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1.
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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2.
Bendamustine-EAM versus R-BEAM after high-dose cytarabine-based induction in newly diagnosed patients with mantle cell lymphoma, a LYSA retrospective study
Costes-Tertrais, D., Hueso, T., Gastinne, T., Thieblemont, C., Oberic, L., Bouabdallah, K., Garciaz, S., Tchernonog, E., Dartigeas, C., Ribrag, V., et al
Bone marrow transplantation. 2022
Abstract
Cytarabine-based immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) consolidation is standard of care for fit patients with Mantle Cell Lymphoma (MCL). BEAM (Carmustine, Etoposide, Aracytine, Melphalan) is among the most frequently used conditioning regimen. Studies comparing BEAM with Bendamustine-EAM (BeEAM) have suggested that patients treated with BeEAM have a better progression-free survival (PFS). We performed a cross-study analysis to better evaluate BeEAM. Thirty-five patients from a retrospective study who received R-DHAP/BeEAM were compared to 245 patients from the LyMa trial (NCT00921414) who all received R-DHAP followed by R-BEAM. PFS and Overall Survival (OS) were estimated using Kaplan-Meier methods. At 2 years there was no difference between R-BEAM and BeEAM in either PFS (84.9% versus 87.9%; p = 0.95) or OS (91.8% versus 94.2%; p = 0.30). Analyses were repeated on a propensity score to reduce biases. Each patient from the BeEAM cohort (n = 30) was matched to three patients from the R-BEAM cohort (n = 90) for age, sex, MIPI score, pre-transplant status disease and rituximab maintenance (RM). PFS and OS at 2 years remained similar between R-BEAM and BeEAM with more renal toxicity in BeEAM group. MCL patients who received R-DHAP induction before ASCT have similar outcome after R-BEAM or BeEAM conditioning regimen.
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3.
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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4.
BeEAM (bendamustine, etoposide, cytarabine, melphalan) prior to autologous stem cell transplant for chemosensitive relapses in patients with follicular lymphoma: a prospective multicentre phase II study in Lymphoma Study Association centres(†)
Ghesquières, H., Dalban, C., Nicolas-Virelizier, E., Jardin, F., Le Bras, F., Le Gouill, S., Casasnovas, O., Vizoso, S., Hernandez, C., Metzger, S., et al
British journal of haematology. 2021
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5.
Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group
Le Gouill, S., Beldi-Ferchiou, A., Alcantara, M., Cacheux, V., Safar, V., Burroni, B., Guidez, S., Gastinne, T., Canioni, D., Thieblemont, C., et al
The Lancet. Haematology. 2020
Abstract
BACKGROUND Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to <66 years) who were eligible for autologous stem-cell transplantation received four cycles of obinutuzumab plus DHAP (obinutuzumab 1000 mg/m(2) intravenously on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4; dexamethasone 40 mg intravenously on days 1-4, cytarabine 2 g/m(2) intravenously every 12 h on day 1, and according to local investigator, cisplatin 100 mg/m(2) by continuous infusion over 24 h on day 1 or carboplatin area under the curve 5 or oxaliplatin 130 mg/m(2)) every 21 days before transplantation, and 3 years of obinutuzumab (1000 mg/m(2) every 2 months) maintenance followed by minimal residual disease-based obinutuzumab on-demand maintenance. The primary outcome was minimal residual disease negativity in the bone marrow after four cycles of obinutuzumab plus DHAP at the end of induction, measured in the efficacy set (all minimal residual disease-informative [bone marrow or peripheral blood] patients who received at least one dose of obinutuzumab). Obinutuzumab plus DHAP was considered effective if bone marrow minimal residual disease negativity was 70% or more by intention to treat. The trial is closed to recruitment and registered with ClinicalTrials.gov, NCT02896582. FINDINGS 86 patients were enrolled between Nov 29, 2016, and May 2, 2018. 81 patients completed induction, 73 underwent autologous stem-cell transplantation, and 69 started maintenance therapy. 55 (75%) of 73 patients in the efficacy set reached minimal residual disease negativity in bone marrow at end of induction. According to the protocol definition, 18 (25%) of 73 patients in the efficacy set were minimal residual disease-positive: 12 patients who were minimal residual disease-positive in the bone marrow, plus two patients who progressed during induction, and four patients who did not have minimal residual disease assessment. The most common grade 3-4 treatment-emergent adverse events were anaemia (grade 3, 26 [31%] of 85 patients; grade 4, three [4%] of 85 patients) and neutropenia (grade 3, 13 [15%] of 85 patients; grade 4, 32 [38%] of 85 patients). 58 serious adverse events occurred during the induction phase. There were no treatment-related deaths. INTERPRETATION Obinutuzumab plus DHAP is a well tolerated regimen and has good activity for inducing minimal residual disease negativity in the bone marrow of transplant-eligible patients with mantle cell lymphoma. Obinutuzumab plus DHAP has potential activity as induction chemotherapy, with bone marrow minimal residual disease negativity potentially predicting long-term disease control. FUNDING Roche SAS.
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6.
Bendamustine-EAM versus BEAM regimen in patients with mantle cell lymphoma undergoing autologous stem cell transplantation in the frontline setting: a multicenter retrospective study from Lymphoma Study Association (LYSA) centers
Hueso, T., Gastinne, T., Garciaz, S., Tchernonog, E., Delette, C., Casasnovas, R. O., Durot, E., Houot, R., Tessoulin, B., Tournilhac, O., et al
Bone marrow transplantation. 2020
Abstract
The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) as conditioning regimen prior to autologous stem-cell transplantation (ASCT) remains the standard of care for patients with mantle cell lymphoma (MCL) who are eligible for transplantation. The replacement of carmustine with bendamustine (BeEAM) was described as a promising alternative in non-Hodgkin lymphoma. The aim of this retrospective study was to compare the BeEAM with the BEAM regimen in MCL patients in the frontline setting. Sixty and 108 patients were included in the BeEAM and the BEAM groups, respectively. At 3 years, progression-free survival (PFS) was significantly higher in the BeEAM than in the BEAM group (84% [73-96] vs. 63% [51-79], p = 0.03). The overall survival was not statistically different between the two groups (p = 0.2). In multivariable analysis, BeEAM regimen remained associated with higher PFS (HR = 0.377, 95% CI, 0.146-0.970; p = 0.043). Subgroup analyses in patients treated with prior rituximab-aracytine induction alone showed that BeEAM improved the PFS compared with BEAM regimen (p = 0.04). Despite the high rate of acute renal failure KDIGO III (32%), treatment-related mortality was not increased with the BeEAM regimen. A prospective randomized trial will be necessary to confirm the beneficial effect of the BeEAM regimen in MCL patients undergoing ASCT.
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7.
Clinical characteristics and outcomes of relapsed follicular lymphoma after autologous stem cell transplantation in the rituximab era
Sesques, P., Bourcier, J., Golfier, C., Lebras, L., Nicolas-Virelizier, E., Hacini, M., Perrin, M. C., Voillat, L., Bachy, E., Traverse-Glehen, A., et al
Hematological oncology. 2020
Abstract
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 years) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = 0.044, HR 2.439, 95% CI [1.025-5.806]), and a high FLIPI score at relapse was associated with PFS (P = 0.028, HR 2.469, 95% CI [1.104-5.521]). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients. This article is protected by copyright. All rights reserved.
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8.
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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9.
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".
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10.
Late Complications and Quality of Life after Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation
Clavert, A., Peric, Z., Brissot, E., Malard, F., Guillaume, T., Delaunay, J., Dubruille, V., Le Gouill, S., Mahe, B., Gastinne, T., et al
Biology of Blood & Marrow Transplantation. 2017;23(1):140-146
Abstract
Late complications (LC) and quality of life (QOL) were analyzed in 110 adult patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) and were alive for more than 2 years after allo-SCT. Overall survival of these patients was 93% (95% confidence interval [CI], 88% to 99%) and 81% (95% CI, 71% to 94%) at 5 and 10 years, respectively. The primary cause of death was a recurrence of primary malignancy. With a median follow-up of 4.6 years (range, 2 to 12.1), chronic graft-versus-host disease (cGVHD) was the most prevalent late effect, with a cumulative incidence of 66% (95% CI, 57% to 74%) at 10 years. Cardiovascular complications were the most prevalent LC with a cumulative incidence of 47% (95% CI, 35% to 59%), followed by pulmonary complications with a cumulative incidence of 33% (95% CI, 21% to 46%) and renal impairment with a cumulative incidence of 34% (95% CI, 25% to 43%) at 10 years. Secondary malignancies occurred with a cumulative incidence of 11% (95% CI, 5% to 20%) at 10 years. In this series, 61 patients (55%) responded to QOL survey. With the use of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and Functional Assessment of Cancer Therapy-Bone Marrow Transplant questionnaires, most of the patients reported good to excellent QOL and patients with cGVHD had significantly lower QOL than patients without cGVHD. In conclusion, QOL after RIC is comparable to that seen after myeloablative conditioning, while the natural history of LC after RIC appears to be different from that described in the standard myeloablative setting, warranting further research in this field. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.