Abstract
Introduction
At Hiwa Cancer Hospital (Sulaymaniyah, Iraqi Kurdistan) after the center was started by a cooperative project in June 2016, autologous transplantation was developed.
Patients and Methods
To develop the project, the capacity-building approach was adopted, with on-site training and coaching of personnel, educational meetings, lectures, on-the-job training, and the implementation of quality management planning.
Results
Here, we report initial results of peripheral-blood stem-cell mobilization and collection of the first 27 patients (age 12 to 61 years; 19 males and 8 females; multiple myeloma, n = 10; plasma cell leukemia, n = 1; Hodgkin lymphoma, n = 12; non-Hodgkin lymphoma, n = 3; and acute myeloid leukemia, n = 1). Only three (11.5%) of 26 patients experienced a failure of mobilization. A median of 6.1 × 106/kg CD34-positive cells per patient were collected (range, 2.4 to 20.8), with two apheretic runs. Twenty-four patients underwent autologous transplantation. All but one transplantation engrafted fully and steadily, with 0.5 and 1.0 × 109/L polymorphonucleates on day 10.5 (range, 8 to 12) and day 11 (range, 9 to 15), respectively, and with 20 and 50 × 109/L platelets on day 13 (range, 10 to 17) and day 17 (range, 2 to 44), respectively. More than 95% of patients are projected to survive 1 year after autograft.
Conclusion
These data are the result of an Italian effort to establish in Iraqi Kurdistan a leading center for hemopoietic stem-cell transplantation. The capacity building approach was used, with on-site training and coaching as instruments for the development of provider ability and problem solving. With future limitations for immigration, this method will be helpful, especially in the field of high-technology medicine.
INTRODUCTION
Hemopoietic stem-cell transplantation (HSCT) is effective for the treatment of many hematologic disorders.1 Unfortunately, not all countries have enough resources and expertise to establish an HSCT program.2 Iraqi Kurdistan recently entered a deep economic crisis that also involved the health system. We have previously described3 the capacity-building process that led to starting an HSCT center at Hiwa Cancer Hospital (HCH; Sulaymaniyah, Iraqi Kurdistan). Activity began in April 2016 and led to the first autologous transplantation in June and an allogeneic transplantation in October of the same year.
Here, we report an analysis of peripheral-blood stem-cell (PBSC) mobilization and collection of the first 27 patients and the engraftment times of 24 patients who underwent autologous transplantation. These results are comparable to those of major European Union and US centers, which confirms the value of capacity building as means to develop high-technology medical procedures in low-to-middle income countries.
PATIENTS AND METHODS
HSCT Center
This study was conducted at the recently established HSCT center of HCH, with six single-bed, HEPA-filtered, positive-pressure sterile rooms, four double-bed clean rooms, and an apheresis unit, with a Fresenius Comtec, an Amicus Fenwall cell separator (Fresenius, Kabi, Bad Homburg, Germany), and a manipulation laboratory for cell separation and cryopreservation.
Capacity Building
The capacity-building approach is a conceptual approach4 that is focused on understanding and surmounting obstacles that prevent organizations from realizing sustainable development goals. This process was adopted at HCH, with on-site training and coaching of personnel for the duration of the project. In particular, in the first 2 months, educational meetings were organized for 55 health care professionals—physicians, nurses, biologists, and managers—with 60 lectures conducted. On-the-job training was developed, and quality management planning was implemented, with organizational charts, a documentation system, and verification of activities for continuous improvement. All procedures were written and coded, verified, and shared with local professionals. Indicators were set to periodically check the trends of the activities.
Patients
Twenty-seven patients with multiple myeloma (MM), plasma-cell leukemia (PCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or acute myeloid leukemia (AML) were recruited to the program from June 2016 to March 2017 (Table 1). All patients received in-depth information on their disease and the HSCT procedure and provided written consent. The Ethical Committee of the College of Medicine, University of Sulaimani, approved the analysis and publication of the retrospective study data.
Table 1.
Characteristics of the 27 Patients at the Time of First Peripheral-Blood Stem-Cell Mobilization Procedure
PBSC Mobilization
PBSC mobilization regimen was determined on the basis of disease and cell target. Initially, granulocyte colony-stimulating factor (G-CSF) alone 5 µg/kg twice a day5 (Sanofi, Paris, France) was administered to patients with MM, as the collection target was 5 × 106/kg CD34-positive cells. Later, the target was set to 10 × 106/kg CD34-positive cells to enable a double autograft, and intermediate (1.5 to 2 g/m2)6 or high-dose cyclophosphamide (4 g/m2) were used,7 always with G-CSF. Patients with lymphoma were mobilized mostly during their salvage chemotherapy. In HL, this was the BeGeV8 combination in eight patients and the IGeV9 in one patient. The mobilization/collection step followed the second or third course, and G-CSF 5 µg/kg twice a day was administered since day 5. A schedule of intermediate-dose cyclophosphamide plus G-CSF was also used in three patients. In patients with NHL, the rituximab plus dexamethasone, cisplatin, cytarabine salvage regimen was used,10 or intermediate-dose cyclophosphamide always followed by G-CSF. A single patient with AML was recruited for autograft. Fludarabine, cytarabine, and G-CSF11 was also used for mobilization. Details of each regimen are listed in Table 2. In all patients, G-CSF was continued until the collection target was reached.
Table 2.
Regimens Used for First Peripheral-Blood Stem-Cell Mobilization
CD34-Positive Cell Collection
After mobilization, blood cell counts were monitored. After chemotherapy-induced pancytopenia or, in the case of G-CSF alone, on day 4 since its beginning, CD34-positive cells were assessed daily by using a stem-cell enumeration kit (BD Biosciences, Brea, CA) and FACS Via flow cytometer (BD Biosciences). Initially, a double platform was employed,13 but a single platform was later used.14 Collections were usually started as CD34-positive cells rose > 20 × 106/L, and only in a minority between 10 and 20 × 106/L, using either the Fresenius Comtec or the Amicus Fenwall cell separator, two to three blood volumes per procedure. An algorithm was used for collection prediction.15 The target was 5 × 106/kg body weight for each planned transplantation for collected CD34-positive cells.16 The number doubled for candidates of double autologous transplantation.
PBSC Manipulation and Cryopreservation
A C-grade manipulation facility with a laminar flow hood was used. Cryopreservation was initially carried at −80°C in a mechanical freezer,17 but cells were later frozen in a liquid nitrogen tank in 10% DMSO (Sigma-Aldrich, St. Louis, MO) in autologous plasma using Fresenius Hemofreeze (Fresenius) bags. At the time of autograft, bags were rapidly thawed in a 37°C water bath and infused.
Autologous Transplantation
For autologous transplantation, we used PBSC alone followed by high-dose chemotherapy. This schedule was based on disease and the availability of drugs. In patients with MM or PCL, patient received high-dose melphalan (140 mg/m2, n = 3; or 200 mg/m2, n = 7).18 In patients with HL or NHL, carmustine, etoposide, cytarabine, melphalan19 was the first choice for treatment (n = 7), but TEAM (n = 5)20 or cyclophosphamide, carmustine, and etoposide (n = 1)21 were used when carmustine was unavailable. TEAM was used in patients with AML. All patients received G-CSF 5 µg/kg since day +5 after autograft and until achievement of > 1.0 × 109/L polymorphonucleates (PMNs).
Transfusions
Blood products were irradiated (2.5 Gy) before transfusion. Packed RBCs were transfused when the Hb level was < 8 g/dL, while platelet concentrates, in the absence of bleeding or fever, were transfused when the platelet count was < 10.0 × 109/L.
Fever Management
At the onset of fever, blood cultures were obtained (one from the central venous catheter, if present) and the patient was immediately started on empirical antibiotics (piperacillin + tazobactam 400 mg/kg daily).
Engraftment
Patients were monitored daily. Myeloid engraftment was defined as the attainment of ≥ 0.5 and 1.0 × 109/L PMNs for 3 consecutive days. Platelet engraftment was defined as ≥ 20.0 and 50.0 × 109/L platelets for 7 consecutive days and without support.
RESULTS
Capacity Building
A quality-based system was developed with a daily morning briefing; weekly seminars; and patient ward rounds, waiting list assessment, and periodical personnel re-evaluation by multiple-choice questionnaire.
Mobilization and Collection
Results of the first PBSC mobilization and collection in 26 patients are summarized in Table 3. We considered failure to be CD34-positive cell peak < 10 × 106/L, although in a patient with AML, we proceeded to apheresis despite a cell peak of 9.7 × 106/L. In total, only three (11.5%) of 26 patients experienced a mobilization failure. Efficiency of the regimens was not significantly different. The day of the start of apheresis is reported in Table 3. Overall, with a median of two apheretic runs and 12,360 mL of blood (range, 3,575 to 17,100 mL) processed per run, 6.1 × 106/kg CD34-positive cells per patient were collected (range, 2.4 to 20.8). The number of harvested CD34-positive cells was inferior to target only in three patients.
Table 3.
Results of Peripheral-Blood Stem-Cell Mobilization and Collection
Second Mobilization Attempts
A second attempt at mobilization was made in two of the three patients who experienced failure, both of whom were patients with MM who experienced failure with G-CSF alone. One received cyclophosphamide 4 g/m2 plus G-CSF and collected 6.2 × 106/kg CD34-positive cells, whereas the other was mobilized with cyclophosphamide 2 g/m2 plus G-CSF and collected 9.8 × 106/kg CD34-positive cells.
Autologous Transplantation and Engraftment
Overall, 24 patients underwent autologous transplantation—nine patients with MM, one with PCL, 10 with HL, three with NHL, and one with AML. The majority (n = 16) of patients were in complete remission; they received 5.3 × 106/kg CD34-positive cells (range, 4.6 to 20). All but one patient achieved full engraftment, with 0.5 and 1.0 × 109/L PMN counts on day 10.5 (range, 8 to 12) and day 11 (range, 9 to 15), respectively, and with 20 and 50 × 109/L platelets on day 13 (range, 10 to 17) and day 17 (range, 12 to 44), respectively. A probability curve for PMNs and platelet recovery is reported in Figure 1. Overall, patients experienced 2 days of fever > 38°C (range, 0 to 11) and received one packed RBC transfusion (range, 0 to 6) and two platelet concentrates (range, 0 to 11). A single 60-year-old female patient died early after the autograft (day +19) as a result of a dramatic cardiac failure, without full engraftment. This death was not clearly related to drug toxicity, as the high-dose regimen—carmustine, etoposide, cytarabine, melphalan—does not contain cyclophosphamide. All patients but one are alive at 150 days (range, 73 to 349) since autograft. As shown in Figure 2 (Kaplan Meier), > 90% of patients are projected to survive and almost 60% are free of progression at 1 year after transplantation.
Fig 1.
Engraftment as cell count achievement after autologous peripheral-blood stem-cell transplantation in 24 patients. Probability curves (Kaplan-Meier). PMN, polymorphonucleate; PLT, platelet.
Fig 2.
Overall survival (left) and progression-free survival (right) analysis of the entire population of patients who underwent autologous transplantation. Vertical ticks represent patients being observed.
DISCUSSION
Use of autologous transplantation is effective in various hematologic neoplasms, such as MM, HL, NHL, and select cases of AML and solid tumors.22 PBSCs are now the standard; however, mobilization and collection of PBSCs represent critical steps.
Here, we report the initial experience at HCH, the first oncology institution of Iraqi Kurdistan, where a capacity-building project was funded by the Italian Agency for Development Cooperation and approved by local health authorities. The predefined target patient population was a group of patients with thalassemia major, but autologous transplantation was assumed to be an intermediate step. In April 2016, an Italian team of experts steered a training program that covered all aspects of HSCT by means of lectures and coaching. The methodology was capacity building4 (Fig 3). In June 2016, the first autologous transplant was successfully performed, and the first allogeneic transplant in October 2016.
Fig 3.
The capacity-building concept.
Mobilization of PBSCs in the blood was initially performed by G-CSF alone, but all protocols gave satisfactory results with a limited number (n = 3) of patients—always patients with MM—who experienced failure. Two of the three patients who experienced failure responded well to a different mobilization regimen. We confirmed that a new effective salvage combination for HL, named BeGeV11 can be successfully used as a PBSC mobilizing regimen. All eight patients who received BeGeV plus G-CSF demonstrated a high CD34-positive cell peak (median, 39.3) and collected the target cell number with a limited number of aphereses.
We assumed engraftment as an end point. Of the 24 patients who underwent autologous transplantation, only one did not achieve full engraftment as a result of sudden death on day +19. All other patients achieved full and steady early engraftment, with low transfusion support and limited days of fever. This reproduces the standard of the European Union and the United States, as confirmed by overall survival analysis (Fig 2), whereas the progression-free survival curve reflects patient referral, with transplants performed after repeated unsuccessful attempts. In future, with better transplant indications, results are expected to improve.
This study is the result of an Italian effort to establish a leading HSCT center in Iraqi Kurdistan. After the start of both the autologous and allogeneic transplantation programs, we now count seven patients with thalassemia and one patient with AML having undergone transplantation from HLA-identical siblings.23 We are planning a study to estimate the whole cost of mobilization, collection, cryopreservation, and autologous transplantation. These data are not available at the moment.
The capacity-building approach4 (Fig 3) is aimed at a sustainable development and strengthening of capacities through the enhancement of local skills. Our organization is based on on-site training, and, together with coaching, this represents an innovative and flexible method for sustainable activity in low-to-middle income countries as an alternative to the training performed abroad in specialized centers. With the current limitations for immigration, more on-site capacity-building projects will be developed.
With limited resources, it is essential to address the point of transplantation medicine. Despite the current economic crisis, the Kurdistan region is a territory rich in natural resources, with a universal health care system. In future, the situation could rapidly improve; however, as the government is spending more than 6 million USD/year to send patients abroad for HSCT, now seems to be the time to develop it locally.
We drove the training since the beginning. Before the clinical program was started, appropriate end points were assessed. In the present report, despite the limited number of patients and the short follow-up, we demonstrate that excellent results can be obtained even in difficult situations when a correct strategy, such as capacity building, is utilized form the start.
AUTHOR CONTRIBUTIONS
Conception and design: Ignazio Majolino, Dereen Mohammed, Michele Vacca, Francesco Ipsevich, Dastan Hassan, Chra Abdullah,Marta Verna, Attilio Rovelli, Valentino Conter
Financial support: Dosti Othman, Ignazio Majolino, Valentino Conter
Administrative support: Dosti Othman, Valentino Conter, Ignazio Majolino
Provision of study material or patients: Dastan Hassan, Chra Abdullah, Rebar Mohammed, Diana Noori, Dlir Ali, Harem Karem, Salah Salih, Michele Vacca, Angelo Ostuni, Claudia Del Fante, Angelo Palmas, Andrea Frigato, Annunziata Manna, Maria Speranza Massei, Stefania Vasta, Marcela Gabriel, Marco Possenti, Kosar Ali
Collection and assembly of data: Ignazio Majolino, Dereen Mohammed, Dastan Hassan, Chra Abdullah, Rebar Mohammed, Diana Noori, Michele Vacca, Francesco Ipsevich, Marta Verna, Attilio Rovelli
Data analysis and interpretation: Ignazio Majolino, Dereen Mohammed, Francesco Ipsevich, Chra Abdullah, Rebar Mohammed, Michele Vacca, Valentino Conter
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Ignazio Majolino
No relationship to disclose
Dereen Mohammed
No relationship to disclose
Dastan Hassan
No relationship to disclose
Francesco Ipsevich
Speakers' Bureau: Therakos
Travel, Accommodations, Expenses: Therakos
Chra Abdullah
No relationship to disclose
Rebar Mohammed
No relationship to disclose
Angelo Palmas
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Janssen Pharmaceuticals, Amgen
Marco Possenti
No relationship to disclose
Diana Noori
No relationship to disclose
Dlir Ali
No relationship to disclose
Harem Karem
No relationship to disclose
Salah Salih
No relationship to disclose
Michele Vacca
Speakers' Bureau: Mallinckrodt
Travel, Accommodations, Expenses: Mallinckrodt
Claudia Del Fante
No relationship to disclose
Angelo Ostuni
No relationship to disclose
Andrea Frigato
No relationship to disclose
Maria Speranza Massei
No relationship to disclose
Annunziata Manna
No relationship to disclose
Stefania Vasta
No relationship to disclose
Marcela Gabriel
No relationship to disclose
Marta Verna
No relationship to disclose
Attilio Rovelli
No relationship to disclose
Valentino Conter
Consulting or Advisory Role: Amgen
Travel, Accommodations, Expenses: Jazz Pharmaceuticals
Kosar Ali
No relationship to disclose
Dosti Othman
No relationship to disclose
REFERENCES
- 1.Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21:1863–1869. doi: 10.1016/j.bbmt.2015.07.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gratwohl A, Pasquini MC, Aljurf M, et al. One million haemopoietic stem-cell transplants: A retrospective observational study. Lancet Haematol. 2015;2:e91–e100. doi: 10.1016/S2352-3026(15)00028-9. [DOI] [PubMed] [Google Scholar]
- 3.Majolino I, Othman D, Rovelli A, et al. The start-up of the first hematopoietic stem cell transplantation center in the Iraqi Kurdistan: A capacity-building cooperative project by the Hiwa Cancer Hospital, Sulaymaniyah, and the Italian Agency for Development Cooperation—An innovative approach. Mediterr J Hematol Infect Dis. 2017;9:e2017031. doi: 10.4084/MJHID.2017.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Garriga M. The capacity building concept. http://www.coastalwiki.org/wiki/The_Capacity_Building_Concept
- 5.Majolino I, Cavallaro AM, Bacigalupo A, et al. Mobilization and collection of PBSC in healthy donors: A retrospective analysis of the Italian Bone Marrow Transplantation Group (GITMO) Haematologica. 1997;82:47–52. [PubMed] [Google Scholar]
- 6.Lerro KA, Medoff E, Wu Y, et al. A simplified approach to stem cell mobilization in multiple myeloma patients not previously treated with alkylating agents. Bone Marrow Transplant. 2003;32:1113–1117. doi: 10.1038/sj.bmt.1704286. [DOI] [PubMed] [Google Scholar]
- 7.Bashey A, Donohue M, Liu L, et al. Peripheral blood progenitor cell mobilization with intermediate-dose cyclophosphamide, sequential granulocyte-macrophage-colony-stimulating factor and granulocyte-colony-stimulating factor, and scheduled commencement of leukapheresis in 225 patients undergoing autologous transplantation. Transfusion. 2007;47:2153–2160. doi: 10.1111/j.1537-2995.2007.01440.x. [DOI] [PubMed] [Google Scholar]
- 8.Santoro A, Mazza R, Pulsoni A, et al. Bendamustine in combination with gemcitabine and vinorelbine is an effective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: Final results of a multicenter phase II study. J Clin Oncol. 2016;34:3293–3299. doi: 10.1200/JCO.2016.66.4466. [DOI] [PubMed] [Google Scholar]
- 9.Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorelbine: A new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica. 2007;92:35–41. doi: 10.3324/haematol.10661. [DOI] [PubMed] [Google Scholar]
- 10.de Latour RP, Chaoui D, Bourhis JH, et al. Mobilization of peripheral blood progenitor cells after DHAP regimen with or without rituximab: A large multicenter comparative study in patients with malignant lymphoma. Leuk Lymphoma. 2007;48:897–904. doi: 10.1080/10428190701281497. [DOI] [PubMed] [Google Scholar]
- 11.Ferrara F, Melillo L, Montillo M, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of acute myeloid leukemia relapsing after autologous stem cell transplantation. Ann Hematol. 1999;78:380–384. doi: 10.1007/s002770050533. [DOI] [PubMed] [Google Scholar]
- 12.Indovina A, Majolino I, Scimè R, et al. High dose cyclophosphamide: Stem cell mobilizing capacity in 21 patients. Leuk Lymphoma. 1994;14:71–77. doi: 10.3109/10428199409049652. [DOI] [PubMed] [Google Scholar]
- 13.Brando B, Siena S, Bregni M, et al. A standardized flow cytometry protocol for mobilized peripheral CD34+ cells estimation and collection for autotransplantation in cancer patients. Eur J Histochem. 1994;38(suppl 1):21–26. [PubMed] [Google Scholar]
- 14.Whitby A, Whitby L, Fletcher M, et al. ISHAGE protocol: Are we doing it correctly? Cytometry B Clin Cytom. 2012;82:9–17. doi: 10.1002/cyto.b.20612. [DOI] [PubMed] [Google Scholar]
- 15.Pierelli L, Maresca M, Piccirillo N, et al. Accurate prediction of autologous stem cell apheresis yields using a double variable-dependent method assures systematic efficiency control of continuous flow collection procedures. Vox Sang. 2006;91:126–134. doi: 10.1111/j.1423-0410.2006.00796.x. [DOI] [PubMed] [Google Scholar]
- 16.Duong HK, Savani BN, Copelan E, et al. Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2014;20:1262–1273. doi: 10.1016/j.bbmt.2014.05.003. [DOI] [PubMed] [Google Scholar]
- 17.Calvet L, Cabrespine A, Boiret-Dupré N, et al. Hematologic, immunologic reconstitution, and outcome of 342 autologous peripheral blood stem cell transplantations after cryopreservation in a -80°C mechanical freezer and preserved less than 6 months. Transfusion. 2013;53:570–578. doi: 10.1111/j.1537-2995.2012.03768.x. [DOI] [PubMed] [Google Scholar]
- 18.Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996;335:91–97. doi: 10.1056/NEJM199607113350204. [DOI] [PubMed] [Google Scholar]
- 19.Caballero MD, Rubio V, Rifon J, et al. BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: Analysis of efficacy, toxicity and prognostic factors. Bone Marrow Transplant. 1997;20:451–458. doi: 10.1038/sj.bmt.1700913. [DOI] [PubMed] [Google Scholar]
- 20.Eder S, Labopin M, Arcese W, et al. Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: A retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Eur J Haematol. 2016;96:90–97. doi: 10.1111/ejh.12553. [DOI] [PubMed] [Google Scholar]
- 21.Shi Y, Liu P, Zhou S, et al. Comparison of CBV, BEAM and BEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non-Hodgkin lymphoma: Efficacy and toxicity. Asia Pac J Clin Oncol. 2017;13:e423–e429. doi: 10.1111/ajco.12610. [DOI] [PubMed] [Google Scholar]
- 22.Hołowiecki J. Indications for hematopoietic stem cell transplantation. Pol Arch Med Wewn. 2008;118:658–663. [PubMed] [Google Scholar]
- 23.Hassan D, Rasool L, Verna M, et al. Hematopoietic stem cell transplantation for children with thalassemia: A start-up cooperative project in Iraqi Kurdistan. 43rd Annual Meeting of the European Group for Blood and Marrow Transplantation; Marseille, France. March 26-29, 2017; [Google Scholar]