ALBERT

Description: Background: Patients (pts) undergoing solid organ (SOT) or allogeneic hematopoietic cell transplants (HCT) are at risk for developing Epstein-Barr (EBV) virus-driven post-transplant lymphoproliferative disorder (PTLD). Pts with EBV+PTLD not responding to rituximab ± chemotherapy after SOT or HCT have poor outcomes. Many SOT and HCT recipients are also not good candidates for aggressive chemotherapy regimens. There is an unmet need for effective and well tolerated therapies in this patient population. Tabelecleucel (tab-cel®) is an investigational, off-the-shelf, allogeneic, EBV-specific, T-cell immunotherapy generated from healthy donors, which functions through native, endogenous T-cell receptors (TCRs) and HLA restrictions. Tabelecleucel is selected for an individual patient from an existing library, based on HLA restriction and matching. Here, we report long-term study results from US centers using tabelecleucel for subjects with EBV+PTLD following HCT or SOT. Methods: Subjects with EBV+PTLD after HCT (n=14) or SOT (n=12) were treated with tabelecleucel on Atara's expanded access program (EAP; ATA129-EBV-201, NCT02822495, ongoing). Subjects received tabelecleucel matched by ≥ 2/10 HLA alleles, including ≥1 HLA allele through which tabelecleucel exerts cytotoxicity (HLA restriction). Key inclusion criteria were: presence of biopsy-proven EBV+PTLD, adequate organ function (ANC ≥ 500/µL +/- cytokine support; platelets ≥ 20,000/µL +/- transfusion support if no ≥ grade 2 bleed in prior 6 months; ALT, AST, T. Bili 〈 3X ULN; Creatinine 〈 3X ULN) and performance status (ECOG ≤ 4 or Lansky ≥ 20), and lack of approved alternative therapies. Non-PTLD-related vasopressor or ventilatory support, pregnancy, concomitant need for T-cell inhibiting medications were exclusionary. Tabelecleucel was given at 1.6-2 x 106 cells/kg/dose on days 1, 8, and 15 of every 5-week cycle with imaging-based response assessment at ~d28 of each cycle. Subjects were treated to maximal response with up to 4 tabelecleucel products (cell lines) with different HLA restrictions, occurrence of an adverse event leading to tabelecleucel discontinuation, or withdrawal of consent. The results presented herein reflect a data snapshot from 3th June 2019. Results: All subjects had received prior rituximab and 7/12 SOT subjects received prior chemotherapy. Intermediate/high risk PTLD-prognostic index (PTLD-IPI; Choquet et al, Ann Hematol 2007) was noted in 79% and 42% of HCT and SOT subjects, respectively. The results are presented in table 1. While the median follow-up time in HCT subjects is short, 3 subjects were followed for over 12 months including 2 who were followed for more than 24 months. In subjects responding to tabelecleucel, 1-year OS was 85.7% in HCT and 100% in SOT, and no deaths were attributable to PTLD progression. In a subset of study subjects (HCT: n=11; SOT: n=11) with adequate ECOG, no CNS disease, and no PTLD-related ventilatory support, who would have likely been eligible for Atara's ongoing phase-3 trials, the ORR was 55% (HCT) and 82% (SOT), with a 2-yr OS of 79% (HCT) and 81% (SOT). The safety profile of tabelecleucel was consistent with previously published data. At the data snapshot for this abstract, no tabelecleucel-related adverse events led to treatment discontinuation or death. In addition, no cytokine release syndrome, organ rejection or tumor flare adverse events were reported in the PTLD subjects treated with tabelecleucel on this EAP. Conclusions: The data demonstrate a high response rate for tabelecleucel in PTLD in both HCT and SOT after initial treatment failure. Longer term follow-up shows a favorable 2-year OS in this predominantly high-risk population for whom there are no approved alternative therapies. Similar outcomes were observed in the subset of subjects potentially eligible for ongoing phase 3 studies of tabelecleucel in relapsed/refractory EBV+PTLD following SOT (NCT03394365) or HCT (NCT03392142). Tabelecleucel appears to be an effective and well-tolerated option in the subset of subjects with EBV+PTLD treated on this EAP. Disclosures Prockop: Atara Biotherapeutics: Other: Support for industry sponsored trails ; Mesoblast: Other: Support for industry sponsored trails . Reshef:Atara: Consultancy, Research Funding; BMS: Consultancy; Shire: Research Funding; Incyte: Consultancy, Research Funding; Magenta: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding. Tsai:Eli Lilly and Company: Employment. Bunin:PRA Health Sciences: Other: Immediate family member employed. Mahadeo:PI for ATARA EBV CTL Trials: Other: Other ; Recipient of unrestricted medical education grant from Jazz: Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Dwivedy Nasta:Debiopharm: Research Funding; Millenium/takeda: Research Funding; Merck: Consultancy, Other: data safety monitorin; 47 (Forty Seven): Research Funding; Roche: Research Funding; Rafael: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria. Hiremath:Atara Biotherapeutics: Employment, Equity Ownership. Yue:Atara Biotherapeutics: Employment, Equity Ownership. Sun:Atara Biotherapeutics: Employment, Equity Ownership. Navarro:GE: Equity Ownership; Pfizer: Equity Ownership; Atara Biotherapeutics: Employment, Equity Ownership, Patents & Royalties; Bluebird Bio: Equity Ownership.

Description: Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients

Description: Background: Identifying factors that influence donor-derived immune response may ultimately enable its therapeutic redirection, lessening risk for complications following allogeneic hematopoietic cell transplantation (alloHCT) like acute graft-versus-host disease (aGvHD) and promoting protection against infection and malignant disease relapse. Viral reactivation seems poised to influence donor-derived immune response, potentially disrupting the balance between immune surveillance in eradicating malignancy and infection and immune tolerance in preventing aGvHD. Cytomegalovirus (CMV) is a clinically-significant virus with immunomodulatory capabilities. However, studies interrogating such effects are limited in the modern transplant era. The primary study aim was to estimate the cumulative incidence of initial CMV reactivation (RA) and aGvHD in alloHCT patients and to assess reciprocal influence between CMV RA and aGvHD. The secondary study aim was to define whether CMV RA predisposed alloHCT patients to infection or increased relapse risk. Methods: Consecutive adult patients (n=324) with acute lymphoblastic leukemia, acute myelogenous leukemia or myelodysplasia whom received initial matched sibling or unrelated donor (MUD) bone marrow (n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center comprised the study cohort. Patient-, transplant-, and infection-related data were retrospectively analyzed (Table 1). Initial CMV RA was defined as plasma quantitative CMV PCR≥1000 viral copies/ml for which CMV-directed antiviral therapy was started. Microbiologically-documented infections were recorded for the first year after alloHCT and categorized as bacterial blood stream infection, invasive fungal infection, human herpes virus 6 viremia, and respiratory viral infection. Cumulative incidences of CMV RA and aGvHD were estimated accounting for competing risks (death from any cause). Association between CMV RA and incidence of aGvHD was evaluated in a proportional sub-distribution hazards model, where CMV RA was treated as a time-dependent covariate with competing risk as death from any cause. Similarly, influence of aGvHD on incidence of CMV RA was evaluated where development of aGvHD was treated as the time-dependent covariate and CMVR RA as the end point of interest. Associations between CMV RA and subsequent infection or disease relapse were similarly analyzed. To evaluate impact of CMV and aGvHD on long-term outcomes, landmark analysis (LMA) at D100 and D365 were compared among four distinct patient groups: (1) No CMV RA, no aGvHD; (2) CMV RA, no aGvHD; (3) No CMV RA, aGvHD; and (4) CMV RA and aGvHD. Results: Most transplant patients had AML in CR1, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Patients who developed aGvHD grades 2 (HR=1.93, 95% CI 1.15-3.23, p=0.013) or grades 3 and 4 (HR=3.36, 95% CI 1.76-6.45, p

Description: Introduction Umbilical cord blood transplantation (UCBT) is often complicated by delayed engraftment and higher rates of engraftment failure. We sought to investigate the outcomes of patients undergoing UCBT2 after engraftment failure compared to those who had autologous hematopoietic recovery and did not receive UCBT2. Methods We reviewed the medical records of 186 patients who received UCBT between 2001 and 2011 at the Case Comprehensive Cancer Center [Seidman Cancer Center, University Hospitals Case Medical Center and Taussig Cancer Institute, Cleveland Clinic]. Standard definitions of engraftment were used. Patients who died or had progressive disease before day 30 were excluded (n=9), as they were considered inevaluable for engraftment. Results Twenty-seven patients (15%) had primary engraftment failure; twelve had autologous hematopoietic recovery and 15 presented no recovery (Table). The median total nucleated cell dose for the first UCBT was 2.56x107 cells/kg (range 1.23 x107 - 5.69x107), not statistically different from patients achieving engraftment (p = 0.29). The cause of engraftment failure could not be identified in 22 patients. Among patients with engraftment failure without autologous recovery, 2 patients did not receive further salvage and died at 40 and 48 days after first UCBT; 2 others received backup autologous hematopoietic cell infusions and 11 received UCBT2. In patients with autologous hematopoietic recovery, 8 did not receive a UCBT2 because disease remission had been attained (n=4), active infection (n=1), relapsed disease beyond 40 days after UCBT (n=1) or absence of compatible donor (n=1). Fifteen patients (engraftment failure [n=11]); autologous recovery, [n=4]) underwent UCBT2, at a median of 43 days (range 33-244) from first to second UCBT. All patients received non–myeloablative second conditioning regimens. Four patients received one UCB unit and 11 received two units. Neutrophil engraftment after UCBT2 was observed in 10 of 15 patients at a median of 30 days (range, 13-35). The median survival for the entire cohort was 272 days (range 40–2130); one year overall survival was 36%. Engraftment and overall survival were not statistically different between those receiving 1 or 2 UCB units for UCBT2. Overall survival was not statistically different between patients who underwent UCBT2 and those who had autologous recovery or backup autologous infusions without further salvage. The proportion of patients in remission was similar in the 2 subgroups (UCBT2, 53%; autologous recovery, 50%). Relapse occurred in 2/15 patients who underwent UCBT2 and 8/10 patients who had autologous recovery or backup infusions. Forty months after transplantation, the cumulative incidence of relapse was 92% after autologous recovery vs. 50% after UCBT2 (Figure). Non–relapse mortality after UCBT2 was 73%. Conclusion Engraftment failure after UCBT frequently has no identifiable cause, and is associated with high morbidity and mortality. UCBT2 is feasible and can result in engraftment in the majority of patients, but is limited by patient condition after transplant as well as the availability of compatible grafts. UCBT2 is associated with significantly better disease control than continued autologous hematopoiesis, but additional efforts are necessary to reduce the high risk of non-relapse mortality in this group of patients. Disclosures: Hill: Celgene: Honoraria, Research Funding.

Description: Background: Primary malignant disease relapse, graft-versus-host disease (GvHD) and infection are the most common causes of death following allogeneic hematopoietic cell transplantation (alloHCT). We investigated whether infection following initial alloHCT influenced subsequent risk for hematologic malignant disease relapse. Methods: Consecutive adult patients (N=324) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or myelodysplasia (MDS) who received initial matched sibling (MSD) or unrelated donor (MUD) bone marrow (BM, n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (UCB, n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center were included. Patient-, transplant-, and infection-related data were retrospectively obtained. Categories for microbiologically-documented infections included bacterial blood stream infection (BSI), viral reactivation (VRA), invasive fungal infection (IFI), and respiratory viral infection (RVI). Correlation between development of infection and relapse was assessed using multi-variable (MV) proportional sub-distribution hazards models, where infection was treated as a time‐dependent covariate and death from any cause as a competing risk. Landmark analyses (LMA) at D14, D28, D56 and D100, which included only those patients who survived without relapse at the indicated time and infection status as a covariate, were performed to predict future relapse. Results: Most transplant recipients had first complete remission AML, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Following alloHCT, 107 (33%) patients experienced disease relapse. Median progression-free survival (PFS) for the entire patient cohort was nearly two years (703 days). Grades 2-4 acute GvHD developed in 164 (51%) patients, and 145 (45%) patients developed limited or extensive chronic GvHD. One- and three-year overall survival (OS) rates for the entire cohort were 63% and 45%, respectively. Cumulative incidence of infection, overall and by infection type, is depicted in Table 1. Patient- and transplant-related factors affecting development of infection are listed in Table 2. Patients who developed infection post-transplant had future relapse risk that was 46% (HR 0.54, 95% CI: 0.36-0.80, p=0.003) less than those patients who did not develop infection, regardless of infection type, in MV proportional sub-distribution hazards model analyses. LMA showed similar patterns in reduced risk for relapse following infection. Although not all reached statistical significance, LMA showed reduced relapse risk associated with early infection: D14 (HR 0.54, 95% CI: 0.27-1.05, p=0.07), D28 (HR 0.53, 95% CI: 0.30-0.93, p=0.03), D56 (HR 0.57, 95% CI: 0.37-0.90, p=0.01), and D100 (HR 0.63, 95% CI: 0.37-1.09, p=0.10). Using infection as a time-dependent covariate, patients with infection had higher risk for infection-related mortality (IRM, HR 2.10, 95% CI: 1.45-3.05, p

Description: Background: Viral infection remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (Bollard/Heslop Blood 2016). Anti-viral agents for treatment of viral infection in immunocompromised patients are limited in efficacy and are associated with significant toxicities (Gerdemann BBMT 2004; Sili Cytother 2012). The use of virus-specific cytotoxic T-lymphocytes (VST) for immunocompromised patients with viral infections has been associated with therapeutic benefit and improved OS (Bollard/Heslop Blood 2016; Sutrave Cytother 2017). Methods of VST production include ex-vivo expansion and direct selection (Gottlieb Cytother 2017). Ex-vivo expansion requires prolonged manufacturing time, is associated with T-cell exhaustion, and results in a limited donor pool. Direct selection is rapid (12-24 hours), can be done locally, allows for expanded HLA matching, permits a low degree of HLA match to the recipient, and can be adapted for many viruses. A multicenter consortium, the Viral Cytotoxic T-Lymphocyte Consortium (VIRCTLC) was created to investigate the safety and efficacy of VST manufactured by direct selection using the IFN-g Cytokine Capture System process automated on the CliniMACS® Prodigy device (Miltenyi Biotec) for immunocompromised patients with viral infection (Figure 1). Objective: Determine the safety and efficacy of VST for the treatment of immunocompromised child, adolescent and young adult (CAYA) patients with refractory, systemic viral infection and/or viral infection and intolerance to appropriate anti-viral medical therapy. Design/Methods: CAYA patients after allo-HSCT, solid organ transplantation (SOT), or with primary immunodeficiency (PID) with refractory adenovirus (ADV), cytomegalovirus (CMV), Epstein Barr virus (EBV) or BK virus (BKV) infections as evidenced by increasing serum RT-PCR DNA (by 1 log) after 7 days or persistent quantitative RT-PCR DNA copies after 14 days of appropriate anti-viral therapy, and/or known resistance to anti-viral agents, and/or intolerance to anti-viral agents were eligible. Related donors with ≥1 HLA A, B, or DR match to recipient and with an adequate T-cell response to virus specific MACS® PepTivators were eligible. Donors were screened with viral specific antigen (PepTivator®) to predict successful VST manufacturing. Peripheral blood mononuclear cells (PBMC) were collected from eligible related donors using non-mobilized apheresis. VST were isolated using the CliniMACS® Prodigy following stimulation of PBMC with specific viral MACS PepTivator® pools, generously provided by Miltenyi Biotec. Production of CD4+ and CD8+ VST was performed as previously described (Feuchtinger Blood 2010). The target cell dose was 0.5x104 CD3+/kg for HLA mismatched haploidentical related donors and 2.5x104 CD3+/kg for matched related donors. Based on response and safety, VST were given every 2 weeks for a maximum of 5 infusions. Results: Eleven patients have been enrolled to date. Seven patients were treated for ADV, 2 for BKV, 1 for CMV, and 1 for EBV. There were 8 males and 3 females enrolled, aged 1-38 years. There were 10 patients post allo-HSCT and 1 patient post SOT. There were 8 haploidentical, related, original allo-HSCT donors and 3 haploidentical, related, third party donors. There have been no matched related donors enrolled to date. The mean±SEM %CD4+ IFN-g+ of total CD4+, %CD8+ IFN-g+ of total CD8+, and %CD3 cells recovered in the final product were 21.5±4.8, 25.0±7.0, and 50.4.2±7.2, respectively. The median number of VST infusions was 2 (1-5). The mean±SEM CD3+ cell dose was 0.49±0.001x104. Ten patients achieved complete response (PCR negative) and 1 patient achieved partial response (PCR≥1 log decrease). The overall response and complete response rates were 100% and 90.9%, respectively. The median time to maximal response was 34 days (7-141) (Table 1). No patient developed aGVHD, cGVHD, infusion reaction or CRS associated with VST. Conclusion: Preliminary results of this pilot study demonstrate that VST are safe, well tolerated and efficacious in CAYA with refractory viral infections after allo-HSCT, SOT or with PID. Manufacturing utilizing the CliniMACS® Prodigy device is rapid, reproducible and effective. Accrual is ongoing. This research is supported by FDA RO10063-01A1. Disclosures Flower: Lentigen Technology Inc/Miltenyi Biotec: Research Funding. O'Donnell:Kiadis Pharma: Other: Licensing of intellectual property. Lee:Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Johnson:Cell Vault: Research Funding; Miltenyi Biotec: Research Funding. Cairo:Technology Inc/Miltenyi Biotec: Research Funding; Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Introduction Congenital dyserythropoietic anemias (CDA) are a rare group of hereditary disorders characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. While some CDA patients respond to interferon α therapy (type I CDA) or splenectomy (type II CDA), others are dependent on chronic red cell transfusions lifelong. Hematopoietic cell transplant (HCT), remains the only curative option for this disease. In 39 patients reviewed by the European Society for Blood and Marrow Transplant (EBMT), graft rejection (GR) was 12% (1-23%), the 3-year overall survival (OS) and event free survival (EFS) were 71% (55-87%) and 45% (45-63%) respectively1. A trend towards higher incidence of GR and severe (Grade III-IV) acute graft versus host disease (GvHD) was observed in patients with iron overload and unrelated donor HCT but these risk factors were not statistically significant1. We report the outcomes in 17 children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) centers. Methods Clinical information on transplant and associated outcomes were collected retrospectively after IRB approval using a common questionnaire. Data were analyzed using descriptive statistics. Comparisons between groups were made using Fisher's exact tests. Survival estimates and corresponding 95% confidence intervals were performed using the Kaplan-Meier method. Results Seventeen patients (11 males) with CDA were eligible by diagnosis and underwent HCT from 2002-2019. The median age at diagnosis was 0.7 (range: 0.2 - 14) years. A majority (n=12) of patients had CDA type II while the remainder either had CDA type I (n=2) or were unknown (n=3). Twelve (71%) patients had evidence of iron overload by biopsy or imaging and 11 received pre-HCT chelation. Three of the 12 patients had liver fibrosis confirmed by biopsy. Thirteen patients had splenomegaly and four underwent splenectomy prior to HCT. Three patients received pre-HCT immunosuppressive therapy (PTIS). Median age at the time of HCT was 5.5 (range: 0.7 - 15) years. The median interval between diagnosis and HCT was 3.8 (range 0 - 12.3) years. Most patients received myeloablative busulfan-based conditioning (n=12); however, 5 patients received nonmyeloablative (n=1) or reduced intensity (n=4) fludarabine-based conditioning regimens. Donor sources included HLA matched sibling (n=3), matched unrelated (n=9), haploidentical (n=1) and mismatched unrelated (n=4) donors. Graft source was bone marrow in all but 2 patients who received umbilical cord blood. The median total nucleated cell (TNC) dose for bone marrow grafts was 6.0 (range: 3.4- 20.6) x 108/kg. Cord blood recipients received a TNC dose of 3.8 x 107 and 4.8 x 107/kg. Five (29%) patients developed acute GvHD grade II-IV, with one patient with grade III-IV acute GvHD (5.8%). Post-HCT complications included veno-occlusive disease (n=3), acute kidney injury (n=1), congestive cardiac failure (n=1), thrombotic microangiopathy (n=1), CMV viremia requiring therapy (n=2), mucormycosis (n=1), streptococcal pneumonia (n=1), recurrent clostridium difficle colitis (n=1), and parvovirus infection (n=1). Four patients developed chronic GvHD (23.5%; 2 limited and 2 extensive). Characteristics and outcomes of the four patients (23.5%) who developed GR are shown in Table 1. With a median follow-up of 3.4 (range: 0.08 - 14) years; fourteen patients are alive. Three patients died from respiratory failure due to adenovirus, congestive cardiac failure and extensive chronic GvHD post 2nd HCT. The 2-year OS, EFS and GvHD-free-rejection-free survival of the entire cohort (95% confidence interval) were 87% (72-100%), 64% (44 -92%), and 58% (39- 88%), respectively (Figure 1). Due to limited sample size, we did not find any patient or HCT-related factors that were associated with GR, OS or GvHD. Conclusion HCT can be curative for patients with CDA. The incidence of GR and GvHD in our CDA cohort was comparable to the recent EBMT report1. Strategies such as aggressive chelation, use of PTIS and perhaps early HCT in the presence of a suitable donor before co-morbidities occur are needed to improve engraftment without increasing risk for toxicities and mortality. Not unexpectedly we observed considerable morbidities in patients who had GR and required a 2nd HCT. Disclosures Pulsipher: Novartis: Honoraria; Bellicum: Honoraria; Jasper: Honoraria; Mesoblast: Honoraria; Miltenyi: Honoraria, Research Funding; Adaptive: Research Funding.