scholarly journals Optimal Conditioning for Older Patients with Acute Myeloid Leukemia (AML) Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Propensity Score Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 42-42 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Ankur Varma ◽  
Piyanuch Kongtim ◽  
Samer Srour ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Secondary Aml

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) is increasingly performed for older patients with AML; however, the optimal conditioning regimen for these patients remains unclear. Methods: We retrospectively evaluated outcomes of 404 patients with AML, ≥60 years receiving AHSCT at our institution between 01/2005-08/2018 who received 4 conditioning regimens: 1) fludarabine+melphalan 100mg/m2 (FM100, N=78), 2) fludarabine+melphalan 140mg/m2 (FM140, N=89), 3) fludarabine+IV busulfan x 4 days with Bu AUC≥5,000/day (equivalent dose 130mg/m2/day) (Bu≥5,000, N=131), 4) fludarabine+IV busulfan x 4 days with Bu AUC 4,000/day (equivalent dose 110mg/m2/day) (Bu4,000, N=106). To adjust for potential selection bias in choices of conditioning regimen, propensity score was calculated and used as a stratifying variable in a multivariable Cox regression model. Factors included in the propensity score calculation were age, secondary AML, ELN2017 genetic risk, remission status before transplant, induction failure, donor type, stem cell source and KPS. Results are presented for the FM100, FM140, Bu≥5,000 and Bu4000, respectively. Median follow-up survivors were 40, 74, 30 and 44 months, respectively (p=0.06). Donors are matched sibling, matched unrelated, haploidentical and mismatched unrelated donor in 126 (31%), 218 (54%), 40 (10%) and 20 (5%) patients, respectively. Patients in the FM100 group were significantly older and had lower KPS. The median age was 67, 64, 64 and 65 years, respectively (p=0.001), while 51%, 32%, 27% and 27% had KPS<90%, respectively (p<0.001). The HCT-CI of ≥3 was present in 57%, 62%, 56% and 70%, respectively (p=0.33), while 42%, 78%, 47% and 51% had high and very high-risk DRI, respectively (p<0.001), and 12%, 46%, 18% and 32% of the patients were transplanted in active disease (p<0.001). No significant differences were seen in both cytogenetic and ELN2017 genetic risk. More patients in FM100 group were treated using a standard of care protocol (73%, 64%, 25% and 31%, respectively, p<0.001). Grade 2-4 aGVHD at day 100 were 26% vs. 26%, 36% and 40% (p=0.04), and extensive cGVHD at 3 years 14% vs. 42%, 36% and 37%, respectively (p=0.07). The NRM at 3 years were 19%, 29%, 25% and 21% (p=0.06), and 3-year relapse rates were 32% vs. 32%, 30% and 55%, respectively (p=0.003). Among 4 groups, FM100 group had a significantly better PFS and GRFS with 5-year PFS for these 4 groups were 44%, 30%, 33% and 22% (p=0.02) and 5-year GRFS were 28%, 20%, 18% and 9% (p=0.006), respectively (Figure 1). For subgroup of patients with KPS <90%, 5-year PFS were 41%, 27%, 28%, 22%, respectively (p=0.007), while there was no significant difference between 4 conditioning groups in patients with high-risk AML defined as either secondary AML, induction failure or high-risk cytogenetics/high ELN2017 risk, suggesting that a more intense conditioning is not beneficial in this group of patients. The survival benefit of FM100 persisted after adjusted for baseline factors, transplant characteristics as well as propensity scores in a multivariable analysis (MVA). In MVA for PFS, HR was 0.57 (p=0.013) for FM100, 0.68 (p=0.056) for FM140 and 0.77 (p=0.137) for Bu> 5000 as compared with Bu 4,000 group (Figure 1). In the MVA for GRFS, HR for FM100, FM140 and Bu> 5000 was 0.53 (p=0.005), 0.78 (p=0.196), and 0.81 (p=0.178), respectively as compared with Bu 4,000 group. Other factors that independently predicted PFS were secondary AML (HR 1.68, p=0.001), remission status before transplant (HR 1.82, p=0.048 for CR with MRD positive, HR 1.87, p=0.043 for CR with unknown MRD status and HR 2.86, p=0.001 for active disease at transplant as compared with CR with MRD negative), KPS (HR 0.98, p=0.005) and use of a mismatched unrelated donor (HR 2.46, p=0.001 compared with matched related donor transplant). Conclusions: Older patients with AML benefit from a reduced-intensity conditioning with FM100 conditioning regimen, which was associated with better survival despite the fact that patients who could not receive more intense conditioning preferentially received this regimen. Higher intensity conditioning does not appear to improve survival in older patients. Alternative approaches to increase in conditioning intensity are needed to improve survival in patients with AML receiving allogeneic hematopoietic stem cell transplantation. Disclosures Ciurea: Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Acrotech: Research Funding; StemLine: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Konopleva:Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Ascentage: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Honoraria; Kisoji: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding.

scholarly journals Outcome of Transformed Fanconi Anaemia Patients after Hematopoietic Stem Cell Transplantation: Analysis on Behalf of European Group for Blood and Marrow Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 646-646
Author(s):  
Stefano Giardino ◽  
Dirk-Jan Eikema ◽  
Regis Peffault De Latour ◽  
Yves Bertrand ◽  
Mahmoud Aljurf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Related Donor

Abstract INTRODUCTION Fanconi anemia (FA) is an inherited bone marrow failure syndrome that carries a high risk of transformation to myelodysplasia (MDS) and acute leukemia. Hematopoietic stem cell transplantation (HSCT) is used to treat FA patients in clonal evolution. The roles of chemotherapy before HSCT and the intensity of conditioning regimens in transformed FA patients are controversial, because of the high sensitivity of FA patients to DNA-damaging agents increases the risk of severe toxicities, the duration of aplasia, the risk of infective complications thus limiting the possibility to administer full dose cytoreductive treatments. The sequence chemotherapy-HSCT has been reported by some groups (MehtaPA et al Pediatr Blood Cancer 2007, Talbot A et al Haematologica 2014, Mitchell R et al Br J Haematol 2014, Ayas M et al J Clin Oncol 2013), but conclusive information is lacking because of small number of patients described without a risk factors' analysis. The aim of this retrospective study is to report the outcome of a large cohort of transformed FA who underwent allo-HSCT and to define the factors that may impact on its outcome. PATIENTS AND METHODS The study was conducted on behalf of the Severe Aplastic Anemia (SAAWP) and Chronic Malignancies Working Parties (CMWP) of the EBMT and was based on data of patients who underwent allo-HSCT between 1999-2016 for transformed FA, defined as a diagnosis of FA in presence of any hematological malignancies or cytogenetic abnormalities, registered in the EBMT Data Base. Clinical and biological information of the disease and details on transplant procedures and outcome were collected by a specific form distributed to Centres participating in the study. RESULTS Data of 71 patients (35 males-36 females) affected by transformed FA (42 MDS, 25 AL, 4 with cytogenetic abnormalities but without blasts) undergoing allo-HSCT were collected from 25 Centres . A matched related donor (MRD) was used in 31% of cases, an unrelated donor (UD) in 56.3% and a mismatched related donor (MMRD) in 12.7%. Bone marrow was the main source of cells (54.3%) followed by cord blood (22.9%), peripheral blood (21.4%) and bone marrow plus peripheral blood (1.4%). The median age at allo-HSCT was 12.7 years (range 9.3-23.4). Thirty seven (52.1%) patients received a chemotherapy before HSCT. Pre-HSCT status of malignancy in available patients was complete remission (CR) in 24% (n = 12/50) and an active disease (no-CR) in 76 % patients (n = 38/50). The conditioning regimen included total body irradiation (TBI) in 37 (52.1%) (radiation dose: ≤ 4.0 Gy in 30; > 4.0 Gy in 7), busulphan (BUS) in 16 (22.6%), no-TBI nor BUS in 18 (25.3%). Median follow-up was 93.7 months (71-110.6). GvHD prophylaxis and transplants' details are summarized in Table 1. All patients engrafted. Median time for neutrophils was 17 days (14-23) and it was 25 days (23-42) for platelets. The 2-and 5-year overall survival (OS) probability were 54% (41-66%) and 45% (32-57%) respectively; the 2- and 5-year event-free survival (EFS) (events being death, relapse and graft loss) 52% (40-65%) and 45% (32-58%). The cumulative incidence of relapse were 15% (7-24%) and 21% (11-31%), , of non-relapse mortality (NRM) were 37% (25-49%) and 39% (27-51%) respectively at 2 and 5-year. Most frequent causes of death were GvHD (33.3%), infections (23.3%) and relapse of malignancy (16.7%). Patients transplanted in CR, (neither blasts, nor major dysplastic features) and from matched related donor had a significantly better outcome (5-year OS: CR 83% (62-100%) vs no-CR 36% (19-52%) [p 0.01], MRD 60% (37-83%) vs UD 47% (31-64%) vs MMRD 12% (0-35%) [p 0.03]; 5-year EFS: CR 83% (62-100%) vs no-CR 34% (17-51%) [p 0.01], MRD 61% (38-83%) vs UD 48% (31-64%) vs MMRD 12% (0-35%) [p 0.02]; 5-year NRM: CR 0% vs no-CR 44% (27-61%) [p 0.007]) vs those engrafted in no-CR and from no-MRD. (Fig 1 a, b, c). No other tested variable (therapy before transplant and conditioning regimen) significantly affected the outcome. CONCLUSION This study on large cohort of FA patients transplanted because of transformation shows that allo-HSCT from MRD has a better outcome and that CR from malignancy before transplant appears to be a major determinant for a favorable outcome. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amyndas Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Impact of Chronic Graft-Versus-Host Disease on Non-Relapse Mortality

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Justin Jiang ◽  
Qiuhong Zhao ◽  
Audrey M. Sigmund ◽  
Patrick Elder ◽  
Don M. Benson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Ohio State University ◽  
State University ◽  
Research Support ◽  
Advisory Committees ◽  
Hematopoietic Stem

Introduction-Chronic graft-versus-host disease (cGVHD) poses as a major late complication of hematopoietic stem cell transplantation. The role of cGVHD as a determinant in transplant-related morbidity and mortality, infectious complications, prolonged immune suppression, and impaired patient-reported quality of life has been extensively studied. Nonetheless, numerous advances in allogeneic hematopoietic stem cell transplant (allo-SCT) in recent years have expanded the indications for allo-SCT to a broader range of patients, including previously excluded older patients. However, long-term health status of older transplant recipients is poorly studied. Notably, the incidence of cGVHD may increase with age. Therefore, the development of cGVHD and the use of immunosuppressive therapy may lead to a higher degree of non-relapse mortality (NRM) in older patients. The objective of this study was to compare the NRM in both younger and older transplant recipients with and without cGVHD. Methods-We performed a retrospective cohort study of patients that underwent allo-SCT at the Ohio State University from 1999 to 2018. Data was analyzed from 1194 patients who survived or have been followed up with by at least day (d) 180 post-transplantation, among which 373 patients had developed cGVHD. Patients were grouped based on their age into a younger and older population. The older population was defined as ≥60 (N=373, 31%) with the younger population defined as <60 (N=821, 69%) years (yr) of age. NRM was defined as death unrelated to relapse, with relapsed mortality as a competing risk. A landmark analysis approach was used to study the association between the age groups to NRM, stratified by whether or not patients had developed cGVHD by d180. Fine and Gray competing risk model was used to build the multivariable regression model controlling for confounding variables, such as gender, donor type, donor source, conditioning regimen, and diagnosis. Results-The median age at allo-SCT was 53.0 yr (range: 18-76) and 61.1% were male. Acute myeloid leukemia accounted for 36.7% of transplants, followed by non-Hodgkin's lymphoma (14.8%), acute lymphoid leukemia (12.7%), and myelodysplastic syndrome (11.0%). Additionally, 58.0% received reduced-intensity conditioning regimen. The majority of stem cell donor types were match unrelated (45.3%) and match related (39.8%). Patients who had developed cGVHD by d180, regardless of age, were at higher risk of NRM compared to patients with no cGVHD (hazard ratio [HR]: 1.52, 95% confidence interval [CI]: 1.16-1.99; p=0.002). To examine the influence of age with NRM, we stratified the analysis by cGVHD status by d180. Among patients developed cGVHD by d180, in both univariable (HR 1.22, 95% CI 0.79-1.9, p=0.373) and multivariable analysis (HR: 1.17, 95% CI: 0.74-1.87; p=0.501), there was no statistically significant difference in NRM between patients ≥60 and <60 yr of age. Among patients without cGVHD by day 180, age ≥60 yr was a significant factor for increased NRM in both univariable (HR: 1.52, 95% CI 1.08-2.15; p=0.017) and multivariable (HR: 1.55, 95% CI: 1.04-2.30; p=0.031) analysis. Conclusion-This study showed that patients with cGVHD by day 180 were at higher risk for higher NRM compared to patients without cGVHD. Among cGVHD patients, there was no difference on the outcome of older patients (≥60 years old) compared to younger ones (<60 years old). This suggests that cGVHD therapy is equally tolerable among different age groups. Disclosures Chaudhry: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy. Vasu:Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR: Consultancy. William:Celgene: Consultancy, Honoraria; Dova: Research Funding; Guidepoint Global: Consultancy; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Seattle Genetics: Research Funding; Incyte: Research Funding. Mims:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Novartis: Speakers Bureau; Agios: Consultancy. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Saad:Magenta Therapeutics: Other: Personal Fees; Incyte Pharmaceuticals: Other: Personal Fees; Amgen: Other: research support; Kadmon: Other: research support; Orcabio: Other: research support. Efebera:Takeda: Honoraria, Speakers Bureau; Pharmacyclics: Research Funding; Celgene: Research Funding; Ohio State University: Current Employment.

scholarly journals Prognostic Value of Cpss Cytogenetic Risk Classification in Patients with CMML after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study of the Chronic Malignancies Working Party of the EBMT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2182-2182
Author(s):  
Christian Koenecke ◽  
Dirk-Jan Eikema ◽  
Sheree Hazelaar ◽  
Dietrich W. Beelen ◽  
Victoria Potter ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract Introduction: The only curative treatment approach for patients with Chronic Myelomonocytic Leukemia (CMML) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for relapse after transplantation. The aim of this large multicentric, international study was to retrospectively determine the impact of cytogenetic information according to the CMML-specific prognostic scoring system (CPSS) on outcome after allogeneic HSCT. Patients and Methods: Patients were selected from the EBMT database who had received a first allogeneic HSCT for the treatment of CMML between 2000 and 2015. 268 centers participated into this study. In total, 1503 patients were included. Impact of CPSS-cytogenetic classification was analyzed regarding overall survival (OS) and cumulative incidence of relapse and non-relapse mortality after HSCT (gray test). Results: 488 female (32.5%) and 1013 male (67.5%) patients were included to the study. Median age at HSCT was 57.6 years (range 0.3-75.4). At time of HSCT, only 422 (28.1%) patients were in complete remission, whereas 1004 (66.8%) had active disease (77 missing). Matched related donor HSCT was performed in 35.7% of the patients, matched unrelated donor HSCT in 57.6%, mismatched related in 3.3% and mismatched unrelated in 3.4%. Bone marrow (12.6%), peripheral blood (84.3%), or both (0.3%) served as the stem cell graft. Cord blood was used as a graft in 2.8%. Myeloablative preparative regimens wereused in 223 patients (15.0%), and less intensive regimens were given to 1268 patients (85.0%). Median survival of patients included into this study was 52.2 months. 637 patients had sufficient cytogenetic information according to CPSS (866 missing), complete relapse information was available in 1385 patients. 143 patients could be categorized into CPSS-high, 85 in intermediate and 375 in low risk cytogenetics, respectively. In univariate analysis high risk CPSS cytogenetic information was found to be strongly associated with OS (low 38% (32-44%), intermediate 41% (30-53%), high 26% (18-34%)), and higher cumulative incidence of relapse (low 40% (35-46%), intermediate 42% (30-54%), high 48% (39-56%)), but not with non relapse mortality (low 28% (23-33%), intermediate 25% (16-35%), high 30% (22-38%)) at 60 months (Figure 1). Conclusion: In this international, multicentric analysis we show that CMML patients with high-risk cytogenetics had significantly worse OS after HSCT than patients with intermediate or low risk cytogenetics according to CPSS. New therapeutic strategies to prevent relapse after HSCT in CMML patients with high-risk cytogenetics are needed. Disclosures Koenecke: Amgen: Consultancy; abbvie: Consultancy; BMS: Consultancy; Roche: Consultancy. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding.

Citrulline Trajectory during Allogeneic Hematopoietic Stem Cell Transplantation Is Correlated to Conditioning Intensity and Non-Relapse Mortality

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Christopher Nunes Gomes ◽  
Valerie Seegers ◽  
Aline Schmidt ◽  
Corentin Orvain ◽  
Alban Villate ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Introduction Citrulline, a non-essential amino acid produced exclusively by enterocytes in the small intestine and involved in the synthesis of L-arginine, is not metabolized by the liver. Therefore citrulline serum concentration is highly correlated with functional enterocyte mass, and decreases with digestive toxicity induced by conditioning therapy (radiotherapy and/or chemotherapy) for hematopoietic stem cell transplantation (HSCT) . Acute Graft-versus-host disease (GvHD), one of the major complications of HSCT, is correlated to conditioning-induced gut barrier damage and may be predicted by pre-transplant serum citrulline level (Rashidi, BBMT 2018). It could be interesting to know whether citrulline kinetics could also represent a biomarker for conditioning toxicity, non-relapse mortality (NRM), and GvHD. The aim of this study is thus to define group-based trajectory modeling, to identify clusters of individual serum citrulline kinetics in the early phase of allogeneic HCST, and to test whether these unsupervised trajectories were correlated with these early complications. Materials and Methods Serum citrulline was quantified by liquid chromatography in blood samples collected from consecutive patients who received an allogeneic HSCT in our institution between July 2014 and November 2019. These samples were drawn at different time-points: pre-transplant (D-7, D-3); day of transplant (D0), and post-transplant (D7, D15, D21). Distinct trajectories were identified for serum citrulline by using the semiparametric mixture model described by Nagin (Nagin, Stat Methods Med Res 2018). Results Among 161 patients (pts) included in the study, with a median age of 53 years (17-72), 98 pts (60.9%) received a reduced-intensity conditioning (RIC), 36 pts (22.4%) reduced-toxicity conditioning (RTC), 18 pts (11.1 %) sequential conditioning, and 9 pts (5.6%) myeloablative conditioning (MAC). Donor were identical sibling (22%), matched unrelated donor (52%) and haploidentical sibling (25%). Graft source was peripheral blood mononuclear cells in 144 pts (89.4%) and bone marrow in 17 pts (10.6%) respectively. HCT-CI score was low, intermediate and high-risk in 38%, 32%, and 30% of pts respectively. Disease-Risk Index (DRI) was low/intermediate in 111 pts (69%) and high/very-high in 50 pts (31%). With a median follow up of 29.1 month, 3-year overall survival (OS), disease-free survival (DFS), and NRM rates were 64.5%, 58.3%, and 18.9%, respectively. The median number of citrulline samples per patient was 7 [3-16]. Median citrulline concentrations before conditioning and at D-3, D0, D7 and D15 were statistically different during RIC, RTC, MAC, and sequential conditioning (p<0,001 respectively) but was not different at D21 (p=0.296). In the whole cohort, 3 citrulline trajectories were determined in an unsupervised method. Patients belonging to these 3 trajectories were different according to intensity of conditioning received with lower citrulline trajectories during MAC and sequential conditioning (p<0.001). In the uper citrulline trajectorie, pts were significantly older (p=0.005). However, citrulline trajectories were not correlated to OS (p = 0.1), NRM (p=0.24), cumulative incidence of acute GvHD (p=0.39) or chronic GvHD (p=0.2). After restricting the analysis to pts who received RIC conditioning (n=98), higher pre-HSCT citrulline concentrations were associated with a lower NRM (p=0.042). Unsupervised analysis in this setting individualized 4 clusters of individual trajectories (figure 1), that did neither distinguish age (p=0.28), DRI (p=0.87), HCT-CI score (p=0.81) nor the incidence of acute (p=0.6) or chronic (p=0.4) GvHD. However, the lowest citrulline trajectory contained significantly more haploidentical transplantations (p=0.004) and less pts who received antithymocyte globulin for GvHD prophylaxis (p=0.005). Interestingly in this RIC cohort, cumulative incidence of NRM at 12 months was 23%, 21%, 8%, and 0% respectively according to the 4 citrulline trajectories (figure 2). Conclusion In patients receiving allogeneic HSCT, the variation of serum citrulline concentrations depends on the intensity of the conditioning regimen. In patients who received RIC conditioning, lower plasma citrulline trajectories are associated with higher NRM. In this setting, citrulline may be an attractive biomarker for predicting conditioning toxicity and NRM. Disclosures Hunault: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria.

Outcomes in Allogeneic Hematopoietic Stem Cell Transplant Patients ≥ 60 Years of Age with a Novel Reduced Intensity Conditioning Regimen Incorporating Extracorporeal Photopheresis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4153-4153
Author(s):  
Furha I. Cossor ◽  
Sandy Wong ◽  
Kenneth B Miller ◽  
Deborah Black ◽  
Raymond L. Comenzo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Extracorporeal Photopheresis ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Blood Stem Cells ◽  
Grade Ii

Abstract Abstract 4153 The optimal preparative regimen for older patients undergoing hematopoietic stem cell transplantation (HSCT) is unclear. We routinely employ a reduced intensity conditioning regimen consisting of extracorporeal photopheresis (ECP) on days −6 and −5, Pentostatin 4 mg/m2/day by continuous infusion on days −4 and −3, and 600 cGy total body irradiation in 3 divided fractions on days −2 and −1 (“PPT regimen”) for patients greater than 60 years of age (Bone Marrow Transp 2004; 33:881). We now report outcomes of 38 consecutive patients ≥ 60 years old (median 62, range 60–70) (M 22, F 16) transplanted at our center between 1/1/00 and 4/1/11 for hematologic malignancies: AML (n=23), MDS (n=10), ALL (n=1), CLL (n=1), NHL (n=2) and MM (n=1). Twenty-six (68.4%) received matched related and 12 (31.6%) 6/6 matched unrelated donor (MUD) grafts. Twenty-five (65.8%) received marrow and 13 (34.2%) peripheral blood stem cell grafts. Median time to neutrophil engraftment was 16 days (3–25). Survival at day 100 was 84% (32/38), with a 13% TRM (5/38) and 3% (1/38) incidence of relapse-related death. Actuarial 1-year overall survival (OS) for all patients was 45% (95% CI 28 – 61%), and median OS in all patients was 10.6 months (95% CI 4.6 – 25.7 months). Estimated 1-year event-free survival, defined as freedom from relapse, progression, or death from any cause, was 44% (95% CI 27 – 59%). Median event-free survival for the entire cohort was 7 months (95% CI 3.6 – 25.6 months). Grade II and grades III/IV acute GvHD (aGvHD) occurred in 8 (21%) and 2 (5%) patients respectively within 1 to 8 weeks of HSCT (median 16 days). After day 100, 6 patients had died, 1 was missing data, and 23 (74% of remaining patients and 60% of the original cohort) had symptoms of GvHD. Fourteen met NIH consensus criteria for chronic GvHD (cGvHD) including 6 with severe classic or overlap cGvHD while 6 had recurrent, 2 persistent and 1 delayed aGvHD. Of those with aGvHD after day 100, 2 patients exhibited ≥ grade III disease. Median time to onset of cGvHD was 4.1 months (3.3 – 11.7). Among patients who received marrow as their stem cell source (n=25), incidence of grades II-IV aGvHD was 32% (24% grade II, 8% grade III/IV), and incidence of any GvHD from day 100 up to date of death or last follow-up was 68%. Among those who received blood stem cells (n=13) incidence of grades II-IV aGvHD was 15% (all grade II) and incidence of GvHD from day 100 until date of death or last follow-up was 83%. There was no statistically significant difference between those who received marrow versus blood stem cells with respect to incidence of either grade II-IV aGvHD or GvHD after day 100 (P =0.27 and 0.36). For those who received MUD transplants (n=12), incidence of grades II-IV aGvHD and of any post-day 100 GvHD were 42% (33% grade II, 8% grade IV) and 75% respectively, and in those who received related donor transplants (n=26) were 19% (15% grade II, 4% grade IV) and 74%, respectively. There was no statistically significant difference between MUD HSCT versus related donor HSCT patients with regard to grade II-IV aGvHD or GvHD after day 100 (P =0.14 and 0.94). In conclusion, our approach was well tolerated by HSCT patients > 60 years old, provided prompt myeloid recovery and had an acceptable incidence of post-day 100 severe chronic (19%) or > grade II late acute GvHD (6%). Disclosures: Off Label Use: Pentostatin and Extracorporeal photopheresis are not FDA approved for conditioning prior to allogeneic transplant. Comenzo:Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Neotope: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adults with Chronic Granulomatous Disease (CGD): A Study of the Inborn Errors Working Party (IEWP) of the EBMT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 970-970 ◽  
Author(s):  
Robert Chiesa ◽  
Junfeng Wang ◽  
Henric-Jan Blok ◽  
Benedicte Neven ◽  
Despina Moshous ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Engraftment Failure

Abstract Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT. Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis. Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT. The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome. Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. Disclosures Chiesa: Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

scholarly journals Outpatient BEAM Using Daily Etoposide and Cytarabine with Autologous Hematopoietic Stem Cell Transplantation for Lymphoma Is Feasible and Decreases Inpatient Length of Stay

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5830-5830
Author(s):  
Naomi Cazeau ◽  
Kathleen Cavalier ◽  
Valkal Bhatt ◽  
Courtney McElrath ◽  
Nicole Lestrange ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Standard Of Care ◽  
Outpatient Setting ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Hospital Days

Introduction: High dose therapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous hematopoietic stem cell transplantation (AHCT) is the most common consolidation therapy for chemosensitive patients with relapsed/refractory Non-Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL) in the US. Inpatient hospitalization is usually required due to the twice daily dosing of etoposide and cytarabine, and patients remain admitted until neutrophil recovery. Utilizing our outpatient transplant program, we aimed to evaluate the feasibility and safety of outpatient BEAM with AHCT using daily dosed etoposide and cytarabine to enhance the patient experience and improve inpatient resource utilization. Methods: We performed a retrospective evaluation of patients treated in the outpatient setting at Memorial Sloan Kettering Cancer Center. Patients were eligible for outpatient AHCT if they did not have a clinical indication for inpatient continuous monitoring. Patients received BEAM conditioning consisting of carmustine on day -6 (300mg/m2), etoposide daily from day -5 through day -2 (200mg/m2/dose), cytarabine daily from day -5 through day -2 (400mg/m2/dose), and melphalan on day -1 (140mg/m2). AHCT on day 0, pegfilgrastim on Day +1, and supportive care were performed as per standard of care and institutional guidelines. Patients were seen daily by an advanced practice provider and HCT attending. Notably, service guidelines were revised to include a delayed emesis prophylactic regimen of oral dexamethasone (2mg bid) and lorazepam (0.5mg TID) from D+1 through D+7, which was initiated after the first three patients were treated. Patients were transfused packed red blood cells (pRBC) for hemoglobin <7g/dl and platelets for <20K/mcl. Results: From October 2018 to July of 2019, 13 patients (Hodgkin's lymphoma (n=5), mantle cell lymphoma (n=4), diffuse large B-cell lymphoma (n=2), T-cell lymphoma (n=2), and grey zone lymphoma (n=1)) were treated. The median age was 40 years (range 26-71), and the majority were male (69%). Median cell dose infused was 5.89 CD34+ cells/kg (range 2.53-10.66). Two patients received cell infusions over 2 days, and three patients received washed cell infusion products. Two patients completed transplant entirely outpatient; the remainder required hospitalization during their transplant course. Reasons for admission included neutropenic fever (n=4), nausea (n=2), tachycardia (n=2), hypoxia (n=1), and other (n=2). Patients were admitted on a median of Day +6 (range Day+1 - Day+11) and remained inpatient for a median of 4 days (range 3-14). Eight patients (62%) returned to the outpatient stem cell transplant clinic for management prior to day 30. One patient was re-hospitalized prior to day 30. The median number of hospital days saved was 13 days/per patient. In total, 170 hospital days were saved with this regimen. Engraftment and toxicities were similar to inpatient administration. Neutrophil engraftment occurred at a median of Day+9 (range 8-11) with a median of 6 days of ANC<500 (IQR 8-11). Platelets comprised most of the transfusion support required, with a median of 4 platelet (range 2-8) and 2 pRBC (range 0-2) transfusions per patient. Grade 2 or higher diarrhea occurred for a median of 3.5 days (range 3-11) with 38% not having any diarrhea. A small percentage of patients required additional antiemetics outside the standard of care (23%). The median weight lost per patient was 2.5kg (range 0 - 10.3kg). Patients received intravenous fluid support with a median of 5 normal saline boluses (range 1-10). All patients maintained normal serum creatinine peri-transplant, with a median maximum serum creatinine of 0.9mg/dl (range 0.7-1.1). Six patients (46%) had engraftment syndrome. All patients were alive with a median follow-up of 91 days (range: 29-205). Conclusion: We found that BEAM followed by AHCT using daily dosed etoposide and cytarabine is feasible and safe for the outpatient setting with tolerability matching that of the traditional inpatient BEAM regimen. Moreover, this treatment method has the potential to reduce a considerable number of inpatient hospital days, while still safely maintaining a threshold for toxicity requiring inpatient admission. Disclosures Bhatt: Incyte: Consultancy. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Spectrum Pharmaceuticals: Consultancy; GSK: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding.

scholarly journals Targeting CXCR4, VLA4, and CXCR2 for Hematopoietic Stem Cell Mobilization

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1916-1916
Author(s):  
Daniel Cancilla ◽  
Haresh Thakellapalli ◽  
Marvin J Meyers ◽  
Michael P. Rettig ◽  
Ezhilarasi Chendamarai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Patent Application ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Mobilization ◽  
Equity Ownership ◽  
Cell Mobilization

Background: Hematopoietic stem cell (HSC) transplant is an essential treatment for a variety of blood disorders and malignancies. A key step in this procedure is the mobilization of donor stem cells. The most commonly used regimen for donor mobilization is a 5-day course of G-CSF. The length of this regimen coupled with the associated side effects emphasizes a need for superior alternatives. In recent years, there has been a growing understanding of mechanisms governing stem cell retention within the bone marrow niche. This has led to the development of new mobilization drugs that specifically target these processes. Two examples of previously described drugs that target mechanisms of stem cell retention are Plerixafor (a CXCR4 inhibitor already in clinical use), and truncated Gro-Beta (tGroβ; a CXCR2 agonist). Another potential target for inducing mobilization is disruption of the interaction between the VLA-4 integrin and its ligand VCAM-1. In this study, we evaluate the efficacy of novel VLA-4 inhibitors (VLA4i) alone and in combination with Plerixafor and/or tGroβ for the purposes of hematopoietic stem cell mobilization. Methods: We synthesized over 15 novel VLA-4 inhibitor molecules and tested their potency using soluble VCAM-1 binding assays. The 5 inhibitors determined to be most potent were then tested in vivo in DBA mice for their ability to mobilize HSCs alone and in combination with tGroβ and/or Plerixafor (n=5). HSC mobilization was measured in wild-type and splenectomized mice via flow cytometry to quantify the proportion of LSK (Lineage- Sca+ cKit+) cells as well as via Colony Forming Unit (CFU) assays. For competitive transplant, mobilized CD45.1+ BALB/c mouse blood (10 uL) was injected into lethally irradiated CD45.2+ BALB/c recipients alongside 2.5x105 CD45.2+ BALB/c bone marrow cells (n=10 / cohort). HSC engraftment was monitored monthly via flow cytometry for ratio of 45.1+ vs. 45.2+ cells in peripheral blood. Results: Firetagrast and BIO5192 are previously characterized VLA4i that have been administered to humans for indications unrelated to HSC mobilization. Our best VLA4i to date, LGB-2019, exhibited similar potency as BIO5192 in preventing the binding of sVCAM-1 to VLA-4 (IC50: 1.7nM) and was >200-fold more potent than firategrast. LGB-2019 showed increased aqueous solubility and mobilized 1.5-fold more murine LSK cells for a longer time period (peak HSC mobilization maintained for 4 hours) than BIO5192 when administered alone. Simultaneous injection of C57BL/6 mice with LGB-2019 (VLA4i), Plerixafor (CXCR4i) and tGro-β (CXCR2a) resulted in a synergistic increase in circulating CFUs (Fig. 1A; 9.8 x 103 CFUs/mL) and LSKs (Fig. 1B; 12.8 LSKs/uL) at 4 hours post-injection. In contrast, 5 days of G-CSF treatment mobilized approximately 3-fold and 8-fold less CFUs and LSKs, respectively (Fig. 1A-B). We saw no significant difference in mobilization for splenectomized vs. wildtype mice (23.4 x 103 CFUs/mL vs. 23.0 x 103 CFUs/mL) when mobilizing DBA/2 mice via VLA4i+CXCR4i+CXCR2a. Three months after competitive transplantation, blood obtained from BALB/c mice mobilized with the triple combination engrafted significantly better than blood obtained from mice treated with G-CSF or the dual combinations (Fig. 1C). Summary: New insights about the stem cell niche have allowed for the development of targeted drugs for the purposes of mobilization. Here, we show that a novel VLA-4 receptor inhibitor in combination with two other known mobilizers induces mobilization of hematopoietic stem and progenitor cells (CFU/LSK) at levels superior to the standard of care G-CSF and in a dramatically shortened time frame. Mouse transplant data also show superior engraftment in lethally irradiated recipients when using the triple cocktail regimen compared to the G-CSF mobilized graft. Secondary transplants are ongoing and will provide a more complete picture of primitive HSC mobilization and serial engraftment properties of the cells. Disclosures Rettig: WashU: Patents & Royalties: Patent Application 16/401,950. Karpova:WashU: Patents & Royalties: Patent Application 16/401,950. Ruminski:WahU: Patents & Royalties: Patent Application 16/401,950. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. DiPersio:Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Equity Ownership; Incyte: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; NeoImmune Tech: Research Funding.

scholarly journals Acceptable Toxicity and Good Hematological and Renal Responses after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency at Transplant: A Prospective SFGM-TC Observational Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-39 ◽  
Author(s):  
Laurent Garderet ◽  
Hafida Ouldjeriouat ◽  
Mohamed-Amine Bekadja ◽  
Elisabeth Daguenet ◽  
Laure Vincent ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Number ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Background: High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in multiple myeloma (MM) patients as upfront and salvage therapy. However, the safety and efficacy of ASCT in patients with renal insufficiency (RI) is controversial, which have led to an inconsistent arbitrary cut-off for creatinine clearance (CrCl) for performing ASCT. Here we analyzed prospectively the outcomes of MM patients with severe RI who underwent ASCT. Methods: We enrolled prospectively 50 newly diagnosed MM patients who had a serum CrCl of &lt;40 mL/min at the time of ASCT and an age of up to 65 years. They all received bortezomib-based induction therapy and had achieved at least a partial response before proceeding to ASCT. The recommended dose of melphalan was 140 mg/m2 and it was advised to infuse at least 3 x106/kg autologous CD34+ cells. Consolidation/maintenance post-ASCT was according to the physician's choice. The primary endpoint was transplant related mortality. Results: The patients characteristics at enrollment are given in Table 1. We focused on 44 patients who were beyond 3 months post-ASCT. Light chain MM was frequent (12%), 10% had high risk cytogenetics, 36% increased serum LDH and 10% extramedullary disease. Induction chemotherapies included bortezomib plus IMiDs in 25/44 patients with ≥2 lines of chemotherapy in 12/44. The pre-transplant disease status was sCR in =5%, CR in =15%, VGPR in =39%, and PR in =41% of patients. The number of days of cytapheresis was 2 or less in 95% of cases and the median number of CD34+ cells collected was 3.3 x 106 (1.3-9.5). The median time from diagnosis to ASCT was 175 days (103-307). HDM was 140 mg/m2 in 42/44 patients and 200 mg/m2 in 2/44. All, except two, received consolidation post ASCT (34% missing) and 52% had maintenance therapy (all lenalidomide except two receiving bortezomib) and 7% had no maintenance (41% pending). Toxicity: We observed one death during the first 100 days post-ASCT, secondary to a septic shock on day 42. The median time to neutrophil engraftment was 12 days (9-68) and to platelet engraftment 13 days (10-70). Among patients receiving RBC transfusions (75%) and platelet transfusions (84%), the median number of RBC transfusions was 3 (1-6) and that of platelet transfusions was 3 (1-10). Response: Nine patients (70%) achieved dialysis independence from the time of diagnosis: 13 patients were on dialysis at diagnosis, 5 at the time of ASCT and 4 three months post-ASCT. Renal function improved post-ASCT in 34% of patients, 14% moving from a CrCl of &lt;40 mL/min to 60 mL/min and 20% to above 60 mL/min. No patient experienced worsened renal function following ASCT. At 100 days post-ASCT, the hematological response had improved in 49% of patients, from PR to VGPR (18%), from PR to CR/sCR (11%) and from VGPR to CR/sCR (20%). The best response obtained was 5% PR, 34% VGPR, 47% CR and 11% sCR with one patient relapsing. Conclusions: In this preliminary analysis, HDM with ASCT proved to be safe and effective in MM patients with RI at transplant. We observed one death among 44 patients within the first 3 months post-ASCT. A more detailed report of the toxicity will be presented during the meeting along with the survival. Disclosures Vincent: takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Mohty:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Karlin:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Morel:Janssen: Honoraria. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding.

scholarly journals JMML Fetal Identity Results Either from Retention of a Physiologic Signature or Aberrant Activation of Master Oncofetal Regulators

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Marion Strullu ◽  
Aurélie Caye-Eude ◽  
Loïc Maillard ◽  
Chloé Arfeuille ◽  
Elodie Lainey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Hierarchical Clustering ◽  
Research Funding ◽  
Gene Set Enrichment Analysis ◽  
Hematopoietic Progenitors ◽  
Advisory Committees ◽  
Hematopoietic Stem

Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare but aggressive myeloproliferative/myelodysplastic neoplasm affecting infants and young children. The narrow age-window of onset suggests that a prenatal environment is needed for JMML oncogenesis. In search of a transcriptional reminiscence of embryo-fetal characteristics that would confirm this hypothesis, we investigated how the gene expression profile of JMML hematopoietic progenitors compared to their healthy counterpart isolated at different stages of ontogeny. Methods: Hematopoietic stem cell and progenitor cell (HSPC) fractions of JMML (n=16), bone marrow (BM) of healthy children (n=7), fetal liver (FL; n=3) and fetal BM (FBM; n=2) were phenotyped and sorted using signatures validated in the fetal and adult BM (Notta et al, Science 2011). RNAseq was performed using the TruSeq® Stranded Total RNASample preparation kit. Unsupervised hierarchical clustering analysis was done with the Bioconductor edgeR package. Differentially expressed genes were identified with the Bioconductor limma package. Results: To eliminate the impact of variations in the HSPC distribution, the JMML transcriptome was assessed on FACS-sorted common myeloid progenitor (CMP), granulocyte-monocyte progenitor (GMP) and megakaryocyte-erythroid progenitor (MEP) cell fractions from 16 JMML and compared to healthy counterparts at different stages of ontogeny (FL, FBM, age-matched children BM). Unsupervised hierarchical clustering separated the samples into 4 groups (C1-4), primarily according to ontogeny, with 14/15 embryo-fetal fractions in C1 and all healthy post-natal progenitors in C2 (CMP, MEP) or C3 (GMP). Most JMML fractions clustered either with the prenatal fractions (C1; 17/47 fractions from 8/16 patients) or in a separate group containing no healthy sample (C4; 23/47 samples from 10/16 patients). Two groups were defined accordingly: one with JMML resembling embryo-fetal samples ('Fetal-JMML'; n=6/16), and a JMML-specific group ('Onco-JMML'; 8/16). Patients with Onco-JMML tended to be older, with a more severe presentation and elevated fetal hemoglobin levels. All PTPN11-mutated JMML were in this group whereas 5/6 Fetal-JMML had NRAS or KRAS mutations. Analysis of differential gene expression between Fetal and Onco-JMML highlighted 344 up-regulated genes versus 19 up-regulated genes in Onco-JMML. Surprisingly, LIN28B and WT1, both known to activate fetal pathways, were the most up-regulated genes in Onco-JMML. These key transcription factors were deregulated as early as the hematopoietic stem cell (HSC) compartment. Gene Set Enrichment Analysis (GSEA) confirmed enrichment in LIN28B and WT1-related signatures and showed enrichment in an AML signature in Onco-JMML. On the other hand, Fetal-JMML showed striking overexpression of monocytic /dendritic cell markers and inflammasome and innate immunity components. GSEA confirmed the strong monocyte identity of Fetal-JMML progenitors compared to onco-JMML or healthy postnatal progenitors. Part of the monocytic markers 'aberrantly' expressed in JMML progenitors was expressed in healthy fetal progenitors. Analysis of the HSC and multipotent progenitor (MPP) fractions showed that up regulation of monocytic markers was limited to the JMML progeny compartments. As we were able to confirm the transcriptional and functional identity of the sorted progenitors, these data suggest an early monocytic priming in these JMML progenitors, reminiscent of the monocyte-biased myelopoiesis characterizing physiologic fetal hematopoiesis. Conclusion: Our findings give a striking example of how ontogeny-related features are involved in childhood oncogenesis. They highlight a strong but complex link beween JMML and development, with a fetal identity resulting either from retention of a physiologic fetal monocytic signature or from aberrant (re)activation of master oncofetal regulators. Intriguingly, although LIN28B is thought to reprogram hematopoietic progenitors into a fetal-like state, its activation does not lead to an overall fetal profile in JMML, suggesting a regulatory mechanism distinct from that of physiological development. These two ontogeny-based signatures are likely to uncover the biology underlying previous classifiers based on AML-like profile or DNA methylation and suggest that a subset of JMML patient may benefit from immunomodulating therapies. Disclosures Dalle: Bellicum: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Baruchel:Jazz Pharmaceuticals: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Astra Zeneca: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Shire: Research Funding; Bellicum: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document