Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1826-1826

Abstract: Introduction: Primary mediastinal B cells lymphoma (PMBCL) is a rare subtype of aggressive non Hodgkin lymphoma (NHL). Despite therapeutic progresses, 10 to 30% of PMBCL patients are primary refractory or experience early relapses (R/R). Despite Autologous hematopoietic cell transplantation (auto-HCT) after bridging therapy or new therapies such as PD-1 inhibitors or CAR-T cells, R/R PMBL patients have a very poor outcome. Allogeneic stem cell transplantation (allo-HCT) is thus a potentially curative treatment for patients who relapsed after salvage therapies. Only limited data have been published about allo-SCT in R/R PMBCL (Herrera A. F, BBMT 2019). In the present study conducted on behalf the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the lymphoma study association (LYSA) group, we investigated the outcomes of allo-transplanted adult R/R PMBCL. Methods This multicenter retrospective study included all adult R/R PMBCL patients reported to the SFGM-TC and who underwent an allo-HCT between 1999 and 2018. Data have been obtained through ProMISe (internet-based system shared by all European transplantation centers) and completed by consulting the medical files of the LYSA group centers. All patients have given signed informed consent. Results Thirty-three patients with R/R PMBCL from 19 French (n=29) and 3 Belgium (n=4) centers were included. The median age at transplant was 33 y (18-61), with a predominance of female patients (58%). Majority of patients had a low HCT-CI score [0 = 9/17 (53%), data missing in 16 patients]. Seventy-six percent of patients had an IPI score between 1 and 2 and Ann Harbor score was ≥ 3 in 56.6% at diagnosis. Median number of treatment lines before allo-HCT was 3 (1-6). All patients received poly-chemotherapies with anthracyclines and anti-CD20 as first-line therapy. Most sixty-one percent of patients had previously undergone auto-HCT and one patient received CAR-T before allo-HCT. Forty one percent of patients were primary refractory. At time of transplant, 50% of patients were in complete response, 40% in partial response, and 10% had a progressive disease. Conditioning regimen was reduced intensity regimen in 63%. Stem cell source was PBSC in 88%. Donors were sibling in 42% or matched related donor in 39%. An alternative donor was chosen in 18%. GVHD prophylaxis included antithymocyte globulin in 61%, and calcineurin inhibitor in 97%. Median follow up was 78 months (3.5-157). Considering the whole cohort, 2y OS, DFS, NRM, and cumulative incidence of relapse were 48% (95%CI: 33-70), 60% (95%CI: 44-82), 18% (95%CI: 7-34), and 34% (95%CI: 18-50) respectively. Cumulative incidences of day 100 grade I-II and III-IV acute GVHD 36% and 0%, respectively. Cumulative incidence was 32% among whom 33% had an extensive cGVHD. Patients with progressive disease at transplantation had worst 2y PFS and OS (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). Conclusion: To our knowledge, this is the largest published study evaluating outcomes of allo-HCT for R/R PMBCL. Although this is a retrospective study with a limited number of patients, the outcomes suggest that allo-HCT is a therapeutic option providing durable remissions for patients with R/R PMBCL. Introduction: Primary mediastinal B cells lymphoma (PMBCL) is a rare subtype of aggressive non Hodgkin lymphoma (NHL). Despite therapeutic progresses, 10 to 30% of PMBCL patients are primary refractory or experience early relapses (R/R). Despite Autologous hematopoietic cell transplantation (auto-HCT) after bridging therapy or new therapies such as PD-1 inhibitors or CAR-T cells, R/R PMBL patients have a very poor outcome. Allogeneic stem cell transplantation (allo-HCT) is thus a potentially curative treatment for patients who relapsed after salvage therapies. Only limited data have been published about allo-SCT in R/R PMBCL (Herrera A. F, BBMT 2019). In the present study conducted on behalf the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the lymphoma study association (LYSA) group, we investigated the outcomes of allo-transplanted adult R/R PMBCL. Methods This multicenter retrospective study included all adult R/R PMBCL patients reported to the SFGM-TC and who underwent an allo-HCT between 1999 and 2018. Data have been obtained through ProMISe (internet-based system shared by all European transplantation centers) and completed by consulting the medical files of the LYSA group centers. All patients have given signed informed consent. Results Thirty-three patients with R/R PMBCL from 19 French (n=29) and 3 Belgium (n=4) centers were included. The median age at transplant was 33 y (18-61), with a predominance of female patients (58%). Majority of patients had a low HCT-CI score [0 = 9/17 (53%), data missing in 16 patients]. Seventy-six percent of patients had an IPI score between 1 and 2 and Ann Harbor score was ≥ 3 in 56.6% at diagnosis. Median number of treatment lines before allo-HCT was 3 (1-6). All patients received poly-chemotherapies with anthracyclines and anti-CD20 as first-line therapy. Most sixty-one percent of patients had previously undergone auto-HCT and one patient received CAR-T before allo-HCT. Forty one percent of patients were primary refractory. At time of transplant, 50% of patients were in complete response, 40% in partial response, and 10% had a progressive disease. Conditioning regimen was reduced intensity regimen in 63%. Stem cell source was PBSC in 88%. Donors were sibling in 42% or matched related donor in 39%. An alternative donor was chosen in 18%. GVHD prophylaxis included antithymocyte globulin in 61%, and calcineurin inhibitor in 97%. Median follow up was 78 months (3.5-157). Considering the whole cohort, 2y OS, DFS, NRM, and cumulative incidence of relapse were 48% (95%CI: 33-70), 60% (95%CI: 44-82), 18% (95%CI: 7-34), and 34% (95%CI: 18-50) respectively. Cumulative incidences of day 100 grade I-II and III-IV acute GVHD 36% and 0%, respectively. Cumulative incidence was 32% among whom 33% had an extensive cGVHD. Patients with progressive disease at transplantation had worst 2y PFS and OS (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). Conclusion: To our knowledge, this is the largest published study evaluating outcomes of allo-HCT for R/R PMBCL. Although this is a retrospective study with a limited number of patients, the outcomes suggest that allo-HCT is a therapeutic option providing durable remissions for patients with R/R PMBCL. Disclosures Sibon: Abbvie: Consultancy; Takeda: Consultancy; iQone: Consultancy; Roche: Consultancy; Janssen: Consultancy. Loschi: AbbVie: Ended employment in the past 24 months, Honoraria; CELGENE/BMS: Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146857

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Acta Oncologica, Informa UK Limited, Vol. 61, No. 11 ( 2022-11-02), p. 1332-1338

Type of Medium: Online Resource

ISSN: 0284-186X , 1651-226X

URL: Article

DOI: 10.1080/0284186X.2022.2130709

Language: English

Publisher: Informa UK Limited

Publication Date: 2022

detail.hit.zdb_id: 1492623-4

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 262-262

Abstract: Introduction Failure to respond to steroid therapy for intestinal acute graft-versus-host disease (aGvHD) is associated with limited further therapeutic options. Fecal microbiotherapy is defined as the perfusion of treated stool from one or several healthy donors via the upper or lower gastrointestinal (GI) route aiming at improving microbial diversity and functionality. Here we report clinical outcomes from a 76-patient cohort with steroid refractory (SR) GI-aGvHD treated with the pooled allogenic fecal microbiotherapeutic MaaT013. Twenty-four patients were treated in the prospective, single-arm, phase IIa, HERACLES study (NCT03359980) while 52 patients were treated in an expanded access program (EAP). Patients and methods For HERACLES, 24 patients with grade III-IV SR-GI-aGvHD were treated with MaaT013 in 26 European sites, as a 2 nd line therapy after SR diagnosis and evaluable for treatment response. In EAP, 52 patients with steroid-dependent or SR-GI-aGvHD (classical n=41, late onset n=3, overlap syndrome n=8) were treated. These patients had previously received and failed 1 to 6 lines (median 3; 40/52 received ruxolitinib) of GvHD systemic treatments. GI-GvHD response was evaluated weekly and 28 days after day (D) 0 (inclusion for HERACLES or 1st dose for EAP). For all patients, GI-overall response rate (ORR) at D28 was defined as the proportion of patients achieving complete response (CR), very good partial response (VGPR) or partial response (PR), compared to D0, without the use of additional systemic therapy. Other endpoints included the best overall response (BOR) achieved at any time, and overall survival (OS). Prepared under GMP, MaaT013 is characterized by a highly consistent richness of 455 ±3% OTUs and an Inverse Simpson index & gt; 20. Treatment comprised 3 MaaT013 doses, each composed of 30 g of feces in 150 mL volume of inoculum (total 90 g of feces from 4 to 8 healthy donors) administered by enema (except for 2 EAP patients by nasogastric tube). All patients received at least 1 MaaT013 dose, 92% (HERACLES) and 87% (EAP) at least 2 doses, and 50% (HERACLES) and 71% (EAP) the full treatment course. In HERACLES, the reasons for not applying the 3 rd dose were death (n=5), physician decision to introduce salvage therapy (n=5), and ICU hospitalization (n=2)). Results In HERACLES, the GI-ORR was 38% including 5 CR, 2 VGPR and 2 PR. In EAP, positive GI-response was achieved in 31/52 patients (60% with 16 CR, 11 VGPR and 4 PR). Considering the GI-BOR, 13/24 (54%) and 35/52 (67%) achieved at least a PR in HERACLES and EAP respectively. In HERACLES, OS was 29% at month (M) 6 and 25% at M12. OS was significantly higher in responding (R) patients (achieving at least PR at D28) compared to non-responding (NR) (44% vs 20% at M6 and 44% vs 13% at M12, logrank p=0.047). In EAP, OS was 48% at M6 and 37% at M12, and significantly higher in R patients compared to NR (71% vs 17% at M6 and 62% vs 6% at M12, logrank p & lt;0.0001). In HERACLES, treatment with MaaT013 was characterized by excellent tolerance: 252 Treatment-Emergent Adverse Events (TEAE) were reported for the 24 patients, the majority being infections (79%) and GI disorders (62%), as expected in GvHD patients. Of these 252 TEAE, only 2% (5 serious events in 2 patients) could not reasonably be excluded from being related to MaaT013 by the investigators. Shotgun sequencing in these 5 TEAE revealed that the causative infectious agents could not be detected in the administered MaaT013. In EAP, the safety profile of MaaT013 was considered satisfactory for all patients. 16S microbiome analyses were performed in the HERACLES population and showed that MaaT013 produced an early increase in α-diversity at genus level with a significant increase in Richness index at all evaluated timepoints (p & lt;0.003). At D28, R patients had higher values of α-diversity indices (Shannon p=0.005 and Richness p=0.038) compared to NR patients, and higher proportions of MaaT013-derived species in the total composition of R microbiota (p=0.043). Conclusion We herein report the treatment of 76 SR-GI-aGvHD patients using a full ecosystem, pooled-donor, high-richness biotherapeutic. The D28 GI-ORR was 38% and 60% in HERACLES and EAP respectively and this clinical benefit positively and significantly impacted OS (44% and 62% M12 in HERACLES and EAP R patients respectively). MaaT013 was shown to be safe and effective in these heavily immunocompromised patients, warranting further exploration of this approach. Figure 1 Figure 1. Disclosures Malard: JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Astellas: Honoraria; Biocodex: Honoraria; Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria. Loschi: CELGENE/BMS: Honoraria; AbbVie: Ended employment in the past 24 months, Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Cluzeau: Agios: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Takeda: Other: travel, accommodations, expenses. Huynh: Jazz Pharmaceuticals: Honoraria. Holler: MaaT Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vehreschild: SocraTec R & D GmbH: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Takeda Pharmaceutical: Research Funding; Seres Therapeutics: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; 3M: Research Funding. Gasc: MaaT Pharma: Current Employment. Plantamura: MaaT Pharma: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147709

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5771-5771

Abstract: Introduction Next generation sequencing (NGS) has allowed to improve knowledge about the genomic landscape of hematological malignancies. Somatic mutations (SM) are valuable new biomarkers but the utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains challenging. We report here an observational multicentric study aimed at assessing the impact of SM testing by NGS in a real-life setting on the diagnosis and treatment of chronic myeloid malignancies (CMM). Patients and Method All patients who benefited from molecular assessment, between 10/2014 and 03/2019 in our University Hospital were included. All provided informed consent for data collection. All NGS requests were validated during a regional multidisciplinary concertation meeting. A custom targeted panel of 34 genes (145kbp i.e. ASXL1,BCOR, BCORL1, CBL, CSF3R, DNMT3A, ETV6, EZH2, GATA2, IDH1, IDH2, JAK2, KDM6A, KIT, KRAS, MPL, NPM1, NRAS, PIGA, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TNFAIP3, TP53, U2AF1, ZRSR2) was applied on DNA extracted from peripheral blood or bone marrow samples. DNA libraries, built with the Haloplex® target enrichment protocol (Agilent Technologies, Santa Clara, CA), were paired-end sequenced (150bp reads) with a MiSeq® Instrument (Illumina, San Diego, CA). Data analysis used an in-house pipeline including three variant callings (GATK HaplotypeCaller, VarScan and SAMTools). In a first group (A), NGS indication was to search for clonal hematopoiesis (CH), defined by the presence of at least one SM, in order to confirm or rule out a diagnosis of Idiopathic Cytopenia of Undetermined Significance (ICUS), Clonal Cytopenia of Undetermined Significance (CCUS), myelodysplastic syndrome (MDS), mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN), aplastic anemia (AA)/hypoplastic myelodysplasia (hMDS) or myeloproliferative neoplasm (MPN), based on recommendations of the WHO classification. In a second group (B), the theranostic impact of SM was studied. Prognostic SMs according to Bejar (2011) were used for MDS and MDS/MPN excluding chronic myelomonocytic leukemia that were analyzed with Itzykson score (2013) and/or CPSS-Mol score (Elena 2016). Prognostic SMs according to Vannucchi (2013) were used for myelofibrosis. Results The median age of the cohort was 60 years old (range: 10-87) with a median follow up of 1.1 years from molecular assessment to last follow-up. Within group A (94 patients), the most frequent blood count anomalies were cytopenia (68%), thrombocytosis (16%), and monocytosis (13%). The karyotype was normal in 77% and failed in 5% of the cases. Non-specific abnormalities (i.e. loss of chr Y, del 20q), were found in 8% of the cases. Before molecular assessment, the diagnoses proposed were ICUS (n=37), suspicion of MDS/MPN (n=16), AA/hMDS (n=16), or MPN (n=25). CH was detected in 31 patients comforting the diagnosis of CMM for 33% of group A (8 CCUS, 3 MDS, 7 MDS/MPN, 6 medullary hypoplasia, 7 MPN) patients. Considering the patients for whom no CH was detected (n=63), the initial suspected diagnosis of CMM was ruled out in 47 patients (i.e. 50% of group A). For the 16 remaining (i.e. 17% of group A), no firm diagnosis could be retained. Within group B (95 patients), NGS identified prognosis SM in 33% of the patients, i.e. poor prognosis SM in 24, including 8/40 MDS, 10/29 MDS/MPN and 6/17 myelofibrosis and good prognosis SM(SF3B1) in 7 of them, respectively 6/40 MDS and 1/29 MDS/MPN. Prognostic SMs had a therapeutic impact in 18/95 pts (19%). Indeed 13 patients with poor prognosis SM had a therapeutic change including 12 allogeneic stem-cell transplantation and 1 hypomethylating agent. Conversely, 5 patients with a good prognosis SM or absence of poor prognosis SM had a de-escalation of treatment intensity. Conclusion The use of NGS in daily practice had a clinical impact in both diagnostic and therapeutic decisions provided that the prescription is made in a critically explored context and not as a systematic test. In this "real life" cohort, the presence or absence of SM was a useful complement for integrated diagnoses in 83% of the patients, allowing to confirm (33%), or exclude (50%) a suspected condition. Moreover, in this cohort 34% of the patients had a SM with a reported prognostic impact and the treatment was modified in 19% of the cases. Yet, it remains necessary to integrate these results with other diagnostic criteria. Disclosures Peterlin: AbbVie Inc: Consultancy; Jazz Pharma: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Chevallier:Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-122958

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 99, No. 8 ( 2020-08), p. 1855-1862

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-020-04074-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 1458429-3

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 980-980

Abstract: Introduction: Allogeneic stem cell transplantation is a potentially curative treatment for patients with high-risk non-Hodgkin lymphoma (NHL). Fludarabine/busulfan based conditioning regimens are widely used in Europe for this purpose. Busulfan dose intensity discriminates between reduced intensity (FB2, 2 days of busulfan at 4 mg/Kg/d per os or 3.2 mg/kg/d iv) and reduced-toxicity myeloablative (FB3/FB4, 3 or 4 days of busulfan at 4 mg/Kg/d per os or 3.2 mg/kg/d iv) conditioning regimens (Bacigalupo, 2009). While some data have been recently published showing some advantages of higher busulfan dose intensity for myeloid malignancies, there is no such data available in the lymphoid setting. Methods: This was a large retrospective study conducted on behalf of the SFGM-TC including all adults allografted in France between January 2004 and December 2014 for NHL (n=378). Clinical data were obtained through ProMISe (Project Manager Internet Server), an internet-based system shared by all French transplantation centers. We aim to compare various outcomes (overall (OS) and lymphoma free (LFS) survivals, relapse incidence (RI), non-relapse mortality (NRM), acute and chronic GVHD) between those who received FB2 (n=277) or FB3/FB4 (n=101) as conditioning regimens. GVHD free relapse free survival (GRFS) was also studied (defined as alive with no previous grade III-IV aGvHD, no moderate or severe chronic GvHD (cGvHD) and no relapse). Results: Both groups were comparable for the following variables: median follow-up (FB2: 24.9 vs FB3/4: 23 months), gender (male 61% vs 53%), disease type (low-grade lymphoma 25% vs 21%, mantle-cell lymphoma 17% vs 13%, high-grade lymphoma 25% vs 21%, T cell lymphoma 32% vs 45%), disease status at transplant (complete remission/very good partial response 64% vs 62%, partial response 28% vs 31%, active disease 8% vs 7%), donor type (sibling 43% vs 49.5%, matched unrelated 56% vs 47), median number of previous courses of treatment (2 vs 2, p=0.44), stem cell source (peripheral blood 96% vs 95%). FB2 patients were significantly older (median 57.3 vs 53.1 years, p=0.07), have been transplanted more recently (median year of transplant: 2011 vs 2010, p=0.001) and have been more previously autografted (69% vs 50.5%, p=0.001). FB3/4 patients have been allotransplanted earlier during the evolution of their disease (median time between diagnosis and allograft 18.2 vs 33.8 months, p 〈 0.0001). The majority of patients (n=353, 98.4%) received ATG as GVHD prophylaxis. Engraftment was observed in 97.8% of FB2 patients vs 100% of FB3/4 cases (p=0.13). In univariate analysis, 2-years OS (FB2 66.5% vs 60.3%, p=0.33), LFS (FB2 57.9% vs 49.8%, p=0.26), RI (FB2 23% vs 29.1%, p=0.32) and NRM (FB2 19% vs 21.1%, p=0.91) were similar between both groups. Cumulative incidence of grade 3-4 acute (FB2 11.2% vs 18%, p=0.08) and extensive chronic (FB2: 17.3% vs 10.7%, p=0.18) GVHD were also comparable as well as 2-year GRFS (FB2: 44.4% vs 42.8%, p=0.38). When considering patients allografted before or after the median time between diagnosis and the time of allograft for the whole cohort ( 〈 or 〉 =30 months), there were also no significant differences between both groups in terms of OS, LFS, RI or NRM. In multivariate analysis there was a trend for worse outcome using FB3/FB4 regimens (OS: HR 1.46, 95%CI: 0.96-2.23, p=0.07; LFS: HR: 1.43, 95%CI: 0.99-2.06, p=0.05; RI: HR 1.54; 95%CI: 0.95-2.48, p=0.07). These results were also confirmed using a propensity score-matching strategy including 184 FB2 and 98 FB3/4 patients. Conclusion: This large retrospective study showed that reduced toxicity myeloablative fludarabine/busulfan regimens did not improve outcomes of adults allografted for NHL. FB2 conditioning regimen still should be considered as the standard of care conditioning regimen in this setting. To validate these results, prospective studies are needed, like the French prospective trial currently ongoing for myeloid diseases (NCT01985061). Also, new conditioning regimens and post-allograft strategies should be tested to improve outcomes of patients. Disclosures Peffault De Latour: NOVARTIS: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.980.980

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3465-3465

Abstract: Introduction: Myeloid Derived Suppressive Cells (MDSC) constitute a heterogeneous population of immature myeloid cells characterized by their capacity to suppress innate and adaptive immune responses. As such, they have been proven, in solid tumors, to modulate malignancy by increasing tumor cell survival, angiogenesis, metastasis and tissue invasion. By contrast, reports on the role of MDSC in either acute myeloid (AML) or lymphoid (ALL) leukemias are very limited with unknown established impact on long-term outcomes. Patients and Methods: This monocentric prospective study included all adult patients eligible for first-line intensive chemotherapy for AML or ALL. The main objective was to investigate the presence of peripheral blood monocytic MDSC at diagnosis and after induction in such patients and to correlate their levels to complete remission (CR/CR with incomplete platelet recovery), cytologic relapse, leukemia-free (LFS) and overall (OS) survivals. Monocytic MDSCs were defined as CD15- CD34- CD16- CD14+ CD33+ CD11b+ DR-/low cells and assessed in a lysis-no-wash flow cytometry technique. Data acquisition was performed on a Navios® flow cytometer (Beckman Coulter, Miami, FL). MDSC were expressed as a percentage (%) of total nucleated cells defined as CD45+. MDSC% were compared to those of 21 healthy controls. The study was registered at the French Commission Nationale de l'Informatique et des Libertés as CNIL 2016-038. All patients gave informed consent. Analyses were performed in July 2021. Results: Between October 2017 and March 2021, 73 AML and 14 ALL were enrolled (Table 1). The median MDSC% in controls was 0.24% (range: 0.02-1.21). This % was significantly higher in AML compared to ALL (0.19% (range: 0-0.54) vs 0.14% (range: 0-0.35), p=0,01) and differed significantly from controls in ALL (p=0.0004) but not in AML (p=0.94). MDSC% after chemotherapy induction were available for 61 AML and 13 ALL at medians of 37,5 and 37 days, respectively. At that time, median MDSC% were similar between AML (0.84%, range: 0-28) and ALL (0.97%, range: 0-4.75) patients (p=0.52) but significantly higher than in controls for AML patients (p=0.001; ALL p=0.07). AML: MDSC% were not correlated to any other factors, especially ELN2017 classification (p=0.79). ROC curves for LFS established the threshold of 0,55% of MDSC at diagnosis as the best cut-off for analyses. MDSC% ( & lt; vs & gt;0,55%) was not predictive of CR/CRp (86.6% n=39/45 vs 78.5% n=22/28, p=0.56). However, 2-year LFS (67.7+8% vs 30.1+10%, p=0.005) and 2-year OS (71.5+8% vs 30.1+10%, p=0.001). (Figure 1) were significantly higher for patients with low MDSC% ( & lt;0.55%). The incidence of cytologic relapse after achieving CR/CRp was significantly lower in these low MDSC% patients (12.8% n=5/39 vs 45.4% n=10/22, p=0.01). The median percentage of MDSC increased significantly between diagnosis (0,19%) and post-induction (0,84%; p=0.001). Median post-induction MDSC% were similar between patients achieving CR/CRp (0.9%, n=53 evaluable) vs others (0.44%, n=8 evaluable, p=0.34). No impact on relapse incidence nor on LFS and OS was observed when comparing patients based on the median post-induction level of MDSC and ROC curves did not identify thresholds able to predict LFS or OS using MDSC% post-induction. Multivariate analysis confirmed the independent prognostic value of MDCS% at diagnosis for AML patients (LFS p=0.026, HR 3.6, 95%CI 1.88-6.91; OS p=0.02-, HR 2.6, 95%CI 1.11-5.95) together with ELN 2017 classification (LFS p=0.0001, HR 2.34, 95%CI 1.10-4.97; OS p=0.01, HR 2.57, 95%CI 1.18-4.11). ALL: MDSC% at diagnosis were not predictive of response as 13/14 patients achieved CR/CRp after induction. The percentage of MDSC increased significantly between diagnosis (0.14%) and post- induction (0.97%; p=0.002). Again, this had no consequence on relapse incidence in CR/CRp patients nor on LFS and OS when comparing patients based on median post induction MDSC%. Discussion: This study evidenced that a higher percentage of peripheral monocytic MDSC at diagnosis predict lower survivals in AML patients because of more relapse. This result has to be confirmed on larger cohorts as it may implicate to propose immune intervention before or in combination with chemotherapy to improve these patients' outcome. Indeed, these cells seem to be an independent biomarker and potentially promising targets for the development of novel therapeutic strategies. Figure 1 Figure 1. Disclosures Moreau: Sanofi: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-149405

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 25, No. 7 ( 2019-07), p. 1465-1471

Type of Medium: Online Resource

ISSN: 1083-8791

URL: Article

DOI: 10.1016/j.bbmt.2019.03.025

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 3056525-X

detail.hit.zdb_id: 2057605-5

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1484-1484

Abstract: The cytokine Fms-like tyrosine kinase 3 ligand (FL) is a key regulator of hematopoiesis. In a previous Phase 1 study testing a radioimmunotherapy regimen for relapsed/refractory acute lymphoblastic leukemia (ALL), responders showed increased soluble FL serum concentration (sFLc) after salvage regimen (Chevallier, Lancet Haematol., 2015). This prospective monocentric study (ClinicalTrials.gov NCT02693899) aimed to assess the impact of sFLc in ALL and acute myeloid leukemia (AML) patients treated according to standard-of-care intensive first-line chemotherapy regimens. Serum samples were collected on days 1, 8, 15, 22 of induction, at days 1, 8, 15 of each intensive consolidation or day 1 of each non intensive consolidation when appropriate, frozen-stored then tested by ELISA (DY308, R & D Systems, Minneapolis, MN). The following outcomes were considered to assess the impact of sFLc: refractory status after induction (≥5% bone marrow blasts or persistent aplasia 〉 45 days), morphologic, immunophenotypic, cytogenetic or molecular relapses, event-free (EFS) and overall survival (OS). All patients provided informed consent. Between May 2016 and January 2018, 80 patients were included. Data were ultimately available for 16 ALL and 62 AML patients. A total of 579 samples were assayed. Analysis of the results disclosed 3 sFLc kinetic profiles during induction i) sustained increase from days 1 to 22 (FLI group), ii) increase from days 1 to 15, then decrease at day 22 (FLD group) and iii) stagnation of low levels all along ( 〈 1000 pg/mL from days 1 to 22, FLL group). The 16 evaluable ALL patients were classified as FLI (n=2), FLD (n=7) and FLL (n=7). All reached a cytologic complete remission after induction and only 2 relapses have been documented so far in this group. No impact of sFLc kinetic profile was seen in this context. Conversely, a significant impact of sFLc during induction (but not during consolidation) was observed in AML patients. The median age in this group was 59 years old (range: 29-71, 〈 60 years n=33). The median follow-up for alive patients was 541 days (range: 154-787). sFLc levels were assayed in 244 samples. Twenty-six patients were classified as FLI (42%), 22 as FLD (35%) and 14 as FLL (23%). Median sFLc at days 1, 8, 15, 22 were as follows for the three groups: FLI: 2, 724, 3673, 5753 pg/mL; FLD: 6, 1229, 6019, 684 pg/mL; and FLL: 0, 60, 124, 81 pg/mL. There was no significant difference between the 3 groups regarding age, ELN 2010 risk-stratification (ELNrs), OMS classification, WBC and bone marrow blasts percentages at diagnosis. When comparing the 3 sFLc groups, almost all refractory patients (n=6) were found in the FLL group (n=5, FLD n=1, FLI n=0, p=0.0007). Three cytologic relapses occurred in the FLI group, 7 in the FLD group (cytologic n=4, molecular n=2, immunophenotypic n=1) and 7 in the FLL group (cytologic n=4, molecular n=2, immunophenotypic n=1). There were more relapses in the FLL group (n=7/9 [78%] vs FLD n=7/21 [33%] vs FLI n=3/26 [11.5%], p=0.0009). In univariate analysis, 2-year EFS and OS were significantly better for the FLI group (79.1+-8 vs FLD 54.9%+-11 vs FLL 11.4%+-10,p 〈 0.001; and 80.4%+-8 vs FLD 58.6%+-11 vs FLL 18.6%+-10, p=0.09,respectively). There was a trend for the association of 2-year EFS (but not OS) with ELNrs (favorable:70.9%+-11, vs Int-1+Int-2:57.1%+-10 vs adverse 33%+-13,p=0.06). Stratification of the patients according to the median sFLc level at day +15 (2952pg/mL) also showed significantly different 2 year EFS at 38.2%+-9 for low levels vs 71.8%+-8 for high levels (p=0.02). The same was true for day +22 median sFLc level (1390pg/mL) at 38.9%+-9 vs 73.6%+-8 (p=0.02). Age had no impact on EFS nor OS. In multivariate analysis considering age, ELNrs, sFLc at days 15 and 22 levels, and sFLc kinetic profile during induction, the latter remained the most powerful factor independently associated with EFS (HR: 3.62; 95%CI: 1,65-7,94, p=0,001; ELNrs: HR: 1.74; 95%CI: 0,98-3.10, p=0.05; sFLc at day+15 p=0,37; sFLc at day+22, p=0.24, age p=NS). sFLc kinetic profile was the sole factor that was also independently associated with OS (HR: 2.60; 95%CI: 1.12-6,07, p=0.02). In conclusion, sFLc kinetic profile during induction appears to be a new powerful early prognostic parameter in AML patients. These results need to be validated on a larger cohort of patients and the mechanism by which induction sFLc levels may impact AML outcome remains to be elucidated. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111694

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3319-3319

Abstract: Introduction Chronic expansion of large granular lymphocytes (LGL) has been reported after classical matched allogeneic hematopoietic stem cell transplantation (SCT) with bone marrow, peripheral (PB) or cord blood (CB) as source of graft. This proliferation is indolent and carries a favorable prognosis. Little is known of the incidence and features of LGL expansions in haplo-SCT with post-transplant cyclophosphamide (PTCy), where the impact of the duration of lymphopenia is also ill-documented. Patients & methods This study included 85 adult patients (pts) who received a haplo-SCT between 11/2013 and 03/2019 for hematological diseases. The 3 conditioning regimen used were i) Baltimore (n=28, 11/2013-05/2017) i.e. fludarabine 30 mg/m²/day (d), d -6 to -2, cyclophosphamide 14.5 mg/kg d -6, low dose total body irradiation (LDTBI) 2 Grays d-1, ii) Clo-Baltimore (n=28, 03/2014-04/2017), i.e. Clofarabine 30 mg/m²/d, d -6 to -2, cyclophosphamide 14.5 mg/kg d -6, LDTBI 2 Grays d -1, iii) CloB2A1 (n=29, 05/2017-03/2019) with Clofarabine 30 mg/m²/d,d -6 to -2, busulfan 3,4 mg/kg d -3 and -2, ATG 2,5 mg/kg d-1. All pts received mobilized PB as SC source on d 0 and PTCY 50 mg/kg/d on d +3 and +4 with cyclosporine and mycophenolate mofetyl as graft versus host disease (GVHD) prophylaxis. All pts provided informed consent for data collection. The duration of lymphopenia ( 〈 1.5x109/L) as well as occurrence, duration and immunophenotype of LGL expansion ( 〉 4x109/L) were recorded. The patients with primary graft failure (n=6) or dead before 3 months (mo) post-SCT were excluded (n=7). Engraftment was monitored by qPCR on PB cells and sorted CD3+ T-cells. TCR-γ/β gene rearrangements of CD3+ collected during sustained lymphocytosis were assessed with the Biomed-2 PCR method (n=7). Data were analyzed considering viral reactivation episodes (CMV, EBV, HHV6 or BK virus), acute or chronic GVHD, relapse and survival. Results The study included 72 adults treated with haplo-SCT (43 males, median age: 59 yo (24-71)) with a median follow-up of 31 mo for alive patients. Most pts had a myeloid disease (64%) and 57% were in complete remission at the time of haplo-SCT. The median duration of lymphopenia was 6 mo (1-49), significantly shorter in pts with a CloB2A1 conditioning (151 d vs. Baltimore 293 d vs. Clo-Baltimore 387 d, p=0.003) or with CMV reactivation (138 d vs 361 d, p 〈 0.0001). Brisk LGL expansion was characterized morphologically in 10 pts (14%), of donor origin in the 9 pts tested. It occurred at a median of 5 mo (2-8), whatever the GVHD prophylaxis. These pts had a shorter duration of lymphopenia (4 vs 10 mo, p=0.0002). The median duration of LGL expansion was 6 mo (0.1-22) with a median lymphocyte count of 5.8x109/L (4.3-19.4). Immunophenotyping disclosed expansions of NK-cells (n=2), CD8+ CD4- T-cells (n=6) or CD4- CD8- TCR gd T-cells (n=2). They were oligoclonal (n=4) or monoclonal (n=3). A recipient CMV+ status was strongly associated with the onset of LGL expansion (89% vs 20%, p=0.0001), and with CMV reactivation (35% vs 4%, p=0.001) but not with that of other viruses. Grade 2-4 acute and chronic GVHD were not correlated with LGL expansion. ROC curve analyses identified that pts with more than 216 d of lymphopenia (AUC=0.83, p 〈 0.001) had a better 2y disease-free survival (DFS) (77% vs 38%, p=0.0008) and 2y overall survival (OS) (81% vs 45%, p =0.0006) (Fig. 1). LGL expansion was associated with a significantly lower incidence of relapse (10% vs 50%, p=0.03), better 2y-DFS (86% vs. 51%, p=0.05) and a trend towards a better 2y-OS (86% vs. 54%, p=0.1) (Fig. 2). Only 1 of these pts has relapsed and died of transplant-related mortality. Neither the recipient's CMV status nor CMV reactivation influenced DFS or OS. Multivariate analysis showed that the disease risk index score (Armand 2014), lymphopenia ( 〉 216 days) and LGL expansion, but not age ( 〉 60yo), were independently associated with a better DFS and OS (p 〈 0.0001). Conclusion A shorter duration of lymphopenia after haplo-SCT confers unexpectedly shorter survivals, suggesting the expansion of non-allo-reactive T-cells with a reduced graft versus leukemia effect. LGL expansion (14%) is not a rare event after haplo-SCT, mainly involves CD8+ T-cells, occurs preferably in CMV+ recipients or in pts with CMV reactivation. It is associated with a favorable outcome, similar to that observed in matched and CB SCT. Disclosures Peterlin: AbbVie Inc: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Chevallier:Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-122093

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7