scholarly journals A DKMS (German Bone Marrow Donor Center) view on cryopreservation of unrelated donor stem cell products during the COVID ‐19 pandemic

2020 ◽  
Author(s):  
Alexander H. Schmidt ◽  
Deborah Buk ◽  
Stefanie N. Bernas ◽  
Thilo Mengling ◽  
Elke Neujahr ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Unrelated Donor ◽  
Donor Center ◽  
Bone Marrow Donor

Psychosocial and Behavioral Issues in Stem Cell Transplantation

2006 ◽  
Author(s):  
Sean Phipps
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Well Being ◽  
Unrelated Donor ◽  
Behavioral Issues ◽  
Leukemic Relapse

Stem cell transplantation (SCT) or bone marrow transplantation (BMT) has evolved from a heroic, experimental therapy of last resort to a standard therapy for many high-risk leukemias and the preferred first option after leukemic relapse (Sanders, 1997; Santos, 2000; Treleaven & Barrett, 1998; Wingard, 1997). The indications for SCT have widened to include a number of other malignant disorders, including lymphomas, solid tumors, and even brain tumors, as well as to a growing number of nonmalignant disorders (Meller & Pinkerton, 1998; Santos, 2000; Treleaven & Barrett, 1998). The growth of bone marrow registries that allow for wider use of unrelated donor transplants and developments in stem cell selection techniques that allow for haplotype transplants using mismatched family donors, including parents, have greatly increased the availability of SCT as a viable treatment option for seriously ill children (Mehta & Powles, 2000). At the same time, advances in supportive care have led to improved survival outcomes and thus to a rapidly growing number of long-term survivors of SCT (Santos, 2000; Treleaven & Barrett, 1998). Yet, despite the extraordinary medical and technical advances that have saved the lives of many children, SCT remains a high-risk medical procedure involving a prolonged and physically demanding treatment regimen that can challenge the coping capacities of patients and their families. Psychosocial research in pediatric SCT has progressed more slowly, but available studies indicate that SCT is a stressful experience that can have a negative impact on the social functioning, self-esteem, and general emotional well-being of survivors (Barrera, Pringle, Sumbler, & Saunders, 2000; McConville et al., 1990; Parsons, Barlow, Levy, Supran, & Kaplan, 1999; Phipps, Brenner, et al., 1995; Phipps & Barclay, 1996; Rodrigue, Graham-Pole, Kury, Kubar, & Hoffman, 1995; Stuber, Nader, Yasuda, Pynoos, & Cohen, 1991; Vannatta, Zeller, Noll, & Koontz, 1998). A number of studies have also focused on parental response to SCT (Barrera et al., 2000; Kronenberger et al., 1998; Manne et al., 2001, 2002; Phipps, Dunavant, Lensing, & Rai, 2004; Rodrigue et al., 1996; Streisand, Rodrigue, Houck, Graham-Pole, & Berlant, 2000). Much of the literature to date has focused on long-term outcomes in survivors, particularly neurocognitive and academic outcomes.

Aplastic Anemia: Pathogenesis and Treatment

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 23-28 ◽  
Author(s):  
Andrea Bacigalupo
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Cell Biology ◽  
Short Interval ◽  
Treatment Strategies ◽  
Prognostic Indicators ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
The Past

Abstract This review highlights some of the contributions that have appeared in the literature in the past decade on the pathogenesis and treatment of aplastic anemia (AA). This summary is brief because the field is vast, spaning from stem cell biology to stem cell disorders, from autoimmunity to transplantation, from graft-versus-host disease to late effects. The immune pathogenesis of AA is now based on several lines of evidence and will be discussed. Immunosuppressive therapy (IST) remains an important option for AA patients who are not candidates for transplantation. Favorable prognostic indicators for IST are young age and a short interval from diagnosis; the neutrophil count seems to have lost its predictive value with current antithymocyte globulin–cyclsoporin combination therapy. The outcome of allogeneic bone marrow transplantations has significantly improved in the past decade, particularly in the unrelated donor setting, to such an extent that treatment strategies may be affected. A short interval between diagnosis and treatment will also improve results for bone marrow transplantation; these rare patients should be referred to an experienced center immediately.

A Comparison of Clinical Outcomes of Non-T-Cell-Depleted (Non-TCD) Unrelated Donor Heamatopietic Stem Cell Transplantation (HSCT) and Non-TCD Haploidentical Related Donor HSCT.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5140-5140
Author(s):  
Feng Chen ◽  
De Pei Wu ◽  
Aining Sun ◽  
Xiao Ma ◽  
Xiaowen Tang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Peripheral Blood Stem Cell ◽  
Ex Vivo ◽  
Unrelated Donor ◽  
Group A ◽  
Related Donor ◽  
Group B

Abstract Unrelated donor HSCT and haploidentical related donor HSCT have been evaluated as alternative transplant options for the approximately 70% of patients without an HLA-identical sibling donor. To compare the clinical outcomes between Non-TCD unrelated donor HSCT and Non-TCD haploidentical HSCT, we studied 55 patients with high-risk or advanced leukemia who underwent Non-TCD HSCT from unrelated or haploidentical related donors from June 2001 to May 2006. Group A including 25 patients received HLA-matched unrelated donor HSCT, group B, including the other 30 patients, received HLA-haploidentical family donor HSCT. 20 recipient/donor pairs were allele matched and 5 pairs were 1–2 alleles disparity mismatched in the group A, HLA-haploidentical family donors in the group B included mother (22 cases), sibling(5 cases) and offspring (3 cases). Patients with myeloid leukemia were conditioned with the regimen consisting of Simustine (MeCCNU) 250mg/m2×1day, Ara-c 4g/ m2×2days, busulfan (Bu) 4mg/kg×3days, and cyclophosphamide (Cy)1.8g/m2×2days, patients with lymphoblastic leukemia were conditioned with the regimen consisting of MeCCNU 250mg/m2×1day, total-body irradition(TBI) 8Gy×1day, Ara-c 4g/ m2×2days, and Cy 1.8g/m2×2days. 15 patients received Non-TCD bone marrow transplantation (BMT), and 10 patients received Non-TCD peripheral blood stem cell transplantation (PBSCT) in the group A. 17 patients received G-CSF-primed bone marrow grafts that had not been depleted ex vivo of T cells, and 13 patients received G-CSF-primed bone marrow grafts plus G-CSF-mobilized peripheral blood stem cell without ex vivo T cell depletion in the group B. Prophylaxis against GVHD was performed with cyclosporine (CSP), short-term methotrexate (MTX), and mycophenolate mofetil (MMF), some patients received the combination of CSP, MTX and MMF plus antithymocyte globulin (ATG). When GVHD developed, methylprednisolone(MP) was given at first, if the response was poor, anti-CD25 monoclonal antibody was given to the patients as quickiy as possible and CSP was replaced with tacrolimus. All patients of the group A and 29 patients of the group B were engrafted successfully. Acute GVHD grades III-IVoccurred in 10 and 11 patients in the group A and B, respectively(the cumulaitive incidence 40% vs 37.9%, P>0.05). 2 patients relapsed in each group (the actuarial probilities of relapse 8% vs 6%, P>0.05). The 2-year probabilities of event-free survival(EFS) for the group A and B were (58.7±5.9)% and (42.2±2.0)%, respectively (P>0.05). 10 patients of the group A and 17 of the group B died of transplantation- related disease. The primary causes of death included severe acute GVHD and pulmonary infection. These results suggested that both Non-TCD unrelated donor HSCT and Non-TCD haploidentical related donor HSCT are effective treatments for patients with refractory or high-risk hematologic malignancies, the high transplantation related mortality due to GVHD and infection is still a major challenge.

Low Relapse without Excessive Transplant-Related Mortality Following Allogeneic Stem Cell Transplantation in Patients with High Risk Secondary Acute Myeloblastic Leukaemia and Myelodysplastic Syndromes, Long-Term Outcomes in a Single Centre Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4308-4308
Author(s):  
Jean El-cheikh ◽  
Luca Castagna ◽  
Sabine Furst ◽  
Catherine Faucher ◽  
Benjamin Esterni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Allogenic Stem Cell Transplantation ◽  
Related Mortality

Abstract Abstract 4308 Allogenic stem cell transplantation (Allo-SCT) as a therapy for secondary acute myeloid leukaemia (sAML) and myelodisplastic syndromes (MDS) is the most powerful treatment option. However, (Allo-SCT) is also complicated by a high risk for treatment-related morbidity and mortality. We analysed retrospectively the data of 70 patients transplanted at our institution from June 1995 to december 2008, 44 patients (63%) with sAML and 26 patients (37%) with MDS was treated with (Allo-SCT); median age at diagnosis was 41 years, (15-70), and the median age of 42, 5 years (16-70) at transplantation; The conditioning regimen was myeloablative combining (cyclophosphamide and TBI) in 16 patients (23%) and 54 patients (77%) was with a reduced intensity conditioning (RIC) regimens combining fludarabine, busulfan, and antithymocyte globulin; 11 patients (16%) were infused with bone marrow (BM), 55 patients (79%) peripherical blood stem cells (PBSC), and 4 patients (5%) cord blood cells; in 49 cases (70%) donor was a HLA identical sibling and in 21 (30%) was a matched unrelated donor; 41 patients (59%) carried high risk cytogenetic features, like (7q-, 5q-, > 3 alterations), while was normal in 24 patients (34%), and in 5 patients (7%) was unknown. Disease status at transplantation was as follow: CR in 24 patients (34%), 34 patients (49%) was refractory or in progression after treatment, and 12 patients (17%) was with a stable disease. With a median follow-up of 55 months (3-150), 30 patients (43%) are alive, the overall survival OS at 2 years and 5 years was 48 % and 39% respectively, and after ten years of follow up, OS was 30%, 95%CI [17.8-50.8]. We observed also that 26 % of refractory patients and 54% of patients in CR are alive at five years of transplantation. The probability of progression after transplantation at five and ten years was 31% with 95%CI [20.-46.5]. 2 years and 5 years treatment related mortality (TRM) was 23% and 26% respectively, and no modification at ten year, 95%CI [14.3-37.3]. TRM occurred in 16 patients (23%). Cause of death was; infections in 5 patients (7%), GvHD in 3 patients (4%), GvHD and infection in 3 patients (4%), multi organ failure (MOF) in 5 patients (7%). In multivariate analysis; OS, PFS or TRM, were not influenced by donor type (HLA id sibling vs others), conditioning regimen (RIC vs MAC), and stem cell source (bone marrow vs PBSC). Allogenic stem cell transplantation can be considered as a good option for the treatment of patients with high risk sAML and MDS when compared with the remission rate at five years of the other nonallogeneic SCT therapies. Disclosures: No relevant conflicts of interest to declare.

Haploidentical Allogeneic Hematopoietic Cell Transplantation as Salvage Therapy for Engraftment Failure After Unrelated and Autologous Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4529-4529
Author(s):  
Yamin Tan ◽  
Huarui Fu ◽  
Yi Luo ◽  
Xiujin Ye ◽  
Li Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Bone Marrow Examination ◽  
Pcr Analysis ◽  
Unrelated Donor ◽  
Haploidentical Transplantation ◽  
Engraftment Failure

Abstract Abstract 4529 Engraftment failure is a rare but life-threatening complication of hematopoietic stem cell transplantation. The treatment of this condition is often challenging. We firstly reported haploidentical donor stem cells transplantation resulted in hematological reconstitution and long-time disease-free survival in a patient who developed engraftment failure after unrelated donor allogeneic stem cell transplantation and failure rescue treatment by re-infusion of autologous “back-up” stem cells. The 39-years-old male patient with acute myeloid leukemia(AML)-M2a achieved complete remission (CR) after one course of induction chemotherapy. He entered a lasting CR with 7 courses post-remission consolidation therapy and decided to receive unrelated donor allogeniec stem cell transplantation. In case of engraftment failure after allo-HSCT, autologous “back-up” cells were harvested after the last course chemotherapy (IDA 15 mg on days 1–2, 10 mg on day 3, Ara-c 300 mg on days 1–3, 200 mg on day 4), and mobilized with G-CSF 5 mg/kg/day for 5 days. The “back-up” cells consisting of 9.94×106/kg CD34+ cells were cryopreservated in liquid nitrogen. Fifteen months after de novo AML, the patient received a myeloablative conditioning regimen of busulfan and cyclophosphamide (busulfan 3.2 mg/kg/day on days -7 to -4, and cyclophosphamide 60 mg/kg/day on days -3 to -2), and an infusion of unrelated allogeneic peripheral stem cells from the Chinese Marrow Donor Program with a HLA-Cw allele mismatch on day 0. The graft contained 11.07×108/kg nucleated cells and 6.35×106/kg CD34+ cells. Pancytopenia was continuously observed during 28 days after transplantation and short tandem repeat-polymerase chain reaction (STR-PCR) analysis showed no donor chimera. As a rescue attempt for graft failure, cryopreservated autologous cells were re-infused on day +28. Unfortunately, pancytopenia was still continuously observed during 23 days after re-infused of “back-up” cells(51 days after unrelated transplantation), and bone marrow examination revealed severe bone marrow hypoplasia. On day +57 and +58 after unrelated transplantation, bone marrow cells containing 2.1×106/kg CD34+ stem cells and peripheral blood cells containing 2.81×106/kg CD34+ stem cells from a haploidentical donor sister (HLA matched in 5/10 alleles by high-resolution genotyping) were infused respectively after reduced-intensity conditioning with fludarabine and ATG (fludarabine 30mg/m2/d on day -5 to -1, ATG 100mg/d on day -4 to -1). Absolute neutrophil count >0.5×109/L was documented on day 12 after haploidentical transplantation. He achieved platelets count >20×109/L on day 28 after haploidentical transplantation. Twenty-nine days after haploidentical transplantation, bone marrow examination showed reconstitution and STR-PCR analysis indicated complete donor chimera. No grades III -IV aGVHD, extensive chronic GVHD, and severe infection after transplantation were observed. Recurrent bone marrow aspiration examinations showed the patient had been in CR. The patient remained alive during a 18-month follow-up after haploidentical transplantation. Our experience suggests that combined haploidentical donor BM and PBSC transplantation after Flu- and ATG-based conditioning could provide an effective therapeutic strategy for engraftment failure after unrelated allo-HSCT in adult patients. Considering the accessibility of haploidentical donors, haploidentical transplantation has the potential to act as a first-line choice for salvage therapy. Disclosures: No relevant conflicts of interest to declare.

Analysis of 127 Stem Cell Donations of the Regional Bone Marrow Donor Bank Europdonor Nijmegen, The Netherlands

2003 ◽  
Vol 44 (6) ◽  
pp. 983-987 ◽  
Author(s):  
E.M.J.W. Koopmans ◽  
A. Schattenberg ◽  
I. Joosten ◽  
F. Preijers ◽  
W.L.A.M. De Kort
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
The Netherlands ◽  
Bone Marrow Donor

scholarly journals Feasibility and Outcome of Hematopoietic Stem Cell Transplantation Combined with Decitabine for Children with Juvenile Myelomonocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5869-5869
Author(s):  
Huaying Liu ◽  
Chunfu Li ◽  
Yuelin He
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia

Abstract Background Juvenile myelomonocytic leukemia(JMML) is a rare clonalmyelodysplastic/myeloproliferative disorder that occurs during infancy and early childhood with poor prognosis. Chemotherapy has not been found to be dffective, and Hematopoietic stem cell transplantation(HSCT) is currently the only curative treatment for JMML. Relapse and engraftment failure are the major causes of HSCT failure in JMML. Patients and method We report the outcomes of 4 patients with JMML who received HSCT combined with Decitabine between 2014-2015. Patient median age was 2 years(range,1-3years), and 3 were boys and 1 girl. Decitabine was given before and after the HSCT for one time(20mg/m2.d X 5d、10mg/m2 .d X 5d). Before HSCT, all the patients received mild chemotherapy(three or four course). The bone marrow evaluations of all the patients before HSCT were complete remission(CR). Two patients received human leukocyte antigen(HLA)-matched HSCT from unrelated donors, and two patients received haploidentical HSCT from parents followed by unrelated cord blood transplantation(UCB). Conditioning regimen of Unrelated donor-PBSCT was Busulfan+fludarabine+Thiotepa+Thymoglobuline, and the conditioning of haplo-HSCT was Busulfan+fludarabine+Cytarabine+Thymoglobuline. The number of nucleated cells of HLA-matched HSCT was 8×108/kg. The number of nucleated cells of Haplo-HSCT was 47.2×108/kg、61.26×108/kg , respectively, and the number of nucleated cells of UCB was 7.23×107/kg、9.4×107/kg, respectively. GVHD prophylaxis was based on post-transplant high-dose cyclophosphamide(PTCy, 50mg/kg on days +3 and +4) combined with mycophenolate plus cyclosporine A or tacrlimus. Results: The median follow-up was 21 months(range,11-27 months). The overall survival(OS) and the Disease free survival(DFS) both were 100%, All the patients got 100% engraftment(Unrelated-donor stem cell engrafted and Haploidentical-donor stem cell engrafted in 2 and 2 patients , respectively). None of the patients developed relaps, the bone marrow evaluations were complete remission(CR) after HSCT. The most common toxicities were infection with neutropenia(100%, n=4), The cumulative incidences of acute GVHD gradesII-III and CMV infection were 50% and 75% respectively. Conclusion: The combination of decitabine and HSCT shows encouraging results with highly effective and less toxicity for JMML. The futhuer study should be developed in the future. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparable Survival Outcomes of Haploidentical Stem Cell Transplantation and Unrelated Bone Marrow Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4644-4644 ◽  
Author(s):  
Junichi Sugita ◽  
Yoshiko Atsuta ◽  
Mio Kurata ◽  
Hirohisa Nakamae ◽  
Naoki Kurita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Research Funding ◽  
Proportional Hazards ◽  
Disease Risk ◽  
Risk Index ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Overall Mortality

Abstract Background: In the absence of an HLA matched related donor, unrelated donor hematopoietic cell transplantation (HCT) is an alternative. Recently, HLA-haploidentical HCT using posttransplant cyclophosphamide (PTCY-haplo) has been increasingly performed. Unrelated donor peripheral blood stem cell transplantation (PBSCT) program was initiated in 2011 in Japan with rather slow increase, therefore, bone marrow is the main stem cell source for HCT from unrelated donors, while PTCY-haplo is mainly PBSCT. We compared outcomes of unrelated donor bone marrow transplant (UBMT) and PTCY-haplo. Methods: This is a retrospective analysis of a registry data of the Japan Society for HCT and the Japanese Data Center for HCT using the Transplant Registry Unified Management Program (TRUMP). Patients with acute leukemia and myelodysplastic syndromes, aged between 16 and 69 years, who undergone their first HCT between 2012 and 2015 were included in the study. HLA-A, -B, -C, and -DRB1 allele-level 8/8 matched (n=1,470), 7/8 matched (n=859), and 6/8 matched (n=186) T-cell replete UBMT recipients, and 140 recipients of PTCY-haplo (PBSCT, n=133; BMT, n=6; PBSCT+BMT, n=1) were identified as subjects for analyses. Adjusted comparison of the groups on overall mortality was performed with the use of the Cox proportional-hazards regression model. For other outcomes with competing risks, Fine and Gray's proportional-hazards model for subdistribution of a competing risk was used. The models were used to estimate adjusted probabilities, with consideration of other significant clinical variables in the final multivariate models. Results: The median age for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 52(16-69), 46.5(17-68), 50(16-69), 50(16-68). According to refined disease risk index (rDRI), patients with high or very high rDRI were 32%, 54%, 34%, 34% for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Myeloablative conditioning was used in 74%, 51%, 73%, 68% of patients for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Median follow-up period of survivors for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 2.79 (0.03-5.603),1.82 (015-3.89), 3.00 (0.09-5.57), 3.17 (0.27-5.58). In adjusted comparison by multivariate analyses setting 8/8 matched UBMT as the reference, PTCY-haplo showed similar overall mortality (relative risk [RR]=0.97, 95% confidence interval [CI], 0.75-1.26, p=0.823), decreased risk of non-relapse mortality (RR=0.43, 95% CI, 0.25-0.74, p=0.003), increased risk of relapse (RR=1.57, 95% CI, 1.21-2.03, p=0.001), and decreased risk of grade II to IV acute GVHD (RR=0.68, 95% CI, 0.48-0.95, p=0.023). Relative risks for 7/8 matched and 6/8 matched UBMT were 1.08 (p=0.223) and 1.27 (p=0.032) for overall mortality, 1.29 (p=0.004) and 1.73 (p<0.001) for non-relapse mortality, 0.89 (p=0.201) and 0.81 (p=0.215) for relapse, and 1.30 (p<0.01) and 1.84 (p<0.001) for grade II to IV acute GVHD. Other predictive variables identified for overall mortality were patient age older than 50 years old compared to younger at transplant, male sex, refined disease risk index of Intermediate, High, or Very High compared to Low, and HCT-CI total points of 1 or 3 or greater compared to 0. Adjusted probabilities for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT at two years post-transplant were 61%, 58%, 52%, 60% for overall survival, 23%, 27%, 21%, 19% for relapse, and 20%, 6%, 24%, 33% for non-relapse mortality (Figure 1). Conclusions: PTCY-haplo showed notably low non-relapse mortality which contributed to comparable short-term survival outcomes with 8/8 matched UBMT. Disclosures Ishiyama: Alexion Pharmaceuticals, Inc.: Honoraria. Ichinohe:Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Mundipharma: Honoraria; Novartis.: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; MSD: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding.

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