Publications by authors named "Noel Milpied"

178 Publications

Non-cryopreserved hematopoietic stem cells in autograft patients with lymphoma: a matched-pair analysis comparing a single center experience with the use of cryopreserved stem cells reported to the European Society for Blood and Marrow Transplantation registry.

Cytotherapy 2021 Mar 4. Epub 2021 Mar 4.

European Society for Blood and Marrow Transplantation Global Committee, Paris, France; Department of Hematology and Cell Therapy, Hôpital Saint-Antoine, Sorbonne University, Paris, France. Electronic address:

Background Aims: Around 50 000 autologous stem cell transplantations are done each year worldwide using cryopreserved peripheral blood stem cells (PBSCs). Cryopreservation is time-consuming and expensive. Since 2007, several retrospective studies have shown that PBSCs can be stored at 4°C for 2-3 days, allowing autologous stem cell transplantation in patients with multiple myeloma receiving high-dose melphalan. Data with non-cryopreserved PBSCs in patients autografted for lymphoma following longer pre-conditioning regimens are limited. In addition, no controlled comparison has been able to detect unforeseen differences.

Methods: The authors compared outcomes of 94 consecutive adult patients with lymphoma (66 with Hodgkin lymphoma) autografted in our department in Oran (Algeria) using PBSCs stored at 4°C, from 2009 to 2018, with patients receiving cryopreserved stem cells reported to the European Society for Blood and Marrow Transplantation registry. Patients autografted in Oran were matched with patients receiving cryopreserved PBSCs in the registry (four controls per patient in Oran).

Results: Neutrophil engraftment was significantly faster with cryopreserved PBSCs (P = 0.003). By day 10, only 17% of patients receiving non-cryopreserved PBSCs engrafted versus 48% for cryopreserved PBSCs. Likewise, platelet recovery to 20 000/mm was significantly faster in patients receiving cryopreserved PBSCs (P = 0.01). However, all patients in both groups had recovered by day 20. There were no significant differences in non-relapse mortality (9% versus 7%, P = 0.4), relapse incidence (22% versus 32%, P = 0.13), progression-free survival (70% versus 61%, P = 0.4) or overall survival (85% versus 75%, P = 0.3).

Conclusions: This analysis suggests that, in patients with lymphoma receiving pre-transplant regimens such as carmustine, etoposide, cytarabine and melphalan, PBSCs stored at 4°C for up to 6 days can be used safely in centers with no cryopreservation facility. However, the kinetics of hematopoietic recovery showed a significant, albeit small, delay in engraftment for both neutrophils and platelets, which favors the use of cryopreservation if available.
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http://dx.doi.org/10.1016/j.jcyt.2020.12.016DOI Listing
March 2021

Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies.

Front Immunol 2020 2;11:613954. Epub 2021 Feb 2.

Department of Hematology and Oncology, Medical University of Graz, Graz, Austria.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
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http://dx.doi.org/10.3389/fimmu.2020.613954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884746PMC
February 2021

Impact of early candidemia on the long-term outcome of allogeneic hematopoietic stem cell transplant in non-leukemic patients: an outcome analysis on behalf of IDWP-EBMT.

Bone Marrow Transplant 2021 Jan 29. Epub 2021 Jan 29.

Department of Pediatric Hematology and Oncology, Collegium Medicum UMK Torun, Bydgoszcz, Poland.

We assessed the incidence and outcome of early candidemia after hematopoietic stem cell transplant (HSCT). The analysis included all first HSCTs performed from 2000 to 2015 in adult and pediatric patients with a non-leukemic disease and recorded in the EBMT registry. Overall survival (OS), non-relapse mortality (NRM), and relapse mortality (RM) were evaluated. Candidemia was diagnosed in 420 of 49,852 patients at a median time of 17 days post HSCT (range 0-100), the cumulative incidence being 0.85%. In 65.5% of episodes, candidemia occurred by day 30 after HSCT. The mortality rate by day 7 was 6.2%, whereas 100-day NRM was higher (HR 3.47, p < 0.0001), and 100-day OS was lower (HR 3.22, p < 0.0001) than that of patients without candidemia. After a median follow-up of 4.3 years, 5-year OS, NRM, and RM for patients with and without candidemia were 50.5% vs. 60.8%, p < 0.0001, 28.2% vs.18.8%, p < 0.0001, and 25.3% vs. 27.2%, p = 0.4, respectively. In conclusion, in non-leukemic transplant patients, the occurrence of an early episode of candidemia is rare but it is still associated with a negative effect on the outcome.
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http://dx.doi.org/10.1038/s41409-021-01212-1DOI Listing
January 2021

A randomized phase 3 trial of auto vs. allo transplantation as part of first-line therapy in poor-risk peripheral T-NHL.

Blood 2020 Dec 17. Epub 2020 Dec 17.

Hôpital Robert Debré, REIMS, France.

Standard first-line therapy for younger patients with peripheral T-cell lymphoma consists of six courses of CHOP or CHOEP consolidated by high-dose therapy and autologous stem cell transplantation (AutoSCT). We hypothesized that consolidative allogeneic transplantation (AlloSCT) could improve outcome. 104 patients with nodal peripheral T-cell lymphoma except ALK+ ALCL, 18 to 60 years of age, all stages and IPI scores except stage 1 and aaIPI 0, were randomized to receive 4 x CHOEP and 1 x DHAP followed by high-dose therapy and AutoSCT or myeloablative conditioning and AlloSCT. The primary endpoint was event-free survival (EFS) at three years. After a median follow-up of 42 months, 3-year EFS of patients undergoing AlloSCT was 43% (95% confidence interval [CI]: 29%; 57%) as compared to 38% (95% CI: 25%; 52%) after AutoSCT. Overall survival at 3 years was 57% (95% CI: 43%; 71%) versus 70% (95% CI: 57%; 82%) after AlloSCT or AutoSCT, without significant differences between treatment arms. None of 21 responding patients proceeding to AlloSCT as opposed to 13 of 36 patients (36%) proceeding to AutoSCT relapsed. Eight of 26 patients (31%) and none of 41 patients died due to transplant-related toxicity after allogeneic and autologous transplantation, respectively. In younger patients with T-cell lymphoma standard chemotherapy consolidated by autologous or allogeneic transplantation results in comparable survival. The strong graft-versus-lymphoma effect after AlloSCT was counterbalanced by transplant-related mortality. CHO(E)P followed by AutoSCT remains the preferred treatment option for transplant-eligible patients. AlloSCT is the treatment of choice for relapsing patients also after AutoSCT.
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http://dx.doi.org/10.1182/blood.2020008825DOI Listing
December 2020

Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party.

Bone Marrow Transplant 2021 Mar 2;56(3):605-613. Epub 2020 Oct 2.

University of Heidelberg, Heidelberg, Germany.

No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients had TP53 CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD °II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.
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http://dx.doi.org/10.1038/s41409-020-01069-wDOI Listing
March 2021

Vinblastine for elderly and frail patients with Hodgkin lymphoma.

Leuk Lymphoma 2020 12 27;61(13):3239-3242. Epub 2020 Jul 27.

Department of Hematology and Cell Therapy, University Hospital, Bordeaux, France.

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http://dx.doi.org/10.1080/10428194.2020.1797009DOI Listing
December 2020

KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma.

N Engl J Med 2020 04;382(14):1331-1342

From the University of Texas M.D. Anderson Cancer Center, Houston (M.W.), and Texas Oncology, Dallas (H.H.); Banner M.D. Anderson Cancer Center, Gilbert, AZ (J.M.); John Theurer Cancer Center, Hackensack, NJ (A.G.); Moffitt Cancer Center, Tampa (F.L.L.), and the University of Miami, Miami (A.B.) - both in Florida; Dana-Farber Cancer Institute, Boston (C.A.J.); Cleveland Clinic Foundation, Cleveland (B.T.H.), and the Ohio State University Comprehensive Cancer Center, Columbus (S.J.); David Geffen School of Medicine at UCLA, Los Angeles (J.M.T.), Stanford University School of Medicine, Stanford (D.B.M.), and Kite, a Gilead company, Santa Monica (W.P., L.Z., J.M.R., R.K.J., A.V.R.) - all in California; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.W.F.); Colorado Blood Cancer Institute, Denver (P.A.M.); Swedish Cancer Institute, Seattle (J.M.P.); the Academic Medical Center, University of Amsterdam, Amsterdam, for the Lunenburg Lymphoma Phase I/II Consortium (M.-J.K.); Centre Hospitalier Universitaire (CHU) Bordeaux, Service d'Hematologie et Therapie Cellulaire, Bordeaux (N.M.), and CHU Rennes, INSERM French Blood Establishment, Rennes (R.H.) - both in France; Fox Chase Cancer Center, Philadelphia (H.F.); Universitätsklinikum Würzburg, Würzburg, Germany (M.S.T.); and the University of Rochester Medical Center, Rochester, NY (P.M.R.).

Background: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.

Methods: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.

Results: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.

Conclusions: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
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http://dx.doi.org/10.1056/NEJMoa1914347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731441PMC
April 2020

Interim PET Assessment of Advanced Hodgkin Lymphoma: Is It Sufficient?

J Nucl Med 2020 11 14;61(11):1694-1695. Epub 2020 Feb 14.

CHU Bordeaux Avenue de Magellan Pessac, France 33604 E-mail:

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http://dx.doi.org/10.2967/jnumed.120.242594DOI Listing
November 2020

Treatment of invasive fungal infections in intensive care units with micafungin: The MYRIADE study.

Mycoses 2020 May 25;63(5):443-451. Epub 2020 Feb 25.

Department of Acute Care, Gustave-Roussy Institute - Cancer Campus Grand Paris, Villejuif, France.

Background: Invasive fungal infections (IFIs) contribute significantly to nosocomial illness in intensive care units (ICUs). Current practice guidelines recommend echinocandins, such as micafungin, for the treatment of invasive candidiasis. However, limited information on their use in real-world practice is available.

Objective: To describe the conditions of the use of micafungin in daily clinical practice and to evaluate its effectiveness and tolerability under real-world conditions.

Patients/methods: This observational, prospective, multicentre study was performed in 34 ICUs in France. The study population consisted of 275 patients ≥16 years old who received treatment with micafungin during the inclusion period. Dose and duration of treatment were at the discretion of the physician.

Results: Proven invasive candidiasis was documented before treatment in 106 patients (38.6%); 263 patients (95.6%) received the recommended dose (100 mg/day); 78 patients (28.8%) were treated for the recommended duration. A successful outcome was observed for 217 patients (79.2%). This proportion was significantly higher (83.3%; P < .0001) in patients treated for ≥14 days. Three patients discontinued treatment due to an adverse event considered related to micafungin. No clear impact of micafungin on hepatic function was observed.

Conclusion: Micafungin was effective in >75% of patients treated for IFIs in ICUs in France; outcomes may be improved with closer adherence to the recommended treatment duration.
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http://dx.doi.org/10.1111/myc.13060DOI Listing
May 2020

Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients.

Bone Marrow Transplant 2020 06 29;55(6):1114-1125. Epub 2020 Jan 29.

Department of Hematology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

To address limitations of the currently used reduced-intensity/myeloablative conditioning (RIC/MAC) classification scheme we aimed to develop a tool that can capture more standardized the conditioning intensity of allogeneic hematopoietic cell transplantation (HCT). We assigned intensity weight scores for frequently used conditioning regimen components and used their sum to generate the transplant conditioning intensity (TCI) score. We retrospectively tested the impact of TCI on 8255 adult (45-65 years) acute myeloid leukemia patients who underwent HCT in first complete remission. A Cox model for early nonrelapse mortality (NRM) yielded a 3-group TCI risk scheme (low, intermediate, high) with respective TCI scores of [1-2], [2.5-3.5] and [4-6]. On multivariate modeling, TCI grouping was highly and better predictive for early (day 100 and 180) NRM, 2-year NRM and relapse (REL) as compared with the RIC/MAC classification. Validation was done on 200 bootstrap samples. Moreover, TCI scoring enabled the identification of a distinct subgroup of RIC and MAC conditioning regimens with an intermediate TCI [2.5-3.5] score that had identical outcomes and which are frequently referred as "reduced toxicity conditioning". TCI scheme provides an improvement of the RIC/MAC classification. We propose TCI as a new tool to define and measure the conditioning regimen intensity.
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http://dx.doi.org/10.1038/s41409-020-0803-yDOI Listing
June 2020

Cardiac failure in patients treated with azacitidine, a pyrimidine analogue: Case reports and disproportionality analyses in Vigibase.

Br J Clin Pharmacol 2020 05 3;86(5):991-998. Epub 2020 Feb 3.

CHU de Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire Bordeaux, France.

Aims: Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure.

Methods: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period.

Results: In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2).

Conclusion: This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease.
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http://dx.doi.org/10.1111/bcp.14211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163380PMC
May 2020

[Treatment of malignant blood diseases in hospital and in the home in the 21st century].

Authors:
Noël Milpied

Soins 2019 Dec;64(841):22-25

Service d'hématologie clinique et thérapie cellulaire, hôpital Haut-Lévêque, 33604 Pessac cedex, France. Electronic address:

Modern day treatment of blood cancers is characterised by the introduction of targeted therapies. Alone or in combination with more traditional treatments, administered in a hospital or an outpatient setting, these new medicines possess specific mechanisms of action and particular side effects in addition to or instead of those of traditional treatments. To understand the changes to the care management of patients taking these new treatments, it is necessary to describe their mechanism of action and their side effects.
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http://dx.doi.org/10.1016/j.soin.2019.10.002DOI Listing
December 2019

Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWP.

Eur J Haematol 2020 Mar 25;104(3):181-189. Epub 2019 Dec 25.

University Hospital Eppendorf, Hamburg, Germany.

Objectives: The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative (NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant.

Methods: A retrospective analysis of the EBMT database (1991-2012) was performed.

Results: A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P < .001) but not after 2002 (HR = 1.2, P = .276).

Conclusion: From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.
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http://dx.doi.org/10.1111/ejh.13352DOI Listing
March 2020

Influence of alternative donor type on early survival after hematopoietic stem cell transplantation for acute myeloid leukemia lacking a sibling donor.

Bone Marrow Transplant 2020 04 29;55(4):749-757. Epub 2019 Oct 29.

CHU (University Hospital) de Grenoble Alpes, Grenoble, France.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for acute myeloid leukemia. In the absence of an HLA-matched related or unrelated donor (MRD or MUD), the best alternative donor source remains controversial. Umbilical cord blood and haploidentical donors offer a shorter delay from indication to transplantation. This retrospective multicentre study of a French registry compares overall survival in the 18 months following registration in the absence of a MRD between four types of donors. Between 2012 and 2016, 1302 patients were transplanted using MUD (control, n = 803), mismatched MUD (n = 219), umbilical cord blood (n = 153) and haploidentical (n = 127) donors. Multivariate analyses were conducted for overall survival after registration, after transplant, and transplant-related mortality. After adjustment for variables, the type of donor did not influence any of the three end points. Our results confirmed the significant negative impact of longer time between registration and transplant: HR = 1.04 [1.02-1.06] (p < 0.0001). This indicates a positive correlation between better survival and shorter registration-to-transplantation wait time. In the absence of a sibling donor, the alternative stem cell source does not impact early survival in acute myeloid leukemia patients. The minimization of registration-to-transplantation time should be considered when weighing the alternative donor options.
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http://dx.doi.org/10.1038/s41409-019-0722-yDOI Listing
April 2020

Benchmarking of survival outcomes following haematopoietic stem cell transplantation: A review of existing processes and the introduction of an international system from the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).

Bone Marrow Transplant 2020 04 21;55(4):681-694. Epub 2019 Oct 21.

Agence de la biomédecine, Paris, France.

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT.
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http://dx.doi.org/10.1038/s41409-019-0718-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113189PMC
April 2020

Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study.

Bone Marrow Transplant 2020 01 16;55(1):224-232. Epub 2019 Sep 16.

Department of Hematology, Hopital Saint Antoine, Paris, France.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for patients with secondary acute myeloid leukemia (sAML), though the impact of conditioning regimens on HCT outcomes for patients with antecedent lymphoid malignancy is largely unknown. This multicenter, retrospective registry study of the ALWP of the EBMT assessed HCT outcomes in this population. In all, 549 patients ≥18 years with sAML following an antecedent lymphoid malignancy treated with first allograft between 2000-2016 were included. Myeloablative (MAC) and reduced intensity conditioning (RIC) was given in 258 (47%) and 291 (53%), respectively. At 2 years, leukemia-free survival (LFS) was 31.7% (95% CI, 27.5-35.9), overall survival (OS) was 37.4% (95% CI, 33-41.8), nonrelapse mortality (NRM) was 28.9% (95% CI, 25-33), and GVHD-free, relapse-free survival (GRFS) was 22.8% (95% CI, 19-26.6). In multivariate analysis, patients receiving RIC regimens had lower risk of NRM (HR: 0.58, CI: 0.40-0.83, p = 0.003), and improved LFS (HR: 0.67, CI: 0.52-0.85, p = 0.001). Patients with prior autologous HCT had inferior LFS (HR: 1.30, CI: 1.01-1.67, p = 0.01). This study demonstrates that sAML patients following prior lymphoid malignancy treated with RIC regimens have a lower risk of NRM and improved LFS, OS, and GFRS. Other variables associated with inferior outcomes include older age, active disease, adverse cytogenetics, and prior auto-HCT.
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http://dx.doi.org/10.1038/s41409-019-0673-3DOI Listing
January 2020

Myeloablative Unrelated Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia.

Biol Blood Marrow Transplant 2019 12 5;25(12):2438-2446. Epub 2019 Aug 5.

Eurocord, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France; Monacord, Centre Scientifique de Monaco, Principauté de Monaco, Monaco. Electronic address:

Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P < .001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P  = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P  = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.031DOI Listing
December 2019

Prognostic utility of pre-transplantation [ F] fluorodeoxyglucose positron emission tomography/computed tomography in patients with diffuse large B-cell lymphoma who underwent rituximab, dexamethasone, high-dose cytarabine, carboplatin salvage chemotherapy.

Br J Haematol 2020 01 6;188(2):268-271. Epub 2019 Aug 6.

Hématologie, CHU Bordeaux, Bordeaux, France.

We analysed the outcomes of 62 patients with refractory/relapsed diffuse large B-cell lymphoma (rrDLBCL) who had pre-transplantation fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) after R-DHAC (rituximab, dexamethasone, high-dose cytarabine, carboplatin) salvage chemotherapy, and were evaluated using Deauville criteria and total lesion glycolysis (TLG). A positive pre-transplantation PET/CT with Deauville score of 5 was associated with shorter progression-free survival (PFS) (P = 0·01), while a Deauville score of 4 was not predictive of outcome. Only pre-transplant TLG was significantly associated with both PFS (P = 0·005) and overall survival (P = 0·03). TLG deserves to be further investigated in prospective studies.
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http://dx.doi.org/10.1111/bjh.16144DOI Listing
January 2020

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Int J Mol Sci 2019 Jul 12;20(14). Epub 2019 Jul 12.

Institut National de la Santé et de la Recherche Médicale, U1035 Bordeaux, France.

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical "3 + 7" treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.
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http://dx.doi.org/10.3390/ijms20143429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679203PMC
July 2019

Killer immunoglobulin-like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment-free remission.

Cancer Med 2019 Sep 9;8(11):4976-4985. Epub 2019 Jul 9.

Institut National de la Santé et de la Recherche Médicale INSERM U1218, Bordeaux, France.

Background: Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells.

Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2.

Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B-positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32-0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment-free remission rates.

Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte-mediated control of leukemic residual disease control in patient with CML relapse.
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http://dx.doi.org/10.1002/cam4.2371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718597PMC
September 2019

Long-term prognosis of septic shock in cancer patients.

Support Care Cancer 2020 Mar 26;28(3):1325-1333. Epub 2019 Jun 26.

Intensive Care and Infectious Disease Unit, CHU Bordeaux, 33000, Bordeaux, France.

Objectives: In the last decades, the number of cancer patients admitted in intensive care units (ICUs) for septic shock has dramatically increased. However, prognosis data remain scarce.

Methods: To assess the 180-day mortality rate in cancer patients admitted to the ICU for septic shock, a 5-year prospective study was performed. All adult patients admitted for septic shock were included and categorized into the following two groups and four subgroups: cancer patients (solid tumor or hematological malignancy) and non-cancer patients (immunocompromised or not). Data were collected and compared between the groups. Upon early ICU admission, the decision to forgo life-sustaining therapy (DFLST) or not was made by consultation among hematologists, oncologists, and the patients or their relatives.

Results: During the study period, 496 patients were admitted for septic shock: 252 cancer patients (119 hematological malignancies and 133 solid tumors) and 244 non-cancer patients. A DFLST was made for 39% of the non-cancer patients and 52% of the cancer patients. The 180-day mortality rate among the cancer patients was 51% and 68% for those with hematological malignancies and solid cancers, respectively. The mortality rate among the non-cancer patients was 44%. In a multivariate analysis, the performance status, Charlson comorbidity index, simplified acute physiology score 2, sequential organ failure assessment score, and DFLST were independent predictors of 180-day mortality.

Conclusions: Despite early admission to the ICU, the 180-day mortality rate due to septic shock was higher in cancer patients compared with non-cancer patients, due to excess mortality in the patients with solid tumors. The long-term prognosis of cancer patients with septic shock is modulated by their general state, severity of organ failure, and DFLST.
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http://dx.doi.org/10.1007/s00520-019-04937-4DOI Listing
March 2020

Use of Micafungin for the Prevention and Treatment of Invasive Fungal Infections in Everyday Pediatric Care in France: Results of the MYRIADE Study.

Pediatr Infect Dis J 2019 07;38(7):716-721

Department of Acute Care, Gustave-Roussy Institute-Cancer Campus Grand Paris, Villejuif, France.

Background: Invasive fungal infections are responsible for significant morbidity and mortality. Safety and effectiveness of antifungal agents is a particular concern in pediatric populations, where data are often limited. Micafungin is an echinocandin with demonstrated antifungal activity against a wide spectrum of Candida spp.; this subanalysis of data from the MYRIADE study describes the use of micafungin and its therapeutic outcomes in pediatric patients, in normal clinical practice.

Methods: MYRIADE was an observational, multicenter, national, prospective, longitudinal study conducted from January 2010 to December 2012, in patients treated with micafungin using a prophylactic or curative strategy, across 17 sites [oncohematology (n = 8), neonatal intensive care units (ICUs) (n = 5) and pediatric ICUs (n = 4)]. The treatment regimen, the achievement of the therapeutic objective and the tolerance were reported.

Results: The study population consisted of 110 pediatric patients (31 neonates, 24 children <2 years old and 55 children ≥2 to <16 years old). The therapeutic objective was achieved in 49/64 (76.6%) oncohematology patients, 28/29 (96.6%) neonatal ICU patients and 12/14 (85.7%) pediatric ICU patients. Twenty-four (21.8%) children developed an adverse event (AE); more AEs were observed in oncohematology patients compared with ICU patients [17 (26.1%) vs. 7 (15.6%)]. Only one serious AE, reported in an oncohematology patient, was considered related to micafungin.

Conclusions: In the first large observational study of micafungin treatment or prophylaxis conducted under real-world conditions in France, micafungin was effective and well tolerated for prophylaxis of invasive fungal infections in pediatric oncohematology patients and for curative purposes in pediatric and neonatal ICU patients.
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http://dx.doi.org/10.1097/INF.0000000000002353DOI Listing
July 2019

Outcomes of Salvage Haploidentical Transplant with Post-Transplant Cyclophosphamide for Rescuing Graft Failure Patients: a Report on Behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2019 09 24;25(9):1798-1802. Epub 2019 May 24.

Bone Marrow Transplant Unit, Saint Louis Hospital, Paris, France.

Prognosis of patients with graft failure is dismal, and retransplantation is the sole option for long-term survival. To address the interest of haploidentical transplantation as a salvage option in this context, we analyzed data from 24 patients with graft failure or loss retransplanted with a haploidentical donor who received post-transplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis (GVHD). Fludarabine-based reduced-intensity conditioning was used in 23 patients and the Baltimore regimen in 14 patients. The median delay between previous and salvage transplantation for graft failure was 63 days (range, 39 to 98). In addition to PTCy, all patients received cyclosporine, and 22 patients also received mycophenolate mofetil for GVHD prophylaxis. With a median follow-up of 353 days (range, 16 to 2010), 1-year overall survival (OS) was 56% (95% confidence interval, 38% to 81%). Transplant complications accounted for 80% of deaths. The cumulative incidence of neutrophil engraftment at day +30 was 79%. Cumulative incidence of grades II to IV acute GVHD at day 100 was 14%, and 1-year cumulative incidence of chronic GVHD was 31%. One-year cumulative incidence of relapse was 13%. Stem cell source did not impact on engraftment, GVHD, relapse, or OS. Salvage haploidentical transplant with PTCy for rescuing graft failure patients leads to an acceptable 1-year OS and might be a valid option in this poor situation.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.013DOI Listing
September 2019

Prospective phase II study of prophylactic low-dose azacitidine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and myelodysplastic syndrome.

Bone Marrow Transplant 2019 11 14;54(11):1815-1826. Epub 2019 May 14.

Hematology Department, AP-HP, Saint-Antoine Hospital, Paris, France.

Thirty patients, with high-risk acute myeloid leukemia (AML, n = 20) or myelodysplastic syndrome (MDS, n = 10), were enrolled in a phase II trial entailing prophylactic post-transplant azacitidine (AZA) plus escalated doses of donor lymphocyte infusion (DLI). The median number of AZA cycles was 5 (1-12) with 10 patients (33%) completing the 12 projected cycles. DLI were performed in 17 patients: 5 received one DLI, 2 received 2 DLI and 8 received 3 infusions. AZA was well tolerated, but discontinued in 20 patients primarily due to graft-versus-host disease (GvHD) and relapse. The cumulative incidence (CI) of grade 1-3 acute GvHD was 31.5% and the chronic GvHD CI was 53% at 2 years. At a median follow-up of 49 months (27-63), 18 patients are alive. The overall and disease-free survivals are 65.5% (CI 95% = 48.2-82.8) at 2 years. Cause of death was mainly relapse for 9 patients. The median time to relapse was 7 months (2.5-58) and the cumulative incidence of relapse at 2 years was 27.6% (CI 95% = 12.8-44.6). These results confirm that AZA is well tolerated as a prophylactic treatment to reduce the risk of post-transplantation relapse and compared favorably to those of patients who receive no post-transplant maintenance.
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http://dx.doi.org/10.1038/s41409-019-0536-yDOI Listing
November 2019

PET-guided, BEACOPP therapy in advanced Hodgkin lymphoma.

Lancet Oncol 2019 04;20(4):e189

Department of Nuclear Medicine, Centre Hospitalier Universitaire, F-33000 Bordeaux, France.

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http://dx.doi.org/10.1016/S1470-2045(19)30162-7DOI Listing
April 2019

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib STAT5-and hypoxia-dependent upregulation of AXL.

Haematologica 2019 10 28;104(10):2017-2027. Epub 2019 Mar 28.

Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, F-33000 Bordeaux

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.
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http://dx.doi.org/10.3324/haematol.2018.205385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886433PMC
October 2019

Outcomes of Advanced Hodgkin Lymphoma after Umbilical Cord Blood Transplantation: A Eurocord and EBMT Lymphoma and Cellular Therapy & Immunobiology Working Party Study.

Biol Blood Marrow Transplant 2018 11 19;24(11):2265-2270. Epub 2018 Jul 19.

Eurocord, Hôpital Saint Louis, Paris, France; Monacord, Centre Scientifique de Monaco, Monaco; Hematology Department, Ospedale Pediatrico Bambin Gesù, Dipartimento di Oncoematologia e Terapia Cellulare e Genica, Rome, Italy. Electronic address:

Allogeneic stem cell transplantation is an alternative for patients with relapsed or refractory Hodgkin lymphoma (HL), but only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 131 adults with HL who underwent UCBT in European Society for Blood and Marrow Transplantation centers from 2003 to 2015. Disease status at UCBT was complete remission (CR) in 59 patients (47%), and almost all patients had received a previous autologous stem cell transplantation. The 4-year progression-free survival (PFS) and overall survival (OS) were 26% (95% confidence interval [CI], 19% to 34%) and 46% (95% CI, 37% to 55%), respectively. Relapse incidence was 44% (95% CI, 36% to 54%), and nonrelapse mortality (NRM) was 31% (95% CI, 23% to 40%) at 4 years. In multivariate analysis refractory/relapsed disease status at UCBT was associated with increased relapse incidence (hazard ratio [HR], 3.14 [95% CI, 1.41 to 7.00], P = .005) and NRM (HR, 3.61 [95% CI, 1.58 to 8.27], P = .002) and lower PFS (HR, 3.45 [95% CI, 1.95 to 6.10], P < .001) and OS (HR, 3.10 [95% CI, 1.60 to 5.99], P = .001). Conditioning regimen with cyclophosphamide + fludarabine + 2 Gy total body irradiation (Cy+Flu+2GyTBI) was associated with decreased risk of NRM (HR, .26 [95% CI, .10 to .64], P = .004). Moreover, Cy+Flu+2GyTBI conditioning regimen was associated with a better OS (HR, .25 [95% CI, .12 to .50], P < .001) and PFS (HR, .51 [95% CI, .27 to .96], P = .04). UCBT is feasible in heavily pretreated patients with HL. The reduced-intensity conditioning regimen with Cy+Flu+2GyTBI is associated with a better OS and NRM. However, outcomes are poor in patients not in CR at UCBT.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.019DOI Listing
November 2018