ALBERT

Description: Introduction: Fludarabine phosphate is commonly used as part of conditioning regimens in children undergoing allogeneic haematopoietic stem cell transplantation (HSCT) for both malignant (n = 47) and non-malignant (n = 39) diseases, but its use has been associated with engraftment failure or mixed chimerism1. The aim of this study was to examine whether suboptimal engraftment is associated with fludarabine pharmacokinetics. Material (or patients) and methods: The clinical pharmacokinetics of fludarabine phosphate was evaluated by studying the free concentrations of the active metabolite, (9B-D-arabinosyl-2 fludarabine, F-Ara-A). Eighty-six HSCTs were studied in 84 children 0.1 to 19 years. Glomerular filtration rate (GFR) was determined by measuring the plasma clearance of diethylenetriaminepentacetic acid (DTPA). The children in this study were treated according to specific HSCT conditioning protocols which varied with respect to the total administered fludarabine dose and the number of days over which it was administered (range: 3 to 6). A weight-based dose of 1 to 2 mg/kg was used in 13 transplants where the patient weighed

Description: Background. Increasing numbers of adolescent and young adult (AYA) with acute leukemia (AL; acute myeloid leukemia [AML] and acute lymphoblastic leukemia [ALL]) are transitioning to long-term survivorship following allogeneic hematopoietic cell transplantation (HCT) and are at risk for certain morbidities after HCT due to myeloablative conditioning (MAC) with total body irradiation (TBI) or non-TBI-based chemotherapy (CT). Using data from the Center for International Blood and Marrow Transplantation Research (CIBMTR), we evaluated late effects (LEs) following MAC HCT and furthermore compared the effect of TBI vs. CT-based MAC on LEs and overall survival (OS) in a large cohort of one-year disease-free AYA survivors following HCT for AL. We hypothesized that the use of TBI, relative to CT-based MAC, would lead to equivalent long-term survival in this population but that TBI conditioning would be associated with significantly increased LEs following HCT. Methods. AYAs (ages 15-39 years at HCT) with AL who received first MAC HCT between 2000-2014 from a HLA matched sibling or 8/8 matched unrelated donor (MUD) and were alive and disease-free at one year following HCT were included. The cumulative incidence (CI) of LEs (avascular necrosis [AN], cataracts, congestive heart failure, myocardial infarction, diabetes [DM], gonadal dysfunction, growth disturbance, hypothyroidism, pancreatitis, renal failure requiring hemodialysis, and strokes/seizures) was estimated at 2, 5 and 10 years after HCT, with death as a competing risk. Multivariable Cox proportional hazard models evaluated patient and HCT risk factors, including the main effect of TBI vs. CT-based MAC, for the most frequently occurring LEs (limited to AML cohort only as majority of ALL patients received TBI) and for OS. Results. The study population included 1,578 one-year disease-free AYA survivors of AML (n=936) or ALL (n=642) who received first MAC HCT with TBI (AML: 449; ALL: 607) or CT (AML: 487; ALL: 35). The median TBI dose was 1200 cGy (range, 550 - 1800). The median age at HCT for AML and ALL was 29 and 26 years, respectively. The majority were male (AML: 54%; ALL: 67%), transplanted in first complete remission (AML: 62%; ALL 59%) with MUD donors (AML: 56%; ALL 55%), and had GVHD prophylaxis consisting of a calcineurin inhibitor and methotrexate (AML: 83%; ALL 83%) without T-cell depletion. The most common TBI and CT-based MAC regimens were TBI/cytoxan and busulfan/cytoxan, respectively. Median follow-up (months) of survivors was 82 (range, 12-194) for AML and 92 (range, 12-194) for ALL. The estimated CI of LEs in AML and ALL patients are shown in Table 1. Multivariable analyses for individual LEs in the AML cohort showed that CT- based MAC was independently associated with a lower risk of cataracts (HR 0.19, 95% CI 0.10 - 0.37). There was no significant association between TBI and secondary malignancies, DM, gonadal dysfunction, or hypothyroidism. cGVHD was independently associated with significantly increased risk of cataracts (HR 2.88, 95% CI 1.58 -5.24), AN (HR 2.55, 95% CI 1.25 - 4.07), and DM (HR 2.85, 95% CI 1.05 - 7.73). Unadjusted long-term HCT survival outcomes for AYAs with AML and ALL did not significantly differ based upon TBI vs. CT-based MAC (Table 2) despite significantly higher disease relapse among the CT cohort (AML only). Limited and severe cGVHD occurred in 12% and 51% of AML patients, respectively, and 13% and 53% of ALL patients, respectively, and did not differ by conditioning. In multivariable analyses for OS, HCT in relapse (HR 2.40, 95% CI 1.59 - 3.63), poor-risk cytogenetics (HR 2.09, 95% CI 1.24 - 3.52), peripheral blood stem cell graft (HR 1.46, 95% CI 1.07 - 1.97), cGVHD (HR 1.36, 95% CI 1.04 - 1.80), and a new malignancy post-HCT (HR 4.40, 95% CI 2.21 - 8.74) were associated with significantly inferior OS in AML. Undergoing HCT in CR2 (HR 1.50, 95% CI 1.09 - 2.07) or in relapse (HR 3.67, 95% CI 2.31 - 5.82), and a new malignancy post-HCT (HR 3.11, 95% CI 1.26 - 7.68) were associated with significantly inferior OS in ALL. Conclusion. AYAs with AL who are disease-free survivors at one-year have favorable long-term HCT outcomes. Long-term survival in this population appears unrelated to a TBI vs. CT-based MAC regimen. Development of cataracts is increased in long-term AYA AML HCT survivors receiving TBI-based MAC. Screening for LEs is important in survivors of AYA HCT for AL, regardless of the use of TBI or CT- based MAC regimens. Disclosures Muffly: Shire Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding.

Description: CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with relapsed/refractory lymphoid malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have utilized patient-reported outcomes (PROs), including PROMIS®measures, to assess outcomes of patients with relapse/refractory chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL) who were treated with CD19-targeted CAR-T cells on a clinical trial in our institution (NCT01865617) and survived at least one year after treatment. Between October 2018 to February 2019, 52 patients (at their 1-5 year anniversary after CAR-T cell therapy) were sent a questionnaire. The questionnaire included the PROMIS Scale v1.2-Global Health and the PROMIS-29 Profile v2.1, as well as 30 additional questions, including questions pertaining to cognitive function. As of February 28, 2019, 40 questionnaires were returned (76.9% response rate) and were included in the analysis. Patients' characteristics are summarized in Table 1. Cognitive function was assessed by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems since their CAR-T cell therapy; answer "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). PROMIS measures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T scores of PROMIS domains of Global Mental health, Global Physical Health, Social Function, anxiety, depression, fatigue, pain and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 participants (47.5%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1), and 7 participants (17.5%) scored ≤ 40 in Global Mental Health, indicating at least one standard deviation worse than the general population mean. On risk factor analysis, younger age was found to be associated with worse Global Mental Health (p=0.02), anxiety (p=0.01) and depression (p=0.01). Anxiety prior to CAR-T cell therapy was associated with increased likelihood of anxiety after CAR-T cell therapy (p=0.001). Multivariate analysis confirmed association between age and PROMIS Global Mental Health score (p=0.03). 15 participants (37.5%) reported cognitive difficulties post CAR-T cell therapy. On multivariate analysis, depression prior to CAR-T cell therapy was statistically significantly associated with higher likelihood of self-reported cognitive difficulties after CAR-T therapy (p=0.02) and there was a trend for association between acute neurotoxicity after CAR-T cell infusion and self-reported long-term cognitive difficulties (p=0.08). Having more cognitive difficulties was associated with worse Global Mental Health (p=0.0001) and worse Global Physical Health (p= 0.01). Similarly, worse scores for pain interference, sleep disturbance, fatigue, depression, anxiety, physical function, and social function were associated with more long-term self-reported cognitive difficulties (p=0.007,p=0.0003, p=0.00006, p=0.01, p=0.0007, p=0.003, p=0.0004 respectively). Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR-T cell therapy. However, despite good overall mean scores, nearly 50% of patients in the cohort reported at least one negative neuropsychiatric outcome (anxiety, depression or cognitive difficulty), and almost 20% scored at least one standard deviation lower than the general US population mean in Global Mental Health, indicating that there is a significant number of patients who would likely benefit from mental health services following CAR-T cell therapy. Younger age, anxiety and depression pre-CAR-T cell therapy, and acute neurotoxicity after CAR-T cell infusion may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings. Disclosures Shaw: Therakos: Other: Speaker Engagement. Lee:AstraZeneca: Research Funding; Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria.

Description: Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for sickle cell disease (SCD). Good outcomes have spurred an increase in the use of HCT for SCD, including an increasing number of trials using alternative donors. As survival improves, assessment of long-term outcomes and potential late effects (LEs) in this patient population is critical. We evaluated the data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) to study incidence and risk factors for LEs following HCT for SCD. Methods: Patients reported to the CIBMTR with a diagnosis of SCD who had undergone their first HCT between 1996 and June 2015 were included in this analysis. Patients with graft failure were excluded. We performed a descriptive analysis of patient, disease, donor, and transplant-related factors. The cumulative incidence (CI) of LEs was estimated at 1, 3, and 7 years post-HCT. The number of pre- versus post-HCT SCD-specific disease complications was computed. Overall survival (OS) probabilities were calculated using the Kaplan-Meier method. Multivariable Cox regression analysis was used to evaluate risk factors related to OS and LEs. Results: The study population consisted of 355 patients. The median age at HCT was 10 years (range 15 years of age was associated with significantly inferior OS (mortality HR 7.26, 95% CI 3.57-14.77). Multivariable analysis for LEs demonstrated an increased risk of diabetes (HR 7.29, 95% CI 2.94-18.08) and pulmonary abnormalities (HR 5.90, 95% CI 1.14-30.42) with unrelated donor, while older age at HCT was associated with avascular necrosis (HR 14.19, 95% CI 1.86-108.47), diabetes (HR 3.45, 95% CI 1.69-7.05), and congestive heart failure (HR 8.02, 95% CI 1.13-56.94). SCD-related symptoms overall decreased from pre- to post-HCT (Table 1), most notably acute chest syndrome, vaso-occlusive pain crises, and stroke. Conclusions: Patients with SCD who have undergone HCT for SCD in recent years have excellent OS, confirmed in this CIBMTR multicenter dataset, with diminished SCD-related symptom burden post-HCT. However, they remain at-risk for a myriad of LEs, with risk factors including older age at HCT and unrelated donor, necessitating systemic organ-based follow up post-HCT. Continued follow-up of this patient population is critical to provide appropriate counseling for medical providers, patients, and families considering HCT as a treatment option for SCD. Disclosures Shaw: Therakos: Other: Speaker Engagement.

Description: Introduction: Many patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with 10-19% blasts (MDS-EB2) do not enter complete remission (CR) following initial induction chemotherapy. At an academic referral center, such patients often stay to receive additional treatment, or return to their home communities for further care. For patients and providers alike, the decision about whether to stay or go after initial treatment failure is often fraught. To better inform such decision-making, in this retrospective single-center analysis, we compared covariate-adjusted survival for patients who elected to stay for further treatment at our center and those who returned to their home communities for subsequent care. Methods: We included adults ≥ age 18 years of age with newly-diagnosed AML or MDS-EB2 treated at our institution between January 2012 and May 2018 who failed to enter CR (〈 5% morphologic bone marrow blasts) or CR with incomplete hematologic recovery (CRi) after their first cycle of induction chemotherapy. We excluded patients who died before they could begin re-induction therapy. Patients who stayed at our institution for additional treatment are referred to as the "stay" group (n=86); patients who left are considered the "go" group (n=35). Multivariable Cox regression analysis was used to account for other measured covariates possibly influencing survival. Results: The go group was older and had a higher median treatment-related mortality (TRM) score (Table 1), the latter predictive of the probability of death within the first 28 days of initial induction therapy. Forty-seven percent of stay patients received high-intensity re-induction (containing cytarabine at individual doses ≥1g/m2) while 50% received low-intensity treatment (e.g. azacitidine, decitabine, or low-dose cytarabine). Twenty-nine percent of go patients received treatment (mostly low-intensity) in the community setting, while 63% received supportive care only. The stay patients had a median of 2 subsequent hospitalizations (range 0-12) and spent a median of 27 days hospitalized after initial treatment failure (range 0-124). Survival was longer in the stay group compared to the go group (median 8.3 vs. 1.8 months, p

Description: Background: Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is a rare disorder caused by ADA gene mutations, leading to lymphotoxic build-up of purine metabolites and profound immunodeficiency. Historically, enzyme replacement therapy (ERT) has been used as a bridge therapy until patients can receive an allogeneic hematopoietic stem cell transplantation (HSCT), ideally from a matched related donor (MRD) or, if none is identified, a non-matched and/or unrelated donor. We developed a self-inactivating lentiviral vector (LV), denoted EFS-ADA LV, encoding the human ADA cDNA sequence under the control of a shortened human elongation factor 1α gene promoter. A fresh or cryopreserved formulation of a drug product (OTL-101), composed of autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with EFS-ADA LV, was evaluated in 2 prospective, non-randomized Phase I/II clinical trials at 2 USA centers. We report on safety and efficacy of OTL-101 in 30 ADA-SCID pediatric gene therapy (GT) subjects treated from 2013-2017 with a median follow up (FU) of 24 months (mo; range 12-26 mo), compared to a historical cohort of 26 ADA-SCID patients treated with HSCT. Methods: UCLA Fresh Study (NCT01852071): Autologous CD34+ HSPCs were isolated from bone marrow and pre-stimulated with cytokines before transduction with EFS-ADA LV to yield OTL-101, which was infused as a fresh formulation in 20 subjects (9 male, 11 female; aged 4 mo-4.3 yrs). Single dose busulfan (4 mg/kg) was administered prior to infusion of OTL-101. Subjects were followed for 24 mo. UCLA Cryo Study (NCT02999984): 10 subjects (4 male, 6 female; aged 5-15 mo) received a cryopreserved formulation of OTL-101, which allowed for an extended shelf-life and full quality control prior to infusion. Busulfan was administered in 2 doses, the first at 3 mg/kg and the second adjusted to target a total area under the curve of 4,900 µM*min (20 ng/mL*hr). At the time of analysis, all subjects reached 12 mo FU (except 1 subject who was withdrawn from the study due to lack of engraftment); 7 subjects reached 18 mo of FU. Historical Control Group: 26 patients (aged 0.2 mo-9.8 yrs) were treated with allogeneic HSCT (MRDs n=12, non-MRDs n=14) at Great Ormond Street Hospital, UK (n=16) or Duke University Children's Hospital, USA (n=10) from 2000-2016. Results: Sustained engraftment of genetically modified HSPCs was observed in 29/30 GT subjects by 6-8 mo and persisted through FU in both studies, based on vector gene marking in granulocytes and CD3+ T cell reconstitution (Figure). Subjects who engrafted maintained long-term metabolic detoxification from deoxyadenosine nucleotides after stopping ERT approximately 1 mo post-GT. At last FU (median 24 mo; range 12-24 mo) in the GT group, overall survival (OS) was 30/30 (100%) and event-free survival (survival in the absence of ERT reinstitution or rescue allogeneic HSCT; EvFS) was 29/30 (97%). OS and EvFS were higher in the GT group at last FU compared with HSCT controls (with or without an MRD) at 2 years (Table). One of 30 OTL-101 subjects (3%) did not engraft and was restarted on ERT; the subject was withdrawn from the study at 5.9 mo and subsequently received a rescue HSCT, whereas 42% of HSCT patients required rescue HSCT, PEG-ADA ERT or died. Among the 20 OTL-101 subjects in the UCLA Fresh Study who reached 2 years FU, 18 (90%) stopped immunoglobin replacement therapy (IgRT), compared to 52% of HSCT patients. Preliminary results were observed in 5/7 (71%) OTL-101 subjects in the UCLA Cryo Study with more limited (18 mo) FU. Twelve OTL-101 subjects experienced one or more serious adverse events, most frequently infections and gastrointestinal events; only 1 of which was considered treatment-related (bacteremia due to product contamination). In the GT group, there were no events of autoimmunity with ≤24 mo FU. Due to the autologous nature of OTL-101, there was no incidence of graft vs host disease (GvHD); in contrast, 8 HSCT patients experienced GvHD events (5 acute, 3 chronic events), 1 of which resulted in death. Conclusions: Based on sustained gene correction and restoration of immune function in all subjects who engrafted, treatment of ADA-SCID with OTL-101 has a favorable benefit-risk profile. Key correlates of engraftment were consistent across the expanded cohort. Importantly, higher rates of OS and EvFS compared with HSCT (with or without an MRD) were observed. Disclosures Kohn: Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor on IP licensed from UC Regents to Orchard Therapeutics. Future royalties may occur., Research Funding; NIH: Research Funding. Shaw:Orchard Therapeutics: Consultancy, Other: Personal fees and non-financial support; NIH: Research Funding. Carbonaro-Sarracino:NIH: Other: Salary while working on project at UCLA 2013-2016, Research Funding; Orchard Therapeutics: Consultancy, Employment. De Oliveira:National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London: Research Funding; CIRM: Research Funding; National Gene Vector Repository: Research Funding; NIAID, NHI: Research Funding; Medical Research Council: Research Funding. Terrazas:California Institute for Regenerative Medicine: Research Funding; Gene Therapy Resource Program, NHLBI/NIH: Research Funding. Hollis:Curative Therapeutics: Consultancy, Other: Personal fees. Trevisan:Orchard Therapeutics: Research Funding. Arduini:Orchard Therapeutics: Employment, Equity Ownership. Lynn:Orchard Therapeutics: Employment, Equity Ownership. Kudari:Orchard Therapeutics: Employment, Equity Ownership. Spezzi:Orchard Therapeutics: Employment, Equity Ownership. Buckley:Duke University: Research Funding. Booth:SOBI: Consultancy; GSK: Honoraria; NovImmune: Consultancy. Thrasher:Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gaspar:Orchard Therapeutics: Employment, Equity Ownership, Patents & Royalties: Lentiviral vector for gene therapy of ADA-SCID.

Description: Background: Infusion of chimeric antigen receptor modified T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) in the absence of lymphodepleting chemotherapy has been shown to be safe with responses seen in patients (pts) with relapsed/refractory (r/r) CD30+ lymphomas (Ramos et al., JCI 2017). We present here the results of a phase 1b/2 trial of CD30.CAR-Ts administered after lymphodepleting chemotherapy in pts with r/r CD30+ Hodgkin (HL) and Non-Hodgkin lymphoma (NHL). Methods: The primary objective of the phase 1b portion of the study was to determine the recommended phase 2 dose level (RP2DL) of CD30.CAR-Ts using a standard 3+3 design. Two dose levels were tested: 1 x 108 CAR-Ts/m2 (DL1) and 2 x 108 CAR-Ts/m2 (DL2). For lymphodepletion, the first 8 pts (including the first 3 pts treated at DL1) received 2 days of bendamustine (benda) 90 mg/m2, while the 10 remaining pts received 3 days of benda 70 mg/m2 and fludarabine (flu) 30 mg/m2, except for one pt who received only 1 day of benda and flu due to possible benda toxicity. Inclusion criteria were age ≥ 18 years, CD30+ disease, and r/r HL or NHL having failed ≥2 prior therapies. Results: At the time of data cut off (7/1/2018), 18 pts with a median age of 40.5 years (range: 23-70) had received CD30.CAR-Ts and undergone response assessment. Sixteen pts had HL, 1 had enteropathy associated T cell lymphoma, and 1 had Sezary syndrome. All pts were heavily pre-treated with a median of 8.5 prior therapies (range: 4-17). All pts had received prior brentuximab vedotin and 13 had prior checkpoint inhibitor therapy. Fourteen pts had prior autologous stem cell transplant (SCT) and 7 had prior allogeneic SCT. Treatment was well tolerated with no dose limiting toxicities; as a consequence, the highest dose level of CAR-T cells (2 x 108 CAR-Ts/m2) was given as the RP2DL. Three pts developed cytokine release syndrome (CRS) (grade 1: 2 pts and grade 2: 1 pt). Grade 1 CRS resolved spontaneously, while the pt with grade 2 CRS responded to tocilizumab. No neurotoxicity was observed. Out of the 18 pts, 4 were in a complete response (CR) before infusion due to bridging chemotherapy and remained disease free at 6 wk follow up. Two of these pts have since relapsed with PFS of 3.8 months and 11.9 months while the other 2 pts are still in CR after 1 year of follow up. The 14 pts with evidence of disease pre-lymphodepletion were included in efficacy analysis. Of these 14 pts, 6 had a CR (43%, all in the benda/flu cohort), 1 had partial response (7%), 2 had stable disease (14%) and 5 had progressive disease (35%) at disease assessment. No responses occurred in the 3 pts treated at DL1. At median follow up of 138 days, the median PFS was 129 days. The median PFS for the 3 evaluable pts who received benda at DL1 was 55 days vs 172 days for the 9 pts who received benda/flu at DL2 (p = 0.039). The median PFS for the 2 evaluable pts at DL2 who received benda lymphodepletion was 85.5 days but this was not included in the comparison due to small sample size. Two out of 14 evaluable pts remain in CR at 1 year. Using PCR on peripheral blood, CD30.CAR-Ts were found to be increased in the circulation of all pts, peaking at wk 2 post infusion, with increasing CAR-T cells in pts receiving greater number of CAR-T cells or more robust lymphodepletion (3.4x103 ± 2.9x103 copies/ug of DNA for DL1-beda vs. 61x103 ± 41x103 for DL2-benda vs. 59x103 ± 22x103 for benda/flu). These differences were confirmed by flow cytometry (CD3+CAR+ cells = 13%±9% for DL1-benda vs 21%±10% for DL2-benda vs 35%±8% for benda/flu). Persistence was also related to dose level and lymphodepletion (0.06x103 ± 0.01x103 vs 0.44x103 ± 0.41x103 vs 28x103 ± 15x103/ug of DNA at wk 4 for DL1-benda, DL2-benda, and benda/flu, respectively). Although both lymphodepletion regimens reduced the lymphocyte counts, only the combination of benda/flu was found to have a significant increase in IL-15 and IL-7 cytokines (13 fold, p

Description: Introduction. There is little information on the effect of donor body mass index (BMI) on mobilization response to Filgrastim (G-CSF), especially in the unrelated donor setting. Obesity has been associated with chronic low-grade inflammation due to chronic activation of the innate immune system. Obesity-induced pro-inflammatory cytokines can interfere with bone marrow SDF1/CXCR4 axis and promote mobilization of progenitor cells leading to persistent leukocytosis and an increase in number of circulating progenitor cells. Given a higher number of circulatory progenitor cells in obese individuals compared to non-obese, a reduced G-CSF dose in obese donors may elicit adequate response, thus reducing the adverse events associated with peripheral blood stem cell (PBSC) collection. The aim of this study is to evaluate the impact of donor BMI on G-CSF mobilized peripheral blood progenitor cell yield in healthy donors. This study also examines whether there is a G-CSF dose threshold above which there is a significant increase in skeletal pain and other acute toxicities from mobilization without an appreciable increase in progenitor cell yield. Methods. The primary outcome was examination of CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF administration as a measure of collection yield. The secondary outcomes were the incidence of skeletal pain and highest toxicity level across selected body symptoms (fatigue, nausea, anorexia, insomnia, dizziness) at 24 hours after first G-CSF dose, day 1 to 5 of G-CSF administration, 2 days and 1-week post collection. The population studied was domestic unrelated G-CSF mobilized PBSC donors reported to the NMDP/CIBMTR between 2006 and 2016. G-CSF dosing was based on the NMDP weight-based dosing schema rounded to the nearest vial content. Donors were divided into normal, overweight, obese, and morbidly obese categories based on BMI. Multivariate analysis of collection yields between cohorts were done using linear regression analysis. Stepwise variable selection was used to add variables to the model: BMI group and G-CSF dose was forced into the final model as the variables of interest. Pain and acute toxicities at each time point were described using frequencies and compared between groups using chi-squared test or Fisher's exact test after adjusting for donor and baseline characteristics. Results. Examination of 20, 884 PBSC donors mobilized by G-CSF revealed a significant increase in collection yield in obese and morbidly obese compared to normal and overweight donors. Median CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF was 29.6, 36.4, 40.8 and 42.9 in normal, overweight, obese and morbidly obese donors, respectively (p

Description: This Special Report, this month’s CME article, details evidence-based guidelines for the selection of optimal unrelated donors and cord blood units for allogeneic hematopoietic cell transplantation.