scholarly journals Hematopoietic Stem Cell Transplant in Novel Agent Era Is Associated with Improved Survival in Relapsed and Refractory Peripheral T-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1640-1640
Author(s):  
Madhav Seshadri ◽  
Zhengming Chen ◽  
Peter Martin ◽  
John P. Leonard ◽  
Tsiporah B. Shore ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Novel Agents ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Novel Agent

Abstract Background Conventional salvage chemotherapy has limited efficacy in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL). In the last decade, several novel agents, including pralatrexate, an antifolate, brentuximab vedotin (BV), a CD30-directed antibody-drug conjugate, and romidepsin, a histone deacetylase inhibitor, have been introduced into clinical practice based on phase 2 data demonstrating efficacy in relapsed/refractory (R/R) diseases. Their impact on real world survival remains to be defined. In this single-center retrospective cohort study we assessed survival including outcomes after hematopoietic stem cell transplant (HSCT) with respect to novel agent exposure. Methods Patients diagnosed with PTCL from 2012-2017 who consented for inclusion in the Weill Cornell lymphoma and bone marrow transplant databases with adequate treatment records were included. Medical records were reviewed for baseline characteristics, treatment course, and outcomes including overall survival and HSCT. Median follow-up time was estimated on overall survival by reverse Kaplan-Meier method. Overall Survival (OS) time was calculated from date of diagnosis to date of death or last follow-up. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test and Cox regression analysis for statistical significance. Results A total of 123 cases were reviewed with median follow-up of 34 months. The major PTCL subtypes were PTCL NOS (N=34, 27.6%), angioimmunoblastic T-cell lymphoma (N=21, 17%), adult T-cell leukemia/lymphoma (N=19, 15.4%), and anaplastic large cell lymphoma (N=14, 11.4%). The most common 1st line chemotherapy regimens were CHOP (N=34, 31.5%), EPOCH (N=21, 19.4%), or CHOEP (N=10, 9.3%). Ninety-two patients had relapsed or refractory disease, and the most common 2nd line therapies were DICE/ICE (N=17, 18.4%), gemcitabine-based regimens (N=6, 7.5%), bendamustine (N=5, 5.4%), hyperCVAD (N=5, 5.4%), or combinations of novel agents. Thirty-three R/R patients received a novel agent, including pralatrexate alone (N=3), BV (N=13), or romidepsin (N=17). Thirty-six R/R patients underwent HSCT, including 26 allogeneic and 10 autologous. Baseline characteristics at diagnosis including age, gender, Ann Arbor stage, ECOG status, and IPI were similar between R/R patients who received a novel agent and those who did not. Although no differences in OS were seen with novel agent use among patients with R/R disease, there was a significant difference in OS among patients who received HSCT and those who did not (p=0.012 by log-rank test). Compared to no HSCT, significantly improved survival was observed in patients receiving allogeneic HSCT (HR = 0.47, p = 0.03) as well as autologous HSCT (HR = 0.27, p= 0.03) by Cox regression survival analysis, both univariate and multivariate when adjusting for interaction with novel agents. Conclusion Data from this single-center retrospective cohort study suggest that hematopoietic stem cell transplant, both autologous and allogeneic, was associated with overall survival benefit in R/R diseases in the novel agent era. The real world impact of novel agents use in PTCL subtypes warrants further study, preferably in a prospectively designed multicenter population study with larger sample size where disease subtypes, therapeutic targets of novel agents, and line of therapies can be sufficiently delineated for response and survival analysis. Disclosures Martin: AstraZeneca: Consultancy; Gilead: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy. Allan:Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Furman:TG Therapeutics: Consultancy; Sunesis: Consultancy; Loxo Oncology: Consultancy; Incyte: Consultancy, Other: DSMB; Gilead: Consultancy; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Verastem: Consultancy; Janssen: Consultancy; AbbVie: Consultancy.

Relapsed subcutaneous panniculitis-like T cell lymphoma: role of haploidentical hematopoietic stem cell transplant

2017 ◽  
Vol 96 (12) ◽  
pp. 2125-2126 ◽  
Author(s):  
Bhagirathbhai Dholaria ◽  
Raj J. Patel ◽  
Jason C. Sluzevich ◽  
Sikander Ailawadhi ◽  
Vivek Roy
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cell Transplant ◽  
Hematopoietic Stem

Allogeneic Hematopoietic Stem Cell Transplant in Advanced Multiple Myeloma: Experience from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5536-5536
Author(s):  
Yizel Elena Paz Nuñez ◽  
Beatriz Aguado Bueno ◽  
Isabel vicuña Andrés ◽  
Ángela Figuera Álvarez ◽  
Miriam González-Pardo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem

Abstract Introduction The prognosis of patients with multiple myeloma (MM) has improved in the last years due to the important advances in the knowledge of the biology of the disease, the implementation of new drugs and the incorporation of autologous hematopoietic stem cell transplant (autoHSCT). The allogenic hematopoietic stem cell transplant (alloHSCT) continues to be controversial: it offers a curative potential but with the cost of high toxicity, limiting the procedure to those young patients with a high-risk disease. This procedure shall be performed in expert centers and, whenever possible, in the context of a clinical trial. In the following we describe the experience of our center with alloHSCT in advance multiple myeloma patients. Patients and methods A total of 18 patients were diagnosed with multiple myeloma received an alloHSCT during a 13 year period (1996-2013), with a median age of 46 ± 5.9 years. All of our patients received an allogenic HLA matched sibling donor with reduced-intensity conditioning. The majority of patients were transplanted because of advanced disease, relapse after an autologous transplant or as part of a sequential transplant in patient with a high risk disease. One patient received, in two occasions, an alloHSCT. Around 70% of patients had received more than 3 previous lines of treatment including, in nearly 95%, an autoHSCT. Patient's characteristics can be found on table 1, characteristics of the procedure can be found in table 2.Table 1.Patient«s CharacteristicsN (%)GenderMale Female10 (55,5%) 9 (44,4%)Secreted ProteinIgGκ IgG λ IgA κ BJ Plasmocitoma8 (44,4%) 4 (22,2%) 2 (11,1%) 3 (16,7%) 1 (5,6%)Debut DS stageII-A II-B III-A III-B Plasmocitoma5 (27,8%) 1 (5,6%) 8 (44,4%) 3 (16,7%) 1 (5,6%)Cytogentics at diagnosisMissing Unfavorable Favorable10 (55,5%) 6 (33,3%) 2 (11,1%)Previous lines of treatment²2 3-4 ³56 (33,3%) 10 (55,5%) 2 (11,1%)Previous autoHSCTYes No17 (94,5%) 1 (5,6%)Previous radiotherapyYes No8 (44,4%) 10 (55,6%)Disease status at transplantComplete remission Partial remission Relapse9 (50,0%) 3 (16,7%) 6 (33,3%)Table 2.Treatment characteristicsN (%)Conditioning regimenMyeloablative Reduced-intensity6 (33,3%) 12 (66.7%)Stem cell sourceBone marrow Peripheral blood4 (22.2%) 14 (77.8%)GVHD prophylaxisCsA+MTXCsA+CSCsA+MMF10 (55.6%) 3 (16.7%) 5 (27.8%)InfectionsYes No16 (88.9%) 2 (11.1%)MucositisYes No12 (66.7%) 6 (33.3%)Acute GVHDYes II-IV III-IV No4 (22.3%) 3 (16.7%) 1 (5.6%) 14 (77.8%)Chronic GVHDNo Limited Extensive8 (44.3%) 5 (27.8%) 5 (27.8%) Results: Transplant related mortality (TRM) before day 100th was one case due to a thromboembolic event. Global TRM was 16.6% (3 cases). The incidence of acute graft versus host disease (aGVHD) was 22%, controlled on most cases when corticosteroids were initiated. More than half of the patients developed chronic graft versus host disease (cGVHD), with an equal distribution on either presentation as limited or extensive. (Table 2) The total number of patients eligible for analysis was 17 (one patient was lost on follow-up). With a median follow up of 11 years, the overall survival (OS) was of 8.06 years [IC 95% 4,33-11,78] (figure 1.) and the estimated progression free survival (PFS) was of 25.83 months [IC 95% 8.87-42.79](figure 2). A total of 5 (29,4%) patients are still alive and 2 (11,7%) of them are in complete remission, of these 1 patient did not have a previous autoHSCT with a follow up of almost 15 years. Conclusions: Our results are similar to those reflected on the literature1-2. However we have to point out that our population is homogenous with advanced MM with more than 3 previous lines of treatment including in most cases auto-HSCT. In spite of this, morbility and mortality in our cohort was acceptable with the limitation of a high rate of cGVHD. There is a need of more studies including more patients to evaluate the role of alloHSCT in the era of new drugs for MM. References 1. Rosi-ol L et al. Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution. Bone Marrow Transplant. 2015. 2. Beaussant Y et al. Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Retrospective Study of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Biol Blood Marrow Transplant. 2015 Disclosures Alegre: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Lymphocyte Recovery Following Autologous Hematopoietic Stem Cell Transplant in Classical Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2913-2913
Author(s):  
Ashley Rose ◽  
Quinto J Gesiotto ◽  
Leidy Isenalumhe ◽  
Farhad Khimani ◽  
Hien D. Liu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Absolute Lymphocyte Count ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
The Ideal

Abstract Introduction: The standard of care for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous hematopoietic stem cell transplant (auto-HCT). Pre-apheresis absolute lymphocyte count (PA-ALC) is an independent prognostic factor for overall survival (OS) after transplant. We aimed to evaluate the effect of absolute lymphocyte count following auto-HCT and hypothesized that a higher post-transplant ALC at day +15 (PT-ALC) correlates with improved OS. Methods: A retrospective review was performed on patients with R/R cHL who underwent auto-HCT at Moffitt Cancer Center from 2000-2020. The following patient characteristics were collected: age at diagnosis, gender, initial stage and presence of B symptoms. Pretransplant variables including chemotherapy, number of cycles, response to therapy, and time from last chemo to apheresis were collected. Receiver-operator characteristics (ROC) curve was used to identify the ideal PT-ALC to predict overall survival. Patients were then identified as high ALC versus low ALC. Mann-Whitney, Pearson Chi-square, and Fisher exact test were used to compare baseline characteristics between the two groups. Univariate analysis of overall survival was done using Log-rank testing and Kaplan-Meier curve. Cox-regression analysis was used to evaluate the factors affecting OS. Results: A total of 259 patients were included in the study, with a median age of 35 years (range 14-76). ROC curve was used to identify the ideal PT-ALC affecting OS, and a cutoff value of 300/uL was determined (AUC 0.60; 95% CI: 0.52-0.68, Figure 1). In this cohort, 52 patients (16.6%) had low PT-ALC and 207 patients (65.9%) had high PT-ALC. There was no significant difference between the two groups in regards to patient age, gender, histology type, stage at presentation, number of salvage cycles, number of CD34 cells collected, or number of days required for apheresis. Patients with a high PT-ALC had higher pre-apheresis ALC (p<0.001). There was a trend toward significance with patients with high PT-ALC receiving non-chemotherapy salvage regimens (p=0.07, Table 1). However, PA-ALC was significantly higher in non-chemotherapy regimen (p=0.007). Patients with high PT-ALC had a longer OS after transplant than those with low PT-ALC, with median OS 11.8 years and 7.7 years, respectively (p=0.012, Figure 2). On multivariate analysis, the only factor associated with improved OS was high PT-ALC (p=0.015, Table 2). Conclusions: High PA-ALC and high PT-ALC are both independent prognostic factors for longer OS in patients with relapsed/refractory Hodgkin lymphoma after auto-HCT. High PA-ALC lead to higher PT-ALC. Although most of our patients received chemotherapy as salvage therapy prior to transplant, there was a trend toward higher PT-ALC in patients who received non-chemotherapy regimens. Future studies are required to determine the role of non-chemotherapy salvage regimens in improving lymphocyte counts during the peri-transplant period and, hence, improved survival. Figure 1 Figure 1. Disclosures Gaballa: Beigene: Consultancy; TG therapeutics: Consultancy, Speakers Bureau; Epizyme: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding; ADC Therapeutics: Consultancy. Chavez: BMS: Speakers Bureau; Merk: Research Funding; ADC Therapeutics: Consultancy, Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; AstraZeneca: Research Funding. Shah: Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Incyte: Research Funding; BeiGene: Consultancy, Honoraria; Jazz Pharmaceuticals: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Amgen: Consultancy; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Servier Genetics: Other; Adaptive Biotechnologies: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Sokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Saeed: Kite Pharma: Consultancy, Other: investigator; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy; Nektar Therapeutics: Consultancy, Other: research investigator; Other-TG therapeutics: Consultancy, Other: investigator; Other-Epizyme, Inc.: Consultancy; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Intensification of Chemotherapy Using a Modified BFM Backbone for Children, Adolescents and Young Adults with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LL) Identifies Highly Chemorefractory Patients Who Benefit from Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3487-3487
Author(s):  
Paul Harker-Murray ◽  
Brent L. Wood ◽  
Meenakshi Devidas ◽  
Zhiguo Chen ◽  
Tal Schechter-Finkelstein ◽  
...  
Keyword(s):  
Young Adults ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Induction Failure ◽  
The Impact

Abstract Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal. The primary goal of T-ALL/T-LL treatment is to prevent relapse. In the phase 3 Children's Oncology Group (COG) clinical trial AALL1231 (NCT02112916), children, adolescents and young adults (age 1-30 years) with T-ALL and T-LL were treated with a modified augmented BFM (aBFM) backbone that used dexamethasone as the only corticosteroid and included two (rather than one) doses of pegaspargase during induction and delayed intensification. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphology, minimal residual disease (MRD) performed by multiparameter flow cytometry at a central reference laboratory) at end of induction and consolidation (T-ALL), and radiographic response for T-LL. Pts were randomized 1:1 to receive/not receive bortezomib during induction and delayed intensification (1.3mg/m 2 x 4 doses per block). VHR T-ALL pts were defined as having day 29 M3 marrow (>25% blasts) or end of consolidation (EOC) MRD >0.1%. 10-15% of T-ALL pts were predicted to be VHR based on COG AALL0434. Pts with induction failure (M3 marrow by morphology) or EOC MRD >0.1% were expected to have 4-yr event-free survival (EFS) of ~66+/-16%. Following consolidation, VHR pts received 3 BFM-based intensification blocks in lieu of interim maintenance (IM). Detectable MRD following the intensification blocks was considered an event and these pts were removed from protocol therapy. VHR ALL pts who had undetectable MRD continued protocol therapy, received delayed intensification, an IM phase with Capizzi escalating methotrexate plus pegaspargase, and maintenance. A secondary aim of AALL1231 was to compare survival in VHR T-ALL pts with EOC MRD ≥ 0.1% but undetectable MRD after intensification of chemotherapy with those who continued to have detectable MRD and were eligible for other treatment strategies, including hematopoietic stem cell transplant (HSCT). This study also analyzed outcomes for pts with M3 marrow at the end of induction. Results: AALL1231 accrued 847 pts (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure. The 3-year EFS for the bortezomib randomization for the SR and IR groups has been reported previously (Teachey, et. al ASH 2020). Because only 2 of 209 T-LL pts were VHR; this report focuses on the outcomes of the 5.2% (32/615) of T-ALL pts who were VHR. In total, 25 VHR T-ALL pts were EOC MRD >0.1%, and 18 of these had MRD sent at the end of HR intensification. Of the 8 pts who became MRD undetectable and continued protocol therapy, only 2 survived (3-year overall survival [OS] 25+15.3%). In contrast, 10 pts who had detectable MRD were taken off protocol and underwent HSCT. Of these 10, only one relapsed (3-year OS 90+12.7%). The 3-year OS for the 10 pts who were M3 at Day 29 was 60.0±17.0%. As there were not enough pts to assess the impact of EOC MRD on pts who were M3 at Day 29, we assessed the impact of EOC MRD on outcomes in M2 (5-25% blasts at Day 29; n = 24) and M3 pts, which defines induction failure in other cooperative groups. M2+M3 T-ALL who were EOC MRD <0.1% (n = 15) had 3-year OS of 86.7±10.0% vs 45.5±15.0% for those with EOC MRD >0.1% (n = 12) pts. Conclusions: T-ALL pts treated on AALL1231 who are EOC MRD ≥0.1% with undetectable MRD after 3 BFM-based intensification blocks had a very poor outcome when treated with standard cytotoxic chemotherapy. In contrast, while patient numbers are small, those pts that remained MRD-positive after 3 intensification blocks and underwent HSCT had an excellent outcome. These data not only impact the recommended treatment for T-ALL pts who are induction and consolidation failures, but also support the importance of the graft-versus-leukemia (GVL) effect in refractory T-ALL. Disclosures Hayashi: Magenta Therapeutics: Consultancy. August: Jazz: Membership on an entity's Board of Directors or advisory committees. Hermiston: Sobi: Consultancy; Novartis: Consultancy. Bollard: Cabeletta Bio: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio and Mana Therapeutics: Other: member and cofounder; SOBI: Other: DSMB. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Teachey: BEAM Therapeutics: Consultancy, Research Funding; NeoImmune Tech: Research Funding; Sobi: Consultancy; Janssen: Consultancy.

scholarly journals Inducible SBDS Deficiency Impairs Bone Marrow Niche Function to Engraft Donor Hematopoietic Stem Cell after Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3199-3199
Author(s):  
Ji Zha ◽  
Lori Kunselman ◽  
Hongbo Michael Xie ◽  
Brian Ennis ◽  
Jian-Meng Fan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mouse Model ◽  
Board Of Directors ◽  
Hematopoietic Stem Cell ◽  
Graft Failure ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Bm Niche ◽  
Deficient Mice

Hematopoietic stem cell (HSC) transplantation (HSCT) is required for curative therapy for patients with high-risk hematologic malignancies, and a number of non-malignant disorders including inherited bone marrow failure syndromes (iBMFS). Strategies to enhance bone marrow (BM) niche capacity to engraft donor HSC have the potential to improve HSCT outcome by decreasing graft failure rates and enabling reduction in conditioning intensity and regimen-associated complications. Several studies in animal models of iBMFS have demonstrated that BM niche dysfunction contributes to both the pathogenesis of iBMFS, as well as impaired graft function after HSCT. We hypothesize that such iBMFS mouse models are useful tools for discovering targetable niche elements critical for donor engraftment after HSCT. Here, we report the development of a novel mouse model of Shwachman-Diamond Syndrome (SDS) driven by conditional Sbds deletion, which demonstrates profound impairment of healthy donor hematopoietic engraftment after HSCT due to pathway-specific dysfunctional signaling within SBDS-deficient recipient niches. We first attempted to delete Sbds specifically in mature osteoblasts by crossing Sbdsfl/flmice with Col1a1Cre+mice. However, the Col1a1CreSbdsExc progenies are embryonic lethal at E12-E15 stage due to developmental musculoskeletal abnormalities. Alternatively, we generated an inducible SDS mouse model by crossing Sbdsfl/flmice with Mx1Cre+ mice, and inducing Sbds deletion in Mx1-inducible BM hematopoietic and osteolineage niche cells by polyinosinic-polycytidilic acid (pIpC) administration. Compared with Sbdsfl/flcontrols, Mx1CreSbdsExc mice develop significantly decreased platelet counts, an inverted peripheral blood myeloid/lymphoid cell ratio, and reduced long-term HSC within BM, consistent with stress hematopoiesis seen in BMF and myelodysplastic syndromes. To assess whether inducible SBDS deficiency impacts niche function to engraft donor HSC, we transplanted GFP+ wildtype donor BM into pIpC-treated Mx1CreSbdsExc mice and Sbdsfl/flcontrols after 1100 cGy of total body irradiation (TBI). Following transplantation, Mx1CreSbdsExc recipient mice exhibit significantly higher mortality than controls (Figure 1). The decreased survival was related to primary graft failure, as Mx1CreSbdsExc mice exhibit persistent BM aplasia after HSCT and decreased GFP+ reconstitution in competitive secondary transplantation assays. We next sought to identify the molecular and cellular defects within BM niche cells that contribute to the engraftment deficits in SBDS-deficient mice. We performed RNA-seq analysis on the BM stromal cells from irradiated Mx1CreSbdsExc mice versus controls, and the results revealed that SBDS deficiency in BM niche cells caused disrupted gene expression within osteoclast differentiation, FcγR-mediated phagocytosis, and VEGF signaling pathways. Multiplex ELISA assays showed that the BM niche of irradiated Mx1CreSbdsExc mice expresses lower levels of CXCL12, P-selectin and IGF-1, along with higher levels of G-CSF, CCL3, osteopontin and CCL9 than controls. Together, these results suggest that poor donor HSC engraftment in SBDS-deficient mice is likely caused by alterations in niche-mediated donor HSC homing/retention, bone metabolism, host monocyte survival, signaling within IGF-1 and VEGF pathways, and an increased inflammatory state within BM niches. Moreover, flow cytometry analysis showed that compared to controls, the BM niche of irradiated Mx1CreSbdsExc mice contained far fewer megakaryocytes, a hematopoietic cell component of BM niches that we previously demonstrated to be critical in promoting osteoblastic niche expansion and donor HSC engraftment. Taken together, our data demonstrated that SBDS deficiency in BM niches results in reduced capacity to engraft donor HSC. We have identified multiple molecular and cellular defects in the SBDS-deficient niche contributing to this phenotype. Such niche signaling pathway-specific deficits implicate these pathways as critical for donor engraftment during HSCT, and suggest their potential role as targets of therapeutic approaches to enhance donor engraftment and improve HSCT outcome in any condition for which HSCT is required for cure. Disclosures Olson: Merck: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

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