 patients (59 in the R-DHACis) required a change in PD, mainly because of PD toxicity. In ITT-analysis, PFS in the R-DHACis and R-DHACa groups were similar (4-year PFS of 65%), while R-DHAOx had a better PFS (4-year PFS of 65% versus 86.5%, respectively, HR?=?0.44, p?=?0.02). The 4-year OS was 92% for R-DHAOx versus 75.9% for R-DHACis/DHACa (HR?=?0.37, p?=?0.03). Similar results were yielded in the PP analysis. Low MIPI and R-DHAOx were independent favorable prognostic markers for both PFS (HR?=?0.44, p?=?0.035) and OS (HR?=?0.36, p?=?0.045). In vitro and in silico analyses confirmed that oxaliplatin has an anti-MCL cytotoxic effect that differs from that of other PD. R-DHAOx before ASCT provides better outcome in transplantation eligible young MCL patients.
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Antithymocyte globulin administration in patients with profound lymphopenia receiving a PBSC purine analog/busulfan-based conditioning regimen allograft
Jullien, M., Guillaume, T., Peterlin, P., Garnier, A., Le Bourgeois, A., Debord, C., Mahe, B., Dubruille, V., Wuilleme, S., Blin, N., et al
Scientific reports. 2020;10(1):15399
Abstract
Graft-versus host disease (GVHD) remains one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (ASCT). Prophylactic T cell depletion via antithymocyte globulin (ATG) during ASCT conditioning is one of the standards of care for GVHD prophylaxis, although the optimal dosing strategy is still unclear. Recent studies have reported that absolute lymphocyte count at the time of ATG administration could predict survivals in ASCT from unrelated donors. Here this issue was examined in 116 patients receiving peripheral blood stem cells (PBSC) ASCT with purine analog/busulfan-based conditioning regimens between 2009 and 2019 in our department. The impact of lymphopenia at the time of ATG administration was evaluated in terms of overall survival, disease-free survival and GVHD-free/relapse-free survival. After a median follow-up of 4 years, no adverse effect of a profound lymphopenia was observed on patients' outcome. Notably, a reduced dose of ATG in patients with profound lymphopenia did not translate into better survivals. This study indicates that ATG can be administered whatever the recipient's lymphocyte counts in patients receiving a PBSC purine analog/busulfan-based conditioning regimen ASCT.
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Influence of donor type (sibling vs matched-unrelated donor vs haplo-identical donor) on outcomes after clofarabine-based reduced-intensity conditioning allograft for myeloid malignancies
Bouard, L., Guillaume, T., Peterlin, P., Garnier, A., Le Bourgeois, A., Duquenne, A., Mahe, B., Dubruille, V., Blin, N., Touzeau, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Clofarabine-based reduced-intensity conditioning (RIC) regimens are well-established schedules for allograft in patients with myeloid malignancies. A retrospective study was conducted including all adults allografted in our department with such a regimen and disease with the aim to assess whether or not the donor type (matched sibling (MSD), unrelated (MUD), or haploidentical (haplo)) impacted outcomes. Between October 2009 and February 2018, 118 patients met the inclusion criteria. Thirty-six, 55 and 27 patients respectively received a graft from a MSD, MUD or haplo donor. Peripheral blood stem cells (PBSC) were the source of graft for all patients. The median age of the whole cohort was 62 years old (range: 20-73) and the median follow-up was 31 months (range: 4.5-106). All patients engrafted except 1 haplo recipient. Neutrophils (>0.5 10(9)/L) and platelets (50 10(9)/L) recoveries were significantly delayed in the haplo-group (p=0.0003; and p<0.0001) compared to MSD and MUD. Acute grade 2-4 or 3-4 graft versus host disease (GVHD) incidences were similar between the three groups as well as the incidence of moderate or severe chronic GVHD. Also, similar 2-year overall survival (OS, 64.7% vs 73.9% vs 60.2%, p=0.39), disease-free survival (DFS, 57.7% vs 70.9% vs and 53.6%, p=0.1) and GVHD-relapse free survival (37.9% vs 54.3% vs 38.9%, p=0.23) were observed between MSD vs MUD vs haplo groups. The same was true when considering only acute myeloid leukemia (AML) cases. In multivariate analysis, the type of donor remained independent of outcomes in this series while myelodysplastic syndrome (vs AML), high disease-risk index and older donor (>=50 years) were associated with lower OS and DFS. These data suggest that haplo-identical donors are an acceptable alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack a MSD or a MUD.
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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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Clofarabine-based reduced intensity conditioning regimen with peripheral blood stem cell graft and post-transplant cyclophosphamide in adults with myeloid malignancies
Chevallier, P., Peterlin, P., Garnier, A., Le Bourgeois, A., Mahe, B., Dubruille, V., Blin, N., Touzeau, C., Gastinne, T., Lok, A., et al
Oncotarget. 2018;9(71):33528-33535
Abstract
Background: The Baltimore reduced-intensity conditioning (RIC) regimen using high-dose post-transplant cyclophosphamide (PTCY) is considered as a standard of care for haploidentical allogeneic stem cell transplantation (allo-SCT). However, it is associated with relatively low survivals and high incidence of relapse, especially when considering myeloid malignancies. Results: This retrospective study included 36 adults (males n = 18; median age: 60.5 years old; haplodonors n = 27; matched donors n = 8) with myeloid malignancies transplanted between March 2014 and March 2017 at the University Hospital of Nantes. Very encouraging results were observed with a 18-month overall survival (OS), disease-free survival (DFS) and relapse incidence (RI) of 72% +/- 7.5%, 63.8 +/- 8%, and 25 +/- 6% respectively, and a GVHD relapse-free survival (GRFS) of 52.6 +/- 8%. In univariate analysis, there were no differences regarding 18-month survivals between patients allografted: i) for acute myeloid leukemia vs myelodysplastic syndrome (OS 70 +/- 11% vs 69.2 +/- 13%, p = 0.3; DFS 64.7 +/- 11% vs 61.5 +/- 13%, p = 0.65), or ii) with haplo-identical vs other donors (OS: 66.2 +/- 9% vs 88.8 +/- 10.4%, p = 0.16; DFS 59 +/- 9.5% vs 77.8%, p = 0.6). Conclusion: The "Clo-Baltimore regimen" is safe and feasible and provides good survivals for patients with myeloid malignancies and haplo-donors. Methods: Here, we report a variant of the Baltimore regimen, where 1) fludarabine was replaced by clofarabine, 2) bone marrow was replaced by peripheral blood stem cells, and 3) tacrolimus was replaced by cyclosporine, in a "Clo-Baltimore regimen".