Simona Sestili - Academia.edu (original) (raw)

Papers by Simona Sestili

Bone Marrow Transplantation

Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophy... more Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dosedependent toxicities, particularly in frail patients. Therefore, we compared the outcomes with a reduced PT-Cy total dose (70 mg/ kg) to those with the standard PT-Cy dose (100 mg/kg) in haploidentical hematopoietic cell transplantation (HCT) patients aged ≥ 65 years and those with cardiac comorbidities. All consecutive patients with a hematological malignancy receiving peripheral blood stem cells (PBSCs) after a thiotepa-based conditioning with low-dose antithymocyte globulin were included. Thirty-three patients received PT-Cy at 70 mg/kg and 25 at 100 mg/kg. PT-Cy dose reduction did not increase the risk of GVHD and was associated with faster neutrophil and platelet recovery, and lower cumulative incidences of bacteremia (38% versus 72%, p = 0.004) and cardiac complications (12% versus 44%, p = 0.028). At 2 years, GVHD-free, relapse-free survival (GRFS) was higher with the reduced dose compared to the standard dose (60% versus 33%, p = 0.04). In conclusion, reducing PT-Cy total dose to 70 mg/kg is a safe and valid approach for elderly patients and those with cardiac comorbidities underdoing haploidentical HCT with PBSCs and low-dose antithymocyte globulin. The reduced PT-Cy dose was associated with improved hematological count recovery, lower incidence of toxicities, and higher GRFS.

Endocrine Research, Aug 22, 2012

Background. Insulin resistance (IR), a link of paramount importance between obesity and cardiovas... more Background. Insulin resistance (IR), a link of paramount importance between obesity and cardiovascular/metabolic complications, seems to be implicated in weight changes. Objective. To determine whether IR could influence weight status during a 1-year intervention program in obese prepubertal children. Methods. Forty-four children with IR (IR group) and 42 children without IR (NIR group) were enrolled. Body mass index standard deviation score (BMI-SDS), waist circumference (WC), and homeostasis model assessment (HOMA-IR) were evaluated. Results. NIR children showed a significant reduction of BMI-SDS and WC at final assessment (p ¼ 0.009 and p ¼ 0.001, respectively), whereas IR children presented unchanged values. HOMA-IR decreased after intervention in the NIR group (p ¼ 0.0008), but was exacerbated in IR children (p ¼ 0.004). A positive and significant association between HOMA-IR at baseline and BMI at follow-up was found (B AE SE ¼ 0.87 AE 0.24, p ¼ 0.001). HOMA-IR at baseline was also significantly associated with WC at follow-up (B AE SE ¼ 2.12 AE 0.69, p ¼ 0.003). Conclusions. IR seems to influence adiposity changes in obese prepubertal children. Further longitudinal studies are needed to verify the relationship between IR and weight loss during childhood.

Current Research in Translational Medicine, Aug 1, 2019

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of... more Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of hematologic diseases whether in remission or in the relapsed/refractory setting [1]. However, this treatment modality is associated with several complications leading to a high risk of morbidity and mortality. Among these complications, poor graft function (PGF) occurs in 5 to 27 % of patients after allo-HSCT [2]. Primary PGF is defined as persistent neutropenia (Absolute Neutrophil Count 0.5 Â 10 9 /L), thrombocytopenia (platelets 20 Â 10 9 /L), and/or anemia (hemoglobin 70 g /L). PGF can be secondary occurring after prompt neutrophil recovery. Moreover, in patients with PGF, the chimerism is full donor and it should be distinguished from graft failure where the chimerism is mixed. The pathogenesis of PGF remains unclear. It has been reported by Wang et al suggested, that dysregulated T cell responses might contribute to the pathogenesis of PGF after allo-HSCT. In patients with PGF they find higher proportions of stimulated CD4+ and CD8 + T cells that produce IFN-g (Th1 and Tc1 respectively) while the proportions of IL-4-producing T cells (Th2 and Tc2 cells) were decreased [3]. In addition to Th1 and Tc1 cells, Th17 cells may also contribute to PGF, given the ratio of Th17 cells to regulatory T cells was dramatically increased in the bone marrow of PGF patients compare to that in patients with goodgraft function patients [4]. Nevertheless, treatment strategies are mainly based on the administration of granulocyte colony stimulating factor (G-CSF) which has a short-term effect [5]. Alternatively, second allo-HSCT have been performed but at the cost of an increased toxicity [6]. Alternative and more recent treatment modality is the infusion of CD34+-selected stem cell "Boost" from the same donor without prior conditioning. We, therefore, therefore retrospectively studied the efficacy and safety of CD34+-selected stem cell "Boost" for the treatment of PGF after allo-HSCT. We included10 patients who received a "Boost" of CD34 +-selected stem cells for poor graft function after allo-HSCT between January 2014 and January 2016. 4 patients were males and 6 were females with a median age of 45 (range, 19-67) years at time of transplant. Underlying hematologic malignancies diagnoses include acute myeloid leukemia in 4 patients, myelofibrosis in 2 patiens, chronic myelomonocytic leukemia in 2 patients, acute

Blood, Nov 5, 2021

Introduction The outcome of conventional allogeneic hematopoietic cell transplantation (HCT) for ... more Introduction The outcome of conventional allogeneic hematopoietic cell transplantation (HCT) for the treatment of patients with refractory myeloid malignancies remains poor. Thiotepa-based sequential conditioning has shown promising results for various refractory hematological malignancies (Duléry R et al. Biol Blood Marrow Transplant. 2018; 24(5):1013-1021). However, no study has evaluated the outcome of this sequential approach specifically in refractory myeloid malignancies. The optimal dose of chemotherapeutic agents used in the conditioning regimen and the feasibility of this sequential approach in patients aged 60 years and above also need to be assessed. Methods All consecutive patients with refractory myeloid malignancy who underwent allogeneic HCT with a thiotepa-based sequential conditioning regimen in Saint Antoine hospital between April 2013 and October 2020 were included. The sequential approach consisted of a broad spectrum cytoreduction with thiotepa, etoposide, and cyclophosphamide (TEC) from day -15 to -10. Then, after a 3-day rest, a reduced-intensity conditioning (RIC) regimen was administered with fludarabine 150 mg/m 2, intravenous busulfan 6.4 mg/kg and thymoglobulin 5 mg/kg from day -6 to -2. From 2013 to 2018, doses of thiotepa (10 mg/kg), etoposide (400 mg/m 2) and/or cyclophosphamide (1600 mg/m 2) could be reduced in patients older than 60 years or with comorbidities. Since September 2018, the use of a reduced TEC-RIC regimen (thiotepa at 5 mg/kg, etoposide 300 mg/m 2 and cyclophosphamide 1200 mg/m 2 from day -13 to -10) became the new standard of care for all patients. After transplant, patients could receive a hypomethylating agent or targeted therapy to prevent relapse. Prophylactic donor lymphocyte infusions were given to enhance the graft-versus-leukemia effect, in the absence of contraindication. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and mycophenolate mofetil for all patients. Post-transplant cyclophosphamide was added in the case of haploidentical HCT. Results Seventy-one patients (median age 61 years, range 15-76) were included. Diagnoses comprised acute myeloblastic leukemia (n=65) and myelodysplastic syndrome/chronic myelomonocytic leukemia (n=6). Donors were haploidentical (n=36), matched related (n=13), unrelated (n=21) and umbilical cord blood (n=1). A reduced TEC-RIC was administrated to 43 (61%) patients, a full dose TEC-RIC to 18 (25%), and a TEC-RIC with a dose reduction only for thiotepa to 10 (14%). With a median follow-up of 45.4 months (95% CI: 36.7-63.6), the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 51%, 41%, and 24%, respectively. Patients receiving a reduced TEC-RIC had a lower cumulative incidence of acute and chronic GVHD (acute grade II-IV GVHD: 14%, acute grade III-IV GVHD: 0%, chronic GVHD: 19%) than the other patients (acute grade II-IV GVHD: 29%, acute grade III-IV GVHD: 18%, chronic GVHD: 29%). The outcomes were not significantly different according to the TEC dose in terms of relapse incidence, OS, and PFS, although the NRM was lower with the reduced TEC-RIC (21% versus 28%, p=0.72). Most notably, patients aged 60 years and above had a 2-year OS and PFS of 48% and 39%, respectively, with no significant difference compared to patients younger than 60 years (Figure). Conclusion Our findings endorse the feasibility and efficacy of a thiotepa-based sequential approach for refractory myeloid malignancies undergoing HCT. The dose reduction did not compromise disease control and expanded the transplant option to older patients, ineligible for a higher dose regimen. Thus, a reduced TEC-RIC sequential regimen can be proposed for selected patients older than 60 years and allows promising outcomes for the treatment of refractory myeloid malignancies. Figure 1 Figure 1. Disclosures Duléry: Gilead: Other: travel support and meeting fees; Takeda: Consultancy; Novartis: Honoraria. Malard: Therakos/Mallinckrodt: Honoraria; Biocodex: Honoraria; Astellas: Honoraria; JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Legrand: Servier: Consultancy. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. 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.

Blood, Nov 5, 2020

Background: Pre- and post-transplant pulmonary function tests (PFT) have been previously analyzed... more Background: Pre- and post-transplant pulmonary function tests (PFT) have been previously analyzed in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). A deterioration in pulmonary function could be observed in this setting and accounts for higher morbidity and mortality. Haploidentical allogeneic stem cell transplantation (HAPLO) with post-transplant cyclophosphamide (PTCY) is increasingly used. Limited data exists on evaluation of PFT after HAPLO and the number of patients who underwent HAPLO in previously published studies is negligible. We report the evolution of PFT as well as pre-transplant characteristics and outcomes after HAPLO in the adult setting. Methods: We retrospectively analyzed 80 HAPLO performed in a single center between 2013 and 2019. All patients with available pre- and post-transplant PFT results were included in the study. The Friedman test was used for comparing PFT at baseline, 100 days and 1 year after HAPLO. Results: The median follow up was 32 (range: 12-74) months. CMV serology was positive in 45% and 65% of patients were male. The median age was 58 (range: 16-73) years. The proportion of surviving patients with available PFT at 3 months and 1 year were 86% and 68%, respectively. Diagnosis was acute myeloid leukemia in 51% and disease risk index was intermediate-low in 75% of the cases. Disease status before HAPLO was complete remission in 61%. Graft source was peripheral blood stem cells in 91% of the cases. Conditioning regimen was reduced intensity in 40% and the most frequent chemotherapy regimen was thiotepa, busulfan and fludarabine. Graft-versus- host disease (GvHD) prophylaxis consisted of Cyclosporine A (CsA) and mycophenolate mofetil in all but one patient who received methotrexate and CsA. All patients received PTCY, 64 (80%) at days 3 and 5 after HAPLO, 7 (9%) at days 3 and 4, and 9 (11%) at day 3 only. Seventy-three (91%) patients received anti-thymocyte globulin. In total, 24% of the patients had previously smoked, 8% had type 2 diabetes, and 23% suffered from hypertension. Three patients had a lung infection at baseline, of which one was bacterial and two were possibly aspergillosis. At screening for HAPLO, five (6%) patients had restrictive lung disease, nine (11%) met the criteria for obstructive lung disease, and diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin was impaired in 74% of the patients. The median forced expiratory volume in the first second (FEV1) was 100 (range: 58-146) before HAPLO, 93 (range: 42-10) at 100 days after HAPLO and 99 (range: 32-144) at 1 year. The median forced vital capacity (FVC) was 106 (range: 57-153), 98 (range: 44-148) and 106 (range: 31-153) at pre HSCT, 100 days and 1 year after HAPLO, respectively. FEV1 and FVC were significantly different over time during the 1 year follow up (p=0.01 and p=0.001, respectively). The median FEV1/FVC was 80 (range 51-105) before HAPLO, 77 (range: 54-103) after 3 months, and 75 (range: 43-100) after 1 year. FEV1/FVC, residual volume, and total lung capacity (TLC) remained stable from baseline to 1 year (p=0.27, p=0.84 and p=0.21, respectively). In contrast, DLCO remained impaired during the follow-up period (p<0.001). The median DLCO was 72 (range: 39-105), 64 (range: 16-105) and 66 (range: 26-104) at baseline, 3 months and 1 year after HAPLO. Twenty-nine patients had an infectious respiratory complication during the follow-up period. Of these, 19 were bacterial, three were viral, two were fungal and five had no microbial documentation. During the 1-year follow-up period, four patients met the criteria for bronchiolitis obliterans syndrome and two for interstitial lung disease. Of these, only one had died at last follow-up. The cumulative incidence of grade II-IV acute GvHD was 21% (95% CI 14-33%). At 1 year, the cumulative incidence of chronic GvHD was 26% (95% CI 18-39%). Non-relapse mortality was 9% (95% CI 4-18%) at 100 days and 14% (95% CI 8-24%) at 1 year. Relapse incidence was 3% (95% CI 1-10%) and 14% (95% CI 8-24%) at 100 days and 1 year, respectively. Overall survival was 73% (95% CI 62-82%). In all, 22 patients died. Cause of death was relapse of hematological disease in 7 (35%), infection in 7 (35%), GvHD in 2 (9%), multi organ failure in 4 (20%) and other causes in 2. Conclusion: We observed a significantly impaired DLCO at baseline, which remained impaired at 3 months and 1 year after HAPLO, but with a substantial stable pulmonary function at 1 year. Malard: Theralos/Mallinckrodt: Honoraria; Sanofi: Honoraria; Keocyt: Honoraria; Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Biocodex: Honoraria; Janssen: Honoraria.

Blood, Nov 13, 2019

Several studies have shown that alteration of the microbiota, particularly in the gastrointestina... more Several studies have shown that alteration of the microbiota, particularly in the gastrointestinal tract, can be associated with graft-versus-host disease (GvHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) usually get exposed to antibiotics (ATB), mainly in the peri-transplant period. Moreover, ATB, specifically those that target anaerobic bacteria, can alter the microbiota in a variety of body organs. This, in turn, renders several organs vulnerable to injury making them more prone to developing diseases such as GvHD. In this study, we evaluate whether the use of ATB, characterized by duration, timing and type, in the peri-transplant period, is associated with an increased incidence of acute GvHD (aGvHD) and aGvHD-related mortality. In this retrospective study, we included 318 consecutive patients who underwent allo-SCT including haploidentical and cord blood transplantation between December 2012 and June 2018 at a single center. ATB exposure was collected and classified into 3 groups according to the date of initiation of ATB: from the start of conditioning to day - 1 of allo-SCT (early ATB exposure), from day 0 to neutrophil engraftment (late ATB exposure) and a third group of patients who did not receive ATB (no ATB exposure). ATB were only initiated if a patient develop fever or show signs of infection. Patients did not receive any prophylactic ATB. Exposure was further categorized as primary or adjunct. Primary exposure included the use of 4 classes of ATB: carbapenems, anti-pseudomonal penicillin, 4thand 5thgeneration cephalosporins and fluoroquinolones. Adjunct ATB comprised other ATB and was further divided into 2 groups according to anaerobic coverage. The median age at transplant was 55 years. The stem cell source was peripheral blood in 85%, bone marrow in 10% and cord blood in 5% of the patients. Ninety-nine percent of the patients received cyclosporine A as GvHD prophylaxis and 80% and 7% of the patients received (along with cyclosporine A), mycophenolate mofetil and methotrexate, respectively. In addition, 35% and 89% of the patients received post-transplant cyclophosphamide and anti-thymocyte globulin, respectively, as GvHD prophylaxis. The median time to neutrophil engraftment was 16 days post-transplant. The median follow-up was 85 months. 93.7% of the patients received ATB in the peri-transplant period with 64.5% of them in the early ATB exposure group, and 29.2% of them in the late ATB exposure group. The 2-year overall survival and progression free survival were 74.3% and 63.6% in patients with early ATB exposure, compared to 79.5% and 70.8% in patients with late ATB exposure (p=0.11 and p=0.07 respectively). The 2-year cumulative incidence of non-relapse mortality was 16.5% in patients with early ATB exposure, compared to 15.1% in patients with late ATB exposure (p=0.63). The 180-days cumulative incidence of grade 2-4 and 3-4 aGvHD were 23.8% and 12.2% in patients with early ATB exposure, compared to 27.2% and 5.4% in patients with late ATB exposure (p=0.64 and p=0.06 respectively). In multivariate analysis, including the most important parameters associated with GvHD (stem cell source and donors, conditioning regimen, sex mismatch and patients age), early ATB initiation was the only parameter associated with a significantly higher risk of severe grade 3-4 aGvHD [HR 0.51 (0.28-0.90); p=0.02]. In conclusion, in the absence of any ATB prophylaxis, early initiation of ATB, before graft infusion,is associated with a significantly higher risk of severe grade 3-4 aGvHD. Weighing risk of morbidity and mortality associated with infections versus later on risk of developing aGvHD is essential. Hence, new strategies should be developed to risk stratify patients with fever and thus to avoid early non necessary ATB exposure especially in those who develop fever during anti-thymocyte globulin infusion. Studies evaluating such strategies will be necessary in the next years. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Malard:Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Sanofi: Honoraria; Keocyte: Honoraria; Janssen: Honoraria; Therakos/Mallinckrodt: Honoraria.

Blood, Nov 29, 2018

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical ... more Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical donor (haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. We recently noticed a relatively high incidence of infectious complications, especially Epstein-Barr virus (EBV) reactivation after haplo-HCT. However, the mechanisms underlying the increased incidence of this complication in the haplo-HCT setting are unknown. We hypothesized that the use of PTCy may be associated with a deficit in innate-like effector T cells essential for preventing EBV reactivation.This study aimed to analyze immune reconstitution following haplo-HCT using peripheral blood stem cells (PBSC) grafts and to evaluate the correlations with EBV reactivation and outcomes. Patients and Methods: One hundred and twenty-three consecutive patients who underwent allo-HCT for hematological malignancies between 2013 and 2016 were included in this single-center retrospective study. All patients received G-CSF mobilized PBSC grafts and ATG 2.5-5 mg/Kg total dose. All patients received a combination of cyclosporine A and mycophenolate mofetil for GvHD prophylaxis, except for patients with a matched related donor (MRD) who received cyclosporine A alone and patients with an haploidentical donor who received PTCy (50mg/kg/d at d3+/-d5). α/β T cells (CD3+, CD4+ and CD8+), γ/δ T cells (pan γ/δ and Vδ2+), mucosal-associated T cells wich express a highly restricted TCR comprising a semi-variant Vα7.2-Jα33 (MAIT), invariant NK T cells, NK cells, B cells, Tregs, monocytes subsets and dendritic cells (myeloid DC, plasmacytoid DC and Slan-DC) were analyzed by multi-color flow cytometry at months (M) 1, 3, 6 and 12 following allo-HCT. Clinical data [acute GvHD (aGvHD), relapse incidence, chronic GvHD (cGvHD), viral reactivations, bacterial and fungal infections, non-relapse mortality (NRM), progression-free survival (PFS), refined GvHD-free and progression-free survival (GPFS), overall survival (OS)] were assessed together with sequential quantitative evaluation of immune subsets. Results: Median age was 55 (range, 17-70) years, with 32 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid malignancies (66%) or lymphoid malignancies (34%). Thirty-three patients (27%) received a graft from a MRD, 65 from an unrelated donor (MUD, 53%), and 25 from a haplo-identical donor (20%). Thirty patients (24%) with refractory disease received a sequential conditioning regimen while the remaining (n=93, 76%) received a RIC/RTC regimen based on fludarabine, busulfan +/- thiotepa. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 34% and 5%, respectively. The 2 years CIs of cGvHD, extensive cGvHD and relapse were 23%, 8% and 17%, respectively. At 2 years, NRM was 7%, PFS was 77%, GPFS was 66% and OS was 83%. The rate of EBV reactivation was significantly increased in haplo-HCT recipients as compared to fully-matched donor recipients (respectively, 68% versus 26%, P&amp;amp;amp;amp;lt; .001). At one month after allo-HCT, the median counts of all immune cells subsets (except monocytes) was significantly lower in haplo-HCT recipients as compared to MRD or MUD recipients. At 3 months, α/β T cells, iNK T cells, NK cells, B cells, Tregs and Slan-DC reached similar median counts in haplo-HCT recipients as compared to MRD or MUD recipients. In contrast, Vδ2+ T cells and MAIT cells median counts remained significantly lower at 3, 6 and 12 months in haplo-HCT recipients compared to MRD or MUD recipients (at M1, M3, M6, M12, the median Vδ2+ T cells counts were 0.05/µL, 0.24/µL, 1.38/µL and 2.97/µL, and MAIT cells were 0.07/µL, 0.70/µL, 1.00/µL and 1.21/µL, respectively). Lower Vδ2+ T-cells and MAIT cells counts at one month was associated with a significantly increased CI of EBV reactivation (respectively, P=.04 and P

Blood, Nov 29, 2018

Introduction: Haploidentical stem cell transplantation (Haplo-SCT) using post-transplant cyclopho... more Introduction: Haploidentical stem cell transplantation (Haplo-SCT) using post-transplant cyclophosphamide is widely used for the treatment of patients with hematologic malignancies especially in patients who lack related or unrelated donors. Several factors were shown to affect hematopoietic recovery after allogeneic hematopoietic stem cell transplantation, including age at transplant, initial diagnosis, stem-cell source, CD34 count in the graft, conditioning regimen intensity, infections, etc. The aim of this study was to evaluate immune reconstitution, neutrophils and platelets recovery, transfusion needs and main transplant outcomes after Haplo-SCT and to identify factors correlated with improved or worsened recovery. Methods: This study included 72 consecutive patients who underwent haploidentical stem cell transplantation between December 2012 and March 2018, in a single center. Graft was either bone marrow (n=21) or peripheral blood stem cells (n=51). Patients were given PT-Cy (50mg/kg/d) for one (n=20) or two days (n=52), cyclosporine, mycophenolate mofetil and ATG for GvHD prophylaxis. Conditioning regimen was reduced toxicity one (RIC) in 69% (n=50) of patients, and a myeloablative one (MAC) in 31% (n=22) of cases . Main transplant outcomes, neutrophil and platelets recovery, and needs for transfusion were evaluated at day +30, day +60 and day +90 after Haplo-SCT. Results: The median CD34+ cells infused was 10.62 x106/kg (range, 1.02-15.06). The median time to neutrophil recovery (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;500/µL) was 16 days post-transplant (range, 5-29). The median time to neutrophil count &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000/µL was 17 days post-transplant (range, 5-32). Platelets recovery (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;20.000/µL) was observed at a median of 13 days post-transplant (range, 10-193). Platelets recovery (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50.000/µL) was documented at a median of 60 days post-transplant (range, 10-193). Forty-five (63%) and 49 (68%) patients had a platelets count &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50.000/µL at days +30 and +60 post-transplant respectively. At day +90 post-transplant, 61 patients were assessable with 56 (92%) of them having a platelets count…

Bone Marrow Transplantation, Oct 12, 2022

Thiotepa, busulfan and fludarabine conditioning regimen in T-cell replete HLA-haploidentical hema... more Thiotepa, busulfan and fludarabine conditioning regimen in T-cell replete HLA-haploidentical hematopoietic stem cell transplantation

Current Research in Translational Medicine, May 1, 2022

Clinical & translational immunology, 2020

ObjectivesHaploidentical haematopoietic cell transplantation (Haplo‐HCT) using peripheral blood s... more ObjectivesHaploidentical haematopoietic cell transplantation (Haplo‐HCT) using peripheral blood stem cell (PBSC) grafts and post‐transplant cyclophosphamide (PTCy) is being increasingly used; however, data on immunological reconstitution (IR) are still scarce.MethodsThis retrospective study evaluated T‐cell immunological reconstitution in 106 adult patients who underwent allogeneic haematopoietic cell transplantation for haematologic malignancies between 2013 and 2016.ResultsAt D30, while conventional T cells reached similar median counts in Haplo‐HCT recipients (n = 19) and controls (n = 87), γδ and Vδ2+ T‐cell median counts were significantly lower in Haplo‐HCT recipients and it persists at least until D360 for Vδ2+ T cells. PTCy induces a significant reduction in early γδ and Vδ2+ T‐cell proliferation at D 7. At one year, the rate of increase in Epstein–Barr virus (EBV) viral load was significantly higher in Haplo‐HCT recipients as compared to controls (61% versus 34%, P = 0.02). In multivariate analysis, a higher γδ T‐cell count (&gt; 4.63 μL−1) at D30 was the only independent parameter significantly associated with a reduced risk of increase in EBV viral load (RR 0.34; 95% CI, 0.15–0.76, P = 0.009).ConclusionImmunological reconstitution of γδ T cells is significantly delayed after Haplo‐HCT using PTCy and low‐dose ATG and is associated with an increased risk of increase in EBV viral load.

Cytotherapy, Aug 1, 2020

Corticosteroids are the standard first line treatment for acute graft-versus-host disease (aGVHD)... more Corticosteroids are the standard first line treatment for acute graft-versus-host disease (aGVHD). However, corticosteroids are associated with many complications and less than half of the patients have durable response. In order to improve outcomes, we performed a retrospective study to analyze the efficacy of the addition of extracorporeal photopheresis (ECP) to low dose corticosteroids in 37 adult patients (median age, 57 years) with skin predominant aGVHD (grade I, n=17; grade II, n=18 and grade III, n=2). All patients received ECP in combination with 1 mg/kg prednisone (n=26) or topical steroids (n=11). Overall response rate (ORR) was 81% after a median of 3 ECP procedures (range, 2-8), including 22 complete responses (CR, 59%) and 8 very good partial responses (VGPR, 22%). The 11 patients treated with topical corticosteroids achieved CR. Furthermore 16 (62%) patients reached prednisone withdrawal at a median of 100 days (range, 42-174 days) after its initiation. Eighteen patients developed chronic GVHD (cGVHD), 11 of them (who were in CR of aGvHD) had a new onset cGVHD and 7 experienced progressive cGVHD (5 non-responding and 2 VGPR patients). A second line immunosuppressive treatment was initiated in only 5 (14%) non-responding patients. With a median follow-up of 31 months (range, 6-57 months) two-year overall survival and non-relapse mortality were 74% and 11%, respectively. Overall, the combination of low-dose corticosteroids and ECP appear to be safe and effective for first-line treatment of skin predominant aGVHD.

Clinical Lymphoma, Myeloma & Leukemia, Jun 1, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cancer, Feb 22, 2018

BACKGROUND: T-cell-depleted, haploidentical transplantations (haplos) are commonly offered to pat... more BACKGROUND: T-cell-depleted, haploidentical transplantations (haplos) are commonly offered to patients who have high-risk, acute leukemia in the absence of a human leukocyte antigen (HLA) full-matched donor. METHODS: To determine the effect of transplantation period, the authors divided 308 adults with de novo, acute leukemia who underwent T-cell-depleted haplo from 2005 to 2015 into 2 groups, according the year in which they underwent transplantation (2005-2011 [n 5 191] and 2012-2015 [n 5 117]). RESULTS: The median age was 41 years in patients who underwent transplantation before 2012 and 46 years in those who underwent transplantation after 2012 (P 5 .04). Most patients had acute myeloid leukemia (75% vs 69%; P 5 .26) and were in first complete remission (CR1) (55% vs 64%; P 5 .12) at the time of transplantation. The cumulative incidence of grade 2, 3, and 4 acute graft-versus-host disease (GvHD) and chronic GvHD were not different between the 2 groups (acute GvHD: 20% vs 22% cumulative incidence in patients who underwent haplo before and after 2012, respectively [P 5 .67]; chronic GvHD: 19% vs 11% cumulative incidence, respectively; P 5 .12]. The 2-year relapse incidence was 20%, the nonrelapse mortality (NRM) rate was 48%, and no difference was observed over time (21% vs 19% [P 5 .72] and 54% vs 38% [P 5 .11] for patients who underwent haplo before and after 2012, respectively). The main cause of NRM was infection. Haplo after 2012 (hazard ratio [HR], 0.57; P 5 .01), younger age (HR, 0.82; P 5 .02), and receipt of a reduced-intensity conditioning (RIC) regimen (HR, 0.53; P 5 .01) were independently associated with lower NRM. The 2-year overall survival rate was 36% and improved after 2012 (29% vs 47% before 2012; P 5 .02); and it was higher for patients who underwent transplantation in CR1 (41% vs 29%; P 5 .01). In multivariate analysis, haplo after 2012 (HR, 0.54; P 5 .003) and receipt of a RIC regimen (HR, 0.54; P 5 .005) were independently associated with better overall survival. Similarly, leukemia-free survival and GvHD-free/relapse-free survival (GRFS) improved over time: the leukemia-free survival rate was 31% (25% vs 43% in the groups who underwent transplantation before and after 2012, respectively; P 5 .05), and the GRFS rate was 24% (19% vs 34%, respectively; P 5 .09). In addition, leukemia-free survival and GRFS improved among patients who received a RIC regimen. CONCLUSIONS: The outcome of patients with acute leukemia who underwent T-cell-depleted haplo has improved over time.

European Journal of Haematology, May 14, 2019

Objectives: This retrospective study analyzed the impact of early cyclosporine-A (CsA) initiation... more Objectives: This retrospective study analyzed the impact of early cyclosporine-A (CsA) initiation (day-3) on the risk of acute graft-versus-host disease (aGvHD) after haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplant cyclophosphamide Methods: Sixty-one consecutives patients who underwent Haplo-HCT were analyzed. Results: At day +180, the cumulative incidences of grade II-IV and grade III-IV aGvHD were 39% and 18%, respectively. Patients having a lowest CsA concentration (<301 ng/mL; the cutoff value used to segregate the patients between low and high CsA concentrations) in the first week after Haplo-HCT had a significantly higher risk of grade II-IV aGvHD (P= .02), severe grade III-IV aGvHD (P = .03), cGvHD (P= .02) and extensive cGvHD (P= .04). In multivariate analysis, a higher CsA concentration (≥301 ng/mL) during the first week following Haplo-HCT was the only parameter significantly associated with a reduced risk of grade II-IV and grade III-IV aGvHD (RR=.21; P=.049 and RR<0.001; P<.0001, respectively). We find no correlation between CsA concentration and relapse, non-relapse mortality, progression free survival, GvHD-free and progression free survival or overall survival. Conclusions: CsA could be initiated early before Haplo-HCT with achievement of high CsA concentration to reduce the risk of aGvHD without any detrimental effect on relapse.

British Journal of Haematology, May 26, 2022

British Journal of Haematology, Mar 4, 2022

Bone Marrow Transplantation, 2016

Bone Marrow Transplantation

Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophy... more Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dosedependent toxicities, particularly in frail patients. Therefore, we compared the outcomes with a reduced PT-Cy total dose (70 mg/ kg) to those with the standard PT-Cy dose (100 mg/kg) in haploidentical hematopoietic cell transplantation (HCT) patients aged ≥ 65 years and those with cardiac comorbidities. All consecutive patients with a hematological malignancy receiving peripheral blood stem cells (PBSCs) after a thiotepa-based conditioning with low-dose antithymocyte globulin were included. Thirty-three patients received PT-Cy at 70 mg/kg and 25 at 100 mg/kg. PT-Cy dose reduction did not increase the risk of GVHD and was associated with faster neutrophil and platelet recovery, and lower cumulative incidences of bacteremia (38% versus 72%, p = 0.004) and cardiac complications (12% versus 44%, p = 0.028). At 2 years, GVHD-free, relapse-free survival (GRFS) was higher with the reduced dose compared to the standard dose (60% versus 33%, p = 0.04). In conclusion, reducing PT-Cy total dose to 70 mg/kg is a safe and valid approach for elderly patients and those with cardiac comorbidities underdoing haploidentical HCT with PBSCs and low-dose antithymocyte globulin. The reduced PT-Cy dose was associated with improved hematological count recovery, lower incidence of toxicities, and higher GRFS.

Endocrine Research, Aug 22, 2012

Background. Insulin resistance (IR), a link of paramount importance between obesity and cardiovas... more Background. Insulin resistance (IR), a link of paramount importance between obesity and cardiovascular/metabolic complications, seems to be implicated in weight changes. Objective. To determine whether IR could influence weight status during a 1-year intervention program in obese prepubertal children. Methods. Forty-four children with IR (IR group) and 42 children without IR (NIR group) were enrolled. Body mass index standard deviation score (BMI-SDS), waist circumference (WC), and homeostasis model assessment (HOMA-IR) were evaluated. Results. NIR children showed a significant reduction of BMI-SDS and WC at final assessment (p ¼ 0.009 and p ¼ 0.001, respectively), whereas IR children presented unchanged values. HOMA-IR decreased after intervention in the NIR group (p ¼ 0.0008), but was exacerbated in IR children (p ¼ 0.004). A positive and significant association between HOMA-IR at baseline and BMI at follow-up was found (B AE SE ¼ 0.87 AE 0.24, p ¼ 0.001). HOMA-IR at baseline was also significantly associated with WC at follow-up (B AE SE ¼ 2.12 AE 0.69, p ¼ 0.003). Conclusions. IR seems to influence adiposity changes in obese prepubertal children. Further longitudinal studies are needed to verify the relationship between IR and weight loss during childhood.

Current Research in Translational Medicine, Aug 1, 2019

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of... more Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of hematologic diseases whether in remission or in the relapsed/refractory setting [1]. However, this treatment modality is associated with several complications leading to a high risk of morbidity and mortality. Among these complications, poor graft function (PGF) occurs in 5 to 27 % of patients after allo-HSCT [2]. Primary PGF is defined as persistent neutropenia (Absolute Neutrophil Count 0.5 Â 10 9 /L), thrombocytopenia (platelets 20 Â 10 9 /L), and/or anemia (hemoglobin 70 g /L). PGF can be secondary occurring after prompt neutrophil recovery. Moreover, in patients with PGF, the chimerism is full donor and it should be distinguished from graft failure where the chimerism is mixed. The pathogenesis of PGF remains unclear. It has been reported by Wang et al suggested, that dysregulated T cell responses might contribute to the pathogenesis of PGF after allo-HSCT. In patients with PGF they find higher proportions of stimulated CD4+ and CD8 + T cells that produce IFN-g (Th1 and Tc1 respectively) while the proportions of IL-4-producing T cells (Th2 and Tc2 cells) were decreased [3]. In addition to Th1 and Tc1 cells, Th17 cells may also contribute to PGF, given the ratio of Th17 cells to regulatory T cells was dramatically increased in the bone marrow of PGF patients compare to that in patients with goodgraft function patients [4]. Nevertheless, treatment strategies are mainly based on the administration of granulocyte colony stimulating factor (G-CSF) which has a short-term effect [5]. Alternatively, second allo-HSCT have been performed but at the cost of an increased toxicity [6]. Alternative and more recent treatment modality is the infusion of CD34+-selected stem cell "Boost" from the same donor without prior conditioning. We, therefore, therefore retrospectively studied the efficacy and safety of CD34+-selected stem cell "Boost" for the treatment of PGF after allo-HSCT. We included10 patients who received a "Boost" of CD34 +-selected stem cells for poor graft function after allo-HSCT between January 2014 and January 2016. 4 patients were males and 6 were females with a median age of 45 (range, 19-67) years at time of transplant. Underlying hematologic malignancies diagnoses include acute myeloid leukemia in 4 patients, myelofibrosis in 2 patiens, chronic myelomonocytic leukemia in 2 patients, acute

Blood, Nov 5, 2021

Introduction The outcome of conventional allogeneic hematopoietic cell transplantation (HCT) for ... more Introduction The outcome of conventional allogeneic hematopoietic cell transplantation (HCT) for the treatment of patients with refractory myeloid malignancies remains poor. Thiotepa-based sequential conditioning has shown promising results for various refractory hematological malignancies (Duléry R et al. Biol Blood Marrow Transplant. 2018; 24(5):1013-1021). However, no study has evaluated the outcome of this sequential approach specifically in refractory myeloid malignancies. The optimal dose of chemotherapeutic agents used in the conditioning regimen and the feasibility of this sequential approach in patients aged 60 years and above also need to be assessed. Methods All consecutive patients with refractory myeloid malignancy who underwent allogeneic HCT with a thiotepa-based sequential conditioning regimen in Saint Antoine hospital between April 2013 and October 2020 were included. The sequential approach consisted of a broad spectrum cytoreduction with thiotepa, etoposide, and cyclophosphamide (TEC) from day -15 to -10. Then, after a 3-day rest, a reduced-intensity conditioning (RIC) regimen was administered with fludarabine 150 mg/m 2, intravenous busulfan 6.4 mg/kg and thymoglobulin 5 mg/kg from day -6 to -2. From 2013 to 2018, doses of thiotepa (10 mg/kg), etoposide (400 mg/m 2) and/or cyclophosphamide (1600 mg/m 2) could be reduced in patients older than 60 years or with comorbidities. Since September 2018, the use of a reduced TEC-RIC regimen (thiotepa at 5 mg/kg, etoposide 300 mg/m 2 and cyclophosphamide 1200 mg/m 2 from day -13 to -10) became the new standard of care for all patients. After transplant, patients could receive a hypomethylating agent or targeted therapy to prevent relapse. Prophylactic donor lymphocyte infusions were given to enhance the graft-versus-leukemia effect, in the absence of contraindication. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and mycophenolate mofetil for all patients. Post-transplant cyclophosphamide was added in the case of haploidentical HCT. Results Seventy-one patients (median age 61 years, range 15-76) were included. Diagnoses comprised acute myeloblastic leukemia (n=65) and myelodysplastic syndrome/chronic myelomonocytic leukemia (n=6). Donors were haploidentical (n=36), matched related (n=13), unrelated (n=21) and umbilical cord blood (n=1). A reduced TEC-RIC was administrated to 43 (61%) patients, a full dose TEC-RIC to 18 (25%), and a TEC-RIC with a dose reduction only for thiotepa to 10 (14%). With a median follow-up of 45.4 months (95% CI: 36.7-63.6), the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 51%, 41%, and 24%, respectively. Patients receiving a reduced TEC-RIC had a lower cumulative incidence of acute and chronic GVHD (acute grade II-IV GVHD: 14%, acute grade III-IV GVHD: 0%, chronic GVHD: 19%) than the other patients (acute grade II-IV GVHD: 29%, acute grade III-IV GVHD: 18%, chronic GVHD: 29%). The outcomes were not significantly different according to the TEC dose in terms of relapse incidence, OS, and PFS, although the NRM was lower with the reduced TEC-RIC (21% versus 28%, p=0.72). Most notably, patients aged 60 years and above had a 2-year OS and PFS of 48% and 39%, respectively, with no significant difference compared to patients younger than 60 years (Figure). Conclusion Our findings endorse the feasibility and efficacy of a thiotepa-based sequential approach for refractory myeloid malignancies undergoing HCT. The dose reduction did not compromise disease control and expanded the transplant option to older patients, ineligible for a higher dose regimen. Thus, a reduced TEC-RIC sequential regimen can be proposed for selected patients older than 60 years and allows promising outcomes for the treatment of refractory myeloid malignancies. Figure 1 Figure 1. Disclosures Duléry: Gilead: Other: travel support and meeting fees; Takeda: Consultancy; Novartis: Honoraria. Malard: Therakos/Mallinckrodt: Honoraria; Biocodex: Honoraria; Astellas: Honoraria; JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Legrand: Servier: Consultancy. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. 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.

Blood, Nov 5, 2020

Background: Pre- and post-transplant pulmonary function tests (PFT) have been previously analyzed... more Background: Pre- and post-transplant pulmonary function tests (PFT) have been previously analyzed in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). A deterioration in pulmonary function could be observed in this setting and accounts for higher morbidity and mortality. Haploidentical allogeneic stem cell transplantation (HAPLO) with post-transplant cyclophosphamide (PTCY) is increasingly used. Limited data exists on evaluation of PFT after HAPLO and the number of patients who underwent HAPLO in previously published studies is negligible. We report the evolution of PFT as well as pre-transplant characteristics and outcomes after HAPLO in the adult setting. Methods: We retrospectively analyzed 80 HAPLO performed in a single center between 2013 and 2019. All patients with available pre- and post-transplant PFT results were included in the study. The Friedman test was used for comparing PFT at baseline, 100 days and 1 year after HAPLO. Results: The median follow up was 32 (range: 12-74) months. CMV serology was positive in 45% and 65% of patients were male. The median age was 58 (range: 16-73) years. The proportion of surviving patients with available PFT at 3 months and 1 year were 86% and 68%, respectively. Diagnosis was acute myeloid leukemia in 51% and disease risk index was intermediate-low in 75% of the cases. Disease status before HAPLO was complete remission in 61%. Graft source was peripheral blood stem cells in 91% of the cases. Conditioning regimen was reduced intensity in 40% and the most frequent chemotherapy regimen was thiotepa, busulfan and fludarabine. Graft-versus- host disease (GvHD) prophylaxis consisted of Cyclosporine A (CsA) and mycophenolate mofetil in all but one patient who received methotrexate and CsA. All patients received PTCY, 64 (80%) at days 3 and 5 after HAPLO, 7 (9%) at days 3 and 4, and 9 (11%) at day 3 only. Seventy-three (91%) patients received anti-thymocyte globulin. In total, 24% of the patients had previously smoked, 8% had type 2 diabetes, and 23% suffered from hypertension. Three patients had a lung infection at baseline, of which one was bacterial and two were possibly aspergillosis. At screening for HAPLO, five (6%) patients had restrictive lung disease, nine (11%) met the criteria for obstructive lung disease, and diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin was impaired in 74% of the patients. The median forced expiratory volume in the first second (FEV1) was 100 (range: 58-146) before HAPLO, 93 (range: 42-10) at 100 days after HAPLO and 99 (range: 32-144) at 1 year. The median forced vital capacity (FVC) was 106 (range: 57-153), 98 (range: 44-148) and 106 (range: 31-153) at pre HSCT, 100 days and 1 year after HAPLO, respectively. FEV1 and FVC were significantly different over time during the 1 year follow up (p=0.01 and p=0.001, respectively). The median FEV1/FVC was 80 (range 51-105) before HAPLO, 77 (range: 54-103) after 3 months, and 75 (range: 43-100) after 1 year. FEV1/FVC, residual volume, and total lung capacity (TLC) remained stable from baseline to 1 year (p=0.27, p=0.84 and p=0.21, respectively). In contrast, DLCO remained impaired during the follow-up period (p<0.001). The median DLCO was 72 (range: 39-105), 64 (range: 16-105) and 66 (range: 26-104) at baseline, 3 months and 1 year after HAPLO. Twenty-nine patients had an infectious respiratory complication during the follow-up period. Of these, 19 were bacterial, three were viral, two were fungal and five had no microbial documentation. During the 1-year follow-up period, four patients met the criteria for bronchiolitis obliterans syndrome and two for interstitial lung disease. Of these, only one had died at last follow-up. The cumulative incidence of grade II-IV acute GvHD was 21% (95% CI 14-33%). At 1 year, the cumulative incidence of chronic GvHD was 26% (95% CI 18-39%). Non-relapse mortality was 9% (95% CI 4-18%) at 100 days and 14% (95% CI 8-24%) at 1 year. Relapse incidence was 3% (95% CI 1-10%) and 14% (95% CI 8-24%) at 100 days and 1 year, respectively. Overall survival was 73% (95% CI 62-82%). In all, 22 patients died. Cause of death was relapse of hematological disease in 7 (35%), infection in 7 (35%), GvHD in 2 (9%), multi organ failure in 4 (20%) and other causes in 2. Conclusion: We observed a significantly impaired DLCO at baseline, which remained impaired at 3 months and 1 year after HAPLO, but with a substantial stable pulmonary function at 1 year. Malard: Theralos/Mallinckrodt: Honoraria; Sanofi: Honoraria; Keocyt: Honoraria; Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Biocodex: Honoraria; Janssen: Honoraria.

Blood, Nov 13, 2019

Several studies have shown that alteration of the microbiota, particularly in the gastrointestina... more Several studies have shown that alteration of the microbiota, particularly in the gastrointestinal tract, can be associated with graft-versus-host disease (GvHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) usually get exposed to antibiotics (ATB), mainly in the peri-transplant period. Moreover, ATB, specifically those that target anaerobic bacteria, can alter the microbiota in a variety of body organs. This, in turn, renders several organs vulnerable to injury making them more prone to developing diseases such as GvHD. In this study, we evaluate whether the use of ATB, characterized by duration, timing and type, in the peri-transplant period, is associated with an increased incidence of acute GvHD (aGvHD) and aGvHD-related mortality. In this retrospective study, we included 318 consecutive patients who underwent allo-SCT including haploidentical and cord blood transplantation between December 2012 and June 2018 at a single center. ATB exposure was collected and classified into 3 groups according to the date of initiation of ATB: from the start of conditioning to day - 1 of allo-SCT (early ATB exposure), from day 0 to neutrophil engraftment (late ATB exposure) and a third group of patients who did not receive ATB (no ATB exposure). ATB were only initiated if a patient develop fever or show signs of infection. Patients did not receive any prophylactic ATB. Exposure was further categorized as primary or adjunct. Primary exposure included the use of 4 classes of ATB: carbapenems, anti-pseudomonal penicillin, 4thand 5thgeneration cephalosporins and fluoroquinolones. Adjunct ATB comprised other ATB and was further divided into 2 groups according to anaerobic coverage. The median age at transplant was 55 years. The stem cell source was peripheral blood in 85%, bone marrow in 10% and cord blood in 5% of the patients. Ninety-nine percent of the patients received cyclosporine A as GvHD prophylaxis and 80% and 7% of the patients received (along with cyclosporine A), mycophenolate mofetil and methotrexate, respectively. In addition, 35% and 89% of the patients received post-transplant cyclophosphamide and anti-thymocyte globulin, respectively, as GvHD prophylaxis. The median time to neutrophil engraftment was 16 days post-transplant. The median follow-up was 85 months. 93.7% of the patients received ATB in the peri-transplant period with 64.5% of them in the early ATB exposure group, and 29.2% of them in the late ATB exposure group. The 2-year overall survival and progression free survival were 74.3% and 63.6% in patients with early ATB exposure, compared to 79.5% and 70.8% in patients with late ATB exposure (p=0.11 and p=0.07 respectively). The 2-year cumulative incidence of non-relapse mortality was 16.5% in patients with early ATB exposure, compared to 15.1% in patients with late ATB exposure (p=0.63). The 180-days cumulative incidence of grade 2-4 and 3-4 aGvHD were 23.8% and 12.2% in patients with early ATB exposure, compared to 27.2% and 5.4% in patients with late ATB exposure (p=0.64 and p=0.06 respectively). In multivariate analysis, including the most important parameters associated with GvHD (stem cell source and donors, conditioning regimen, sex mismatch and patients age), early ATB initiation was the only parameter associated with a significantly higher risk of severe grade 3-4 aGvHD [HR 0.51 (0.28-0.90); p=0.02]. In conclusion, in the absence of any ATB prophylaxis, early initiation of ATB, before graft infusion,is associated with a significantly higher risk of severe grade 3-4 aGvHD. Weighing risk of morbidity and mortality associated with infections versus later on risk of developing aGvHD is essential. Hence, new strategies should be developed to risk stratify patients with fever and thus to avoid early non necessary ATB exposure especially in those who develop fever during anti-thymocyte globulin infusion. Studies evaluating such strategies will be necessary in the next years. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Malard:Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Sanofi: Honoraria; Keocyte: Honoraria; Janssen: Honoraria; Therakos/Mallinckrodt: Honoraria.

Blood, Nov 29, 2018

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical ... more Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical donor (haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. We recently noticed a relatively high incidence of infectious complications, especially Epstein-Barr virus (EBV) reactivation after haplo-HCT. However, the mechanisms underlying the increased incidence of this complication in the haplo-HCT setting are unknown. We hypothesized that the use of PTCy may be associated with a deficit in innate-like effector T cells essential for preventing EBV reactivation.This study aimed to analyze immune reconstitution following haplo-HCT using peripheral blood stem cells (PBSC) grafts and to evaluate the correlations with EBV reactivation and outcomes. Patients and Methods: One hundred and twenty-three consecutive patients who underwent allo-HCT for hematological malignancies between 2013 and 2016 were included in this single-center retrospective study. All patients received G-CSF mobilized PBSC grafts and ATG 2.5-5 mg/Kg total dose. All patients received a combination of cyclosporine A and mycophenolate mofetil for GvHD prophylaxis, except for patients with a matched related donor (MRD) who received cyclosporine A alone and patients with an haploidentical donor who received PTCy (50mg/kg/d at d3+/-d5). α/β T cells (CD3+, CD4+ and CD8+), γ/δ T cells (pan γ/δ and Vδ2+), mucosal-associated T cells wich express a highly restricted TCR comprising a semi-variant Vα7.2-Jα33 (MAIT), invariant NK T cells, NK cells, B cells, Tregs, monocytes subsets and dendritic cells (myeloid DC, plasmacytoid DC and Slan-DC) were analyzed by multi-color flow cytometry at months (M) 1, 3, 6 and 12 following allo-HCT. Clinical data [acute GvHD (aGvHD), relapse incidence, chronic GvHD (cGvHD), viral reactivations, bacterial and fungal infections, non-relapse mortality (NRM), progression-free survival (PFS), refined GvHD-free and progression-free survival (GPFS), overall survival (OS)] were assessed together with sequential quantitative evaluation of immune subsets. Results: Median age was 55 (range, 17-70) years, with 32 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid malignancies (66%) or lymphoid malignancies (34%). Thirty-three patients (27%) received a graft from a MRD, 65 from an unrelated donor (MUD, 53%), and 25 from a haplo-identical donor (20%). Thirty patients (24%) with refractory disease received a sequential conditioning regimen while the remaining (n=93, 76%) received a RIC/RTC regimen based on fludarabine, busulfan +/- thiotepa. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 34% and 5%, respectively. The 2 years CIs of cGvHD, extensive cGvHD and relapse were 23%, 8% and 17%, respectively. At 2 years, NRM was 7%, PFS was 77%, GPFS was 66% and OS was 83%. The rate of EBV reactivation was significantly increased in haplo-HCT recipients as compared to fully-matched donor recipients (respectively, 68% versus 26%, P&amp;amp;amp;amp;lt; .001). At one month after allo-HCT, the median counts of all immune cells subsets (except monocytes) was significantly lower in haplo-HCT recipients as compared to MRD or MUD recipients. At 3 months, α/β T cells, iNK T cells, NK cells, B cells, Tregs and Slan-DC reached similar median counts in haplo-HCT recipients as compared to MRD or MUD recipients. In contrast, Vδ2+ T cells and MAIT cells median counts remained significantly lower at 3, 6 and 12 months in haplo-HCT recipients compared to MRD or MUD recipients (at M1, M3, M6, M12, the median Vδ2+ T cells counts were 0.05/µL, 0.24/µL, 1.38/µL and 2.97/µL, and MAIT cells were 0.07/µL, 0.70/µL, 1.00/µL and 1.21/µL, respectively). Lower Vδ2+ T-cells and MAIT cells counts at one month was associated with a significantly increased CI of EBV reactivation (respectively, P=.04 and P

Blood, Nov 29, 2018

Introduction: Haploidentical stem cell transplantation (Haplo-SCT) using post-transplant cyclopho... more Introduction: Haploidentical stem cell transplantation (Haplo-SCT) using post-transplant cyclophosphamide is widely used for the treatment of patients with hematologic malignancies especially in patients who lack related or unrelated donors. Several factors were shown to affect hematopoietic recovery after allogeneic hematopoietic stem cell transplantation, including age at transplant, initial diagnosis, stem-cell source, CD34 count in the graft, conditioning regimen intensity, infections, etc. The aim of this study was to evaluate immune reconstitution, neutrophils and platelets recovery, transfusion needs and main transplant outcomes after Haplo-SCT and to identify factors correlated with improved or worsened recovery. Methods: This study included 72 consecutive patients who underwent haploidentical stem cell transplantation between December 2012 and March 2018, in a single center. Graft was either bone marrow (n=21) or peripheral blood stem cells (n=51). Patients were given PT-Cy (50mg/kg/d) for one (n=20) or two days (n=52), cyclosporine, mycophenolate mofetil and ATG for GvHD prophylaxis. Conditioning regimen was reduced toxicity one (RIC) in 69% (n=50) of patients, and a myeloablative one (MAC) in 31% (n=22) of cases . Main transplant outcomes, neutrophil and platelets recovery, and needs for transfusion were evaluated at day +30, day +60 and day +90 after Haplo-SCT. Results: The median CD34+ cells infused was 10.62 x106/kg (range, 1.02-15.06). The median time to neutrophil recovery (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;500/µL) was 16 days post-transplant (range, 5-29). The median time to neutrophil count &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000/µL was 17 days post-transplant (range, 5-32). Platelets recovery (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;20.000/µL) was observed at a median of 13 days post-transplant (range, 10-193). Platelets recovery (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50.000/µL) was documented at a median of 60 days post-transplant (range, 10-193). Forty-five (63%) and 49 (68%) patients had a platelets count &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50.000/µL at days +30 and +60 post-transplant respectively. At day +90 post-transplant, 61 patients were assessable with 56 (92%) of them having a platelets count…

Bone Marrow Transplantation, Oct 12, 2022

Thiotepa, busulfan and fludarabine conditioning regimen in T-cell replete HLA-haploidentical hema... more Thiotepa, busulfan and fludarabine conditioning regimen in T-cell replete HLA-haploidentical hematopoietic stem cell transplantation

Current Research in Translational Medicine, May 1, 2022

Clinical & translational immunology, 2020

ObjectivesHaploidentical haematopoietic cell transplantation (Haplo‐HCT) using peripheral blood s... more ObjectivesHaploidentical haematopoietic cell transplantation (Haplo‐HCT) using peripheral blood stem cell (PBSC) grafts and post‐transplant cyclophosphamide (PTCy) is being increasingly used; however, data on immunological reconstitution (IR) are still scarce.MethodsThis retrospective study evaluated T‐cell immunological reconstitution in 106 adult patients who underwent allogeneic haematopoietic cell transplantation for haematologic malignancies between 2013 and 2016.ResultsAt D30, while conventional T cells reached similar median counts in Haplo‐HCT recipients (n = 19) and controls (n = 87), γδ and Vδ2+ T‐cell median counts were significantly lower in Haplo‐HCT recipients and it persists at least until D360 for Vδ2+ T cells. PTCy induces a significant reduction in early γδ and Vδ2+ T‐cell proliferation at D 7. At one year, the rate of increase in Epstein–Barr virus (EBV) viral load was significantly higher in Haplo‐HCT recipients as compared to controls (61% versus 34%, P = 0.02). In multivariate analysis, a higher γδ T‐cell count (&gt; 4.63 μL−1) at D30 was the only independent parameter significantly associated with a reduced risk of increase in EBV viral load (RR 0.34; 95% CI, 0.15–0.76, P = 0.009).ConclusionImmunological reconstitution of γδ T cells is significantly delayed after Haplo‐HCT using PTCy and low‐dose ATG and is associated with an increased risk of increase in EBV viral load.

Cytotherapy, Aug 1, 2020

Corticosteroids are the standard first line treatment for acute graft-versus-host disease (aGVHD)... more Corticosteroids are the standard first line treatment for acute graft-versus-host disease (aGVHD). However, corticosteroids are associated with many complications and less than half of the patients have durable response. In order to improve outcomes, we performed a retrospective study to analyze the efficacy of the addition of extracorporeal photopheresis (ECP) to low dose corticosteroids in 37 adult patients (median age, 57 years) with skin predominant aGVHD (grade I, n=17; grade II, n=18 and grade III, n=2). All patients received ECP in combination with 1 mg/kg prednisone (n=26) or topical steroids (n=11). Overall response rate (ORR) was 81% after a median of 3 ECP procedures (range, 2-8), including 22 complete responses (CR, 59%) and 8 very good partial responses (VGPR, 22%). The 11 patients treated with topical corticosteroids achieved CR. Furthermore 16 (62%) patients reached prednisone withdrawal at a median of 100 days (range, 42-174 days) after its initiation. Eighteen patients developed chronic GVHD (cGVHD), 11 of them (who were in CR of aGvHD) had a new onset cGVHD and 7 experienced progressive cGVHD (5 non-responding and 2 VGPR patients). A second line immunosuppressive treatment was initiated in only 5 (14%) non-responding patients. With a median follow-up of 31 months (range, 6-57 months) two-year overall survival and non-relapse mortality were 74% and 11%, respectively. Overall, the combination of low-dose corticosteroids and ECP appear to be safe and effective for first-line treatment of skin predominant aGVHD.

Clinical Lymphoma, Myeloma & Leukemia, Jun 1, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cancer, Feb 22, 2018

BACKGROUND: T-cell-depleted, haploidentical transplantations (haplos) are commonly offered to pat... more BACKGROUND: T-cell-depleted, haploidentical transplantations (haplos) are commonly offered to patients who have high-risk, acute leukemia in the absence of a human leukocyte antigen (HLA) full-matched donor. METHODS: To determine the effect of transplantation period, the authors divided 308 adults with de novo, acute leukemia who underwent T-cell-depleted haplo from 2005 to 2015 into 2 groups, according the year in which they underwent transplantation (2005-2011 [n 5 191] and 2012-2015 [n 5 117]). RESULTS: The median age was 41 years in patients who underwent transplantation before 2012 and 46 years in those who underwent transplantation after 2012 (P 5 .04). Most patients had acute myeloid leukemia (75% vs 69%; P 5 .26) and were in first complete remission (CR1) (55% vs 64%; P 5 .12) at the time of transplantation. The cumulative incidence of grade 2, 3, and 4 acute graft-versus-host disease (GvHD) and chronic GvHD were not different between the 2 groups (acute GvHD: 20% vs 22% cumulative incidence in patients who underwent haplo before and after 2012, respectively [P 5 .67]; chronic GvHD: 19% vs 11% cumulative incidence, respectively; P 5 .12]. The 2-year relapse incidence was 20%, the nonrelapse mortality (NRM) rate was 48%, and no difference was observed over time (21% vs 19% [P 5 .72] and 54% vs 38% [P 5 .11] for patients who underwent haplo before and after 2012, respectively). The main cause of NRM was infection. Haplo after 2012 (hazard ratio [HR], 0.57; P 5 .01), younger age (HR, 0.82; P 5 .02), and receipt of a reduced-intensity conditioning (RIC) regimen (HR, 0.53; P 5 .01) were independently associated with lower NRM. The 2-year overall survival rate was 36% and improved after 2012 (29% vs 47% before 2012; P 5 .02); and it was higher for patients who underwent transplantation in CR1 (41% vs 29%; P 5 .01). In multivariate analysis, haplo after 2012 (HR, 0.54; P 5 .003) and receipt of a RIC regimen (HR, 0.54; P 5 .005) were independently associated with better overall survival. Similarly, leukemia-free survival and GvHD-free/relapse-free survival (GRFS) improved over time: the leukemia-free survival rate was 31% (25% vs 43% in the groups who underwent transplantation before and after 2012, respectively; P 5 .05), and the GRFS rate was 24% (19% vs 34%, respectively; P 5 .09). In addition, leukemia-free survival and GRFS improved among patients who received a RIC regimen. CONCLUSIONS: The outcome of patients with acute leukemia who underwent T-cell-depleted haplo has improved over time.

European Journal of Haematology, May 14, 2019

Objectives: This retrospective study analyzed the impact of early cyclosporine-A (CsA) initiation... more Objectives: This retrospective study analyzed the impact of early cyclosporine-A (CsA) initiation (day-3) on the risk of acute graft-versus-host disease (aGvHD) after haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplant cyclophosphamide Methods: Sixty-one consecutives patients who underwent Haplo-HCT were analyzed. Results: At day +180, the cumulative incidences of grade II-IV and grade III-IV aGvHD were 39% and 18%, respectively. Patients having a lowest CsA concentration (<301 ng/mL; the cutoff value used to segregate the patients between low and high CsA concentrations) in the first week after Haplo-HCT had a significantly higher risk of grade II-IV aGvHD (P= .02), severe grade III-IV aGvHD (P = .03), cGvHD (P= .02) and extensive cGvHD (P= .04). In multivariate analysis, a higher CsA concentration (≥301 ng/mL) during the first week following Haplo-HCT was the only parameter significantly associated with a reduced risk of grade II-IV and grade III-IV aGvHD (RR=.21; P=.049 and RR<0.001; P<.0001, respectively). We find no correlation between CsA concentration and relapse, non-relapse mortality, progression free survival, GvHD-free and progression free survival or overall survival. Conclusions: CsA could be initiated early before Haplo-HCT with achievement of high CsA concentration to reduce the risk of aGvHD without any detrimental effect on relapse.

British Journal of Haematology, May 26, 2022

British Journal of Haematology, Mar 4, 2022

Bone Marrow Transplantation, 2016